bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-Term Electroacupuncture Stimulation Prevents Osteoporosis in Ovariectomised Osteopaenic Rats through Multiple Signalling Pathways
Authors: Zheng Xuefeng , Nie Yan , Sun Chengtao , Wu Guangwen , Cai Qiaoyan , Huang Shu , Lin Yanping 
Published: April 2018

Background The pathogenic mechanisms of postmenopausal osteoporosis (PMOP) development are complex and are related to multiple cellular signalling transduction pathways. The aim of this study was to compare the effects of electroacupuncture (EA) at GV4/GV6 versus BL20/BL23 on the bones in ovariectomised (OVX) rats to explore the pathways that mediate the effects of EA on bone. Methods Forty female Sprague-Dawley rats were allocated to one of four groups (n=10 rats each) that received sham surgery (Sham group), OVX surgery only (OVX group), OVX surgery plus EA at GV4/GV6 (GV group) and OVX surgery plus EA at BL20/BL23 (BL group). Bone turnover markers osteocalcin (OC) and tartrate-resistant acid phosphatase 5b (TRACP 5b) were measured in serum, and bone mineral density (BMD) of the lumbar vertebrae and histomorphology of the femur were evaluated. Moreover, the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) was detected by ELISA. The expression of lipoprotein receptor-related protein (LRP) 5, β-catenin, runt-related transcription factor (Runx) 2 involving Wnt/β-catenin signalling and p38, c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 involving mitogen-activated protein kinase signalling were determined by Western blotting. Results The two EA-treated groups demonstrated increased levels of OC and the BMD of lumbar vertebrae, decreased levels of TRACP 5b and improved bone microstructure in the femur, compared with the untreated OVX group (P<0.05). Histomorphology analysis showed that EA treatment significantly increased the values of the trabeculae (µm), trabecular area (%) and trabecular bone number (per mm) and reduced trabecular separation (mm), compared with the OVX group. In addition, the ratio of OPG to RANKL and LRP5, β-catenin and Runx2 expression were significantly upregulated, while the expression of phosphorylated (p)-p38 and p-JNK were downregulated in EA-treated groups compared with the OVX group. Conclusion EA attenuates PMOP and it appears that the mechanism involves the regulation of multiple targets and pathways.
Predicting opioid use disorder in patients with chronic pain who present to the emergency department
Authors: Gardner Robert Andrew , Brewer Kori L , Langston Dennis B 
Published: April 2018

BackgroundEmergency department (ED) patients with chronic pain challenge providers to make quick and accurate assessments without an in-depth pain management consultation. Emergency physicians need reliable means to determine which patients may receive opioid therapy without exacerbating opioid use disorder (OUD).MethodsEighty-nine ED patients with a chief complaint of chronic pain were enrolled. Researchers administered questionnaires and reviewed medical and state prescription monitoring database information. Participants were classified as either OUD or non-OUD. Statistical analysis included a bivariate analysis comparing differences between groups and multivariate logistic regression evaluating ORs.ResultsThe 45 participants categorised as OUD had a higher proportion of documented or reported psychiatric diagnoses (p=0.049), preference of opioid treatment (p=0.005), current oxycodone prescription (p=0.043), borrowed pain medicine (p=0.004) and non-authorised dose increase (p<0.001). The state prescription monitoring database revealed the OUD group to have an increased number of opioid prescriptions (p=0.005) and pills (p=0.010). Participants who borrowed pain medicine and engaged in non-authorised dose increase were 5.2 (p=0.025, 95% CI 1.24 to 21.9) and 6.1 times (p=0.001, 95% CI 1.55 to 24.1) more likely to have OUD, respectively.LimitationsMajor limitations of our study include a small sample size, self-reported measures and convenience sample which may introduce selection bias.ConclusionPatients with chronic pain with OUD have distinguishable characteristics. Emergency physicians should consider such evidence-based variables prior to opioid therapy to ameliorate the opioid crisis and limit implicit bias.
Opioid analgesia on the battlefield: a retrospective review of data from Operation HERRICK
Authors: Lewis Pip , Wright C , Hooper C 
Published: April 2018

