bluuebunny/crossref_metadata_2025 huggingface dataset:
The protective effect of olive cake treatment on oxidant/antioxidant biomarkers, on serum, red blood cells and liver, in streptozotocin-induced diabetic rats fed cholesterol-enriched diet
Authors: Zidan Yahiaoui , Bouderbala Sherazede , Hayet Cherrad , Malika Bouchenak
Published: October 2019

Purpose

The purpose of this study is to determine the effect of olive cake (OC) on lipid peroxidation as well as antioxidant enzymes activities of serum, red blood cells (RBCs) and liver, in streptozotocin (STZ)-induced-diabetic rat fed cholesterol-enriched diet.

Design/methodology/approach

Hypercholesterolemic male rats were rendered diabetic (HC-D) by a single intraperitoneal injection dose of STZ (35 mg/kg BW). HC-D rats were divided into two groups fed for 28d a diet supplemented with OC at 7.5 percent (HC-D-OC) or not (HC-D). A control group (C) was submitted to standard diet containing 20 per cent casein for the same experimental period.

Findings

RBCs, serum and liver thiobarbituric acid reactive substances (TBARS) contents were significantly increased in HC-D, compared to C group (p= 0.04,p= 0.02 and 0.03). These values were significantly decreased (48 per cent and 64 per cent;p= 0.02 andp= 0.0007) in serum and liver of HC-D-OC vs HC-D group. In RBCs, superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST) activities were, respectively, 1.5, 2- and 1.7-fold higher (p= 0.03,p= 0.008 andp= 0.03) in HC-D group compared to HC group. In serum and liver, SOD, CAT and GST activities were, respectively, 1.3-, 2.6- and 1.6-fold increased (p= 0.03,p= 0.007 andp= 0.02). In HC-D-OC compared to HC-D group, RBCs glutathione peroxidase (GSH-Px), CAT and GST activities were, respectively, 2.1-, 3.3- and 2.1-fold higher (p= 0.04,p= 0.0009 andp= 0.03). In serum, SOD and CAT activities were, respectively, 1.5- and 1.9-fold increased (p= 0.02,p= 0.02). In liver, SOD, GSH-PX, CAT and GST activities were significantly increased (p= 0.005,p= 0.03,p= 0.02 andp= 0.04).

Originality/value

In diabetic rats-fed cholesterol-enriched diet, OC was able to reduce oxidative stress by decreasing lipid peroxidation and increasing antioxidant enzymes activities in serum, RBCs and liver.
Macronutrients modulate survival to infection and immunity in Drosophila
Authors: Ponton Fleur , Morimoto Juliano , Robinson Katie , Kumar Sheemal S. , Cotter Sheena C. , Wilson Kenneth , Simpson Stephen J.
Published: October 2019

Immunity and nutrition are two essential modulators of individual fitness. However, while the implications of immune function and nutrition on an individual's lifespan and reproduction are well established, the interplay between feeding behaviour, infection and immune function remains poorly understood. Asking how ecological and physiological factors affect immune responses and resistance to infections is a central theme of eco‐immunology.

In this study, we used the fruit fly, Drosophila melanogaster, to investigate how infection through septic injury modulates nutritional intake and how macronutrient balance affects survival to infection by the pathogenic Gram‐positive bacterium Micrococcus luteus.

Our results show that infected flies maintain carbohydrate intake, but reduce protein intake, thereby shifting from a protein‐to‐carbohydrate (P:C) ratio of ~1:4 to ~1:10 relative to non‐infected and sham‐infected flies. Strikingly, the proportion of flies dying after M. luteus infection was significantly lower when flies were fed a low‐P high‐C diet, revealing that flies shift their macronutrient intake as means of nutritional self‐medication against bacterial infection.

These results are likely due to the effects of the macronutrient balance on the regulation of the constitutive expression of innate immune genes, as a low‐P high‐C diet was linked to an upregulation in the expression of key antimicrobial peptides.

Together, our results reveal the intricate relationship between macronutrient intake and resistance to infection and integrate the molecular cross‐talk between metabolic and immune pathways into the framework of nutritional immunology.
Winter damage is more important than summer temperature for maintaining the krummholz growth form above alpine treeline
Authors: Maher Colin T. , Nelson Cara R. , Larson Andrew J.
Published: October 2019

Understanding the processes that control alpine treelines, the elevational limits of tree growth forms, has been a central question in ecology and is growing in importance with concern over climate change. Cool summer air temperatures are currently thought to be the ultimate limiter of upright tree growth at alpine treelines globally. However, winter damage has long been recognized as a shaping force near alpine treelines. Low‐growing krummholz growth forms provide an opportunity to test hypotheses about the controls of upright growth in environments above current treelines.

To distinguish between effects of growing season temperature, winter damage and their interaction on preventing upright growth in krummholz, we conducted a field experiment on krummholz growth forms of Pinus albicaulis over the summer and winter of 2015–2016 at 10 mountain top sites in the Tobacco Root Mountains, Montana, USA. We experimentally manipulated four factors using a fully crossed design: shoot position (natural low position in the krummholz mat vs. propped up above the krummholz mat), summer warming (warming chamber vs. ambient), winter exposure (shelter cage vs. exposed), and elevation position (local high vs. low krummholz limits). We also conducted an observational study of the climatic conditions associated with recent natural emergent stem establishment from krummholz.

