bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein-engineered molecules carrying GAD65 epitopes and targeting CD35 selectively down-modulate disease-associated human B lymphocytes
Authors: Manoylov I K , Boneva G V , Doytchinova I A , Mihaylova N M , Tchorbanov A I
Published: April 2019

Type 1 diabetes mellitus is an autoimmune metabolic disorder characterized by chronic hyperglycemia, the presence of autoreactive T and B cells and autoantibodies against self-antigens. A membrane-bound enzyme on the pancreatic beta-cells, glutamic acid decarboxylase 65 (GAD65), is one of the main autoantigens in type 1 diabetes. Autoantibodies against GAD65 are potentially involved in beta-cell destruction and decline of pancreatic functions. The human complement receptor type 1 (CD35) on B and T lymphocytes has a suppressive activity on these cells. We hypothesized that it may be possible to eliminate GAD65-specific B cells from type 1 diabetes patients by using chimeric molecules, containing an anti-CD35 antibody, coupled to peptides resembling GAD65 B/T epitopes. These molecules are expected to selectively bind the anti-GAD65 specific B cells by the co-cross-linking of the immunoglobulin receptor and CD35 and to deliver a suppressive signal. Two synthetic peptides derived from GAD65 protein (GAD65 epitopes) and anti-CD35 monoclonal antibody were used for the construction of two chimeras. The immunomodulatory activity of the engineered antibodies was tested in vitro using peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients. A reduction in the number of anti-GAD65 IgG antibody-secreting plasma cells and increased percentage of apoptotic B lymphocytes was observed after treatment of these PBMCs with the engineered antibodies. The constructed chimeric molecules are able to selectively modulate the activity of GAD65-specific B lymphocytes and the production of anti-GAD65 IgG autoantibodies by co-cross-linking of the inhibitory CD35 and the B cell antigen receptor (BCR). This treatment presents a possible way to alter the autoimmune nature of these cells.
Patients with tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) are hypersensitive to Toll-like receptor 9 stimulation
Authors: Negm O H , Singh S , Abduljabbar W , Hamed M R , Radford P , McDermott E M , Drewe E , Fairclough L , Todd I , Tighe P J
Published: April 2019

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNFRSF1A, which encodes tumour necrosis factor receptor 1 (TNF-R1). Our aim was to understand the influence of TRAPS mutations on the response to stimulation of the pattern recognition Toll-like receptor (TLR)-9. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from TRAPS patients and healthy controls: serum levels of 15 proinflammatory cytokines were measured to assess the initial inflammatory status. Interleukin (IL)-1β, IL-6, IL-8, IL-17, IL-22, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor (TGF)-β were significantly elevated in TRAPS patients’ sera, consistent with constitutive inflammation. Stimulation of PBMCs with TLR-9 ligand (ODN2006) triggered significantly greater up-regulation of proinflammatory signalling intermediates [TNF receptor-associated factor (TRAF 3), IL-1 receptor-associated kinase-like 2 (IRAK2), Toll interacting protein (TOLLIP), TRAF6, phosphorylated transforming growth factor-β-activated kinase 1 (pTAK), transforming growth factor-β-activated kinase-binding protein 2 (TAB2), phosphorylated TAK 2 (pTAB2), IFN-regulatory factor 7 (IRF7), receptor interacting protein (RIP), nuclear factor kappa B (NF-κB) p65, phosphorylated NF-κB p65 (pNF-κB p65) and mitogen-activated protein kinase kinase (MEK1/2)] in TRAPS patients’ PBMCs. This up-regulation of proinflammatory signalling intermediates and raised serum cytokines occurred despite concurrent anakinra treatment and no overt clinical symptoms at time of sampling. These novel findings further demonstrate the wide-ranging nature of the dysregulation of innate immune responses underlying the pathology of TRAPS and highlights the need for novel pathway-specific therapeutic treatments for this disease.
Network analysis of a stakeholder community combatting illegal wildlife trade
Authors: Moshier Andrea , Steadman Janna , Roberts David L.
Published: April 2019

The illegal wildlife trade has emerged as a growing and urgent environmental issue. Stakeholders involved in the efforts to curb wildlife trafficking include nongovernmental organizations (NGOs), academia, and state government and enforcement bodies. The extent to which these stakeholders work and communicate among each other is fundamental to effectively combatting illicit trade. Using the United Kingdom as a case study, we used a social network analysis and semistructured interviews of stakeholders to assess communication relationships in the counter wildlife trafficking community. The NGOs consistently occupied 4 of the 5 most central positions in the generated networks, whereas academic institutions routinely occupied 4 of the 5 most peripheral positions. However, NGOs were the least diverse in their communication practices compared with the other stakeholder groups. Stakeholders identified personal relationships as the most important aspect of functioning communication. Participant insights also showed that stakeholder‐specific variables (e.g., ethical and confidentiality concerns), competition, and fundraising can have a confounding effect on intercommunication. Evaluating communication networks and intrastakeholder communication trends is essential to creating cohesive, productive, and efficient responses to the challenges of combatting illegal wildlife trade.

