bluuebunny/crossref_metadata_2025_split huggingface dataset:
In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring
Authors: Bech Laura Fuglsang , Polcwiartek Christoffer , Kragholm Kristian , Andersen Mikkel Porsborg , Rohde Christopher , Torp-Pedersen Christian , Nielsen Jimmi , Hagstrøm Søren 
Published: August 2018

ObjectivesIn utero exposure to antiepileptic drugs has previously been associated with adverse outcome among offspring, but evidence on longer term milestone development remains limited. We investigated the association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring and assessed which antiepileptic drugs carried the highest risk.MethodsThis population-based case–cohort study used Danish nationwide register data from 2005 to 2008. Cases were offspring exposed to antiepileptic drugs in utero, and controls were unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions. Offspring were followed from birth until the first year of compulsory education from 2011 to 2015. Learning disabilities were defined as mental retardation, specific developmental disorders, autism spectrum disorders, emotional/behavioural disorders or having special educational needs. Logistic regression was used to compute ORs with 95% CIs adjusted for potential confounding.ResultsOf 117 475 incident singleton births, 636 cases and 434 controls were included (median age: 6.1 years, males: 55.7%). Learning disabilities were identified among 7.1% cases compared with 3.7% for controls. During any trimester, the adjusted OR of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17). Among cases not exposed to polytherapy (n=556), in utero exposure to lamotrigine compared with another antiepileptic drug was associated with the lowest adjusted risk (OR 0.42, 95% CI 0.19 to 0.92), and valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59).ConclusionIn utero exposure to antiepileptic drugs was significantly associated with learning disabilities among offspring. Lamotrigine should preferentially be considered over, for example, valproate if clinically feasible.
Country-wide surveillance of norovirus outbreaks in the Portuguese Army, 2015–2017
Authors: Lopes-João António , Mesquita J R , de Sousa R , Oleastro M , Silva C , Penha-Gonçalves C , Nascimento M S J 
Published: August 2018

IntroductionGastrointestinal infections are among the most common foodborne and waterborne diseases in military populations, with direct implications in operational efficiency and force readiness. Through the surveillance system of reportable acute gastrointestinal illness in the Portuguese Army, four norovirus outbreaks were identified between October 2015 and October 2017 in mainland Portugal and the Azores archipelago. The present study documents the epidemiological, clinical and laboratory investigations of these norovirus outbreaks.MethodsCases were investigated and epidemiological questionnaires were distributed to all soldiers in each military setting where the outbreaks occurred. Stool samples from soldiers with acute gastroenteritis illness were collected and screened for common enteropathogenic agents. Food and water samples served on the settings were also collected for microbiological investigation. Norovirus-positive samples were further characterised by sequence analysis using a public automated genotyping tool.ResultsThe four outbreaks affected a total of 99 soldiers among the 618 stationed on base units and in a military exercise. A total of 27 soldiers provided a stool sample, of which 20 were positive for norovirus by real-time PCR. Phylogenetic analysis showed that the noroviruses involved were all genogroup II, namely GII.17, GII.Pe-GII.4 Sydney 2012, GII.P2-GII.2 and GII.P16-GII.2. Of note, 30 soldiers had to receive treatment at the military hospital due to severity of symptoms.ConclusionIn this short, two-year surveillance period, a total of four norovirus gastroenteritis outbreaks were detected in the Portuguese Army which caused a considerable morbidity, showing once again the impact of norovirus on Army effectiveness and force readiness.
Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severeE. colipneumonia
Authors: Park Jeonghyun , Kim Seonguk , Lim Hyungsun , Liu Airan , Hu Shuling , Lee JaeHoon , Zhuo Hanjing , Hao Qi , Matthay Michael A , Lee Jae-W 
Published: August 2018

