bluuebunny/crossref_metadata_2025 huggingface dataset:
Verizon Lecture: Why Is It So Difficult to Be an Ethical Leader?
Authors: Ciulla Joanne B.
Published: July 2018

In some ways it is more important to understand why it is difficult for leaders to be ethical than it is to understand how to be an ethical leader. By being aware of the common temptations and moral pitfalls of leadership, leaders are better able to avoid them. Like all areas of applied ethics, leadership has its own set of problems that stem from the roles leaders play and their relationship and responsibilities to followers and others. Moreover, leadership is ethically challenging because it and requires control of the self, the ego, and the use of power. This article examines some of the aspects of leadership that make it ethically difficult.
Workplace support and breastfeeding duration: The mediating effect of breastfeeding intention and self‐efficacy
Authors: Wallenborn Jordyn T. , Perera Robert A. , Wheeler David C. , Lu Juan , Masho Saba W.
Published: July 2018

Background

Given the large proportion of mothers in the United States work force, understanding the implications of workplace support on breastfeeding outcomes is an important public health priority. The current study investigates if (a) workplace support directly influences the working mothers’ breastfeeding intention, self‐efficacy, and duration, and (b) workplace support indirectly influences breastfeeding duration through the mediating effect of breastfeeding intention and self‐efficacy.

Methods

Data from the longitudinal Infant Feeding Practices Survey II were analyzed. The main predictor variable, workplace support, was based on a Likert scale from “not at all supportive” to “very supportive.” Both mediators, exclusive breastfeeding intention and self‐efficacy, were dichotomized (yes; no) while the study outcome, breastfeeding duration, was continuous. Structural equation modeling was used to obtain direct and indirect effects of breastfeeding intention and confidence in attaining breastfeeding goals.

Results

After adjusting for confounders, there was a statistically significant direct effect between self‐efficacy, breastfeeding intention, and breastfeeding duration. A statistically significant indirect effect of workplace support on breastfeeding duration through self‐efficacy in attaining breastfeeding goals was also observed. The mediation ratios of the indirect effects showed that self‐efficacy in attaining breastfeeding goals accounted for 40.8% (P‐value=0.032) of the total effect; however, all other mediation ratios did not show statistical significance.

Conclusions

Self‐efficacy is an important predictor for breastfeeding duration. Workplaces may help bolster women's self‐efficacy by providing environments that are supportive to breastfeeding working mothers. Future research is needed to identify breastfeeding policies that boost self‐efficacy.
Inclusive sound and music serious games in a large‐scale responsive environment
Authors: Mandanici Marcella , Altieri Federico , Rodà Antonio , Canazza Sergio
Published: July 2018

In the last years, applications based on large‐scale responsive environments have risen up as a convincing aid for learning simple as well as complex concepts in a playful way. The full‐body interaction that characterizes these environments supports different learning styles and it is particularly fit for inclusion of participants with disabilities, due to its richness in emotional engagement and ease of use. This paper contains a short review of some serious games developed on a large‐scale responsive environment and devoted to music teaching and training of blind children. Authors present technology‐enhanced learning activities with the employment of three experimental applications: Harmonic Walk for teaching tonal harmony and melody harmonization; Jazz Improvisation for music re‐composition and score parts listening; and Following the Cuckoo Sound for helping blind children to walk straight. Quantitative and qualitative results report a great user engagement and a satisfying amount of successful records in formal task activities, which encourage further research to enhance education through large‐scale responsive environments applications and full‐body interaction. Moreover, the experience gained with blind children emphasizes the inclusive opportunities of these environments for the training and rehabilitation of disabled people.
Knockdown of HIF‐1α impairs post‐ischemic vascular reconstruction in the brain via deficient homing and sprouting bmEPCs
Authors: Liu Yang , Ran He , Xiao Yaping , Wang Hongjin , Chen Yi , Chen Weihai , Xu Xiaoyu
Published: July 2018

Although the critical role of hypoxia inducible factor‐1α (HIF‐1α) in cerebral neovascularization after stroke has been well characterized, the details regarding the regulation of endothelial progenitor cell (EPC)‐dependent neovascularization by HIF‐1α are not completely understood. Using lentiviral shRNA to knockdown HIF‐1α, we showed that HIF‐1α plays a central role in bone marrow‐derived EPC (bmEPC) homing and sprouting in the post‐acute stage of ischemic Sprague Dawley (SD) rat brains. First, knockdown of HIF‐1α decreased the homing of both endogenous and exogenous bmEPCs to the ischemic brain. Additionally, the knockdown impaired the incorporation and sprouting of bmEPCs in the ischemic brain. In vitro, knockdown of HIF‐1α inhibited the spheroid sprouting and tube formation of bmEPCs. Mechanically, the HIF‐1α‐dependent recruitment of bmEPCs to the ischemic brain was relative to the CXCL12/CXCR4 axis and HMGB1, which were relative to astrocytes. In addition, the loss of HIF‐1α resulted in deficient expression levels of VEGF‐A, Flk‐1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes. These findings suggested that HIF‐1α implicates in bmEPC homing via CXCL12/CXCR4 and HMGB1 and that it promotes bmEPC sprouting via VEGF‐A/flk1‐NRP1/Dll4.
Endocannabinoid regulation of homeostatic feeding and stress‐induced alterations in food intake in male rats
Authors: Sticht Martin A , Lau David J , Keenan Catherine M , Cavin Jean‐Baptiste , Morena Maria , Vemuri Venkata Kiran , Makriyannis Alexandros , Cravatt Benjamin F , Sharkey Keith A , Hill Matthew N
Published: July 2018

Background and Purpose

Stress is known to reduce food intake. Many aspects of the stress response and feeding are regulated by the endocannabinoid system, but the roles of anandamide (AEA) and 2‐arachidonoyl glycerol (2‐AG) in stress‐induced anorexia are unclear.