Article impact statement: Communication among those combatting illegal wildlife trade is confounded by stakeholder variables (ethics, confidentiality), competition, and fundraising.
Next generation of dentists moving to amalgam‐free dentistry: Survey of posterior restorations teaching in North America
Authors: Zabrovsky Asher , Neeman Levy Tal , Bar‐On Hilit , Beyth Nurit , Ben‐Gal Gilad
Published: April 2019

Objectives

The dental field is gradually reducing the use of amalgam and moving towards adhesive restoration. This change is in accordance with the advancement and improvement of composite resin materials and adhesion systems. Consequently, posterior cavity preparations teaching should be re‐examined to determine whether dental schools are adapting their curriculum to fit the current trends in dentistry and what rationale supports their decisions.

Methods

An online questionnaire was constructed to assess the time dedicated to teaching composite materials and amalgam, in addition to the principles of posterior preparations, for composite restorations in North American dental schools.

Results

A total 33 schools responded to the questionnaire. A large variation was found in teaching methods and techniques of posterior restorations. The reasoning for teaching amalgam restorations was diverse as were the principles of composite resin preparation taught.

Conclusion

No agreed principles of cavity preparation for resin composite restorations were found, as opposed to explicit agreement on amalgam cavity preparations. The results demonstrate a lack of clear guidelines for cavity preparation of resin composite restorations. Dental schools may benefit when a consensus on this topic is achieved.
Administration of enrofloxacin during late pregnancy failed to induce lesions in the resulting newborn foals
Authors: Ellerbrock R. E. , Canisso I. F. , Roady P. J. , Litsky A. , Durgam S. , Podico G. , Li Z. , Lima F. S.
Published: April 2019

Background

A recent study demonstrated that enrofloxacin and ciprofloxacin cross the equine placenta without causing gross cartilage or tendon lesions in the 9‐month fetus; however, long‐term effects of in utero fluoroquinolone exposure remain unknown.

Objectives

To assess effects of fetal exposure to enrofloxacin on the resulting foal's cartilage and tendon strength.

Study design and methods

Healthy mares at 280 days’ gestation were allocated into four groups: untreated (n = 5), therapeutic treatment (7.5 mg/kg enrofloxacin, PO × 14 days, n = 6), supratherapeutic treatment (15 mg/kg, PO × 14 days, n = 6) and no mare treatment with treatment of the foals post‐partum (n = 2). Mares were allowed to carry pregnancy to term, and foals were maintained on pasture for 5 weeks. After that foals were euthanized, and their articular cartilage and extensor and flexor tendons were examined macroscopically and histologically for lesions. Tendon strength was tested by loading until failure.

Results

Administration of enrofloxacin at recommended doses in late gestation did not result in cartilaginous lesions or clinical lameness in any foal by 5 weeks old. Tensile strength was greater in hind tendons than front tendons, but no difference was found between foals born from treated and control mares. Expectedly, osteochondral changes were present both in foals born from enrofloxacin‐treated mares and in negative control foals with no apparent association with fluoroquinolone treatment during pregnancy.

Main limitations

Only one time point in gestation was evaluated, and mares treated in the study were healthy at time of treatment. Additionally, it is possible that the assessments performed herein were not sensitive enough to detect subtle or functional changes in the articular cartilage. Further studies are needed to determine if enrofloxacin administration during late pregnancy potentiates osteochondral alterations in the first year of life.

Conclusions

While this study did not assess other stages of gestation or long‐term foal outcomes, short‐term administration of enrofloxacin to late gestation mares did not result in macroscopic or microscopic lesions in the resulting foals by 5 weeks of age.
Modelling of crack propagation in rocks under SHPB impacts using a damage method
Authors: Wang Meng , Wang Fei , Zhu Zheming , Dong Yuqing , Mousavi Nezhad Mohaddeseh , Zhou Lei
Published: April 2019

Rock dynamic fracture is a complex problem and has received considerable attention during the last few decades. In this paper, tensile crack softening failure criterion is used to study impact‐induced crack initiation and propagation in rocks. In order to examine applicability of the criterion, under realistic loading and boundary conditions, three boundary conditions were analyzed in details and an impacting experiment using single cleavage semicircle compression (SCSC) specimens had been successfully simulated. A good agreement was achieved between the simulation and experimental results. It was concluded that the boundary conditions play an important role in rock dynamic fracturing. When a stress wave propagates from a material with low wave impedance to a material of high wave impedance, the compression wave is partially reflected back and the process of fast cracking is suppressed. In addition, with the change of the tensile strength and the fracture energy, the crack initiation modes can be divided into four types.
Fatigue analysis of ductile and brittle behaving steels under variable amplitude multiaxial loading
Authors: Sharifimehr Shahriar , Fatemi Ali
Published: April 2019

The analysis of fatigue behavior under multiaxial variable amplitude stress states, despite its wide applicability, has not been fully studied. Issues such as varying degrees of nonproportionality of the load history, cycle counting, damage accumulation, failure behavior of the material, and mean stress fluctuations which can significantly affect the results of these analyses have not been well understood. In this study, a methodology for the analysis of fatigue behavior under multiaxial variable amplitude loading conditions is employed which accounts for the aforementioned issues. At its core, the applied methodology uses critical plane analysis based on the failure behavior of each material to assess the fatigue damage. In order to evaluate the performance of the analysis method, axial, torsional, and combined axial‐torsional variable amplitude tests were performed on one ductile and one brittle behaving steel. The applied methodology resulted in close estimation of the experimental fatigue life for both ductile and brittle behaving steels.
Cr isotopic insights into ca. 1.9 Ga oxidative weathering of the continents using the Beaverlodge Lake paleosol, Northwest Territories, Canada
Authors: Toma Jonathan , Holmden Chris , Shakotko Paul , Pan Yuanming , Ootes Luke
Published: April 2019

