bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three Approaches to Modeling Gene‐Environment Interactions in Longitudinal Family Data: Gene‐Smoking Interactions in Blood Pressure
Authors: Basson Jacob , Sung Yun Ju , de las Fuentes Lisa , Schwander Karen L. , Vazquez Ana , Rao Dabeeru C. 
Published: December 2015

ABSTRACTBlood pressure (BP) has been shown to be substantially heritable, yet identified genetic variants explain only a small fraction of the heritability. Gene‐smoking interactions have detected novel BP loci in cross‐sectional family data. Longitudinal family data are available and have additional promise to identify BP loci. However, this type of data presents unique analysis challenges. Although several methods for analyzing longitudinal family data are available, which method is the most appropriate and under what conditions has not been fully studied. Using data from three clinic visits from the Framingham Heart Study, we performed association analysis accounting for gene‐smoking interactions in BP at 31,203 markers on chromosome 22. We evaluated three different modeling frameworks: generalized estimating equations (GEE), hierarchical linear modeling, and pedigree‐based mixed modeling. The three models performed somewhat comparably, with multiple overlaps in the most strongly associated loci from each model. Loci with the greatest significance were more strongly supported in the longitudinal analyses than in any of the component single‐visit analyses. The pedigree‐based mixed model was more conservative, with less inflation in the variant main effect and greater deflation in the gene‐smoking interactions. The GEE, but not the other two models, resulted in substantial inflation in the tail of the distribution when variants with minor allele frequency <1% were included in the analysis. The choice of analysis method should depend on the model and the structure and complexity of the familial and longitudinal data.
Many Phenotypes Without Many False Discoveries: Error Controlling Strategies for Multitrait Association Studies
Authors: Peterson Christine B. , Bogomolov Marina , Benjamini Yoav , Sabatti Chiara 
Published: December 2015

ABSTRACTThe genetic basis of multiple phenotypes such as gene expression, metabolite levels, or imaging features is often investigated by testing a large collection of hypotheses, probing the existence of association between each of the traits and hundreds of thousands of genotyped variants. Appropriate multiplicity adjustment is crucial to guarantee replicability of findings, and the false discovery rate (FDR) is frequently adopted as a measure of global error. In the interest of interpretability, results are often summarized so that reporting focuses on variants discovered to be associated to some phenotypes. We show that applying FDR‐controlling procedures on the entire collection of hypotheses fails to control the rate of false discovery of associated variants as well as the expected value of the average proportion of false discovery of phenotypes influenced by such variants. We propose a simple hierarchical testing procedure that allows control of both these error rates and provides a more reliable basis for the identification of variants with functional effects. We demonstrate the utility of this approach through simulation studies comparing various error rates and measures of power for genetic association studies of multiple traits. Finally, we apply the proposed method to identify genetic variants that impact flowering phenotypes in Arabidopsis thaliana, expanding the set of discoveries.
A Review of New Pharmacologic Treatments for Patients With Chronic Heart Failure With Reduced Ejection Fraction
Authors: Nguyen Elaine , Weeda Erin R. , White C. Michael 
Published: December 2015

AbstractHeart failure (HF) impacts an estimated 5.7 million Americans, and its prevalence is projected to increase to more than 8 million Americans in the next 15 years. Key clinical trials have established an evidence‐based foundation for treatment of heart failure with reduced ejection fraction (HFrEF). Ivabradine and sacubitril/valsartan, which inhibit the f‐channel and the angiotensin receptor and neprilysin, respectively, were recently approved by the Food and Drug Administration for HFrEF. In systolic heart failure, treatment with the If inhibitor ivabradine significantly reduced the combined endpoint of cardiovascular mortality or heart failure hospital admission vs placebo (P < .05). In the Prospective Comparison of angiotensin receptor‐neprilysin inhibitor (ARNI) with angiotensin‐converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure trial, sacubitril/valsartan significantly reduced the combined endpoint of cardiovascular death or heart failure hospitalization vs enalapril (P < .001). The place of therapy with ivabradine and sacubitril/valsartan is defined by these trials and their interplay with guideline‐directed medical therapy. Ivabradine and sacubitril/valsartan increase pharmacotherapy options for the treatment of HFrEF but are not yet first‐line agents. Clinical application will be better defined in the coming years as practitioners increase their familiarity with ivabradine and sacubitril/valsartan.
Population Pharmacokinetic and Pharmacodynamic Modeling of AZD4901 and Simulation to Support Dose Selection for the Phase 2a Study
Authors: Xu Hongmei , Li Jianguo , Webber Lorraine , Kakkar Rahul , Chen Yingxue , Al‐Huniti Nidal 
Published: December 2015