Experimental Approach

Effects of acute restraint stress on endocannabinoids were investigated in male Sprague–Dawley rats. Systemic and central pharmacological inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) was used to assess the effects of elevated AEA and 2‐AG on homeostatic feeding and on food consumption after stress. Animals were pretreated with the FAAH inhibitor, PF‐04457845, or the MAGL inhibitor, MJN110, before 2 h acute restraint stress or 2 h homecage period without food.

Key Results

Restraint stress decreased hypothalamic and circulating AEA, with no effect in the gastrointestinal tract, while 2‐AG content in the jejunum (but not duodenum) was reduced. PF‐04457845 (30 μg), given i.c.v., attenuated stress‐induced anorexia via CB1 receptors, but reduced homeostatic feeding in unstressed animals through an unknown mechanism. On the other hand, systemic administration of MJN110 (10 mg·kg−1) reduced feeding, regardless of stress or feeding status and inhibited basal intestinal transit in unstressed rats. The ability of MAGL inhibition to reduce feeding in combination with stress was independent of CB1 receptor signalling in the gut as the peripherally restricted CB1 receptor antagonist, AM6545 did not block this effect.

Conclusions and Implications

Our data reveal diverse roles for 2‐AG and AEA in homeostatic feeding and changes in energy intake following stress.

Linked Articles

This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations
Authors: de Witte Wilhelmus E A , Versfelt Joost W , Kuzikov Maria , Rolland Solene , Georgi Victoria , Gribbon Philip , Gul Sheraz , Huntjens Dymphy , van der Graaf Piet Hein , Danhof Meindert , Fernández‐Montalván Amaury , Witt Gesa , de Lange Elizabeth C M
Published: July 2018

Background and Purpose

Target binding kinetics influence the time course of the drug effect (pharmacodynamics) both (i) directly, by affecting the time course of target occupancy, driven by the pharmacokinetics of the drug, competition with endogenous ligands and target turnover, and (ii) indirectly, by affecting signal transduction and homeostatic feedback. For dopamine D2 receptor antagonists, it has been hypothesized that fast receptor binding kinetics cause fewer side effects, because part of the dynamics of the dopaminergic system is preserved by displacement of these antagonists.

Experimental Approach

Target binding kinetics of D2 receptor antagonists and signal transduction after dopamine and D2 receptor antagonist exposure were measured in vitro. These data were integrated by mechanistic modelling, taking into account competitive binding of endogenous dopamine and the antagonist, the turnover of the second messenger cAMP and negative feedback by PDE turnover.

Key Results

The proposed signal transduction model successfully described the cellular cAMP response for 17 D2 receptor antagonists with widely different binding kinetics. Simulation of the response to fluctuating dopamine concentrations revealed that a significant effect of the target binding kinetics on the dynamics of the signalling only occurs at endogenous dopamine concentration fluctuations with frequencies below 1 min−1.

Conclusions and Implications

Signal transduction and feedback are important determinants of the time course of drug effects. The effect of the D2 receptor antagonist dissociation rate constant (koff) is limited to the maximal rate of fluctuations in dopamine signalling as determined by the dopamine koff and the cAMP turnover.
Collateral resistance to taxanes in enzalutamide‐resistant prostate cancer through aberrant androgen receptor and its variants
Authors: Shiota Masaki , Dejima Takashi , Yamamoto Yoshiaki , Takeuchi Ario , Imada Kenjiro , Kashiwagi Eiji , Inokuchi Junichi , Tatsugami Katsunori , Kajioka Shunichi , Uchiumi Takeshi , Eto Masatoshi
Published: July 2018

Currently, the optimal sequential use of androgen receptor (AR) axis‐targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide‐resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane‐resistant cells showed no collateral resistance to enzalutamide; taxane‐resistant cells expressed comparable protein levels of full‐length AR and AR variants. Knockdown of both full‐length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full‐length AR rendered cells resistant to taxanes. Consistently, the prostate‐specific antigen response and progression‐free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.
Early adversities, family support, and child well‐being: The moderating role of environmental sensitivity
Authors: Scrimin Sara , Osler Gabriele , Pozzoli Tiziana , Moscardino Ughetta
Published: July 2018

Background

Children's well‐being in terms of physical, emotional, social, and academic outcomes is largely influenced by environmental characteristics, with the presence of childhood adversities constituting a risk factor, and support provided by the family working as a protective factor. Yet the role of individual differences in children's sensitivity to environmental influences in these relations is still underexplored; following the differential susceptibility model, it could be a potential moderator.