The ca. 1.9 Ga Beaverlodge Lake paleosol was studied using redox‐sensitive Cr isotopes in order to determine the isotopic response to paleoweathering of a rhyodacite parent rock 500 million years after the Great Oxidation Event. Redox reactions occurring in modern weathering environments produce Cr(VI) that is enriched in heavy Cr isotopes compared to the igneous inventory. Cr(VI) species are soluble and easily leached from soils into streams and rivers, thus, leaving particle‐reactive and isotopically light Cr(III) species to build up in soils. The Beaverlodge Lake paleosol and two other published weathering profiles of similar age, the Flin Flon and Schreiber Beach paleosols, are not as isotopically light as modern soils, indicating that rivers were not as isotopically heavy at that time. Considering that the global average δ53Cr value for the oxidative weathering flux of Cr to the oceans today is just 0.27 ± 0.30‰ (1σ) based on a steady‐state analysis of the modern ocean Cr cycle, the oxidative weathering flux of Cr to the oceans at ca. 1.9 Ga would have likely been shifted to lower δ53Cr values, and possibly lower than the igneous inventory (–0.12 ± 0.10‰, 2σ). Mn oxides are the main oxidant of Cr(III) in modern soils, but there is no evidence that they formed in the studied paleosols. Cr(VI) may have formed by direct oxidation of Cr(III) using molecular oxygen or H2O2, but neither pathway is as efficient as Mn oxides for producing Cr(VI). The picture that emerges from this and other studies of Cr isotope variation in ca. 1.9 Ga paleosols is of atmospheric oxygen concentrations that are high enough to oxidize iron, but too low to oxidize Mn, resulting in low Cr(VI) inventories in Earth surface environments.
Traceability in global governance
Authors: MUIRHEAD JACOB , PORTER TONY
Published: April 2019

An increasingly important challenge in global governance, which in some issue areas has been labelled ‘traceability’, has been to track the cross‐border travels of objects that are associated with positive or negative effects. However, the common properties and identifiable patterns of variation of traceability across issue areas or industries have been insufficiently explored. We identify key properties of traceability systems, including the variation and interactions between the physical properties of the traced object, the positive or negative effects with which it is associated, the monitoring technology, and the institutionalized power relations that activate and constrain traceability systems. We examine and compare traceability systems for food safety, conflict minerals, pharmaceuticals, carbon emissions, money laundering and financial transactions. Understanding traceability in this way is important not only for these cases, but also for understanding interactions between objects, infrastructures, as well as monitoring and political mechanisms in global governance more generally.
Predictive factors of anemia during sofosbuvir and ribavirin therapy for genotype 2 chronic hepatitis C patients
Authors: Urabe Ayako , Sakamori Ryotaro , Tahata Yuki , Yamada Ryoko , Imai Yasuharu , Hagiwara Hideki , Tamura Shinji , Fukui Hiroyuki , Yamada Yukinori , Kaneko Akira , Hijioka Taizo , Kodama Takahiro , Hikita Hayato , Tatsumi Tomohide , Takehara Tetsuo
Published: April 2019

Aim

Sofosbuvir (SOF) and ribavirin (RBV) combination therapy has improved the sustained virologic response (SVR) rate and shortened the treatment duration for patients with chronic hepatitis C virus (HCV) genotype 2 infection. Ribavirin‐induced hemolytic anemia is one of the most troublesome side‐effects of SOF/RBV therapy; however, factors associated with this condition have not been fully elucidated. We aimed to identify a safer way to complete treatment with SOF/RBV therapy by examining factors related to RBV‐induced hemolytic anemia and identifying patients who did not develop anemia.

Methods

Two hundred and one patients with genotype 2 chronic hepatitis C treated with SOF/RBV therapy were studied. Significant factors associated with the decline in hemoglobin (Hb) levels from the baseline were analyzed.

Results

The SVR rate was 96.5% (194 out of 201 patients) based on intent‐to‐treat analysis. In multivariate analysis, inosine triphosphatase (ITPA) gene variation (P < 0.0001) and estimated glomerular filtration rate (eGFR) (0.001) were significantly associated with a decrease in Hb levels less than 2 g/dL. All patients were divided into four groups by ITPA and eGFR at baseline, and we identified patients with ITPA CA/AA and eGFR >75 as a group that did not develop anemia.