Experimentally propped shoots that were exposed in winter experienced the highest mortality (10%–50%), while propped shoots in shelter cages and shoots located within the krummholz mat, whether caged or not, had low mortality (0%–10%). Summer warming had little influence on shoot mortality. Surviving mat shoots had marginally higher growth rates than surviving propped shoots during the early growing season after treatments were established. Natural emergent stem establishment was associated with warmer than average summer temperatures, but also warmer winter temperatures, lower winter wind speeds, and lower snowpack.

Synthesis. Our results suggest winter damage plays a more important role than does growing season temperature in maintaining the krummholz growth form. While warming may increase opportunities for emergent shoot establishment above krummholz mats, establishment of upright trees in the krummholz zone will also require climatic change that reduces wind and snow transport which cause winter damage.
Predictions of kelp distribution shifts along the northern coast of Japan
Authors: Sudo Kenji , Watanabe Kentaro , Yotsukura Norishige , Nakaoka Masahiro
Published: October 2019

Japanese kelps are important because they perform a valuable ecosystem function of coastal kelp forest formation, and they are important food resources. The present study aimed to predict future shifts in major kelp species in northern Japan under different climate change scenarios. From a database of cold temperate kelp species in Japan, we extracted 1,958 data points to estimate the distribution of 11 kelp species that inhabit the waters around northern Japan. Distributions of the past (1980s) and the future (2040s and 2090s) were estimated using a species distribution model (MaxEnt). Variation in summer and winter sea surface temperatures was the factor most responsible for the estimated distribution patterns for most species; the length of natural rocky coasts and wave height were also important for some species. A forecast of shifts in distributions based on different Intergovernmental Panel on Climate Change scenarios showed that kelp species diversity in Japan would significantly decrease. By the 2090s, their habitat range overall was estimated to decline to 30–51% of that of the 1980s with moderate warming (Representative concentration pathways [RCP] 4.5) and to 0–25% with severe warming (RCP 8.5). The model predicted that 6 of 11 cold temperate kelp species may become extinct around Japan by the 2090s (RCP 8.5). Commercially important species, such as Saccharina japonica, are also expected to decline greatly, which may affect kelp fisheries and aquaculture in northern Japan.
Dry soil determines the pseudoviviparous reproduction in Comanthera nivea (Eriocaulaceae) in the Campos Rupestres in south‐eastern Brazil
Authors: Lombello Juliana C. , Biondi Michel , Teodoro Grazielle S. , Coelho Flávia F.
Published: October 2019

Pseudovivipary is an asexual reproduction strategy correlated with extreme environments. Comanthera nivea occurs in habitats with low water retention. This study investigated the effect of soil moisture availability on C. nivea pseudoviviparous reproduction and flowering. We established four permanent plots (1 × 1 m), two in a shaded area, in which we marked 15 rosettes in each plot, and two in a full‐sun area, in which we marked 10 rosettes in each plot. We made monthly observations from August 2016 to January 2017, to quantify the number of flower heads and of pseudoviviparous ramets per rosette, and measured soil moisture. Our results showed a high correlation between soil moisture and flowering. Flowering in C. nivea occurs in periods of increased soil moisture, whereas pseudoviviparous reproduction occurs in the driest period. The advantages of a pseudoviviparous canopy‐forming strategy in habitats with scarcity of water in the soil are discussed.
Additive influences of acute early life stress and sex on vulnerability for aversion‐resistant alcohol drinking
Authors: Radke Anna K. , Held Isabel T. , Sneddon Elizabeth A. , Riddle Collin A. , Quinn Jennifer J.
Published: October 2019

Acute early life stress (ELS) alters stress system functioning in adulthood and increases susceptibility to posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). The current study assessed the effects of acute, infant ELS on alcohol drinking, including aversion‐resistant drinking, in male and female Long Evans rats. Acute ELS was induced using a stress‐enhanced fear learning (SEFL) protocol that consisted of 15 footshocks delivered on postnatal day (PND) 17. Alcohol drinking during adolescence and adulthood was measured with a two‐bottle choice intermittent alcohol access paradigm. Aversion‐resistant drinking was assessed in adulthood by adding quinine (0.01, 0.1, and 1.0 g/L) to the alcohol bottle after 5 to 6 weeks and 11 to 12 weeks of drinking. ELS had minimal influences on adolescent and adult alcohol consumption and preference. However, ELS, sex, and alcohol exposure history all influenced aversion‐resistant alcohol drinking in an additive fashion. Higher concentrations of quinine were tolerated in females, ELS‐exposed rats, and after 11 to 12 weeks of drinking. Tests of quinine sensitivity in a separate cohort of animals found that rats can detect concentrations of quinine as low as 0.001 g/L in water and that quinine sensitivity is not influenced by sex or ELS exposure. These results agree with reports of sex differences in aversion‐resistant drinking and are the first to demonstrate an influence of ELS on this behavior. Our results also suggest that a single traumatic stress exposure in infancy may be a promising model of comorbid PTSD and AUD and useful in studying the interactions between ELS, sex, and alcohol dependence.
Atypically grown large periradicular cyst affecting adjacent teeth and leading to confounding diagnosis of non‐endodontic pathology
Authors: Ricucci Domenico , Amantea Massimiliano , Girone Christian , Siqueira José F.
Published: October 2019