BackgroundAcute pain secondary to trauma is commonly encountered on the battlefield. The use of morphine to manage pain during combat has been well established since the 19th century. Despite this, there is relatively little research on analgesia use in this environment. This study aims to review the use and complications of morphine and other opioids during Operation HERRICK.MethodsA database search of the Joint Theatre Trauma Registry was completed looking for all incidences of morphine, fentanyl or naloxone use from February 2007 to September 2014. Microsoft Excel was used to analyse the results.ResultsOpioid analgesia was administered to 5801 casualties. Morphine was administered 6742 times to 3808 patients. Fentanyl was administered 9672 times to 4318 patients. Naloxone was used 18 times on 14 patients, giving a complication rate of 0.24%. Opioid doses prior to naloxone administration range from 0 to 72 mg of morphine and from 0 to 100 mcg of fentanyl. Four casualties (two local civilians and two coalition forces) received naloxone despite no recorded opioids being administered. Opium abuse was prevalent among the local population in Afghanistan, and this could explain the rationale behind two local national casualties receiving naloxone without any documented opioids being given.ConclusionThe use of opioids in a battlefield environment is extremely safe. Complication rates are similar to previously published data which is reassuring. The efficacy of different opioids was not covered by this study, and further analysis is required, particularly following the introduction of oral transmucosal fentanyl citrate and the availability of novel non-opioid analgesics.
Insulin-like growth factor-binding protein-4 inhibits epithelial growth and proliferation in the rodent intestine
Authors: Austin Kaori , Tsang Derek , Chalmers Jennifer A. , Maalouf Michael F. , Brubaker Patricia L. 
Published: April 2018

Insulin-like growth factor-binding protein-4 (IGFBP-4) is a binding protein that modulates the action of insulin-like growth factor-1 (IGF-1), a growth factor whose presence is required for the intestinotrophic effects of glucagon-like peptide-2 (GLP-2). GLP-2 is a gut hormone that uses both IGF-1 and epidermal growth factor (EGF) as intermediary factors to promote intestinal growth. Therefore, to elucidate the mechanism through which IGFBP-4 regulates IGF-1 activity in the intestine, proliferation assays were conducted using rat intestinal epithelial cells (IEC-6). IGF-1 and EGF synergistically enhanced proliferation, an effect that was dose-dependently decreased by IGFBP-4 ( P < 0.05–0.001) in an IGF-1 receptor (R)- and MEK1/2- but not a phosphatidylinositol 3-kinase-dependent manner ( P > 0.05 for IGFBP-4 effects with IGF-1R and MEK1/2 inhibitors). Intestinal organoids derived from IGFBP-4 knockout mice demonstrated significantly greater Ki-67 expression and an enhanced surface area increase in response to IGF-1 treatment, compared with organoids from control mice ( P < 0.05–0.01). GLP-2 is also known to increase the mucosal expression of IGFBP-4 mRNA. To investigate whether this occurs through the actions of its intermediaries, IGF-1 and EGF, inducible intestinal epithelial-IGF-1R knockout and control mice were treated for 10 days with and without the pan-ErbB inhibitor, CI-1033. However, no differences in mucosal IGFBP-4 mRNA expression were found for any of the treatment groups ( P > 0.05). Consistently, IEC-6 cells treated with IGF-1 and/or EGF displayed no alteration in IGFBP-4 mRNA or in cellular and secreted IGFBP-4 protein ( P > 0.05). Overall, this study establishes that endogenous IGFBP-4 plays an important role in inhibiting IGF-1-induced intestinal epithelial proliferation and that mucosal IGFBP-4 expression is independent of IGF-1 and EGF. NEW & NOTEWORTHY This study demonstrates, for the first time, the inhibitory role of locally expressed insulin-like growth factor-binding protein-4 (IGFBP-4) on the intestinal proliferative actions of IGF-1 and supports the notion of the synergistic roles of IGF-1 and EGF in promoting intestinal epithelial growth. In turn, intestinal IGFBP-4 expression was not found to be regulated by IGF-1 and/or EGF.
Small-conductance Ca2+-activated K+channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy
Authors: Tenma Taro , Mitsuyama Hirofumi , Watanabe Masaya , Kakutani Naoya , Otsuka Yutaro , Mizukami Kazuya , Kamada Rui , Takahashi Masayuki , Takada Shingo , Sabe Hisataka , Tsutsui Hiroyuki , Yokoshiki Hisashi 
Published: April 2018

The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca2+-activated K+(SK) channels are activated during hypoxia via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K+channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K+channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr286(p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy.NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca2+-activated K+channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca2+-activated K+channels interact with phosphorylated Ca2+/calmodulin-dependent protein kinase II at Thr286in hypertrophied hearts.
APTO-253 Is a New Addition to the Repertoire of Drugs that Can Exploit DNA BRCA1/2 Deficiency
Authors: Tsai Cheng-Yu , Sun Si , Zhang Hongying , Local Andrea , Su Yongxuan , Gross Larry A. , Rice William G. , Howell Stephen B. 
Published: April 2018