BackgroundWe previously reported that microvesicles (MVs) released by human mesenchymal stem cells (MSC) were as effective as the cells themselves in bothEscherichia colilipopolysaccharide and live bacteria-induced acute lung injury (ALI) mice models. However, it remained unclear whether the biological effect of MSC MV can be applied to human ALI.MethodsIn the current study, we tested the therapeutic effects of MSC MVs in a well-established ex vivo perfused human model of bacterial pneumonia. Using human donor lungs not used for transplantation, we instilledE. colibacteria intrabronchially and, 1 hour later, administered MSC MVs into the perfusate as therapy.ResultsAfter 6 hours, instillation ofE. colibacteria caused influx of inflammatory cells, which resulted in significant inflammation, lung protein permeability and pulmonary oedema formation. Administration of MSC MV significantly increased alveolar fluid clearance and reduced protein permeability and numerically lowered the bacterial load in the injured alveolus. The beneficial effect on bacterial killing was more pronounced with pretreatment of MSCs with a Toll-like receptor 3 agonist, polyinosinic:polycytidylic acid (Poly (I:C)), prior to the isolation of MVs. Isolated human alveolar macrophages had increased antimicrobial activity with MSC MV treatment in vitro as well. Although oxygenation and lung compliance levels were similar between injury and treatment groups, administration of MSC MVs numerically decreased median pulmonary artery pressure at 6 hours.ConclusionsIn summary, MSC MVs increased alveolar fluid clearance and reduced lung protein permeability, and pretreatment with Poly (I:C) enhanced the antimicrobial activity of MVs in an ex vivo perfused human lung with severe bacteria pneumonia.
Commercial tobacco and indigenous peoples: a stock take on Framework Convention on Tobacco Control progress
Authors: Maddox Raglan , Waa Andrew , Lee Kelley , Nez Henderson Patricia , Blais Genevieve , Reading Jeff , Lovett Raymond 
Published: August 2018

BackgroundThe health status and needs of indigenous populations of Australia, Canada and New Zealand are often compared because of the shared experience of colonisation. One enduring impact has been a disproportionately high rate of commercial tobacco use compared with non-indigenous populations. All three countries have ratified the WHO Framework Convention on Tobacco Control (FCTC), which acknowledges the harm caused to indigenous peoples by tobacco.Aim and objectivesWe evaluated and compared reporting on FCTC progress related to indigenous peoples by Australia, Canada and New Zealand as States Parties. The critiqued data included disparities in smoking prevalence between indigenous and non-indigenous peoples; extent of indigenous participation in tobacco control development, implementation and evaluation; and what indigenous commercial tobacco reduction interventions were delivered and evaluated.Data sourcesWe searched FCTC: (1) Global Progress Reports for information regarding indigenous peoples in Australia, Canada and New Zealand; and (2) country-specific reports from Australia, Canada and New Zealand between 2007 and 2016.Study selectionTwo of the authors independently reviewed the FCTC Global and respective Country Reports, identifying where indigenous search terms appeared.Data extractionAll data associated with the identified search terms were extracted, and content analysis was applied.ResultsIt is difficult to determine if or what progress has been made to reduce commercial tobacco use by the three States Parties as part of their commitments under FCTC reporting systems. There is some evidence that progress is being made towards reducing indigenous commercial tobacco use, including the implementation of indigenous-focused initiatives. However, there are significant gaps and inconsistencies in reporting. Strengthening FCTC reporting instruments to include standardised indigenous-specific data will help to realise the FCTC Guiding Principles by holding States Parties to account and building momentum for reducing the high prevalence of commercial tobacco use among indigenous peoples.
Effects of regular exercise on ventricular myocyte biomechanics and KATPchannel function
Authors: Wang Xinrui , Fitts Robert H. 
Published: August 2018

Exercise training is known to protect the heart from ischemia and improve function during exercise by reducing cardiomyocyte action potential duration (APD) and increasing contractility. The cellular mechanisms involve β-adrenergic regulation and the ATP-sensitive K+(KATP) channel, but how each alters function of the left ventricle and sex specificity is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to wheel-running (TRN) or sedentary (SED) groups. After 6–8 wk of training, myocytes were isolated from the left ventricle and field stimulated at 1, 2, and 5 Hz. TRN significantly increased cardiomyocyte contractility, the kinetics of the Ca2+transient, and responsiveness to the adrenergic receptor agonist isoproterenol (ISO), as reflected by an increased sarcomere shortening. Importantly, we demonstrated a TRN-induced upregulation of KATPchannels, which was reflected by elevated content, current density, and the channel’s contribution to APD shortening at high activation rates and in the presence of the activator pinacidil. TRN induced increase in KATPcurrent occurred throughout the left ventricle, but channel subunit content showed regional specificity with increases in Kir6.2 in the apex and SUR2A in base regions. In summary, TRN elevated cardiomyocyte cross-bridge kinetics, Ca2+sensitivity, and the responsiveness of contractile function to β-adrenergic receptor stimulation in both sexes. Importantly, upregulation of the KATPchannel accelerates repolarization and shortens APD during stress and exercise. These adaptations have clinical importance, as increased contractility and reduced APD would help protect cardiac output and reduce intracellular Ca2+overload during stresses such as regional ischemia.NEW & NOTEWORTHY Our results demonstrate that regular exercise significantly increased ventricular myocyte shortening and relaxation velocity and the rate of rise in intracellular Ca2+transient and enhanced the response of biomechanics and Ca2+reuptake to β-adrenergic stimulation. Importantly, exercise training upregulated the cardiomyocyte sarcolemma ATP-sensitive K+channel across the left ventricle in both sexes, as reflected by elevated channel subunit content, current density, and the channel’s contribution to reduced action potential duration at high activation rates.
Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium
Authors: Jadapalli Jeevan Kumar , Wright Griffin W. , Kain Vasundhara , Sherwani Mohammad Asif , Sonkar Ravi , Yusuf Nabiha , Halade Ganesh V. 
Published: August 2018

