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Σάββατο 16 Δεκεμβρίου 2017

Scholar : ΦΩΝΗΤΙΚΕΣ ΧΟΡΔΕΣ - νέα αποτελέσματα

[PDF] Το μοιρολόι του Πόντου. Βιβλιογραφία & ηχογραφήσεις.

Γ Αμπερίδης - 2017
Page 1. ΤΕΙ ΗΠΕΙΡΟΥ ΣΧΟΛΗ ΚΑΛΛΙΤΕΧΝΙΚΩΝ ΣΠΟΥΔΩΝ ΤΜΗΜΑ ΛΑΪΚΗΣ ΚΑΙ ΠΑΡΑΔΟΣΙΑΚΗΣ
ΜΟΥΣΙΚΗΣ ΠΤΥΧΙΑΚΗ ΕΡΓΑΣΙΑ ΤΟ ΜΟΙΡΟΛΟΙ ΤΟΥ ΠΟΝΤΟΥ ΒΙΒΛΙΟΓΡΑΦΙΑ & ΗΧΟΓΡΑΦΗΣΕΙΣ
Φοιτητής: Αμπερίδης Γεώργιος Επιβλέπων: Γεώργιος Κοκκώνης …
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[PDF] Ιορδάνης Τσομίδης: ένας «μάγος» της πενιάς. Το πορτραίτο του καλλιτέχνη μέσα από τα ταξίμια του.

ΙΣ Αγγελινάς - 2017
Page 1. ΤΕΙ ΗΠΕΙΡΟΥ ΣΧΟΛΗ ΜΟΥΣΙΚΗΣ ΤΕΧΝΟΛΟΓΙΑΣ ΤΜΗΜΑ ΛΑΙΚΗΣ ΚΑΙ
ΠΑΡΑΔΟΣΙΑΚΗΣ ΜΟΥΣΙΚΗΣ ΠΤΥΧΙΑΚΗ ΕΡΓΑΣΙΑ ΘΕΜΑ Ιορδάνης Τσομίδης: ένας
«μάγος» της πενιάς Το πορτραίτο του καλλιτέχνη μέσα από τα ταξίμια του …
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Scholar : ΦΩΝΗΤΙΚΕΣ ΧΟΡΔΕΣ - νέα αποτελέσματα

[PDF] Το μοιρολόι του Πόντου. Βιβλιογραφία & ηχογραφήσεις.

Γ Αμπερίδης - 2017
Page 1. ΤΕΙ ΗΠΕΙΡΟΥ ΣΧΟΛΗ ΚΑΛΛΙΤΕΧΝΙΚΩΝ ΣΠΟΥΔΩΝ ΤΜΗΜΑ ΛΑΪΚΗΣ ΚΑΙ ΠΑΡΑΔΟΣΙΑΚΗΣ
ΜΟΥΣΙΚΗΣ ΠΤΥΧΙΑΚΗ ΕΡΓΑΣΙΑ ΤΟ ΜΟΙΡΟΛΟΙ ΤΟΥ ΠΟΝΤΟΥ ΒΙΒΛΙΟΓΡΑΦΙΑ & ΗΧΟΓΡΑΦΗΣΕΙΣ
Φοιτητής: Αμπερίδης Γεώργιος Επιβλέπων: Γεώργιος Κοκκώνης …
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[PDF] Ιορδάνης Τσομίδης: ένας «μάγος» της πενιάς. Το πορτραίτο του καλλιτέχνη μέσα από τα ταξίμια του.

ΙΣ Αγγελινάς - 2017
Page 1. ΤΕΙ ΗΠΕΙΡΟΥ ΣΧΟΛΗ ΜΟΥΣΙΚΗΣ ΤΕΧΝΟΛΟΓΙΑΣ ΤΜΗΜΑ ΛΑΙΚΗΣ ΚΑΙ
ΠΑΡΑΔΟΣΙΑΚΗΣ ΜΟΥΣΙΚΗΣ ΠΤΥΧΙΑΚΗ ΕΡΓΑΣΙΑ ΘΕΜΑ Ιορδάνης Τσομίδης: ένας
«μάγος» της πενιάς Το πορτραίτο του καλλιτέχνη μέσα από τα ταξίμια του …
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Αυτή η Ειδοποίηση του Μελετητή Google σας προσφέρεται από τη Google

Ακύρωση ειδοποίησης
Δημιουργία λίστας των ειδοποιήσεών μου


Copyright

Publication date: January 2018
Source:Radiologic Clinics of North America, Volume 56, Issue 1





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Contributors

Publication date: January 2018
Source:Radiologic Clinics of North America, Volume 56, Issue 1





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Multiparametric MR imaging of the Prostate

Publication date: Available online 29 November 2017
Source:Radiologic Clinics of North America
Author(s): Alessandro Furlan, Amir A. Borhani, Antonio C. Westphalen

Teaser

mp-MRI of the prostate is a complex study that combines anatomic and functional imaging. The complexity of this technique, along with an increasing demand, has brought new challenges to imaging interpretation. The Prostate Imaging Reporting and Data System provides radiologists with guidelines to standardize interpretation. This article discusses the interpretation of the pulse sequences recommended in the Prostate Imaging Reporting and Data System version 2 guidelines, reviews advanced quantitative imaging tools, and discusses future directions.


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CME Accreditation Page

Publication date: January 2018
Source:Radiologic Clinics of North America, Volume 56, Issue 1





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Forthcoming Issues

Publication date: January 2018
Source:Radiologic Clinics of North America, Volume 56, Issue 1





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Oral and Maxillofacial Radiology

Publication date: January 2018
Source:Radiologic Clinics of North America, Volume 56, Issue 1
Author(s): Dania Tamimi




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Prostate Cancer and the Evolving Role of Biomarkers in Screening and Diagnosis

Publication date: Available online 26 November 2017
Source:Radiologic Clinics of North America
Author(s): Joseph F. Rodriguez, Scott E. Eggener

Teaser

The diagnosis and management of prostate cancer have substantially changed over the last 3 decades. Serum prostate-specific antigen (PSA) was adopted for screening in the 1990s after it was found to be a sensitive indicator of disease. Because of a lack of specificity for significant disease, indiscriminate PSA testing led to overdiagnosis and overtreatment. Several biomarkers have been developed that are superior to PSA in stratifying a man's risk for harboring potentially lethal prostate cancer.


