bluuebunny/crossref_metadata_2025 huggingface dataset:
Usage Count: A New Indicator to Detect Research Fronts
Authors: Liang Guoqiang , Hou Haiyan , Hu Zhigang , Huang Fu , Wang Yajie , Zhang Shanshan
Published: February 2017

Purpose

Research fronts build on recent work, but using times cited as a traditional indicator to detect research fronts will inevitably result in a certain time lag. This study attempts to explore the effects of usage count as a new indicator to detect research fronts in shortening the time lag of classic indicators in research fronts detection.

Design/methodology/approach

An exploratory study was conducted where the new indicator “usage count” was compared to the traditional citation count, “times cited,” in detecting research fronts of the regenerative medicine domain. An initial topic search of the term “regenerative medicine” returned 10,553 records published between 2000 and 2015 in the Web of Science (WoS). We first ranked these records with usage count and times cited, respectively, and selected the top 2,000 records for each. We then performed a co-citation analysis in order to obtain the citing papers of the co-citation clusters as the research fronts. Finally, we compared the average publication year of the citing papers as well as the mean cited year of the co-citation clusters.

Findings

The citing articles detected by usage count tend to be published more recently compared with times cited within the same research front. Moreover, research fronts detected by usage count tend to be within the last two years, which presents a higher immediacy and real-time feature compared to times cited. There is approximately a three-year time span among the mean cited years (known as “intellectual base”) of all clusters generated by usage count and this figure is about four years in the network of times cited. In comparison to times cited, usage count is a dynamic and instant indicator.

Research limitations

We are trying to find the cutting-edge research fronts, but those generated based on co-citations may refer to the hot research fronts. The usage count of older highly cited papers was not taken into consideration, because the usage count indicator released by WoS only reflects usage logs after February 2013.

Practical implications

The article provides a new perspective on using usage count as a new indicator to detect research fronts.

Originality/value

Usage count can greatly shorten the time lag in research fronts detection, which would be a promising complementary indicator in detection of the latest research fronts.
More on narrative closure
Authors: Klauk Tobias , Köppe Tilmann , Onea Edgar
Published: February 2017

In this article, we shall contribute to the theory of narrative closure. In pre-theoretical terms, a narrative features closure if it has an ending. We start by giving a general introduction into the closure phenomenon. Next, we offer a reconstruction of Noël Carroll’s (2007. Narrative closure. Philosophical Studies 135. 1–15) erotetic account of narrative closure, according to which a narrative exhibits closure (roughly) if readers have a “feeling of finality” which in turn is based on the judgment that the presiding macro questions posed by the plot of the narrative get answered. We then discuss a number of questions raised by Carroll’s account, namely whether a definition of “narrative closure” based on his account is either too inclusive or too exclusive; whether narrative closure is a property of narratives or of plots; whether narrative closure comes in grades; whether “narrative closure” is a restrictive notion; and whether “narrative closure” should be ascribed online (incrementally) or on the basis of all-things-consideredex postinterpretations. Our answers to these questions are couched in terms of refined definitions, for this allows us to keep track of the progress and facilitates comparisons between the different proposals developed. Finally, we offer a definition of “narrative closure” that summarizes our amendments to Carroll’s theory.
Entropy Production in Chemical Reactors
Authors: Kingston Diego , Razzitte Adrián C.
Published: February 2017

We have analyzed entropy production in chemically reacting systems and extended previous results to the two limiting cases of ideal reactors, namely continuous stirred tank reactor (CSTR) and plug flow reactor (PFR). We have found upper and lower bounds for the entropy production in isothermal systems and given expressions for non-isothermal operation and analyzed the influence of pressure and temperature in entropy generation minimization in reactors with a fixed volume and production. We also give a graphical picture of entropy production in chemical reactions subject to constant volume, which allows us to easily assess different options. We show that by dividing a reactor into two smaller ones, operating at different temperatures, the entropy production is lowered, going as near as 48 % less in the case of a CSTR and PFR in series, and reaching 58 % with two CSTR. Finally, we study the optimal pressure and temperature for a single isothermal PFR, taking into account the irreversibility introduced by a compressor and a heat exchanger, decreasing the entropy generation by as much as 30 %.
Developing Cross-cultural Competences through International Employees Flow – Experience of Subsidiaries Providing Business Services
Authors: Purgał-Popiela Joanna
Published: February 2017

This paper is aimed to explore how international mobility (IM) practices are used to support the development of cross-cultural competences in two Polish-based subsidiaries providing business services within MNCs1. It is based on case study analyses, which allowed to include different points of view, i.e. head of HR, Polish ex-assignees, and co-workers of foreign assignees. Research reveals differences in terms of cross-cultural competence content and the manner in which it is enhanced by IM practices.
A retrospective analysis of longitudinal changes in bone mineral content in cystic fibrosis
Authors: Chirita-Emandi Adela , Shepherd Sheila , Kyriakou Andreas , McNeilly Jane D. , Dryden Carol , Corrigan Donna , Devenny Anne , Ahmed Syed Faisal
Published: February 2017

Background:

We aimed to describe the longitudinal changes in bone mineral content and influencing factors, in children with cystic fibrosis (CF).

