bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer
Authors: Corcoran Ryan B. , André Thierry , Atreya Chloe E. , Schellens Jan H.M. , Yoshino Takayuki , Bendell Johanna C. , Hollebecque Antoine , McRee Autumn J. , Siena Salvatore , Middleton Gary , Muro Kei , Gordon Michael S. , Tabernero Josep , Yaeger Rona , O'Dwyer Peter J. , Humblet Yves , De Vos Filip , Jung A. Scott , Brase Jan C. , Jaeger Savina , Bettinger Severine , Mookerjee Bijoyesh , Rangwala Fatima , Van Cutsem Eric
Published: February 2018

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.

Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR.

See related commentary by Janku, p. 389.

See related article by Hazar-Rethinam et al., p. 417.

This article is highlighted in the In This Issue feature, p. 371
Taking Warfarin with Heparin Replacement and Direct Oral Anticoagulant Is a Risk Factor for Bleeding after Endoscopic Submucosal Dissection for Early Gastric Cancer
Authors: Sanomura Yoji , Oka Shiro , Tanaka Shinji , Yorita Naoki , Kuroki Kazutaka , Kurihara Mio , Mizumoto Takeshi , Yoshifuku Yoshikazu , Chayama Kazuaki
Published: February 2018

Background: Although bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) remains problematic, especially in patients taking anticoagulants, there are differing views on the ideal and optimal management for these patients. This study investigated the risk of bleeding after ESD in patients taking anticoagulants. Methods: We enrolled 61 consecutive patients taking anticoagulants (anticoagulant group) and 968 patients taking no antithrombotic agents (non-antithrombotic group) treated with ESD for EGC between December 2010 and October 2016. We analyzed the risk factors for bleeding after ESD in relation to the various clinical factors. Results: Incidences of bleeding after ESD were significantly higher (14%; 11/76) in the anticoagulant group compared to the non-antithrombotic group (3%; 40/1,167). Moreover, bleeding after ESD was significantly more common in patients in the warfarin monotherapy group (14%; 5/37) and in the direct oral anticoagulant (DOAC) monotherapy group (22%; 4/18), compared to the non-antithrombotic group. Multivariate analysis revealed that dialysis, the use of anticoagulants, and an operation time ≥75 min were independent risk factors for bleeding after ESD. Conclusions: Our data suggest that patients who take warfarin and receive heparin bridging, and those who take DOAC medication, are prone to bleeding after ESD for EGC.
Functional Dyspepsia and Irritable Bowel Syndrome: Beyond Rome IV
Authors: Stanghellini Vincenzo
Published: February 2018

Background: The correct diagnosis of functional gastrointestinal disorders (FGIDs) is quite a challenge. The overlaps between syndromes can complicate the interpretation of clinical data. Summary: The incidence of functional digestive disorders and irritable bowel syndrome are still underestimated with the currently applied diagnostic tools, and the management of the seemingly elusive disease is not satisfactory. For this reason, the “Rome” criteria were created to provide a better understanding and classification of FGIDs. Key Messages: Rome diagnostic criteria and recommendations should be used in the design and performance of clinical studies in the field of functional dyspepsia and irritable bowel syndrome.
Repeatability and Reproducibility of Foveal Avascular Zone Area Measurement on Normal Eyes by Different Optical Coherence Tomography Angiography Instruments
Authors: Pilotto Elisabetta , Frizziero Luisa , Crepaldi Anna , Della Dora Enrico , Deganello Davide , Longhin Evelyn , Convento Enrica , Parrozzani Raffaele , Midena Edoardo
Published: February 2018

Purpose: To compare the foveal avascular zone (FAZ) area measurements produced by different optical coherence tomography angiography (OCTA). Methods: Healthy enrolled volunteers underwent OCTA using 2 different devices: Spectralis HRA+OCTA (Heidelberg Engineering, Heidelberg, Germany) and RS-3000 Advance (Nidek, Gamagori, Japan). Two graders measured FAZ in both superficial (SCP) and deep (DCP) retinal capillary plexuses. The SCP and DCP en face images were visualized automatically segmenting 2 separate slabs defined by the arbitrary segmentation lines created by the software of each OCT device. One grader repeated each measure twice. Results: Fifty-nine eyes were included. The mean FAZ was 0.33 ± 0.09 mm2 at the SCP and 0.57 ± 0.17 mm2 at the DCP measured with RS-3000 versus 0.30 ± 0.08 and 0.35 ± 0.08 mm2, respectively, measured with Spectralis. The measurements of the 2 devices were significantly different (p < 0.0001). The intraoperator agreement was excellent at the SCP (intraclass correlation coefficient, ICC: 0.97 with Spectralis and 0.96 with RS-3000). At the DCP, it was good with Spectralis and fair with RS-3000 (ICC: 0.85 and 0.64, respectively). The interoperator agreement was excellent for Spectralis and good for RS-3000 at the SCP (ICC: 0.97 and 0.93, respectively). It was good at the DCP with both devices (ICC: 0.74 with RS-3000 and 0.81 with Spectralis). Conclusions: FAZ measurements obtained with different OCTA devices differ. These findings should be considered in follow-up studies of patients with retinal vascular diseases.
Complement Activation in Capillary Cerebral Amyloid Angiopathy
Authors: Matsuo Ko , Shindo Akihiro , Niwa Atsushi , Tabei Ken-ichi , Akatsu Hiroyasu , Hashizume Yoshio , Akiyama Haruhiko , Ayaki Takashi , Maki Takakuni , Sawamoto Nobukatsu , Takahashi Ryosuke , Oikawa Shinji , Tomimoto Hidekazu
Published: February 2018

