bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connexins in the control of vasomotor function
Authors: Pogoda K. , Kameritsch P. , Mannell H. , Pohl U. 
Published: June 2018

AbstractVascular endothelial cells, as well as smooth muscle cells, show heterogeneity with regard to their receptor expression and reactivity. For the vascular wall to act as a functional unit, the various cells’ responses require integration. Such an integration is not only required for a homogeneous response of the vascular wall, but also for the vasomotor behaviour of consecutive segments of the microvascular arteriolar tree. As flow resistances of individual sections are connected in series, sections require synchronization and coordination to allow effective changes of conductivity and blood flow. A prerequisite for the local coordination of individual vascular cells and different sections of an arteriolar tree is intercellular communication. Connexins are involved in a dual manner in this coordination. (i) By forming gap junctions between cells, they allow an intercellular exchange of signalling molecules and electrical currents. In particular, the spread of electrical currents allows for coordination of cell responses over longer distances. (ii) Connexins are able to interact with other proteins to form signalling complexes. In this way, they can modulate and integrate individual cells' responses also in a channel‐independent manner. This review outlines mechanisms allowing the vascular connexins to exert their coordinating function and to regulate the vasomotor reactions of blood vessels both locally, and in vascular networks. Wherever possible, we focus on the vasomotor behaviour of small vessels and arterioles which are the main vessels determining vascular resistance, blood pressure and local blood flow.
Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients
Authors: Labenz C. , Baron J. S. , Toenges G. , Schattenberg J. M. , Nagel M. , Sprinzl M. F. , Nguyen‐Tat M. , Zimmermann T. , Huber Y. , Marquardt J. U. , Galle P. R. , Wörns M.‐A. 
Published: June 2018

SummaryBackgroundMinimal hepatic encephalopathy (HE) and HE grade 1 (HE1) according to the West Haven criteria have recently been grouped as one entity named—covert HE‐ (CHE). Data regarding the impact of CHE on health‐related quality of life (HRQoL) and sleep quality are controversial.AimFirst, to determine whether CHE affects HRQoL and sleep quality of cirrhotic patients and second, whether minimal HE (MHE) and HE1 affect HRQoL and sleep quality to a comparable extent.MethodsA total of 145 consecutive cirrhotic patients were enrolled. HE1 was diagnosed clinically according to the West Haven criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Score were used to detect MHE. Chronic Liver Disease Questionnaire (CLDQ) was used to assess HRQoL and Pittsburgh Sleep Quality Index (PSQI) was applied to assess sleep quality.ResultsCovert HE was detected in 59 (40.7%) patients (MHE: n = 40; HE1: n = 19). Multivariate analysis identified CHE (P < 0.001) and female gender (P = 0.006) as independent predictors of reduced HRQoL (CLDQ total score). CHE (P = 0.021), low haemoglobin (P = 0.024) and female gender (P = 0.003) were identified as independent predictors of poor sleep quality (PSQI total score). Results of CLDQ and PSQI were comparable in patients with HE1 and MHE (CLDQ: 4.6 ± 0.9 vs 4.5 ± 1.2, P = 0.907; PSQI: 11.3 ± 3.8 vs 9.9 ± 5.0, P = 0.3).ConclusionCovert HE was associated with impaired HRQoL and sleep quality. MHE and HE1 affected both outcomes to a comparable extent supporting the use of CHE as a clinically useful term for patients with both entities of HE in clinical practice.
The Work of Anthropology Reconsidered: Career Diversity and the Future of Doctoral Education
Authors: Lyon Sarah 
Published: June 2018