Methods:

One hundred children (50 females) had dual X-ray absorptiometry (DXA) performed. Of these, 48 and 24 children had two to three scans, respectively over 10 years of follow-up. DXA data were expressed as lumbar spine bone mineral content standard deviation score (LSBMCSDS) adjusted for age, gender, ethnicity and bone area. Markers of disease, anthropometry and bone biochemistry were collected retrospectively.

Results:

Baseline LSBMCSDS was >0.5 SDS in 13% children, between −0.5; 0.5 SDS, in 50% and ≤−0.5 in the remainder. Seventy-eight percent of the children who had baseline LSBMCSDS >−0.5, and 35% of the children with poor baseline (LSBMCSDS<−0.5), showed decreasing values in subsequent assessments. However, mean LS BMC SDS did not show a significant decline in subsequent assessments (−0.51; −0.64; −0.56; p=0.178). Lower forced expiratory volume in 1 s percent (FEV1%) low body mass index standard deviation scores (BMI SDS) and vitamin D were associated with reduction in BMC.

Conclusions:

Bone mineral content as assessed by DXA is sub-optimal and decreases with time in most children with CF and this study has highlighted parameters that can be addressed to improve bone health.
Vascular risk factors are associated with retinal arteriolar narrowing and venular widening in children and adolescents with type 1 diabetes
Authors: Keel Stuart , Itsiopoulos Catherine , Koklanis Konstandina , Vukicevic Meri , Cameron Fergus , Brazionis Laima
Published: February 2017

Background:

The aim of the study was to describe the relationship of retinal arteriolar and venular calibre with vascular risk factors in children and adolescents with type 1 diabetes.

Methods:

In this hospital-based cross-sectional study, the medical files of 483 children and adolescents with type 1 diabetes were audited to collect retinal images and relevant clinical data. Retinal vascular calibre was measured using standardised protocols.

Results:

After multivariable adjustments, a vascular risk profile that included: older age, higher serum creatinine, higher systolic blood pressure (SBP), higher body mass index (BMI), abnormal estimated glomerular filtration rate (eGFR), lower high-density lipoproteins (HDL) cholesterol, longer duration of diabetes and higher serum sodium was associated with narrower central retinal artery equivalent (CRAE) (95% CI=−4.10/−0.76, p=0.004). A specific risk profile, including higher total cholesterol level, higher BMI, lower physical activity level, higher HbA

Conclusions:

In summary, these findings support evidence that cardiovascular disease may have its origins early in life. Prospective and/or intervention studies are required to confirm whether the observed associations are involved in the causal pathway for retinal vascular calibre.
The significance of physiotherapy in the treatment of children with multiple traumatic injuries
Authors: Wolański Wojciech , Bęgowska-Falkowska Aleksandra , Słonka Karina , Hyla-Klekot Lidia
Published: February 2017

Rapid development of civilization, observed in the contemporary world, makes human life easier, but at the same time, it brings a lot of dangers and threats. Constant ‘race against the clock’, moving from one place to another, stress and fatigue result in a growing number of traffic accidents which claim the lives and health of adults as well as children. Most of the injuries are multiple traumatic injuries that affect two or more bodily organs or systems and cause damage to at least two body areas. They constitute exceptionally difficult, interdisciplinary therapeutic problem which is the most frequent cause of death and development of a disease in children over 3 years old.

The aim of this research study was to conduct a retrospective analysis of physiotherapeutic procedures applied in the course of treatment of multiple trauma in children hospitalized in the Voivodship Medical Centre in Opole (Wojewódzkie Centum Medyczne).

It was carried out in the group of 9 children aged 5-17 in the years of 2011-2013. As multiorgan injuries in children affect a developing body, they require a professional, interdisciplinary, therapeutic proceeding. The analysis of the ways of treatment shows that after securing basic vital functions of the children and the stabilization of their health, physiotherapy takes its turn. Its main role is to restore child’s physical ability, which was disordered due to the injury, as much as it is possible. According to the analysis of clinical and therapeutic progress in all 9 patients suffering from multi-organ injuries, an attempt has been undertaken to set the scheme of physiotherapeutic proceeding in such cases. Preparing the scheme, all basic rules of physiotherapeutic proceeding have been taken into consideration, namely, introducing therapeutic activities as soon as possible taking into account patient’s condition and the extent of damage/injury.