This article reports a case of a large osteolytic lesion in the mandible, mostly associated with the apices of the premolars, and suspected as having a non‐endodontic origin because the 2 premolars responded positively to the cold sensibility test. The distal border of the lesion reached the mesial root of the first molar, which also had a small lesion in its distal aspect. Cone‐beam computed tomography revealed that the large lesion communicated with the small molar lesion. Because the large lesion was suspected as having a non‐endodontic origin, surgery was scheduled for enucleation and biopsy. The molar was root canal‐retreated, and the 2 premolars treated. Histologic analysis of the premolar pulps showed vitality but advanced degenerative changes. The lesion was histologically diagnosed as an inflammatory periradicular cyst, which originated in the first molar and had an atypical growth to the premolar area. Follow‐up revealed that the affected area healed uneventfully.
Outcomes of women at high familial risk for breast cancer: An 8‐year single‐center experience
Authors: Lammert Jacqueline , Skandarajah Anita R. , Shackleton Kylie , Calder Patricia , Thomas Susan , Lindeman Geoffrey J. , Mann Gregory Bruce
Published: October 2019

Objectives

The value of a high‐risk surveillance program for mutation carriers and women at high familial breast cancer risk has not been extensively studied. A Breast and Ovarian Cancer Risk Management Clinic (BOCRMC) was established at the Royal Melbourne Hospital in 2010 to provide multimodality screening and risk management strategies for this group of women. The aims of this study were to evaluate the program and describe breast cancer diagnoses for BRCA1, BRCA2, and other germline mutation carriers as well as high‐risk noncarriers attending the BOCRMC.

Methods

Clinical data from mutation carriers and noncarriers with a ≥25% lifetime risk of developing breast cancer who attended between 2010 and 2018 were extracted from clinic records and compared. The pattern and mode of detection of cancer were determined.

Results

A total of 206 mutation carriers and 305 noncarriers attended the BOCRMC and underwent screening on at least one occasion. Median age was 37 years. After a median follow‐up of 34 months, 15 (seven invasive) breast cancers were identified in mutation carriers, with seven (six invasive) breast cancers identified in noncarriers. Of these, 20 (90.9%) were detected by annual screening, whereas two (9.1%) were detected as interval cancers (both in BRCA1 mutation carriers). Median size of the invasive breast cancers was 11 mm (range: 1.5‐30 mm). The majority (76.9%) were axillary node negative. In women aged 25‐49 years, the annualized cancer incidence was 1.6% in BRCA1, 1.4% in BRCA2 mutation carriers, and 0.5% in noncarriers. This compares to 0.06% annualized cancer incidence in the general Australian population.

Conclusions

Screening was effective at detecting early‐stage cancers. The incidence of events in young noncarriers was substantially higher than in the general population. This potentially justifies ongoing management through a specialty clinic, although further research to better personalize risk assessment in noncarriers is required.
The VAC regimen for adult rhabdomyosarcoma: Differences between adolescent/young adult and older patients
Authors: Nakano Kenji , Ae Keisuke , Matsumoto Seiichi , Takahashi Shunji
Published: October 2019

Background

Compared to pediatric patients, adult rhabdomyosarcoma (RMS) patients have poor prognoses, but the differences in prognoses and treatment sensitivity between adolescent/young adult (AYA) patient and older RMS patients have not been established.

Aim

To evaluate and compare the efficacy and safety of the vincristine/dactinomycin/cyclophosphamide (VAC) regimen, that is, the standard combination chemotherapy regimen for pediatric RMS, in AYA and older patients.

Methods

We retrospectively reviewed the clinical records of adolescent and adult RMS patients treated at our institution and patients treated with the VAC were enrolled in the analyses. The differences in the efficacy and safety of VAC between the AYA patients (15‐39 years old) and older patients (≥40 years old) were compared.

Results

Total of 23 patients were enrolled (14 AYA patients and nine older patients) were enrolled. With the median follow‐up of 89.4 weeks (range 17.7–263.1 weeks), the median progression‐free survival (PFS) and overall survival (OS) of the VAC regimen were 61.4 weeks (95% CI, 32.6–90.3) and 104.0 weeks (95% CI, 43.8–164.2), respectively, with no significant differences in the PFS or OS between the AYA and older patients. There were no differences in the response rate of the VAC between AYA (64.3%) and older (66.7%), either. Safety profiles were similar between the AYA and older groups, but exposure to antitumor drugs of the VAC tended to be lower in the older group; median number of total cycle of the VAC was 13 in AYA and 10 in older, cumulative cyclophosphamide dose was 16.8 g/m2 in AYA and 12.8 g/m2 in older, and number of vincristine skips was six in AYA and 12 in older, respectively.