Methods

Participants were 227 children (mean age 7.05 years) and their parents, who were interviewed on the number of experienced childhood adversities and family supportive resources, as well as on child well‐being and environmental sensitivity.

Results

Path analysis showed that, as expected, the number of family adversities was negatively associated with children's physical and emotional comfort and perceived academic performance, whereas supportive resources provided by the family were positively related to child well‐being. Of importance, children's environmental sensitivity moderated these associations emphasizing the negative effects of a stressful environment on physical and social functioning and increasing the positive effect of a supportive environment on children's social performance.

Conclusions

The present data lend support to a diathesis–stress model, with highly sensitive children being more susceptible to both negative and positive environmental influences in relation to well‐being. Interventions may focus on providing clinical support to these children in the context of particularly aversive environments.
Effect of low‐dose dexamethasone on patients with elevated early follicular phase progesterone level and pregnancy outcomes in IVF‐ET treatment: A randomized controlled clinical trial
Authors: Liu Shan , Shi Lin , Wang Tao , Shi Juanzi
Published: July 2018

Objective

To evaluate the effect of low‐dose dexamethasone on patients with elevated early follicular progesterone levels in IVF‐ET treatment.

Design

Randomized controlled trial.

Setting

In vitro fertilization (IVF) centre.

Patient(s)

A total of 459 patients undergoing a first IVF/ICSI cycle.

Intervention(s)

If progesterone concentration exceeded 1.9 nmol/L on days 3‐4 of ovarian stimulation, the patients in dexamethasone (DEX) group were treated with oral dexamethasone 0.75 mg/d, and the patients in control group received no extra treatment.

Main outcome measure

The cumulative live‐birth rate (per cycle started) in 2 years.

Results

The total dose of gonadotropins (1987 ± 536 IU in DEX group vs 2135 ± 701 IU in control group, P = 0.009) and the serum concentrations of progesterone on human chorionic gonadotropin (HCG) day (3.1 ± 1.4 nmol/L in DEX group vs 4.0 ± 1.3 nmol/L in control group, P < 0.001) were both significantly lower in DEX group than that in control. No significant differences between the two groups were observed in the number of oocytes, two pronuclear (2PN) embryos and clinical pregnancy rate. In addition, the cumulative live‐birth rate was significantly higher in the DEX group than that in controls (70.0% vs 61.1%, P = 0.029, 95% confidence interval: 1.01‐2.19).

Conclusion(s)

Progesterone secretion can be suppressed by dexamethasone, and dexamethasone may sensitize the ovary to gonadotropin stimulation in IVF treatment. In addition, the cumulative live‐birth rate was significantly higher in the DEX group than in controls, and the obstetric and neonatal outcomes support the safety of DEX treatment in IVF.
A comparison of physical activity from Actigraph GT3X+ accelerometers worn on the dominant and non‐dominant wrist
Authors: Buchan Duncan S. , McSeveney Fiona , McLellan Gillian
Published: July 2018

The purpose of this study was to evaluate the agreement between several activity measures using raw acceleration data from accelerometers worn concurrently on the dominant and non‐dominant wrist. Fifty‐five adults (31·9 ± 9·7 years, 26 males) wore two ActiGraph GT3X+ monitors continuously for 1 day, one on their non‐dominant wrist and the other on their dominant wrist. Paired t‐tests were undertaken with sequential Holm‐Bonferroni corrections to compare wear time, moderate‐vigorous physical activity (MVPA), time spent in 10‐min bouts of MVPA (MVPA10 min) and the average magnitude of dynamic wrist acceleration (ENMO). Level of agreement between outcome variables from the wrists was examined using intraclass correlation coefficients (ICC, single measures, absolute agreement) with 95% confidence intervals and limits of agreement (LoA). Time spent across acceleration levels in 40 mg resolution were also examined. There were no significant differences between the non‐dominant and dominant wrist for ENMO, wear time, MVPA or MVPA10 min. Agreement between wrists was strong for most outcomes (ICC ≥0·92) including wear time, ENMO, MVPA, MVPA10 min and the distribution of time across acceleration levels. Agreement was strong in the low acceleration bands (ICC = 0·970 and 0·922) with a mean bias of 3·08 min (LoA −55·18 to 61·34) and −5·43 (LoA −43·47 to 32·62). In summary, ENMO, MVPA, MVPA10 min, wear time and the distribution of time across acceleration levels compared well at the group level. The LOA from the two lowest acceleration levels suggest further work over a longer monitoring period is needed to determine whether outputs from each wrist are comparable.
Belatacept for maintenance immunosuppression in cardiothoracic transplantation: The potential frontier
Authors: Ensor Christopher R. , Goehring Kimberly C. , Iasella Carlo J. , Moore Cody A. , Lendermon Elizabeth A. , McDyer John F. , Morrell Matthew R. , Sciortino Christopher M. , Venkataramanan Raman , Wiland Anne M.
Published: July 2018

