bluuebunny/crossref_metadata_2025_split huggingface dataset:
Violence, Nonviolence, and the Effects of International Human Rights Law
Authors: Lupu Yonatan , Wallace Geoffrey P. R. 
Published: February 2019

AbstractUnder what conditions are individuals more likely to approve of human rights abuses by their governments? While various theoretical expectations have been offered about public approval of repression, many of them have not been directly tested. We analyze the effects of differing opposition tactics, differing government tactics, and legal constraints on approval of repression through a series of survey experiments in India, Israel, and Argentina. Our results indicate that violent action by opposition groups consistently increases support for government repression. In the context of contentious politics, we find that the effects of international law vary by national context. While our respondents in India were less likely to approve of their government when told the government violated international law, the same information likely increased approval of the government in our Israel experiment. The findings provide insights into the microfoundations of existing theories and suggest areas for theory refinement.
Treatment and management of adrenal cancer in a specialized Australian endocrine surgical unit: approaches, outcomes and lessons learnt
Authors: Kwok Grace T. Y. , Zhao Jing‐Ting , Glover Anthony R. , Ip Julian C. Y. , Sywak Mark , Clifton‐Bligh Roderick , Clarke Stephen , Robinson Bruce , Sidhu Stan B. 
Published: February 2019

BackgroundAdrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21‐year experience in managing adrenocortical carcinoma with a view towards outcomes and lessons learnt.MethodsA retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken.ResultsThirty‐five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immunohistochemical marker Ki‐67 index were strong prognostic indicators for survival.ConclusionsEarly stage, complete resection and Ki‐67 <10% are the best prognosticators for survival. Aggressive surgical resection at index operation and of recurrent oligometastatic disease along with multimodal adjuvant treatment has led to long‐term survivors of patients with Stage 4 disease in our aggregate cohort.
Pharmacokinetics of ticarcillin–clavulanate in premature infants
Authors: Watt Kevin M. , Hornik Christoph P. , Balevic Stephen J. , Mundakel Gratias , Cotten C. Michael , Harper Barrie , Benjamin Daniel K. , Anand Ravinder , Laughon Matthew , Smith P. Brian , Cohen‐Wolkowiez Michael ,   on behalf of the Best Pharmaceuticals for Children Act — Pediatric Trials Network Steering Committee
Published: February 2019

Ticarcillin–clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin–clavulanate dosing are lacking. We enrolled 15 premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin–clavulanate. The infants had a median (range) postnatal age (PNA) of 18 days (6–44 days) and gestational age of 25 weeks (23–28 weeks). Clearance was lower in infants with a PNA <14 days (0.050 L/kg/h [range 0.043–0.075]) compared with a PNA ≥14–45 days (0.078 L/kg/h [0.047–0.100]), consistent with maturation of renal function. Dosing simulations determined that ticarcillin 75 mg/kg q12h (PNA <14 days) or q8h (PNA ≥ 14–45 days) achieved the target exposure for organisms with a minimum inhibitory concentration ≤16 μ/mL in >90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 μg/mL), increased dosing frequency or extended infusion are necessary.
Central nervous system effects of the histamine‐3 receptor antagonist CEP‐26401, in comparison with modafinil and donepezil, after a single dose in a cross‐over study in healthy volunteers
Authors: Baakman Anne C. , Zuiker Rob , van Gerven Joop M.A. , Gross Nicholas , Yang Ronghua , Fetell Michael , Gershon Ari , Gilgun‐Sherki Yossi , Hellriegel Edward , Spiegelstein Ofer 
Published: February 2019