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg−1·wk−1), and the second group was injected with 7.5 mg·kg−1·wk−1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD2, PGE2, and 6-keto-PG2α) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169+ metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169+ cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.
Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 Axis
Authors: Prete Alessandro , Lo Agnes S. , Sadow Peter M. , Bhasin Swati S. , Antonello Zeus A. , Vodopivec Danica M. , Ullas Soumya , Sims Jennifer N. , Clohessy John , Dvorak Ann M. , Sciuto Tracey , Bhasin Manoj , Murphy-Ullrich Joanne E. , Lawler Jack , Karumanchi S. Ananth , Nucera Carmelo 
Published: August 2018

Abstract

Purpose:
The BRAFV600E oncogene modulates the papillary thyroid carcinoma (PTC) microenvironment, in which pericytes are critical regulators of tyrosine-kinase (TK)-dependent signaling pathways. Although BRAFV600E and TK inhibitors are available, their efficacy as bimodal therapeutic agents in BRAFV600E-PTC is still unknown.

Experimental Design:
We assessed the effects of vemurafenib (BRAFV600E inhibitor) and sorafenib (TKI) as single agents or in combination in BRAFWT/V600E-PTC and BRAFWT/WT cells using cell-autonomous, pericyte coculture, and an orthotopic mouse model. We also used BRAFWT/V600E-PTC and BRAFWT/WT-PTC clinical samples to identify differentially expressed genes fundamental to tumor microenvironment.

Results:
Combined therapy blocks tumor cell proliferation, increases cell death, and decreases motility via BRAFV600E inhibition in thyroid tumor cells in vitro. Vemurafenib produces cytostatic effects in orthotopic tumors, whereas combined therapy (likely reflecting sorafenib activity) generates biological fluctuations with tumor inhibition alternating with tumor growth. We demonstrate that pericytes secrete TSP-1 and TGFβ1, and induce the rebound of pERK1/2, pAKT and pSMAD3 levels to overcome the inhibitory effects of the targeted therapy in PTC cells. This leads to increased BRAFV600E-PTC cell survival and cell death refractoriness. We find that BRAFWT/V600E-PTC clinical samples are enriched in pericytes, and TSP1 and TGFβ1 expression evoke gene-regulatory networks and pathways (TGFβ signaling, metastasis, tumor growth, tumor microenvironment/ECM remodeling functions, inflammation, VEGF ligand–VEGF receptor interactions, immune modulation, etc.) in the microenvironment essential for BRAFWT/V600E-PTC cell survival. Critically, antagonism of the TSP-1/TGFβ1 axis reduces tumor cell growth and overcomes drug resistance.

Conclusions:
Pericytes shield BRAFV600E-PTC cells from targeted therapy via TSP-1 and TGFβ1, suggesting this axis as a new therapeutic target for overcoming resistance to BRAFV600E and TK inhibitors.
Engineered T Cells in Synovial Sarcoma: Persistence Pays Off!
Authors: Keung Emily Z. , Tawbi Hussein A. 
Published: August 2018

Abstract
Summary: Synovial sarcoma (SS) is an aggressive malignancy that typically affects adolescents and young adults and is associated with poor prognosis. Although SS has failed to respond to immune checkpoint blockade, other strategies designed to generate an immune response, including adoptive cell therapies targeting the cancer testis antigen NY-ESO-1, have shown encouraging results. In this issue, D'Angelo and colleagues confirm the safety and feasibility of adoptive T-cell therapy with autologous T cells engineered to express NY-ESO-1c259, an affinity-enhanced T-cell receptor recognizing an HLA-A2–restricted NY-ESO-1–derived peptide, and demonstrate encouraging antitumor responses in 50% of treated patients, particularly in the setting of persistence of polyfunctional NY-ESO-1c259–expressing T cells in circulation for at least 6 months. Cancer Discov; 8(8); 914–7. ©2018 AACR.
See related article by D'Angelo et al., p. 944.
Bound Together?
Authors: Ben-Ur Aviva 
Published: August 2018