Current immunosuppressive regimens with calcineurin inhibitors have improved the management of patients after transplantation. However, their adverse effects are linked to increased morbidity and limit the long‐term survival of heart and lung transplant recipients. Belatacept, a costimulation inhibitor interfering with the interaction between CD28 on T cells and the B7 ligands on antigen presenting cells, has shown success and is currently approved for use in renal transplant recipients. Furthermore, it lacks many of the cardiovascular, metabolic, neurologic, and renal adverse of effects of calcineurin inhibitors that have the largest impact on long‐term survival in cardiothoracic transplant. Additionally, it requires no therapeutic drug monitoring and is only administered once a month. Limitations to belatacept use have been observed that must be considered when comparing immunosuppression options. Despite this, maintenance immunosuppression with belatacept has the potential to improve outcomes in cardiothoracic transplant recipients, as it has with kidney transplant recipients. However, no large clinical trials investigating belatacept for maintenance immunosuppression in heart and lung transplant recipients exist. There is a large need for focused research of belatacept in cardiothoracic transplantation. Belatacept is a viable treatment option for maintenance immunosuppression, and it is reasonable to pursue more evidence in cardiothoracic transplant recipients.
Short‐term outcomes of multicenter prospective cohort study of gastric endoscopic resection: ‘Real‐world evidence’ in Japan
Authors: Suzuki Haruhisa , Takizawa Kohei , Hirasawa Toshiaki , Takeuchi Yoji , Ishido Kenji , Hoteya Shu , Yano Tomonori , Tanaka Shinji , Endo Masaki , Nakagawa Masahiro , Toyonaga Takashi , Doyama Hisashi , Hirasawa Kingo , Matsuda Mitsuru , Yamamoto Hironori , Fujishiro Mitsuhiro , Hashimoto Satoru , Maeda Yuki , Oyama Tsuneo , Takenaka Ryuta , Yamamoto Yoshinobu , Naito Yuji , Michida Tomoki , Kobayashi Nozomu , Kawahara Yoshiro , Hirano Masaaki , Jin Mario , Hori Shinichiro , Niwa Yasumasa , Hikichi Takuto , Shimazu Taichi , Ono Hiroyuki , Tanabe Satoshi , Kondo Hitoshi , Iishi Hiroyasu , Ninomiya Motoki ,   Ichiro Oda for J‐WEB/EGC group
Published: July 2018

Objectives

A Japanese multicenter prospective cohort study examining endoscopic resection (ER) for early gastric cancer (EGC) has been conducted using a Web registry developed to determine the short‐term and long‐term outcomes based on absolute and expanded indications. We hereby present the short‐term outcomes of this study.

Methods

All consecutive patients with EGC or suspected EGC undergoing ER at 41 participating institutions between July 2010 and June 2012 were enrolled and prospectively registered into the Web registry. The baseline characteristics were entered before ER, and the short‐term outcomes were collected at 6 months following ER.

Results

Nine thousand six hundred and sixteen patients with 10 821 lesions underwent ER (endoscopic submucosal dissection [ESD]: 99.4%). The median procedure time was 76 min, and R0 resections were achieved for 91.6% of the lesions. Postoperative bleeding and intraoperative perforation occurred in 4.4% and 2.3% of the patients, respectively. Significant independent factors correlated with a longer procedure time (120 min or longer) were as follows: tumor size >20 mm, upper‐third location, middle‐third location, local recurrent lesion, ulcer findings, gastric tube, male gender, and submucosa. Histopathologically, 10 031 lesions were identified as common‐type gastric cancers. The median tumor size was 15 mm. Noncurative resections were diagnosed for 18.3% of the lesions. Additional surgery was performed for 48.6% (824 lesions) of the 1695 noncurative ER lesions with a possible risk of lymph node (LN) metastasis. Among them, 64 (7.8%) exhibited LN metastasis.

Conclusions

This multicenter prospective study showed favorable short‐term outcomes for gastric ESD.
Capacity of a body shape index and body roundness index to identify diabetes mellitus in Han Chinese people in Northeast China: a cross‐sectional study
Authors: Zhao Q. , Zhang K. , Li Y. , Zhen Q. , Shi J. , Yu Y. , Tao Y. , Cheng Y. , Liu Y.
Published: July 2018

Aim

To assess the capacity of a body shape index and body roundness index to identify people with diabetes mellitus and those with prediabetes, and to determine whether a body shape index and/or body roundness index is superior to the traditional overall adiposity index, BMI, in Han Chinese people in Northeast China.

Methods

A total of 15 078 participants were enrolled from Jilin province in 2012 using a multi‐stage stratified random cluster sampling method. Demographic data were collected, and anthropometric indices and biochemical indices were measured. Receiver‐operating characteristic curves were used to compare the validity of each anthropometric index, and the area under the receiver‐operating characteristic curve was calculated for each anthropometric index.

Results

Body roundness index had the highest areas under the receiver‐operating curve for prediabetes, diagnosed diabetes and undiagnosed diabetes in both men and women (all P<0.01). The optimum threshold values for body roundness index for prediabetes, undiagnosed diabetes and diagnosed diabetes, respectively, were 2.8, 3.7 and 3.3 in men, and 3.4, 3.8 and 3.6 in women. The cumulative proportions of prediabetes, undiagnosed diabetes and diagnosed diabetes identified by the optimum threshold values of body roundness index were 79.2%, 67.5% and 77.0% (82.3%, 62.5% and 75.3% in men; 74.6%, 74.9% and 78.3% in women), respectively.