Background: Cerebral amyloid angiopathy (CAA) is classified as type 1 with capillary amyloid β (Aβ) or type 2 without capillary Aβ. While it is known that CAA activates complement, an inflammatory mediator, there is no information on the relationship between capillary Aβ and complement activation. Methods: We evaluated 34 autopsy brains, including 22 with CAA and 12 with other neurodegenerative diseases. We assessed the vascular density of CAA by analyzing the expression of complement (C1q, C3d, C6, C5b-9), macrophage scavenger receptor (MSR), and apolipoprotein E (ApoE). Results: Capillary immunostaining for C1q, C3d, MSR, and ApoE was identified almost exclusively in CAA-type1 brains. There was intense expression of C1q, C3d, MSR, and ApoE, as well as weaker expression of C5b-9 and C6 in the arteries/ arterioles of both CAA subtypes, but not in control brains. C5b-9 and C6 were preferentially expressed in arteries/arterioles with subcortical hemorrhage or cortical superficial siderosis. Triple immunofluorescence revealed that C1q, C3d, and ApoE were colocalized with Aβ in CAA brain capillaries. Conclusion: Complement, MSR, and ApoE were only coexpressed in the presence of Aβ accumulation in capillaries, suggesting a role for complement activation in the propagation of Aβ. Additionally, C5b-9 expression may be associated with hemorrhagic brain injury in CAA.
Production and Molecular Cytogenetic Characterization of a Durum Wheat-Thinopyrum elongatum 7E Disomic Addition Line with Resistance to Fusarium Head Blight
Authors: Liu Huiping , Dai Yi , Chi Dawn , Huang Shuai , Li Haifeng , Duan Yamei , Cao Wenguang , Gao Yong , Fedak George , Chen Jianmin
Published: February 2018

Wheatgrass, Thinopyrum elongatum (2n = 2x = 14, EE), is an important wild relative of wheat with many excellent traits, including resistance to Fusarium head blight (FHB), that can be used for durum wheat improvement. Through hybridization of the durum cultivar “Langdon” with the amphiploid 8801 (AABBEE), a disomic alien addition line (2n = 30) with a pair of Th. elongatum 7E chromosomes was obtained and confirmed using chromosome-specific molecular markers of Th. elongatum and genomic in situ hybridization (GISH). This line is meiotically and reproductively stable, generally forming 15 bivalents at meiosis including 14 pairs from Langdon and 1 from Th. elongatum with 2 chiasmata each as revealed by GISH analysis. At the adult growth stages under field conditions, this addition line shows high resistance to FHB, with less than 16% infection on visual observation in 2 years (2014 and 2015). This addition line is shorter in height and has narrower leaves and shorter spikes as compared to its parent Langdon. So the linkage group 7E might be a further source of wheat improvement by targeted introgression approaches.
Management and Survival of Pleural Mesothelioma: A Record Linkage Study
Authors: Carioli Greta , Bonifazi Martina , Rossi Marta , Zambelli Alberto , Franchi Matteo , Zocchetti Carlo , Gasparini Stefano , Corrao Giovanni , La Vecchia Carlo , Negri Eva
Published: February 2018

Background: Pleural mesothelioma (PM) is a rare, highly lethal tumor. A definite consensus on its management has yet to be established. Objectives: To assess management, overall survival (OS), and their predictors in a cohort of patients from Lombardy, the largest Italian region (about 10 million inhabitants). Methods: Through a record linkage between Lombardy health care administrative databases, we identified patients diagnosed with PM in 2006–2011 without history of cancer, evaluating their management. OS from PM diagnosis was estimated using the Kaplan-Meier method. Predictors of OS and of treatment were assessed using Cox regression models with time-dependent covariates when appropriate. Results: Out of 1,326 patients, 754 (56.9%) received treatment for PM: 205 (15.5%) underwent surgery, and 696 (52.5%) used chemotherapy. Surgery was spread across several hospitals, and most patients diagnosed in nonspecialized centers (70%) underwent surgery in the same centers. Age at diagnosis was a strong inverse determinant of surgery. Determinants of receiving chemotherapy were younger age, a more recent first diagnosis, and first diagnosis in a specialized center. OS was 45.4% at 1 year, 24.8% at 2 years, and 9.6% at 5 years (median 11 months). OS decreased with age, and was higher for those who underwent surgery, but not for those treated with chemotherapy. Conclusions: Management of PM varied widely in clinical practice, and significant predictors of treatment were younger age and recent diagnosis, though a high proportion of patients were not treated. Patients were treated in various hospitals, indicating the importance of concentrating serious rare neoplasms in Comprehensive Cancer Centers (as recognized by the Italian Health Ministry).
A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect
Authors: Aleksiūnienė Beata , Preiksaitiene Egle , Morkūnienė Aušra , Ambrozaitytė Laima , Utkus Algirdas
Published: February 2018

Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4-5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23.1 region, arr[GRCh37] 1q22q23.1(155630752_157193893)×1. Real-time PCR analysis confirmed its de novo origin. The deleted region encompasses 50 protein-coding genes, including the morbid genes APOA1BP, ARHGEF2, LAMTOR2, LMNA, NTRK1, PRCC, RIT1, SEMA4A, and YY1AP1. Although the unique phenotype observed in our patient can arise from the haploinsufficiency of the dosage-sensitive LMNA gene, the dosage imbalance of other genes implicated in the rearrangement could also contribute to the phenotype. Further studies are required for the delineation of the phenotype associated with this rare chromosomal alteration and elucidation of the critical genes for manifestation of the specific clinical features.
A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors
Authors: Costa Roberta , Civello Davide Antonio , Bernardinelli Emanuele , Vanoni Simone , Zopf Michaela , Scantamburlo Giada , Nofziger Charity , Patsch Wolfgang , Paulmichl Markus , Dossena Silvia
Published: February 2018

Background/Aims: In the human genome, more than 400 genes encode ion channels, which are ubiquitously expressed and often coexist and participate in almost all physiological processes. Therefore, ion channel blockers represent fundamental tools in discriminating the contribution of individual channel types to a physiological phenomenon. However, unspecific effects of these compounds may represent a confounding factor. Three commonly used chloride channel inhibitors, i.e. 4,4′-diisothiocyano-2,2′-stilbene-disulfonic acid (DIDS), 5-nitro-2-[(3-phenylpropyl) amino]benzoic acid (NPPB) and the anti-inflammatory drug niflumic acid were tested to identify the lowest concentration effective on Cl- channels and ineffective on K+ channels. Methods: The activity of the above mentioned compounds was tested by whole cell patch-clamp on the swelling-activated Cl- current ICl,swell and on the endogenous voltage-dependent, outwardly rectifying K+ selective current in human kidney cell lines (HEK 293/HEK 293 Phoenix). Results: Micromolar (1-10 µM) concentrations of DIDS and NPPB could not discriminate between the Cl- and K+ selective currents. Specifically, 1 µM DIDS only affected the K+ current and 10 µM NPPB equally affected the Cl- and K+ currents. Only relatively high (0.1-1 mM) concentrations of DIDS and prolonged (5 minutes) exposure to 0.1-1 mM NPPB preferentially suppressed the Cl- current. Niflumic acid preferentially inhibited the Cl- current, but also significantly affected the K+ current. The endogenous voltage-dependent, outwardly rectifying K+ selective current in HEK 293/HEK 293 Phoenix cells was shown to arise from the Kv 3.1 channel, which is extensively expressed in brain and is involved in neurological diseases. Conclusion: The results of the present study underscore that sensitivity of a given physiological phenomenon to the Cl- channel inhibitors NPPB, DIDS and niflumic acid may actually arise from an inhibition of Cl- channels but can also result from an inhibition of voltage-dependent K+ channels, including the Kv 3.1 channel. The use of niflumic acid as anti-inflammatory drug in patients with concomitant Kv 3.1 dysfunction may result contraindicated.
The Contribution of Whole Blood Viscosity to the Process of Aortic Valve Sclerosis
Authors: Sercelik Alper , Besnili Abbas Fikret 
Published: February 2018

Objective: We aimed to investigate whether increased whole blood viscosity (WBV) could be an important factor for the occurrence of aortic valve sclerosis (AVS). Subjects and Methods: A total of 209 patients were enrolled in the study. WBV was calculated using the hematocrit and total plasma protein at a low shear rate (LSR) and a high shear rate (HSR). AVS was defined as irregular valve thickening and calcification (without evidence of outflow obstruction) documented by a peak transvalvular velocity < 2.5 m/s on echocardiographic examination. The patient group consisted of 109 patients with AVS (77 females, 32 males), and 100 subjects without AVS (65 females, 35 males) were assigned to the control group. Results: In the AVS group, WBV values were significantly higher for HSR (17.4 ± 0.5 vs. 17.1 ± 0.7 208 s–1, p < 0.001) and LSR (65.9 ± 12.5 vs. 59.7 ± 16.7 0.5 s–1, p = 0.002). In multivariate logistic regression analysis, WBV at HSR and LSR were independent predictors of AVS (odds ratio, OR: 2.24, 95% confidence interval, CI: 1.38–3.64, p = 0.001; OR: 1.026, 95% CI: 1.006–1.046, p = 0.01, respectively). Receiver-operating characteristic (ROC) curve analysis indicated that a WBV cutoff value of 65.4 at LSR had a sensitivity of 46.8% and a specificity of 60.0% (area under the ROC curve, AUC: 0.615, 95% CI: 0.535–0.696, p = 0.004), and a WBV cutoff value of 17.1 at HSR had a sensitivity of 61.5% and specificity of 53% (AUC: 0.648, 95% CI: 0.571–0.725, p < 0.001) for the prediction of AVS. Conclusion: This study demonstrated that WBV was independently associated with AVS. WBV could be an indicator of inflammation and vessel remodeling without evidence of outflow obstruction.
ЕФЕКТИВНІСТЬ МОТИВАЦІЙНОГО НАВЧАННЯ ПАЦІЄНТІВ ІЗ ФІБРИЛЯЦІЄЮ ПЕРЕДСЕРДЬ ТА АРТЕРІАЛЬНОЮ ГІПЕРТЕНЗІЄЮ
Authors: Antetska V. , Savchenko I. , Smachylo I. , Stepova M.
Published: February 2018

