bluuebunny/crossref_metadata_2025 huggingface dataset:
Did Children in Single-Parent Households Have a Higher Probability of Emotional Instability during the COVID-19 Pandemic? A Nationwide Cross-Sectional Study in Japan
Authors: Naito Takuto , Tomata Yasutake , Otsuka Tatsui , Tsuno Kanami , Tabuchi Takahiro
Published: April 2022

The influence of public health measures against COVID-19 in Japan on child mental health by household type is unknown. This study aimed to investigate whether COVID-19 and the declaration of a state of emergency in Japan affected children’s mental health between single-parent and two-parent households disproportionately. A large cross-sectional online survey was conducted from August to September 2020. The study included 3365 parents with children aged 0–14 years old who reported their children’s mental status during the declared state of emergency. Emotional instability was reported dichotomously by parents. As the primary result, the probability of emotional instability was higher in single-parent households compared with that in two-parent households after adjustments for potential covariates; the adjusted prevalence ratio (95% CI) was 1.26 (1.07–1.49). Our findings suggest a disproportionate impact on children’s mental health due to the pandemic.
A Textual Analysis of Logograms in Chinese IPO Roadshows: How Agreement between Investors and Management Relates to Pricing and Performance
Authors: Brau James C. , Cicon James , Owen Stephen R.
Published: April 2022

We analyze the interaction between management and investors during Chinese IPO roadshows through Jaccard Similarity analysis of written Chinese logograms. We provide evidence that when agreement is high, investor optimism increases, leading to relatively large first-day underpricing. We further show that high agreement biases investors to systematically overestimate IPO prospects leading to poor long-run abnormal performance. Jaccard Similarity is different from current content analysis methodologies because it is language and culture agnostic, requiring no a priori construction of thematic dictionaries. Elimination of such dictionaries removes the danger that the researcher has imposed predispositions upon the study.
LPS Response Is Impaired by Urban Fine Particulate Matter
Authors: de Souza Xavier Costa Natália , Ribeiro Júnior Gabriel , dos Santos Alemany Adair Aparecida , Belotti Luciano , Frota Cavalcante Marcela , Ribeiro Susan , Matera Veras Mariana , Kallás Esper Georges , Saldiva Paulo Hilário Nascimento , Dolhnikoff Marisa , Ferraz da Silva Luiz Fernando
Published: April 2022

Fine particulate matter (PM2.5) is a complex mixture of components with diverse chemical and physical characteristics associated with increased respiratory and cardiovascular diseases mortality. Our study aimed to investigate the effects of exposure to concentrated PM2.5 on LPS-induced lung injury onset. BALB/c male mice were exposed to either filtered air or ambient fine PM2.5 in an ambient particle concentrator for 5 weeks. Then, an acute lung injury was induced with nebulized LPS. The animals were euthanized 24 h after the nebulization to either LPS or saline. Inflammatory cells and cytokines (IL-1β, IL-4, IL-5, IL-6, IL-10, IL-17, TNF) were assessed in the blood, bronchoalveolar lavage fluid (BALF), and lung tissue. In addition, lung morphology was assessed by stereological methods. Our results showed that the PM+LPS group showed histological evidence of injury, leukocytosis with increased neutrophils and macrophages, and a mixed inflammatory response profile, with increased KC, IL-6, IL-1β, IL-4, and IL-17. Our analysis shows that there is an interaction between the LPS nebulization and PM2.5 exposure, differently modulating the inflammatory response, with a distinct response pattern as compared to LPS or PM2.5 exposure alone. Further studies are required to explain the mechanism of immune modulation caused by PM2.5 exposure.
Gestational Exercise Increases Male Offspring’s Maximal Workload Capacity Early in Life
Authors: Beleza Jorge , Stevanović-Silva Jelena , Coxito Pedro , Rocha Hugo , Santos Paulo , Ascensão António , Ramon Torrella Joan , Magalhães José
Published: April 2022

Mothers’ antenatal strategies to improve the intrauterine environment can positively decrease pregnancy-derived intercurrences. By challenging the mother–fetus unit, gestational exercise (GE) favorably modulates deleterious stimuli, such as high-fat, high-sucrose (HFHS) diet-induced adverse consequences for offspring. We aimed to analyze whether GE alters maternal HFHS-consumption effects on male offspring’s maximal workload performance (MWP) and in some skeletal muscle (the soleus—SOL and the tibialis anterior—TA) biomarkers associated with mitochondrial biogenesis and oxidative fitness. Infant male Sprague-Dawley rats were divided into experimental groups according to mothers’ dietary and/or exercise conditions: offspring of sedentary control diet-fed or HFHS-fed mothers (C–S or HFHS–S, respectively) and of exercised HFHS-fed mothers (HFHS–E). Although maternal HFHS did not significantly alter MWP, offspring from GE dams exhibited increased MWP. Lower SOL AMPk levels in HFHS–S were reverted by GE. SOL PGC-1α, OXPHOS C-I and C-IV subunits remained unaltered by maternal diet, although increased in HFHS–E offspring. Additionally, GE prevented maternal diet-related SOL miR-378a overexpression, while upregulated miR-34a expression. Decreased TA C-IV subunit expression in HFHS–S was reverted in HFHS–E, concomitantly with the downregulation of miR-338. In conclusion, GE in HFHS-fed dams increases the offspring’s MWP, which seems to be associated with the intrauterine modulation of SM mitochondrial density and functional markers.
Pdx1 Is Transcriptionally Regulated by EGR-1 during Nitric Oxide-Induced Endoderm Differentiation of Mouse Embryonic Stem Cells
Authors: Salguero-Aranda Carmen , Beltran-Povea Amparo , Postigo-Corrales Fátima , Hitos Ana Belén , Díaz Irene , Caballano-Infantes Estefanía , Fraga Mario F. , Hmadcha Abdelkrim , Martín Franz , Soria Bernat , Tapia-Limonchi Rafael , Bedoya Francisco J. , Tejedo Juan R. , Cahuana Gladys M.
Published: April 2022

