bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high‐dose statin
Authors: Fazio Sergio , Robertson David G. , Joh Tenshang , Wan Hong , Riel Tom , Forgues Philippe , Baum Charles M. , Garzone Pamela D. , Gumbiner Barry 
Published: October 2017

SummaryAimsTwo multiple‐dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL‐C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.MethodsThe results from the two phase II, double‐blinded, randomized, placebo‐controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL‐C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL‐C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL‐C dipped to ≤25 mg/dL and resumed if LDL‐C returned to ≥40 mg/dL. The primary endpoint was percent LDL‐C reduction from baseline at Week 12.ResultsAt Week 12, the reductions from baseline in LDL‐C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL‐C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL‐C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12.ConclusionsThese studies demonstrated that bococizumab safely and effectively lowered LDL‐C in hypercholesterolemic subjects on high doses of statin.
Comparative safety of systemic and low‐bioavailability steroids in inflammatory bowel disease: Systematic review and network meta‐analysis
Authors: Bonovas Stefanos , Nikolopoulos Georgios K. , Lytras Theodore , Fiorino Gionata , Peyrin‐Biroulet Laurent , Danese Silvio 
Published: October 2017

AimsOral systemic corticosteroids have been used to induce remission in patients with active inflammatory bowel disease (IBD) for over 50 years; however, the wide array of adverse events (AEs) associated with these drugs prompted the development of steroid compounds with targeted delivery and low systemic bioavailability. This study assessed corticosteroids' comparative harm using network meta‐analysis.MethodsWe searched PubMed, Scopus, Embase, the Cochrane Library, clinical trial registries, regulatory authorities' websites and major conference proceedings, through March 2017. Randomized controlled trials that recruited adult IBD patients and compared oral systemic corticosteroids (prednisone/prednisolone) or compounds/formulations with low systemic bioavailability (budesonide, budesonide MMX, and beclomethasone dipropionate) with placebo, or against each other, were considered eligible for inclusion. Two reviewers independently extracted study data and outcomes, and rated each trial's risk‐of‐bias.ResultsWe identified and synthesized evidence from 31 trials including 5689 IBD patients. Budesonide MMX was associated with significantly fewer corticosteroid‐related AEs than oral systemic corticosteroids [odds ratio (OR): 0.25, 95% confidence interval (CI): 0.13–0.49] and beclomethasone (OR: 0.35, 95% CI: 0.13–1.00), but not significantly fewer AEs than budesonide (OR: 0.64, 95% CI: 0.37–1.11); it performed equally good with placebo. By contrast, the occurrence of serious AEs, and treatment discontinuations due to AEs, did not differ between the comparator treatments.ConclusionsBudesonide MMX is associated with fewer corticosteroid‐related AEs than its comparator steroid treatments for adult IBD patients. Further high‐quality research is warranted to illuminate the steroid drugs' comparative safety profiles.
Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5‐HT1A receptor‐mediated suppression of nausea and anxiety in rats
Authors: Pertwee Roger G , Rock Erin M , Guenther Kelsey , Limebeer Cheryl L , Stevenson Lesley A , Haj Christeene , Smoum Reem , Parker Linda A , Mechoulam Raphael 
Published: October 2017

Background and PurposeThe aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU‐580) and cannabidiolic acid (CBDA) to enhance 5‐HT1A receptor activation in vitro and produce 5‐HT1A‐mediated reductions in nausea and anxiety in vivo.Experimental ApproachWe investigated the effects of HU‐580 and CBDA on (i) activation by 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin of human 5‐HT1A receptors in CHO cell membranes, using [35S]‐GTPγS binding assays, (ii) gaping by rats in acute and anticipatory nausea models, and (iii) stress‐induced anxiety‐like behaviour, as indicated by exit time from the light compartment of a light–dark box of rats subjected 24 h earlier to six tone‐paired foot shocks.Key ResultsHU‐580 and CBDA increased the Emax of 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin in vitro at 0.01–10 and 0.1–10 nM, respectively, and reduced signs of (i) acute nausea at 0.1 and 1 μg·kg−1 i.p. and at 1 μg·kg−1 i.p., respectively, and (ii) anticipatory nausea at 0.01 and 0.1 μg·kg−1, and at 0.1 μg·kg−1 i.p. respectively. At 0.01 μg·kg−1, HU‐580, but not CBDA, increased the time foot‐shocked rats spent in the light compartment of a light–dark box. The anti‐nausea and anti‐anxiety effects of 0.01 or 0.1 μg·kg−1 HU‐580 were opposed by the 5‐HT1A antagonist, WAY100635 (0.1 mg·kg−1 i.p.).Conclusions and ImplicationsHU‐580 is more potent than CBDA at enhancing 5‐HT1A receptor activation, and inhibiting signs of acute and anticipatory nausea, and anxiety. Consequently, HU‐580 is a potential medicine for treating some nausea and anxiety disorders and possibly other disorders ameliorated by enhancement of 5‐HT1A receptor activation.
Vortioxetine exerts anti‐inflammatory and immunomodulatory effects on human monocytes/macrophages
Authors: Talmon Maria , Rossi Silvia , Pastore Anna , Cattaneo Carlo Ignazio , Brunelleschi Sandra , Fresu Luigia Grazia 
Published: October 2017