AimsIn previous studies, the histamine‐3 receptor antagonist CEP‐26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose‐dependent disruption of sleep. In the current study, 3 low‐dose levels of CEP‐26401 were compared with modafinil and donepezil.MethodsIn this double‐blind, placebo‐ and positive‐controlled, randomized, partial 6‐way cross‐over study, 40 healthy subjects received single doses of placebo, CEP‐26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose.ResultsThe main endpoint between‐errors of the spatial working memory‐10‐boxes task only improved for the 125 μg dose of CEP‐26401 with a difference of 2.92 (confidence interval [CI] –1.21 to 7.05), 3.24 (CI –1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 μg dose of CEP‐26401, −1.65 (CI –0.572 to 1.96) for modafinil and − 3.55 (CI –7.13 to 0.03) for donepezil. CEP‐26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N‐back, but a dose‐related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP‐26401 significantly changed several subjective visual analogue scales, which was strongest at 25 μg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone.DiscussionOf the doses tested, the 25 μg dose of CEP‐26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP‐26401 can have beneficial effects in clinical practice remains to be studied.
Predictive modeling for response to lithium and quetiapine in bipolar disorder
Authors: Kim Thomas T. , Dufour Steven , Xu Colin , Cohen Zachary D. , Sylvia Louisa , Deckersbach Thilo , DeRubeis Robert J. , Nierenberg Andrew A. 
Published: February 2019

AbstractObjectivesLithium and quetiapine are known to be effective treatments for bipolar disorder. However, little information is available to inform prediction of response to these medications. Machine‐learning methods can identify predictors of response by examining variables simultaneously. Further evaluation of models on a test sample can estimate how well these models would generalize to other samples.MethodsData (N = 482) were drawn from a randomized clinical trial of outpatients with bipolar I or II disorder who received adjunctive personalized treatment plus either lithium or quetiapine. Elastic net regularization (ENR) was used to generate models for lithium and quetiapine; these models were evaluated on a test set.ResultsPredictions from the lithium model explained 17.4% of the variance in actual observed scores of patients who received lithium in the test set, while predictions from the quetiapine model explained 32.1% of the variance of patients that received quetiapine. Of the baseline variables selected, those with the largest parameter estimates were: severity of mania; attention‐deficit/hyperactivity disorder (ADHD) comorbidity; nonsuicidal self‐injurious behavior; employment; and comorbidity with each of two anxiety disorders (social phobia/society anxiety and agoraphobia). Predictive accuracy of the ENR model outperformed the simple and basic theoretical models.ConclusionENR is an effective approach for building optimal and generalizable models. Variables identified through this methodology can inform future research on predictors of response to lithium and quetiapine, as well as future modeling efforts of treatment choice in bipolar disorder.
Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage
Authors: Mao Zhang , Han Xu , Chen Dahong , Xu Youwei , Xu Lina , Yin Lianhong , Sun Huijun , Qi Yan , Fang Lingling , Liu Kexin , Peng Jinyong 
Published: February 2019

Background and purposeDioscin shows potent effects against cancers. We aimed to elucidate its pharmacological effects and mechanisms of action on hepatocellular carcinoma (HCC) in vivo and in vitro.Experimental approachEffects of dioscin were investigated in SMMC7721 and HepG2 cells, diethylnitrosamine‐induced primary liver cancer in rats, and cell xenografts in nude mice. Isobaric tags for relative and absolution quantitation (iTRAQ)‐based proteomics was used to find dioscin's targets and investigate its mechanism.Key resultsIn SMMC7721 and HepG2 cells dioscin markedly inhibited cell proliferation and migration, induced apoptosis, autophagy, and DNA damage. It inhibited DEN‐induced primary liver cancer in rats, markedly changed body weights and restored levels of α fetoprotein, alanine transaminase, aspartate transaminase, γ‐glutamyltransferase, alkaline phosphatase, and Ki67. It also inhibited growth of xenografts in mice. In SMMC7721 cells, 191 differentially expressed proteins were found after dioscin, based on iTRAQ‐based assay. TP53‐inducible glycolysis and apoptosis regulator (TIGAR) was identified as being significantly down‐regulated by dioscin. Dioscin induced cell apoptosis, autophagy, and DNA damage via increasing expression levels of p53, cleaved PARP, Bax, cleaved caspase‐3/9, Beclin‐1, and LC3 and suppressing those of Bcl‐2, p‐Akt, p‐mammalian target of rapamycin (mTOR), CDK5, p‐ataxia telangiectasia‐mutated gene (ATM). The transfection of TIGAR siRNA into SMMC7721 cells and xenografts in nude mice further confirmed that the potent activity of dioscin against HCC is evoked by adjusting TIGAR‐mediated inhibition of p53, Akt/mTOR, and CDK5/ATM pathways.Conclusions and implicationsThe data suggest that dioscin has potential as a therapeutic, and TIGAR as a drug target for treating HCC.
The δ‐opioid receptor positive allosteric modulator BMS 986187 is a G‐protein‐biased allosteric agonist
Authors: Stanczyk M. Alexander , Livingston Kathryn E. , Chang Louise , Weinberg Zara Y. , Puthenveedu Manojkumar A. , Traynor John R. 
Published: February 2019

