bluuebunny/crossref_metadata_2025 huggingface dataset:
Dzieci – ideologia – indoktrynacja. Czasopismo „Płomyczek” w okresie II Rzeczypospolitej, PRL i III RP
Authors: Mrozek Justyna
Published: January 2020

The main purpose of this article is to answer the following questions: did the current sociopolitical situation determine the contents of kid’s Płomyczek magazine and if so, how. These questions suggest a hidden agenda of the periodical as a tool of indoctrination. The study was conducted on issues ofPłomyczek from the period of the Second Polish Republic, the Polish People’s Republic and the Third Polish Republic. The research shows similarities between the ideology in the said period and the content of Płomyczek, however indoctrination took place only during the Second Polish Republic and the Polish People’s Republic. Issues from the Third Polish Republic, unlike the earlier ones, criticized current politicians and stimulated reflective thinking.
Różnice dydaktyczne i edukacja. Rekonstrukcja przestrzeni narracyjnej w ujęciu Doroty Klus-Stańskiej (na przykładzie książki Paradygmaty dydaktyki. Myśleć teorią o praktyce)
Authors: Połonnikow Aleksandr
Published: January 2020

The article is dedicated to the narrative space of D. Klus-Stańska’s book: Paradygmaty dydaktyki. Myśleć teorią o praktyce (Wydawnictwo Naukowe PWN, 2018). The research perspective adopted in it is oriented towards the analysis of difficulties encountered in the practice of the written scientific text, the aim of which is to present educational constructs of different quality and at the same time to facilitate students’ navigation within their multiplicity. The study also assesses the educational procedures of the author, who experiments with the organization of a scientific text addressed to students and its graphic design. In the course of analyses, the specificity of the author’s textual techniques was identified, involving e.g. contextualisation of the languages described and their linguistic deconstruction, as well as intertextual exposition of educational narratives.
TEDARİK ZİNCİRİ YÖNETİMİNDE SATIN ALMA FONKSİYONUNUN DEĞİŞEN KARAKTERİ: STRATEJİK SATIN ALMA
Authors: AKTURAN Ulun
Published: January 2020

Satmalma, tekrar satmak veya üretimde kullanmak üzere yönetsel ve stratejik amaçları gerçekleştirmek için araç gereçlerin, esas parçaların elde edilmesidir. Satınalma, maliyetleri azaltmada ve operasyonel verimliliği sağlamada etkin bir araç olmasından dolayı önemli bir fonksiyondur. Satmalmada hem firma ihtiyaçlarının en etkin biçimde karşılanması hem de tedarikçilerle ilişkilerin etkin bir biçimde yürütülmesi esastır. Satmalma fonksiyonunun bu iki yönlü rolü, fonksiyonun diğer firma fonksiyonlarıyla daha bütünleştirilmesini gerektirmiştir. Bu çalışmada satmalma fonksiyonunun stratejik gelişimi ortaya koymak amaçlanmaktadır. Bu bağlamda satmalma fonksiyonunun gelişimi içerisinde geleneksel yaklaşım ve stratejik yaklaşım tanımlanmakta, stratejik satmalma süreci açıklanmakta, stratejik satmalmanın önemi ortaya konmaktadır.
MÜŞTERİ SADAKATİNİ GÜÇLENDİRMEDE HİZMET İYİLEŞTİRME ÇABALARININ ROLÜ
Authors: YÜKSEL ÇAKIR Fatma
Published: January 2020

Müşteri sadakati, bir işletmenin başarısı açısından önemli bir faktör olarak kabul edilmektedir. Hizmet iyileştirme, hizmet başarısızlıklarını belirleyen, müşteri problemlerini etkin bir şekilde çözümleyen, bu problemlerin asıl nedenini sınıflandıran, hizmet sistemini değerlendirme ve iyileştirme konusunda diğer performans ölçümleriyle ilişkilendirilebilen veriler sağlayan bir süreçtir. Hizmet iyileştirme stratejilerinin etkinliği, başarısızlığın memnuniyete dönüştürülmesi açısından önemli bir konudur. Müşterilerinin istek ve beklentilerini üstün bir hizmet kalitesi ile karşılayan işletmeler müşteri memnuniyetini en yüksek düzeyde başarabileceklerdir. Ve böylelikle varlıklarını sürdürebilecek, pazar paylarını, kârlarını ve dolayısıyla pazarlama etkinliğini artırabileceklerdir. Müşteri memnuniyetini başarmanın sonucunda müşterilerin işletmeye olan güven ve bağlılıklarının artması, uzun dönemli hizmet etkinliğinin sağlanmasında etkili bir faktör olan firma ile müşteri arasındaki ilişkiyi daha düzenli kılar ve güçlendirir.
POLİTİK DAVRANIŞ ve ÖRGÜTSEL ADALET ALGISI ARASINDAKİ İLİŞKİNİN BELİRLENMESİNE YÖNELİK BİR ARAŞTIRMA
Authors: YOLAÇ Sema
Published: January 2020