The analysis proved that physiotherapy in multiple trauma is a complicated process that involves many techniques, methods and procedures. Moreover, every physiotherapeutic treatment ought to be adjusted individually to the patient depending on their condition and dysfunctions. Skilful management of the rehabilitation process significantly accelerates patient’s recovery to the extent of proper physical function, and limits the degree of disability after multipletrauma.
The effect of rehabilitation on the perceived level of fatigue of patients with multiple sclerosis
Authors: Pasiut Szymon , Juda Katarzyna , Mirek Elżbieta , Szymura Jadwiga
Published: February 2017

Fatigue is one of the three major symptoms affecting about 70-90% of multiple sclerosis patients (MS, ICD-10 G35), and a predominant symptom in nearly 50% of the patients. Fatigue is defined as a subjective feeling of lack of energy to start and continue an activity, which is not related to depression, or muscle weakening. There are similarities and differences between the fatigue experienced by healthy individuals, and the fatigue in multiple sclerosis patients. In both instances, fatigue becomes more intense as a result of stress, or physical and mental effort. Fatigue usually subsides after a rest, or a good night’s sleep. In MS patients, fatigue can be caused by even light physical, or mental exertion, and it takes longer than normal to go away. Rest, or sleep do not reduce its intensity.

The main objective of the study was to assess the effect of a two-week rehabilitation programme on the perceived level of fatigue in multiple sclerosis patients.

The study included 32 patients with clinically confirmed MS who underwent a comprehensive 2-week rehabilitation programme. The study was conducted at the “Ostoja” Centre for Multiple Sclerosis Patients in Wola Batorska from 15 July to 13 October 2013. It was based on a self-designed questionnaire which contained the basic patient data (age, sex), information on duration of the disease, type of MS the patient had been diagnosed with, as well as the Kurtzke Expanded Disability Status Scale, and the Fatigue Severity Scale. The respondents were assessed twice: on the first and last day of their stay in the Centre. The statistical analysis was carried out using the STATISTICA 10.0 software.

The analysis revealed a statistically highly significant dependence between the two-week rehabilitation programme and the perceived level of fatigue. This means that the perceived level of fatigue in MS patients was significantly reduced as a result of the rehabilitation programme used.

After the two-week rehabilitation programme, the perceived level of fatigue in MS patients significantly decreased. The two-week rehabilitation programme significantly reduced the number of patients suffering from chronic fatigue symptoms as assessed on the Fatigue Severity Scale.
Rheological properties and crystallization behaviors of long chain branched polyethylene prepared by melt branching reaction
Authors: Liang Xiao-kun , Luo Zhu , Yang Le , Wei Jiang-tao , Yuan Xia , Zheng Qiang
Published: February 2017

Long chain branched polyethylene (LCBPE) without gel was prepared by melt branching reaction in a Haake torque rheometer in the presence of peroxide and different multi-functional acrylate monomers, and the optimal reaction time was determined according to the transient torque curves. The Fourier transform infrared (FTIR) results indicated that multi-functional monomers had been grafted onto HDPE backbone. Rheometer, 13C NMR, and high-temperature gel permeation chromatography (HT-GPC) coupled with triple detectors were used to characterize the microstructure of the LCBPE. The results showed the LCB content and the degree of branching increased with the increasing of functionality of the multi-functional monomers. Moreover, the LCBPE samples exhibited higher apparent zero shear rate activation energy and clear strain-hardening behavior compared with pure HDPE. Various rheological plots including viscosity, storage modulus, loss angle, and Cole-Cole plots were used to distinguish LCBPE from linear HDPE. A possible mechanism for melt branching reaction was also discussed in this paper. Differential scanning calorimetry (DSC) and polarized optical microscopy (POM) were used to study the influences of LCB on the crystallization behavior and crystal morphology of all samples. It was found that the melt temperature and crystal morphologies of LCBPE were evidently different from that of pure HDPE due to the introduction of LCB.
CXCL13 levels are more increased in cerebrospinal fluid and plasma of patients with acute infectious than in non-infectious diseases of the central nervous system
Authors: Țilea Brîndușa , Voidăzan Septimiu , Bălașa Rodica , Huțanu Adina , Fodor Andrea
Published: February 2017

Background: During the acute inflammatory process, the CXCL13 chemokine plays an important role in B cell recruitment within the central nervous system (CNS).

Objective: The objective of the study consisted of the evaluation of CXCL13 chemokine cerebral spinal fluid (CSF) and plasma levels in patients with acute infectious and non-infectious neurological diseases correlated with pleocytosis and CSF protein levels.

Material and method: This retrospective study was conducted over one year and included 72 patients. Thirty-eight patients (52.8%) suffering from infectious neurological disease, acute viral and bacterial meningitis, meningoencephalitis, and 34 patients (44.2%) diagnosed with non-infectious neurological diseases.

CXCL13 chemokine CSF and plasma levels were determined through the ELISA technique with the Human CXCL13/BLC/BCA-1 kit. CSF cell count, glucose and protein levels, along with anti-Borrelia burgdorferi antibodies were monitored using the ELISA technique.

Results: CXCL13 chemokine levels in the CSF of patients with acute infectious neurological diseases showed a median value of 23.07 pg/mL, which was significantly higher in comparison with the median value of 11.5 pg/mL of patients with noninfectious neurological diseases (p-0.03). CXCL13 median plasma concentration in patients with infectious neurological diseases was 108.1 pg/mL, in comparison with the second patient category, 50.7 pg/ml (p-0.001). We observed a statistically significant association between CXCL13 concentrations, CSF cell count and proteins. The higher the CXCL13 chemokine level, the more increased the cell count was.