Background and PurposeThe δ‐opioid receptor is an emerging target for the management of chronic pain and depression. Biased signalling, the preferential activation of one signalling pathway over another downstream of δ‐receptors, may generate better therapeutic profiles. BMS 986187 is a positive allosteric modulator of δ‐receptors. Here, we ask if BMS 986187 can directly activate the receptor from an allosteric site, without an orthosteric ligand, and if a signalling bias is generated.Experimental ApproachWe used several clonal cell lines expressing δ‐receptors, to assess effects of BMS 986187 on events downstream of δ‐receptors by measuring G‐protein activation, β‐arrestin 2 recruitment, receptor phosphorylation, loss of surface receptor expression, ERK1/ERK2 phosphorylation, and receptor desensitization.Key ResultsBMS 986187 is a G protein biased allosteric agonist, relative to β‐arrestin 2 recruitment. Despite showing direct and potent G protein activation, BMS 986187 has a low potency to recruit β‐arrestin 2. This appears to reflect the inability of BMS 986187 to elicit any significant receptor phosphorylation, consistent with low receptor internalization and a slower onset of desensitization, compared with the full agonist SNC80.Conclusions and ImplicationsThis is the first evidence of biased agonism mediated through direct binding to an allosteric site on an opioid receptor, without a ligand at the orthosteric site. Our data suggest that agonists targeting δ‐receptors, or indeed any GPCR, through allosteric sites may be a novel way to promote signalling bias and thereby potentially produce a more specific pharmacology than can be observed by activation via the orthosteric site.
A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension
Authors: Yang Peiran , Read Cai , Kuc Rhoda E. , Nyimanu Duuamene , Williams Thomas L. , Crosby Alexi , Buonincontri Guido , Southwood Mark , Sawiak Stephen J. , Glen Robert C. , Morrell Nicholas W. , Davenport Anthony P. , Maguire Janet J. 
Published: February 2019

Background and PurposeApelin is an endogenous vasodilatory and inotropic peptide that is down‐regulated in human pulmonary arterial hypertension, although the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein‐biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced β‐arrestin‐mediated receptor internalisation with chronic use.Experimental ApproachMale Sprague–Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily i.p. injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI, and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation, and apoptosis of human pulmonary artery endothelial cells was investigated.Key ResultsMM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline‐induced changes in cardiac structure and function, including right ventricular end‐systolic and end‐diastolic volumes, ejection fraction, and left ventricular end‐diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline‐induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial NOS phosphorylation and expression, promoted proliferation, and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro.Conclusion and ImplicationsOur findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein‐biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.
Goblet cell hyperplasia as a feature of neutrophilic asthma
Authors: Alagha Khuder , Bourdin Arnaud , Vernisse Charlotte , Garulli Céline , Tummino Céline , Charriot Jérémy , Vachier Isabelle , Suehs Carey , Chanez Pascal , Gras Delphine 
Published: February 2019