AbstractIn recent years, discussion about the training and job placement of PhD students in the humanities and social sciences has increasingly been informed by broader conversations about the crisis in higher education and the persistent decline in the availability of tenure‐track academic jobs. This article analyzes 28 semi‐structured interview transcripts from the Society for Applied Anthropology's Oral History Project to explore how one group of anthropologists experience and value their livelihood pursuits and how diverse career paths impact scholarly identities within broader political economic contexts. Specifically, it explores three central themes: First, rather than viewing nonacademic work as entirely separate from their scholarly pursuits, many of the interviewed anthropologists described a flexible career trajectory shaped through repeated pivots between academic and practicing spheres. Second, the anthropologists identified multiple ways in which their nonacademic work was shaped by their unique anthropological insights and how, in turn, their work as practicing anthropologists enhanced and even deepened their scholarly engagement. Third, the interviewed anthropologists acknowledged the multiple challenges they faced in pursuing work beyond the tenure track. The manuscript ends by considering how we might build on these insights into anthropological career diversity in order to profitably rethink the purpose and form of doctoral education within our discipline.
Medical cannabis: aligning use to evidence‐based medicine approach
Authors: Bar‐Lev Schleider Lihi , Abuhasira Ran , Novack Victor 
Published: June 2018

AbstractDuring the past decade we have been witnessing a rise in medical cannabis use, yet the evidence for the safety and efficacy of the various cannabinoid compounds is scarce. The State of Israel has always been at the forefront of clinical and translational research in support of Evidence Based Medicine. With respect to cannabis Israel has created a medical and regulatory environment that enables clinical studies with cannabis which may lead to improved Evidence Based use of these compounds. This opinion paper discusses selected studies into the safety and effects of cannabis derived products.
Use of antipsychotics and risk of breast cancer: a Danish nationwide case–control study
Authors: Pottegård Anton , Lash Timothy L. , Cronin‐Fenton Deirdre , Ahern Thomas P. , Damkier Per 
Published: June 2018

AimsSome antipsychotics increase prolactin levels, which might increase the risk of breast cancer. Existing evidence is conflicting and based on sparse data, especially for the increasingly used second‐generation antipsychotics. We conducted a nationwide case–control study of the association between antipsychotic use and incident breast cancer.MethodsFrom the Danish Cancer Registry, we identified women with a first‐time diagnosis of breast cancer 2000–2015 (n = 60 360). For each case, we age‐matched 10 female population controls. Using conditional logistic regression, we calculated odds ratios (ORs) for breast cancer associated with use of antipsychotics. We stratified antipsychotics by first‐ and second‐generation status and by ability to induce elevation of prolactin.ResultsIn total, 4951 cases (8.1%) and 47 643 controls (7.9%) had ever used antipsychotics. Long‐term use (≥10 000 mg olanzapine equivalents) was associated with breast cancer, with an adjusted OR of 1.18 [95% confidence interval (CI), 1.06, 1.32]. A weak dose–response pattern was seen, with ORs increasing to 1.27 (95% CI 1.01, 1.59) for ≥50 000 mg olanzapine equivalents. Associations were similar for first‐ and second‐generation antipsychotics (ORs 1.17 vs. 1.11), but also for nonprolactin inducing‐antipsychotics (OR 1.17). Stratifying by oestrogen receptor status, positive associations were seen for oestrogen receptor‐positive cancers (long‐term use: OR 1.29; 95% CI 1.13, 1.47) while no associations were observed for oestrogen receptor‐negative cancers.ConclusionsOverall, our results do not suggest a clinically important association between antipsychotic use and risk of breast cancer. The importance of drug‐induced prolactin elevation is unclear but may lead to a slightly increased risk of oestrogen receptor‐positive breast cancer.
Effects of cannabidiol plus naltrexone on motivation and ethanol consumption
Authors: Viudez‐Martínez Adrián , García‐Gutiérrez María S , Fraguas‐Sánchez Ana Isabel , Torres‐Suárez Ana Isabel , Manzanares Jorge 
Published: June 2018

