bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug Therapies for Chronic Cholestatic Liver Diseases
Authors: Wagner Martin , Fickert Peter
Published: September 2019

Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.
Selenoprotein W deficiency does not affect oxidative stress and insulin sensitivity in the skeletal muscle of high-fat diet-fed obese mice
Authors: Shin Min-Gyeong , Cha Hye-Na , Park Soyoung , Kim Yong-Woon , Kim Jong-Yeon , Park So-Young
Published: September 2019

Selenoprotein W (SelW) is a selenium-containing protein with a redox motif found abundantly in the skeletal muscle of rodents. Previous in vitro studies suggest that SelW plays an antioxidant role; however, relatively few in vivo studies have addressed the antioxidant role of SelW. Since oxidative stress is a causative factor for the development of insulin resistance in obese subjects, we hypothesized that if SelW plays a role as an antioxidant, SelW deficiency could aggravate the oxidative stress and insulin resistance caused by a high-fat diet. SelW deficiency did not affect insulin sensitivity and H2O2 levels in the skeletal muscle of control diet-fed mice. SelW levels in the skeletal muscle were decreased by high-fat diet feeding for 12 wk. High-fat diet induced obesity and insulin resistance and increased the levels of H2O2 and oxidative stress makers, which were not affected by SelW deficiency. High-fat diet feeding increased the expression of antioxidant enzymes; however, SelW deficiency did not affect the expression levels of antioxidants. These results suggest that SelW does not play a protective role against oxidative stress and insulin resistance in the skeletal muscle of high-fat diet-fed obese mice.
Nod2 deficiency functionally impairs adaptation to short bowel syndrome via alterations of the epithelial barrier function
Authors: Berlin Peggy , Reiner Johannes , Witte Maria , Wobar Jakob , Lindemann Sabeth , Barrantes Israel , Kreikemeyer Bernd , Bastian Manuela , Schäffler Holger , Bannert Karen , Jaster Robert , Lamprecht Georg
Published: September 2019

Nucleotide-binding oligomerization domain-containing protein 2 ( NOD2) gene mutations are a risk factor for Crohn’s disease and also associated with worse outcome in short bowel syndrome (SBS) patients independent of the underlying disease. The aim of this study was to analyze the effect of Nod2 deficiency on barrier function and stool microbiome after extensive ileocecal resection in mice. Male C57BL6/J wild-type (WT) and Nod2-knockout (KO) mice underwent 40% ileocecal resection. Sham control mice received simple transection of the ileum. Clinical outcome was monitored daily. Barrier function was measured with Ussing chambers using FITC-4-kDa-Dextran flux, transmucosal electrical resistance, and dilution potentials. Immunofluorescence of claudin-2 was studied. Composition of the stool microbiome was assessed by 16S rRNA gene sequencing. Resected Nod2-KO mice had impaired clinical outcome compared with resected WT mice. This was accompanied by increased stool water contents and increased plasma aldosterone. Histomorphological adaptation was independent of Nod2. Barrier function studies revealed impaired sodium to chloride permeability and altered claudin-2 localization in the absence of Nod2. Resection induced decreases of bacterial diversity and a shift of bacteriodetes-to-firmicutes ratios. Ileum and cecum resection-induced increase in proteobacteria was absent in Nod2-deficient mice. Verrucomicrobia were temporarily increased in Nod2-KO mice. Nod2 deficiency functionally impairs adaptation to short bowel syndrome via a lesser increase of epithelial sodium pore permeability, altered epithelial barrier function, and the microbiome.

NEW & NOTEWORTHY NOD2 gene mutations are associated with the development of severe short bowel syndrome and intestinal failure. The influence of Nod2 mutations on intestinal adaptation in experimental short bowel syndrome has not been studied yet. Here, we provide data that Nod2 deficiency worsens clinical outcome and functional adaptation under SBS conditions in mice, indicating that NOD2 is required for successful adaptation after ileocecal resection.
Dysbiosis: from fiction to function
Authors: Tiffany Connor R. , Bäumler Andreas J.
Published: September 2019

Advances in data collection technologies reveal that an imbalance (dysbiosis) in the composition of host-associated microbial communities (microbiota) is linked to many human illnesses. This association makes dysbiosis a central concept for understanding how the human microbiota contributes to health and disease. However, it remains problematic to define the term dysbiosis by cataloguing microbial species names. Here, we discuss how incorporating the germ-organ concept, ecological assumptions, and immunological principles into a theoretical framework for microbiota research provides a functional definition for dysbiosis. The generation of such a framework suggests that the next logical step in microbiota research will be to illuminate the mechanistic underpinnings of dysbiosis, which often involves a weakening of immune mechanisms that balance our microbial communities.
OATP1B3-1B7, a novel organic anion transporting polypeptide, is modulated by FXR ligands and transports bile acids
Authors: Malagnino Vanessa , Hussner Janine , Issa Ali , Midzic Angela , Meyer zu Schwabedissen Henriette E.
Published: September 2019