SummaryBackgroundGoblet cell hyperplasia (GCH) is a pathological finding classically reported across asthma severity levels and usually associated with smoking. Multiple biological mechanisms may contribute to excessive mucus production.ObjectiveWe aimed to decipher the clinical meanings and biological pathways related to GCH in non‐smokers with asthma.MethodsCough and sputum assessment questionnaire (CASA‐Q) responses at entry and 1 year later were compared to clinical and functional outcomes in 59 asthmatic patients. GCH was assessed through periodic‐acid shift (PAS) staining on endobronchial biopsies obtained at entry in a subset of 32 patients.ResultsPeriodic‐acid shift‐staining analysis revealed a double wave distribution discriminating patients with (>10% of the epithelial area) or without GCH. CASA‐Q scores were mostly driven by overall asthma severity (P < 0.0001). CASA‐Q scores remained stable at 1 year and were independently associated with BAL eosinophil content irrespective of the presence of GCH. GCH was unrelated to the presence of bronchiectasis at CT, GERD or chronic rhinosinusitis, but correlated well with neutrophilic inflammatory patterns observed upon BAL cellular analysis (P = 0.002 at multivariate analysis). BALF bacterial loads were unrelated to GCH or to CASA‐Q.Conclusions and Clinical RelevanceGoblet cell hyperplasia is disconnected from chronic cough and sputum when assessed by a specific questionnaire. GCH is related to neutrophilic asthma whereas symptoms are related to airway eosinophilia. The clinical counterpart of GCH is unlikely assessed by the CASA‐Q.
Difference in cytokines, chemokines and growth factors produced by blood–brain barrier‐ and blood–nerve barrier‐composing cells
Authors: Oishi Mariko , Shimizu Fumitaka , Sano Yasuteru , Takeshita Yukio , Maeda Toshihiko , Fujikawa Susumu , Honda Masaya , Sato Ryota , Kanda Takashi 
Published: February 2019

AbstractObjectivesThe blood–brain barrier (BBB) and blood–nerve barrier (BNB) comprise the brain/peripheral nerve‐specific barrier system, formed by microvascular endothelial cells, pericytes and astrocytes in the BBB, and microvascular endothelial cells and pericytes in the BNB. The differences in the detailed cellular biology among these cells are still unclear. The purpose of the present study was to quantify and compare the cytokine/chemokine/growth factor levels in BBB‐ and BNB‐ composing cells.MethodsWe quantified the levels of 27 cytokines/chemokines/growth factors in human umbilical vein endothelial cells, human brain and peripheral nerve microvascular endothelial cells, pericytes, and astrocytes using a multiplexed fluorescent bead‐based immunoassay system.ResultsBasic fibroblast growth factor and regulated on activation, normal T cell expressed and secreted were mainly produced by both astrocytes and peripheral pericytes. Vascular endothelial growth factor and interferon‐inducible protein of 10 kDa were secreted by astrocytes. Interleukin‐1β, interleukin‐6, interleukin‐8 and macrophage chemoattractant protein‐1 were produced more abundantly by brain and peripheral nerve pericytes than by astrocytes. Larger amounts of basic fibroblast growth factor; interferon‐inducible protein of 10 kDa; regulated on activation, normal T cell expressed and secreted; and tumor necrosis factor‐α were secreted by brain microvascular endothelial cells than by peripheral nerve microvascular endothelial cells or human umbilical vein endothelial cells.ConclusionsSimilar to brain pericytes and astrocytes, peripheral nerve pericytes produce several cytokines, chemokines and growth factors. This suggests that these cells contribute to the barrier functions in the BNB, in the same manners as brain pericytes and astrocytes do in the BBB.
A global perspective on implant education: Cluster analysis of the “first dental implant experience” of dentists from 84 nationalities
Authors: Dragan Irina F. , Pirc Miha , Rizea Cristina , Yao Jie , Acharya Aneesha , Mattheos Nikos 
Published: February 2019