Background and PurposeA crosstalk between the immune system and depression has been postulated, with monocytes/macrophages and cytokines having a key role in this interaction. In this study, we examined whether vortioxetine, a multimodal anti‐depressive drug, was endowed with anti‐inflammatory and antioxidative activity, leading to immunomodulatory effects on human monocytes and macrophages.Experimental ApproachHuman monocytes were isolated from buffy coats and used as such or differentiated into M1 and M2 macrophages. Cells were treated with vortioxetine before or after differentiation, and their responsiveness was evaluated. This included oxy‐radical and TNFα production, TNFα and PPARγ gene expression and NF‐κB translocation.Key ResultsVortioxetine significantly reduced the PMA‐induced oxidative burst in monocytes and in macrophages (M1 and M2), causing a concomitant shift of macrophages from the M1 to the M2 phenotype, demonstrated by a significant decrease in the expression of the surface marker CD86 and an increase in CD206. Moreover, treatment of monocytes with vortioxetine rendered macrophages derived from this population less sensitive to PMA, as it reduced the oxidative burst, NF‐kB translocation, TNFα release and expression while inducing PPARγ gene expression. FACS analysis showed a significant decrease in the CD14+/CD16+/CD86+ M1 population.Conclusions and ImplicationsThese results demonstrate that in human monocytes/macrophages, vortioxetine has antioxidant activity and anti‐inflammatory effects driving the polarization of macrophages towards their alternative phenotype. These findings suggest that vortioxetine, alongside its antidepressive effect, may have immunomodulatory properties.
Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation
Authors: Kumagai Takashi , Nakaseko Chiaki , Nishiwaki Kaichi , Yoshida Chikashi , Ohashi Kazuteru , Takezako Naoki , Takano Hina , Kouzai Yasuji , Murase Tadashi , Matsue Kosei , Morita Satoshi , Sakamoto Junichi , Wakita Hisashi , Sakamaki Hisashi , Inokuchi Koiti ,   the Kanto CML and Shimousa Hematology Study Groups
Published: October 2017

Tyrosine kinase inhibitors (TKI) improve the prognosis of patients with chronic myelogenous leukemia (CML) by inducing substantial deep molecular responses (DMR); some patients have successfully discontinued TKI therapy after maintaining DMR for ≥1 year. In this cessation study, we investigated the optimal conditions for dasatinib discontinuation in patients who maintained DMR for ≥2 years. This study included 54 patients with CML who were enrolled in a D‐STOP multicenter prospective trial, had achieved DMR, and had discontinued dasatinib after 2‐year consolidation. Peripheral lymphocyte profiles were analyzed by flow cytometry. The estimated 12‐month treatment‐free survival (TFS) was 62.9% (95% confidence interval: 48.5%‐74.2%). During dasatinib consolidation, the percentage of total lymphocytes and numbers of CD3− CD56+ natural killer (NK) cells, CD16+ CD56+ NK cells and CD56+ CD57+ NK‐large granular lymphocytes (LGL) were significantly higher in patients with molecular relapse after discontinuation but remained unchanged in patients without molecular relapse for >7 months. At the end of consolidation, patients whose total lymphocytes comprised <41% CD3− CD56+ NK cells, <35% CD16+ CD56+ NK cells, or <27% CD56+ CD57+ NK‐LGL cells had higher TFS relative to other patients (77% vs 18%; P < .0008; 76% vs 10%; P < .0001; 84% vs 46%; P = .0059, respectively). The increase in the number of these NK cells occurred only during dasatinib consolidation. In patients with DMR, dasatinib discontinuation after 2‐year consolidation can lead to high TFS. This outcome depends significantly on a smaller increase in NK cells during dasatinib consolidation.
T cell suppression in the bone marrow of visceral leishmaniasis patients: impact of parasite load
Authors: Kumar P , Misra P , Thakur C P , Saurabh A , Rishi N , Mitra D K 
Published: October 2017

