bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis
Authors: Barna Barbara P. , Malur Anagha , Thomassen Mary Jane
Published: April 2021

Poorly soluble environmental antigens, including carbon pollutants, are thought to play a role in the incidence of human sarcoidosis, a chronic inflammatory granulomatous disease of unknown causation. Currently, engineered carbon products such as multiwall carbon nanotubes (MWCNT) are manufactured commercially and have been shown to elicit acute and chronic inflammatory responses in experimental animals, including the production of granulomas or fibrosis. Several years ago, we hypothesized that constructing an experimental model of chronic granulomatosis resembling that associated with sarcoidosis might be achieved by oropharyngeal instillation of MWCNT into mice. This review summarizes the results of our efforts to define mechanisms of granuloma formation and identify potential therapeutic targets for sarcoidosis. Evidence is presented linking findings from the murine MWCNT granuloma model to sarcoidosis pathophysiology. As our goal was to determine what pulmonary inflammatory pathways might be involved, we utilized mice of knock-out (KO) backgrounds which corresponded to deficiencies noted in sarcoidosis patients. A primary example of this approach was to study mice with a myeloid-specific knock-out of the lipid-regulated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) which is strikingly depressed in sarcoidosis. Among the major findings associated with PPARγ KO mice compared to wild-type were: (1) exacerbation of granulomatous and fibrotic histopathology in response to MWCNT; (2) elevation of inflammatory mediators; and (3) pulmonary retention of a potentially antigenic ESAT-6 peptide co-instilled with MWCNT. In line with these data, we also observed that activation of PPARγ in wild-type mice by the PPARγ-specific ligand, rosiglitazone, significantly reduced both pulmonary granuloma and inflammatory mediator production. Similarly, recognition of a deficiency of ATP-binding cassette (ABC) lipid transporter ABCG1 in sarcoidosis led us to study MWCNT instillation in myeloid-specific ABCG1 KO mice. As anticipated, ABCG1 deficiency was associated with larger granulomas and increased levels of inflammatory mediators. Finally, a transcriptional survey of alveolar macrophages from MWCNT-instilled wild-type mice and human sarcoidosis patients revealed several common themes. One of the most prominent mediators identified in both human and mouse transcriptomic analyses was MMP12. Studies with MMP12 KO mice revealed similar acute reactions to those in wild-type but at chronic time points where wild-type maintained granulomatous disease, resolution occurred with MMP12 KO mice suggesting MMP12 is necessary for granuloma progression. In conclusion, these studies suggest that the MWCNT granuloma model has relevance to human sarcoidosis study, particularly with respect to immune-specific pathways.
The Role of Formyl Peptide Receptors in Permanent and Low-Grade Inflammation: Helicobacter pylori Infection as a Model
Authors: Cuomo Paola , Papaianni Marina , Capparelli Rosanna , Medaglia Chiara
Published: April 2021

Formyl peptide receptors (FPRs) are cell surface pattern recognition receptors (PRRs), belonging to the chemoattractant G protein-coupled receptors (GPCRs) family. They play a key role in the innate immune system, regulating both the initiation and the resolution of the inflammatory response. FPRs were originally identified as receptors with high binding affinity for bacteria or mitochondria N-formylated peptides. However, they can also bind a variety of structurally different ligands. Among FPRs, formyl peptide receptor-like 1 (FPRL1) is the most versatile, recognizing N-formyl peptides, non-formylated peptides, and synthetic molecules. In addition, according to the ligand nature, FPRL1 can mediate either pro- or anti-inflammatory responses. Hp(2-20), a Helicobacter pylori-derived, non-formylated peptide, is a potent FPRL1 agonist, participating in Helicobacter pylori-induced gastric inflammation, thus contributing to the related site or not-site specific diseases. The aim of this review is to provide insights into the role of FPRs in H. pylori-associated chronic inflammation, which suggests this receptor as potential target to mitigate both microbial and sterile inflammatory diseases.
A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels
Authors: Ogata Jun , Hirao Kentaro , Nishioka Kenya , Hayashida Arisa , Li Yuanzhe , Yoshino Hiroyo , Shimizu Soichiro , Hattori Nobutaka , Imai Yuzuru
Published: April 2021

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.
Hypersensitivity Induced by Intrathecal Bradykinin Administration Is Enhanced by N-oleoyldopamine (OLDA) and Prevented by TRPV1 Antagonist
Authors: Uchytilova Eva , Spicarova Diana , Palecek Jiri
Published: April 2021

Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes TRPV1, whereas noxious peripheral stimulation increases BK level in the spinal cord. Here, we investigated the involvement of spinal TRPV1 in thermal and mechanical hypersensitivity, evoked by intrathecal (i.t.) administration of BK and an endogenous agonist of TRPV1, N-oleoyldopamine (OLDA), using behavioral tests and i.t. catheter implantation, and administration of BK-induced transient thermal and mechanical hyperalgesia and mechanical allodynia. All these hypersensitive states were enhanced by co-administration of a low dose of OLDA (0.42 µg i.t.), which was ineffective only under the control conditions. Intrathecal pretreatment with TRPV1 selective antagonist SB366791 prevented hypersensitivity induced by i.t. co-administration of BK and OLDA. Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal TRPV1 channels.
Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells
Authors: Costa Ambra , Ceresa Davide , De Palma Antonella , Rossi Rossana , Turturo Sara , Santamaria Sara , Balbi Carolina , Villa Federico , Reverberi Daniele , Cortese Katia , De Biasio Pierangela , Paladini Dario , Coviello Domenico , Ravera Silvia , Malatesta Paolo , Mauri Pierluigi , Quarto Rodolfo , Bollini Sveva
Published: April 2021