Abstract
APTO-253 is a small molecule with antiproliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]. The intracellular content of Fe(253)3 exceeded that of the native drug by approximately 18-fold, and Fe(253)3 appears to be the most active form. Treatment of cells with APTO-253 caused DNA damage, which led us to ask whether cells deficient in homologous recombination (i.e., loss of BRCA1/2 function) were hypersensitive to this drug. It was found that loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 of a magnitude similar to the effects of PARP inhibitors, olaparib. Raji cells selected for 16-fold acquired resistance had 16-fold reduced accumulation of Fe(253)3. RNA-seq analysis revealed that overexpression of the ABCG2 drug efflux pump is a key mechanism of resistance. ABCG2-overexpressed HEK-293 cells were resistant to APTO-253, and inhibition of ABCG2 reversed resistance to APTO-253 in Raji/253R. APTO-253 joins the limited repertoire of drugs that can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression. Mol Cancer Ther; 17(6); 1167–76. ©2018 AACR.
Long-Term Risk of Hemorrhagic Stroke in Young Patients With Congenital Heart Disease
Authors: Giang Kok Wai , Mandalenakis Zacharias , Dellborg Mikael , Lappas Georgios , Eriksson Peter , Hansson Per-Olof , Rosengren Annika 
Published: April 2018

Background and Purpose—
The risk of ischemic stroke is increased in patients with congenital heart disease (CHD); however, data on the risk of hemorrhagic stroke, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), are lacking.

Methods—
The Swedish Patient Register was used to identify all patients who were born with a diagnosis of CHD between 1970 and 1993. Each patient was compared with 10 randomly selected controls from the general population, matched for age, sex, and county. Follow-up data were collected until December 2011 for both cases and controls.

Results—
Of 21 982 patients with CHD, 70 developed ICH and 57 developed SAH up to the age of 42 years. CHD patients had more than an 8× higher risk (incidence rate ratio, 8.23; 95% confidence interval, 6–11.2) of developing ICH and almost an 8× higher risk of developing SAH (incidence rate ratio, 7.64; 95% confidence interval, 5.41–10.7) compared with controls. The absolute risk of ICH and SAH was low, with incidence rates of 1.18 and 0.96 cases per 10 000 person-years, respectively. Patients with severe nonconotruncal defects (incidence rate ratio, 16.5; 95% confidence interval, 5.63–51.2) or coarctation of the aorta (incidence rate ratio, 17.3; 95% confidence interval, 6.63–51.8) had the highest relative risk of developing hemorrhagic stroke, with incidence rates of 3.22 and 2.79 cases per 10 000 person-years, respectively.

Conclusions—
The relative risk of hemorrhagic stroke among children and young adults with CHD was almost 8× higher than that of matched controls from the general population, although the absolute risk was low. The highest risk of ICH and SAH occurred in patients with severe nonconotruncal defects and coarctation of the aorta.
Identifying suitable habitats and current conservation status of a rare and elusive reptile in Iran
Authors: Chefaoui Rosa M. , Hosseinzadeh Mahboubeh Sadat , Mashayekhi Meysam , Safaei-Mahroo Barbod , Kazemi Seyed Mahdi 
Published: April 2018

Abstract
Knowledge gaps regarding species distribution and abundance are great in remote regions with political instability, and they might be even larger concerning elusive and rare species. We predict the potential distribution for Hierophis andreanus, a poorly known endemic snake in the Iranian Plateau, and assess its conservation status in relation to existing protected areas. We used a maximum entropy modeling tool and Mahalanobis distance to produce an ensemble species distribution model. The most suitable habitats where located mainly in mountain ranges and adjacent areas of Iran and Afghanistan. Mean temperature and slope were the most important predictors for our models. Furthermore, just five localities for H. andreanus were inside the Iranian protected areas. A 10 km expansion from existing boundaries of protected areas in all directions would double protected localities to 10, and a 20 km buffer would result in 13 protected localities. Our findings are particularly valuable to select locations to conduct new surveys and produce a more reliable estimate of current population size to improve conservation and management for this reptile in the Irano-Anatolian region.
Expanding the Boundaries of Orthodoxy?
Authors: Pietsch Andreas 
Published: April 2018

Abstract
The article argues for a re-assessment of the widespread assumption that Friedrich Breckling should be considered the editor of the 1687/90 German edition of the works of the sixteenth-century “Familist” author Hiel. After discussing the evidence which had seemed to point towards such a role for Breckling, the article draws on unedited material to demonstrate that the Hiel edition should instead be ascribed to Loth Fischer. This sheds new light on the religious and intellectual attitudes of the heterodox Lutheran theologian Breckling. When compared to his contemporary Gottfried Arnold, Breckling not only questioned the contemporary boundaries of orthodoxy, but also re-negotiated them, integrating elements from older heterodox traditions.
The Kabbalistic “Teaching Panel” of Princess Antonia
Authors: Morlok Elke 
Published: April 2018