Conclusions

BMI, a body shape index and body roundness index may identify the presence of diabetes. Among the three anthropometric indices, BMI had the weakest association with diabetes. Body roundness index is an alternative index for assessing diabetes in Han Chinese people in Northeast China.
Left atrial function in children and young adult cancer survivors treated with anthracyclines
Authors: Patel Nisha R. , Chyu Christopher K. , Satou Gary M. , Halnon Nancy J. , Nguyen Kim‐Lien
Published: July 2018

Background

The left atrium (LA) modulates left ventricular filling pressure and is a strong prognosticator in heart failure. Although anthracycline exposure may lead to impaired left ventricular (LV) function, the effects on LA function are not well‐described in the younger population. We aim to evaluate LA function in children exposed to anthracyclines.

Methods

Children exposed to anthracyclines with pre‐ and post‐treatment echocardiographic imaging were enrolled. Measures of LA function (LA ejection fraction [LA EF], global longitudinal strain [GLS], and peak GLS rate) were quantified using 2D speckle tracking echocardiography pre‐ and post‐anthracycline therapy and were compared. Segments with poor tracking were excluded.

Results

Fifty‐five children (age 13 [SD 5] years) treated with anthracyclines were evaluated. LA EF, GLS, and peak GLS rate were lower after anthracycline exposure. Mean changes were as follows: LA EF (pre‐73.5 [SD 7.7]% vs post‐70.6 [SD 8.2]%, P = 0.06), GLS (−34.2 [SD 8.4]% vs −31.9 [SD 7.1]%, P = 0.09), peak GLS rate (2.2 [SD 0.8] s−1 vs 2.0 [SD 0.6] s−1, P = 0.18). When stratified by pre‐ (≤12 years old) vs post‐puberty (>12 years old), prepubescent patients (n = 21) had statistically significant changes in pre/post LA GLS (P = 0.01) and LA EF (P = 0.01). In models adjusted for radiation dose, age, gender, body surface area, or cumulative anthracycline dose, there were no significant relationships in the absolute difference between pre/post LA EF (P = 0.34) or LA GLS (P = 0.18).

Conclusions

In children exposed to anthracyclines, short‐term effects on LA function were minimal in those with preserved LV EF. Age‐dependent LA susceptibility to anthracycline requires further study.
Subclinical cardiac disease in ankylosing spondylitis
Authors: Ozen Selin , Ozen Anil , Unal Ertekin U. , Tufekcioglu Omac , Ataman Sebnem , Yalcin Ayse P.
Published: July 2018

Objectives

To investigate aortic stiffness and subclinical left ventricular systolic dysfunction in ankylosing spondylitis (AS) patients.

Methods

A cross‐sectional study of 55 AS patients being treated with antitumor necrosis factor alpha (anti–TNF‐α) biological agents, conventional synthetic disease‐modifying antirheumatic drugs (csDMARDS), and non steroidal anti‐inflammatory drugs (NSAIDs) and 20 controls matched for conventional cardiovascular risk factors. Aortic stiffness, ejection fraction, and left ventricular global longitudinal strain (LVGLS) were evaluated using transthoracic echocardiography and 2D Doppler echocardiography.

Results

Aortic stiffness was higher in AS patients when compared to controls (P = 0.009). Stiffness increased in those being treated with csDMARDs when compared to the control group and those on anti–TNF‐α biologics (P ˂0.001). AS patients’ LVGLS values were worse than those of the control group (P < 0.001) and also worse in patients on csDMARDs and anti–TNF‐α biologics when compared to those being treated with NSAIDs (P < 0.001).

Conclusions

Subclinical cardiac dysfunction occurs in AS patients despite well controlled musculoskeletal disease. Aortic stiffness and LVGLS increases in AS patients. Anti‐TNF biological agents may somewhat protect arterial compliance. We believe that all AS patients should be investigated for cardiac dysfunction and followed up accordingly.
Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain
Authors: King Anna N. , Sehgal Amita
Published: July 2018

A central question in the circadian biology field concerns the mechanisms that translate ~24‐hr oscillations of the molecular clock into overt rhythms. Drosophila melanogaster is a powerful system that provided the first understanding of how molecular clocks are generated and is now illuminating the neural basis of circadian behavior. The identity of ~150 clock neurons in the Drosophila brain and their roles in shaping circadian rhythms of locomotor activity have been described before. This review summarizes mechanisms that transmit time‐of‐day signals from the clock, within the clock network as well as downstream of it. We also discuss the identification of functional multisynaptic circuits between clock neurons and output neurons that regulate locomotor activity.
Peripheral delta opioid receptors mediate duloxetine antiallodynic effect in a mouse model of neuropathic pain
Authors: Ceredig Rhian Alice , Pierre Florian , Doridot Stéphane , Alduntzin Unai , Salvat Eric , Yalcin Ipek , Gaveriaux‐Ruff Claire , Barrot Michel , Massotte Dominique
Published: July 2018