Background and PurposeThe aim of this study was to explore if the administration of naltrexone together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately.Experimental ApproachThe effects of low doses of naltrexone (0.7 mg·kg−1, p.o.) and/or CBD (20 mg·kg−1·day−1, s.c.) on ethanol consumption and motivation to drink were evaluated in the oral‐ethanol self‐administration paradigm in C57BL/6 mice. Gene expression analyses of the opioid μ receptor (Oprm1) in the nucleus accumbens (NAc), tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and the 5‐HT1A receptor in the dorsal raphe nucleus (DR) were carried out by real‐time PCR. The role of 5‐HT1A receptors in the ethanol reduction induced by the administration of CBD + naltrexone was analysed by using the 5‐HT1A receptor antagonist WAY100635 (0.3 mg·kg−1, i.p.).Key ResultsThe administration of CBD + naltrexone significantly reduced motivation and ethanol intake in the oral self‐administration procedure in a greater proportion than the drugs given alone. Only the combination of both drugs significantly reduced Oprm1, TH and 5‐HT1A gene expressions in the NAc, VTA and DR respectively. Interestingly, the administration of WAY100635 significantly blocked the actions of CBD + naltrexone but had no effects by itself.Conclusion and ImplicationsThe combination of low doses of CBD plus naltrexone were more effective than either CBD or naltrexone alone at reducing ethanol consumption and the motivation to drink. These effects appear to be mediated, at least in part, by 5‐HT1A receptors.
A long‐acting FGF21 alleviates hepatic steatosis and inflammation in a mouse model of non‐alcoholic steatohepatitis partly through an FGF21‐adiponectin‐IL17A pathway
Authors: Bao Lichen , Yin Jun , Gao Wen , Wang Qun , Yao Wenbing , Gao Xiangdong 
Published: June 2018

Background and PurposeNon‐alcoholic steatohepatitis (NASH) is the most severe form of non‐alcoholic fatty liver disease and is a serious public health problem around the world. There are currently no approved treatments for NASH. FGF21 has recently emerged as a promising drug candidate for metabolic diseases. However, the disadvantages of FGF21 as a clinically useful medicine include its short plasma half‐life and poor drug‐like properties. Here, we have explored the effects of PsTag600‐FGF21, an engineered long‐acting FGF21 fusion protein, in mice with NASH and describe some of the underlying mechanisms.Experimental ApproachA long‐acting FGF21 was prepared by genetic fusion with a 600 residues polypeptide (PsTag600). We used a choline‐deficient high‐fat diet‐induced model of NASH in mice. The effects on body weight, insulin sensitivity, inflammation and levels of hormones and metabolites were studied first. We further investigated whether PsTag600‐FGF21 attenuated inflammation through the Th17‐IL17A axis and the associated mechanisms.Key ResultsPsTag600‐FGF21 dose‐dependently reduced body weight, blood glucose, and insulin and lipid levels and reversed hepatic steatosis. PsTag600‐FGF21 enhanced fatty acid activation and mitochondrial β‐oxidation in the liver. The profound reduction in hepatic inflammation in NASH mice following PsTag600‐FGF21 was associated with inhibition of IL17A expression in Th17 cells. Furthermore, PsTag600‐FGF21 depended on adiponectin to exert its suppression of Th17 cell differentiation and IL17A expression.Conclusions and ImplicationsOur data have uncovered some of the mechanisms by which PsTag600‐FGF21 suppresses hepatic inflammation and further suggest that PsTag600‐FGF21 could be an effective approach in NASH treatment.
Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin in vasoconstriction
Authors: Yin Anyue , Yamada Akihiro , Stam Wiro B , van Hasselt Johan G C , van der Graaf Piet H 
Published: June 2018

Background and PurposeDevelopment of combination therapies has received significant interest in recent years. Previously, a two‐receptor one‐transducer (2R‐1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R‐1T model to characterize the interaction of noradrenaline and arginine‐vasopressin on vasoconstriction and performed inter‐species scaling to humans using this mechanism‐based model.Experimental ApproachContractile data were obtained from in vitro rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine‐vasopressin with or without pretreatment with the irreversible α‐adrenoceptor antagonist, phenoxybenzamine. Data were analysed using the 2R‐1T model to characterize the observed exposure–response relationships and drug–drug interaction. The model was then scaled to humans by accounting for differences in receptor density.Key ResultsWith receptor affinities set to published values, the 2R‐1T model satisfactorily characterized the interaction between noradrenaline and arginine‐vasopressin in rat small mesenteric arteries (relative standard error ≤20%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries.Conclusions and ImplicationsThe 2R‐1T model can be of relevance to quantitatively characterize the interaction between two drugs that interact via different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments.
Apolipoprotein E favours the blunting by high‐fat diet of prostacyclin receptor activation in the mouse aorta
Authors: Cheng Yanhua , Vanhoutte Paul M , Leung Susan W S 
Published: June 2018