AbstractObjectivesThe aim of this cross‐sectional study was to explore the demographic and educational patterns related to the dentists’ first implant dental experience.Material and methodsParticipants of a Massive Open Online Course in implant dentistry who have placed and restored implants completed a 25‐item online questionnaire investigating their pathway of education and assessing their experience with the “first implant placement.” Exploratory analysis included hierarchical clustering using 9 demographic categorical factors.ResultsA total of 1015 respondents from 84 countries formed 5 distinct clusters. Age and work experience were dominant clustering traits, decreasing from Cluster 1 to Cluster 5. Clusters 1 and 3 represented “senior” and “younger” general dental practitioners, respectively, whilst Clusters 2 and 4 represented post‐graduate educated clinicians. Cluster 5 represented recent graduates. Asia, South America and Africa were over‐represented in “younger” clusters. Time in practice was a significant determinant of attitudes, followed by completion of post‐graduate education. There were significant differences in reported patterns of challenges and complications depending on dentists’ time in practice, age and post‐graduate education. Challenge in implant positioning was more frequently identified by “young post‐graduate” educated dentists. Recent graduates reported having the fewest complications of all clusters. Obtaining implant education in University settings was most frequently recommended by clusters of dentists with post‐graduate education.ConclusionsTime in practice is a parameter to be considered when designing implant education. The absence of structured education and mentorship might lead to inability to properly assess treatment outcomes and identify complications. Quality‐assured and practice‐directed education is needed at a global level, to support in particular, recent graduates who now seem to engage with implant dentistry early in their career.
Four‐dimensional functional cortical maps of visual and auditory language: Intracranial recording
Authors: Nakai Yasuo , Sugiura Ayaka , Brown Erik C. , Sonoda Masaki , Jeong Jeong‐Won , Rothermel Robert , Luat Aimee F. , Sood Sandeep , Asano Eishi 
Published: February 2019

SummaryObjectiveThe strength of presurgical language mapping using electrocorticography (ECoG) is its outstanding signal fidelity and temporal resolution, but the weakness includes limited spatial sampling at an individual patient level. By averaging naming‐related high‐gamma activity at nonepileptic regions across a large number of patients, we provided the functional cortical atlases animating the neural dynamics supporting visual‐object and auditory‐description naming at the whole brain level.MethodsWe studied 79 patients who underwent extraoperative ECoG recording as epilepsy presurgical evaluation, and generated time‐frequency plots and animation videos delineating the dynamics of naming‐related high‐gamma activity at 70‐110 Hz.ResultsNaming task performance elicited high‐gamma augmentation in domain‐specific lower‐order sensory areas and inferior‐precentral gyri immediately after stimulus onset. High‐gamma augmentation subsequently involved widespread neocortical networks with left hemisphere dominance. Left posterior temporal high‐gamma augmentation at several hundred milliseconds before response onset exhibited a double dissociation; picture naming elicited high‐gamma augmentation preferentially in regions medial to the inferior‐temporal gyrus, whereas auditory naming elicited high‐gamma augmentation more laterally. The left lateral prefrontal regions including Broca's area initially exhibited high‐gamma suppression subsequently followed by high‐gamma augmentation at several hundred milliseconds before response onset during both naming tasks. Early high‐gamma suppression within Broca's area was more intense during picture compared to auditory naming. Subsequent lateral‐prefrontal high‐gamma augmentation was more intense during auditory compared to picture naming.SignificanceThis study revealed contrasting characteristics in the spatiotemporal dynamics of naming‐related neural modulations between tasks. The dynamic atlases of visual and auditory language might be useful for planning of epilepsy surgery. Differential neural activation well explains some of the previously reported observations of domain‐specific language impairments following resective epilepsy surgery. Video materials might be beneficial for the education of lay people about how the brain functions differentially during visual and auditory naming.