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Imaging of Benign Odontogenic Lesions

Publication date: January 2018
Source:Radiologic Clinics of North America, Volume 56, Issue 1
Author(s): William C. Scarfe, Shiva Toghyani, Bruno Azevedo

Teaser

Numerous benign cysts or solid tumors may present in the jaws. These arise from tooth-forming tissues in the dental alveolus or from nonodontogenic tissues in the basal bone of the mandible and maxilla. Radiologists provide 2 deliverables to assist in diagnosis and management: (1) appropriately formatted images demonstrating the location and extent of the lesion and (2) interpretive reports highlighting specific radiologic findings and an impression providing a radiologic differential diagnosis. This article provides guidance on essential image protocols for planning treatments, a radiologic differential diagnostic algorithm based on location and pattern recognition, and a summary of the main features of benign odontogenic lesions.


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MR Imaging for Prostate Cancer Screening and Active Surveillance

Publication date: Available online 6 December 2017
Source:Radiologic Clinics of North America
Author(s): Sasha C. Druskin, Katarzyna J. Macura

Teaser

The current prostate cancer management paradigm has been criticized in recent years for contributing to the overdiagnosis and overtreatment of the disease. Active surveillance is an avenue by which to reduce overtreatment, but patient selection and monitoring remain a challenge. The use of prostate MR imaging has been growing in recent years and has been incorporated into prostate cancer screening and patient selection and monitoring for active surveillance. This review article discusses the current evidence for the use of MR imaging in each of those settings.


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Prostate MR Imaging for Post-Treatment Evaluation and Recurrence

Publication date: Available online 27 November 2017
Source:Radiologic Clinics of North America
Author(s): Sonia Gaur, Baris Turkbey

Teaser

Prostate multiparametric MR imaging (mpMRI) plays an important role in local evaluation after treatment of prostate cancer. After radical prostatectomy, radiation therapy, and focal therapy, mpMRI can be used to visualize normal post-treatment changes and to diagnose locally recurrent disease. An understanding of the various treatments and expected changes is essential for complete and accurate post-treatment mpMRI interpretation.


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Radiographic Evaluation of Sleep-Disordered Breathing

Publication date: January 2018
Source:Radiologic Clinics of North America, Volume 56, Issue 1
Author(s): Douglas D. Steffy, Clarence S. Tang

Teaser

Sleep-disordered breathing and obstructive sleep apnea are becoming more prevalent in today's population. Management of these conditions can be difficult and this diagnosis is often overlooked by clinicians. An increased awareness and understanding of craniofacial structures and anatomic relationships can aid the clinician in identifying at-risk patients, and improve treatment outcomes. An airway review of 3-dimensional computed tomography imaging can identify (1) anatomic variations that contribute to obstructive airway complications, and (2) measurable dimensions to identify at risk patients. This article provides instruction on the key anatomic landmarks and imaging protocols for radiographic airway evaluation.


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Role of Prostate MR Imaging in Radiation Oncology

Publication date: Available online 14 December 2017
Source:Radiologic Clinics of North America
Author(s): Cynthia Ménard, Eric Paulson, Tufve Nyholm, Patrick McLaughlin, Gary Liney, Piet Dirix, Uulke A. van der Heide

Teaser

The use of prostate MR imaging in radiotherapy continues to evolve. This article describes its current application in the selection of treatment regimens, integration in treatment planning or simulation, and assessment of response. An expert consensus statement from the annual MR in RT symposium is presented, as a list of 21 key quality indicators for the practice of MR imaging simulation in prostate cancer. Although imaging requirements generally follow PIRADSv2 guidelines, additional requirements specific to radiotherapy planning are described. MR imaging–only workflows and MR imaging–guided treatment systems are expected to replace conventional computed tomography–based practice, further adding specific requirements for MR imaging in radiotherapy.


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MR Imaging–Guided Focal Treatment of Prostate Cancer

Publication date: Available online 12 December 2017
Source:Radiologic Clinics of North America
Author(s): Sherif G. Nour

Teaser

Focal treatment of prostate cancer has evolved from a concept to a practice in the recent few years and is projected to fill an existing need, bridging the gap between conservative and radical traditional treatment options. With its low morbidity and rapid recovery time compared with whole-gland treatment alternatives, focal therapy is poised to gain more acceptance among patients and health care providers. As our experience with focal treatment matures and evidence continues to accrue, the landscape of this practice might look quite different in the future.


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Multiparametric Prostate MR Imaging: Impact on Clinical Staging and Decision Making

Publication date: Available online 11 December 2017
Source:Radiologic Clinics of North America
Author(s): Petar Duvnjak, Ariel A. Schulman, Jamie N. Holtz, Jiaoti Huang, Thomas J. Polascik, Rajan T. Gupta

Teaser

Meaningful changes to the approach of prostate cancer staging and management have been made over the past decade with increasing demand for high-quality multiparametric MR imaging (mpMRI) of the prostate. This article focuses on the evolving paradigm of prostate cancer staging, with emphasis on the role of mpMRI on staging and its integration into clinical decision making. Current prostate cancer staging systems are defined and mpMRI's role in the detection of non–organ-confined disease and how it has an impact on the selection of appropriate next steps are discussed. Several imaging pitfalls, limitations, and future directions of mpMRI also are discussed.


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Future Perspectives and Challenges of Prostate MR Imaging

Publication date: Available online 9 December 2017
Source:Radiologic Clinics of North America
Author(s): Baris Turkbey, Peter L. Choyke

Teaser

MR imaging is an important part of prostate cancer diagnosis. Variations in quality and skill in general practice mean results are not as impressive as they were in academic centers. This observation provides an impetus to improve the method. Improved quality assurance will likely result in better outcomes. Improved characterization of clinically significant prostate cancer may assist in making MR imaging more useful. Improved methods of registering MR imaging with transrectal ultrasound imaging and robotic arms controlling the biopsy can reduce the impact of inexperienced operators and make the entire system of MR imaging-guided biopsies more robust.