Background and PurposeNO‐mediated, endothelium‐dependent relaxations of isolated arteries are blunted by ageing and high‐fat diets, as well as by apolipoprotein E deletion. The present study was designed to test the hypothesis that apolipoprotein E deletion impairs endothelium‐dependent responses to prostacyclin (IP) receptor activation.Experimental ApproachFive‐week‐old ApoE+/+ and ApoE−/− mice were fed normal chow or high‐fat diet for 29 weeks. The aortae were isolated for the measurements of isometric tension in Halpern–Mulvany myographs. Levels of proteins were assessed by Western blotting and immunofluorescence, and cyclic nucleotide levels by elisa.Key ResultsThe IP receptor agonist, iloprost, induced endothelium‐, NO‐synthase‐ and IP‐dependent relaxations in aortae of young ApoE+/+ mice. High‐fat diet favoured activation of thromboxane receptors by iloprost, causing contraction. Apolipoprotein E was present in aortae of ApoE+/+ mice, especially in endothelium. Its presence was augmented by high‐fat diet. Its deletion potentiated iloprost‐induced relaxations in aortae of young mice and prevented the blunting of this response by high‐fat diet. Levels of cAMP were higher, but those of cGMP were lower in the aorta of ApoE−/− than in ApoE+/+ mice of the same age. The levels of IP receptor protein were not different between ApoE+/+ and ApoE−/− mice.Conclusions and ImplicationsIloprost induced an endothelium‐dependent relaxation in the aorta of young healthy mice which involved both the cGMP and cAMP pathways. This response was blunted by prolonged exposure to a high‐fat diet. Apolipoprotein E deletion potentiated relaxations to IP receptor activation, independently of age and diet.
Intravenous immunoglobulin treatment in multiple sclerosis: A prospective, rater‐blinded analysis of relapse rates during pregnancy and the postnatal period
Authors: Winkelmann Alexander , Rommer Paulus Stefan , Hecker Michael , Zettl Uwe Klaus 
Published: June 2018

SummaryBackgroundMultiple sclerosis (MS) affects predominantly young women. Currently available disease‐modifying drugs have neither been approved during pregnancy nor nursing.AimsEvaluating the effect of treatment with intravenous immunoglobulin (IVIg) in MS patients with desire to have a baby.MethodsIn all, 70 MS patients were either treated with IVIg before conception, during first trimester of pregnancy and 12 months postnatal (group I, n = 38) or started IVIg after delivery for 12 months (group II, n = 23) or were untreated (group III, n = 9). Relapse rates and disease progression were analyzed.ResultsPre‐gestational relapse rates differed between groups. Lowest relapse rates were observed during late pregnancy, followed by an elevated relapse rate after delivery compared to the pre‐pregnancy year and the first trimester. Only in group I, the postnatal relapse rate did not exceed the relapse rate before conception. IVIg treatment did not influence disease progression after delivery.ConclusionsIn MS patients, IVIg treatment during and/or after delivery is an option to reduce the incidence of relapses during pregnancy and the postnatal period. Surprisingly, untreated patients becoming pregnant showed an increase in the relapse rate in the first trimester compared with the pre‐gestational period. How alterations of hormone status during pregnancy affect disease activity in MS has to be further investigated.
Spatial relationship between climatic diversity and biodiversity conservation value
Authors: Wang Junjun , Wu Ruidong , He Daming , Yang Feiling , Hu Peijun , Lin Shiwei , Wu Wei , Diao Yixin , Guo Yang 
Published: June 2018