Conclusions

The results presented here suggest that patients with ITPA CA/AA and eGFR >75 had no reduction in Hb levels during the treatment with SOF/RBV in HCV genotype 2‐infected patients. Adding RBV to direct‐acting antiviral therapy might not be problematic in certain patients, at least in terms of the occurrence of anemia.
The characteristics of internet‐based venue sex‐seeking and mobility among money boys in Tianjin, China
Authors: Guo C , Yu M , Deng X , Gong H , Li Y , Li C , Liu Y , Guo M , Gong X , Feng S , Xu J , Li Z , Gao Y , Yang J , Cui Z , Ma J
Published: April 2019

Objectives

Internet‐based venue sex‐seeking is prevalent among money boys (MBs), as is a high degree of mobility, which is crucial for HIV transmission in key populations with high risks of HIV infection. However, correlation studies in MBs are scarce because of the secretive nature of this hard‐to‐reach subpopulation. We conducted this project to explore the characteristics of MBs.

Methods

This survey was conducted from December 2014 to June 2015 in Tianjin; a total of 330 MBs were recruited by convenience sampling. Demographic and behavioural data were collected for analysis.

Results

Among the investigated MBs, 38 (11.52%) were HIV positive, 147 (44.55%) reported using internet‐based venues to seek sexual partners and 257 (77.88%) had travelled to two or more destinations in the past 6 months. Compared with non‐internet‐based venue‐using MBs, internet‐based venue‐using MBs were more likely to have part‐time employment as MBs, to have a longer duration of working in the sex trade, to engage in finger intercourse and to present a history of substance abuse and sexually transmitted infections. However, internet‐based venue‐using MBs were less likely to exhibit consistent condom usage and undergo HIV testing. Origin of residence data showed that most MBs were from northern China, with Tianjin, Beijing and Shanghai as the main travel destinations. Mobile MBs were characterized as a group who were fully engaged in the sex trade and frequently took part in sexual activities but had a weak sense of self‐protection.

Conclusions

Internet‐based venue sex‐seeking and mobility are prevalent in MBs. Renewed efforts in internet‐based health promotion and school‐based primary health examination programmes may benefit more mobile and/or internet‐based venue sex‐seeking MBs.
Diet in hidradenitis suppurativa: a review of published and lay literature
Authors: Silfvast‐Kaiser Annika , Youssef Ronnie , Paek So Yeon
Published: April 2019

Hidradenitis suppurativa (HS) is a chronic, recurring, inflammatory skin disorder resulting in skin abscesses and sinus tracts of the skin folds. Hidradenitis suppurativa remains a disease with limited treatment options. Management of disease activity with dietary modification has been of considerable interest to the HS patient community. Limited evidence exists to support dietary changes for treatment of HS. Strategies such as eliminating dairy products, limiting simple carbohydrate and sugar intake, and avoiding nightshades (Solanaceae) and foods containing brewer's yeast have been reported to be helpful in some patients. Several supplements have also been touted as beneficial. Herein, we review the existing dietary recommendations in both peer‐reviewed and lay literature in an attempt to consolidate and evaluate existing information, while stimulating further inquiry into the role of diet in HS. Although dietary modifications are often of considerable interest to HS patients, there is a paucity of data regarding diet as it relates to HS. It is unclear whether diet may prove to be of value in limiting the severity of HS. Further research is needed to determine the potential benefits of these dietary changes.
Dental anxiety in schoolchildren with molar incisor hypomineralization—A population‐based cross‐sectional study
Authors: Menoncin Bruna Letícia Vessoni , Portella Paula Dresch , Ramos Bruna Luiza Maximo , Assunção Luciana Reichert da Silva , de Souza Juliana Feltrin , Menezes José Vitor Nogara Borges
Published: April 2019

Background

Identifying patients with high levels of DA helps to define the most adequate oral healthcare strategy, especially for pediatric patients.

Aim

To investigate the association between parental reports of dental anxiety (DA) and molar incisor hypomineralization (MIH) in schoolchildren.

Design

A cross‐sectional study was conducted in a representative sample of 731 8‐year‐old schoolchildren from the city of Curitiba, Brazil, who were clinically examined (k ≥ 0.75) for the diagnosis of MIH and dental caries using the EAPD criteria and dmft/DMFT index, respectively. Parents/guardians reported children's DA using the Dental Anxiety Question (DAQ) and answered a self‐administered structured questionnaire addressing socioeconomic and demographic characteristics. Associations were evaluated using Poisson regression analysis with robust variance (P < 0.05).

Results

A significant association was found between DA and MIH (PR = 1.20; 95%CI: 1.01‐1.42;P = 0.038), but this association lost its significance when adjusted for the other characteristics (PR = 1.13; 95%CI: 0.93‐1.38;P = 0.215). Caries experience in primary teeth was associated with lower levels of DA (PR = 0.83; 95%CI: 0.71‐0.96;P = 0.0013). The most recent visit to the dentist due to pain increased the levels of DA (PR = 1.18; 95%CI: 1.07‐1.30;P = 0.001).

Conclusions

The presence of MIH in schoolchildren was not associated with parental reports of DA.
Divergence before and after the isolation of islands: Phylogeography of the Bradybaena land snails on the Ryukyu Islands of Japan
Authors: Hirano Takahiro , Kameda Yuichi , Saito Takumi , Chiba Satoshi
Published: April 2019

Aim

Vicariance events have been proposed as a major source of lineage divergence on continental islands, whereas dispersal events followed by isolation have been proposed as the major cause on oceanic islands. However, organisms on continental islands may include taxa with characteristics similar to those on oceanic islands. Lineage divergence unassociated with the geological events that separated islands may also have occurred. This study addresses these possibilities through morphological and molecular phylogeographic analyses of land snails (Bradybaena) on continental islands.