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Technique of Multiparametric MR Imaging of the Prostate

Publication date: Available online 6 December 2017
Source:Radiologic Clinics of North America
Author(s): Andrei S. Purysko, Andrew B. Rosenkrantz

Teaser

Multiparametric MR imaging provides detailed anatomic assessment of the prostate as well as information that allows the detection and characterization of prostate cancer. To obtain high-quality MR imaging of the prostate, radiologists must understand sequence optimization to overcome commonly encountered technical challenges. This review discusses the techniques that are used in state-of-the-art MR imaging of the prostate, including imaging protocols, hardware considerations, and important aspects of patient preparation, with an emphasis on the recommendations provided in the prostate imaging-reporting and data system version 2 guidelines.


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Environmental metabolomics with data science for investigating ecosystem homeostasis

Publication date: February 2018
Source:Progress in Nuclear Magnetic Resonance Spectroscopy, Volume 104
Author(s): Jun Kikuchi, Kengo Ito, Yasuhiro Date
A natural ecosystem can be viewed as the interconnections between complex metabolic reactions and environments. Humans, a part of these ecosystems, and their activities strongly affect the environments. To account for human effects within ecosystems, understanding what benefits humans receive by facilitating the maintenance of environmental homeostasis is important. This review describes recent applications of several NMR approaches to the evaluation of environmental homeostasis by metabolic profiling and data science. The basic NMR strategy used to evaluate homeostasis using big data collection is similar to that used in human health studies. Sophisticated metabolomic approaches (metabolic profiling) are widely reported in the literature. Further challenges include the analysis of complex macromolecular structures, and of the compositions and interactions of plant biomass, soil humic substances, and aqueous particulate organic matter. To support the study of these topics, we also discuss sample preparation techniques and solid-state NMR approaches. Because NMR approaches can produce a number of data with high reproducibility and inter-institution compatibility, further analysis of such data using machine learning approaches is often worthwhile. We also describe methods for data pretreatment in solid-state NMR and for environmental feature extraction from heterogeneously-measured spectroscopic data by machine learning approaches.

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Mkp-1 Protects Mice Against Toxin-Induced Liver Damage by Promoting the Nrf2 Cytoprotective Response

Publication date: Available online 11 December 2017
Source:Free Radical Biology and Medicine
Author(s): Lin Luo, Yeru Chen, Hongyan Wang, Shengcun Wang, Kaihua Liu, Xin Li, Xiu Jun Wang, Xiuwen Tang
The present study was undertaken to investigate the possible protective effect of mitogen-activated protein kinase phosphatase 1 (Mkp-1) on toxin-induced hepatic injury. Here, we uncovered a positive feedback loop between Mkp-1, a dual threonine/tyrosine phosphatase, and nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial regulator of the defense system in the liver. Mkp-1-/- mice exhibited decreased protein levels of Nrf2, phase II gene products, and reduced glutathione (GSH) in the liver. Induction of detoxifying enzymes by the Nrf2 activator butylated hydroxyanisole (BHA) or sulforaphane, was attenuated in the liver and small intestines of Mkp-1-/- mice, indicating that the Nrf2 signaling pathway is impaired as a result of Mkp-1 deficiency. Mkp-1-/- mice suffered more severe liver injury after a single exposure to hepatotoxin carbon tetrachloride (CCl4) than their wild-type (WT) counterparts. BHA partially rescued the CCl4-induced liver damage in WT mice, but not in Mkp-1-/- mice, suggesting the requirement of Mkp-1 in the activation of Nrf2 signaling against the liver injury. Mechanistically, Mkp-1 upregulated Nrf2 through a direct interaction with the Neh2 domain in the transcription factor, while Nrf2 enhanced the expression of Mkp-1 mRNA by binding to the ARE site at −1719 to −1710 bp in the Mkp-1 promoter. Our results reveal novel role of Mkp-1 in the maintenance of redox homeostasis in the liver. Thus, strategies aimed at augmenting Mkp-1 expression may be beneficial in protecting the liver and may provide novel therapeutic approaches to toxin-induced liver injury.

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ROS-induced ROS release in plant and animal cells

Publication date: Available online 2 December 2017
Source:Free Radical Biology and Medicine
Author(s): Sara I. Zandalinas, Ron Mittler
Reactive oxygen species (ROS) play a key signaling role in plant and animal cells. Among the many cellular mechanisms used to generate and transduce ROS signals, ROS-induced ROS release (RIRR) is emerging as an important pathway involved in different human pathologies and plant responses to environmental stress. RIRR is a process in which one cellular compartment or organelle generates or releases ROS, triggering the enhanced production or release of ROS by another compartment or organelle. It was initially described in animal cells and proposed to mediate mitochondria-to-mitochondria communication, but later expanded to include communication between mitochondria and plasma membrane-localized NADPH oxidases. In plants a process of RIRR was demonstrated to mediate long distance rapid systemic signaling in response to biotic and abiotic stress. This process is thought to involve the enhanced production of ROS by one cell that triggers the enhanced production of ROS by a neighboring cell in a process that propagates the enhanced "ROS production state" all the way from one part of the plant to another. In contrast to the intracellular nature of the RIRR process of animal cells, the plant RIRR process is therefore primarily studied at the cell-to-cell communication level. Studies on intracellular (organelle-to-organelle, or organelle-to-NADPH oxidase) RIRR pathways are very scarce in plants, whereas studies on cell-to-cell RIRR are very scarce in animals. Here we will attempt to highlight what is known in both systems and what each system can learn from the other.