We previously reported that c-KIT+ human amniotic-fluid derived stem cells obtained from leftover samples of routine II trimester prenatal diagnosis (fetal hAFS) are endowed with regenerative paracrine potential driving pro-survival, anti-fibrotic and proliferative effects. hAFS may also be isolated from III trimester clinical waste samples during scheduled C-sections (perinatal hAFS), thus offering a more easily accessible alternative when compared to fetal hAFS. Nonetheless, little is known about the paracrine profile of perinatal hAFS. Here we provide a detailed characterization of the hAFS total secretome (i.e., the entirety of soluble paracrine factors released by cells in the conditioned medium, hAFS-CM) and the extracellular vesicles (hAFS-EVs) within it, from II trimester fetal- versus III trimester perinatal cells. Fetal- and perinatal hAFS were characterized and subject to hypoxic preconditioning to enhance their paracrine potential. hAFS-CM and hAFS-EV formulations were analyzed for protein and chemokine/cytokine content, and the EV cargo was further investigated by RNA sequencing. The phenotype of fetal- and perinatal hAFS, along with their corresponding secretome formulations, overlapped; yet, fetal hAFS showed immature oxidative phosphorylation activity when compared to perinatal ones. The profiling of their paracrine cargo revealed some differences according to gestational stage and hypoxic preconditioning. Both cell sources provided formulations enriched with neurotrophic, immunomodulatory, anti-fibrotic and endothelial stimulating factors, and the immature fetal hAFS secretome was defined by a more pronounced pro-vasculogenic, regenerative, pro-resolving and anti-aging profile. Small RNA profiling showed microRNA enrichment in both fetal- and perinatal hAFS-EV cargo, with a stably- expressed pro-resolving core as a reference molecular signature. Here we confirm that hAFS represents an appealing source of regenerative paracrine factors; the selection of either fetal or perinatal hAFS secretome formulations for future paracrine therapy should be evaluated considering the specific clinical scenario.
Beneficial Effects of Phenolic Compounds on Gut Microbiota and Metabolic Syndrome
Authors: Kasprzak-Drozd Kamila , Oniszczuk Tomasz , Stasiak Mateusz , Oniszczuk Anna
Published: April 2021

The human intestine contains an intricate community of microorganisms, referred to as the gut microbiota (GM), which plays a pivotal role in host homeostasis. Multiple factors could interfere with this delicate balance, including genetics, age, medicines and environmental factors, particularly diet. Growing evidence supports the involvement of GM dysbiosis in gastrointestinal (GI) and extraintestinal metabolic diseases. The beneficial effects of dietary polyphenols in preventing metabolic diseases have been subjected to intense investigation over the last twenty years. As our understanding of the role of the gut microbiota advances and our knowledge of the antioxidant and anti-inflammatory functions of polyphenols accumulates, there emerges a need to examine the prebiotic role of dietary polyphenols. This review firstly overviews the importance of the GM in health and disease and then reviews the role of dietary polyphenols on the modulation of the gut microbiota, their metabolites and how they impact on host health benefits. Inter-dependence between the gut microbiota and polyphenol metabolites and the vital balance between the two in maintaining the host gut homeostasis are also discussed.
Loss of the Metastasis Suppressor NME1, But Not of Its Highly Related Isoform NME2, Induces a Hybrid Epithelial–Mesenchymal State in Cancer Cells
Authors: Huna Anda , Nawrocki-Raby Béatrice , Padilla-Benavides Teresita , Gavard Julie , Coscoy Sylvie , Bernard David , Boissan Mathieu
Published: April 2021