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP‐expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP‐positive populations using a knock‐in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP‐positive small peptidergic sensory neurons (calcitonin gene‐related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP‐positive free nerve endings in the skin. These changes were not present in nerve‐injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine‐treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing.
Soil aeration: the relation between air‐filled pore volume and redox potential
Authors: Dorau K. , Luster J. , Mansfeldt T.
Published: July 2018

The soil water content affects rates of oxygen diffusion and redox potentials (EH). When water‐saturated soils become aerated, a switch from reducing to oxidizing conditions occurs. However, limited information is available on the air‐filled pore volume (ϵ) at which this shift happens. To obtain values of ϵ, undisturbed soil cores were taken from a Fluvisol and a Gleysol that differed in structure and clay content. Experiments on submergence and drying following a new experimental design were performed in the laboratory. After submergence, the cores were sealed with a glass hood to exclude oxygen and to achieve reducing conditions (EH < −100 mV). We then aerated the sample by removal of glass plugs in the hood and measured EH consecutively by platinum (Pt) electrodes and ϵ by matric potential readings on an hourly basis. From the drying curve we determined two characteristic values: (i) ϵPt reaction indicates the air‐filled pore volume at which a response of the Pt electrode to contact with oxygen occurs (i.e. EH increase > 5 mV hour−1) and (ii) ϵPt aeration indicates when oxidizing soil conditions are present (i.e. EH > 300 mV at pH 7). The Fluvisol was characterized by an ϵPt reaction value of 0.036 ± 0.006 cm3 cm−3 and an ϵPt aeration value of 0.047 ± 0.005, whereas for the Gleysol these values were 0.048 ± 0.008 and 0.085 ± 0.007 cm3 cm−3, respectively. We aimed to obtain such characteristic values for different soils to estimate the aeration status of a soil when ϵ is known, but EH measurements were unavailable.

Highlights

We studied the relation between EH and air‐filled pore volume (ϵ) for two soils varying in texture.

Two characteristic ϵ values are proposed: ϵPt reaction (EH increases > 5 mV hour−1) and ϵPt aeration (EH > 300 mV at pH7).

ϵPt aeration was larger for a clayey Gleysol than a sandy Fluvisol, but ϵPt reaction was similar.

Small‐scale heterogeneity in soil structure had no effect on the EH–ϵ relation.
Multiple‐stressor effects on freshwater fish: Importance of taxonomy and life stage
Authors: Lange Katharina , Bruder Andreas , Matthaei Christoph D. , Brodersen Jakob , Paterson Rachel A.
Published: July 2018

Interactions among multiple anthropogenic stressors threaten freshwater fish and pose challenges for fisheries management and conservation. Previous studies of multiple‐stressor effects on freshwater fish suggest a prevalence of antagonistic interactions. However, taxonomy, life stage and/or environmental context likely modify the magnitude and direction of fish responses to multiple stressors. Stressor intensity, impact mechanism, exposure time and ecosystem size may further affect interaction outcomes. Large‐scale studies quantifying how these variables moderate stressor interactions are lacking. To address this knowledge gap, we performed a meta‐analysis of 29 factorial multiple‐stressor experiments to examine the influence of seven potential moderator variables on the magnitude and direction of stressor interactions. Using weighted random‐effects meta‐analytic models, we demonstrate the importance of taxonomic identity and life stage for interaction outcomes. In particular, Cypriniformes showed stronger antagonisms than Salmoniformes, as did larval fish compared to juveniles. Interaction outcomes also varied among the measured fish responses with survival yielding stronger antagonisms than biomass. Increasing experimental duration and volume of the experimental units both drove interactions towards synergisms, supporting findings from previous studies that synergisms take time and space to develop. In an era when the number of stressors affecting freshwater systems is increasing rapidly, our study provides a vital step towards identifying generalities in multiple‐stressor outcomes and thus improved predictions of multiple‐stressor impacts. Furthermore, our meta‐analysis complements studies in real streams, rivers and lakes by providing an experimentally derived context for the growing number of multiple‐stressor assessments in research, management and conservation of freshwater fish.
The Theory and Practice of Corporate Risk Management: Evidence from the Field
Authors: Giambona Erasmo , Graham John R. , Harvey Campbell R. , Bodnar Gordon M.
Published: July 2018

We survey more than 1,100 risk managers from around the world regarding their risk management policies. We find evidence consistent with some traditional theories of risk management, but not with all. We then study “why” or “why not” firms hedge and find that almost 90% of risk managers in nonfinancial firms hedge to increase expected cash flow. We also find that 70% to 80% of risk managers hedge to smooth earnings or to satisfy shareholders’ expectations. Our analysis also suggests that regulatory changes implemented to increase market stability (e.g., Dodd‐Frank Act) could discourage corporate hedging. Finally, we provide evidence regarding hedging in six areas of risk: interest rate, foreign exchange, commodity, energy, credit, and geopolitical. We find that operational hedging is more common than financial hedging in all risk areas except foreign exchange.
Late Quaternary climate legacies in contemporary plant functional composition
Authors: Blonder Benjamin , Enquist Brian J. , Graae Bente J. , Kattge Jens , Maitner Brian S. , Morueta‐Holme Naia , Ordonez Alejandro , Šímová Irena , Singarayer Joy , Svenning Jens‐Christian , Valdes Paul J. , Violle Cyrille
Published: July 2018