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CKIP-1 affects the polyubiquitination of Nrf2 and Keap1 via mediating Smurf1 to resist HG-induced renal fibrosis in GMCs and diabetic mice kidneys

Publication date: Available online 14 December 2017
Source:Free Radical Biology and Medicine
Author(s): Wenyan Gong, Zhiquan Chen, Yezi Zou, Lei Zhang, Junying Huang, Peiqing Liu, Heqing Huang
Our previous study indicated that Casein kinase 2 interacting protein-1 (CKIP-1) could promote the activation of the nuclear factor E2-related factor 2 (Nrf2)/ antioxidant response element (ARE) pathway, playing a significant role in inhibiting the fibrosis of diabetic nephropathy (DN). However, the underlying mechanism is still unknown. Here, we investigated whether CKIP-1 affects the polyubiquitination of Nrf2 and its cytosolic inhibitor kelch like ECH-associated protein 1 (Keap1) via mediating Smad ubiquitylation regulatory factor-1 (Smurf1) to promote the activation of the Nrf2/ARE signaling and resist high glucose (HG)-induced renal fibrosis in glomerular mesangial cells (GMCs) and diabetic mice kidneys. Results showed that the expression of Smurf1 increased in HG-induced GMCs, with a paramount upregulation at 1h. Overexpression of wild-type Smurf1 plasmid further promoted the HG-induced the over-production of fibronectin (FN) and intercellular adhesionmolecule-1 (ICAM-1), and depletion of Smurf1 dramatically reduced the expression of FN and ICAM-1. Overexpression of CKIP-1 decreased the K48-linked polyubiquitination and increased the K63-linked polyubiquitination of Nrf2 as well as enhanced the K48-linked polyubiquitination and reduced K63-linked polyubiquitination of Keap1, promoting the activation of the Nrf2/ARE pathway. Overexpression of Smurf1 increased the K48-linked polyubiquitination and decreased the K63-linked polyubiquitination of Nrf2, and down-regulated the K48-linked polyubiquitination and up-regulated the K63-linked polyubiquitination of Keap1, inhibiting the activation of the Nrf2/ARE pathway. CKIP-1 promoted the degradation of Smurf1 by increasing the ubiquitination of Smurf1. Treatment of CKIP-1 adenovirus infection reduced the Smurf1 levels, promoted the activation of the Nrf2/ARE pathway as well as suppressed the production of reactive oxygen species (ROS), and then improved the failure of renal function of diabetic mice. Experiments above suggested that CKIP-1 affects the polyubiquitination of Nrf2 and Keap1 and promotes the Nrf2-ARE pathway through down-regulating Smurf1 to resist HG-induced up-regulation of FN and ICAM-1 in GMCs and diabetic mice kidneys.

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SIRT6 protects against hepatic ischemia/reperfusion injury by inhibiting apoptosis and autophagy related cell death

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Song Zhang, Shuai Jiang, Haiping Wang, Wencheng Di, Chao Deng, Zhenxiao Jin, Wei Yi, Xiao Xiao, Yongzhan Nie, Yang Yang
Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury.

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Licochalcone A activates Keap1-Nrf2 signaling to suppresses arthritis via phosphorylation of p62 at serine 349

Publication date: Available online 9 December 2017
Source:Free Radical Biology and Medicine
Author(s): Xiaohui Su, Ting Li, Zhongqiu Liu, Qingchun Huang, Kangsheng Liao, Rutong Ren, Linlin Lu, Xiaoxiao Qi, Maojie Wang, Jianyu Chen, Hua Zhou, Elaine Lai-Han Leung, Hudan Pan, Juan Liu, Hui Wang, Lufen Huang, Liang Liu
Licochalcone A (LCA) is derived from glycyrrhizae radix with antimicrobial, antitumor and anti-inflammatory activities. However, the anti-arthritic function of LCA and underlying mechanism has not been yet explored. The current study investigated the anti-arthritic effect of LCA and elucidated the underlying mechanism. The results showed that LCA significantly suppressed arthritis via the activation of QSTM1 (p62)/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling in the collage-induced arthritis (CIA) model of DBA mice. In coincided with the results, this anti-arthritic effect of LCA was remarkably diminished in the collagen antibody-induced arthritis (CAIA) model of Nrf2-/- mice. These findings indicate that p62/Nrf2 signaling is a crucial pathway for the induction and treatment of arthritis. To further validate the effect of LCA on the arthritis, rheumatoid arthritis synovial fibroblasts (RASFs) isolated from the synovium of RA patients were employed in the study. In coincided with in vivo results, LCA inhibited the cell proliferation and arrested the cell cycle, induced apoptosis, suppressed pro-inflammatory cytokine secretion and increased expression of antioxidant enzymes via the activation of Keap1-Nrf2 signaling by enhancing p62 phosphorylation and expression, Nrf2 accumulation and Nrf2 nucleus translocation. Findings in the current study provide evidence that p62-Keap1-Nrf2 axis is a pivotal signaling pathway in development of arthritis and therapeutic efficacy of drugs, and LCA activates of Keap1-Nrf2 signaling to suppress arthritis by phosphorylation of p62 at Ser349. Collectively, LCA is valuable to be further investigated as a lead compound for application in anti-arthritis, and interference with the interaction between Nrf2 and Keap1 by phosphorylation of p62 may be a promising strategy for the discovery of anti-arthritic agents.