AbstractSignificant and reversible reductions in testosterone levels were observed with AZD4901 in both preclinical and clinical testing. A comprehensive population pharmacokinetic/pharmacodynamic (PK/PD) modeling of AZD4901 concentration and testosterone relationship from 3 phase 1 studies was performed using NONMEM to support dose selection for phase 2a development. A 2‐compartment model with first‐order absorption and first‐order elimination best described AZD4901 PK. Circadian rhythm of baseline testosterone concentrations was well described by a cosine function. An indirect response model with inhibition of testosterone production was used to link the AZD4901 concentration to testosterone response. The AZD4901 concentration to yield 50% maximum testosterone suppression (IC50) was estimated to be 230 ng/mL. Based on simulations, following 40 mg twice daily (BID) treatment, the AZD4901 steady‐state trough concentration will be much higher compared to 80 mg once daily (QD). The AZD4901 concentration time above IC50 after 40 mg BID is 84% of the time of the dosing interval compared to only 49% after 80 mg QD. The mean predicted testosterone concentrations at steady state are lower and overall less variable over 24 hours for 40 mg BID dosing compared to 80 mg QD dosing. Population PK and PK/PD analyses demonstrated that AZD4901 40 mg BID is a better dosing strategy to more consistently suppress testosterone during the entire dosing interval. Consequently, 40 mg BID dosing was suggested in a phase 2a trial in females with polycystic ovary syndrome, and the trial resulted in a positive outcome as shown by significant testosterone decrease compared to placebo.
Hindlimb musculature of the largest living rodent Hydrochoerus hydrochaeris (Caviomorpha): Adaptations to semiaquatic and terrestrial styles of life
Authors: García‐Esponda César M. , Candela Adriana M. 
Published: December 2015

ABSTRACTThe caviomorph species Hydrochoerus hydrochaeris (Cavioidea), or capybara, is the largest living rodent. This species is widely distributed, from northern South America to Uruguay and eastern Argentina, inhabiting in a wide variety of densely vegetated lowlands habitats in the proximity of water. Hydrochoerus hydrochaeris not only runs with agility, like other members of the Cavioidea, but it can also swim and dive easily. For these reasons, it has been classified as a cursorial as well as semiaquatic species. However, comprehensive anatomical descriptions of the osteology and myology of the capybara are not available in the literature and analyses on its swimming abilities are still required. We hypothesize that some of the characters of the hindlimb of H. hydrochaeris could reveal a unique morphological arrangement associated with swimming abilities. In this study, an anatomical description of the hindlimb musculature of H. hydrochaeris, and a discussion of the possible functional significance of the main muscles is provided. In addition, we explore the evolution of some myological and osteological characters of the capybara in the context of the cavioids. We concluded that most of the muscular and osteological features of the hindlimb of H. hydrochaeris are neither adaptations to a specialized cursoriality, nor major modifications for an aquatic mode of life. Hydrochoerus hydrochaeris share several features with other cavioids, being a generalized cursorial species in the context of this clade. However, it shows some adaptations of the hindlimb for enhancing propulsion through water, of which the most notable seems to be the shortening of the leg, short tendons of most muscles of the leg, and a well‐developed soleus muscle. These adaptations to a semiaquatic mode of life could have been acquired during the most recent evolutionary history of the hydrochoerids. J. Morphol. 277:286–305, 2016. © 2015 Wiley Periodicals, Inc.
Extracellular matrix‐blood composite injection reduces post‐traumatic osteoarthritis after anterior cruciate ligament injury in the rat
Authors: Proffen Benedikt L. , Sieker Jakob T. , Murray Martha M. , Akelman Matthew R. , Chin Kaitlyn E. , Perrone Gabriel S. , Patel Tarpit K. , Fleming Braden C. 
Published: December 2015