The transcription factor, early growth response-1 (EGR-1), is involved in the regulation of cell differentiation, proliferation, and apoptosis in response to different stimuli. EGR-1 is described to be involved in pancreatic endoderm differentiation, but the regulatory mechanisms controlling its action are not fully elucidated. Our previous investigation reported that exposure of mouse embryonic stem cells (mESCs) to the chemical nitric oxide (NO) donor diethylenetriamine nitric oxide adduct (DETA-NO) induces the expression of early differentiation genes such as pancreatic and duodenal homeobox 1 (Pdx1). We have also evidenced that Pdx1 expression is associated with the release of polycomb repressive complex 2 (PRC2) and P300 from the Pdx1 promoter; these events were accompanied by epigenetic changes to histones and site-specific changes in the DNA methylation. Here, we investigate the role of EGR-1 on Pdx1 regulation in mESCs. This study reveals that EGR-1 plays a negative role in Pdx1 expression and shows that the binding capacity of EGR-1 to the Pdx1 promoter depends on the methylation level of its DNA binding site and its acetylation state. These results suggest that targeting EGR-1 at early differentiation stages might be relevant for directing pluripotent cells into Pdx1-dependent cell lineages.
MicroRNA 3928 Suppresses Glioblastoma through Downregulation of Several Oncogenes and Upregulation of p53
Authors: Mulcahy Elizabeth Q. X. , Zhang Ying , Colόn Rossymar R. , Cain Shelby R. , Gibert Myron K. , Dube Collin J. , Hafner Markus , Abounader Roger
Published: April 2022

Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor. Despite decades of research, therapeutic advances that significantly prolong life are non-existent. In recent years, microRNAs (miRNAs) have been a focus of study in the pathobiology of cancer because of their ability to simultaneously regulate multiple genes. The aim of this study was to determine the functional and mechanistic effects of miR-3928 in GBM both in vitro and in vivo. To the best of our knowledge, this is the first article investigating the role of miR-3928 in GBM. We measured endogenous miR-3928 expression levels in a panel of patient-derived GBM tissue samples and cell lines. We found that GBM tissue samples and cell lines express lower levels of miR-3928 than normal brain cortex and astrocytes, respectively. Therefore, we hypothesized that miR-3928 is a tumor suppressive microRNA. We verified this hypothesis by showing that exogenous expression of miR-3928 has a strong inhibitory effect on both cell growth and invasiveness of GBM cells. Stable ex vivo overexpression of miR-3928 in GBM cells led to a reduction in tumor size in nude mice xenografts. We identified many targets (MDM2, CD44, DDX3X, HMGA2, CCND1, BRAF, ATOH8, and BMI1) of miR-3928. Interestingly, inhibition of the oncogene MDM2 also led to an upregulation of wild-type p53 expression and phosphorylation. In conclusion, we find that miR-3928, through the downregulation of several oncogenes and upregulation and activation of wild-type p53, is a strong tumor suppressor in GBM. Furthermore, the fact that miR-3928 can target many important dysregulated proteins in GBM suggests it might be a “master” regulatory microRNA that could be therapeutically exploited.
The Methyltransferase HemK Regulates the Virulence and Nutrient Utilization of the Phytopathogenic Bacterium Xanthomonas citri Subsp. citri
Authors: Shi Yu , Yang Xiaobei , Ye Xiaoxin , Feng Jiaying , Cheng Tianfang , Zhou Xiaofan , Liu Ding Xiang , Xu Linghui , Wang Junxia
Published: April 2022

Citrus canker, caused by the bacterium Xanthomonas citri subsp. citri (Xcc), seriously affects fruit quality and yield, leading to significant economic losses around the world. Understanding the mechanism of Xcc virulence is important for the effective control of Xcc infection. In this report, we investigate the role of a protein named HemK in the regulation of the virulence traits of Xcc. The hemK gene was deleted in the Xcc jx-6 background, and the ΔhemK mutant phenotypically displayed significantly decreased motility, biofilm formation, extracellular enzymes, and polysaccharides production, as well as increased sensitivity to oxidative stress and high temperatures. In accordance with the role of HemK in the regulation of a variety of virulence-associated phenotypes, the deletion of hemK resulted in reduced virulence on citrus plants as well as a compromised hypersensitive response on a non-host plant, Nicotiana benthamiana. These results indicated that HemK is required for the virulence of Xcc. To characterize the regulatory effect of hemK deletion on gene expression, RNA sequencing analysis was conducted using the wild-type Xcc jx-6 strain and its isogenic ΔhemK mutant strain, grown in XVM2 medium. Comparative transcriptome analysis of these two strains revealed that hemK deletion specifically changed the expression of several virulence-related genes associated with the bacterial secretion system, chemotaxis, and quorum sensing, and the expression of various genes related to nutrient utilization including amino acid metabolism, carbohydrate metabolism, and energy metabolism. In conclusion, our results indicate that HemK plays an essential role in virulence, the regulation of virulence factor synthesis, and the nutrient utilization of Xcc.
Co-Application with Tannic Acid Prevents Transdermal Sensitization to Ovalbumin in Mice
Authors: Izumi Eri , Tanahashi Nana , Kinugasa Serina , Hidaka Shota , Zaima Nobuhiro , Moriyama Tatsuya
Published: April 2022