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Topical electrophilic nitro-fatty acids potentiate cutaneous inflammation

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Alicia R. Mathers, Cara D. Carey, Meaghan E. Killeen, Sonia R. Salvatore, Laura K. Ferris, Bruce A. Freeman, Francisco J. Schopfer, Louis D. Falo
Endogenous electrophilic fatty acids mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction and gene expression. Nitro-fatty acids and other electrophilic fatty acids may thus be useful for the prevention and treatment of immune-mediated diseases, including inflammatory skin disorders. In this regard, subcutaneous (SC) injections of nitro oleic acid (OA-NO2), an exemplary nitro-fatty acid, inhibit skin inflammation in a model of allergic contact dermatitis (ACD). Given the nitration of unsaturated fatty acids during metabolic and inflammatory processes and the growing use of fatty acids in topical formulations, we sought to further study the effect of nitro-fatty acids on cutaneous inflammation. To accomplish this, the effect of topically applied OA-NO2 on skin inflammation was evaluated using established murine models of contact hypersensitivity (CHS). In contrast to the effects of subcutaneously injected OA-NO2, topical OA-NO2 potentiated hapten-dependent inflammation inducing a sustained neutrophil-dependent inflammatory response characterized by psoriasiform histological features, increased angiogenesis, and an inflammatory infiltrate that included neutrophils, inflammatory monocytes, and γδ T cells. Consistent with these results, HPLC-MS/MS analysis of skin from psoriasis patients displayed a 56% increase in nitro-conjugated linoleic acid (CLA-NO2) levels in lesional skin compared to non-lesional skin. These results suggest that nitro-fatty acids in the skin microenvironment are products of cutaneous inflammatory responses and, in high local concentrations, may exacerbate inflammatory skin diseases.

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Anti-tumor effects of cold atmospheric pressure plasma on vestibular schwannoma demonstrate its feasibility as an intra-operative adjuvant treatment

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Yeo Jun Yoon, Michelle J. Suh, Hyun Young Lee, Hae June Lee, Eun Ha Choi, In Seok Moon, Kiwon Song
Vestibular schwannoma (VS), although a benign intracranial tumor, causes morbidities by brainstem compression. Since chemotherapy is not very effective in most Nf2-negative schwannomas, surgical removal or radiation therapy is required. However, depending on the size and site of the tumor, these approaches may cause loss of auditory or vestibular functions, and severely decrease the post-surgical wellbeing. Here, we examined the feasibility of cold atmospheric pressure plasma (CAP) as an intra-operative adjuvant treatment for VS after surgery. Cell death was efficiently induced in both human HEI-193 and mouse SC4 VS cell lines upon exposure to CAP for seven minutes. Interestingly, both apoptosis and necroptosis were simultaneously induced by CAP treatment, and cell death was not completely inhibited by pan-caspase and receptor-interacting serine/threonine-protein kinase 1 (RIK1) inhibitors. Upon CAP exposure, cell death phenotype was similarly observed in patient-derived primary VS cells and tumor mass. In addition, CAP exposure after the surgical removal of primary tumor efficiently inhibited tumor recurrence in SC4-grafted mouse models. Collectively, these results strongly suggest that CAP should be developed as an efficient adjuvant treatment for VS after surgery to eliminate the possible remnant tumor cells, and to minimize the surgical area in the brain for post-surgical wellbeing.

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Aging and Parkinson's Disease: Inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Vittorio Calabrese, Aurelia Santoro, Daniela Monti, Rosalia Crupi, Rosanna Di Paola, Saverio Latteri, Salvatore Cuzzocrea, Mario Zappia, James Giordano, Edward J. Calabrese, Claudio Franceschi
In order to better understand the pathogenesis of Parkinson's Disease (PD) it is important to consider possible contributory factors inherent to the aging process, as age-related changes in a number of physiological systems (perhaps incurred within particular environments) appear to influence the onset and progression of neurodegenerative disorders. Accordingly, we posit that a principal mechanism underlying PD is inflammaging, i.e. the chronic inflammatory process characterized by an imbalance of pro- and anti-inflammatory mechanisms which has been recognized as operative in several age-related, and notably neurodegenerative diseases. Recent conceptualization suggests that inflammaging is part of the complex adaptive mechanisms ("re-modeling") that are ongoing through the lifespan, and which function to prevent or mitigate endogenous processes of tissue disruption and degenerative change(s). The absence of an adequate anti-inflammatory response can fuel inflammaging, which propagates on both local (i.e.- from cell to cell) and systemic levels (e.g.- via exosomes and other molecules present in the blood). In general, this scenario is compatible with the hypothesis that inflammaging represents a hormetic or hormetic-like effect, in which low levels of inflammatory stress may prompt induction of anti-inflammatory mediators and mechanisms, while sustained pro-inflammatory stress incurs higher and more durable levels of inflammatory substances, which, in turn prompt a local-to-systemic effect and more diverse inflammatory response(s). Given this perspective, new treatments of PD may be envisioned that strategically are aimed at exerting hormetic effects to sustain anti-inflammatory responses, inclusive perhaps, of modulating the inflammatory influence of the gut microbiota.

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Characterization of covalent modifications of HDL apoproteins by endogenous oxidized phospholipids

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Detao Gao, Eugene A. Podrez
High density lipoprotein (HDL) is cardioprotective, unless it is pathologically modified under oxidative stress. Covalent modifications of lipid-free apoA-I, the most abundant apoprotein in HDL, compromise its atheroprotective functions. HDL is enriched in oxidized phospholipids (oxPL) in vivo in oxidative stress. Furthermore, oxidized phospholipids can covalently modify HDL apoproteins. We have now carried out a systematic analysis of modifications of HDL apoproteins by endogenous oxPL. Human HDL or plasma were oxidized using a physiologically relevant MPO−H2O2−NO2 system or AIPH, or were exposed to synthetic oxPL. Protein adduction by oxPL was assessed using LC-MS/MS and MALDI-TOF MS. The pattern of HDL apoprotein modification by oxPL was independent of the oxidation systems used. ApoA-I and apoA-II were the major modification targets. OxPL with a γ-hydroxy (or oxo)-alkenal were mostly responsible for modifications, and the Michael adduct was the most abundant adduct. Histidines and lysines in helices 5–8 of apoA-I were highly susceptible to oxPL modifications, while lysines in helices 1, 2, 4 and 10 were resistant to modification by oxPL. In plasma exposed to oxidation or synthetic oxPL, oxPL modification was highly selective, and four histidines (H155, H162, H193 and H199) in helices 6–8 of apoA-I were the main modification target. H710 and H3613 in apoB-100 of LDL and K190 of human serum albumin were also modified by oxPL but to a lesser extent. Comparison of oxPL with short chain aldehyde HNE using MALDI-TOF MS demonstrated high selectivity and efficiency of oxPL in the modification of HDL apoproteins. These findings provide a novel insight into a potential mechanism of the loss of atheroprotective function of HDL in conditions of oxidative stress.