Conclusion

There were no significant differences in responses to the VAC among AYA and older patients with RMS. With the appropriate dose modification, the VAC regimen could be a feasible treatment option for RMS patients >40 years old.
Time‐Varying Aggregate Short‐Selling in Korea
Authors: Lee Kuan‐Hui , Wang Shu‐Feng
Published: October 2019

This study examines the variation in aggregate short‐selling by foreigners, individuals, and institutional investors in relation to market return and other market‐wide variables in the Korean stock market. First, we find that aggregate short‐selling has strong seasonal components. In contrast to the existing literature, which shows contrarian‐style short‐selling at the stock level, we find momentum‐style short‐selling by foreigners and individual investors at the aggregate level. That is, they significantly increase their short‐selling following a short‐term down market. In addition, we show that past US market return is negatively related to aggregate short‐selling by foreign investors. Vector‐autoregression and impulse‐response analyses reveal that aggregate short‐selling is significantly affected by changes in market return, but not vice versa.
The Impact of Venture Capital Investment on the Performance of Peer‐to‐Peer Lending Platforms: Evidence from China
Authors: Gu Dingwei , Lu Tian , Luo Pinliang , Zhang Chenghong
Published: October 2019

The Chinese peer‐to‐peer (P2P) lending market is expanding quickly but has a relatively poor level of operation. Using panel‐structured data from a leading P2P lending portal in China, we investigate the effects of venture capital (VC) investment on the performance of P2P lending platforms. Specifically, we identify a short‐term signaling effect and a long‐term governance effect of VC investment on platform performance in terms of transaction volume, and numbers of lenders and borrowers. However, we only find a decrease in average interest rates after venture capitalists’ (VCs’) entry in the long run. Moreover, we verify both the effects of investment from listed VCs, but no signaling effect and a weak governance effect of investment from non‐listed VCs. Our analysis provides new insights into how VC investment improves the performance of target firms.
Food and Drug Administration vs European Medicines Agency: Review times and clinical evidence on novel drugs at the time of approval
Authors: Joppi Roberta , Bertele Vittorio , Vannini Tommaso , Garattini Silvio , Banzi Rita
Published: October 2019

The Food and Drug Administration (FDA) and European Medicines Agency (EMA) now have expedited review procedures for new drugs. We compared the review times of medicines licensed by the 2 agencies and explored differences in the evidence submitted. In 2015–2017 the FDA licensed 113 drugs, 66 of which reached Europe. The median review time was longer at the EMA than FDA and was shorter for drugs undergoing FDA‐expedited programmes compared to the same drugs approved by the EMA through the standard procedure. We identified differences regarding the evidence submitted to the 2 regulators for 7 drugs. The greater use of expedited programmes by the FDA and administrative time at the European Commission mainly explain the later access of new drugs to the European market. The additional evidence submitted to the EMA is generally scant and limited to a few drugs.
Population pharmacokinetics and pharmacodynamics of dobutamine in neonates on the first days of life
Authors: Hallik Maarja , Ilmoja Mari‐Liis , Standing Joseph F. , Soeorg Hiie , Jalas Tiiu , Raidmäe Maila , Uibo Karin , Köbas Kristel , Sõnajalg Margit , Takkis Kalev , Veigure Rūta , Kipper Karin , Starkopf Joel , Metsvaht Tuuli
Published: October 2019

Aims

To describe the pharmacokinetics (PK) and concentration‐related effects of dobutamine in critically ill neonates in the first days of life, using nonlinear mixed effects modelling.

Methods

Dosing, plasma concentration and haemodynamic monitoring data from a dose‐escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5–20 μg kg−1 min−1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors.

Results

Twenty‐eight neonates with median (range) gestational age of 30.4 (22.7–41.0) weeks and birth weight (BW) of 1618 (465–4380) g were included. PK data were adequately described by 1‐compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h−1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model.

Conclusion

In the postnatal transitional period, PK of dobutamine was described by a 1‐compartmental linear model, CL related to BW and PMA. A concentration–response relationship with haemodynamic variables has been established.
A case–control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine‐induced gastrointestinal toxicity
Authors: Helsby Nuala A. , Duley John , Burns Kathryn E. , Bonnet Claire , Jeong Soo Hee , Brenman Elliott , Barlow Paula , Sharples Katrina , Porter David , Findlay Michael
Published: October 2019

Aims

A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case–control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5‐fluorouracil or capecitabine.

Methods

Patients (n = 37) received a 250 mg (per os) dose of THY and a cumulative urine sample was collected for 0–4 h. The urinary amounts of THY and metabolite dihydrothymine (DHT) were determined by liquid chromatography/mass spectrometry. Genomic DNA was analysed for DPYD gene variants. Renal function was estimated from blood creatinine levels. Cases (n = 9) and noncases (n = 23) of severe (grade ≥ 3) gastrointestinal toxicity were defined based on Common Terminology Criteria for Adverse Events.