Epithelial–mesenchymal transition (EMT) is important for the initial steps of metastasis. Although it is well accepted that the nucleoside diphosphate kinase NME1 is a metastasis suppressor, its effect on EMT remains poorly documented, as does that of its closely related isoform, NME2. Here, by using gene silencing, inactivation and overexpression strategies in a variety of cellular models of cancer, we show that NME1 is a powerful inhibitor of EMT. Genetic manipulation of NME2, by contrast, had no effect on the EMT phenotype of cancer cells, indicating a specific function of NME1 in EMT regulation. Loss of NME1 in epithelial cancer cells resulted in a hybrid phenotype intermediate between epithelial and mesenchymal cells, which is known to be associated with cells with a highly metastatic character. Conversely, overexpression of NME1 in mesenchymal cancer cells resulted in a more epithelial phenotype. We found that NME1 expression was negatively associated with EMT markers in many human cancers and was reduced in human breast tumor cell lines with the aggressive ‘triple-negative’ phenotype when compared to human breast tumor cell lines positive for estrogen receptor. We show that NME1, but not NME2, is an inhibitor of essential concerted intracellular signaling pathways involved in inducing EMT, including the AKT and MAPK (ERK, p38, and JNK) pathways. Additionally, NME1 depletion considerably altered the distribution of E-cadherin, a gatekeeper of the epithelial phenotype, shifting it from the plasma membrane to the cytosol and resulting in less E-cadherin on the cell surface than in control cells. Functional aggregation and dispersion assays demonstrated that inactivation of NME1 decreases E-cadherin-mediated cell–cell adhesion. We conclude that NME1, but not NME2, acts specifically to inhibit EMT and prevent the earliest stages of metastasis.
Experimental and Computational Studies on Structure and Energetic Properties of Halogen Derivatives of 2-Deoxy-D-Glucose
Authors: Ziemniak Marcin , Zawadzka-Kazimierczuk Anna , Pawlędzio Sylwia , Malinska Maura , Sołtyka Maja , Trzybiński Damian , Koźmiński Wiktor , Skora Stanisław , Zieliński Rafał , Fokt Izabela , Priebe Waldemar , Woźniak Krzysztof , Pająk Beata
Published: April 2021

The results of structural studies on a series of halogen-substituted derivatives of 2-deoxy-D-glucose (2-DG) are reported. 2-DG is an inhibitor of glycolysis, a metabolic pathway crucial for cancer cell proliferation and viral replication in host cells, and interferes with D-glucose and D-mannose metabolism. Thus, 2-DG and its derivatives are considered as potential anticancer and antiviral drugs. X-ray crystallography shows that a halogen atom present at the C2 position in the pyranose ring does not significantly affect its conformation. However, it has a noticeable effect on the crystal structure. Fluorine derivatives exist as a dense 3D framework isostructural with the parent compound, while Cl- and I-derivatives form layered structures. Analysis of the Hirshfeld surface shows formation of hydrogen bonds involving the halogen, yet no indication for the existence of halogen bonds. Density functional theory (DFT) periodic calculations of cohesive and interaction energies (at the B3LYP level of theory) have supported these findings. NMR studies in the solution show that most of the compounds do not display significant differences in their anomeric equilibria, and that pyranose ring puckering is similar to the crystalline state. For 2-deoxy-2-fluoro-D-glucose (2-FG), electrostatic interaction energies between the ligand and protein for several existing structures of pyranose 2-oxidase were also computed. These interactions mostly involve acidic residues of the protein; single amino-acid substitutions have only a minor impact on binding. These studies provide a better understanding of the structural chemistry of halogen-substituted carbohydrates as well as their intermolecular interactions with proteins determining their distinct biological activity.
The Effects of Muscle Cell Aging on Myogenesis
Authors: Moustogiannis Athanasios , Philippou Anastassios , Taso Orjona , Zevolis Evangelos , Pappa Maria , Chatzigeorgiou Antonios , Koutsilieris Michael
Published: April 2021

The process of myogenesis gradually deteriorates as the skeletal muscle ages, contributing to muscle mass loss. The aim of this study is to investigate the effect of senescence/aging on skeletal myogenesis, in vitro. A model of multiple cell divisions of C2C12 myoblasts was used to replicate cell senescence. Control and aged myoblasts were investigated during myogenesis, i.e., at days 0, 2, and 6of differentiation. SA-β-gal activity and comet assay were used as markers of aging and DNA damage. Flow cytometry was performed to characterize potential differences in cell cycle between control and aged cells. Alterations in the mRNA and/or protein expression of myogenic regulatory factors (MRFs), IGF-1 isoforms, apoptotic, atrophy, inflammatory, metabolic and aging-related factors were evaluated. Compared with the control cells, aged myoblasts exhibited G0/G1 cell cycle arrest, DNA damage, increased SA-β-gal activity, and increased expression of aging-related factors p16 and p21 during differentiation. Moreover, aged myoblasts showed a reduction in the expression of MRFs and metabolic/anabolic factors, along with an increased expression of apoptotic, atrophy and inflammatory factors. A diminished differentiation capacity characterized the aged myoblasts which, in combination with the induction of apoptotic and atrophy factors, indicated a disrupted myogenic lineage in the senescent muscle cells.
Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects
Authors: Sabra Mohamed , Karbasiafshar Catherine , Aboulgheit Ahmed , Raj Sidharth , Abid M. Ruhul , Sellke Frank W.
Published: April 2021

Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.
Gut Microbiota and Bipolar Disorder: An Overview on a Novel Biomarker for Diagnosis and Treatment
Authors: Lucidi Lorenza , Pettorruso Mauro , Vellante Federica , Di Carlo Francesco , Ceci Franca , Santovito Maria Chiara , Di Muzio Ilenia , Fornaro Michele , Ventriglio Antonio , Tomasetti Carmine , Valchera Alessandro , Gentile Alessandro , Kim Yong-Ku , Martinotti Giovanni , Fraticelli Silvia , Di Giannantonio Massimo , De Berardis Domenico
Published: April 2021