Conclusions: CXCL13 levels in the CSF was significantly increased in patients with acute infectious neurological diseases compared with patients with non-infectious diseases. Moreover, CXCL13 chemokine concentration was significantly correlated with the number of cells and proteins in the CSF of patients suffering from neuroinfections.
Microbial biofilm in human health - an updated theoretical and practical insight
Authors: Licker Monica , Moldovan Roxana , Hogea Elena , Muntean Delia , Horhat Florin , Baditoiu Luminița , Rogobete Alexandru Florin , Tîrziu Emil , Zambori Csilla
Published: February 2017

The term biofilm designates an aggregate of microorganisms belonging to one or more species which adhere to various surfaces but also to each another. These microbial communities are included and interconnected within an organic structure known as slime, composed of protein substances, polysaccharides, and DNA.

The Center for Disease prevention and control considers infections with bacteria in biofilms among the 7 most important challenges which must be overcome in order to improve the safety of health services. The risk of microbial biofilm development exists for a long list of medical devices and equipment, as well as in certain diseases such as cystic fibrosis. An aggravating aspect is represented by the almost 1,000 times higher antimicrobial resistance of bacteria growing and multiplying within biofilms. Thus, in case of biofilm-infected medical devices, the resistance to antimicrobial treatments requires the removal of the device which essentially means the failure of the exploratory or therapeutic intervention in question.

The role of microbial biofilms in medical pathology is a subject that raises interest for both researchers and clinicians in order to establish new methods for prevention and treatment of biofilms. This paper is intended as an overview in the management of microbial biofilms, presenting future insights, with technological progress in microscopy, molecular genetics, and genome analysis. Therefore the present paper will focus on describing the mechanisms involved in biofilm development, biofilm related infections, methods of detection and quantification of microbial communities and therapeutical approaches.
GJB2 and GJB6 genes mutations in children with non-syndromic hearing loss
Authors: Lazăr Călin , Popp Radu , Al-Khzouz Camelia , Mihuț Gheorghe , Grigorescu-Sido Paula
Published: February 2017

Introduction. At the moment there is not enough data in Romania about the incidence of the main genetic mutations which can cause hearing loss.

Objective. The current research aims to determine on a representative sample the prevalence of two mutations of genes GJB2 -c.35delG and p.W24X- and two mutations of genes GJB6 -del(GJB6-D13S1830), del(GJB6-D13S1854) respectively - in patients with congenital nonsyndromic sensorineural hearing loss (CNSHL).

Methods: The sample group included 179 children with CNSHL. The evaluation consist in: a.Clinical, laboratory and imagistic examination; b.ENT exam and audiological evaluation. c.Two methods (semi-nested PCR technique followed by RFLP, validated with ARMS-PCR analysis) for detection of c.35delG and pW24X mutations; d.PCR-multiplex technique for detecting del(GJB6-D13S1830) and del (GJB6-D13S1854).

Results: The audiological diagnosis was: profound hearing loss in 116 patients (64.8%), severe hearing loss in 29 children (16.2%) and moderate hearing loss in 34 patients (representing 19% of the trial patients). The prevalence for the three mutations was: 27.3 % for c.35delG, 3.6 % for p.W24X and 0.28% for del(GJB6-D13S1830). The detection of the three mutations (two on GJB2 gene and one on GJB 6 gene) has allowed to establish the genetic cause for deafness in 45 patients, representing 25.14% of the sample group. Our study is reporting the first case in Romania with a mutation of gene GJB6. Mutation del(GJB6-D13S1854) lacked in all 179 patients.

Conclusion: The prevalence data obtained in the current research are comparable to data communicated by studies from other European countries.
Can we find accessible and relevant markers for sepsis outcome?
Authors: Cioară Andreea Paula , Flonta Mirela , Binder Astrid , Pop Andreea , Siladi Violeta , Todor Nicolae , Cristea Victor , Lupse Mihaela
Published: February 2017

Background and Aim: Sepsis is a life-threatening disease with high mortality, therefore establishing early diagnostic and finding reliable prognostic biomarkers is vital. We aimed to investigate the prognostic role, as a single value, of serum procalcitonin, C-reactive protein, serum lactate, platelets number and serum glucose level in septic patients, all measured in the first 24 hours after hospital admittance.

Materials and methods: This retrospective study included 241 adult patients with sepsis, severe sepsis or septic shock. We use data from patients observation sheets. Data that were collected include: demographic parameters, comorbidities, necessity of mechanical ventilation and laboratory variables. We performed the statistical analysis with the chi square test for nonparametric data and to analyse the accuracy of prediction we used the receiver - operator curves with the level of significance set at p < 0.05.

Results: From 241 patients with a median age of 68 years, 127 (52.69%) were male.113 patients had severe sepsis. 89 patients (36.9%) died and male had an increase mortality rate. Most cases were respiratory sepsis (45.20%). The highest mortality rate was in septic shock (51.2%). Procalcitonin, C-reactive protein and glucose serum level at admittance were not correlated with mortality. The serum levels of creatinine >1.67 mg/dL and serum lactate >1.9 mmol/L at admittance were correlated with mortality (p < 0.01). The cutoff value of 121×103/uL platelets number was also correlated with mortality (p < 0.01).