У статті висвітлено результативність змодельованої програми мотиваційного навчання пацієнтів із фібриляцією передсердь та артеріальною гіпертензією. Встановлено, що проведення мотиваційного навчання із залученням середнього медичного персоналу для таких пацієнтів підвищує їх зацікавленість до свого здоров’я, що врешті-решт приводить до зміни способу життя, регулярного контролю пульсу та артеріального тиску, і як наслідок – покращує якість життя та прихильність до лікування.
РОЛЬ МЕДИЧНОЇ СЕСТРИ У СФЕРІ ОХОРОНИ ПСИХІЧНОГО ЗДОРОВ’Я
Authors: Shomodi J. S. , Krynytska I. Ya.
Published: February 2018

У статті викладено сучасні дані щодо професійних та етичних якостей медичної сестри у сфері охорони психічного здоров’я на сучасному етапі та нових компетенцій в роботі середнього медичного персоналу.
НАУКОВІ ПІДХОДИ ДО ПРОБЛЕМИ ЗДОРОВ’ЯЗБЕРЕЖЕННЯ
Authors: Morvaniuk V. Yu.
Published: February 2018

У статті висвітлено питання, що єдина зброя людини в захисті здоров’я – це культура його збереження. Визначено наукові підходи до вирішення проблеми здоров’я збереження.
ДІАГНОСТИЧНА ЗНАЧИМІСТЬ ПОКАЗНИКІВ ОПЕРАЦІЙНО-АНЕСТЕЗІОЛОГІЧНОГО РИЗИКУ В РОБОТІ МЕДИЧНОЇ СЕСТРИ.
Authors: Malanchuk L. M. , Pavlyak I. S.
Published: February 2018

У статті визначено і проаналізовано динаміку і наслідок перебігу післяопераційного періоду в 85 пацієнтів із гострою і хронічною абдомінальною патологією у відділенні реанімації та інтенсивної терапії залежно від тяжкості хворого при госпіталізації та операційно-анестезіологічного ризику. Виявлено, що зі збільшенням балів операційно-анестезіологічного ризику і оцінки тяжкості хворого за шкалою APACHE ІІ при госпіталізації, достовірно збільшується летальність хворих у післяопераційний період.
МЕДИКО-СОЦІАЛЬНІ АСПЕКТИ КАРДІОЛОГІЧНОЇ ПАТОЛОГІЇ У ПАЦІЄНТІВ ОФТАЛЬМОЛОГІЧНОГО ПРОФІЛЮ
Authors: Shahbun I. V. , Levytska L. V. , Radionova I. V.
Published: February 2018

У статті обґрунтовано актуальність досліджуваної проблеми, передбачено вивчення медико-соціальних аспектів здоров’я населення, підвищення медичної культури та популяризації здорового способу життя, чітких навичок профілактичної роботи медичної сестри у цьому аспекті.
ФАНТОМНИЙ БІЛЬ – ОДНА З ОСНОВНИХ ПРОБЛЕМ ПЕРЕНЕСЕНОЇ АМПУТАЦІЇ
Authors: Pinchuk O. I. , Konovalenko S. O.
Published: February 2018

У статті проаналізовано проблему фантомного болю в осіб, які перенесли ампутації верхніх або нижніх кінцівок, та можливі методи його усунення.
ПОШИРЕНІСТЬ СИНДРОМУ ЕМОЦІЙНОГО ВИГОРАННЯ У МЕДИЧНОГО ПЕРСОНАЛУ І ФАКТОРИ, ЯКІ СПРИчинЯЮТЬ ЙОГО РОЗВИТОК
Authors: Golovenko H. V. , Sopel O. M.
Published: February 2018

У статті проаналізовано поширеність синдрому професійного вигорання  в Україні та за її межами, а також фактори, що спричиняють виникнення даного захворювання.
ОСОБЛИВОСТІ ЗМІН КАРДІОГЕМОДИНАМІКИ У ПАЦІЄНТІВ ІЗ СТАБІЛЬНОЮ СТЕНОКАРДІЄЮ ТА ГІПОФУНКЦІЄЮ ЩИТОПОДІБНОЇ ЗАЛОЗИ
Authors: Volobueva A. V. , Kyrychok I. B. , Vasylenko M. A.
Published: February 2018

У хворих на стенокардію навантаження за умов йододефіциту часто порушуються процеси обміну, вегетативної регуляції та гемодинаміки. Щоб з’ясувати особливості змін діастолічної функції лівого шлуночка у хворих на стабільну стенокардію навантаження у поєднанні з субклінічним гіпотиреозом, обстежено дві ґрупи пацієнтів: 23 – хворих на ішемічну хворобу серця: стабільну стенокардію навантаження ІІ–ІІІ функціонального класу та 21 – на стенокардію у поєднанні з субклінічним гіпотиреозом. Визначали основні показники діастолічної функції лівого шлуночка.Порівняно з пацієнтами з ізольованою стабільною стенокардією навантаження відповідного функціонального класу у хворих на стабільну стенокардію навантаження у поєднанні з субклінічним гіпотиреозом зафіксовано більш виражені прояви діастолічної дисфункції лівого шлуночка, із частішим виявленням псевдонормального типу.
ОСОБЛИВОСТІ СЕСТРИНСЬКОГО ДІАГНОЗУ В КЛІНІЦІ НЕДОНОШЕНИХ НОВОНАРОДЖЕНИХ
Authors: Ustyantseva O. V. , Luchyshyn N. Yu.
Published: February 2018