Transdermal sensitization to allergens is of great concern as a sensitization route for food allergies. This skin-mediated invasion and sensitization to allergens is involved in skin barrier breakdown and inflammation, followed by the production of several kinds of cytokines. Cytokines such as thymic stromal lymphopoietin and thymus and activation-regulated chemokine are also involved. In this study, we investigated the suppressive effect of tannic acid (TA) on transdermal sensitization using ovalbumin (OVA), a major egg-white allergen. We also analyzed the mechanisms associated with the inhibitory effects of TA. The results showed that the co-application with TA prevents transdermal sensitization to OVA. As possible mechanisms, its anti-inflammatory and astringent effect on the skin and binding ability with the protein were considered. These results indicate that TA could be applied to cosmetics and lotions, which could suppress the transdermal sensitization to allergens.
Glycoproteomic and Phenotypic Elucidation of B4GALNT2 Expression Variants in the SID Histo-Blood Group System
Authors: Stenfelt Linn , Nilsson Jonas , Hellberg Åsa , Liew Yew Wah , Morrison Jenny , Larson Göran , Olsson Martin L.
Published: April 2022

The Sda histo-blood group antigen (GalNAcβ1-4(NeuAcα2-3)Galβ-R) is implicated in various infections and constitutes a potential biomarker for colon cancer. Sd(a−) individuals (2–4% of Europeans) may produce anti-Sda, which can lead to incompatible blood transfusions, especially if donors with the high-expressing Sd(a++)/Cad phenotype are involved. We previously reported the association of B4GALNT2 mutations with Sd(a−), which established the SID blood-group system. The present study provides causal proof underpinning this correlation. Sd(a−) HEK293 cells were transfected with different B4GALNT2 constructs and evaluated by immunostaining and glycoproteomics. The predominant SIDnull candidate allele with rs7224888:T>C (p.Cys406Arg) abolished Sda synthesis, while this antigen was detectable as N- or O-glycans on glycoproteins following transfection of wildtype B4GALNT2. Surprisingly, two rare missense variants, rs148441237:A>G and rs61743617:C>T, found in a Sd(a−) compound heterozygote, gave results similar to wildtype. To elucidate on whether Sd(a++)/Cad also depends on B4GALNT2 alterations, this gene was sequenced in five individuals. No Cad-specific changes were identified, but a detailed erythroid Cad glycoprotein profile was obtained, especially for glycophorin-A (GLPA) O-glycosylation, equilibrative nucleoside transporter 1 (S29A1) O-glycosylation, and band 3 anion transport protein (B3AT) N-glycosylation. In conclusion, the p.Cys406Arg β4GalNAc-T2 variant causes Sda-deficiency in humans, while the enigmatic Cad phenotype remains unresolved, albeit further characterized.
Antisense Oligonucleotide Induction of the hnRNPA1b Isoform Affects Pre-mRNA Splicing of SMN2 in SMA Type I Fibroblasts
Authors: Toosaranont Jarichad , Ruschadaariyachat Sukanya , Mujchariyakul Warasinee , Arora Jantarika Kumar , Charoensawan Varodom , Suktitipat Bhoom , Palmer Thomas N. , Fletcher Sue , Wilton Steve D. , Mitrpant Chalermchai
Published: April 2022

Spinal muscular atrophy (SMA) is a severe, debilitating neuromuscular condition characterised by loss of motor neurons and progressive muscle wasting. SMA is caused by a loss of expression of SMN1 that encodes the survival motor neuron (SMN) protein necessary for the survival of motor neurons. Restoration of SMN expression through increased inclusion of SMN2 exon 7 is known to ameliorate symptoms in SMA patients. As a consequence, regulation of pre-mRNA splicing of SMN2 could provide a potential molecular therapy for SMA. In this study, we explored if splice switching antisense oligonucleotides could redirect the splicing repressor hnRNPA1 to the hnRNPA1b isoform and restore SMN expression in fibroblasts from a type I SMA patient. Antisense oligonucleotides (AOs) were designed to promote exon 7b retention in the mature mRNA and induce the hnRNPA1b isoform. RT-PCR and western blot analysis were used to assess and monitor the efficiency of different AO combinations. A combination of AOs targeting multiple silencing motifs in hnRNPA1 pre-mRNA led to robust hnRNPA1b induction, which, in turn, significantly increased expression of full-length SMN (FL-SMN) protein. A combination of PMOs targeting the same motifs also strongly induced hnRNPA1b isoform, but surprisingly SMN2 exon 5 skipping was detected, and the PMO cocktail did not lead to a significant increase in expression of FL-SMN protein. We further performed RNA sequencing to assess the genome-wide effects of hnRNPA1b induction. Some 3244 genes were differentially expressed between the hnRNPA1b-induced and untreated SMA fibroblasts, which are functionally enriched in cell cycle and chromosome segregation processes. RT-PCR analysis demonstrated that expression of the master regulator of these enrichment pathways, MYBL2 and FOXM1B, were reduced in response to PMO treatment. These findings suggested that induction of hnRNPA1b can promote SMN protein expression, but not at sufficient levels to be clinically relevant.
Towards a Deeper Understanding of Chlamydia trachomatis Pathogenetic Mechanisms: Editorial to the Special Issue “Chlamydia trachomatis Pathogenicity and Disease”
Authors: Filardo Simone , Di Pietro Marisa , Sessa Rosa
Published: April 2022

Chlamydia trachomatis, an obligate intracellular Gram-negative bacterium, is characterized by a wide range of different serotypes responsible for several local or systemic human diseases, including genital tract manifestations (D–K), trachoma (A–C), and lymphogranuloma venereum (L1–3) [...]
Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture
Authors: Xu Lili , Su Bijia , Mo Lijun , Zhao Chenye , Zhao Zhenlin , Li Hongwei , Hu Zhiming , Li Jinlong
Published: April 2022