Organic anion transporting polypeptide (OATP) 1B3–1B7 (LST-3TM12) is a member of the OATP1B [solute carrier organic anion transporter ( SLCO) 1B] family. This transporter is not only functional but also expressed in the membrane of the smooth endoplasmic reticulum of hepatocytes and enterocytes. OATP1B3–1B7 is a splice variant of SLCO1B3 in which the initial part is encoded by SLCO1B3, whereas the rest of the mRNA originates from the gene locus of SLCO1B7. In this study, we not only showed that SLCO1B3 and the mRNA encoding for OATP1B3–1B7 share the 5′ untranslated region but also that silencing of an initial SLCO1B3 exon lowered the amount of SLCO1B3 and of SLCO1B7 mRNA in Huh-7 cells. To validate the assumption that both transcripts are regulated by the same promoter we tested the influence of the bile acid sensor farnesoid X receptor (FXR) on their transcription. Treatment of Huh-7 and HepaRG cells with activators of this known regulator of OATP1B3 not only increased SLCO1B3 but also OATP1B3–1B7 mRNA transcription. Applying a heterologous expression system, we showed that several bile acids interact with OATP1B3–1B7 and that taurocholic acid and lithocholic acid are OATP1B3–1B7 substrates. As OATP1B3–1B7 is located in the smooth endoplasmic reticulum, it may grant access to metabolizing enzymes. In accordance are our findings showing that the OATP1B3–1B7 inhibitor bromsulphthalein significantly reduced uptake of bile acids into human liver microsomes. Taken together, we report that OATP1B3–1B7 transcription can be modulated with FXR agonists and antagonists and that OATP1B3–1B7 transports bile acids.

NEW & NOTEWORTHY Our study on the transcriptional regulation of the novel organic anion transporting polypeptide (OATP) 1B3–1B7 concludes that the promoter of solute carrier organic anion transporter ( SLCO) 1B3 governs SLCO1B3–1B7 transcription. Moreover, the transcription of OATP1B3–1B7 can be modulated by farnesoid X receptor (FXR) agonists and antagonists. FXR is a major regulator in bile acid homeostasis that links OATP1B3–1B7 to this physiological function. Findings in transport studies with OATP1B3–1B7 suggest that this transporter interacts with the herein tested bile acids.
Characterization of cystic fibrosis airway smooth muscle cell proliferative and contractile activities
Authors: Jang Joyce Hojin , Panariti Alice , O’Sullivan Michael J. , Pyrch Melissa , Wong Chris , Lauzon Anne-Marie , Martin James G.
Published: September 2019

Cystic fibrosis (CF) is a genetic disease that causes multiple airway abnormalities. Two major respiratory consequences of CF are airway hyperresponsiveness (AHR) and airway remodeling. Airway smooth muscle (ASM) is hypothesized to be responsible for the airway dysfunction, since their thickening is involved in remodeling, and excessive contraction by the ASM may cause AHR. It is unclear whether the ASM is intrinsically altered to favor increased contractility or proliferation or if microenvironmental influences induce pathological behavior in vivo. In this study, we examined the contractile and proliferative properties of ASM cells isolated from healthy donor and CF transplant lungs. Assays of proliferation showed that CF ASM proliferates at a higher rate than healthy cells. Through calcium analysis, no differences in contractile activation in response to histamine were found. However, CF ASM cells lagged in their reuptake of calcium in the sarcoplasmic reticulum. The combination CFTR corrector and potentiator, VX-809/770, used to restore CFTR function in CF ASM, resulted in a reduction in proliferation and in a normalization of calcium reuptake kinetics. These results show that impaired CFTR function in ASM cells causes intrinsic changes in their proliferative and contractile properties.
Clinically relevant model of pneumococcal pneumonia, ARDS, and nonpulmonary organ dysfunction in mice
Authors: Gotts Jeffrey E. , Bernard Olivier , Chun Lauren , Croze Roxanne H. , Ross James T. , Nesseler Nicolas , Wu Xueling , Abbott Jason , Fang Xiaohui , Calfee Carolyn S. , Matthay Michael A.
Published: September 2019

Pneumonia is responsible for more deaths in the United States than any other infectious disease. Severe pneumonia is a common cause of acute respiratory failure and acute respiratory distress syndrome (ARDS). Despite the introduction of effective antibiotics and intensive supportive care in the 20th century, death rates from community-acquired pneumonia among patients in the intensive care unit remain as high as 35%. Beyond antimicrobial treatment, no targeted molecular therapies have yet proven effective, highlighting the need for additional research. Despite some limitations, small animal models of pneumonia and the mechanistic insights they produce are likely to continue to play an important role in generating new therapeutic targets. Here we describe the development of an innovative mouse model of pneumococcal pneumonia developed for enhanced clinical relevance. We first reviewed the literature of small animal models of bacterial pneumonia that incorporated antibiotics. We then did a series of experiments in mice in which we systematically varied the pneumococcal inoculum and the timing of antibiotics while measuring systemic and lung-specific end points, producing a range of models that mirrors the spectrum of pneumococcal lung disease in patients, from mild self-resolving infection to severe pneumonia refractory to antibiotics. A delay in antibiotic treatment resulted in ongoing inflammation and renal and hepatic dysfunction despite effective bacterial killing. The addition of fluid resuscitation to the model improved renal function but worsened the severity of lung injury based on direct measurements of pulmonary edema and lung compliance, analogous to patients with pneumonia and sepsis who develop ARDS following fluid administration.
Volume-CLEM: a method for correlative light and electron microscopy in three dimensions
Authors: Hegermann Jan , Wrede Christoph , Fassbender Susanne , Schliep Ronja , Ochs Matthias , Knudsen Lars , Mühlfeld Christian
Published: September 2019