Results

The median THY/DHT ratios were 6.2 (interquartile range 2.9–6.4) in cases, including the 2 patients who were DPYD heterozygous carriers. However, this was not significantly different (P = .07) from the THY/DHT in noncases (median 2.6, interquartile range 2.8–4.2). Although creatinine clearance was lower (P = .001) in cases, renal function could not discriminate cases from noncases. However, logistic regression analysis using both of these explanatory variables could discriminate most cases (receiver operating characteristic area 0.8792, 95% confidence interval 0.72–1.00).

Conclusions

The THY challenge test combined with a patient's renal function may be useful as a phenotypic diagnostic test to detect risk of life‐threatening fluoropyrimidine gastrointestinal toxicity.
Comparison of pharmacokinetics, safety and tolerability of secukinumab administered subcutaneously using different delivery systems in healthy volunteers and in psoriasis patients
Authors: Bruin Gerard , Hockey Hans‐Ulrich P. , La Stella Phillip , Sigurgeirsson Bárdur , Fu Rong , Patekar Manmath , Charef Pascal , Woessner Ralph , Boutouyrie‐Dumont Bruno
Published: October 2019

Aims

The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL.

Methods

A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration–time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1‐mL prefilled syringe or 1 × 2‐mL prefilled syringe.

Results

Mean serum concentration–time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1‐year phase 3 study in patients confirmed PK results observed in the phase 1 study.

Conclusion

Collective evidence from both studies demonstrated that 2‐mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.
Sex‐specific behavioural deficits induced at early life by prenatal exposure to the cannabinoid receptor agonist WIN55, 212‐2 depend on mGlu5 receptor signalling
Authors: Manduca Antonia , Servadio Michela , Melancia Francesca , Schiavi Sara , Manzoni Olivier J. , Trezza Viviana
Published: October 2019

Background and Purpose

Marijuana is the illicit drug most commonly used among pregnant and breastfeeding women. Different studies reported long‐term adverse effects induced by in utero exposure to the main component of marijuana, Δ9‐tetrahydrocannabinol (THC), both in rodents and in humans. However, little is known about any potential sex‐dependent effects of marijuana consumption during pregnancy on newborns at early developmental ages.

Experimental Approach

We studied the effects of prenatal exposure to the cannabinoid receptor agonist WIN55,212‐2 (WIN; 0.5 mg·kg−1 from GD5 to GD20) on the emotional reactivity and cognitive performance of male and female rat offspring from infancy through adolescence and tested the role of mGlu5 receptor signalling in the observed effects.

Key Results

Prenatally WIN‐exposed male infant pups emitted less isolation‐induced ultrasonic vocalizations compared with male control pups, when separated from the dam and siblings and showed increased locomotor activity while females were spared. These effects were normalized when male pups were treated with the positive allosteric modulator of mGlu5 receptor CDPPB. When tested at the prepubertal and pubertal periods, WIN‐prenatally exposed rats of both sexes did not show any difference in social play behaviour, anxiety and temporal order memory.

Conclusions and Implications

We reveal a previously undisclosed sexual divergence in the consequences of fetal cannabinoids on newborns at early developmental ages, which is dependent on mGlu5 receptor signalling. These results provide new impetus for the urgent need to investigate the functional and behavioural substrates of prenatal cannabinoid exposure in both the male offspring and the female offspring.
Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv7 channels
Authors: Zavaritskaya Olga , Dudem Srikanth , Ma Dongyu , Rabab Kaneez E. , Albrecht Sarah , Tsvetkov Dmitry , Kassmann Mario , Thornbury Keith , Mladenov Mitko , Kammermeier Claire , Sergeant Gerard , Mullins Nicholas , Wouappi Ornella , Wurm Hannah , Kannt Aimo , Gollasch Maik , Hollywood Mark A. , Schubert Rudolf
Published: October 2019

Background and Purpose

BK channels play important roles in various physiological and pathophysiological processes and thus have been the target of several drug development programmes focused on creating new efficacious BK channel openers, such as the GoSlo‐SR compounds. However, the effect of GoSlo‐SR compounds on vascular smooth muscle has not been studied. Therefore, we tested the hypothesis that GoSlo‐SR compounds dilate arteries exclusively by activating BK channels.

Experimental Approach

Experiments were performed on rat Gracilis muscle, saphenous, mesenteric and tail arteries using isobaric and isometric myography, sharp microelectrodes, digital droplet PCR and the patch‐clamp technique.

Key Results

GoSlo‐SR compounds dilated isobaric and relaxed and hyperpolarised isometric vessel preparations and their effects were abolished after (a) functionally eliminating K+ channels by pre‐constriction with 50 mM KCl or (b) blocking all K+ channels known to be expressed in vascular smooth muscle. However, these effects were not blocked when BK channels were inhibited. Surprisingly, the Kv7 channel inhibitor XE991 reduced their effects considerably, but neither Kv1 nor Kv2 channel blockers altered the inhibitory effects of GoSlo‐SR. However, the combined blockade of BK and Kv7 channels abolished the GoSlo‐SR‐induced relaxation. GoSlo‐SR compounds also activated Kv7.4 and Kv7.5 channels expressed in HEK 293 cells.