The gut microbiota is the set of microorganisms that colonize the gastrointestinal tract of living creatures, establishing a bidirectional symbiotic relationship that is essential for maintaining homeostasis, for their growth and digestive processes. Growing evidence supports its involvement in the intercommunication system between the gut and the brain, so that it is called the gut–brain–microbiota axis. It is involved in the regulation of the functions of the Central Nervous System (CNS), behavior, mood and anxiety and, therefore, its implication in the pathogenesis of neuropsychiatric disorders. In this paper, we focused on the possible correlations between the gut microbiota and Bipolar Disorder (BD), in order to determine its role in the pathogenesis and in the clinical management of BD. Current literature supports a possible relationship between the compositional alterations of the intestinal microbiota and BD. Moreover, due to its impact on psychopharmacological treatment absorption, by acting on the composition of the microbiota beneficial effects can be obtained on BD symptoms. Finally, we discussed the potential of correcting gut microbiota alteration as a novel augmentation strategy in BD. Future studies are necessary to better clarify the relevance of gut microbiota alterations as state and disease biomarkers of BD.
Molecular Dynamics Simulations Based on 1-Phenyl-4-Benzoyl-1-Hydro-Triazole ERRα Inverse Agonists
Authors: Gao Zhipei , Du Yongli , Sheng Xiehuang , Shen Jingkang
Published: April 2021

Estrogen-related receptor α (ERRα), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERRα inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERRα. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.
Degradome Analysis of Tomato and Nicotiana benthamiana Plants Infected with Potato Spindle Tuber Viroid
Authors: Navarro Beatriz , Gisel Andreas , Serra Pedro , Chiumenti Michela , Di Serio Francesco , Flores Ricardo
Published: April 2021

Viroids are infectious non-coding RNAs that infect plants. During infection, viroid RNAs are targeted by Dicer-like proteins, generating viroid-derived small RNAs (vd-sRNAs) that can guide the sequence specific cleavage of cognate host mRNAs via an RNA silencing mechanism. To assess the involvement of these pathways in pathogenesis associated with nuclear-replicating viroids, high-throughput sequencing of sRNAs and degradome analysis were carried out on tomato and Nicotiana benthamiana plants infected by potato spindle tuber viroid (PSTVd). Both hosts develop similar stunting and leaf curling symptoms when infected by PSTVd, thus allowing comparative analyses. About one hundred tomato mRNAs potentially targeted for degradation by vd-sRNAs were initially identified. However, data from biological replicates and comparisons between mock and infected samples reduced the number of bona fide targets—i.e., those identified with high confidence in two infected biological replicates but not in the mock controls—to only eight mRNAs that encode proteins involved in development, transcription or defense. Somewhat surprisingly, results of RT-qPCR assays revealed that the accumulation of only four of these mRNAs was inhibited in the PSTVd-infected tomato. When these analyses were extended to mock inoculated and PSTVd-infected N. benthamiana plants, a completely different set of potential mRNA targets was identified. The failure to identify homologous mRNA(s) targeted by PSTVd-sRNA suggests that different pathways could be involved in the elicitation of similar symptoms in these two species. Moreover, no significant modifications in the accumulation of miRNAs and in the cleavage of their targeted mRNAs were detected in the infected tomato plants with respect to the mock controls. Taken together, these data suggest that stunting and leaf curling symptoms induced by PSTVd are elicited by a complex plant response involving multiple mechanisms, with RNA silencing being only one of the possible components.
Evidence for Range Expansion and Origins of an Invasive Hornet Vespa bicolor (Hymenoptera, Vespidae) in Taiwan, with Notes on Its Natural Status
Authors: Lu Sheng-Shan , Takahashi Junichi , Yeh Wen-Chi , Lu Ming-Lun , Huang Jing-Yi , Lin Yi-Jing , Sung I-Hsin
Published: April 2021

The invasive alien species (IAS) Vespa bicolor is the first reported hornet that has established in Taiwan and is concerning as they prey on honeybee Apis mellifera, which leads to colony losses and public concerns. Thus, the aim of this study was to assess the current status of V. bicolor abundance, dispersal, and impact and to trace the origins of Taiwan’s V. bicolor population. Our studies took place in five areas in northern to central Taiwan. We used mtDNA in the phylogenetic analyses. Field survey and ecological niche modeling (ENM) were used to understand the origins and current range of the invasive species. Two main subgroups of V. bicolor in the phylogenetic tree were found, and a clade with short branch lengths in Southeastern China and Taiwan formed a subgroup, which shows that the Taiwan population may have invaded from a single event. Evidence shows that V. bicolor is not a severe pest to honeybees in the study area; however, using ENM, we predict the rapid dispersion of this species to the cooler and hilly mountain areas of Taiwan. The management of V. bicolor should also involve considering it a local pest to reduce loss by beekeepers and public fear in Taiwan. Our findings highlight how the government, beekeepers, and researchers alike should be aware of the implications of V. bicolor’s rapid range expansion in Taiwan, or in other countries.
GHz Superconducting Single-Photon Detectors for Dark Matter Search
Authors: Paolucci Federico , Giazotto Francesco
Published: April 2021