ABSTRACTThe objective of this study was to determine if an injection of a novel extracellular matrix scaffold and blood composite (EMBC) after anterior cruciate ligament (ACL) injury would have a mitigating effect on post‐traumatic osteoarthritis (PTOA) development in rat knees. Lewis rats underwent unilateral ACL transection and were divided into three groups as follows: (1) no further treatment (ACLT; n = 10); (2) an intra‐articular injection of EMBC on day 0 (INJ0; n = 11); and (3) an intra‐articular injection of EMBC on day 14 (INJ14; n = 11). Ten additional animals received capsulotomy only (n = 10, SHAM group). The OARSI histology scoring of the tibial cartilage and micro‐CT of the tibial epiphysis were performed after 35 days. The ratio of intact/treated hind limb forces during gait was determined using a variable resistor walkway. The OARSI cartilage degradation sum score and total degeneration width were significantly greater in the ACLT group when compared to the INJ0 (p = 0.031, and p = 0.005) and INJ14 (p = 0.022 and p = 0.04) group. Weight bearing on the operated limb only decreased significantly in the ACLT group (p = 0.048). In the rat ACL transection model, early or delayed injection of EMBC ameliorated the significant decrease in weight bearing and cartilage degradation seen in knees subjected to ACL transection without injection. The results indicate that the injection of EMBC may slow the process of PTOA following ACL injury and may provide a promising treatment for PTOA. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:995–1003, 2016.
Calculating the hip center of rotation using contralateral pelvic anatomy
Authors: Durand‐Hill Matthieu , Henckel Johann , Satchithananda Keshthra , Sabah Shiraz , Hua Jia , Hothi Harry , Langstaff Ronald J. , Skinner John , Hart Alister 
Published: December 2015

ABSTRACTFailure to place an artificial hip in the optimal center of rotation results in poor hip function and costly complications. The aim of this study was to develop robust methodology to estimate hip center of rotation (hCoR) from preoperative computed tomography (CT) scans, using contralateral anatomy, in patients with unilateral diseased hips. Ten patients (five male, five female) with normal pelvic anatomy, and one patient with a unilateral dysplastic acetabulum were recruited from the London Implant Retrieval center image bank. 3D models of each pelvis were generated using commercial software. Two methods for estimation of hCoR were compared. Method 1 used a mirroring technique alone. Method 2 utilized mirroring and automatic alignment. Predicted versus actual hCoR co‐ordinates were compared using intraclass correlation coefficients and paired T‐tests. Both methods predicted hCoR with excellent agreement to original co‐ordinates (>0.9) in all axes. Both techniques allowed prediction of the hCoR within ± 5 mm in all axes. Both techniques provided useful clinical information for planning acetabular reconstruction in patients with unilateral defects. Method 1 was less complex and is suitable for patients with developmental and degenerative pathologies. Method 2 may provide greater accuracy in a discrete group of patients with normal development prior to pathology (e.g., acetabular fractures). © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1077–1083, 2016.
Micro‐fractional, directional skin tightening: A porcine model
Authors: Russe Elisabeth , Purschke Martin , Farinelli William A. , Wang Ying , Doukas Apostolos G. , Limpiangkanan Wikunda , Sakamoto Fernanda H. , Tam Joshua , Wechselberger Gottfried , Anderson Richard Rox 
Published: December 2015