The functional composition of plant communities is commonly thought to be determined by contemporary climate. However, if rates of climate‐driven immigration and/or exclusion of species are slow, then contemporary functional composition may be explained by paleoclimate as well as by contemporary climate. We tested this idea by coupling contemporary maps of plant functional trait composition across North and South America to paleoclimate means and temporal variation in temperature and precipitation from the Last Interglacial (120 ka) to the present. Paleoclimate predictors strongly improved prediction of contemporary functional composition compared to contemporary climate predictors, with a stronger influence of temperature in North America (especially during periods of ice melting) and of precipitation in South America (across all times). Thus, climate from tens of thousands of years ago influences contemporary functional composition via slow assemblage dynamics.
Extending the Latent Dirichlet Allocation model to presence/absence data: A case study on North American breeding birds and biogeographical shifts expected from climate change
Authors: Valle Denis , Albuquerque Pedro , Zhao Qing , Barberan Albert , Fletcher Robert J.
Published: July 2018

Understanding how species composition varies across space and time is fundamental to ecology. While multiple methods having been created to characterize this variation through the identification of groups of species that tend to co‐occur, most of these methods unfortunately are not able to represent gradual variation in species composition. The Latent Dirichlet Allocation (LDA) model is a mixed‐membership method that can represent gradual changes in community structure by delineating overlapping groups of species, but its use has been limited because it requires abundance data and requires users to a priori set the number of groups. We substantially extend LDA to accommodate widely available presence/absence data and to simultaneously determine the optimal number of groups. Using simulated data, we show that this model is able to accurately determine the true number of groups, estimate the underlying parameters, and fit with the data. We illustrate this method with data from the North American Breeding Bird Survey (BBS). Overall, our model identified 18 main bird groups, revealing striking spatial patterns for each group, many of which were closely associated with temperature and precipitation gradients. Furthermore, by comparing the estimated proportion of each group for two time periods (1997–2002 and 2010–2015), our results indicate that nine (of 18) breeding bird groups exhibited an expansion northward and contraction southward of their ranges, revealing subtle but important community‐level biodiversity changes at a continental scale that are consistent with those expected under climate change. Our proposed method is likely to find multiple uses in ecology, being a valuable addition to the toolkit of ecologists.
Performance enhancement of biological methanation with trickle bed reactors by liquid flow modulation
Authors: Ullrich Timo , Lemmer Andreas
Published: July 2018

Experiments were carried out to investigate the influence of liquid flow modulation of trickle bed reactors (TBR) on biological hydrogen methanation (BHM). The modulation promises to improve the gas‐liquid mass transfer and has already been demonstrated in trickle bed reactors of other fields of application. Therefore, the influence of four different circulation intervals with pauses from two to 1,440 min was investigated in TBR for BHM. The results showed that as pause intervals without sprinkling became longer, the methane content increased from 88.61 ± 1.58 vol‐% at a circulation interval of 2 min to up to 97.19 ± 0.46 vol‐% at a circulation interval of 1,440 min. The analysis of the process liquid indicated a stable biological process at any trial phase. This study demonstrated that the performance of TBR on BHM can be significantly improved by liquid flow modulation, thus significantly reducing operating costs.
Potency estimates for recombinant factor IX in the one‐stage clotting assay are influenced by more than just the choice of activated partial thromboplastin time reagent
Authors: Wilmot Helen V. , Gray Elaine
Published: July 2018

The activated partial thromboplastin time (APTT) one‐stage clotting (OSC) assay is used to potency label factor IX (FIX) therapeutics and to monitor the treatment of deficient patients. Studies have highlighted differences in potency estimates for FIX therapeutics depending on what activator type the APTT reagent contains. During the study to replace the 4th International Standard (IS) for FIX Concentrate, it was noted that for the recombinant FIX (rFIX) candidates, a potency difference of 20% was obtained by some between laboratories using the reagent DAPTTIN.

This study was designed to investigate this discrepancy.

Two plasma‐derived (pdFIX) and 2 rFIX materials were assayed against the 4th IS for FIX concentrate (07/182) using the OSC assay. Three different APTT reagents were used (DAPTTIN, SynthAFax and SynthASil), plus 4 different activation times.

The pdFIX samples were not affected by activation time or APTT reagent, with expected potencies recovered in all assays and at all activation times. For rFIX, expected potencies were recovered using SynthASil, but SynthAFax generated potencies around 20% lower. This was consistent across the activation times. For DAPTTIN, potencies for rFIX dropped progressively and by up to 30% as activation time increased from 120 to 300 seconds.

This study demonstrates that activation time as well as choice of APTT reagent can result in discrepancies in the potency estimation of rFIX. These factors should be taken into account when assaying rFIX.
Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non‐alcoholic fatty liver disease: A prospective, single‐arm trial (LEAD trial)
Authors: Sumida Yoshio , Murotani Kenta , Saito Miyoko , Tamasawa Atsuko , Osonoi Yusuke , Yoneda Masashi , Osonoi Takeshi
Published: July 2018

Aims

No pharmacological therapies are approved for non‐alcoholic fatty liver disease (NAFLD). Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, has been developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this prospective, single‐arm study is to evaluate the efficacy of luseogliflozin on hepatic fat content and glycated hemoglobin (HbA1c) in T2DM patients with NAFLD.