У статті проаналізовано характеристики медсестринського діагностичного пошуку в процесі надання медичної допомоги передчасно народженим дітям.Сестринський догляд дозволяє покращити оцінювання стану недоношеної дитини, вдосконалити догляд та мінімізувати стрес.
СЕСТРИНСЬКА ДІЯЛЬНІСТЬ ПРИ ВИХОДЖУВАННІ НЕДОНОШЕНИХ ДІТЕЙ: СУЧАСНІ ПІДХОДИ
Authors: Shylo K. A.
Published: February 2018

У статті проаналізовано сучасні підходи до сестринської діяльності при виходжуванні недоношених дітей.
Tissue Factor
Authors: Grover Steven P. , Mackman Nigel
Published: February 2018

Tissue factor (TF) is the high-affinity receptor and cofactor for factor (F)VII/VIIa. The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis. TF is expressed on perivascular cells and epithelial cells at organ and body surfaces where it forms a hemostatic barrier. TF also provides additional hemostatic protection to vital organs, such as the brain, lung, and heart. Under pathological conditions, TF can trigger both arterial and venous thrombosis. For instance, atherosclerotic plaques contain high levels of TF on macrophage foam cells and microvesicles that drives thrombus formation after plaque rupture. In sepsis, inducible TF expression on monocytes leads to disseminated intravascular coagulation. In cancer patients, tumors release TF-positive microvesicles into the circulation that may contribute to venous thrombosis. TF also has nonhemostatic roles. For instance, TF-dependent activation of the coagulation cascade generates coagulation proteases, such as FVIIa, FXa, and thrombin, which induce signaling in a variety of cells by cleavage of protease-activated receptors. This review will focus on the roles of TF in protective hemostasis and pathological thrombosis.
Mouse Platelet Ral GTPases Control P-Selectin Surface Expression, Regulating Platelet–Leukocyte Interaction
Authors: Wersäll Andreas , Williams Chris M. , Brown Edward , Iannitti Tommaso , Williams Neil , Poole Alastair W.
Published: February 2018

Objective—

RalA and RalB GTPases are important regulators of cell growth, cancer metastasis, and granule secretion. The purpose of this study was to determine the role of Ral GTPases in platelets with the use of platelet-specific gene-knockout mouse models.

Approach and Results—

This study shows that platelets from double knockout mice, in which both GTPases have been deleted, show markedly diminished (≈85% reduction) P-selectin translocation to the surface membrane, suggesting a critical role in α-granule secretion. Surprisingly, however, there were only minor effects on stimulated release of soluble α- and δ-granule content, with no alteration in granule count, morphology, or content. In addition, their expression was not essential for platelet aggregation or thrombus formation. However, absence of surface P-selectin caused a marked reduction (≈70%) in platelet–leukocyte interactions in blood from RalAB double knockout mice, suggesting a role for platelet Rals in platelet-mediated inflammation.

Conclusions—

Platelet Ral GTPases primarily control P-selectin surface expression, in turn regulating platelet–leukocyte interaction. Ral GTPases could therefore be important novel targets for the selective control of platelet-mediated immune cell recruitment and inflammatory disease.
Effects of Increasing Exercise Intensity and Dose on Multiple Measures of HDL (High-Density Lipoprotein) Function
Authors: Sarzynski Mark A. , Ruiz-Ramie Jonathan J. , Barber Jacob L. , Slentz Cris A. , Apolzan John W. , McGarrah Robert W. , Harris Melissa N. , Church Timothy S. , Borja Mark S. , He Yumin , Oda Michael N. , Martin Corby K. , Kraus William E. , Rohatgi Anand
Published: February 2018

Objective—

Measures of HDL (high-density lipoprotein) function are associated with cardiovascular disease. However, the effects of regular exercise on these measures is largely unknown. Thus, we examined the effects of different doses of exercise on 3 measures of HDL function in 2 randomized clinical exercise trials.

Approach and Results—

Radiolabeled and boron dipyrromethene difluoride–labeled cholesterol efflux capacity and HDL-apoA-I (apolipoprotein A-I) exchange were assessed before and after 6 months of exercise training in 2 cohorts: STRRIDE-PD (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes; n=106) and E-MECHANIC (Examination of Mechanisms of exercise-induced weight compensation; n=90). STRRIDE-PD participants completed 1 of 4 exercise interventions differing in amount and intensity. E-MECHANIC participants were randomized into 1 of 2 exercise groups (8 or 20 kcal/kg per week) or a control group. HDL-C significantly increased in the high-amount/vigorous-intensity group (3±5 mg/dL;
P
=0.02) of STRRIDE-PD, whereas no changes in HDL-C were observed in E-MECHANIC. In STRRIDE-PD, global radiolabeled efflux capacity significantly increased 6.2% (SEM, 0.06) in the high-amount/vigorous-intensity group compared with all other STRRIDE-PD groups (range, −2.4 to −8.4%; SEM, 0.06). In E-MECHANIC, non-ABCA1 (ATP-binding cassette transporter A1) radiolabeled efflux significantly increased 5.7% (95% CI, 1.2–10.2%) in the 20 kcal/kg per week group compared with the control group, with no change in the 8 kcal/kg per week group (2.6%; 95% CI, −1.4 to 6.7%). This association was attenuated when adjusting for change in HDL-C. Exercise training did not affect BODIPY-labeled cholesterol efflux capacity or HDL-apoA-I exchange in either study.