The acidic tumor microenvironment stands as a major obstacle to the efficient elimination of tumor cells. Norcantharidin (NCTD) is a powerful antitumor agent with multiple bioactivities. However, the effect of NCTD under acidic conditions is still unclear. Here, we report that NCTD can efficiently kill bladder cancer (BC) cells in acidic culture, and more intriguingly, NCTD can induce immunogenic cell death (ICD), thereby promoting antitumor immunity. In NCTD-treated BC cells, the surface-exposed calreticulin (ecto-CALR) was significantly increased. Consistently, co-culture with these cells promoted dendritic cell (DC) maturation. The NCTD-induced ICD is autophagy dependent, as autophagy inhibition completely blocked the NCTD-induced ecto-CALR and DC maturation. In addition, the DC showed a distinct maturation phenotype (CD80high CD86low) in acidic culture, as compared to that in physiological pH (CD80 high CD86high). Finally, the NCTD-induced ICD was validated in a mouse model. NCTD treatment significantly increased the tumor-infiltrating T lymphocytes in MB49 bladder cancer mice. Immunizing mice with NCTD-treated MB49 cells significantly increased tumor-free survival as compared to control. These findings demonstrate that NCTD could induce ICD in an acidic environment and suggest the feasibility to combine NCTD with anticancer immunotherapy to treat BC.
Jasmonate Signaling Pathway Modulates Plant Defense, Growth, and Their Trade-Offs
Authors: Li Cong , Xu Mengxi , Cai Xiang , Han Zhigang , Si Jinping , Chen Donghong
Published: April 2022

Lipid-derived jasmonates (JAs) play a crucial role in a variety of plant development and defense mechanisms. In recent years, significant progress has been made toward understanding the JA signaling pathway. In this review, we discuss JA biosynthesis, as well as its core signaling pathway, termination mechanisms, and the evolutionary origin of JA signaling. JA regulates not only plant regeneration, reproductive growth, and vegetative growth but also the responses of plants to stresses, including pathogen as well as virus infection, herbivore attack, and abiotic stresses. We also focus on the JA signaling pathway, considering its crosstalk with the gibberellin (GA), auxin, and phytochrome signaling pathways for mediation of the trade-offs between growth and defense. In summary, JA signals regulate multiple outputs of plant defense and growth and act to balance growth and defense in order to adapt to complex environments.
Lanthanide-Dependent Methanol Metabolism of a Proteobacteria-Dominated Community in a Light Lanthanide-Rich Deep Environment
Authors: Daszczyńska Agnieszka , Krucoń Tomasz , Stasiuk Robert , Koblowska Marta , Matlakowska Renata
Published: April 2022

This study investigated the occurrence and diversity of proteobacterial XoxF-type methanol dehydrogenases (MDHs) in the microbial community that inhabits a fossil organic matter- and sedimentary lanthanide (Ln3+)-rich underground mine environment using a metagenomic and metaproteomic approach. A total of 8 XoxF-encoding genes (XoxF-EGs) and 14 protein sequences matching XoxF were identified. XoxF-type MDHs were produced by Alpha-, Beta-, and Gammaproteobacteria represented by the four orders Methylococcales, Nitrosomonadales, Rhizobiales, and Xanthomonadales. The highest number of XoxF-EG- and XoxF-matching protein sequences were affiliated with Nitrosomonadales and Rhizobiales, respectively. Among the identified XoxF-EGs, two belonged to the XoxF1 clade, five to the XoxF4 clade, and one to the XoxF5 clade, while seven of the identified XoxF proteins belonged to the XoxF1 clade, four to the XoxF4 clade, and three to the XoxF5 clade. Moreover, the accumulation of light lanthanides and the presence of methanol in the microbial mat were confirmed. This study is the first to show the occurrence of XoxF in the metagenome and metaproteome of a deep microbial community colonizing a fossil organic matter- and light lanthanide-rich sedimentary environment. The presented results broaden our knowledge of the ecology of XoxF-producing bacteria as well as of the distribution and diversity of these enzymes in the natural environment.
Polysaccharides from European Black Elderberry Extract Enhance Dendritic Cell Mediated T Cell Immune Responses
Authors: Stich Lena , Plattner Stephan , McDougall Gordon , Austin Ceri , Steinkasserer Alexander
Published: April 2022

European black elderberry (Sambucus nigra L.) is a popular way to treat common colds or influenza infections. Mechanistically, this might be due to a direct antiviral effect or a stimulatory effect on the immune system of the host. Here, we evaluated the modulatory effects of black elderberry derived water extract (EC15) and its polysaccharide enriched fractions (CPS, BOUND, and UNBOUND) in comparison to a conventional alcoholic extract (EE25), regarding the phenotypical and functional properties of dendritic cells (DCs), which are essential cells to induce potent T cell responses. Interestingly, the water extract and its polysaccharide fractions potently induced DC maturation, while the ethanol extract did not. Moreover, the capacity to stimulate T cells by these matured DCs, as assessed using MLR assays, was statistically higher when induced by the water extracted fractions, compared to immature DCs. On the other hand, the ethanol extract EE25 did not induce T cell stimulation. Finally, the cytokine expression profiles of these DC—T cell cocultures were assessed and correlated well with increased T cell stimulation. Also, the expression of inflammatory cytokines, such as IL-6, TNF-α, and IFN-γ was highly increased in the presence of the elderberry water extract EC15, and the polysaccharide enriched CPS, BOUND, and UNBOUND fractions, but not by EE25. Thus, from these data, we conclude that the polysaccharides present in water-derived elderberry fractions induce potent immune-modulatory effects, which represents the basis for a strong immune-mediated response to viruses including influenza.
First Trimester Prediction of Preterm Delivery in the Absence of Other Pregnancy-Related Complications Using Cardiovascular-Disease Associated MicroRNA Biomarkers
Authors: Hromadnikova Ilona , Kotlabova Katerina , Krofta Ladislav
Published: April 2022