Summary
Visceral leishmaniasis (VL) is a disseminated and lethal disease of reticulo-endothelial system caused by protozoan parasites Leishmania donovani and L. infantum, which are known to induce host T cell suppression. To understand the impact of parasite load on T cell function, the present was focused on parasite load with T cell function in bone marrow of 26 VL patients. We observed significant enrichment of forkhead box protein 3 (FoxP3)+ (P = 0·0003) and interleukin (IL)-10+ FoxP3+ regulatory T cells (Treg) (P = 0·004) in the bone marrow (BM) of patients with high parasite load (HPL) compared with low parasite load (LPL). Concordantly, T effector cells producing interferon (IFN)-γ (P = 0·005) and IL-17A (P = 0·002) were reduced in the BM of HPL. Blocking of Treg-cell derived suppressive cytokines [(IL-10 and transforming growth factor (TGF)-β] rescued the effector T cells and their functions. However, it was observed that TGF-β levels were dominant, favouring Treg cell differentiation. Furthermore, the low ratio of IL-6/TGF-β favours the suppressive milieu in HPL patients. Here we show the change in levels of various cytokines with the parasitic load during active VL, which could be helpful in devising newer immunotherapeutic strategies against this disease.
Inclusion of Biodiversity in Habitat Restoration Policy to Facilitate Ecosystem Recovery
Authors: Hughes A. Randall , Grabowski Jonathan H. , Leslie Heather M. , Scyphers Steven , Williams Susan L. 
Published: October 2017

AbstractMaintaining biodiversity is a central tenet of conservation, in part because biodiversity influences ecosystem functions across terrestrial, freshwater, and marine systems. Biodiversity‐ecosystem function relationships have clear relevance for the design of habitat restoration efforts, yet the degree to which biodiversity has been incorporated into restoration practice is unclear. We conducted a review of the published literature on habitat restoration to evaluate this potential science‐practice gap. The number of published restoration studies including the term biodiversity has increased slightly from 1990 to 2015 relative to the broader restoration literature. A greater percentage of empirical restorations, and a higher percentage of those with a biodiversity component, were from terrestrial than freshwater or marine ecosystems. The majority of studies considered biodiversity as a response to restoration rather than incorporating it in the restoration design. In fact, nearly half of the studies in our database that actively transplanted species manipulated only a single target species. Little consideration was given to genetic or trophic diversity despite their documented importance for ecosystem function. Given the limited resources available for and high economic costs associated with habitat restoration projects, we recommend policies that account for biodiversity to bridge this gap and maximize ecosystem function and restoration success.
Children prenatally exposed to maternal anxiety devote more attentional resources to neutral pictures
Authors: van den Heuvel Marion I. , Henrichs Jens , Donkers Franc C.L. , Van den Bergh Bea R.H. 
Published: October 2017

AbstractMaternal anxiety during pregnancy can negatively affect fetal neurodevelopment, predisposing the offspring to a higher risk of behavioral and emotional problems later in life. The current study investigates the association between maternal anxiety during pregnancy and child affective picture processing using event‐related brain potentials (ERPs). Mothers reported anxiety during the second trimester using the anxiety subscale of the Symptom Checklist (SCL‐90). At age 4 years, child affective picture processing (N = 86) was measured by recording ERPs during viewing of neutral, pleasant, and unpleasant pictures selected from the International Affective Pictures System. The late positive potential (LPP)—an ERP component reflecting individual differences in affective processing—was used as child outcome. The expected positive association between maternal anxiety and LPP amplitude for unpleasant pictures was not found. Nevertheless, we found a positive association between maternal anxiety during pregnancy and LPP amplitudes for neutral pictures in the middle and late time window at anterior locations (all p < .05). These associations remained significant after adjusting for maternal postnatal anxiety and gestational age at birth and after FDR correction for multiple comparisons. Our study provides neurophysiological evidence that children prenatally exposed to higher maternal anxiety devote more attentional resources to neutral pictures, but not to unpleasant pictures. Possibly, these children show enhanced vigilance for threat when viewing neutral pictures. Although useful in dangerous environments, this enhanced vigilance may predispose children prenatally exposed to higher maternal anxiety to developing behavioral and/or emotional problems later in life. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=kEzYi6IS2HA
Seizure outcome after corpus callosotomy in a large paediatric series
Authors: Graham David , Gill Deepak , Dale Russell C , Tisdall Martin M ,   Corpus Callosotomy Outcomes Study Group
Published: October 2017

AimTo describe 20 years of experience with corpus callosotomy at Great Ormond Street Hospital for Children, London and the Children's Hospital at Westmead, Sydney.MethodRecords of patients who underwent corpus callosotomy between January 1995 and December 2015 were reviewed. Complications of surgery and changes in seizure type and frequency, injuries, and use of antiepileptic drugs were recorded. Drop attacks were analysed using Kaplan–Meier event‐free survival curves. Multivariable regression analysis was used to assess the effect of clinical characteristics on outcome at last follow‐up.ResultsInclusion criteria were met for 55 patients younger than 18 years of age. Median follow‐up length was 36 months. At the last follow‐up, 26 out of 55 patients (47%) had rare or no drop attacks. In those without a good outcome at final follow‐up, 26 out of 29 (90%) had drop attacks return within 12 months of surgery. There were no preoperative predictors of developing drop attacks postoperatively. The median number of antiepileptic drugs significantly reduced from three to two. Transient neurological complications were experienced by 11 out of 55 patients (20%) and 6 out of 55 patients had surgical complications (11%).InterpretationCorpus callosotomy is a well‐tolerated procedure that is effective at reducing the severity of drop attacks in paediatric patients. Drop attacks that do return are likely to do so within 12 months and the number of antiepileptic drugs can be significantly reduced.What this paper adds

Corpus callosotomy is an effective palliative treatment and well tolerated in children.