Generation of three-dimensional (3D) data sets from serial sections of tissues imaged by light microscopy (LM) allows identification of rare structures by morphology or fluorescent labeling. Here, we demonstrate a workflow for correlative LM and electron microscopy (EM) from 3D LM to 3D EM, using the same sectioned material for both methods consecutively. The new approach is easy to reproduce in routine EM laboratories and applicable to a wide range of organs and research questions.
E3 ligase MDM2 mediates urea transporter-A1 ubiquitination under either constitutive or stimulatory conditions
Authors: Su Hua , Ye Chen , Sands Jeff M. , Zhang Chun
Published: September 2019

Posttranslational modifications are essential for the regulation of urea transporter-A1 (UT-A1), among which ubiquitination is a rather attractive and complex issue. Previously, our group reported that murine double minute 2 (MDM2) is one of the E3 ubiquitin ligases for UT-A1, and, later, we showed that ubiquitination contributes to the subcellular trafficking and stability of UT-A1. In the present study, we discovered that MDM2 interacts with UT-A1 in an AP50 (a component of the clathrin-coated pit)-dependent manner. However, their binding is irrelevant to the phosphorylatory status of UT-A1. Next, our findings indicated that MDM2 decreases the stability of either total or membrane UT-A1. On the cell membrane, MDM2 and ubiquitinated UT-A1 are both distributed in the lipid raft domain, and their linkage is obviously enhanced under forskolin (FSK) stimulation. In line with these results, in the diabetic rat, not only MDM2 but also ubiquitinated UT-A1 are intensified. Also, in vitro high glucose and angiotensin II play similar roles as FSK does on the association of MDM2 with UT-A1. In conclusion, MDM2 binds with UT-A1 and mediates its ubiquitination and degradation in an AP50-dependent manner, and their binding capacity is strengthened under FSK and diabetic milieu.
Complement C1r serine protease contributes to kidney fibrosis
Authors: Xavier Sandhya , Sahu Ranjit K. , Bontha Sai Vineela , Mas Valeria , Taylor Ronald P. , Megyesi Judit , Thielens Nicole M. , Portilla Didier
Published: September 2019

We have previously reported that complement activation precedes the development of kidney fibrosis; however, little is known about the cellular mechanisms involved in this transition. We hypothesized that increased expression of C1 complex protease C1r, the initiator of complement activation, contributes to tubulointerstitial fibrosis and tested this idea in mice with global deletion of C1r. Although expression of C1r in untreated wild-type (WT) mice was higher in the liver compared with kidney tissue, administration of folic acid (FA) led to upregulation of C1r mRNA and protein levels only in kidney tissue. Immunohistochemistry and in situ hybridization experiments localized increased expression of C1r and C1s proteases to renal tubular epithelial cells. C1r-null mice had reduced acute tubular injury and inflammation measured 2 days after FA administration compared with WT mice. C1r deletion reduced expression of C1s, C3 fragment formation, and organ fibrosis measured 14 days after FA administration. Differential gene expression performed in kidney tissue demonstrated that C1r-null mice had reduced expression of genes associated with the acute phase response, complement, proliferation of connective tissue cells (e.g., platelet-derived growth factor receptor-β), and reduced expression of genes associated with inflammation compared with FA-treated WT mice. In vitro experiments in renal epithelial cells demonstrated that C1s expression is dependent on increased C1r expression and that interferon-γ induces the expression of these two proteases. We conclude that increased expression of C1 complex proteases is associated with increased tissue inflammation and complement C3 formation and represents an important pathogenic mechanism leading to FA-mediated tubulointerstitial fibrosis.
Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis
Authors: Menshikh Anna , Scarfe Lauren , Delgado Rachel , Finney Charlene , Zhu Yuantee , Yang Haichun , de Caestecker Mark P.
Published: September 2019

Acute kidney injury (AKI) is a strong independent predictor of mortality and often results in incomplete recovery of renal function, leading to progressive chronic kidney disease (CKD). Many clinical trials have been conducted on the basis of promising preclinical data, but no therapeutic interventions have been shown to improve long-term outcomes after AKI. This is partly due to the failure of preclinical studies to accurately model clinically relevant injury and long-term outcomes on CKD progression. Here, we evaluated the long-term effects of AKI on CKD progression in three animal models reflecting diverse etiologies of AKI: repeat-dose cisplatin, rhabdomyolysis, and ischemia-reperfusion injury. Using transdermal measurement of glomerular filtration rate as a clinically relevant measure of kidney function and quantification of peritubular capillary density to measure capillary rarefaction, we showed that repeat-dose cisplatin caused capillary rarefaction and decreased renal function in mice without a significant increase in interstitial fibrosis, whereas rhabdomyolysis-induced AKI led to severe interstitial fibrosis, but renal function and peritubular capillary density were preserved. Furthermore, long-term experiments in mice with unilateral ischemia-reperfusion injury showed that restoration of renal function 12 wk after a contralateral nephrectomy was associated with increasing fibrosis, but a reversal of capillary rarefaction was seen at 4 wk. These data demonstrate that clear dissociation between kidney function and fibrosis in these models of AKI to CKD progression and suggest that peritubular capillary rarefaction is more strongly associated with CKD progression than renal fibrosis.
A peek into Epac physiology in the kidney
Authors: Tomilin Viktor N. , Pochynyuk Oleh
Published: September 2019