Abstract
This introduction reviews the historiographical trajectory of the “slave community” and “resistance” paradigms and argues that the assumption of group solidarity underpinning them continues to inform much of the current-day scholarship on slaves and free people of African descent in the hemispheric Americas. After briefly reviewing the four contributions to this journal issue, this article proposes as an alternative the “unsentimental approach” to slavery studies and points to a number of recent publications that collectively stand as a harbinger of this historiographical seachange, one that does not shy away from evidence of economically exploitative slaveholding among free people of African origin, intra-slave violence, or alliances that linked enslaved and free people of African descent to other groups.
Sustaining Faith
Authors: Freedman Katherine 
Published: August 2018

Abstract
This article uses the case study of the small Quaker community on seventeenth-century Antigua, as well as sources from Quakers on Barbados and from Quaker missionaries travelling throughout Britain’s Atlantic empire, to question the role of Quakers as anti-slavery pioneers. Quaker founder George Fox used a paternalistic formulation of hierarchy to contend that enslavement of other human beings was compatible with Quakerism, so long as it was done in a nurturing way—an argument that was especially compelling given the sect’s desperate need in the seventeenth century to establish itself economically or risk its destruction by the post-Restoration British State. By exploring the crucial economic role that the slave-based economies of the West Indies played in establishing the Quakers as a powerful sect in the eighteenth-century North American colonies, this article demonstrates that it was impossible for Quakers to follow through in establishing a nurturing form of slavery, particularly within the brutal context of the West Indian sugar colonies.
Spanish Imperial Vassalage and the Social Reproduction of Slavery in Colonial Cuba
Authors: Morrison Karen Y. 
Published: August 2018

Abstract
With the social reproduction of slavery in colonial Cuba as its center point, this essay draws on the recent historiographical acknowledgment of the way vassalage mediated the often starkly drawn social distinctions between whites and enslaved people within colonial Spanish America. Inside the region’s emergent, capitalist political economy, feudal vassalage continued to define each social sector’s rights and responsibilities vis-á-vis the Spanish Crown. The rights of enslaved vassals derived from their potential contributions to the Spanish monarchy’s imperial survival, in their capacity to populate the extensive empire with loyal Catholic subjects and potential military defenders. These concerns also justified the Spanish monarchial state’s ability to intervene between its slaveholding vassals and its enslaved vassals, by limiting private property rights over enslaved people and operating in ways that did not fully conform to capitalist profit motives. Awareness of such sovereign-vassal interdependencies challenges historians to broaden their understanding of the relationship between capitalism and slavery to include the remnants of feudal social-political forms, even into the nineteenth century.
Lumbar Facet Joint Kinematics and Load Effects During Dynamic Lifting
Authors: Chowdhury Suman K. , Byrne Ryan M. , Zhou Yu , Zhang Xudong 
Published: August 2018

Objective: To examine the lumbar facet joint kinematics in vivo during dynamic lifting and the effects of the load lifted. Background: Although extensive efforts have been dedicated to investigating the risk factors of low back pain (LBP) associated with load handling in the workplace, the biomechanics of lumbar facet joints during such activities is not well understood. Method: Fourteen healthy participants performed a load-lifting task while a dynamic stereo-radiography system captured their lumbar motion continuously. Data from 11 participants were included for subsequent analysis. A randomized block design was employed to study the load effect (4.5 kg, 9.0 kg, and 13.5 kg) on bilateral facet joint motions at approximately 60°, 40°, 20°, and 0° trunk-flexion postures. The facet orientations were also examined. Results: Significant load effects were found for the flexion and lateral bending and superior-inferior translation of the facet joints. The L5-S1 displayed greater lateral bending and twisting, which was due to its more posterolateral orientation than the L2-L3, L3-L4, and L4-L5 facet joints. The left-right asymmetry in facet orientation was observed, most prominently at L3-L4 and L5-S1 facet joints. Conclusion: The lumbar facet joint kinematics are affected by the magnitude of the lifted load and are dependent on the orientations of articulating adjacent facets. Application: This study provided new insights into the role of lumbar facet joints in vivo during lifting. Alterations in the facet joint kinematics due to vigorous functional demand can be one of the primary but overlooked mechanical factors in the causation of LBP.