The composition of dark matter is one of the puzzling topics in astrophysics. To address this issue, several experiments searching for the existence of axions have been designed, built and realized in the last twenty years. Among all the others, light shining through walls experiments promise to push the exclusion limits to lower energies. For this reason, effort is put for the development of single-photon detectors operating at frequencies <100 GHz. Here, we review recent advancements in superconducting single-photon detection. In particular, we present two sensors based on one-dimensional Josephson junctions with the capability to be in situ tuned by simple current bias: the nanoscale transition edge sensor (nano-TES) and the Josephson escape sensor (JES). These two sensors are the ideal candidates for the realization of microwave light shining through walls (LSW) experiments, since they show unprecedented frequency resolutions of about 100 GHz and 2 GHz for the nano-TES and JES, respectively.
Flecainide How and When: A Practical Guide in Supraventricular Arrhythmias
Authors: Lavalle Carlo , Magnocavallo Michele , Straito Martina , Santini Luca , Forleo Giovanni Battista , Grimaldi Massimo , Badagliacca Roberto , Lanata Luigi , Ricci Renato Pietro
Published: April 2021

Transcatheter ablation was increasingly and successfully used to treat symptomatic drug refractory patients affected by supraventricular arrhythmias. Antiarrhythmic drug treatment still plays a major role in patient management, alone or combined with non-pharmacological therapies. Flecainide is an IC antiarrhythmic drug approved in 1984 from the Food and Drug Administration for the suppression of sustained ventricular tachycardia and later for acute cardioversion of atrial fibrillation and for sinus rhythm maintenance. Currently, flecainide is mostly used for sinus rhythm maintenance in atrial fibrillation (AF) patients without structural cardiomyopathy although recent studies enrolling different patient populations have demonstrated a good effectiveness and safety profile. How should we interpret the results of the CAST after the latest evidence? Is it possible to expand the indications of flecainide, and therefore, its use? This review aims to highlight the main characteristics of flecainide, as well as its optimal clinical use, delineating drug indications and contraindications and appropriate monitoring, based on the most recent evidence.
Efficacy and Safety of Intravenous Ferric Carboxymaltose in Patients with Postoperative Anemia Following Same-Day Bilateral Total Knee Arthroplasty: A Randomized Controlled Trial
Authors: Kim Man Soo , Koh In Jun , Choi Keun Young , Yang Sung Cheol , In Yong
Published: April 2021

(1) Background: The purpose of this study was to evaluate the efficacy and safety of intravenous (IV) ferric carboxymaltose (FCM) to treat acute postoperative anemia following same-day bilateral total knee arthroplasty (TKA). (2) Methods: A total of 118 patients who underwent same-day bilateral TKA were randomly assigned to two groups: an FCM group (FCM infusion, 58 patients) and a Control group (placebo with normal saline, 60 patients). The primary endpoint was the number of responders with a Hb increase of two or more points by the second postoperative week. The secondary endpoints were Hb level, iron metabolism variables and blood transfusion rate at 2, 6 and 12 weeks after surgery. (3) Results: The FCM group had more Hb responders than the Control group (62.1% vs. 31.6%, p < 0.001). The Hb level was significantly higher in the FCM group during 12 weeks after surgery (all p < 0.05). Ferritin, iron and transferrin saturation levels were significantly higher in the FCM group from 2 to 12 weeks postoperatively (all p < 0.05). There was no difference in transfusion rate after surgery (p > 0.05). (4) Conclusion: In patients with postoperative anemia after same-day bilateral TKA, IV FCM infusion significantly improved Hb response two weeks after surgery without severe adverse events compared to placebo. In contrast, transfusion rate and various parameters of quality of life assessment up to 12 weeks did not vary between these groups. Level of evidence: Level I.
Racial Disparities in the Utilization and Outcomes of Temporary Mechanical Circulatory Support for Acute Myocardial Infarction-Cardiogenic Shock
Authors: Vojjini Rahul , Patlolla Sri Harsha , Cheungpasitporn Wisit , Kumar Arnav , Sundaragiri Pranathi R. , Doshi Rajkumar P. , Jaffe Allan S. , Barsness Gregory W. , Holmes David R. , Rab S. Tanveer , Vallabhajosyula Saraschandra
Published: April 2021