Örgütsel davranış literatüründe politik davranışla ilgili araştırma ve incelemeler giderek artmaktadır. Yöneticiler örgütsel başarı ve örgütün uyum içinde yönetiminde sözkonusu kavramı daha fazla dikkate alma gereği duymaktadırlar. Örgüt üyelerinin adalete ilişkin algıları onların örgüt içinde davranışlarını büyük ölçüde etkilemektedir. Bu bağlamda politik davranış ve örgütsel adalet kavramları çalışmada farklı boyutlarıyla ele alınarak açıklanmaya çalışılmıştır. Politik davranış ve örgütsel adalet ilişkisini belirlemek üzere bir anket çalışması yapılmıştır. Anket, farklı sektörlerde farklı alanlarda faaliyette bulunan işletme çalışanlarına uygulanmıştır. Çalışmada politik davranışı belirlemek amacıyla faktör analizi yapılmış ve politik davranışın boyutları ortaya konmuştur. Daha sonra politik davranış ve örgütsel adalet arasındaki ilişkiyi belirlemek amacıyla korelasyon analizi yapılmıştır. Sonuç olarak politik davranış ve örgütsel adalet arasında negatif bir ilişki tespit edilmiştir.
TÜKETİCİLERİN FARKLI PERAKENDECİ DENKLİĞİ ALGILAMA SEVİYELERİNE GÖRE PERAKENDECİ DENKLİĞİ BOYUTLARININ ALGILANMASINDA, SATINALMA NİYETİNDE VE DEMOGRAFİK ÖZELLİKLERDEKİ FARKLILIKLAR
Authors: YENİÇERİ Tülay , YARAŞ Eyyup
Published: January 2020

Tüketicilerin algılamalarıyla şekillenen “perakendeci denkliği” son yıllarda perakendecilik sektörü açısından öne çıkan bir kavram olarak göze çarpmaktadır. Perakendeci denkliği, perakendeciler için gerek tüketici odaklı hareket etmeyi sağlaması gerekse de perakendeci firmanın piyasadaki performansının bir göstergesi olması açısından önemlidir. Bu çalışmada perakendeci denkliğini farklı düzeylerde algılayan tüketicilerin mağaza bağlılığı, mağaza bilinilirliği, hizmet kalitesi, algılanan ürün kalitesi, fiyat/değer, alışveriş niyeti ve sosyo-demografik özellikler bakımından farklılık gösterip göstermediği araştırılmaktadır. Çalışmada tüketicileri,
perakendeci denkliğini algılamalarına göre gruplandırabilmek amacıyla hiyerarşik olmayan kümeleme analizi kullanılmıştır. Daha sonra araştırma hipotezlerini test etmek için kademeli ayırma analizi kullanılmıştır. Çalışmanın sonucunda
perakendeci denkliğinin başarısını değerlendirmede üç grup oluşturdukları ve her üç grubun (perakendeci denkliğini düşük, orta ve yüksek düzeyde algılayanlar) özellikle mağaza bağlılığı, mağaza bilinilirliği, fiyat/değer ve alışveriş niyeti bakımından farklılaştığı tespit edilmiştir.
ÇALIŞANLARIN ÖRGÜTE GÜVENLERİNİN ÖRGÜTSEL VATANDAŞLIK DAVRANIŞI ÜZERİNDEKİ ETKİSİ (İSTANBUL İLİNE BAĞLI BİR İLÇE BELEDİYESİNDE ARAŞTIRMA)
Authors: AYANOĞLU ŞİŞMAN Fatma , GEMLİK H. Nilay
Published: January 2020

Araştırmada örgütsel güvenin, örgütsel vatandaşlık davranışı üzerindeki etkisi belirlenmeye çalışılmıştır. Özellikle kamu kuruluşlarında bu tür çalışmaların az olması sebebiyle, araştırma için bir kamu kuruluşu tercih edilmiştir. Araştırmaya İstanbul’da bir ilçe belediyesinde görev yapan bütün işçi ve memurlar dahil edilmiştir. Araştırmada öncelikle deneklerin cinsiyet, görev, eğitim durumları, yaş ve kıdem gibi demografik özelliklerine ilişkin frekanslar belirlenmiştir. Daha sonra örgütsel güven ölçeği ve örgütsel vatandaşlık davranışı ölçeklerinin güvenilirlik ve faktör analizleri yapılmıştır. Ardından ölçeklerin faktörleri ile demografik değişkenler arasındaki ilişki tek tek analiz edilmiştir. Tüm bu analizlerden sonra örgütsel güven ölçeği ile örgütsel vatandaşlık davranışı ölçeği arasındaki ilişkinin tespit edilebilmesi için regresyon analizi yapılmıştır. Sonuç olarak örgütsel güven düzeyinin yüksek veya düşük olmasının örgütsel vatandaşlık davranışını etkilediği saptanmıştır.
SON DÖNEM POPÜLER TÜRK SİNEMASINDA (2000-2004) ULUSAL KÜLTÜR BAĞLAMINDA TEMA VE KONU SORUNSALI
Authors: KARAKAYA Serdar
Published: January 2020

Başlangıcından bugüne Türk Sineması; sansür, endüstrileşememe, televizyonla rekabet, yaratıcı senaryo, oyunculuk, salonsuzluk ve buna benzer onlarca sorunla var olagelmiştir. Bu sorunların kimi zamanla etkisini yitirmiş zamanla arttırmıştır. Bununla beraber endüstrileşememe ve gösterim sorunları da artarak sürmektedir. Son dönemde ise 1980’li yıllarda baş gösteren tema ve konu kısırlığı sorunu yeniden nüksetmiş, Popüler Türk Sinemasında var olmaya çalışan yapımcı-senarist ve yönetmenler ciddi bir tema ve konu kısırlığına saplanmıştır. Bunun sonucu olarak; Popüler Türk Sineması kendi toplumundan ve ulusal kültürden uzaklaşmış, ‘bize’ ait olmayan, ‘bizi’ anlatmayan hikâyelere yönelmiştir. Sinemacının temel çıkış noktası egemen Hollywood yapımları ve yayılmacı kültür haline gelmiştir.
Bu çalışmada Popüler Türk Sinemasının yaşadığı bu olgu ana batlarıyla irdelenecek, filmler bazında tema ve konu değerlendirmeleri yapılarak beş yılı kapsayan bu dönemde sinemamızın yöneldiği egemen tema ve konular ortaya çıkarılacaktır. Bu yönelişin nedenleri üzerinde durulup sonuç bölümünde önerilere değinilecektir.
Analysis of Laser Therapy Effects on Squamous Cell Carcinoma Patients: A System Biology Study
Authors: Mansouri Vahid , Rezaei-Tavirani Mostafa , Zadeh-Esmaeel Mohammad-Mehdi , Rezaei-Tavirani Sina , Razzaghi Mohammadreza , Okhovatian Farshad , Rostami-Nejad Mohammad , Ahmadzade Alireza
Published: January 2020