cAMP is a critical second messenger of numerous endocrine signals affecting water-electrolyte transport in the renal tubule. Exchange protein directly activated by cAMP (Epac) is a relatively recently discovered downstream effector of cAMP, having the same affinity to the second messenger as protein kinase A, the classical cAMP target. Two Epac isoforms, Epac1 and Epac2, are abundantly expressed in the renal epithelium, where they are thought to regulate water and electrolyte transport, particularly in the proximal tubule and collecting duct. Recent characterization of renal phenotype in mice lacking Epac1 and Epac2 revealed a critical role of the Epac signaling cascade in urinary concentration as well as in Na+ and urea excretion. In this review, we aim to critically summarize current knowledge of Epac relevance for renal function and to discuss the applicability of Epac-based strategies in the regulation of systemic water-electrolyte homeostasis.
Automatic encoding of a target position relative to a natural scene
Authors: Nishimura Nobuyuki , Uchimura Motoaki , Kitazawa Shigeru
Published: September 2019

We previously showed that the brain automatically represents a target position for reaching relative to a large square in the background. In the present study, we tested whether a natural scene with many complex details serves as an effective background for representing a target. In the first experiment, we used upright and inverted pictures of a natural scene. A shift of pictures significantly attenuated prism adaptation of reaching movements as long as they were upright. In one-third of participants, adaptation was almost completely cancelled whether the pictures were upright or inverted. It was remarkable that there were two distinct groups of participants, one who relies fully on the allocentric coordinate and the other who depended only when the scene was upright. In the second experiment, we examined how long it takes for a novel upright scene to serve as a background. A shift of the novel scene had no significant effects when it was presented for 500 ms before presenting a target, but significant effects were recovered when presented for 1,500 ms. These results show that a natural scene serves as a background against which a target is automatically represented once we spend 1,500 ms in the scene.

NEW & NOTEWORTHY Prism adaptation of reaching was attenuated by a shift of natural scenes as long as they were upright. In one-third of participants, adaptation was fully canceled whether the scene was upright or inverted. When an upright scene was novel, it took 1,500 ms to prepare the scene for allocentric coding. These results show that a natural scene serves as a background against which a target is automatically represented once we spend 1,500 ms in the scene.
Retention and generalizability of balance recovery response adaptations from trip perturbations across the adult life span
Authors: König Matthias , Epro Gaspar , Seeley John , Potthast Wolfgang , Karamanidis Kiros
Published: September 2019

For human locomotion, varying environments require adjustments of the motor system. We asked whether age affects gait balance recovery adaptation, its retention over months, and the transfer of adaptation to an untrained reactive balance task. Healthy adults (26 young, 27 middle-aged, and 25 older; average ages 24, 52, and 72 yr, respectively) completed two tasks. The primary task involved treadmill walking: either unperturbed (control; n = 39) or subject to unexpected trip perturbations (training; n = 39). A single trip perturbation was repeated after a 14-wk retention period. The secondary transfer task, before and after treadmill walking, involved sudden loss of balance in a lean-and-release protocol. For both tasks, the anteroposterior margin of stability (MoS) was calculated at foot touchdown. For the first (i.e., novel) trip, older adults required one more recovery step ( P = 0.03) to regain positive MoS compared with younger, but not middle-aged, adults. However, over several trip perturbations, all age groups increased their MoS for the first recovery step to a similar extent (up to 70%) and retained improvements over 14 wk, although a decay over time was found for older adults ( P = 0.002; middle-aged showing a tendency for decay: P = 0.076). Thus, although adaptability in reactive gait stability control remains effective across the adult life span, retention of adaptations over time appears diminished with aging. Despite these robust adaptations, the perturbation training group did not show superior improvements in the transfer task compared with age-matched controls (no differences in MoS changes), suggesting that generalizability of acquired fall-resisting skills from gait-perturbation training may be limited.

NEW & NOTEWORTHY The human neuromotor system preserves its adaptability across the adult life span. However, although adaptability in reactive gait stability control remains effective as age increases, retention of recovery response adaptations over time appears to be reduced with aging. Furthermore, acquired fall-resisting skills from single-session perturbation training seem task specific, which may limit the generalizability of such training to the variety of real-life falls.
The SLC9A-C Mammalian Na+/H+Exchanger Family: Molecules, Mechanisms, and Physiology
Authors: Pedersen S. F. , Counillon L.
Published: September 2019

Na+/H+exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+and H+across cellular membranes. They belong to an ancient family of highly evolutionarily conserved proteins, and they play essential physiological roles in all phyla. In this review, we focus on the mammalian Na+/H+exchangers (NHEs), the solute carrier (SLC) 9 family. This family of electroneutral transporters constitutes three branches: SLC9A, -B, and -C. Within these, each isoform exhibits distinct tissue expression profiles, regulation, and physiological roles. Some of these transporters are highly studied, with hundreds of original articles, and some are still only rudimentarily understood. In this review, we present and discuss the pioneering original work as well as the current state-of-the-art research on mammalian NHEs. We aim to provide the reader with a comprehensive view of core knowledge and recent insights into each family member, from gene organization over protein structure and regulation to physiological and pathophysiological roles. Particular attention is given to the integrated physiology of NHEs in the main organ systems. We provide several novel analyses and useful overviews, and we pinpoint main remaining enigmas, which we hope will inspire novel research on these highly versatile proteins.
Cigarette Smoking Is Negatively Associated with the Prevalence of Type 2 Diabetes in Middle-Aged Men with Normal Weight but Positively Associated with Stroke in Men
Authors: Wang Su , Chen Jie , Wang Yuzhong , Yang Yu , Zhang Danyu , Liu Chao , Wang Kun
Published: September 2019