Conclusions—

Regular prolonged vigorous exercise improves some but not all measures of HDL function. Future studies are warranted to investigate whether the effects of exercise on cardiovascular disease are mediated in part by improving HDL function.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifiers: NCT00962962 and NCT01264406.
CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients
Authors: Gille Andreas , D’Andrea Denise , Tortorici Michael A. , Hartel Gunter , Wright Samuel D.
Published: February 2018

Objective—

CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered to patients with stable atherosclerotic disease versus healthy volunteers.

Approach and Results—

Measurements of apoA-I, HDL unesterified cholesterol, HDL esterified cholesterol, pre–β1-HDL, and CEC were determined in samples from patients with stable atherosclerotic disease before and after intravenous administration of CSL112. These measures were compared with 2 prior studies in healthy volunteers for differences in CEC at baseline and after CSL112 infusion. Patients with stable atherosclerotic disease exhibited significantly lower ATP-binding cassette transporter 1–mediated CEC at baseline (
P
<0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled;
P
≤0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre–β1-HDL (
P
=0.5) or CEC (
P
=0.1) after infusion of CSL112. Similar elevation in CEC was observed in patients with low or high baseline HDL function (based on tertiles of apoA-I–normalized CEC;
P
=0.1242). These observations were extended and confirmed using cholesterol esterification as an additional measure.

Conclusions—

CSL112 shows comparable, strong, and immediate effects on CEC despite underlying cardiovascular disease. CSL112 is, therefore, a promising novel therapy for lowering the burden of atherosclerosis and reducing the risk of recurrent cardiovascular events.
Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing
Authors: Giudicessi John R. , Roden Dan M. , Wilde Arthur A.M. , Ackerman Michael J.
Published: February 2018

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient’s genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.
Blood Pressure Profile 1 Year After Severe Preeclampsia
Authors: Benschop Laura , Duvekot Johannes J. , Versmissen Jorie , van Broekhoven Valeska , Steegers Eric A.P. , Roeters van Lennep Jeanine E.
Published: February 2018

Preeclampsia increases the long-term risk of cardiovascular disease, possibly through occurrence of hypertension after delivery, such as masked hypertension, night-time hypertension, and an adverse systolic night-to-day blood pressure (BP) ratio. These types of hypertension are often unnoticed and can only be detected with ambulatory BP monitoring (ABPM). We aimed to determine hypertension prevalence and 24-hour BP pattern with ABPM and office BP measurements in women 1 year after severe preeclampsia. This is a retrospective cohort study. As part of a follow-up program after severe preeclampsia, 200 women underwent ABPM and an office BP measurement 1 year after delivery. We calculated hypertension prevalence (sustained hypertension, masked hypertension, and white-coat hypertension) and systolic night-to-day BP ratio (dipping pattern). Medical files and questionnaires provided information on preexisting hypertension and antihypertensive treatment. One year after delivery, 41.5% of women had hypertension (sustained hypertension, masked hypertension, or white-coat hypertension) with ABPM. Masked hypertension was most common (17.5%), followed by sustained hypertension (14.5%) and white-coat hypertension (9.5%). With sheer office BP measurement, only 24.0% of women would have been diagnosed hypertensive. Forty-six percent of women had a disadvantageous dipping pattern. Hypertension is common 1 year after experiencing severe preeclampsia. Masked hypertension and white-coat hypertension are risk factors for future cardiovascular disease and can only be diagnosed with ABPM. Therefore, ABPM should be offered to all these women at high risk of developing hypertension and possibly future cardiovascular disease.
Microvasospasms After Experimental Subarachnoid Hemorrhage Do Not Depend on Endothelin A Receptors
Authors: Liu Hanhan , Dienel Ari , Schöller Karsten , Schwarzmaier Susanne M. , Nehrkorn Kathrin , Plesnila Nikolaus , Terpolilli Nicole A.
Published: February 2018

Background and Purpose—

Perturbations in cerebral microcirculation (eg, microvasospasms) and reduced neurovascular communication determine outcome after subarachnoid hemorrhage (SAH). ET-1 (endothelin-1) and its receptors have been implicated in the pathophysiology of large artery spasms after SAH; however, their role in the development of microvascular dysfunction is currently unknown. Here, we investigated whether inhibiting ET
A
(endothelin A) receptors can reduce microvasospasms after experimentally induced SAH.

Methods—

SAH was induced in male C57BL/6 mice by filament perforation of the middle cerebral artery. Three hours after SAH, a cranial window was prepared and the pial and parenchymal cerebral microcirculation was measured in vivo using two-photon microscopy before, during, and after administration of the ET
A
receptor inhibitor clazosentan. In separate experiments, the effect of clazosentan treatment on neurological outcome was measured 3 days after SAH.

Results—

Clazosentan treatment had no effect on the number or severity of SAH-induced cerebral microvasospasms nor did it affect neurological outcome.