Good outcomes for the first 12 months after surgery were likely to continue.

The number of antiepileptic drugs can be significantly reduced after corpus callosotomy.

Patients with fewer than three types of seizure had better outcomes.

There were fewer injuries from drop attacks after surgery.
Decomposing the German East–West wage gap
Authors: Kluge Jan , Weber Michael 
Published: October 2017

AbstractWages in East Germany are persistently lower than in West Germany. We study the micro‐level determinants of this spatial wage gap, using an Oaxaca–Blinder decomposition and rich linked employer–employee data. In total, up to one half of the aggregate wage differential can be attributed to structural differences in worker, establishment and regional characteristics. Regional price and establishment size differentials alone account for one quarter of the wage gap at the median. Price level differentials are even more relevant towards the top of the wage distribution. Towards the bottom, differences in union coverage become more important. Our findings are quite stable over the period from 1996 to 2010.
Wealth inequality in Sweden, 1750–1900†
Authors: Bengtsson Erik , Missiaia Anna , Olsson Mats , Svensson Patrick 
Published: October 2017

AbstractThis article examines the evolution of wealth inequality in Sweden from 1750 to 1900, contributing both to the debate on early modern and modern inequality and to the general debate on the pattern of inequality during industrialization. The pre‐industrial period (1750–1850) is for the first time examined for Sweden at the national level. The study uses a random sample of probate inventories from urban and rural areas across the country, adjusted for age and social class. Estimates are provided for the years 1750, 1800, 1850, and 1900. The results show a gradual growth in inequality as early as the mid‐eighteenth century, with the sharpest rise in the late nineteenth century. Whereas the early growth in inequality was connected to changes in the countryside and in agriculture, the later growth was related to industrialization encompassing both compositional effects and strong wealth accumulation among the richest. The level of inequality in Sweden in 1750 was lower than for other western European countries, but by 1900 Sweden was just as unequal.
Predicting the genetic impact of stocking in Brook Charr (Salvelinus fontinalis) by combining RAD sequencing and modeling of explanatory variables
Authors: Létourneau Justine , Ferchaud Anne‐Laure , Le Luyer Jérémy , Laporte Martin , Garant Dany , Bernatchez Louis 
Published: October 2017

AbstractIn fisheries management, intensive stocking programs are commonly used to enhance population abundance and maintain stock productivity. However, such practices are increasingly raising concerns as multiple studies documented adverse genetic and evolutionary impacts of stocking on wild populations. Improvement of stocking management relies on a better understanding of the dynamic of introgressive hybridization between wild and domestic population and on assessment of the genetic state of wild populations after stocking cessation. In Québec, Canada, over five million captive‐reared Brook Charr (Salvelinus fontinalis) are stocked every year to support recreational fishing activities. Here, we investigated how variation in stocking history and environmental variables, including water temperature, pH, and dissolved oxygen, may influence the impact of stocking practices on the genetic integrity of wild Brook Charr populations. We collected DNA samples (n = 862, average of 30 individuals per lake) from 29 lakes that underwent different stocking intensity through time and also collected environmental parameters for each sampled lake. An average of 4,580 high‐quality filtered SNPs was obtained for each population using genotyping by sequencing (GBS), which were then used to quantify the mean domestic membership of each sampled population. An exhaustive process of model selection was conducted to obtain a best‐fitted model that explained 56% of the variance observed in mean domestic genetic membership. The number of years since the mean year of stocking was the best explanatory variable to predict variation in mean domestic genetic membership whereas environmental characteristics had little influence on observed patterns of admixture. Our model predictions also revealed that each sampled wild population could potentially return to a wild genetic state (absence of domestic genetic background) after stocking cessation. Overall, our study provides new insights on factors determining level of introgressive hybridization and suggests that stocking impacts could be reversible with time.
Unilateral polydactyly in two foals
Authors: Gray A. , Marcos S. , Thomas A. , Lepage O. M. 
Published: October 2017

SummaryThis case report describes unilateral supernumerary digits of the forelimb in two foals. A diagnosis of polydactyly of the right forelimb in one case and of the left forelimb in the other was made by clinical examination and radiographic interpretation. Surgical excision was performed under general anaesthesia with a good cosmetic and functional outcome in both cases.