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Caffeic Acid and Resveratrol Ameliorate Cellular Damage in Cell and Drosophila Models of Spinocerebellar Ataxia Type 3 through Upregulation of Nrf2 Pathway

Publication date: Available online 13 December 2017
Source:Free Radical Biology and Medicine
Author(s): Yu-Ling Wu, Jui-Chih Chang, Wei-Yong Lin, Chien-Chun Li, Mingli Hsieh, Haw-Wen Chen, Tsu-Shing Wang, Wen-Tzu Wu, Chin-San Liu, Kai-Li Liu
Polyglutamine (polyQ)-expanded mutant ataxin-3 protein, which is prone to misfolding and aggregation, leads to cerebellar neurotoxicity in spinocerebellar ataxia type 3 (SCA3), an inherited PolyQ neurodegenerative disease. Although the exact mechanism is unknown, the pathogenic effects of mutant ataxin-3 are associated with dysregulation of transcription, protein degradation, mitochondrial function, apoptosis, and antioxidant potency. In the present study we explored the protective role and possible mechanism of caffeic acid (CA) and resveratrol (Res) in cells and Drosophila expressing mutant ataxin-3. Treatment with CA and Res increased the levels of antioxidant and autophagy protein expression with consequently corrected levels of reactive oxygen species, mitochondrial membrane potential, mutant ataxin-3, and the aggregation of mutant ataxin-3 in SK-N-SH-MJD78 cells. Moreover, in SK-N-SH-MJD78 cells, CA and Res enhanced the transcriptional activity of nuclear factor erythroid-derived-2-like 2 (Nrf2), a master transcription factor that upregulates the expression of antioxidant defense genes and the autophagy gene p62. CA and Res improved survival and motor performance in SCA3 Drosophila. Additionally, the above-mentioned protective effects of CA were also observed in CA-supplemented SCA3 Drosophila. Notably, blockade of the Nrf2 pathway by use of small interfering RNA annulled the health effects of CA and Res on SCA3, which affirmed the importance of the increase in Nrf2 activation by CA and Res. Additional studies are need to dissect the protective role of CA and Res in modulating neurodegenerative progression in SCA3 and other polyQ diseases.

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Structure and function of a novel antioxidant peptide from the skin of tropical frogs

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Eder Alves Barbosa, Ana Oliveira, Alexandra Plácido, Renato Socodato, Camila C. Portugal, Ana Carolina Mafud, Alicia S. Ombredane, Daniel C. Moreira, Nuno Vale, Lucinda J. Bessa, Graziella A. Joanitti, Cláudia Alves, Paula Gomes, Cristina Delerue-Matos, Yvonne Primerano Mascarenhas, Mariela M. Marani, João B. Relvas, Manuela Pintado, José Roberto S.A. Leite
The amphibian skin plays an important role protecting the organism from external harmful factors such as microorganisms or UV radiation. Based on biorational strategies, many studies have investigated the cutaneous secretion of anurans as a source of bioactive molecules. By a peptidomic approach, a novel antioxidant peptide (AOP) with in vitro free radical scavenging ability was isolated from Physalaemus nattereri. The AOP, named antioxidin-I, has a molecular weight [M+H]+ = 1543.69Da and a TWYFITPYIPDK primary amino acid sequence. The gene encoding the antioxidin-I precursor was expressed in the skin tissue of three other Tropical frog species: Phyllomedusa tarsius, P. distincta and Pithecopus rohdei. cDNA sequencing revealed highly homologous regions (signal peptide and acidic region). Mature antioxidin-I has a novel primary sequence with low similarity compared with previously described amphibian's AOPs. Antioxidin-I adopts a random structure even at high concentrations of hydrophobic solvent, it has poor antimicrobial activity and poor performance in free radical scavenging assays in vitro, with the exception of the ORAC assay. However, antioxidin-I presented a low cytotoxicity and suppressed menadione-induced redox imbalance when tested with fibroblast in culture. In addition, it had the capacity to substantially attenuate the hypoxia-induced production of reactive oxygen species when tested in hypoxia exposed living microglial cells, suggesting a potential neuroprotective role for this peptide.

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Relevance of 4-F4t-neuroprostane and 10-F4t-neuroprostane to neurological diseases

Publication date: Available online 9 December 2017
Source:Free Radical Biology and Medicine
Author(s): Cinzia Signorini, Claudio De Felice, Thierry Durand, Jean-Marie Galano, Camille Oger, Silvia Leoncini, Lucia Ciccoli, Marisa Carone, Monica Ulivelli, Caterina Manna, Alessio Cortelazzo, Jetty Chung-Yung Lee, Joussef Hayek
F4-neuroprostanes (F4-NeuroPs) are non-enzymatic oxidized products derived from docosahexaenoic acid (DHA) and are suggested to be oxidative damage biomarkers of neurological diseases. However, 128 isomers can be formed from DHA oxidation and among them, 4(RS)−4-F4t-NeuroP (4-F4t-NeuroP) and 10(RS)−10-F4t-NeuroP (10-F4t-NeuroP) are the most studied.Here, we report the identification and the clinical relevance of 4-F4t-NeuroP and 10-F4t-NeuroP in plasma of four different neurological diseases, including multiple sclerosis (MS), autism spectrum disorders, (ASD) Rett syndrome (RTT), and Down syndrome (DS).The identification and the optimization of the method were carried out by gas chromatography/negative-ion chemical ionization tandem mass spectrometry (GC/NICI-MS/MS) using chemically synthesized 4-F4t-NeuroP and 10-F4t-NeuroP standards and in oxidized DHA liposome.Both 4-F4t-NeuroP and 10-F4t-NeuroP were detectable in all plasma samples from MS (n = 16), DS (n= 16), ASD (n= 9) and RTT (n = 20) patients. While plasma 10-F4t-NeuroP content was significantly higher in patients of all diseases as compared to age and gender matched healthy control subjects (n= 61), 4-F4t-NeuroP levels were significantly higher in MS and RTT as compared to healthy controls. Significant positive relationships were observed between relative disease severity and 4-F4t-NeuroP levels (r = 0.469, P <0.0001), and 10-F4t-NeuroP levels (r = 0.757, P < 0.0001). The study showed that the plasma amount ratio of 10-F4t-NeuroP to 4-F4t-NeuroP and the plasma amount as individual isomer can be used to discriminate between different brain diseases.Overall, by comparing the different types of disease, our plasma data indicates that 4-F4t-NeuroP and 10-F4t -NeuroP: i) are biologically synthesized in vivo and circulated; ii) are related to clinical severity of neurological diseases iii) are useful to identify shared pathogenetic pathways in distinct brain diseases, and iv) appears to be distinctive for different neurological conditions, thus representing potentially new biological disease markers. Our data strongly suggest that in vivo DHA oxidation follows preferential chemical rearrangements according to different brain diseases.