Location

Samples were mainly collected on the Ryukyu and Izu Islands in Japan.

Methods

Molecular phylogenetic analyses using mtDNA (16S rRNA+COI) and nDNA (18S rRNA+ITS1+5.8S rRNA+ITS2+28S rRNA) were conducted for 225 individuals comprising B. circulus, B. phaeogramma and four of its subspecies endemic to the Ryukyu Islands. Shell and genital morphologies were also examined using qualitative and statistical methods.

Results

The Bradybaena populations examined were phylogenetically classified into six major clades whose divergence occurred during either Miocene‐Pliocene or Pliocene‐Pleistocene. Although phylogeographic patterns estimated on the basis of the 16S rRNA gene support the vicariance hypothesis for the origin of the major clades of Bradybaena, the phylogeographic patterns estimated by COI showed that these major clades resulted from diversification before the archipelagos separated from the continent. Both of these phylogeographic patterns suggest that genetic divergence occurred by dispersal from the southern to northern islands after divergence of major clades. The inferred phylogenies document parallel morphological evolution, yielding phylogenetic, morphological and taxonomic incongruences that created mosaic geographical patterns in the distribution of nominal taxa.

Main conclusions

Lineage diversification in endemic species on continental islands can occur before archipelago separation or subsequently via dispersal, as is seen in species on oceanic islands. Mechanisms other than vicariance should also be considered when estimating processes that created geographical patterns of genetic variations on continental islands.
Audio peer feedback to promote deep learning in online education
Authors: Filius Renée M. , de Kleijn Renske A.M. , Uijl Sabine G. , Prins Frans J. , van Rijen Harold V.M. , Grobbee Diederick E.
Published: April 2019

We investigated the relation between providing and receiving audio peer feedback with a deep approach to learning within online education. Online students were asked to complete peer feedback assignments. Data through a questionnaire with 108 respondents and 14 interviews were used to measure to what extent deep learning was perceived and why. Results support the view that both providing and receiving audio peer feedback indeed promote deep learning. As a consequence of the peer feedback method, the following student mechanisms were triggered: “feeling personally committed,” “probing back and forth,” and “understanding one's own learning process.” Particularly important for both providing and receiving feedback is feeling personally committed. Results also show that mechanisms were a stronger predictor for deep learning when providing than when receiving. Given the context in which instructors face an increasing number of students and a high workload, students may be supported by online audio peer feedback as a method to choose a deep approach to learning.
Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts
Authors: Tisdale James E. , Jaynes Heather A. , Overholser Brian R. , Sowinski Kevin M. , Kovacs Richard J.
Published: April 2019

Introduction

Higher progesterone concentrations are protective against drug‐induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug‐induced torsades de pointes (TdP).

Methods and Results

Female New Zealand white rabbits (2.5‐3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21‐day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs‐Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15‐minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo‐treated rabbits (3.8 [range, 2.8‐5.1] vs 0.7 [0.4‐1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22‐72] vs 53 [34‐62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone‐treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone‐treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT
c interval and short‐term beat‐to‐beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone‐treated rabbits.

Conclusions

Pretreatment with progesterone reduces the incidence of drug‐induced TdP, bigeminy, and trigeminy in isolated perfused AV node‐ablated rabbit hearts.
Frequency of isolated cutaneous involvement in adult mastocytosis: a cohort study
Authors: Fradet M. , Negretto M. , Tournier E. , Laurent C. , Apoil P.A. , Evrard S. , Degboe Y. , Del Mas V. , Lamant L. , Dubreuil P. , Laroche M. , Mailhol C. , Hermine O. , Paul C. , Bulai Livideanu C.
Published: April 2019

Background

Mastocytosis is characterized by the accumulation/proliferation of abnormal mast cells. The frequency of isolated cutaneous involvement in adults with mastocytosis has not been fully determined. The main objective of our study was to assess the frequency of isolated cutaneous mastocytosis (CM) in adults with mastocytosis skin lesions. The second objective was to compare the clinical, histological, biological and imaging features in patients with isolated CM and patients with systemic mastocytosis (SM).

Methods

We included all patients with histology‐proven mastocytosis skin lesions between January 2009 and December 2017. The mastocytosis diagnosis was made according to the international diagnostic criteria. All data were collected from a dedicated specific case report.

Results

Among 160 patients with mastocytosis skin lesions, 25 patients had isolated CM (15.6%), 105 had SM and 30 (18.7%) patients had undetermined mastocytosis. Skin KIT mutation (OR: 51.9, 95% CI: 3.9–678, P = 0.001) and high bone marrow tryptase (OR: 97.4, 95% CI: 10.3–915, P = 0.001) were strong predictors of SM. The prevalence of osteoporosis was higher in the SM population than in the isolated CM population. Moreover, a decrease in bone mineral density over a short period of follow‐up (1–2 years) was associated with SM. There were no differences between the two groups regarding the frequency of mast cell activation symptoms, the presentation of skin lesions, the number of mast cells in the dermis and the level of serum tryptase. We propose considering the KIT mutation status and bone marrow tryptase levels to aid the diagnosis of isolated CM in adult mastocytosis patients.