Conclusion and Implications

This study shows that GoSlo‐SR compounds are effective relaxants in vascular smooth muscle and mediate their effects by a combined activation of BK and Kv7.4/Kv7.5 channels. Activation of Kv1, Kv2 or Kv7.1 channels or other vasodilator pathways seems not to be involved.
PRRX1‐induced epithelial‐to‐mesenchymal transition in salivary adenoid cystic carcinoma activates the metabolic reprogramming of free fatty acids to promote invasion and metastasis
Authors: Jiang Ya‐ping , Tang Ya‐ling , Wang Sha‐sha , Wu Jia‐shun , Zhang Mei , Pang Xin , Wu Jing‐biao , Chen Yu , Tang Ya‐Jie , Liang Xin‐hua
Published: October 2019

Objectives

Increasing evidences demonstrate a close correlation between epithelial‐to‐mesenchymal transition (EMT) induction and cancer lipid metabolism. However, the molecular mechanisms have not been clarified.

Materials and methods

In our study, the relative expression level of PRRX1 was detected, its relationship with free fatty acid (FFA) and PPARG2 was analysed in 85 SACC tissues and 15 salivary glands from the benign salivary tumours. We also compared the FFAs composition and levels in these SACC cells. PPARG2 was detected in PRRX1‐induced FFAs treatment as well as Src and MMP‐9 were detected in FFAs treatment–induced invasion and migration of SACC cells, and ChIP test was performed to identify the target interactions.

Results

Our data showed that overexpression of PRRX1 induced EMT and facilitated the invasion and migration of SACC cells, and PRRX1 expression was closely associated with high FFAs level and poor prognosis of SACC patients. Furthermore, PRRX1 silence led to the increase of PPARG2 and the reduction of FFAs level and the migration and invasion of SACC cells. And inhibition of PPARG2 rescued FFAs level and migration and invasion capabilities of SACC cells. Free fatty acids treatment induced an increase of Stat5‐DNA binding activity via Src‐ and MMP‐9‐dependent pathway.

Conclusions

Collectively, our findings showed that the PRRX1/PPARG2/FFAs signalling in SACC was important for accelerating tumour metastasis through the induction of EMT and the metabolic reprogramming of FFAs.
BEVA primary care clinical guidelines: Analgesia
Authors: Bowen I. M. , Redpath A. , Dugdale A , Burford J. H. , Lloyd D. , Watson T. , Hallowell G. D.
Published: October 2019

Primary care guidelines provide a reference point to guide clinicians based on a systematic review of the literature, contextualised by expert clinical opinion. These guidelines develop a modification of the GRADE framework for assessment of research evidence (vetGRADE) and applied this to a range of clinical scenarios regarding use of analgesic agents. Key guidelines produced by the panel included recommendations that horses undergoing routine castration should receive intratesticular local anaesthesia irrespective of methods adopted and that horses should receive NSAIDs prior to surgery (overall certainty levels high). Butorphanol and buprenorphine should not be considered appropriate as sole analgesic for such procedures (high certainty). The panel recommend the continuation of analgesia for 3 days following castration (moderate certainty) and conclude that phenylbutazone provided superior analgesia to meloxicam and firocoxib for hoof pain/laminitis (moderate certainty), but that enhanced efficacy has not been demonstrated for joint pain. In horses with colic, flunixin and firocoxib are considered to provide more effective analgesia than meloxicam or phenylbutazone (moderate certainty). Given the risk of adverse events of all classes of analgesic, these agents should be used only under the control of a veterinary surgeon who has fully evaluated a horse and developed a therapeutic, analgesic plan that includes ongoing monitoring for such adverse events such as the development of right dorsal colitis with all classes of NSAID and spontaneous locomotor activity and potentially ileus with opiates. Finally, the panel call for the development of a single properly validated composite pain score for horses to allow accurate comparisons between medications in a robust manner.
Age‐related severity and distribution of haemophilic arthropathy of the knee, ankle and elbow among Chinese patients with haemophilia
Authors: Liu Sha , Zhou Rong‐fu , Jin Zhi‐bin , Wu Min , Zhang Ping‐yang
Published: October 2019

Introduction and aims

Age‐related severity and distribution of haemophilic arthropathy (HA) among Chinese patients with haemophilia using the Haemophilia Early Detection with Ultrasound (HEAD‐US) system have not been extensively studied.

Methods

In our study, 89 patients with moderate and severe haemophilia were recruited. A total of 534 joints (knees, ankles and elbows on both sides included) were evaluated using musculoskeletal ultrasound (MSKUS) and scored using the HEAD‐US system.

Results

Prevalence and average number of HA were 39.1% and 0.7, 90.6% and 3.2, 94.1% and 4.5, and 100% and 4.3 for ages ≤10, 11‐20, 21‐30 and 31‐40 years, respectively. Prevalence and mean number of knee, ankle and elbow arthropathies also increased with age, although joint damages progressed in unparallel patterns. A significant difference in synovium subscores was observed between patients aged <10 and >10 years. An increasing tendency was observed in cartilage and subchondral bone subscores along with age before 30 years. No significant difference in mean joint scores was found between patients receiving on‐demand therapy and those receiving on‐demand to low‐dose prophylactic therapy.