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Potentiation of glutathione loss and nerve cell death by the transition metals iron and copper: Implications for age-related neurodegenerative diseases

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Pamela Maher
There is growing evidence for alterations in iron and copper homeostasis during aging that are exacerbated in neurodegenerative diseases such as Alzheimer's disease (AD). However, how iron and copper accumulation leads to nerve cell damage in AD is not clear. In order to better understand how iron and copper can contribute to nerve cell death, a simple, well-defined in vitro model of cell death, the oyxtosis assay, was used. This assay uses glutamate to induce glutathione (GSH) depletion which initiates a form of oxidative stress-induced programmed cell death. A reduction in GSH is seen in the aging brain, is associated with cognitive dysfunction and is accelerated in many CNS diseases including AD. It is shown that both iron and copper potentiate both GSH loss and cell death in this model. Iron and copper also potentiate cell death induced by other GSH depleters but not by compounds that induce oxidative stress via other pathways. At least part of the effects of copper on GSH are related to its ability to reduce the activity of glutamate cysteine ligase, the rate limiting enzyme in GSH synthesis. Both metals also alter several signaling pathways involved in modulating nerve cell death. Together, these results suggest that in vivo iron and copper may specifically enhance nerve cell death under conditions where GSH levels are reduced.

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Neuroprotection afforded by circadian regulation of intracellular glutathione levels: a key role for miRNAs

Publication date: Available online 2 December 2017
Source:Free Radical Biology and Medicine
Author(s): Chisato Kinoshita, Koji Aoyama, Toshio Nakaki
Circadian rhythms are approximately 24-hour oscillations of physiological and behavioral processes that allow us to adapt to daily environmental cycles. Like many other biological functions, cellular redox status and antioxidative defense systems display circadian rhythmicity. In the central nervous system (CNS), glutathione (GSH) is a critical antioxidant because the CNS is extremely vulnerable to oxidative stress; oxidative stress, in turn, causes several fatal diseases, including neurodegenerative diseases. It has long been known that GSH level shows circadian rhythm, although the mechanism underlying GSH rhythm production has not been well-studied. Several lines of recent evidence indicate that the expression of antioxidant genes involved in GSH homeostasis as well as circadian clock genes are regulated by post-transcriptional regulator microRNA (miRNA), indicating that miRNA plays a key role in generating GSH rhythm. Interestingly, several reports have shown that alterations of miRNA expression as well as circadian rhythm have been known to link with various diseases related to oxidative stress. A growing body of evidence implicates a strong correlation between antioxidative defense, circadian rhythm and miRNA function, therefore, their dysfunctions could cause numerous diseases. It is hoped that continued elucidation of the antioxidative defense systems controlled by novel miRNA regulation under circadian control will advance the development of therapeutics for the diseases caused by oxidative stress.

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Elevated plasma 8-iso-prostaglandin F2α levels in human smokers originate primarily from enzymatic instead of non-enzymatic lipid peroxidation

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Thomas J. van 't Erve, Fred B. Lih, Maria B. Kadiiska, Leesa J. Deterding, Ronald P. Mason
It is widely accepted that free radicals in tobacco smoke lead to oxidative stress and generate the popular lipid peroxidation biomarker 8-iso-prostaglandin F2α (8-iso-PGF2α). However, 8-iso-PGF2α can simultaneously be produced in vivo by the prostaglandin-endoperoxide synthases (PGHS) induced by inflammation. This inflammation-dependent mechanism has never been considered as a source of elevated 8-iso-PGF2α in tobacco smokers.The goal of this study is to quantify the distribution of chemical- and PGHS-dependent 8-iso-PGF2α formation in the plasma of tobacco smokers and non-smokers. The influences of gender and hormonal contraceptive use were accounted for. The distribution was determined by measuring the 8-iso-PGF2α/prostaglandin F2α (PGF2α) ratio.When comparing smokers (n = 28) against non-smokers (n = 30), there was a statistically significant increase in the 8-iso-PGF2α concentration. The source of this increased 8-iso-PGF2α was primarily from PGHS. When stratifying for gender, the increase in 8-iso-PGF2α in male smokers (n = 9) was primarily from PGHS. Interestingly, female smokers on hormonal contraceptives had increased 8-iso-PGF2α in both pathways, whereas those not on hormonal contraceptives did not have increased 8-iso-PGF2α.In conclusion, increased plasma 8-iso-PGF2α in tobacco smokers has complex origins, with PGHS-dependent formation as the primary source. Accounting for both pathways provides a definitive measurement of both oxidative stress and inflammation.