Abstract
This article explores the complex interweaving of kabbalistic and Christological concepts within the kabbalistic “teaching panel” (Lehrtafel) of Princess Antonia of Württemberg. The essay discusses the artwork in the context of visual representations of the ten sefirot, the divine attributes or vessels in Jewish mysticism. Executed as an altarpiece for the church in Bad Teinach in Southern Germany, the work integrates the sefirot into a pansophic concept that served devotional and educational purposes with a salvific goal. The article argues that, with the Lehrtafel, Antonia and her teachers created a devotional object that could be accessed by both regular Christian laity and experts who possessed deeper knowledge of Kabbalah.
Domesticating Religious “Fanaticism” in Eighteenth-Century Germany
Authors: Grote Simon 
Published: April 2018

Abstract
The decline of “fanaticism” in eighteenth-century Germany, a myth propagated by self-proclaimed proponents of Enlightenment, continues to shape historians’ representations of the ascendancy of “religious” Enlightenment. To discredit this myth and suggest a means of replacing it, this essay departs from the conventional attention to university theology as a history of ideas and proposes adding a book-historical perspective. Its focus is the German Pietist theologian Joachim Lange (1670–1744). Condemned by critics as a “fanatic” by virtue of his alleged intellectual kinship with French Reformed theologian Pierre Poiret (1646–1719), Lange is best known today for his vehement and ultimately ineffectual opposition to Enlightenment’s theological standard-bearers at the University of Halle. But Lange’s kinship with Poiret was only partial, and the stark contrast between the careers of two of Lange’s textbooks reveals that although his theological star was falling by the 1730s, elements of Lange’s ostensibly outmoded theology continued to find an audience into the nineteenth century, through the enormous commercial success of his Latin grammar.
Forecast Terminology: Composition and Interpretation of Public Weather Forecasts2,3
Authors: Murphy Allan H. , Brown Barbara G. 
Published: April 2018

Worded forecasts, which generally consist of both verbal and numerical expressions, play an important role in the communication of weather information to the general public. However, relatively few studies of the composition and interpretation of such forecasts have been conducted. Moreover, the studies that have been undertaken to date indicate that many expressions currently used in public forecasts are subject to wide ranges of interpretation (and to misinterpretation) and that the ability of individuals to recall the content of worded forecasts is quite limited. This paper focuses on forecast terminology and the understanding of such terminology in the context of short-range public weather forecasts.
The results of previous studies of forecast terminology (and related issues) are summarized with respect to six basic aspects or facets of worded forecasts. These facets include: 1) events (the values of the meteorological variables): 2) terminology (the words used to describe the events); 3) words versus numbers (the use of verbal and/or numerical expressions); 4) uncertainty (the mode of expression of uncertainty); 5) amount of information (the number of items of information); and 6) content and format (the selection of items of information and their placement). In addition, some related topics are treated briefly, including the impact of verification systems, the role of computer-worded forecasts, the implications of new modes of communication, and the use of weather forecasts.
Some conclusions and inferences that can be drawn from this review of previous work are discussed briefly, and a set of recommendations are presented regarding steps that should be taken to raise the level of understanding and enhance the usefulness of worded forecasts. These recommendations are organized under four headings: 1) studies of public understanding, interpretation, and use; 2) management practices; 3) forecaster training and education; and 4) public education.
Summary Report of the Workshop on the Interactions of Climate and Energy
Authors: Knox J. B. , Moses H. , MacCracken M. C. 
Published: April 2018

The joint Industry/DOE Workshop on the Interactions of Climate and Energy was designed to bring the providers of climate information and services together with users and representatives of the oil, gas, coal, and electric utility sectors of the U.S. energy industry. Primary discussion topics included current uses of climate data, the perceived impacts of climatic anomalies on the energy sector, ways to improve the uses of climate data, and recommendations for future research by the climate community. This opportunity for such interaction generated a universal agreement among the participants that more frequent exchanges between the providers and users of climate information be planned and that better communication between the providers and users of climate data and services be established.
The workshop proceedings, which is being published by the Department of Energy, presents studies on the application of existing data to the diagnosis of the climatic component in energy supply and demand and the short-term prediction of regional scale energy requirements. Staff members of the National Oceanic and Atmospheric Administration's (NOAA) National Climate Data Center (NCDC) and Climate Analysis Center (CAC) review the currently available climate data and services. Four panel reports identify and enumerate the impacts of climate on each of the segments of the energy industry and offer recommendations for improvements, further research, and, in some cases, concepts for practical demonstrations of immediate potential value to the pertinent energy sector.
The panel findings and the presentations of the invited speakers contain several common themes: the need for improved data formats, the significant potential benefits of increased lead time for the seasonal climate forecast, and the necessity for improved accuracy in the forecasts of monthly and seasonal means and extremes of temperature and precipitation. Workshop participants fully recognized the difficulty of making “real” progress on some of these commonly stated objectives; however, they also recognized that the benefits of striving to achieve these goals may, indeed, be sufficiently great to justify the quest for progress through focused research efforts.