Introduction: The Mechanism of laser therapy and also its safety are 2 important features of the application of different types of lasers in medicine. This study aims to investigate the critically affected genes after the treatment of squamous cell carcinoma patients. Methods: The gene expression profiles of 4 squamous cell carcinoma patients that were treated via chemoradiotherapy (CRT) plus the laser and 3 similar patients without laser exposure from Gene Expression Omnibus (GEO) were downloaded and were screened to find critical genes via network analysis. The STRING database, Cytoscape software, and the Clue GO plug-in of Cytoscape software were used. Results: The genes HSX70 and NCC27 were determined as neighbors and HSPA1B, CLIC1, RAB13, PPIF, and LCE3D as hub genes. The over-expression of LCE3D was interpreted as the side effect of laser therapy. Apoptosis and the cell cycle were the dominant biological processes regulated by the HSP molecules in the laser-treated patients. Conclusion: The laser affected the main biological processes and simultaneously issued side effects
Radiation Therapy in Patients With Brain Cancer: Post-proteomics Interpretation
Authors: Asadzadeh-Aghdaei Hamid , Okhovatian Farshad , Razzaghi Zahra , Heidari Mohammadhossein , Vafaee Reza , Nikzamir Abdolrahim
Published: January 2020

Introduction: Radiation therapy (RT) as a common method for cancer treatment could result in some side effects. The molecular investigation is one of the approaches that could assist in decrypting the molecular mechanisms of this incident. For this aim, protein-protein interaction (PPI) network analysis as a complementary study of the proteome is conducted to explore the RT effect on brain cancer after the early stage of exposure prior to the appearance of the skin lesion. Methods: Cytoscape 3.7.2 and its plug-ins were used to analyze the network of differential expression of proteins (DEPs) in the treatment condition, and the centrality and pathway enrichment was conducted by the use of NetworkAnalyzer and ClueGO+CluePedia. Results: A network of 15 DEPs indicated that 6 nodes were key players in the network stability and SERPINC1 and F5 were from the query proteins. The pathways of post-translational protein phosphorylation, platelet degranulation, and complement and coagulation cascades were the most highlighted ones for the central nodes that could be affected in RT. Conclusion: The central proteins of the network of early-stage treatments could have additional importance in the mechanisms of radiotherapy response prior to skin lesions. Introduced biomarkers can be used for the patients’ follow-up. These candidates are worth precise attention for this type of therapy after approving by validation studies.
An Open-Label Study of Low-Level Laser Therapy Followed by Autologous Fibroblast Transplantation for Healing Grade 3 Burn Wounds in Diabetic Patients
Authors: Nilforoushzadeh Mohammad Ali , Kazemikhoo Nooshafarin , Mokmeli Soheila , Zare Sona , Dahmardehei Mostafa , Vaghar Doost Reza , Momeni Mahnoush , Ansari Fereshteh
Published: January 2020

Introduction: Low-level laser therapy (LLLT) has been used as an effective therapeutic modality since the mid-1960s. Although there have been several clinical studies using LLLT in wound healing, especially diabetic, pressure and venous ulcers, there are few reports of using this technique in burn ulcers. Autologous fibroblast transplantation is a novel treatment for patients with burns or venous ulcers. In this study for the first time, we used LLLT along with autologous fibroblast skin transplantation to treat grade 3 burn ulcers in diabetic patients. This case series describes the successful management of grade 3 burn ulcers in 10 diabetic patients using autologous fibroblast transplantation along with LLLT. Methods: After the approval of the Tehran University Ethics Committee (IR.TUMS.REC.1394.1683) and the Iran Registry of Clinical Trials (IRCT2016050226069N3), 10 diabetic patients with 10 grade 3 burn ulcers, who were a candidate for skin graft surgery, entered the study. Donor skin was biopsied using a 3 mm punch. Fibroblasts were extracted and cultured in vitro in the GMP Technique laboratory. The patients were treated using LLLT in 3-4 weeks during the time that fibroblast cultures became ready to use. Laser irradiation was done using red light, 650 nm, 150 mW, 1 J/cm2 for the bed of the ulcer and infra-red light 808 nm, 200 mW, 6 J/cm2 for the margins every other day for 10 sessions. Results: The mean wound size before treatment was 16.28 cm2 . All patients’ burn wounds healed completely after 10-12 weeks. Conclusion: We conclude that this method can be used as an effective method for treating large wounds, especially in complicated patients including the diabetics.
Comparison of Antibacterial Effects of Photodynamic Therapy, Modified Triple Antibiotic Paste and Calcium Hydroxide on Root Canals Infected With Enterococcus faecalis: An In Vitro Study
Authors: Asnaashari Mohammad , Eghbal Mohammad Jafar , Sahba Yaghmayi Amirali , Shokri Mehdi , Azari-Marhabi Saranaz
Published: January 2020