Conclusions

Haemophilic arthropathy developed in early childhood and progressed mainly before 30 years of age among Chinese patients with haemophilia, although in different ways among the knee, ankle and elbow.
Genetic characterization of 15 autosomal STRs in the interior Sindhi population of Pakistan and their phylogenetic relationship with other populations
Authors: Adnan Atif , Rakha Allah , Nazir Shahid , Rehman Ziaur , Lu Jie , Xuan Jin‐Feng
Published: October 2019

Genetic structure of a population can be influenced by evolutionary processes and cultural histories which can alter the frequencies of different variants at particular genetic markers. These characteristics make DNA evidence suitable for forensic applications. Little relevant data are available from the interior Sindhi population; thus, in the current study, we have investigated 15 autosomal STRs in 181 unrelated individuals belonging to the interior parts of Sindh Pakistan, to establish its lineage and parameters of forensic interest. These STRs revealed a high power of discrimination (CPD), power of exclusion (CPE) and matching probability (CMP) are 0.9999999999999999968997, 0.99998612 and 3.1003 × 10–18 respectively. The genetic distances, neighbour‐joining (NJ) tree, interactivity test and principal component analysis (PCA) based on 15 autosomal STR loci showed that the interior Sindhi population had a closer genetic relationship with Pakistani populations and distant relationships with regional (India and Afghanistan) populations. The present findings exhibited that STRs included in AmpFLSTR Identifiler kit (Applied Biosystems) are genetically polymorphic in the interior Sindhi population of Pakistan. This study provides valuable population genetic data for the genetic information study, forensic human individual identification and paternity testing.
A longitudinal study on psychological reactions and resilience among young survivors of a burn disaster in Taiwan 2015–2018
Authors: Wu Chia‐Yi , Lee Ming‐Been , Lin Chi‐Hung , Kao Shu‐Chen , Tu Chung‐Chieh , Chang Chia‐Ming
Published: October 2019

Aim

To investigate the long‐term psychological reactions and resilient process of the young survivors after a large‐scale burn disaster of the Formosa Color Dust Explosion in Taiwan.

Design

Longitudinal study with follow‐up interviews using standardized questionnaire during November 2015–June 2018.

Methods

The burn survivors received structured assessment in the four‐wave interviews including the five‐item Brief Symptom Rating Scale, nine‐item Concise Mental Health Checklist, and two‐item Patient Health Questionnaire for depressive symptoms and suicide risk assessment. Post‐traumatic psychological symptoms were assessed through the four‐item Startle, Physiological Arousal, Anger, and Numbness Scale, and six‐item Impact of Event Scale.

Findings

The response rates were 65.1%, 74.2%, 76.9%, and 78.5% across the four‐wave interviews among 484 burn survivors. The participants were mean‐aged 23.1 years with just over half having 40% or more burn wounds in total body surface area. The respondents at each wave were similar in gender, age, and per cent of total body surface area burned. In the first 2 years of recovery, the respondents showed resilience in coping with stress of trauma under family and social support. While there was a decreasing trend of psychological symptoms over the first 2 years, hypnotic use and alcohol consumption remained at about 10% in the final interview, which were accompanied by psychological symptom recurrence.

Conclusion

Young burn survivors recovered both psychologically and physically under supportive care and personal resilience in 2 years after the burn event, yet post‐traumatic mental distress and coping efforts after 2 years during community reintegration should be detected and managed. Early prevention and detection of mental health deterioration is needed even after 2 years of burn disasters.

Impact

The study demonstrated post‐burn longitudinal changes on psychological reactions. Nursing staffs may help young burn survivors identify mental distress and stress management needs in the long‐term psychological adaptation process.
Advancement of global health: Recommendations from the Global Advisory Panel on the Future of Nursing & Midwifery (GAPFON®)
Authors: Klopper Hester C. , Madigan Elizabeth , Vlasich Cynthia , Albien Anouk , Ricciardi Richard , Catrambone Cathy , Tigges Elizabeth
Published: October 2019

Aims

To discuss nurses' contributions to global health through their participation in GAPFON®.

Design

Discussion paper that reviews literature related to global health, global nursing and midwifery based on the contributions of the GAPFON® report.

Data sources

A literature search of electronic databases was conducted for published articles during 2014–2018 in English focusing on the main themes of the GAPFON® report. Manual searches of relevant journals and internet sites were also undertaken.

Results

Recommendations and strategies were discussed that could have an impact on the advancement of the nursing profession's contribution to global health based on the GAPFON® report outcomes.

Implications for Nursing

GAPFON® provides a framework to synergize and converge our activities to address professional issues around the globe, through implementation of the suggested strategies identified in the GAPFON® report. GAPFON® has engaged with nursing and midwifery leaders around the globe to determine both the most pressing health issues and professional issues in regions and the report is a synthesis of all the data, reflecting regional and global challenges. This article explores ways of how the report can be used as a basis for engagement with decision makers in global health.