Conclusion

Only a small minority of adults with mastocytosis skin lesions has isolated cutaneous involvement. In 18.7% of mastocytosis cases, even complete workup does not allow for a precise classification of patients.
Characteristics, risk factors and treatment reality in livedoid vasculopathy – a multicentre analysis
Authors: Weishaupt C. , Strölin A. , Kahle B. , Kreuter A. , Schneider S. W. , Gerss J. , Eveslage M. , Drabik A. , Goerge T.
Published: April 2019

Background

Livedoid vasculopathy (LV) is a rare cutaneous thrombotic disease. It is characterized by occlusion of dermal vessels resulting in livedo racemosa, ulceration and atrophie blanche. Clear guidelines for diagnosis and treatment are missing.

Objective

The purpose of this study was to better characterize epidemiology, clinical appearance and treatment reality of LV in a well‐defined patient cohort.

Methods

The cohort was allocated within a prospective, multicentre, phase IIa trial that investigated the effect of rivaroxaban in LV.

Results

Analysis of 27 patients revealed that LV patients had an increased Body Mass Index (BMI; 11/27), hypertension (19/27) and increased levels of lipoprotein (a) (5/12) and homocysteine (10/12) in the blood. The female‐to‐male ratio was 2.1 : 1, and the median age was 53.0 years [interquartile range (IQR) 40.5–68]. Investigation of the clinical appearance found that 82% of patients had livedo racemosa, and the ankle region was most likely to be affected by ulceration (56–70%). The analysis of patient treatment history showed that heparin was most effective (12/17), while anti‐inflammatory regimens were, although often used (17/24), not effective (0/17).

Conclusion

We add clinical clues for a data supported diagnosis of LV, and we provide evidence that anticoagulants should be administered in monotherapy first line (EudraCT number 2012‐000108‐13‐DE).
On the Value of Virtual Currencies
Authors: BOLT WILKO , VAN OORDT MAARTEN R.C.
Published: April 2019

Our economic framework suggests that the exchange rate of virtual currency is determined by three components. First, the current value of transactions in virtual currency which absorb part of the exchange rate risk. Second, the decisions and expectations of forward‐looking investors to buy virtual currency (thereby effectively regulating its supply). Third, the elements that jointly drive future consumer adoption and merchant acceptance of virtual currency. The model predicts that, as virtual currency becomes more established, the exchange rate will become less sensitive to the impact of shocks to speculators' beliefs. This undermines the notion that excessive exchange rate volatility will prohibit widespread use of virtual currency.
What They Don't Know Won't Hurt Them: Parents’ Judgments About Lying to Their Adolescents
Authors: Gingo Matthew , Roded Alona D. , Turiel Elliot
Published: April 2019

This research examined judgments about parents lying to their adolescents. Ninety‐six participants from four primarily Caucasian groups (24 parents of 18‐year‐olds, 24 parents of 14‐year‐olds, 24 18‐year‐olds, and 24 14‐year‐olds) assessed hypothetical situations in which a parent lies to their adolescent about their past experience engaging in risky activities such as drug use and shoplifting. Evaluations and justifications for deception varied as a function of the domain of each act, the age of the adolescent being lied to, and consideration of parents’ duty to foster a protective and trusting relationship. Results are discussed in terms of parents’ and adolescents’ reasoning about deception to achieve and resist socialization goals in several (moral, personal, prudential, and multifaceted) social‐cognitive domains.
Montmorillonite improved the intestinal mucosal barrier functions of laying hens in late production
Authors: Chen Ji Fa , Liu Xu , Qu Xiangyong , Guo Songchang
Published: April 2019

This study was conducted to investigate the effects of dietary supplementation with montmorillonite (MMT) on performance, intestinal endotoxin concentration, gut mucosal oxidation status, intestinal morphology and permeability, and immunological barrier function of laying hens during late production. Four hundred and eighty 75‐week‐old laying hens (Lohmann Brown) were randomly assigned to five treatments with eight replicates per treatment and 12 hens in each replicate. The hens were fed the basal diet supplemented with 0 (control), 0.3, 0.6, 0.9, or 1.2 g MMT/kg for 70 days. Compared with the control, supplemented with 0.9 g MMT/kg increased egg mass significantly (p < 0.05) during weeks 1–5 of the experiment. Supplemented with 0.6 and 0.9 g MMT/kg also increased the endotoxin concentration in the ileal digesta (p < 0.05), but decreased the MDA concentration in the ileum significantly (p < 0.05). The T‐AOC in the jejunum of the group fed 0.3 g MMT/kg was significantly increased (p < 0.05). Compared with the control, the villus height:crypt depth of ileum from the groups fed 0.6, 0.9, and 1.2 g MMT/kg increased significantly (p < 0.05). The sIgA concentration of jejunum in the groups fed 0.6 and 0.9 g MMT/kg was higher (p < 0.05) than the control. The MMT supplementation linearly increased (p < 0.05) the mRNA expression of claudin‐1 and claudin‐5 in the jejunum. Dietary MMT supplementation down‐regulated the mRNA expression of NF‐κB P65 and TNF‐α in the jejunum in a linear and quadratic manner (p < 0.05). The IL‐1β mRNA expression of jejunum in the group fed 0.6 g MMT/kg was lower (p < 0.05) than the control. In conclusion, dietary supplementation with MMT may improve the gut barrier functions and suggests that 0.9 g/kg of MMT in diets may be the optimal supplemental level for laying hens in late production.
How diverse were ferns in the Baltic amber forest?
Authors: Sadowski Eva‐Maria , Seyfullah Leyla J. , Regalado Ledis , Skadell Laura E. , Gehler Alexander , Gröhn Carsten , Hoffeins Christel , Hoffeins Hans Werner , Neumann Christian , Schneider Harald , Schmidt Alexander R.
Published: April 2019