Introduction: A pivotal issue to achieve success in the treatment of the root canal is root canal disinfection. One of the most important bacteria that infect the root canal is Enterococcus faecalis. This study seeks to examine the effectiveness of 3 methods for disinfecting the root canal: photodynamic therapy, modified triple antibiotic paste (MTAP), and calcium hydroxide. Methods: Sixty-two single-rooted extracted anterior teeth were collected. After cleaning and disinfecting the teeth, their crowns were cut at the CEJ point. The root canals were shaped to the working length up to file F3 ProTaper (F1, F2, F3). EDTA 17% and sodium hypochlorite 2.5% were used for 5 minutes to wash and remove the smear layer, and then the apical foramen was sealed using composite. After that, the teeth were sterilized in an autoclave at 121°C for 15 minutes. Then 10 samples were taken randomly as the negative control. The remaining samples were immersed and cultivated in a suspension containing E. faecalis for 21 days. Then the samples were divided into 5 groups: 2 positive control groups, 1 group treated with the antibiotic paste with the concentration of 1 mg/mL, 1 group treated with calcium hydroxide, and 1 group treated with photodynamic therapy. Then, to collect the biofilm, the ProTaper file F4 was used. After that, the microbial suspension was provided and counting the colonies was carried out to compare the groups. Results: The findings indicated that the amount of CFU/mg of MTAP samples, including clindamycin, metronidazole, ciprofloxacin in the concentration of 1 mg/mL and photodynamic therapy and calcium hydroxide was lower than that in the control group. Antibiotic paste cleansed the root canal up to 99.9%. Photodynamic therapy reduced the amount of CFU/mg to 98.8%, and calcium hydroxide reduced the amount of CFU/mg to 94.13%. Conclusion: Using photodynamic therapy causes a reduction in the biofilm and inhibits the growth of the E. faecalis bacterium. In addition, in this study, MTAP with a concentration of 1 mg/mL was used, which expunged the bacteria completely. Meanwhile, calcium hydroxide had the weakest effect of all on the E. faecalis bacterium.
Laser Therapy for Peyronie’s Disease: A Randomized Control Double-Blind Pilot Study
Authors: Allameh Farzad , Razzaghi Mohammadreza , Rayegani Seyed Mansoor , Fallah-Karkan Morteza , Ranjbar Arash , Rahavian Amirhosein , Javadi Atefeh , Ghiasy Saleh , Razzaghi Zahra
Published: January 2020

Introduction: The management of Peyronie’s disease (PD) has remained a therapeutic dilemma for physicians and there is no gold standard treatment. In this paper, we decided to investigate the beneficial effect of the intralesional administration of verapamil compared with the intralesional administration of verapamil plus a low-intensity laser (LIL). Methods: Research was activated from May 2016 to May 2018 and a total of 38 men aged 18 years and older completed the investigation. The subjects were randomly divided into 2 groups. Group 1 was composed of 22 patients that were treated only by verapamil (5 mg) plus a sham laser weekly for 6 weeks, and group 2 consisted of 22 patients that received a laser, using the BTL–6000 HIGH-INTENSITY LASER 12 W machine and the same protocol of intralesional verapamil injection. The visual analogue scale (VAS) was used to evaluate pain during an erection, penile ultrasonography was used to measure plaque size, the penile curvature angle degree was measured using the photographs taken during an erection, and the International Index of Erectile Function questionnaire was used to assess erectile function. The follow-up treatment lasted for nine months, with visits performed in the 3rd and 9th months. Results: All study parameters decreased significantly after treatment in both arms, but the reduction in pain and penile curvature improvements in combination therapy revealed more significant changes in 3 months (p = .035, p=.032). Nevertheless, these improvements were not seen in the follow-up session after 9 months. Conclusion: A laser appears to be safe treatment modality in carefully-selected patients with PD. It has moderate efficacy in the short term.
Muscle Recovery Is Highlighted by IR Laser Therapy
Authors: Razzaghi Mohammadreza , Rostami-Nejad Mohammad , Rezaei-Taviran Mostafa , Zamanian Azodi Mona , Okhovatian Farshad , Mansouri Vahid , Ahmadi Nayebali
Published: January 2020

Introduction:In sports medicine, laser application has been well-established for the recovery of muscles. The mechanisms by which benefits of this kind of therapy can be studied is molecular research approach. Protein-protein interaction network analysis as one of the important complementary studies of proteomics can accelerate this goal by the identification of novel contributing markers.Methods:By the use of Cytoscape V3.7.1 and its applications, a network of differential expressed proteins (DEPs) from IR laser treatment samples were constructed and analyzed. Six hub-bottlenecks were determined, 4 of which were from differentially expressed proteins.Results:ClueGO discovered 4 biological processes related to these hub-bottlenecks that their function could alter due to IR laser therapy.Conclusion:In fact, by the expression changes of hub-bottlenecks including the up-regulation of HSP90s, one of the prominent biological processes in muscle recovery could be activated. This process is called nitric oxide synthase (NOS) activation that could be proposed as one of the underlying mechanisms of IR laser treatments in muscle recovery.
Topographic Mapping as a Basic Principle of Functional Organization for Visual and Prefrontal Functional Connectivity
Authors: O’Rawe Jonathan F. , Leung Hoi-Chung
Published: January 2020