Racial disparities in utilization and outcomes of mechanical circulatory support (MCS) in patients with acute myocardial infarction-cardiogenic shock (AMI-CS) are infrequently studied. This study sought to evaluate racial disparities in the outcomes of MCS in AMI-CS. The National Inpatient Sample (2012–2017) was used to identify adult AMI-CS admissions receiving MCS support. MCS devices were classified as intra-aortic balloon pump (IABP), percutaneous left ventricular assist device (pLVAD) or extracorporeal membrane oxygenation (ECMO). Self-reported race was classified as white, black and others. Outcomes included in-hospital mortality, hospital length of stay and discharge disposition. During this period, 90,071 admissions were included with white, black and other races constituting 73.6%, 8.3% and 18.1%, respectively. Compared to white and other races, black race admissions were on average younger, female, with greater comorbidities, and non-cardiac organ failure (all p < 0.001). Compared to the white race (31.3%), in-hospital mortality was comparable in black (31.4%; adjusted odds ratio (aOR) 0.98 (95% confidence interval (CI) 0.93–1.05); p = 0.60) and other (30.2%; aOR 0.96 (95% CI 0.92–1.01); p = 0.10). Higher in-hospital mortality was noted in non-white races with concomitant cardiac arrest, and those receiving ECMO support. Black admissions had longer lengths of hospital stay (12.1 ± 14.2, 10.3 ± 11.2, 10.9 ± 1.2 days) and transferred less often (12.6%, 14.2%, 13.9%) compared to white and other races (both p < 0.001). In conclusion, this study of AMI-CS admissions receiving MCS devices did not identify racial disparities in in-hospital mortality. Black admissions had longer hospital stay and were transferred less often. Further evaluation with granular data including angiographic and hemodynamic parameters is essential to rule out racial differences.
Chronic Inflammation Impairs Male Fertility—A Case-Control Study in Ulcerative Colitis Patients
Authors: Wdowiak Artur , Gujski Mariusz , Bojar Iwona , Raczkiewicz Dorota , Bartosińska Joanna , Wdowiak-Filip Anita , Filip Rafał
Published: April 2021

Recent evidence indicates that a systemic state of inflammation may exert a negative effect on male fertility. The aim of this study is to evaluate sperm quality parameters in male patients with ulcerative colitis (UC). Between December 2019 and December 2020 semen analyses are performed in 50 patients with UC in clinical remission. The control group consists of 50 healthy volunteers. Total sperm count, sperm count, percentage of morphologically normal spermatozoa, viability, and progressive motility, are significantly lower in the study group than in healthy males (p < 0.001). The DNA fragmentation index (DFI) and oxidation-reduction potential (ORP) are significantly higher in the study group (28.9% and 1.55% on average, respectively) than in healthy males (14.6% and 0.79% on average, respectively). Bacteriospermia is more clearly observed in the study group (p = 0.037), and the most frequent pathogen is Enterococcus faecalis. The DFI and ORP are significantly higher in bacteria carriers, compared to males without microbial pathogens from both the study and control groups (p < 0.001). To conclude, UC patients have worse basic sperm parameters compared to their healthy counterparts. Deterioration of semen parameters, as well as an intensified DNA fragmentation could be a result of oxidative stress intensification.
Psychological Distress, Fear of COVID-19, and Resilient Coping Abilities among Healthcare Workers in a Tertiary First-Line Hospital during the Coronavirus Pandemic
Authors: Collantoni Enrico , Saieva Anna Maria , Meregalli Valentina , Girotto Cristian , Carretta Giovanni , Boemo Deris Gianni , Bordignon Greta , Capizzi Alfio , Contessa Cristina , Nesoti Maria Vittoria , Donato Daniele , Flesia Luca , Favaro Angela
Published: April 2021

The COVID-19 pandemic is causing a heavy burden in hospital healthcare workers (HCW) in terms of increased work, organizational changes, risk exposure, and social stigma. The present study aims at evaluating the psychological outcome among HCWs at the final stages of the first wave of the COVID-19 pandemic. This cross-sectional and survey-based study was conducted during June 2020 among 996 HCWs of the University Hospital of Padova. All the subjects completed questionnaires investigating the perception of risk of infecting or being infected by COVID-19, psychopathological variables, and coping abilities. Compared to physicians and healthcare assistants, nurses showed higher levels of depression (p = 0.002), insomnia (p < 0.001), and generalized anxiety (p = 0.001). Females reported increased concerns about the possibility of infecting others (p = 0.046), greater anxiety (p < 0.001), COVID-19 related fears (p < 0.001), depression (p < 0.001), and post-traumatic distress (p < 0.001) than males. Being employed in a COVID-19 unit, being transferred to other units, and living with children and the elderly were factors associated with higher levels of psychological distress. Greater coping abilities were detected in physicians, and in those HCWs employed in COVID units. Our findings evidenced that the psychological consequences of the pandemic were non-homogeneously distributed across HCWs categories and pointed out the presence of specific in-hospital and out-of-hospital risk factors.
Diminished Systemic Amino Acids Metabolome and Lipid Peroxidation in Ureteropelvic Junction Obstruction (UPJO) Infants Requiring Surgery
Authors: Begou Olga , Pavlaki Antigoni , Deda Olga , Bollenbach Alexander , Drabert Kathrin , Gika Helen , Farmaki Evangelia , Dotis John , Printza Nikoleta , Theodoridis Georgios , Tsikas Dimitrios
Published: April 2021