The aim of the study was to determine if aberrant expression profile of cardiovascular disease associated microRNAs would be able to predict within 10 to 13 weeks of gestation preterm delivery such as spontaneous preterm birth (PTB) or preterm prelabor rupture of membranes (PPROM) in the absence of other pregnancy-related complications (gestational hypertension, preeclampsia, fetal growth restriction, or small for gestational age). In addition, we assessed if aberrant expression profile of cardiovascular disease associated microRNAs would be able to predict preterm delivery before and after 34 weeks of gestation. The retrospective study was performed within the period November 2012 to March 2020. Whole peripheral blood samples were collected from 6440 Caucasian individuals involving 41 PTB and 65 PPROM singleton pregnancies. A control group, 80 singleton term pregnancies, was selected on the base of equal sample storage time. Gene expression of 29 selected cardiovascular disease associated microRNAs was studied using real-time RT-PCR. Downregulation of miR-16-5p, miR-20b-5p, miR-21-5p, miR-24-3p, miR-26a-5p, miR-92a-3p, miR-126-3p, miR-133a-3p, miR-145-5p, miR-146a-5p, miR-155-5p, miR-210-3p, miR-221-3p and miR-342-3p was observed in pregnancies with preterm delivery before 37 (≤36 + 6/7) weeks of gestation. Majority of downregulated microRNAs (miR-16-5p, miR-24-3p, miR-26a-5p, miR-92a-3p, miR-133a-3p, miR-145-5p, miR-146a-5p, miR-155-5p, miR-210-3p, and miR-342-3p) was associated with preterm delivery occurring before 37 (≤36 + 6/7) weeks of gestation. The only miR-210-3p was downregulated in pregnancies with preterm delivery before 34 (≤33 + 6/7) weeks of gestation. The type of preterm delivery also had impact on microRNA gene expression profile. Downregulation of miR-24-3p, miR-92a-3p, miR-155-5p, and miR-210-3p was a common feature of PTB and PPROM pregnancies. Downregulation of miR-16-5p, miR-20b-5p, miR-26a-5p, miR-126-3p, miR-133a-3p, miR-146a-5p, miR-221-3p, and miR-342-3p appeared just in PTB pregnancies. No microRNA was uniquely dysregulated in PPROM pregnancies. The combination of 12 microRNAs (miR-16-5p, miR-20b-5p, miR-21-5p, miR-24-3p, miR-26a-5p, miR-92a-3p, miR-133a-3p, miR-145-5p, miR-146a-5p, miR-155-5p, miR-210-3p, and miR-342-3p, AUC 0.818, p < 0.001, 74.53% sensitivity, 75.00% specificity, cut off > 0.634) equally as the combination of 6 microRNAs (miR-16-5p, miR-21-5p, miR-24-3p, miR-133a-3p, miR-155-5p, and miR-210-3p, AUC 0.812, p < 0.001, 70.75% sensitivity, 78.75% specificity, cut off > 0.652) can predict preterm delivery before 37 weeks of gestation in early stages of gestation in 52.83% pregnancies at 10.0% FPR. Cardiovascular disease associated microRNAs represent promising biomarkers with very good diagnostical potential to be implemented into the current routine first trimester screening programme to predict preterm delivery.
An Overview of Vanadium and Cell Signaling in Potential Cancer Treatments
Authors: Ferretti Valeria , León Ignacio
Published: April 2022

Vanadium is an ultratrace element present in higher plants, animals, algae, and bacteria. In recent years, vanadium complexes have been studied to be considered as a representative of a new class of nonplatinum metal anticancer drugs. Nevertheless, the study of cell signaling pathways related to vanadium compounds has scarcely been reported on and reviewed thus far; this information is highly critical for identifying novel targets that play a key role in the anticancer activity of these compounds. Here, we perform a review of the activity of vanadium compounds over cell signaling pathways on cancer cells and of the underlying mechanisms, thereby providing insight into the role of these proteins as potential new molecular targets of vanadium complexes.
Seven COVID-19 Patients Treated with C-Reactive Protein (CRP) Apheresis
Authors: Esposito Fabrizio , Matthes Harald , Schad Friedemann
Published: April 2022

Background: The fulminant course of COVID-19, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with a high mortality rate and still lacks a causative treatment. C-reactive protein (CRP) has been shown to increase dramatically during the disease progression and correlates with deleterious outcomes. Selective CRP apheresis can reduce circulating CRP levels fast and effective. Methods: Seven hospitalized patients with documented severe COVID-19 progression, elevated CRP plasma levels (>100 mg/L) and signs of respiratory failure were treated with CRP apheresis. Two to twelve CRP apheresis sessions were performed generally in 24 h time intervals and depending on CRP plasma levels. Results: All patients had comorbidities. CRP apheresis reduced CRP plasma levels by up to 84% within a few hours, without exhibiting side effects in any patient. Despite signs of severe lung infiltration in all patients, only one patient died. The other patients showed improvements within the chest X-ray after CRP apheresis and were able to recover regardless of intubation and/or ECMO (4 patients). All remaining six patients were discharged from the hospital in good clinical condition. Conclusions: This case series presents a mortality rate of only 14%, which is dramatically lower than expected from the presented CRP levels as well as comorbidities and ventilation requirements. Our clinical observations regarding the here presented seven patients support the hypothesis that CRP is a candidate to be therapeutically targeted in the early stage of severe COVID-19.
Etiology, Risk Factors and Clinical Outcomes in Infective Endocarditis Patients Requiring Cardiac Surgery
Authors: Meidrops Kristians , Burkhardt Franziska Johanna , Osipovs Janis Davis , Petrosina Eva , Groma Valerija , Stradins Peteris
Published: April 2022