Background. The prevalence of diabetes and potentially related complications, including stroke, is rapidly increasing in China. The long-term effects of lifestyle may affect glucose metabolism in the general population. Although some studies have shown an association between smoking and the risk of type 2 diabetes mellitus (T2DM), the relationship remains unclear. Furthermore, the relationship between smoking and stroke in patients with T2DM has not been fully elucidated. Objective. We investigated the influence of cigarette smoking on T2DM and stroke in China. Detailed questionnaires about smoking status and anthropometric measurement were completed by participants, and oral glucose tolerance testing (OGTT), hemoglobin A1c (HbA1c), homeostasis model assessment of IR (HOMA-IR), and blood lipids were measured. Results. In total, 8196 adults aged 40 years or older were included. We found a reduced risk of impaired glucose regulation (IGR) and T2DM in male smokers with normal weight (body mass index BMI<25 kg/m2 or waist circumference WC<90 cm) compared with nonsmokers after adjusting for age, alcohol intake, physical activity, educational level, family history of diabetes, SBP, DBP, TG, TC, HDL-C, and LDL-C. However, no significant association was detected in male current smokers with overweight/obesity or female smokers. In addition, compared with nonsmokers without T2DM, current smokers with T2DM had a significantly higher risk of stroke (odds ratio: 2.64, 95% confidence interval: 1.25–5.57; P=0.011) after adjusting for confounders. Conclusions. Smoking was negatively associated with T2DM in Chinese men of normal body weight, but no significant association was found for men with overweight/obesity or women. In addition, smoking was positively associated with nonfatal stroke, especially in patients with T2DM. Further prospective studies are needed to examine the association between smoking, diabetes, and stroke in different ethnic groups.
Retrograde Intramedullary Nail Fixation for Derotational Femoral Osteotomy for Recurrent Femoropatellar Instability
Authors: Barahona Maximiliano , Zamorano Alvaro , Barrientos Cristian , Guzmán Mauricio , Sato Yoshiro , Hinzpeter Jaime
Published: September 2019

Axial alignment of the femur and tibia is often misdiagnosed in patients with patellofemoral stability problems. Femoral torsion is critical for patellofemoral biomechanics, so it must be evaluated in every patient before the plan of surgery is decided. This case describes a femoral derotational osteotomy due to excessive internal torsion of the femur fixed with a retrograde femoral nail. This type of fixation provides a biomechanical advantage compared to plates. At the two-year follow-up, the patient achieved excellent results, reaching a functional score of 91 points on the Lysholm scale. Derotational femoral osteotomy should be considered in patellofemoral pathology, and a retrograde femoral nail is a valid fixation method for this surgery.
A Contemporary Systematic Approach to Assessing the Patient with Heart Failure with Reduced Ejection Fraction: Multimodal Noninvasive and Invasive Evaluation
Authors: Wan Siu-Hin , McKie Paul M. , Bois John P.
Published: September 2019

Heart failure with reduced ejection fraction (HFrEF) is a progressive clinical syndrome commonly associated with left ventricle dilatation and characterized by reduced cardiac output, secondary pulmonary and systemic venous congestion, and inadequate peripheral oxygen delivery. It is common yet complex and requires synthesis of evidence-based guidelines along with strong clinical acumen. The following is a review of an illustrative case that highlights the important clinical considerations in diagnosis, assessment, and management of HFrEF commonly encountered in practice. Explanations provided highlight of the relevant pathophysiology of HFrEF as well as detailed explanations of interpretation of examinations and both noninvasive and invasive assessment in heart failure. The example provided would hopefully serve as a potential point of reference for trainees as well as healthcare practitioners for patients with HFrEF.
18F-FDG-PET/CT Imaging in Advanced Glottic Cancer: A Tool for Clinical Decision in Comparison with Conventional Imaging
Authors: Paone G. , Martucci F. , Espeli V. , Ceriani L. , Treglia G. , Ruberto T. , Richetti A. , Piantanida R. , Giovanella L.
Published: September 2019