Congenital anomalies of the urinary tract, and particularly of obstructive nephropathy such as ureteropelvic junction obstruction (UPJO) in infants, can later lead to chronic kidney disease and hypertension. Fundamental questions regarding underlying mechanisms remain unanswered. The aim of the present study was to quantitate the systemic amino acids metabolome in 21 UPJO infants requiring surgery (Group A) and 21 UPJO infants under conservative treatment (Group B). Nineteen healthy age-matched infants served as controls (Group C). Serum amino acids involved in several pathways and representative metabolites, including the L-arginine-derived nitric oxide (NO) metabolites nitrite and nitrate and the lipid peroxidation biomarker malondialdehyde (MDA) were measured by gas chromatography–mass spectrometry (GC–MS) methods using their stable-isotope labeled analogs as internal standards after derivatization to their methyl esters N-pentafluoropropionic amides (amino acids) and to their pentafluorobenzyl derivatives (nitrite, nitrate, MDA). The concentrations of the majority of the biomarkers were found to be lower in Group A compared to Group B. Statistical analysis revealed clear differentiation between the examined study groups. Univariate statistical analysis highlighted serum homoarginine (q = 0.006), asymmetric dimethylarginine (q = 0.05) and malondialdehyde (q = 0.022) as potential biomarkers for UPJO infants requiring surgery. Group A also differed from Group B with respect to the diameter of the preoperative anterior–posterior renal pelvis (AP) as well as regarding the number and extent of inverse correlations between AP and the serum concentrations of the biomarkers. In Group A, but not in Group B, the AP diameter strongly correlated with hydroxy-proline (r = −0.746, p = 0.0002) and MDA (r = −0.754, p = 0.002). Our results indicate a diminished amino acids metabolome in the serum of UPJO infants requiring surgery comparing to a conservative group.
Development and Internal Validation of Fatty Liver Prediction Models in Obese Children and Adolescents
Authors: Bedogni Giorgio , Tamini Sofia , Caroli Diana , Cicolini Sabrina , Domenicali Marco , Sartorio Alessandro
Published: April 2021

To develop predictive models of fatty liver (FL), we performed a cross-sectional retrospective study of 1672 obese children with a median (interquartile range) age of 15 (13–16) years. The outcome variable was FL diagnosed by ultrasonography. The potential predictors were: (1) binary: sex; (2) continuous: age, body mass index (BMI), waist circumference (WC), alanine transaminase (ALT), aspartate transaminase, gamma-glutamyltransferase, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), HDL-cholesterol, LDL-cholesterol, triglycerides, mean arterial pressure, uric acid, and c-reactive protein; (3) ordinal: Pubertal status. Bootstrapped multivariable logistic regression with fractional polynomials was used to develop the models. Two models were developed and internally validated, one using BMI and the other using WC as the anthropometric predictor. Both models included ALT, HOMA-IR, triglycerides, and uric acid as predictors, had similar discrimination (c-statistic = 0.81), and were similarly well calibrated as determined by calibration plots. These models should undergo external validation before being employed in clinical or research practice.
Saliva Is a Valid Alternative to Nasopharyngeal Swab in Chemiluminescence-Based Assay for Detection of SARS-CoV-2 Antigen
Authors: Amendola Alessandra , Sberna Giuseppe , Lalle Eleonora , Colavita Francesca , Castilletti Concetta , Menchinelli Giulia , Posteraro Brunella , Sanguinetti Maurizio , Ippolito Giuseppe , Bordi Licia , Capobianchi Maria ,   on behalf of INMI COVID-19 Study Group
Published: April 2021

Diagnostic methods based on SARS-CoV-2 antigens detection are a promising alternative to SARS-CoV-2 RNA amplification. We evaluated the automated chemiluminescence-based Lumipulse® G SARS-CoV-2 Ag assay on saliva samples, using Simplexa™ COVID-19 Direct assay as a reference test. Analytical performance was established on a pool of healthy donors’ saliva samples spiked with the 2019-nCoV/Italy-INMI1 isolate, whereas clinical performance was assessed on fresh saliva specimens collected from hospitalized patients with suspect or confirmed COVID-19 diagnosis. The limit of detection (LOD) was 0.65 Log TCID50/mL, corresponding to 18,197 copies/mL of SARS-CoV-2 RNA. Antigen concentrations and SARS-CoV-2 RNA were highly correlated (r = 0.99; p < 0.0001). Substantial agreement (80.3%) and significant correlation (r = −0.675; p = 0.0006) were observed between Lumipulse® G assay results and Ct values on clinical samples, with 52.4% sensitivity and specificity 94.1%. Sensitivity exceeded 90.0% when calculated on samples with Ct < 25, and specificity was 100% when excluding samples from recovered patients with previous COVID-19 diagnosis. Overall, chemiluminescence-based antigen assay may be reliably applied to saliva samples to identify individuals with high viral loads, more likely to transmit the virus. However, the low positive predictive value in a context of low SARS-CoV-2 prevalence underscores the need for confirmatory testing in SARS-CoV-2 antigen-positive cases.
Derivation and Validation of Essential Predictors and Risk Index for Early Detection of Diabetic Retinopathy Using Electronic Health Records
Authors: Wang Ru , Miao Zhuqi , Liu Tieming , Liu Mei , Grdinovac Kristine , Song Xing , Liang Ye , Delen Dursun , Paiva William
Published: April 2021