The organization of region-to-region functional connectivity has major implications for understanding information transfer and transformation between brain regions. We extended connective field mapping methodology to 3-D anatomic space to derive estimates of corticocortical functional organization. Using multiple publicly available human (both male and female) resting-state fMRI data samples for model testing and replication analysis, we have three main findings. First, we found that the functional connectivity between early visual regions maintained a topographic relationship along the anterior-posterior dimension, which corroborates previous research. Higher order visual regions showed a pattern of connectivity that supports convergence and biased sampling, which has implications for their receptive field properties. Second, we demonstrated that topographic organization is a fundamental aspect of functional connectivity across the entire cortex, with higher topographic connectivity between regions within a functional network than across networks. The principle gradient of topographic connectivity across the cortex resembled whole-brain gradients found in previous work. Last but not least, we showed that the organization of higher order regions such as the lateral prefrontal cortex demonstrate functional gradients of topographic connectivity and convergence. These organizational features of the lateral prefrontal cortex predict task-based activation patterns, particularly visual specialization and higher order rules. In sum, these findings suggest that topographic input is a fundamental motif of functional connectivity between cortical regions for information processing and transfer, with maintenance of topography potentially important for preserving the integrity of information from one region to another.
Longitudinal Development of Brain Iron Is Linked to Cognition in Youth
Authors: Larsen Bart , Bourque Josiane , Moore Tyler M. , Adebimpe Azeez , Calkins Monica E. , Elliott Mark A. , Gur Ruben C. , Gur Raquel E. , Moberg Paul J. , Roalf David R. , Ruparel Kosha , Turetsky Bruce I. , Vandekar Simon N. , Wolf Daniel H. , Shinohara Russell T. , Satterthwaite Theodore D.
Published: January 2020

Brain iron is vital to multiple aspects of brain function, including oxidative metabolism, myelination, and neurotransmitter synthesis. Atypical iron concentration in the basal ganglia is associated with neurodegenerative disorders in aging and cognitive deficits. However, the normative development of brain iron concentration in adolescence and its relationship to cognition are less well understood. Here, we address this gap in a longitudinal sample of 922 humans aged 8–26 years at the first visit (M = 15.1, SD = 3.72; 336 males, 486 females) with up to four multiecho T2* scans each. Using this sample of 1236 imaging sessions, we assessed the longitudinal developmental trajectories of tissue iron in the basal ganglia. We quantified tissue iron concentration using R2* relaxometry within four basal ganglia regions, including the caudate, putamen, nucleus accumbens, and globus pallidus. The longitudinal development of R2* was modeled using generalized additive mixed models (GAMMs) with splines to capture linear and nonlinear developmental processes. We observed significant increases in R2* across all regions, with the greatest and most prolonged increases occurring in the globus pallidus and putamen. Further, we found that the developmental trajectory of R2* in the putamen is significantly related to individual differences in cognitive ability, such that greater cognitive ability is increasingly associated with greater iron concentration through late adolescence and young-adulthood. Together, our results suggest a prolonged period of basal ganglia iron enrichment that extends into the mid-twenties, with diminished iron concentration associated with poorer cognitive ability during late adolescence.

SIGNIFICANCE STATEMENTBrain tissue iron is essential to healthy brain function. Atypical basal ganglia tissue iron levels have been linked to impaired cognition in iron deficient children and adults with neurodegenerative disorders. However, the normative developmental trajectory of basal ganglia iron concentration during adolescence and its association with cognition are less well understood. In the largest study of tissue iron development yet reported, we characterize the developmental trajectory of tissue iron concentration across the basal ganglia during adolescence and provide evidence that diminished iron content is associated with poorer cognitive performance even in healthy youth. These results highlight the transition from adolescence to adulthood as a period of dynamic maturation of tissue iron concentration in the basal ganglia.
Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response
Authors: Court Angela C , Le‐Gatt Alice , Luz‐Crawford Patricia , Parra Eliseo , Aliaga‐Tobar Victor , Bátiz Luis Federico , Contreras Rafael A , Ortúzar María Ignacia , Kurte Mónica , Elizondo‐Vega Roberto , Maracaja‐Coutinho Vinicius , Pino‐Lagos Karina , Figueroa Fernando E , Khoury Maroun
Published: January 2020

Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune‐mediated diseases. They exert immunoregulatory and tissue‐restoring effects. MSC‐mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose‐dependent MitoT from mitochondria‐labeled MSCs mainly to CD4+ T cells, rather than CD8+ T cells or CD19+ B cells. Artificial transfer of isolated MSC‐derived mitochondria increases the expression of mRNA transcripts involved in T‐cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFβ1, leading to an increase in a highly suppressive CD25+FoxP3+ population. In a GVHD mouse model, transplantation of MitoT‐induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4+, CD8+, and IFN‐γ+ expressing cell infiltration. These findings point to a unique CD4+ T‐cell reprogramming mechanism with pre‐clinical proof‐of‐concept data that pave the way for the exploration of organelle‐based therapies in immune diseases.
Durvalumab-induced diabetic ketoacidosis followed by hypothyroidism
Authors: Patel Shivani , Chin Venessa , Greenfield Jerry R
Published: January 2020

Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200–1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40–4.80) and low free T4: 5.9 pmol/L (reference range: 8.0–16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI).

Learning points:

Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.

Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.

Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.

Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.
Significant cardiac disease complicating Graves’ disease in previously healthy young adults
Authors: Witczak J K , Ubaysekara N , Ravindran R , Rice S , Yousef Z , Premawardhana L D
Published: January 2020

Graves’ disease is associated with tachydysrythmia, cardiac ischaemia and cardiomyopathy – all uncommon in young adults without previous cardiac disease. We present three young individuals who developed cardiac complications after periods of uncontrolled Graves’ disease. Subject 1: A 34-year-old female had severe thyrotoxic symptoms for weeks. Investigations showed fT4: 98.4 (11–25 pmol/L), fT3: 46.9 (3.1–6.8 pmol/L), TSH <0.01 (0.27–4.2 mU/L) and thyrotrophin receptor antibody (TRAb): 34.8 (<0.9 U//l). She had appropriate treatment but several weeks later she became breathless despite improving thyroid function. Echocardiography showed a pericardial effusion of 2.9 cm. She responded well to steroids and NSAIDs but developed active severe Graves’ orbitopathy after early total thyroidectomy. Subject 2: A 28-year-old male developed thyrotoxic symptoms (fT4: 38 pmol/L, fT3: 13.9 pmol/L, TSH <0.01 (for over 6 months) and TRAb: 9.3 U/L). One month after starting carbimazole, he developed acute heart failure (HF) due to severe dilated cardiomyopathy – EF 10–15%. He partially recovered after treatment – EF 28% and had early radioiodine treatment. Subject 3: A 42-year-old woman who had been thyrotoxic for several months (fT4: 54.3; fT3 >46.1; TSH <0.01; TRAb: 4.5) developed atrial fibrillation (AF) and heart failure. Echocardiography showed cardiomegaly – EF 29%. She maintains sinus rhythm following early total thyroidectomy (EF 50%). Significant cardiac complications may occur in previously fit young adults, who have had uncontrolled Graves’ disease for weeks to months. Cardiac function recovers in the majority, but early definitive treatment should be discussed to avoid Graves’ disease relapse and further cardiac decompensation.

Learning points:

Cardiac complications of Graves’ disease are uncommon in young adults without previous cardiac disease.

These complications may however occur if Graves’ disease had been poorly controlled for several weeks or months prior to presentation.

Persistent symptoms after adequate control should alert clinicians to the possibility of cardiac disease.

Specific treatment of Graves’ disease and appropriate cardiac intervention results in complete recovery in the majority and carries a good prognosis.

Early definitive treatment should be offered to them to prevent cardiac decompensation at times of further relapse.
Adrenocortical carcinoma masquerading as pheochromocytoma: a histopathologic dilemma
Authors: Shetty Impana , Fuller Sarah , Raygada Margarita , Merino Maria J , Thomas B J , Widemann Brigitte C , Reilly Karlyne M , Pacak Karel , Del Rivero Jaydira
Published: January 2020

Adrenocortical carcinoma (ACC) is an aggressive cancer that originates in the cortex of the adrenal gland and generally has a poor prognosis. ACC is rare but can be more commonly seen in those with cancer predisposition syndromes (e.g. Li-Fraumeni and Lynch Syndrome). The diagnosis of ACC is sometimes uncertain and it requires the use of precise molecular pathology; the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. We describe a case of a 57-year-old woman with Lynch Syndrome and metastatic ACC who was initially diagnosed as having pheochromocytoma. The tumor was first identified at 51 years of age by ultrasound followed by a CT scan. She underwent a left adrenalectomy, and the histopathology identified pheochromocytoma. Two years later, she had tumor recurrence with imaging studies showing multiple lung nodules. Following a wedge resection by video-assisted thoracoscopic surgery (VATS), histopathology was read as metastatic pheochromocytoma at one institution and metastatic ACC at another institution. She later presented to the National Institutes of Health (NIH) where the diagnosis of ACC was confirmed. Following her ACC diagnosis, she was treated with mitotane and pembrolizumab which were stopped due to side effects and progression of disease. She is currently receiving etoposide, doxorubicin, and cisplatin (EDP). This case highlights the importance of using a multi-disciplinary approach in patient care. Thorough evaluation of the tumor’s pathology and analysis of the patient’s genetic profile are necessary to obtain the correct diagnosis for the patient and can significantly influence the course of treatment.

Learning points:

Making the diagnosis of ACC can be difficult as the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma.

Patients with Lynch Syndrome should undergo surveillance for ACC as there is evidence of an association between Lynch Syndrome and ACC.

Conducting a complete tumor immunoprofile and obtaining a second opinion is very important in cases of suspected ACC in order to confirm the proper diagnosis.

A multi-disciplinary approach including genetic testing and a thorough evaluation of the tumor’s pathology is imperative to ensuring that the patient receives an accurate diagnosis and the appropriate treatment.
Continuous decline in bone mineral density and deterioration of bone microarchitecture 7 years after Roux-en-Y gastric bypass surgery
Authors: Hansen Stinus , Jørgensen Niklas Rye , Hermann Anne Pernille , Støving Rene Klinkby
Published: January 2020

Objective

Roux-en-Y-gastric bypass (RYGB) surgery is an effective treatment for morbid obesity. A possible overlooked side effect is negative bone metabolic consequences.

Design

A seven-year prospective study following ten women and seven men after RYGB (baseline mean age 43 ± 8 years, BMI 42 ± 6 kg/m2).

Methods

Lumbar spine and total hip bone mineral density (BMD) using dual energy x-ray absorptiometry, distal radius and tibia bone geometry, volumetric BMD, microarchitecture and finite element estimated bone strength using high-resolution peripheral quantitative CT and biochemical markers of bone remodelling were assessed at baseline, 2 and 7 years.

Results

Compared to baseline, body weight was 24 ± 10% lower after 2 years and 21 ± 11% after 7 years. During the 7 years of follow-up, radius and tibia vBMD had declined 13 ± 8% and 8 ± 7% from baseline to 2 years and further 10 ± 7% and 7 ± 8% from 2 to 7 years (all P < 0.001). At both radius and tibia, cortical thickness declined and cortical porosity increased. From baseline to 7 years, there were clear indications of deteriorations of the trabecular network with fewer, more widely spaced and more in-homogeneously distributed trabeculae in both radius and tibia. Overall, declines in estimated bone strength of 16 ± 9% in radius and 16 ± 7% in tibia were observed (both P < 0.001).