Background and ObjectiveSkin changes are among the most visible signs of aging. Fractional ablative lasers improve skin quality by making small skin wounds that heal rapidly without scarring. While they improve skin texture and discoloration, there is minimal effect on skin laxity. This study was performed to assess skin shrinkage performed by removing multiple small full‐thickness skin columns with coring needles combined with wound closure.Materials and MethodsIn 5 swine 116 squares (3 cm2) were demarcated for treatment and control sites. In treatment sites 10% of the skin was removed by full‐thickness skin coring needles (19 gauge) and afterwards closed and compressed with an elastic adhesive dressing. This procedure was compared to puncturing the skin with standard hypodermic needles (without tissue removal) and subsequent closure with compressive dressing. Area and shape of sites were measured before and 28 days after treatment.ResultsTest and control sites healed within a week without scarring. Coring with wound closure caused significant shrinkage after 28 days. The treated skin area was reduced by 9% (P < 0.0001) and the direction of shrinkage was influenced by the direction of wound closure. Coring without wound closure and puncturing the skin without tissue removal produced an insignificant 3% decrease in area.ConclusionSignificant minimally invasive skin tightening in a preferred direction can be achieved by removing skin with coring needles followed by wound closure. The direction of shrinkage is influenced by the direction of micro‐hole closure, irrespective of the skin tension lines. This approach may allow reshaping the skin in a desired direction without scarring. Lasers Surg. Med. 48:264–269, 2016. © 2015 Wiley Periodicals, Inc.
The MeteoMet project – metrology for meteorology: challenges and results
Authors: Merlone A. , Lopardo G. , Sanna F. , Bell S. , Benyon R. , Bergerud R. A. , Bertiglia F. , Bojkovski J. , Böse N. , Brunet M. , Cappella A. , Coppa G. , del Campo D. , Dobre M. , Drnovsek J. , Ebert V. , Emardson R. , Fernicola V. , Flakiewicz K. , Gardiner T. , Garcia‐Izquierdo C. , Georgin E. , Gilabert A. , Grykałowska A. , Grudniewicz E. , Heinonen M. , Holmsten M. , Hudoklin D. , Johansson J. , Kajastie H. , Kaykısızlı H. , Klason P. , Kňazovická L. , Lakka A. , Kowal A. , Müller H. , Musacchio C. , Nwaboh J. , Pavlasek P. , Piccato A. , Pitre L. , de Podesta M. , Rasmussen M. K. , Sairanen H. , Smorgon D. , Sparasci F. , Strnad R. , Szmyrka‐ Grzebyk A. , Underwood R. 
Published: December 2015

ABSTRACTThe study describes significant outcomes of the ‘Metrology for Meteorology’ project, MeteoMet, which is an attempt to bridge the meteorological and metrological communities. The concept of traceability, an idea used in both fields but with a subtle difference in meaning, is at the heart of the project. For meteorology, a traceable measurement is the one that can be traced back to a particular instrument, time and location. From a metrological perspective, traceability further implies that the measurement can be traced back to a primary realization of the quantity being measured in terms of the base units of the International System of Units, the SI. These two perspectives reflect long‐standing differences in culture and practice and this project – and this study – represents only the first step towards better communication between the two communities.The 3 year MeteoMet project was funded by the European Metrology Research Program (EMRP) and involved 18 European National Metrological Institutes, 3 universities and 35 collaborating stakeholders including national meteorology organizations, research institutes, universities, associations and instrument companies.The project brought a metrological perspective to several long‐standing measurement problems in meteorology and climatology, varying from conventional ground‐based measurements to those made in the upper atmosphere. It included development and testing of novel instrumentation as well as improved calibration procedures and facilities, instrument intercomparison under realistic conditions and best practice dissemination. Additionally, the validation of historical temperature data series with respect to measurement uncertainties and a methodology for recalculation of the values were included.
Quercetin oppositely regulates insulin‐mediated glucose disposal in skeletal muscle under normal and inflammatory conditions: The dual roles of AMPK activation
Authors: Liu Kang , Mei Fan , Wang Yapu , Xiao Na , Yang Lele , Wang Yilei , Li Jia , Huang Fang , Kou Junping , Liu Baolin , Qi Lian‐Wen 
Published: December 2015