This study assessed the role of18F-FDG PET-CT (PET/CT) to detect the cartilage and paraglottic infiltration in advanced glottic cancer comparing the results with those of conventional imaging (CI) (contrast-enhanced computed tomography and/or magnetic resonance). In addition, we assessed the prognostic value of quantitative parameters, measured on baseline PET/CT, in terms of event-free survival (EFS) and overall survival (OS). We retrospectively analyzed 27 patients with glottic squamous cell carcinoma stage III and IVA, treated in our institute between 2010 and 2016, comparing PET/CT, performed for staging and radiotherapy planning, and CI findings. Cohen’sKwas used to compare concordance between PET/CT and CI. Imaging findings were correlated with endoscopic evaluation and histological reports (gold standard (GS)). All lesions shown by CI were also detected by PET/CT imaging, and in 5 cases, a better definition of local infiltration was achieved with PET/CT than CI (5 CT). Sensitivity, specificity, and accuracy of PET/CT and CT were 95%, 86%, and 93% and 70%, 86%, and 74% for, respectively. MRI showed sensitivity and specificity of 100%. One false-negative (FN) cases and 1 false-positive (FP) case were observed with PET/CT with no difference compared to MRI (10 cases). Six FN cases and 1 FP case were observed with CT. Cohen’sKwas 0.60 (PET vs. CI) and 0.80 (PET vs. GS). Patients were followed-up for at least 24 months to calculate EFS and OS. 13 local recurrence and 7 deaths were recorded. Among quantitative PET parameters, baseline MTV was the most powerful predictor of outcome. Our data suggest a reliable sensitivity and accuracy of PET/CT in the evaluation of local extension, proving a useful method for initial local staging in addition to the well-established role in lymph-node and distant sites assessment. Furthermore, pretreatment MTV provides better prognostic information than other PET/CT parameters.
Generative Reversible Data Hiding by Image-to-Image Translation via GANs
Authors: Zhang Zhuo , Fu Guangyuan , Di Fuqiang , Li Changlong , Liu Jia
Published: September 2019

The traditional reversible data hiding technique is based on cover image modification which inevitably leaves some traces of rewriting that can be more easily analyzed and attacked by the warder. Inspired by the cover synthesis steganography-based generative adversarial networks, in this paper, a novel generative reversible data hiding (GRDH) scheme by image translation is proposed. First, an image generator is used to obtain a realistic image, which is used as an input to the image-to-image translation model with CycleGAN. After image translation, a stego image with different semantic information will be obtained. The secret message and the original input image can be recovered separately by a well-trained message extractor and the inverse transform of the image translation. The experimental results have verified the effectiveness of the scheme.
A New Method for Reliability‐Based Sensitivity Analysis of Dynamic Random Systems
Authors: Wang Qianqian , Wang Changchun , Wang Hui
Published: September 2019

A novel numerical method for investigating time‐dependent reliability and sensitivity issues of dynamic systems is proposed, which involves random structure parameters and is subjected to stochastic process excitation simultaneously. The Karhunen–Loève (K‐L) random process expansion method is used to express the excitation process in the form of a series of deterministic functions of time multiplied by independent zero‐mean standard random quantities, and the discrete points are made to be the same as Legendre integration points. Then, the precise Gauss–Legendre integration is used to solve the oscillation differential functions. Considering the independent relationship of the structural random parameters and the parameters of random process, the time‐varying moments of the response are evaluated by the point estimate method. Combining with the fourth‐moment method theory of reliability analysis, the dynamic reliability response can be evaluated. The dynamic reliability curve is useful for getting the weakness time so as to avoid breakage. Reliability‐based sensitivity analysis gives the importance sort of the distribution parameters, which is useful for increasing system reliability. The result obtained by the proposed method is accurate enough compared with that obtained by the Monte Carlo simulation (MCS) method.
Orthodontic Treatment of Bilateral Impacted Mandibular Canines and a Mupparapu Type 2 Transmigration
Authors: Vera-Guerra José Antonio , Herrera-Atoche José Rubén , Colomé-Ruiz Gabriel Eduardo
Published: September 2019

Dental transmigration is a rare condition that mainly affects the mandibular canines. Since the tooth involved is usually impacted and its crown has crossed the midline towards the opposite side, the treatment options frequently are surgical removal or radiographic follow-up, and, in some cases, orthodontic traction is possible. In 2002, Mupparapu presented a classification for lower canines in transmigration according to their position within the mandible. This paper is aimed at describing the orthodontic treatment of a female patient with two impacted mandibular canines, one of them in a Mupparapu type 2 transmigration position (horizontal impaction position near the lower mandibular border and below the incisors’ root apices). Additionally, the paper discusses the biomechanical orthodontic design and the alternative treatment options for these complex cases.
ZEB1 Collaborates with ELK3 to Repress E-Cadherin Expression in Triple-Negative Breast Cancer Cells
Authors: Cho Hyeon-Ju , Oh Nuri , Park Ji-Hoon , Kim Kwang-Soo , Kim Hyung-Keun , Lee Eunbyeol , Hwang Sohyun , Kim Seong-Jin , Park Kyung-Soon
Published: September 2019

ZEB1 has intrinsic oncogenic functions that control the epithelial-to-mesenchymal transition (EMT) of cancer cells, impacting tumorigenesis from its earliest stages. By integrating microenvironment signals and being implicated in feedback regulatory loops, ZEB1 appears to be a central switch that determines EMT and metastasis of cancer cells. Here, we found that ZEB1 collaborates with ELK3, a ternary complex factor belonging to the ETS family, to repress E-cadherin expression. ZEB1 functions as a transcriptional activator of ELK3. We first identified that ELK3 and ZEB1 have a positively correlated expression in breast cancer cells by using multiple databases for correlation analysis. Molecular analysis revealed that ZEB1 functions as a transcriptional activator of ELK3 expression. GST pull-down assay and coimmunoprecipitation analysis of wild-type or domain deletion mutants of ZEB1 and ELK3 showed that these 2 proteins directly bound each other. Furthermore, we demonstrated that ZEB1 and ELK3 collaborate to repress the expression of E-cadherin, a representative protein that initiates EMT. Our finding suggested that ELK3 is a novel factor of the ZEB1/E-cadherin axis in triple-negative breast cancer cells.