Conclusions: Our findings suggest that serum creatinine, serum lactate and the platelets number could be used as prognostic markers in septic patients at admittance.
OXA-48-Carbapenemase-Producing Klebsiella pneumoniae infections - the first cases diagnosed in Romanian National Institute of Infectious Diseases
Authors: Popescu Cristina , Popescu Gabriel Adrian , Dorobăț Olga , Rafilă Alexandru , Tănase Diana , Mikula Claudia , Weissensteiner Gudrun , Huhulescu Steliana
Published: February 2017

We report first description of clinical cases of OXA-48 carbapenemase-producing Klebsiella pneumoniae originating from patients hospitalized in the most important Infectious Diseases Hospital from Romania, between December 2012 and March 2013. All strains were isolated from patients who were previously admitted in surgical wards. None of the patients had been admitted in a hospital outside of Romania.
The Robin, Erithacus Rubecula (Passeriformes, Turdidae), as a Component of Heterotrophic Consortia of Forest Cenoses, Northeast Ukraine. Part 2
Authors: Chaplygina A. B. , Yuzyk D. I. , Savynska N. O.
Published: February 2017

The role of the robin as a determinant of heterotrophic consortia is considered. The robin is a consort of determinants of autotrophic consortia, which core is represented mostly by dominating species of deciduous trees (Quercus robur Linnaeus, 1753, Tilia cordata Miller, 1768, Acer platanoides Linnaeus, 1753, Acer campestre Linnaeus, 1753), and also by sedges (Carex sp.) and grasses (Poaceae), connected with the determinants by fabric links. The robin also belongs to the concentr of the second and higher orders as a component of forest biogeocenoses and it is also the main determinant in species composition of the insects inhabiting bird nests. As a result of the taxonomic analysis of invertebrates in the robin nests, it has been found out that the most numerous class was Insecta (9 orders and 27 families), with the dominance of Coleoptera (30.7 %). The nidicolous fauna of the robin (38 species) was dominated by zoophages along with parasites and hematophages such as Hippoboscidae (46.4 %). The percentage of phytophages and saprophages among the invertebrate nest inhabitants was somewhat less (21 % each), then followed necrophages (12 %). Zoophages and parasites also dominated according to the number of objects in the nests (42 %; n = 150), the less was the portion of phytophages (34 %), saprophages (18 %), and necrophages (6 %). The highest number of species and objects of zoophages was recorded for climax and mature biocenoses (oak forests in NNP “HL” and pine cenoses in NNP “H””).
New Details of the Eurasian Beaver’s, Castor Fiber (Rodentia, Castoridae), Expansion in the Lowland Part of Transcarpathia, Ukraine
Authors: Barkasi Z.
Published: February 2017

The present paper contains information on a new beaver colony discovered in the Chornyi mochar tract, which is located in the lowland part of Transcarpathia (= Zakarpattia Region). This rodent species disappeared from the territory of Transcarpathia most likely in the 18th century. Its first reappearance was recorded in 2003. Since, the Eurasian beaver has demonstrated a rapid expansion, primarily along the main rivers. The discovered by us colony allows to suggest that the beaver is continuing its dispersal, entering far into the main river’s tributaries and other shallower water bodies. Consequently, we are witnessing not only the expansion of the species’ geographical range, but also the enlargement of the number of habitat types occupied by the animal. The possibilities and supposed consequences of the species’ further expansion within the tract are shown as well.
Key to the Species of Ukrainian Notodontid Moths (Lepidoptera, Notodontidae) On the Egg Characters
Authors: Dolinskaya I. V.
Published: February 2017

A key for identification of 39 species from 20 genera of Ukrainian notodontid moths based on the the eggs is provided. Reliable diagnostic characters, which do not disappear with the injury of eggs or eggs preserved for a long time in alcohol were used. The characters as egg shape, egg and chorion colour, shape of gnawed holes in eggs before setting out of caterpillars, the type of oviposition and the chorionic sculpture are applied. Clear characters that are typical for the live eggs, which vary in the process of egg development are revealed. These are characters of egg colour and pattern. In the key such characters are kept by stable signs that do not disappear aft er eggs traumatizing. The key is illustrated in details with photographs made using a digital camera and scanning electron microscope.
Development Stability and Cytogenetic Homeostasis of Perca Fluviatilis (Perciformes, Percidae) in the Rivers of Rivne Region
Authors: Klimenko M. O. , Biedunkova O. O.
Published: February 2017