Conclusion

Seven years after RYGB, evidence of continuous declines in BMD and ongoing deterioration of bone microarchitecture and reduced estimated bone strength compared to baseline and 2 years post-surgery results were found. These findings emphasize the need for regular assessment of bone health in patients with prior RYGB.
Who is afraid of non-normal data? Choosing between parametric and non-parametric tests
Authors: le Cessie Saskia , Goeman Jelle J , Dekkers Olaf M
Published: January 2020

When statistically comparing outcomes between two groups, researchers have to decide whether to use parametric methods, such as the t-test, or non-parametric methods, like the Mann–Whitney test. In endocrinology, for example, many studies compare hormone levels between groups, or at different points in time. Many papers apply non-parametric tests to compare groups. We will explain that non-parametric tests have clear drawbacks in medical research, and, that’s the good news, they are often not necessary.
PGRN exerts inflammatory effects via SIRT1-NF-κB in adipose insulin resistance
Authors: Li Huixia , Zhang Zhuanmin , Feng Dongxu , Xu Lin , Li Fang , Liu Jiali , Jin Xinxin , Qian Zhuang , Kang Xiaomin , Sun Hongzhi
Published: January 2020

Progranulin (PGRN), a multifunctional protein implicated in embryonic development and immune response, was recently introduced as a novel marker of chronic inﬂammation related with insulin resistance in obesity and type 2 diabetes mellitus. However, the potential mechanisms of PGRN on insulin signaling pathways are poorly understood. In this study, PGRN mediated the chemotaxis of RAW264.7, impaired insulin action and stimulated production of inflammatory factors in adipocytes, which was accompanied by increased c-Jun N-terminal kinase (JNK) activation and serine phosphorylation of insulin receptor substrate-1. PGRN knockdown partially led to an increase in insulin action as well as a decrease in the JNK activation and extracellular signal-regulated kinase phosphorylation in cells exposed to tumor-necrosis factor-α (TNF-α). Meanwhile, PGRN treatment resulted in an elevation of transcription factor nuclear factor κB (NF-κB) nuclear translocation and acetylation, and increased Il-1b, Il6, Tnf-a expression, whereas NF-κB inhibition reversed PGRN-induced insulin action impairment and inflammatory gene expression. Finally, we showed that sirtuin 1 (SIRT1) expression was downregulated by PGRN treatment, whereas SIRT1 overexpression improved PGRN-induced insulin resistance, NF-κB activation, and inflammatory gene expression. Our results suggest that PGRN regulates adipose tissue inflammation possibly by controlling the gain of proinflammatory transcription in a SIRT1-NF-κB dependent manner in response to inducers such as fatty acids and endoplasmic reticulum stress.
Hypoxia: involved but not essential for endometrial breakdown in mouse menstural-like model
Authors: Chen Xihua , Wu Bin , Wang Shufang , Liu Jianbing , Gao Haijun , Zhou Fang , Nan Nan , Zhang Bonan , Wang Jiedong , Xu Xiangbo , He Bin
Published: January 2020

Menstruation is a specific physiological phenomenon that occurs in women. However, molecular mechanisms underlying this phenomenon are still unclear. According to the classical theory, tissue hypoxia resulting from vasoconstriction of the spiral arteries after progesterone (P4) withdrawal initiates the breakdown of the endometrium at the earliest stage of menstruation. However, this theory has been challenged by previous studies that have questioned the function and even the existence of hypoxia during menstruation. In this study, we not only provide convincing evidence that hypoxia exists during endometrial breakdown, but also further explore the role of hypoxia and hypoxia-inducible factor 1 (HIF1) in this process. Based on mouse menstrual-like model and experiments with human decidual stromal cells, we observed that P4 withdrawal induced both hypoxia and HIF1 activation; however, endometrial breakdown was triggered only by P4 withdrawal. Hypoxia significantly enhanced the mRNA expression of specific matrix metalloproteinases (MMPs) under the conditions of P4 withdrawal. In conclusion, hypoxia is involved but not an essential component of endometrial breakdown during menstruation.
Dynamic profile of EVs in porcine oviductal fluid during the periovulatory period
Authors: Laezer Inga , Palma-Vera Sergio E , Liu Fan , Frank Marcus , Trakooljul Nares , Vernunft Andreas , Schoen Jennifer , Chen Shuai
Published: January 2020

In mammals, around the time of ovulation, the hormonal profile dynamically changes in synchrony with reproductive events occurring in the oviduct, that is, sperm arrival, fertilization, and early embryo development. Extracellular vesicles (EVs) have been recently recognized as key components of the embryonic milieu; however, composition and function of oviductal EVs during this crucial period remains to be further explored. Therefore, we initially characterized EVs from porcine oviductal fluid specifically around the critical ovulation window: that is, estrus (E), late estrus (LE, day of expected ovulation), post ovulation (PO), and additionally diestrus (D). Total EV numbers gradually rose from D to E, LE and PO (P < 0.05), which corresponded to the total EV protein amount (P < 0.05). Strikingly, the mean size of EVs in PO was significantly smaller than in E and LE groups, which also had a lesser proportion of small EVs (P < 0.05). The EV protein cargoes during the periovulatory period were further analyzed by mass spectrometry. Qualitative analysis detected 1118 common proteins, which are most enriched in the cellular component of EVs/exosomes. Hierarchical clustering indicated similar protein profile within the biological replicates, but large discrepancy among stages. Further quantitative analysis discovered 34 and 4 differentially expressed proteins in the comparison between E and PO and in the comparison between E and LE, respectively. The dynamic EV protein profile together with the quick adaption in EV size and quantity suggests that porcine oviductal EV secretion are under the hormonal influence during the estrus cycle.
Inflammaging is associated with shifted macrophage ontogeny and polarization in the aging mouse ovary
Authors: Zhang Zijing , Schlamp Florencia , Huang Lu , Clark Haley , Brayboy Lynae
Published: January 2020