Conclusions—

Our results indicate that ET
A
receptors, which mediate large artery spasms after SAH, do not seem to play a role in the development of microarterial spasms, suggesting that posthemorrhagic spasms are mediated by distinct mechanisms in large and small cerebral vessels. Given that cerebral microvessel dysfunction is a key factor for outcome after SAH, further research into the mechanisms that underlie posthemorrhagic microvasospasms is urgently needed.
Towards an updated checklist of the Libyan flora
Authors: GAWHARI AHMED M. H. , JURY STEPHEN L. , CULHAM ALASTAIR
Published: February 2018

The Libyan flora was last documented in a series of volumes published between 1976 and 1989. Since then there has been a substantial realignment of family and generic boundaries and the discovery of many new species. The lack of an update or revision since 1989 means that the Libyan Flora is now out of date and requires a reassessment using modern approaches. Here we report initial efforts to provide an updated checklist covering 43 families out of the 150 in the published flora of Libya, including 138 genera and 411 species. Updating the circumscription of taxa to follow current classification results in 11 families (Coridaceae, Guttiferae, Leonticaceae, Theligonaceae, Tiliaceae, Sterculiaceae, Bombacaeae, Sparganiaceae, Globulariaceae, Asclepiadaceae and Illecebraceae) being included in other generally broader and less morphologically well-defined families (APG-IV, 2016). As a consequence, six new families: Hypericaceae, Adoxaceae, Lophiocarpaceae, Limeaceae, Gisekiaceae and Cleomaceae are now included in the Libyan Flora. This update results in those 43 families being represented by 38 accounts. Fifty-five percent of species remain unchanged, the remaining 45% are reclassified at the family, genus or species level based on modern treatments, illustrating the need for this update and the urgent need for a review of the entire floristic treatment of Libya in support of the conservation of Libya’s biodiversity.
The lestevoides species group of the genus Geodromicus Redtenbacher, 1857 (Insecta: Coleoptera: Staphylinidae: Omaliinae)
Authors: SHAVRIN ALEXEY V.
Published: February 2018

The lestevoides species group of the genus Geodromicus Redtenbacher, 1857 is erected. Seventeen species of the group from the East Asia, including G. smetanai sp. n. (Sichuan, China), are reviewed and keyed. Geodromicus iburinus (Watanabe, 1990) and G. nipponensis (Watanabe, 1990) are revalidated; G. hermani (Watanabe, 1991) syn.n. is synonymized with G. nipponensis (Watanabe, 1990); G. kirschenblati Tichomirova, 1973 is resynonymized with G. sibiricus Bernhauer, 1915; lectotypes for G. chinensis Bernhauer, 1938 and G. lestevoides (Sharp, 1889) are designated. The distributional maps for eight species are provided; the genital structures of fourteen species are figured.
Total evidence analysis of the phylogenetic relationships of bandicoots and bilbies (Marsupialia: Peramelemorphia): reassessment of two species and description of a new species
Authors: TRAVOUILLON KENNY J. , PHILLIPS MATTHEW J.
Published: February 2018

The phylogenetic relationships of bandicoots and bilbies have been somewhat problematic, with conflicting results between morphological work and molecular data. This conflict makes it difficult to assess the taxonomic status of species and subspecies within this order, and also prevents accurate evolutionary assessments. Here, we present a new total evidence analysis, combining the latest cranio-dental morphological matrix containing both modern and fossil taxa, with molecular data from GenBank. Several subspecies were scored in the morphological dataset to match the molecular data available. Both parsimony and Bayesian analyses were performed, giving similar topologies except for the position of four fossil taxa. Total evidence dating places the peramelemorphian crown origin close to the Oligocene/Miocene boundary, and the radiations of most modern genera beginning in the Late Miocene or Early Pliocene. Our results show that some species and subspecies require taxonomic reassessment, and are revised here. We also describe a new, extinct species from the Nullarbor region. This suggests that the number of recently extinct peramelemorphian species is likely to further increase.
Helping adolescents to better support their peers with a mental health problem: A cluster-randomised crossover trial of teen Mental Health First Aid
Authors: Hart Laura M , Morgan Amy J , Rossetto Alyssia , Kelly Claire M , Mackinnon Andrew , Jorm Anthony F
Published: February 2018

Background:

teen Mental Health First Aid (tMHFA) is a classroom-based training programme for students aged 15–18 years to improve supportive behaviours towards peers, increase mental health literacy and reduce stigma. This research evaluated tMHFA by comparing it to a matched emergency Physical First Aid (PFA) training programme.

Methods:

A cluster-randomised crossover trial matched four public schools in two pairs and then randomised each to first receive tMHFA or PFA for all Year 10 students. In the subsequent calendar year, the new Year 10 cohort received the opposite intervention, giving eight cohorts. Online surveys were administered at baseline and 1 week post-training, measuring quality of first aid intentions, mental health literacy, problem recognition and stigmatising beliefs, towards fictional adolescents with depression and suicidality (John) and social anxiety (Jeanie).

Results:

A total of 1942 students were randomised (979 received tMHFA, 948 received PFA), 1605 (84%) analysed for the John vignette at baseline and 1116 (69% of baseline) provided post-training data. The primary outcomes, ‘helpful first aid intentions’ towards John/Jeanie, showed significant group-by-time interactions with medium effect sizes favouring tMHFA ( ds = 0.50–0.58). Compared to PFA, tMHFA students also reported significantly greater improvements in confidence supporting a peer ( ds = 0.22–0.37) and number of adults rated as helpful ( ds = 0.45–0.46) and greater reductions in stigmatising beliefs ( ds = 0.12–0.40) and ‘harmful first aid intentions’ towards John/Jeanie ( ds = 0.15–0.41).