Implications:

ELK3 is a novel factor in the ZEB1/E-cadherin axis and ZEB1 has a dual role in ELK3 as a transcriptional activator and as a collaborator to repress E-cadherin expression in triple-negative breast cancer cells.
Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma with Myxoid Stroma in a Hereditary Retinoblastoma Survivor
Authors: Peck Travis , Gervasio Kalla A. , Zhang Paul J.L. , Shields Carol L. , Lally Sara E. , Eagle Jr. Ralph C. , Milman Tatyana
Published: September 2019

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) is an indolent, locally aggressive mesenchymal neoplasm, most often confined to the lower extremities and retroperitoneum and rarely identified in the orbit. Diagnosis of ALT/WDL can be challenging due to its frequent morphologic overlap with benign adipose lesions and other more aggressive liposarcoma subtypes, including myxoid liposarcoma. We describe a 26-year-old female with a history of hereditary retinoblastoma and external-beam radiotherapy to the orbit, who developed orbital liposarcoma. Although initial morphologic assessment raised the consideration of myxoid liposarcoma, subsequent fluorescein in situ hybridization studies demonstrated MDM2 and DDIT3 coamplification without DDIT3 rearrangement, supporting the diagnosis of ALT/WDL with myxoid stroma. The literature review of previously reported orbital myxoid liposarcomas revealed a morphologic overlap of documented tumors with ALT/WDL, dedifferentiated liposarcoma, and pleomorphic liposarcoma with myxoid stroma as well as an absence of immunohistochemical and molecular genetic data supportive of the diagnosis of myxoid liposarcoma. This case emphasizes the potential overlap of ALT/WDL with myxoid liposarcoma and the increasing importance of molecular genetic studies in the diagnosis, prognosis, and management of orbital liposarcoma.
Cognitive Reserve Mediates the Relation between Openness to Experience and Smaller Decline in Executive Functioning
Authors: Ihle Andreas , Zuber Sascha , Gouveia Élvio R. , Gouveia Bruna R. , Mella Nathalie , Desrichard Olivier , Cullati Stéphane , Oris Michel , Maurer Jürgen , Kliegel Matthias
Published: September 2019

Aims: We investigated the mediating role of leisure activity engagement in the longitudinal relation between openness to experience and subsequent change in executive functioning over 6 years as measured through performance changes in the Trail Making Test (TMT). Methods: We analyzed longitudinal data from 897 older adults (mean = 74.33 years in the first wave) tested on TMT parts A and B in two waves 6 years apart. Participants reported information on leisure activity engagement and openness to experience. Results: Latent change score modeling revealed that 37.2% of the longitudinal relation between higher openness to experience in the first wave of data collection and a smaller subsequent increase in TMT completion time from the first to the second wave (i.e., a smaller decline in executive functioning) was mediated via a higher frequency of leisure activities in the first wave. Conclusion: Individuals with higher openness to experience show greater activity engagement in old age. By enhancing their cognitive reserve, this activity engagement may finally result in smaller subsequent decline in executive functioning.
Data Logging Evidence of Cochlear Implant Use in Single-Sided and Bilateral Deafness
Authors: Rauch Ann-Kathrin , Kagermann Stephanie , Wesarg Thomas , Jakob Till Fabian , Aschendorff Antje , Ihorst G. , Speck Iva , Arndt Susan
Published: September 2019

Purpose: This study analyses data logs in order to investigate the usage pattern of cochlear implant (CI) recipients with single-sided deafness (SSD-CI) and bilaterally deaf, uni- or bilaterally implanted CI recipients (Uni-CI and Bil-CI). Data logging is available from SCAN, an automated auditory scene classifier which categorizes auditory input into 6 listening environments. Methods: CI usage data were retrospectively available from data logs of 206 CI recipients using the Nucleus 6 system obtained between January 2013 and June 2015. For all recipients, we analysed time on air and time spent in the listening environments. For statistical analysis, we matched the CI recipients according to age and duration of CI experience and classified them into 4 age groups. Results: SSD-CI showed a similar time on air compared to Uni- and Bil-CI. Usage behaviour of SSD-CI was comparable to Uni- and Bil-CI regarding exposure to music, speech in quiet and speech in noise. With increasing age, exposure to quiet increased and exposure to music decreased across all CI recipient groups in relation to time on air. Conclusion: In total, the CI usage pattern of SSD-CI is comparable for the majority of listening environments and age groups to that of Uni- and Bil-CI. The results of our study show that SSD-CI benefit equally from CI implantation.
Influence of Obesity on Work Ability, Respiratory Symptoms, and Lung Function in Adults with Asthma
Authors: Klepaker Geir , Svendsen Martin Veel , Hertel Jens Kristoffer , Holla Øystein Lunde , Henneberger Paul Keefer , Kongerud Johny , Fell Anne Kristin Møller
Published: September 2019