The fertility of women declines sharply after age 35 and is essentially lost upon menopause at age 51. The ovary plays an important part in aging-associated changes in women’s physiology since it is an essential component of both the reproductive and endocrine systems. Several previous studies in mice have shown that the ovarian tissue goes through drastic changes over the course of aging and exhibits signs of aging-associated chronic inflammation (inflammaging), which may contribute to the marked decline of oocyte quality in aged individuals. To further examine aging-associated gene expression changes in the ovary and to characterize the development of inflammaging, we performed detailed transcriptomic analysis of whole ovaries from mice of six different age groups over the mouse reproductive lifespan and identified more than 5000 genes with significant expression change over the course of aging. Intriguingly, we found aging-associated changes in the expression of several markers that indicate alterations in the composition of ovarian macrophages, which are known to be central players of inflammaging. Using flow cytometry, we analyzed and compared macrophage populations and polarization in young and old ovaries and found a significant increase in monocyte recruitment and macrophage alternative activation (M2) in the old ovaries compared to those in young. Our results are consistent with previous findings of aging-associated increase of fibrosis in the ovarian stromal extracellular matrix, and they provide new clues about the development of inflammaging in the mammalian ovary.
Immunoregulation of the decidualization program: focus on the endoplasmic reticulum stress
Authors: Soczewski Elizabeth , Grasso Esteban , Gallino Lucila , Hauk Vanesa , Fernández Laura , Gori Soledad , Paparini Daniel , Perez Leirós Claudia , Ramhorst Rosanna
Published: January 2020

Decidualization denotes the reprogramming of endometrial stromal cells that includes the secretion of different mediators like cytokines, chemokines, and the selective recruitment of immune cells. This physiological process involves changes in the secretome of the endometrial stromal cells leading to the production of immunomodulatory factors. The increased amount of protein secretion is associated with a physiological endoplasmic reticulum (ER) stress and the resulting unfolded protein response (UPR), allowing the expansion of ER and the machinery to assist the protein folding. Notably, the signaling pathways involved in the ER stress and the UPR are interconnected with the onset of a sterile inflammatory response, as well as with angiogenesis. Both of these processes have a key role in decidualization and placentation, therefore, alterations in them could lead to pregnancy complications. In this review, we will discuss how the induction of ER stress and the UPR processes that accompanies the decidualization are associated with embryo implantation and whether they might condition pregnancy outcome. The ER stress activates/triggers sensing proteins which, among others, induces kinase/RNAse-TXNIP expression, activating the NLRP3 inflammasome. This multiprotein system allows caspase-1 activation, which catalyzes the cleavage of the inactive IL-1β proform toward the mature secretory form, with pro-implantatory effects. However, the sterile inflammatory response should be later controlled in favor of a tolerogenic microenvironment to sustain pregnancy. In accordance, alterations of the ER stress and UPR processes can be reflected in recurrent implantation failures (RIF), recurrent pregnancy loss (RPL), or complications associated with deficient placentation, such as preeclampsia (PE).
Steroid synthesis and metabolism in the equine placenta during placentitis
Authors: El-Sheikh Ali H , Legacki E L , Scoggin K E , Loux S C , Dini P , Esteller-Vico A , Conley A J , Stanley S D , Ball B A
Published: January 2020

Equine placentitis is associated with alterations in maternal peripheral steroid concentrations, which could negatively affect pregnancy outcome. This study aimed to elucidate the molecular mechanisms related to steroidogenesis and steroid-receptor signaling in the equine placenta during acute placentitis. Chorioallantois (CA) and endometrial (EN) samples were collected from mares with experimentally induced placentitis (n = 4) and un-inoculated gestationally age-matched mares (control group; n = 4). The mRNA expression of genes coding for steroidogenic enzymes (3βHSD, CYP11A1, CYP17A1, CYP19A1, SRD5A1, and AKR1C23) was evaluated using qRT-PCR. The concentration of these enzyme-dependent steroids (P5, P4, 5αDHP, 3αDHP, 20αDHP, 3β-20αDHP, 17OH-P, DHEA, A4, and estrone) was assessed using liquid chromatography-tandem mass spectrometry in both maternal circulation and placental tissue. Both SRD5A1 and AKR1C23, which encode for the key progesterone metabolizing enzymes, were downregulated (P < 0.05) in CA from the placentitis group compared to controls, and this downregulation was associated with a decline in tissue concentrations of 5αDHP (P < 0.05), 3αDHP (P < 0.05), and 3β-20αDHP (P = 0.052). In the EN, AKR1C23 was also downregulated in the placentitis group compared to controls, and this downregulation was associated with a decline in EN concentrations of 3αDHP (P < 0.01) and 20αDHP (P < 0.05). Moreover, CA expression of CYP19A1 tended to be lower in the placentitis group, and this reduction was associated with lower (P = 0.057) concentrations of estrone in CA. Moreover, ESR1 (steroid receptors) gene expression was downregulated (P = 0.057) in CA from placentitis mares. In conclusion, acute equine placentitis is associated with a local withdrawal of progestins in the placenta and tended to be accompanied with estrogen withdrawals in CA.