Background: Infective endocarditis, which may be caused by various microbial agents, severely affects the innermost layer of the heart and often leads to poor clinical outcomes. The purpose of this study was to investigate the etiology, risk factors and short and long-term outcomes of infective endocarditis caused by various bacterial agents in patients requiring cardiac surgery. Methods: One hundred and forty-four patients aged 18 years or above with indications for cardiac surgery due to S. aureus, Streptococcus spp., E. faecalis or coagulase-negative staphylococci caused infective endocarditis were included in this study. Results: S. aureus, Streptococcus spp., E. faecalis and coagulase-negative staphylococci were the causative agents of infective endocarditis in 44 (30.6%), 35 (24.3%), 33 (22.9%) and 32 (22.2%) patients, respectively. The presence of bicuspid aortic valve was the most common predisposing factor confirmed in 19 (23.5%), whereas intravenous drug usage was the most common in 17 (11.8%) patients. No significant differences in intrahospital mortality due to infective endocarditis caused by various bacterial agents were found, however, the worsening of long-term prognosis of endocarditis caused by S. aureus when compared to E. faecalis was confirmed (p = 0.03). The presence of S. aureus was associated with significantly higher rates of embolic complications (p = 0.003). The presence of coagulase-negative staphylococci was associated with prosthetic valve endocarditis (p = 0.015) and perivalvular complications (p = 0.024). Conclusions: In contrast to E. faecalis, the presence of S. aureus determines the worsening of the long-term mortality from infective endocarditis. Perivalvular complications are associated with the presence of coagulase-negative staphylococci.
Has the Removing of the Mesentery during Ileo-Colic Resection an Impact on Post-Operative Complications and Recurrence in Crohn’s Disease? Results from the Resection of the Mesentery Study (Remedy)
Authors: Mineccia Michela , Maconi Giovanni , Daperno Marco , Cigognini Maria , Cherubini Valeria , Colombo Francesco , Perotti Serena , Baldi Caterina , Massucco Paolo , Ardizzone Sandro , Ferrero Alessandro , Sampietro Gianluca M.
Published: April 2022

Some evidence suggests a reduction in clinical and surgical recurrence after mesenteric resection in Crohn’s Disease (CD). The aim of the REsection of the MEsentery StuDY (Remedy) was to assess whether mesenteric removal during surgery for ileocolic CD has an impact in terms of postoperative complications, endoscopic and ultrasonographic recurrences, and long-term surgical recurrence. Among the 326 patients undergoing primary resection between 2009 and 2019 in two referral centers, in 204 (62%) the mesentery was resected (Group A) and in 122 (38%) it was retained (Group B). Median follow-up was 4.7 ± 3 years. Groups were similar in the peri-operative course. Endoscopic and ultrasonographic recurrences were 44.6% and 40.4% in Group A, and 46.7% and 41.2% in Group B, respectively, without statistically significant differences. The five-year time-to-event estimates, compared with the Log-rank test, were 3% and 4% for normal or thickened mesentery (p = 0.6), 2.8% and 4% for resection or sparing of the mesentery (p = 0.6), and 1.7% and 5.4% in patients treated with biological or immunosuppressants versus other adjuvant therapy (p = 0.02). In Cox’s model, perforating behavior was a risk factor, and biological or immunosuppressant adjuvant therapy protective for surgical recurrence. The resection of the mesentery does not seem to reduce endoscopic and ultrasonographic recurrences, and the five-year recurrence rate.
Mortality and Epidemiological Changes in Proximal Hip Fractures in the Course of a Pandemic
Authors: Popp Domenik , Nia Arastoo , Silvaieh Sara , Diendorfer Cornelia , Schmoelz Lukas , Thalmann Georg , Frank Stefan , Döring Kevin , Hajdu Stefan , Widhalm Harald K.
Published: April 2022

Background: Coronavirus disease 2019 (COVID-19) has had an immense impact on the treatment protocols of orthopedic and trauma departments, yet its specific effect on mortality in patients with hip fractures due to possible surgical delays is still unclear. The purpose of this paper was to investigate whether the COVID-19 pandemic worsened the mortality rate of hip fracture patients. Patients and methods: This study comprised 175 prospectively included patients who (1) suffered from hip fractures, (2) presented during the Austrian state of emergency period from 15 March 2020 to 30 May 2021, and (3) were admitted to a level I trauma center. This cohort was compared with a retrospective control group of 339 patients admitted for hip fractures during the same timeframe in 2017, 2018, and 2019. Results: An admission reduction of 22% in the COVID period compared with the pre-COVID period was evident (p = 0.018). The 30-day mortality rate was 14.67% (pre-COVID) compared with 15.18% (p = 0.381). No differences in surgical complication rates or relationships between comorbidity burden and survival were observed. There were no significant changes in demographic variables, except for admission rate, gender (p = 0.013), and place of accident (p = 0.049). Conclusion: Surgeons should be reassured to take COVID-19 precautions, as this study did not show higher perioperative mortality due to COVID-19 measures. Under the current circumstances, with possibly reduced surgical and hospital bed capacities, it is expected that hip fractures may continue to require a high degree of resources.
Predictors Associated with Adverse Pregnancy Outcomes in a Cohort of Women with Systematic Lupus Erythematosus from Romania—An Observational Study (Stage 2)
Authors: Vicoveanu Petronela , Vasilache Ingrid-Andrada , Nemescu Dragos , Carauleanu Alexandru , Scripcariu Ioana-Sadiye , Rudisteanu Dorina , Burlui Alexandra , Rezus Elena , Socolov Demetra
Published: April 2022