Conclusion

Advances in the professional areas embedded in the GAPFON® Model are expected to lead to capacity building, evidence‐based practice and ultimately improved quality of global health care. The strategies for implementation identified by regional stakeholders can have an impact on the global health agenda by focusing on nurses and midwives as the drivers of this change.
Blockchain in Additive Manufacturing and its Impact on Supply Chains
Authors: Kurpjuweit Stefan , Schmidt Christoph G. , Klöckner Maximilian , Wagner Stephan M.
Published: October 2019

Additive manufacturing (AM) appears to be a particularly attractive use case for blockchain. This research combines inductive in‐depth interviews with the Delphi method to explore what potentials blockchain technology in AM creates, which adoption barriers firms need to overcome, and how supply chains will be affected by the integration of these two potentially disruptive technologies. The results suggest opportunities that are related to intellectual property (IP) rights management, the monitoring of printed parts throughout their lifecycle, process improvements, and data security. The most important barriers for blockchain adoption in AM are an absence of blockchain‐skilled specialists on the labor market, missing governance mechanisms, and a lack of firm‐internal technical expertise. By addressing important limitations of AM, blockchain is expected to improve the competitiveness of AM in parts’ production, catalyzing the trend toward more decentralized manufacturing resulting in more agile, resilient, and flexible supply chains and reduced logistics costs. Beyond that, blockchain‐based AM platforms are expected to enhance supply chain visibility, drive supply chain digitalization, support supply chain finance, and contribute to the emergence of shared factory systems.
An EMT‐related gene signature for the prognosis of human bladder cancer
Authors: Cao Rui , Yuan Lushun , Ma Bo , Wang Gang , Qiu Wei , Tian Ye
Published: October 2019

The transition from non–muscle‐invasive bladder cancer (NMIBC) to muscle‐invasive bladder cancer (MIBC) is detrimental to bladder cancer (BLCA) patients. Here, we aimed to study the underlying mechanism of the subtype transition. Gene set variation analysis (GSVA) revealed the epithelial‐mesenchymal transition (EMT) signalling pathway with the most positive correlation in this transition. Then, we built a LASSO Cox regression model of an EMT‐related gene signature in BLCA. The patients with high risk scores had significantly worse overall survival (OS) and disease‐free survival (DFS) than those with low risk scores. The EMT‐related gene signature also performed favourably in the accuracy of prognosis and in the subtype survival analysis. Univariate and multivariate Cox regression analyses demonstrated that the EMT‐related gene signature, pathological N stage and age were independent prognostic factors for predicting survival in BLCA patients. Furthermore, the predictive nomogram model was able to effectively predict the outcome of BLCA patients by appropriately stratifying the risk score. In conclusion, we developed a novel EMT‐related gene signature that has tumour‐promoting effects, acts as a negative independent prognostic factor and might facilitate personalized counselling and treatment in BLCA.
Monetary Policy Uncertainty and the Response of the Yield Curve to Policy Shocks
Authors: TILLMANN PETER
Published: October 2019

This paper studies the nonlinear response of the term structure of interest rates to monetary policy shocks and presents a new stylized fact. We show that uncertainty about monetary policy changes the way the term structure responds to monetary policy. A policy tightening leads to a significantly smaller increase in long‐term bond yields if policy uncertainty is high at the time of the shock. We also look at the decomposition of bond yields into expectations about future policy and the term premium. The weaker response of yields is driven by the fall in term premia, which fall more strongly if uncertainty about policy is high. Conditional on a monetary policy shock, higher uncertainty about monetary policy tends to make securities with longer maturities relatively more attractive to investors. As a consequence, investors demand even lower term premia. These findings are robust to the measurement of monetary policy uncertainty, the definition of the monetary policy shock, and to changing the model specification.
Does class size matter in postgraduate education?
Authors: Gaggero Alessio , Haile Getinet
Published: October 2019

The paper examines the impact of class size on postgraduate (PG) grades using administrative data from one of the largest Schools of a Russell Group University in the UK. As well as estimating fixed effects models on the population of PG candidates in the School, we exploit a policy change aimed at reducing class size to implement a regression discontinuity design. We find that class size does impact overall grades adversely; and the policy aimed at reducing class size impacts grades favourably. Our findings are robust to alternative specifications as well as being supported by the validity tests we conducted.
Fiscal rule compliance, poverty and social exclusion in the Eurozone
Authors: Bonasia Mariangela , Canale Rosaria Rita , Capasso Salvatore , D’Uva Marcella
Published: October 2019

This paper develops a simple model of the effects of fiscal adjustments on poverty. Our theory suggests that in richer countries the effects of fiscal adjustment are stronger the more complex is the poverty measure. By examining a panel of 16 EU countries in the period 2005–2015, the paper finds that structural public balance adjustments may harm the welfare of poorer individuals. The empirical estimation hinges on a comprehensive index of poverty and social exclusion, the AROPE index. The results suggest that rigid fiscal rules require specific alternative policies to sustain the welfare of poorer individuals during downturns.