The article presents the results of the study on nuclear damages or injuries of red blood cells (RBCs) and asymmetry of meristic characters of the European perch (Perca fluviatilis Linnaeus 1758) that lives in small and medium rivers of Rivne Region. The research has found that the species representatives living in the small rivers demonstrated worse cytogenetic homeostasis indicators compared to the fish from the medium rivers: the lowest frequency of P. fluviatilis’ nuclear damages appeared to be 4.25 times higher for the individuals living in the small rivers given the noticeable excess of spontaneous mutations by average damage frequency. Fish morphological homeostasis demonstrates a tendency to injuries in small rivers as well. The functional relationships between the studied parameters which have been established by the author were “close” for the fish from the small rivers and primary “moderate” for the fish from the medium rivers. It is concluded that the enhanced activity of the stressors existing in the water environment affects the physiological state of the P. fluviatilis species.
Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine
Authors: Doyle Hillary H. , Eidson Lori N. , Sinkiewicz David M. , Murphy Anne Z.
Published: February 2017

Although morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require two to three times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal μ-opioid receptor, morphine binds to the innate immune receptor toll-like receptor 4 (TLR4) localized primarily on microglia. Morphine action at TLR4 initiates a neuroinflammatory response that directly opposes the analgesic effects of morphine. Here, we test the hypothesis that the attenuated response to morphine observed in females is the result of increased microglia activation in the periaqueductal gray (PAG), a central locus mediating the antinociceptive effects of morphine. We report that, whereas no overall sex differences in the density of microglia were noted within the PAG of male or female rats, microglia exhibited a more “activated” phenotype in females at baseline, with the degree of activation a significant predictor of morphine half-maximal antinociceptive dose (ED50) values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males and was accompanied by increased transcription levels of IL-1β and a significant rightward shift in the morphine dose–response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone potentiated morphine antinociception significantly in females such that no sex differences in ED50were observed. These results demonstrate that PAG microglia are sexually dimorphic in both basal and LPS-induced activation and contribute to the sexually dimorphic effects of morphine in the rat.

SIGNIFICANCE STATEMENTWe demonstrate that periaqueductal gray (PAG) microglia contribute to the sexually dimorphic effects of morphine. Specifically, we report that increased activation of microglia in the PAG contributes to the attenuated response to morphine observed in females. Our data further implicate the innate immune receptor toll-like receptor 4 (TLR4) as an underlying mechanism mediating these effects and establish that TLR4 inhibition in the PAG of females reverses the sex differences in morphine responsiveness. These data suggest novel methods to improve current opioid-based pain management via inhibition of glial TLR4 and illustrate the necessity for sex-specific research and individualized treatment strategies for the management of pain in men and women.
A Unique “Angiotensin-Sensitive” Neuronal Population Coordinates Neuroendocrine, Cardiovascular, and Behavioral Responses to Stress
Authors: de Kloet Annette D. , Wang Lei , Pitra Soledad , Hiller Helmut , Smith Justin A. , Tan Yalun , Nguyen Dani , Cahill Karlena M. , Sumners Colin , Stern Javier E. , Krause Eric G.
Published: February 2017

Stress elicits neuroendocrine, autonomic, and behavioral responses that mitigate homeostatic imbalance and ensure survival. However, chronic engagement of such responses promotes psychological, cardiovascular, and metabolic impairments. In recent years, the renin-angiotensin system has emerged as a key mediator of stress responding and its related pathologies, but the neuronal circuits that orchestrate these interactions are not known. These studies combine the use of the Cre-recombinase/loxP system in mice with optogenetics to structurally and functionally characterize angiotensin type-1a receptor-containing neurons of the paraventricular nucleus of the hypothalamus, the goal being to determine the extent of their involvement in the regulation of stress responses. Initial studies use neuroanatomical techniques to reveal that angiotensin type-1a receptors are localized predominantly to the parvocellular neurosecretory neurons of the paraventricular nucleus of the hypothalamus. These neurons are almost exclusively glutamatergic and send dense projections to the exterior portion of the median eminence. Furthermore, these neurons largely express corticotrophin-releasing hormone or thyrotropin-releasing hormone and do not express arginine vasopressin or oxytocin. Functionally, optogenetic stimulation of these neurons promotes the activation of the hypothalamic-pituitary–adrenal and hypothalamic-pituitary–thyroid axes, as well as a rise in systolic blood pressure. When these neurons are optogenetically inhibited, the activity of these neuroendocrine axes are suppressed and anxiety-like behavior in the elevated plus maze is dampened. Collectively, these studies implicate this neuronal population in the integration and coordination of the physiological responses to stress and may therefore serve as a potential target for therapeutic intervention for stress-related pathology.

SIGNIFICANCE STATEMENTChronic stress leads to an array of physiological responses that ultimately rouse psychological, cardiovascular, and metabolic impairments. As a consequence, there is an urgent need for the development of novel therapeutic approaches to prevent or dampen deleterious aspects of “stress.” While the renin-angiotensin system has received some attention in this regard, the neural mechanisms by which this endocrine system may impact stress-related pathologies and consequently serve as targets for therapeutic intervention are not clear. The present studies provide substantial insight in this regard. That is, they reveal that a distinct population of angiotensin-sensitive neurons is integral to the coordination of stress responses. The implication is that this neuronal phenotype may serve as a target for stress-related disease.
NDR1 protein kinase promotes IL‐17‐ and TNF‐α‐mediated inflammation by competitively binding TRAF3
Authors: Ma Chunmei , Lin Wenlong , Liu Zhiyong , Tang Wei , Gautam Rahul , Li Hui , Qian Youcun , Huang He , Wang Xiaojian
Published: February 2017