AbstractCapturing the full range of climatic diversity in a reserve network is expected to improve the resilience of biodiversity to climate change. Therefore, a study on systematic conservation planning for climatic diversity that explicitly or implicitly hypothesizes that regions with higher climatic diversity support greater biodiversity is needed. However, little is known about the extent and generality of this hypothesis. We used the case of Yunnan, southwest China, to quantitatively classify climatic units and modeled 4 climatic diversity indicators, including the variety (VCU), rarity (RCU), endemism (ECU) of climatic units, and a composite index of climatic diversity (CICD). We used 5 schemes that reliably identify priority conservation areas (PCAs) to identify areas with high biodiversity conservation value. We then investigated the spatial relationships between the 4 climatic diversity indicators and the results of the 5 PCA schemes and assessed the representation of climatic diversity within the existing nature reserves. The CICD was the best indicator of areas with high conservation value, followed by ECU and RCU. Contrary to conventional knowledge, VCU was not positively associated with biodiversity conservation value. The rarer or more endemic climatic units tended to have higher reserve coverage than the more common units. However, only 28 units, covering 10.5% of the land in Yunnan, had >17% of their areas protected. In addition to climatic factors, topography and human disturbances also significantly affected the relationship between climatic diversity and biodiversity conservation value. Our results suggest that climatic diversity can be an effective surrogate for establishing a more robust reserve network under climate change in Yunnan. Our study improves understanding of the relationship between climatic diversity and biodiversity and helps build an evidence‐based foundation for systematic conservation planning that targets climatic diversity in response to climate change.
Bacterial meningitis as a cause of death in lung transplant donors: Early outcomes in recipients
Authors: Grewal Harpreet S. , Highland Kristin B. , McCurry Kenneth , Akindipe Olufemi , Budev Marie , Mehta Atul C. 
Published: June 2018

AbstractBackgroundLung transplant remains an established treatment for end‐stage lung disease, but limited organ availability remains a major barrier and contributor to waitlist mortality.1 Only 20% of available organs are considered suitable for lung transplantation (Am J Transplant, 16, 2016 and 141; Thorac Surg Clin, 25, 2015 and 35). Successful lung transplantation has been reported from donors infected with bacterial or fungal organisms, but there is a paucity of evidence regarding the use of donors with bacterial meningitis (Transplant Proc, 32, 2000 and 75; Transplantation, 64, 1997 and 365; Ann Thorac Surg, 86, 2008 and 1554).MethodThe Cleveland Clinic lung transplant database was retrospectively reviewed for patients between January 1998 and December 2014. Post‐transplantation outcomes collected included graft dysfunction, infectious complications, and survival.ResultsThe recipients were identified as having lungs from donors with bacterial meningitis. All recipients remained free of infectious organisms responsible for bacterial meningitis related in the donor. Severe primary graft dysfunction (PGD) was not seen in these recipients.ConclusionIn our study, lung transplantation from increased risk donors with bacterial meningitis was not associated with an increased risk of early infectious complications in recipients. Donors with bacterial meningitis should be considered for lung donation and may expand the donor pool safely.
Transesophageal ultrasonography during orthotopic liver transplantation: Show me more
Authors: Vetrugno Luigi , Barnariol Federico , Bignami Elena , Centonze Grazia D. , De Flaviis Adelisa , Piccioni Federico , Auci Elisabetta , Bove Tiziana 
Published: June 2018

The first perioperative transesophageal echocardiography (TEE) guidelines published 21 years ago were mainly addressed to cardiac anesthesiologists. TEE has since expanded its role outside this setting and currently represents an invaluable tool to assess chamber sizes, ventricular hypertrophy, and systolic, diastolic, and valvular function in patients undergoing orthotopic liver transplantation (OLT). Right‐sided microemboli, right ventricular dysfunction, and patent foramen ovale (PFO) are the most common intra‐operative findings described during OLT. However, left ventricular outflow tract obstruction and left ventricular ballooning syndrome are more difficult to recognize and less frequent. Transesophageal ultrasonography (TEU) during OLT is also underused. Its applications are as follows: (1) assistance in the difficult placement of pulmonary arterial catheters; (2) help with catheterization of great vessels for external veno‐venous bypass placement; (3) intra‐operative evaluation of surgical liver anastomosis patency, if feasible, through the liver window; and (4) intra‐operative investigation of “acute hypoxemia” due to pulmonary and cardiac issues using trans‐esophageal lung ultrasound (TELU). The aims of this review are as follows: (1) to summarize the uses of TEE and TEU throughout all phases of OLT, and (2) to describe other new feasible applications.