Diabetic retinopathy (DR) is a leading cause for blindness among working-aged adults. The growing prevalence of diabetes urges for cost-effective tools to improve the compliance of eye examinations for early detection of DR. The objective of this research is to identify essential predictors and develop predictive technologies for DR using electronic health records. We conducted a retrospective analysis on a derivation cohort with 3749 DR and 94,127 non-DR diabetic patients. In the analysis, an ensemble predictor selection method was employed to find essential predictors among 26 variables in demographics, duration of diabetes, complications and laboratory results. A predictive model and a risk index were built based on the selected, essential predictors, and then validated using another independent validation cohort with 869 DR and 6448 non-DR diabetic patients. Out of the 26 variables, 10 were identified to be essential for predicting DR. The predictive model achieved a 0.85 AUC on the derivation cohort and a 0.77 AUC on the validation cohort. For the risk index, the AUCs were 0.81 and 0.73 on the derivation and validation cohorts, respectively. The predictive technologies can provide an early warning sign that motivates patients to comply with eye examinations for early screening and potential treatments.
Cutaneous Mastocytosis in Childhood—Update from the Literature
Authors: Sandru Florica , Petca Răzvan-Cosmin , Costescu Monica , Dumitrașcu Mihai Cristian , Popa Adelina , Petca Aida , Miulescu Raluca-Gabriela
Published: April 2021

Mastocytosis (M) represents a systemic pathology characterized by increased accumulation and clonal proliferation of mast cells in the skin and/or different organs. Broadly, M is classified into two categories: Cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In children, CM is the most frequent form. Unfortunately, pathogenesis is still unclear. It is thought that genetic factors are involved, but further studies are necessary. As for features of CM, the lesions differ in clinical forms. The most important fact is evaluating a pediatric patient with CM. It must comprise laboratory exams (with baseline dosing of total serum tryptase), a skin biopsy (with a pathological exam and, if the diagnosis is unclear, immunohistochemical tests), and a complete clinical evaluation. It is also defining to distinguish between CM and other diseases with cutaneous involvement. As for the management of CM in children, the first intervention implies eliminating trigger factors. The available cures are oral H1 and/or H2 antihistamines, oral cromolyn sodium, oral methoxypsoralen therapy with long-wave psoralen plus ultraviolet A radiation, potent dermatocorticoid, and calcineurin inhibitors. In children, the prognosis of CM is excellent, especially if the disease’s onset is in the first or second years of life.
Identifying Glycemic Variability in Diabetes Patient Cohorts and Evaluating Disease Outcomes
Authors: Nwadiugwu Martin C. , Bastola Dhundy R. , Haas Christian , Russell Doug
Published: April 2021

Glycemic variability (GV) is an obstacle to effective blood glucose control and an autonomous risk factor for diabetes complications. We, therefore, explored sample data of patients with diabetes mellitus who maintained better amplitude of glycemic fluctuations and compared their disease outcomes with groups having poor control. A retrospective study was conducted using electronic data of patients having hemoglobin A1C (HbA1c) values with five recent time points from Think Whole Person Healthcare (TWPH). The control variability grid analysis (CVGA) plot and coefficient of variability (CV) were used to identify and cluster glycemic fluctuation. We selected important variables using LASSO. Chi-Square, Fisher’s exact test, Bonferroni chi-Square adjusted residual analysis, and multivariate Kruskal–Wallis tests were used to evaluate eventual disease outcomes. Patients with very high CV were strongly associated (p < 0.05) with disorders of lipoprotein (p = 0.0014), fluid, electrolyte, and acid–base balance (p = 0.0032), while those with low CV were statistically significant for factors influencing health status such as screening for other disorders (p = 0.0137), long-term (current) drug therapy (p = 0.0019), and screening for malignant neoplasms (p = 0.0072). Reducing glycemic variability may balance alterations in electrolytes and reduce differences in lipid profiles, which may assist in strategies for managing patients with diabetes mellitus.
Virtual Reality in Neurorehabilitation: An Umbrella Review of Meta-Analyses
Authors: Voinescu Alexandra , Sui Jie , Stanton Fraser Danaë
Published: April 2021

Neurological disorders are a leading cause of death and disability worldwide. Can virtual reality (VR) based intervention, a novel technology-driven change of paradigm in rehabilitation, reduce impairments, activity limitations, and participation restrictions? This question is directly addressed here for the first time using an umbrella review that assessed the effectiveness and quality of evidence of VR interventions in the physical and cognitive rehabilitation of patients with stroke, traumatic brain injury and cerebral palsy, identified factors that can enhance rehabilitation outcomes and addressed safety concerns. Forty-one meta-analyses were included. The data synthesis found mostly low- or very low-quality evidence that supports the effectiveness of VR interventions. Only a limited number of comparisons were rated as having moderate and high quality of evidence, but overall, results highlight potential benefits of VR for improving the ambulation function of children with cerebral palsy, mobility, balance, upper limb function, and body structure/function and activity of people with stroke, and upper limb function of people with acquired brain injury. Customization of VR systems is one important factor linked with improved outcomes. Most studies do not address safety concerns, as only nine reviews reported adverse effects. The results provide critical recommendations for the design and implementation of future VR programs, trials and systematic reviews, including the need for high quality randomized controlled trials to test principles and mechanisms, in primary studies and in meta-analyses, in order to formulate evidence-based guidelines for designing VR-based rehabilitation interventions.