Interleukin 17 (IL‐17) is an important inducer of tissue inflammation and is involved in numerous autoimmune diseases. However, how its signal transduction is regulated is not well understood. Here, we report that nuclear Dbf2‐related kinase 1 (NDR1) functions as a positive regulator of IL‐17 signal transduction and IL‐17‐induced inflammation. NDR1 deficiency or knockdown inhibits the IL‐17‐induced phosphorylation of p38, ERK1/2, and p65 and the expression of chemokines and cytokines, whereas the overexpression of NDR1 promotes IL‐17‐induced signaling independent of its kinase activity. Mechanistically, NDR1 interacts with TRAF3 and prevents its binding to IL‐17R, which promotes the formation of an IL‐17R‐Act1‐TRAF6 complex and downstream signaling. Consistent with this, IL‐17‐induced inflammation is significantly reduced in NDR1‐deficient mice, and NDR1 deficiency significantly protects mice from MOG‐induced experimental autoimmune encephalomyelitis (EAE) and 2,4,6‐trinitrobenzenesulfonic acid (TNBS)‐induced colitis likely by its inhibition of IL‐17‐mediated signaling pathway. NDR1 expression is increased in the colons of ulcerative colitis (UC) patients. Taken together, these findings suggest that NDR1 is involved in the development of autoimmune diseases.
MYC‐driven inhibition of the glutamate‐cysteine ligase promotes glutathione depletion in liver cancer
Authors: Anderton Brittany , Camarda Roman , Balakrishnan Sanjeev , Balakrishnan Asha , Kohnz Rebecca A , Lim Lionel , Evason Kimberley J , Momcilovic Olga , Kruttwig Klaus , Huang Qiang , Xu Guowang , Nomura Daniel K , Goga Andrei
Published: February 2017

How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC‐driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl‐tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC‐driven tumors. We find that fewer glutamine‐derived carbons are incorporated into GSH in tumor tissue relative to non‐tumor tissue. Expression of GCLC, the rate‐limiting enzyme of GSH synthesis, is attenuated by the MYC‐induced microRNA miR‐18a. Inhibition of miR‐18a in vivo leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC‐driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC‐dependent attenuation of GCLC by miR‐18a contributes to GSH depletion in vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine.
Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours
Authors: De Sousa Sunita M C , McCabe Mark J , Wu Kathy , Roscioli Tony , Gayevskiy Velimir , Brook Katelyn , Rawlings Lesley , Scott Hamish S , Thompson Tanya J , Earls Peter , Gill Anthony J , Cowley Mark J , Dinger Marcel E , McCormack Ann I
Published: February 2017

Objective

Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel.

Design

We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia. A custom NGS panel was performed on germline DNA to interrogate eight FPTS genes. Genome data were analysed via a custom bioinformatic pipeline, and validation was performed by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed in cases with heightened suspicion for MEN1, CDKN1B and AIP mutations. The main outcomes were frequency and pathogenicity of rare variants in AIP, CDKN1B, MEN1, PRKAR1A, SDHA, SDHB, SDHC and SDHD.

Results

Forty-four patients with pituitary tumours, 14 of whom had a personal history of other endocrine tumours and/or a family history of pituitary or other endocrine tumours, were referred from endocrine tertiary-referral centres across Australia. Eleven patients (25%) had a rare variant across the eight FPTS genes tested: AIP (p.A299V, p.R106C, p.F269F, p.R304X, p.K156K, p.R271W), MEN1 (p.R176Q), SDHB (p.A2V, p.S8S), SDHC (p.E110Q) and SDHD (p.G12S), with two patients harbouring dual variants. Variants were classified as pathogenic or of uncertain significance in 9/44 patients (20%). No deletions/duplications were identified in MEN1, CDKN1B or AIP.

Conclusions

A high yield of rare variants in genes implicated in FPTS can be found in selected patients using an NGS panel. It may also identify individuals harbouring more than one rare variant.
Protein kinase C regulates Twist1 expression via NF-κB in prostate cancer
Authors: Shiota Masaki , Yokomizo Akira , Takeuchi Ario , Kashiwagi Eiji , Dejima Takashi , Inokuchi Junichi , Tatsugami Katsunori , Uchiumi Takeshi , Eto Masatoshi
Published: February 2017

The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that protein kinase C (PKC) activation followed by Twist1 and androgen receptor (AR) induction played a critical role in castration resistance, but the precise molecular mechanism remains unknown. This study aimed to elucidate the relevant molecular mechanism, focusing on NF-κB transcription factor. We examined the activity of NF-κB after PKC inhibition, and the expression of Twist1 and AR after inhibition of NF-κB in human prostate cancer cells. We also investigated the status of PKC/NF-κB after inhibition of AR signaling in cells resistant to hormonal therapy. As a result, inhibition of PKC signaling using knockdown and small-molecule inhibition of PKC suppressed RelA activity, while blocking NF-κB suppressed Twist1 and AR expression. Conversely, inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction. Finally, NF-κB was activated in both castration-resistant and enzalutamide-resistant cells. In conclusion, NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.
Gja1 acts downstream of Acvr1 to regulate uterine decidualization via Hand2 in mice
Authors: Yu Hai-Fan , Yue Zhan-Peng , Wang Kai , Yang Zhan-Qing , Zhang Hong-Liang , Geng Shuang , Guo Bin
Published: February 2017