Methods

Forty T2DM patients with NAFLD were treated with luseogliflozin 2.5 mg/day for 24 weeks. Primary end‐points were changes in HbA1c and hepatic steatosis evaluated by magnetic resonance imaging–hepatic fat fraction from baseline. Secondary end‐points were changes in metabolic and hepatic function‐related parameters, including hepatic fibrosis markers (Fibrosis‐4 index, NAFLD fibrosis score, type IV collagen 7S. and Wisteria floribunda agglutinin‐positive Mac‐2 binding protein).

Results

Not only HbA1c and transaminase activities but also hepatic fat content were significantly decreased after 24 weeks of therapy with luseogliflozin. The reduction of hepatic fat content was significantly correlated with the reduction of alanine aminotransferase. Although hepatic fibrosis markers were unchanged, serum ferritin levels reduced and serum albumin significantly increased after the treatment.

Conclusion

Luseogliflozin can be a novel promising agent for the treatment of T2DM patients with NAFLD. Prospective randomized controlled trials are warranted to confirm this impact of luseogliflozin onT2DM with NAFLD.
Compromised NLRP3 and AIM2 inflammasome function in autoimmune NZB/W F1 mouse macrophages
Authors: Thygesen Sara J , Takizawa Karli E , Robertson Avril A B , Sester David P , Stacey Katryn J
Published: July 2018

Inflammasomes are protein complexes activated by infection and cellular stress that promote caspase‐1 activation and subsequent inflammatory cytokine processing and cell death. It has been anticipated that inflammasome activity contributes to autoimmunity. However, we previously showed that macrophages from autoimmune New Zealand Black (NZB) mice lack NLRP3 inflammasome function, and their absent in melanoma 2 (AIM2) inflammasome responses are compromised by high expression of the AIM2 antagonist protein p202. Here we found that the point mutation leading to lack of NLRP3 expression occurred early in the NZB strain establishment, as it is shared with the related obese strain New Zealand Obese, but not with the unrelated New Zealand White (NZW) strain. The first cross progeny of NZB and NZW mice develop more severe lupus nephritis than the NZB strain. We have compared AIM2 and NLRP3 inflammasome function in macrophages from NZB, NZW, and NZB/W F1 mice. The NZW parental strain showed strong inflammasome function, whereas the NZB/W F1 have haploinsufficient expression of NLRP3 and show reduced NLRP3 and AIM2 inflammasome responses, particularly at low stimulus strength. It remains to be established whether the low inflammasome function could contribute to loss of tolerance and the onset of autoimmunity in NZB and NZB/W F1. However, with amplifying inflammatory stimuli through the course of disease, the NLRP3 response in the NZB/W F1 may be sufficient to contribute to kidney damage at later stages of disease.
Nocturnal blood pressure patterns and cardiovascular outcomes in patients with masked hypertension
Authors: Presta Vivianne , Figliuzzi Ilaria , D'Agostino Michela , Citoni Barbara , Miceli Francesca , Simonelli Francesca , Coluccia Roberta , Musumeci Maria Beatrice , Ferrucci Andrea , Volpe Massimo , Tocci Giuliano
Published: July 2018

Masked hypertension (MHT) is characterized by normal clinic and above normal 24‐hour ambulatory blood pressure (BP) levels. We evaluated clinical characteristics and CV outcomes of different nocturnal patterns of MHT. We analyzed data derived from a large cohort of adult individuals, who consecutively underwent home, clinic, and ambulatory BP monitoring at our Hypertension Unit between January 2007 and December 2016. MHT was defined as clinic BP <140/90 mm Hg and 24‐hour BP ≥ 130/80 mm Hg, and stratified into three groups according to dipping status: (a) dippers, (b) nondippers, and (c) reverse dippers. From an overall sample of 6695 individuals, we selected 2628 (46.2%) adult untreated individuals, among whom 153 (5.0%) had MHT. In this group, 67 (43.8%) were nondippers, 65 (42.5%) dippers, and 21 (13.7%) reverse dippers. No significant differences were found among groups regarding demographics, clinical characteristics, and prevalence of risk factors, excluding older age in reverse dippers compared to other groups (P < 0.001). Systolic BP levels were significantly higher in reverse dippers than in other groups at both 24‐hour (135.6 ± 8.5 vs 130.4 ± 6.0 vs 128.2 ± 6.8 mm Hg, respectively; P < 0.001) and nighttime periods (138.2 ± 9.1 vs 125.0 ± 6.3 vs 114.5 ± 7.7 mm Hg; P < 0.001). Reverse dipping was associated with a significantly higher risk of stroke, even after correction for age, gender, BMI, dyslipidemia, and diabetes (OR 18.660; 95% IC [1.056‐33.813]; P = 0.046). MHT with reverse dipping status was associated with higher burden of BP and relatively high risk of stroke compared to both dipping and nondipping profiles, although a limited number of CV outcomes have been recorded during the follow‐up.