Background: Pregnancy in women with systemic lupus erythematosus (SLE) is accompanied by adverse pregnancy outcomes (APOs). We aimed to investigate the association between clinical, sonographic, and laboratory parameters and APOs (preeclampsia, intrauterine growth restriction, premature birth, and maternal mortality). Methods: This observational retrospective study included all pregnancies in women with SLE who attended two tertiary maternity hospitals from Romania between January 2013 and December 2020. Clinical, sonographic, and laboratory variables were examined. Bivariate associations of APO status and each predictor variable were evaluated, and significant predictors were further included in a classification model based on discriminant analysis. Results: Predictors of APOs included BMI > 25 kg/m2, personal history of lupus nephritis or chronic hypertension, proteinuria, low C3, SLE Disease Activity Index 2000 (SLEDAI-2k score ≥ 4 and physician’s global-assessment (PGA) score ≥ 1 throughout pregnancy, increased mean uterine arteries pulsatility index in the first and second trimesters, cerebroplacental ratio < 1 in the second and third trimesters, and small fetal abdominal circumference in the third trimester. Glucocorticoids, methyldopa, and aspirin use appeared to be protective against APOs. Conclusions: This study provides a comprehensive analysis of the most important predictors for APOs in pregnant patients with SLE, which could constitute a basis for further research.
Management and Long-Term Follow-Up of Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1: Single Center Experience
Authors: Yavropoulou Maria P. , Vlachou Sofia , Tsoli Marina , Fostira Florentia , Kaltsas Gregory , Kassi Eva
Published: April 2022

Background: Primary hyperparathyroidism (PHPT) in the most common and earliest manifestation of multiple endocrine neoplasia type-1 (MEN1). Epidemiological data have been reported in MEN1 patients but data on long-term follow-up focusing on PHPT are scarce. Methods: In this retrospective cohort study, we included patients diagnosed with MEN1-related PHPT that were under regular follow-up in our institution. Results: Data on 68 patients (39 males), with a mean age at MEN1-diagnosis of 39 ± 13.06 years, were analyzed. Pancreatic neuroendocrine tumors were encountered in 82% (71% nonsecreting) followed by pituitary adenomas in 66% (49% nonsecreting). Mean age at PHPT diagnosis was 35.2 ± 4.0 years. Parathyroidectomy was performed in 57 patients (82.3%), of whom 56% achieved long-term remission, while 12.2% and 31.5% had persistent and recurrent disease, respectively (median follow-up of 4 years; range 1–21 years). Cinacalcet restored serum calcium levels in 33.8%, both as first and as a second line treatment. Permanent hypoparathyroidism occurred in 19.2%. MEN1 pathogenic variants were identified in 77.2% of the tested individuals, but no genotype-phenotype associations were reported. Conclusions: MEN1-related PHPT involves a multiglandular disease and its management remains a therapeutic challenge, as recurrent disease can develop even after 20 years of follow-up. Prolonged follow-up of these patients at referral centers is critical for their optimal management.
Prevalence of Arrhythmia in Adults after Fontan Operation
Authors: Okólska Magdalena , Karkowski Grzegorz , Kuniewicz Marcin , Bednarek Jacek , Pająk Jacek , Róg Beata , Łach Jacek , Legutko Jacek , Tomkiewicz-Pająk Lidia
Published: April 2022

Structural, hemodynamic, and morphological cardiac changes following Fontan operation (FO) can contribute to the development of arrhythmias and conduction disorders. Sinus node dysfunction, junction rhythms, tachyarrhythmias, and ventricular arrhythmias (VAs) are some of the commonly reported arrhythmias. Only a few studies have analyzed this condition in adults after FO. This study aimed to determine the type and prevalence of arrhythmias and conduction disorders among patients who underwent FO and were under the medical surveillance of the John Paul II Hospital in Krakow. Data for the study were obtained from 50 FO patients (mean age 24 ± 5.7 years; 28 men (56%)). The median follow-up time was 4 (2–9) years. Each patient received a physical examination, an echocardiographic assessment, and a 24 h electrocardiogram assessment. Bradyarrhythmia was diagnosed in 22 patients (44%), supraventricular tachyarrhythmias in 14 patients (28%), and VAs in 6 patients (12%). Six patients required pacemaker implantation, and three required radiofrequency catheter ablation (6%). Arrythmias is a widespread clinical problem in adults after FO. It can lead to serious haemodynamic impairment, and therefore requires early diagnosis and effective treatment with the use of modern approaches, including electrotherapy methods.
Plasma Thallium Concentration, Kidney Function, Nephrotoxicity and Graft Failure in Kidney Transplant Recipients
Authors: Kremer Daan , Riemersma Niels L. , Groothof Dion , Sotomayor Camilo G. , Eisenga Michele F. , Post Adrian , Knobbe Tim J. , Touw Daan J. , Bakker Stephan J. L.
Published: April 2022

The nephrotoxic effects of heavy metals have gained increasing scientific attention in the past years. Recent studies suggest that heavy metals, including cadmium, lead, and arsenic, are detrimental to kidney transplant recipients (KTR) even at circulating concentrations within the normal range, posing an increased risk for graft failure. Thallium is another highly toxic heavy metal, yet the potential consequences of the circulating thallium concentrations in KTR are unclear. We measured plasma thallium concentrations in 672 stable KTR enrolled in the prospective TransplantLines Food and Nutrition Biobank and Cohort Study using inductively coupled plasma mass spectrometry. In cross-sectional analyses, plasma thallium concentrations were positively associated with kidney function measures and hemoglobin. We observed no associations of thallium concentration with proteinuria or markers of tubular damage. In prospective analyses, we observed no association of plasma thallium with graft failure and mortality during a median follow-up of 5.4 [interquartile range: 4.8 to 6.1] years. In conclusion, in contrast with other heavy metals such as lead, cadmium, and arsenic, there is no evidence of tubular damage or thallium nephrotoxicity for the range of circulating thallium concentrations observed in this study. This is further evidenced by the absence of associations of plasma thallium with graft failure and mortality in KTR.
Validation of an Arrhythmogenic Right Ventricular Cardiomyopathy Risk-Prediction Model in a Chinese Cohort
Authors: Zhang Nixiao , Wang Chuangshi , Gasperetti Alessio , Song Yanyan , Niu Hongxia , Gu Min , Duru Firat , Chen Liang , Zhang Shu , Hua Wei
Published: April 2022