Although Gja1 has been proved to play an important role in uterine decidualization, its regulatory mechanism remains largely unknown. Here, we showed that Gja1 was highly expressed in the decidual cells and promoted the proliferation of uterine stromal cells and expression of Prl8a2 and Prl3c1, which were two well-known differentiation markers for decidualization. Further analysis revealed that Gja1 might act downstream of Acvr1 and cAMP to regulate the differentiation of uterine stromal cells. Administration of cAMP analog 8-Br-cAMP to Acvr1 siRNA-transfected stromal cells resulted in an obvious increase of Gja1 expression, whereas PKA inhibitor H89 impeded the induction of Gja1 elicited by Acvr1 overexpression, indicating that cAMP–PKA signal mediates the regulation of Acvr1 on Gja1 expression. In uterine stromal cells, knockdown of Gja1 blocked the cAMP induction of Hand2. Moreover, siRNA-mediated downregulation of Hand2 impaired the stimulatory effects of Gja1 overexpression on the expression of Prl8a2 and Prl3c1, whereas constitutive expression of Hand2 reversed the inhibitory effects of Gja1 siRNA on stromal differentiation. Meanwhile, Gja1 might play a vital role in the crosstalk between Acvr1 and Hand2. Collectively, Gja1 may act downstream of cAMP–PKA signal to mediate the effects of Acvr1 on the differentiation of uterine stromal cells through targeting Hand2.
Akt signaling as a mediator of cardiac adaptation to low birth weight
Authors: Wang Kimberley C W , Botting Kimberley J , Zhang Song , McMillen I Caroline , Brooks Doug A , Morrison Janna L
Published: February 2017

Intrauterine insults, such as poor nutrition and placental insufficiency, can alter cardiomyocyte development, and this can have significant long-term implications for heart health. Consequently, epidemiological studies have shown that low-birth-weight babies have an increased risk of death from cardiovascular disease in adult life. In addition, intrauterine growth restriction can result in increased left ventricular hypertrophy, which is the strongest predictor for poor health outcomes in cardiac patients. The mechanisms responsible for these associations are not clear, but a suboptimal intrauterine environment can program alternative expression of genes such as cardiac IGF-2/H19, IGF-2R and AT1R through either an increase or decrease in DNA methylation or histone acetylation at specific loci. Furthermore, hypoxia and other intrauterine insults can also activate the IGF-1 receptor via IGF-1 and IGF-2, and the AT1 receptor via angiotensin signaling pathways; both of which can result in the phosphorylation of Akt and the activation of a range of downstream pathways. In turn, Akt activation can increase cardiac angiogenesis and cardiomyocyte apoptosis and promote a reversion of metabolism in postnatal life to a fetal phenotype, which involves increased reliance on glucose. Cardiac Akt can also be indirectly regulated by microRNAs and conversely can target microRNAs that will eventually affect other specific cardiac genes and proteins. This review aims to discuss our understanding of this complex network of interactions, which may help explain the link between low birth weight and the increased risk of cardiovascular disease in adult life.
Incidence and mortality of kidney cancer and its relationship with HDI (Human Development Index) in the world in 2012
Authors: Mohammadian Maryam , Pakzad Reza , Towhidi Farhad , Makhsosi Behnam Reza , Ahmadi Abbas , Salehiniya Hamid
Published: February 2017

Background and aims. Kidney cancer is among the cancers that have the highest growth rate in all age and racial groups in the world and is as the most deadly type of urinary tract cancer. Since awareness about this cancer incidence status and mortality is essential for better planning, this study aimed to investigate the incidence and mortality rate of kidney cancer and its relationship with the development index in the world in 2012.Method. This study was an ecological study conducted based on GLOBOCAN project of the World Health Organization (WHO) for the countries in the world. The correlation between Standardized Incidence Rates (SIRs) and Standardized Mortality Rates (SMRs) of kidney cancer with HDI and its components was assessed using SPSS18.Results. In total, 337,860 incidence cases (213,924 were men and 123,936 women) and 143,406 deaths (90,802 cases in men and 52,604 in women) of kidney cancer were recorded in 2012. A positive correlation of 0.731 was seen between SIR of kidney cancer and HDI (p≤0.001). Also, a negative correlation of 0.627was seen between SMR of kidney cancer and HDI (p≤0.001). Conclusion. The incidence and mortality rate of kidney cancer is higher in developed countries. A significant positive correlation has been seen between the standardized incidence and mortality rate of kidney cancer with the Human Development Index and its components. We need more studies to examine variation in incidence and mortality of kidney cancer and its related factors in the world.