Background: Asthma is defined by variable respiratory symptoms and lung function, and may influence work ability. Similarly, obesity may contribute to respiratory symptoms, affect lung function, and reduce work ability. Thus, assessment of the influence of obesity on work ability, respiratory symptoms, and lung function in adults with asthma is needed. Objectives: We hypothesized that patients with obesity and asthma have more respiratory symptoms and reduced work ability and lung function compared with normal-weight patients with asthma. Methods: We examined 626 participants with physician-diagnosed asthma, aged 18–52 years, recruited from a cross-sectional general population study using a comprehensive questionnaire including work ability score, the asthma control test (ACT), height and weight, and spirometry with reversibility testing. Results: Participants with a body mass index (BMI) ≥30 kg/m2 (i.e., obese) had a higher symptom score (OR 1.78, 95% CI 1.14–2.80), current use of asthma medication (1.60, 1.05–2.46), and incidence of ACT scores ≤19 (poor asthma control) (1.81, 1.03–3.18) than participants with BMI ≤24.9 kg/m2 (i.e., normal weight). Post-bronchodilator forced vital capacity (FVC) as a percentage of predicted (β coefficient –4.5) and pre-bronchodilator forced expiratory volume in 1 s as a percentage of predicted (FEV1) (β coefficient –4.6) were negatively associated with BMI ≥30 kg/m2. We found no statistically significant association of BMI >30 kg/m2 (compared to BMI <24.9 kg/m2) with sick leave (1.21, 0.75–1.70) or reduced work ability (1.23, 0.74–2.04). Conclusions: There were indications that patients with obesity had a higher symptom burden, poorer asthma control, higher consumption of asthma medication, and reduced lung function, in particular for FVC, compared with normal-weight patients.
Chinese Expert Recommendation for Diagnosis and Treatment of Massive Hemoptysis
Authors: Jin Faguang , Li Qiang , Bai Chong , Wang Hongwu , Li Shiyue , Song Yong , Zeng Yiming , Zhou Rui , Li Wangping , Hu Chengping , Zhang Jie , Zhou Hongmei , Zhang Haitao
Published: September 2019

Massive hemoptysis is one of emergency and critical diseases of the respiratory system. The definition of massive hemoptysis has always been different in the literature, which often depends on the quantitative estimation of the amount of hemoptysis, such as the amount of hemoptysis being in the range of 300–600 mL within 24 h, or hemoptysis more than 3 times within 1 week. Each amount of hemoptysis that is greater than 100 mL can be considered as massive hemoptysis, but the amount of hemoptysis is difficult to accurately estimate. Therefore, massive hemoptysis can be defined as any life-threatening hemoptysis and any hemoptysis that may cause airway obstruction and asphyxia. Massive hemoptysis accounts for approximately 5% of all hemoptysis cases and usually indicates the presence of a potentially severe respiratory or systemic disease. The mortality rate of massive hemoptysis is about 6.5–38%. The cause of death is generally shock caused by airway obstruction or excessive bleeding, and asphyxia is the main cause of death. At present, due to insufficient understanding of massive hemoptysis, there are limited technical means in the etiological diagnosis and untimely or improper treatment, resulting in high mortality of massive hemoptysis. Therefore, the diagnosis and treatment of massive hemoptysis needs to be standardized.
Bifonazole Exerts Anti-Inflammatory Effects in Human Three-Dimensional Skin Equivalents after UVB or Histamine Challenge
Authors: Huth Laura , Marquardt Yvonne , Heise Ruth , Fietkau Katharina , Becker Norbert-Heinz , Huth Sebastian , Baron Jens Malte
Published: September 2019

Background: In addition to its role as a broad-spectrum imidazole antifungal drug, data from animal models as well as human clinical trials also demonstrated an anti-inflammatory efficacy of bifonazole (BFZ). In the histamine wheal test and after UV radiation, BFZ showed antiphlogistic effects that were comparable to those of hydrocortisone. However, the underlying molecular mechanisms of the anti-inflam­matory properties of BFZ are poorly understood. Methods: Performing an in vitro study we used full-thickness three-dimensional (3D) skin models containing macrophages as mediators of inflammation. We conducted two sets of experiments. In a first set we exposed our models to UVB irradiation to provoke an inflammation. A second approach used the addition of histamine into the culture medium. In both approaches, models were treated topically with a BFZ-containing ointment or a placebo ointment for 24 h, and then the effects were examined histologically as well as with microarray and quantitative real-time PCR analyses. Results: Histological examination showed that the BFZ-containing ointment reconstituted UVB- and histamine-mediated disorders within the skin models. Performing gene expression profiling in models that were treated with the BFZ-containing ointment after UVB irradiation, we detected an upregu­lation of differentiation markers (fillagrin, loricrin, and keratin 1), antimicrobial peptides (DEFB103A), and members of the cytochrome P450 family (CYP1A1 and CYP1B1) as well as a downregulation of genes that are involved in immune response (CCL22, CXCL12, CCL7, IRF1, ICAM1, TLR3, and RARRES3) and matrix metalloproteinases (MMP12 and MMP7). Models that were treated with the BFZ-containing ointment after histamine application showed an upregulation of members of the cytochrome P450 family (CAP1A1, CYP1B1, and CYP24A1) and a downregulation of immune response-associated genes (CXCL6, CXCL12, CCL8, IL6, and IL32). Conclusion: We present the first in vitro study showing anti-inflammatory effects of BFZ in human 3D skin models. To our knowledge, this is the first time that these effects could be translated from human clinical trials into an in vitro test system, allowing a more detailed examination of molecular mechanisms that were regulated by BFZ.