Diverse temperate forest types and a high atmospheric humidity have recently been suggested for the Eocene source area of Baltic amber. However, ferns are astonishingly rare as inclusions in this amber, which is in contrast to other seed‐free land plants, fungi, and lichens. Moreover, the identities of some of the few described putative fern taxa are dubious, and some fossils were even assigned to the Paleozoic seed fern generaAlethopteris,Pecopterisand to the form genusSphenopteriscontaining Paleozoic and Mesozoic fern‐like leaf fossils. Here, we review previously described fern inclusions from Baltic amber and identify further fern‐like leaf inclusions as belonging to the extant angiosperm genusComptonia(sweet ferns, Myricaceae). We conclude that only one taxon,Matonia striata(Matoniaceae), can with confidence be identified as a Polypodiopsida representative. Although “Pecopteris”humboldtianais so far only known as sterile foliage, its leaf morphology strongly suggests that also this taxon belongs to the Polypodiopsida rather than to any other tracheophyte lineage. We propose accommodating “Pecopteris”humboldtianain the new genusBerendtiopteris. “Alethopteris”serrataand “Sphenopteris” phyllocladoidesare not to be regarded as evidence of ferns from Baltic amber. Reinvestigation of the holotypes of these two taxa did not reveal to which tracheophyte lineages these fossils belong. We suggest that the scarcity of fern remains from Baltic amber may reflect both a relatively low fern diversity in the source area of the fossil resin, and an absence or rarity of epiphytic and climbing ferns as observed in modern temperate forest ecosystems.
A Critical Appraisal of Amish Studies’ De Facto Paradigm, “Negotiating with Modernity”
Authors: Anderson Cory , Donnermeyer Joseph , Longhofer Jeffrey , Reschly Steven D.
Published: April 2019

The predominant paradigm for Amish research over the past three decades has been “negotiating with modernity” (NWM). NWM explains how the Amish as a distinctive American culture and religion have overcome the threats modernity poses to their existence. This article argues that NWM has been accepted and replicated uncritically and without empirical testing due to properties making it inherently untestable. We first synthesize the central NWM literature, as the paradigm has never been fully constructed in one place. We then call attention to two sets of impairments that prevent empirical tests. First, the perspective contains several logical fallacies and terminology problems. NWM reifies “the Amish” as its unit of analysis; creates circular variable relationships (the Amish are Amish because they are not something else); employs terms problematically, notably “modernity” and “modernization”; dichotomizes phenomena; and is grounded in no particular theoretical tradition. Second, we argue that the production of knowledge within core NWM literature has not been sufficiently substantiated. Data collection procedures and methodological strategies are unclear or undefined and scientific peer review is relatively low. We conclude by suggesting more promising theoretical directions for Amish studies.
Off‐therapy precipitous HBsAg decline predicts HBsAg loss after finite entecavir therapy in HBeAg‐negative patients
Authors: Jeng Wen‐Juei , Chang Ming‐Ling , Liaw Yun‐Fan
Published: April 2019

Cessation of nucleos(t)ide analogue (Nuc) therapy in HBeAg‐negative patients may increase HBsAg loss rate in patients with sustained remission (SR) and non‐retreated clinical relapsers (CR). To investigate and compare the HBsAg kinetics from end of treatment (EOT) to HBsAg loss in these patients, serial serum samples after EOT from 36 SR and 12 CR with HBsAg loss (study group) and an 1:1 matched control who remained HBsAg‐seropositive (control group) were assayed retrospectively for quantitative HBsAg (qHBsAg). The results showed that study group SR and CR had comparable EOT features except SR had lower EOT qHBsAg (67.5 vs 350.5 IU/mL; P = 0.02; < 100 IU/mL: 58.3% vs 25%; P = 0.09). All showed gradual qHBsAg decrease then “precipitous HBsAg decline” (>0.5 log10 IU/mL in 1 year) prior to HBsAg loss. Patients with EOT qHBsAg <100 showed earlier (<12 months) “precipitous HBsAg decline” (91.7% vs 58.3%; P = 0.017) and sooner HBsAg loss (5.5 vs 21.9 months; P = 0.026). The control group also showed gradual qHBsAg decrease but less frequent “precipitous HBsAg decline” (39.6% vs 100%; P < 0.001) which occurred later (15.1 vs 5.7 months; P = 0.003) and was less steep (slope −0.6 vs −1.65 log10 IU/mL/year; P < 0.001). HBsAg loss was achieved in 92.9% of the patients with “precipitous HBsAg decline” >0.76 log10IU/mL in 1 year. In conclusion, both the SR and CR groups showed gradual HBsAg decrease followed by a “precipitous HBsAg decline”, which is a prerequisite for HBsAg loss. Lower EOT HBsAg in the SR group and qHBsAg <100 IU/mL may reflect better immune control hence followed by sooner HBsAg loss.
A homologue of the fungal tetraspanin Pls1 is required for Epichloë festucae expressorium formation and establishment of a mutualistic interaction with Lolium perenne
Authors: Green Kimberly A. , Eaton Carla J. , Savoian Matthew S. , Scott Barry
Published: April 2019