ScopeQuercetin is a dietary flavonoid whose role in the regulation of the activity of insulin remains controversial. Our study aimed to investigate how quercetin and its major metabolite quercetin‐3‐glucuronide (Q‐3‐G) regulate insulin‐mediated glucose disposal in skeletal muscle under normal and inflammatory conditions.Methods and resultsUnder normal conditions, quercetin impaired glucose and insulin tolerance and attenuated insulin‐mediated phosphorylation of Akt substrate of 160 kDa (AS160) and TBC1D1 without affecting Akt activity in male Institute of Cancer Research (ICR) mice. However, under inflammatory conditions, quercetin exhibited an opposite effect in these animals. In C2C12 cells, quercetin also decreased insulin‐stimulated AS160 and TBC1D1 phosphorylation and glucose uptake in the absence of an inflammatory insult, whereas it improved the action of insulin under inflammatory conditions. Knockdown of adenosine 5′‐monophosphate‐activated protein kinase α (AMPKα) blocked the differential effects of quercetin under both conditions. Unlike quercetin, Q‐3‐G had no influence on insulin‐induced phosphorylation of AS160 and TBC1D1 and glucose uptake in C2C12 myotubes under normal conditions. Q‐3‐G displayed a similar regulation with quercetin in glucose disposal under inflammatory conditions.ConclusionQuercetin suppressed insulin‐mediated glucose disposal in skeletal muscle tissue/cells under normal conditions while it ameliorated impaired glucose uptake under inflammatory conditions with activation of AMPK. In contrast, Q‐3‐G ameliorated insulin resistance in skeletal cells under inflammatory conditions without affecting glucose disposal under normal conditions.
Antidepressive‐like effects and antioxidant activity of green tea and GABA green tea in a mouse model of post‐stroke depression
Authors: Di Lorenzo Arianna , Nabavi Seyed Fazel , Sureda Antoni , Moghaddam Akbar Hajizadeh , Khanjani Sedigheh , Arcidiaco Patrizia , Nabavi Seyed Mohammad , Daglia Maria 
Published: December 2015

ScopeGrowing evidence suggests that oxidative stress plays a role in the development of chronic diseases such as cardiovascular disease and some psychiatric disorders. Tea consumption exerts beneficial effects against damage induced by cerebral ischemia‐reperfusion in ischemic stroke and depressive symptoms in depression. The aim of this study was to evaluate, in vivo, the protective activity of green tea (GT) and GABA green tea (GGT) against post‐stroke depression (PSD), a common consequence of stroke.Methods and resultsThe antidepressive‐like effects of GT and GGT were determined by behavioral tests in a mouse model of post‐stroke depression. The antioxidant activity was evaluated by GSH, SOD, and TBARS measurements on mouse brain. The chemical composition of tea extracts was characterized through chromatographic methods. GGT and GT resulted active in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior, and at least in part, antioxidant endogenous defenses. The higher polyphenol, theanine, glutamine, and caffeine content may justify the higher activity found in GGT.ConclusionsThis work represents the first attempt to demonstrate the positive effect of tea, and especially GGT, on post‐stroke depression and to correlate this effect with the antioxidant activity and phytochemical composition of tea.
Impaired recovery from peritoneal inflammation in a mouse model of mild dietary zinc restriction
Authors: Phillips Brett E. , Geletzke Abby K. , Smith Philip B. , Podany Abigail B. , Chacon Alexander , Kelleher Shannon L. , Patterson Andrew D. , Soybel David I. 
Published: December 2015

ScopeMild dietary zinc (Zn) deficiency is wide‐spread in human populations, but the effect on Zn‐dependent processes of immune function and healing are not well understood. The consequences of mild dietary Zn restriction were examined in two mouse models of inflammation and recovery.Methods and resultsMale C57BL/6 mice were fed a Zn adequate diet (ZA, 30 mg Zn/kg diet), or diets containing sub‐optimal Zn levels (ZM, 15 mg Zn/kg diet; ZD, 10 mg Zn/kg diet) for 30 days before a thioglycollate peritonitis challenge. Plasma lipid profiles were distinct, with greater Zn restriction resulting in a greater impact on metabolites. The milder ZM diet was selected for immune studies. Peritoneal macrophages from ZM mice displayed increased phagocytosis and amplified pro‐inflammatory cytokine (IL‐1β, IL‐6, and TNFα) release compared to ZA, at baseline and after a secondary LPS challenge. Splenocytes isolated from ZM mice displayed an increase in IL‐6 and a reduction in anti‐inflammatory IL‐4 compared to ZA. Cytokine levels in plasma were unaltered. Following mechanical manipulation of the intestines to induce ileus, ZM mice had delayed intestinal transit compared to ZA.ConclusionMild Zn deficiency enhances local inflammatory responses, amplifying macrophage functions and delaying recovery from acute insults within the peritoneum.