Background: The novel arrhythmogenic right ventricular cardiomyopathy (ARVC)-associated ventricular arrhythmias (VAs) risk-prediction model endorsed by Cadrin-Tourigny et al. was recently developed to estimate visual VA risk and was identified to be more effective for predicting ventricular events than the International Task Force Consensus (ITFC) criteria, and the Heart Rhythm Society (HRS) criteria. Data regarding its application in Asians are lacking. Objectives: We aimed to perform an external validation of this algorithm in the Chinese ARVC population. Methods: The study enrolled 88 ARVC patients who received implantable cardioverter-defibrillator (ICD) from January 2005 to January 2020. The primary endpoint was appropriate ICD therapies. The novel prediction model was used to calculate a priori predicted VA risk that was compared with the observed rates. Results: During a median follow-up of 3.9 years, 57 (64.8%) patients received the ICD therapy. Patients with implanted ICDs for primary prevention had non-significantly lower rates of ICD therapy than secondary prevention (5-year event rate: 0.46 (0.13–0.66) and 0.80 (0.64–0.89); log-rank p = 0.098). The validation study revealed the C-statistic of 0.833 (95% confidence interval (CI) 0.615–1.000), and the predicted and the observed patterns were similar in primary prevention patients (mean predicted–observed risk: −0.07 (95% CI −0.21, 0.09)). However, in secondary prevention patients, the C-statistic was 0.640 (95% CI 0.510–0.770) and the predicted risk was significantly underestimated (mean predicted–observed risk: −0.32 (95% CI −0.39, −0.24)). The recalibration analysis showed that the performance of the prediction model in secondary prevention patients was improved, with the mean predicted–observed risk of −0.04 (95% CI −0.10, 0.03). Conclusions: The novel risk-prediction model had a good fitness to predict arrhythmic risk in Asian ARVC patients for primary prevention, and for secondary prevention patients after recalibration of the baseline risk.
Extracorporeal Shockwave Therapy in the Treatment of Nonunion in Long Bones: A Systematic Review and Meta-Analysis
Authors: Sansone Valerio , Ravier Domenico , Pascale Valerio , Applefield Rachel , Del Fabbro Massimo , Martinelli Nicolò
Published: April 2022

Background: Nonunion is one of the most challenging problems in the field of orthopedics. The aim of this study was to perform a systematic review of the literature to evaluate the effectiveness of extracorporeal shockwave therapy (ESWT) in the treatment of nonunion in long bones. Methods: We conducted a search of three databases (PubMed, Scopus, and Web of Science) and found 646 total publications, of which 23 met our inclusion criteria. Results: Out of 1200 total long bone nonunions, 876 (73%) healed after being treated with ESWT. Hypertrophic cases achieved 3-fold higher healing rates when compared to oligotrophic or atrophic cases (p = 0.003). Metatarsal bones were the most receptive to ESWT, achieving a healing rate of 90%, followed by tibiae (75.54%), femurs (66.9%) and humeri (63.9%). Short periods between injury and treatment lead to higher healing rates (p < 0.02). Conversely, 6 months of follow-up after the treatment appears to be too brief to evaluate the full healing potential of the treatment; several studies showed that healing rates continued to increase at follow-ups beyond 6 months after the last ESWT treatment (p < 0.01). Conclusions: ESWT is a promising approach for treating nonunions. At present, a wide range of treatment protocols are used, and more research is needed to determine which protocols are the most effective.
Safety, Efficacy and Long-Term Outcomes of Patients Treated with the Occlutech Paravalvular Leak Device for Significant Paravalvular Regurgitation
Authors: Onorato Eustaquio Maria , Alamanni Francesco , Muratori Manuela , Smolka Grzegorz , Wojakowski Wojtek , Pysz Piotr , Zorinas Aleksejus , Zakarkaite Diana , Eltchaninoff Hélène , Litzer Pierre-Yves , Godart François , Calvert Patrick , Christou Christos , Mussayev Abdurashid , Missiroli Bindo , Buzaev Igor , Curello Salvatore , Tesorio Tullio , Bartorelli Antonio Luca
Published: April 2022

Between December 2014 and March 2021, 144 patients with aortic (Ao) or mitral (Mi) paravalvular leaks (PVLs) were enrolled at 21 sites in 10 countries. Safety data were available for 137 patients, who were included in the safety analysis fraction (SAF), 93 patients with Mi PVLs and 44 patients with Ao PVLs. The full analysis set (FAS) comprised 112 patients with available stratum (aortic/mitral leak) as well as baseline (BL), 180-day or later assessments (2 years). Procedural success (implantation of the device with a proper closure of the PVL, defined as reduction in paravalvular regurgitation of ≥one grade as assessed by echocardiography post implantation) was achieved in 91.3% of FAS patients with Mi PVLs and in 90.0% of those with Ao PVLs. The proportion of patients suffering from significant or severe heart failure (HF), classified as New York Heart Association (NYHA) class III/IV, decreased from 80% at baseline to 14.1% at 2-year follow-up (FAS). The proportion of FAS patients needing hemolysis-related blood transfusion decreased from 35.5% to 3.8% and from 8.1% to 0% in Mi patients and Ao patients, respectively. In total, 35 serious adverse events (SAEs) were reported in 27 patients (19.7%) of the SAF population. The SAEs considered possibly or probably related to the device included device embolization (three patients), residual leak (two patients) and vascular complication (one patient). During follow-up, 12/137 (8.8%) patients died, but none of the deaths was considered to be device-related. Patients implanted with the Occlutech Paravalvular Leak Device (PLD) showed long-lasting improvements in clinical parameters, including NYHA class and a reduced dependency on hemolysis-related blood transfusions.