Epichloë festucae is an endophytic fungus that forms a mutualistic symbiotic association with the grass host Lolium perenne. Endophytic hyphae exit the host by an appressorium‐like structure known as an expressorium. In plant‐pathogenic fungi, the tetraspanin Pls1 and the NADPH oxidase component Nox2 are required for appressorium development. Previously we showed that the homologue of Nox2, NoxB, is required for E. festucae expressorium development and establishment of a mutualistic symbiotic interaction with the grass host. Here we used a reverse genetics approach to functionally characterize the role of the E. festucae homologue of Pls1, PlsA. The morphology and growth of ΔplsA in axenic culture was comparable to wild‐type. The tiller length of plants infected with ΔplsA was significantly reduced. Hyphae of ΔplsA had a proliferative pattern of growth within the leaves of L. perenne with increased colonization of the intercellular spaces and the vascular bundles. The ΔplsA mutant was also defective in expressorium development although the phenotype was not as severe as for ΔnoxB, highlighting potentially distinct roles for PlsA and NoxB in signalling through the NoxB complex. Hyphae of ΔplsA proliferate below the cuticle surface but still occasionally form an expressorium‐like structure that enables the mutant hyphae to exit the leaf to grow on the surface. These expressoria still form a septin ring‐like structure at the point of cuticle exit as found in the wild‐type strain. These results establish that E. festucae PlsA has an important, but distinct, role to NoxB in expressorium development and plant symbiosis.
The actions of ghrelin in the paraventricular nucleus: energy balance and neuroendocrine implications
Authors: Dos‐Santos Raoni C. , Reis Luís C. , Perello Mario , Ferguson Alastair V. , Mecawi André S.
Published: April 2019

Ghrelin is a peptide mainly produced and secreted by the stomach. Since its discovery, the impact of ghrelin on the regulation of food intake has been the most studied function of this hormone; however, ghrelin affects a wide range of physiological systems, many of which are controlled by the hypothalamic paraventricular nucleus (PVN). Several pathways may mediate the effects of ghrelin on PVN neurons, such as direct or indirect effects mediated by circumventricular organs and/or the arcuate nucleus. The ghrelin receptor is expressed in PVN neurons, and the peripheral or intracerebroventricular administration of ghrelin affects PVN neuronal activity. Intra‐PVN application of ghrelin increases food intake and decreases fat oxidation, which chronically contribute to the increased adiposity. Additionally, ghrelin modulates the neuroendocrine axes controlled by the PVN, increasing the release of vasopressin and oxytocin by magnocellular neurons and corticotropin‐releasing hormone by neuroendocrine parvocellular neurons, while possibly inhibiting the release of thyrotropin‐releasing hormone. Thus, the PVN is an important target for the actions of ghrelin. Our review discusses the mechanisms of ghrelin actions in the PVN, and its potential implications for energy balance, neuroendocrine, and integrative physiological control.
The presentation of neuroendocrine self‐peptides in the thymus: an essential event for individual life and vertebrate survival
Authors: Geenen Vincent , Trussart Charlotte , Michaux Hélène , Halouani Aymen , Jaïdane Hela , Collée Caroline , Renard Chantal , Daukandt Marc , Ledent Philippe , Martens Henri
Published: April 2019

Confirming Burnet's early hypothesis, elimination of self‐reactive T cells in the thymus was demonstrated in the late 1980s, and an important question immediately arose about the nature of the self‐peptides expressed in the thymus. Many genes encoding neuroendocrine‐related and tissue‐restricted antigens (TRAs) are transcribed in thymic epithelial cells (TECs). They are then processed for presentation by proteins of the major histocompatibility complex (MHC) expressed by TECs and thymic dendritic cells. MHC presentation of self‐peptides in the thymus programs self‐tolerance by two complementary mechanisms: (1) negative selection of self‐reactive “forbidden” T cell clones starting already in fetal life, and (2) generation of self‐specific thymic regulatory T lymphocytes (tTreg cells), mainly after birth. Many studies, including the discovery of the transcription factors autoimmune regulator (AIRE) and fasciculation and elongation protein zeta family zinc finger (FEZF2), have shown that a defect in thymus central self‐tolerance is the earliest event promoting autoimmunity. AIRE and FEZF2 control the level of transcription of many neuroendocrine self‐peptides and TRAs in the thymic epithelium. Furthermore, AIRE and FEZF2 mutations are associated with the development of autoimmunity in peripheral organs. The discovery of the intrathymic presentation of self‐peptides has revolutionized our knowledge of immunology and is opening novel avenues for prevention/treatment of autoimmunity.