Conclusions:

tMHFA is an effective and feasible programme for increasing supportive first aid intentions and mental health literacy in adolescents in the short term. tMHFA could be widely disseminated to positively impact on help seeking for adolescent mental illness.
Smad6 Methylation Represses NFκB Activation and Periodontal Inflammation
Authors: Zhang T. , Wu J. , Ungvijanpunya N. , Jackson-Weaver O. , Gou Y. , Feng J. , Ho T.V. , Shen Y. , Liu J. , Richard S. , Jin J. , Hajishengallis G. , Chai Y. , Xu J.
Published: February 2018

The balance between pro- and anti-inflammatory signals maintains tissue homeostasis and defines the outcome of chronic inflammatory diseases such as periodontitis, a condition that afflicts the tooth-supporting tissues and exerts an impact on systemic health. The induction of tissue inflammation relies heavily on Toll-like receptor (TLR) signaling, which drives a proinflammatory pathway through recruiting myeloid differentiation primary response gene 88 (MyD88) and activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). TLR-induced production of proinflammatory cytokines and chemokines is reined in by anti-inflammatory cytokines, including the transforming growth factor β (TGFβ) family of cytokines. Although Smad6 is a key mediator of TGFβ-induced anti-inflammatory signaling, the exact mechanism by which TGFβ regulates TLR proinflammatory signaling in the periodontal tissue has not been addressed to date. In this study, we demonstrate for the first time that the ability of TGFβ to inhibit TLR-NFκB signaling is mediated by protein arginine methyltransferase 1 (PRMT1)–induced Smad6 methylation. Upon methylation, Smad6 recruited MyD88 and promoted MyD88 degradation, thereby inhibiting NFκB activation. Most important, Smad6 is expressed and methylated in the gingival epithelium, and PRMT1-Smad6 signaling promotes tissue homeostasis by limiting inflammation. Consistent with this, disturbance of Smad6 methylation exacerbates inflammation and bone loss in experimental periodontitis. The dissected mechanism is therapeutically important, as it highlights the manipulation of PRMT1-Smad6 signaling as a novel promising strategy to modulate the host immune response in periodontitis.
Ideology and state terror
Authors: Scharpf Adam
Published: February 2018

How does ideology influence state terror? Studies on state repression have looked at the leaders’ decisionmaking to explain how much violence states use against internal enemies. However, government leaders usually rely on their security forces to produce violence. I argue that distinct ideological beliefs within the military apparatus produce different levels of repression even if leaders are determined to terrorize the population. I expect officers who share the ideology of their leader to willingly execute the government’s repressive program, while officers who do not share the leader’s convictions refuse to terrorize civilians. I study these dynamics in the case of Argentina’s Dirty War (1975–81) during which the government tasked its ideologically divided army with a nationwide terror campaign. Combining qualitative and quantitative data from historical sources, I identify the ideological beliefs and repressive behavior of military commanders. Consistent with my expectation, I find that loyal nationalist officers in the infantry, artillery, and communications branch of the army perpetrated significantly more violence than liberal cavalry officers who rejected the junta’s terror program. The results demonstrate that ideological beliefs within the state’s security apparatus can lead to violent outcomes that deviate from government orders.
Exploring the Effects of Working Memory on Time Perception in Attention Deficit Hyperactivity Disorder
Authors: Lee Hom-Yi , Yang En-Lin
Published: February 2018

Children with attention deficit hyperactivity disorder (ADHD) are often reported to have deficits of time perception. However, there is a strong relation between performance on tasks of working memory and time perception. Thus, it is possible that the poor performance of children with ADHD on time perception results from their deficit of working memory. In this study, the working memory of participants was separately assessed; therefore, we could explore the relationship between working memory and time perception of children with ADHD. Fifty-six children with ADHD and those of healthy controls completed tasks measuring working memory and time perception. The results showed that the time discrimination ability of children with ADHD was poorer than that of controls. However, there was a strong association between time perception and working memory. After controlling working memory and intelligence, the time discrimination ability of children with ADHD was not significantly poorer than that of controls. We suggest that there is an interdependent relationship between time perception and working memory for children with ADHD.
Forgiving Usually Takes Time: A Lesson Learned by Studying Interventions to Promote Forgiveness
Authors: Worthington Everett L. , Kurusu Taro A. , Collins Wanda , Berry Jack W. , Ripley Jennifer S. , Baier Sasha N.
Published: February 2018

Numerous accounts of research on promoting forgiveness in group settings have been published, indicating that forgiveness can be promoted successfully in varying degrees. Many have suggested that empathy-based interventions are often successful. It takes time to develop empathy for an offender. We report three studies of very brief attempts to promote forgiveness in psychoeducational group settings. The studies use ten-minute, one-hour, two-hour, and 130–minute interventions with college students. The studies test whether various components–-namely, pre-intervention videotapes and a letter-writing exercise–-of a more complex model (the Pyramid Model to REACH Forgiveness) can produce forgiveness. Each study is reported on its own merits, but the main lesson is that the amount of forgiveness is related to time that participants spend empathizing with the transgressor. A brief intervention of two hours or less will probably not reliably promote much forgiveness; however, one might argue that it starts people on the road to forgiving.