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Editorial Board

Publication date: December 2017
Source:Free Radical Biology and Medicine, Volume 113





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Iron induced RNA-oxidation in the general population and in mouse tissue

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Vanja Cejvanovic, Laura Kofoed Kjær, Helle Kirstine Mørup Bergholdt, Arendse Torp-Pedersen, Trine Henriksen, Allan Weimann, Christina Ellervik, Henrik Enghusen Poulsen
Iron promotes formation of hydroxyl radicals by the Fenton reaction, subsequently leading to potential oxidatively generated damage of nucleic acids. Oxidatively generated damage to RNA, measured as 8-oxo-7,8-dihydroguanosine (8-oxoGuo) in urine, is increased in patients with genetic iron overload, which have led us to test the hypothesis that high iron status, assessed by iron biomarkers and genetic disposition, increases urinary excretion of 8-oxoGuo. In a general Danish population study we used a Mendelian randomization design with HFE genotypes as a proxy for iron status and supplemented with ex vivo experiments in mice muscle tissue exposed to iron(II) sulfate to attempt to clarify this hypothesis.The biomarkers ferritin, transferrin, and transferrin saturation (TS) were associated with 8-oxoGuo (in linear univariable and multivariable regression analyses: P < 0.001). Mendelian randomization indicated a causal pathway between genetically elevated iron biomarkers (assessed by ferritin and TS) and high levels of 8-oxoGuo. The ex vivo experiments showed a monotonically increase in 8-oxoGuo with increased iron concentration (ANOVA: P = 0.0008) that was prevented with iron chelation (P = 0.01).Our results indicate a causal relationship between iron biomarkers and 8-oxoGuo. Furthermore, the ex vivo experiment shows a mechanistic link between iron and 8-oxoGuo formation. Both iron overload and the biomarker 8-oxoGuo have been linked to e.g. diabetes, which merits future studies to investigate if iron induced 8-oxoGuo is involved in disease development.

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The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Natalia S. Nemeria, Gary Gerfen, Pradeep Reddy Nareddy, Luying Yang, Xu Zhang, Michal Szostak, Frank Jordan
Herein are reported unique properties of the novel human thiamin diphosphate (ThDP)-dependent enzyme 2-oxoadipate dehydrogenase (hE1a), known as dehydrogenase E1 and transketolase domain-containing protein 1 that is encoded by the DHTKD1 gene. It is involved in the oxidative decarboxylation of 2-oxoadipate (OA) to glutaryl-CoA on the final degradative pathway of L-lysine and is critical for mitochondrial metabolism. Functionally active recombinant hE1a has been produced according to both kinetic and spectroscopic criteria in our toolbox leading to the following conclusions: (i) The hE1a has recruited the dihydrolipoyl succinyltransferase (hE2o) and the dihydrolipoyl dehydrogenase (hE3) components of the tricarboxylic acid cycle 2-oxoglutarate dehydrogenase complex (OGDHc) for its activity. (ii) 2-Oxoglutarate (OG) and 2-oxoadipate (OA) could be oxidized by hE1a, however, hE1a displays an approximately 49-fold preference in catalytic efficiency for OA over OG, indicating that hE1a is specific to the 2-oxoadipate dehydrogenase complex. (iii) The hE1a forms the ThDP-enamine radical from OA according to electron paramagnetic resonance detection in the oxidative half reaction, and could produce superoxide and H2O2 from decarboxylation of OA in the forward physiological direction, as also seen with the 2-oxoglutarate dehydrogenase hE1o component. (iv) Once assembled to complex with the same hE2o and hE3 components, the hE1o and hE1a display strikingly different regulation: both succinyl-CoA and glutaryl-CoA significantly reduced the hE1o activity, but not the activity of hE1a.

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Diacerein alleviates kidney injury through attenuating inflammation and oxidative stress in obese insulin-resistant rats

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Nuttawud Chueakula, Krit Jaikumkao, Phatchawan Arjinajarn, Anchalee Pongchaidecha, Varanuj Chatsudthipong, Nipon Chattipakorn, Anusorn Lungkaphin
A link between inflammation with obesity and metabolic syndrome has been found in patients with chronic kidney disease (CKD). Diacerein is an anthraquinone used to treat osteoarthritis that exerts anti-inflammatory action by inhibiting the synthesis and activity of proinflammatory cytokines. This study aimed to investigate the protective effect of diacerein on renal function and renal organic anion transporter 3 (Oat3) function in obese insulin-resistant condition. Obese insulin-resistant rats were induced by feeding a high-fat diet in male Wistar rats for 16 weeks. Diacerein or metformin (positive control) (30mg/kg/day) was administered orally for 4 weeks after insulin resistance had been confirmed. Obese insulin-resistant rats showed an impaired renal function as indicated by the increased serum creatinine and microalbuminuria along with the decreased renal Oat3 function and expression. Importantly, diacerein treatment not only improved insulin resistance but also restored renal function. The decreased renal malondialdehyde level, expressions of PKCα, angiotensin 1 receptor (AT1R), Nrf2, and HO-1, and increased expression of SOD2 were observed in diacerein treatment group, indicating the attenuation of renal oxidative stress condition. Moreover, renal inflammation and renal damage were also alleviated in diacerein-treated rats. Our results demonstrated for the first time that diacerein was effective to improve renal function and renal Oat3 function in obese insulin-resistance condition mediated by suppressing renal oxidative stress and inflammation. These findings suggest that anti-inflammatory agents can be used therapeutically to improve metabolic disorder and prevent organ dysfunctions in pre-diabetic condition.

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Psoriasis and risk of malignant lymphoma: A population-based cohort study

Abstract

In patients with psoriasis, the risk of lymphoma has been a subject of controversy and data from larger studies are limited1-4. We therefore investigated the 5-year risk of new-onset Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) (excluding cutaneous T-cell lymphoma [CTCL]), and CTCL, respectively, in patients with psoriasis.

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Dermatologists across Europe underestimate depression and anxiety: results from 3635 dermatological consultations

Abstract

Background

It was recently demonstrated that a significant number of patients with common skin diseases across Europe are clinically depressed and anxious. Studies have shown that physicians not trained as psychiatrist underdiagnose depression. This has not been explored among dermatologists.

Objectives

To estimate the concordance between clinical assessment of depression and anxiety by a dermatologist and assessment with the Hospital Anxiety and Depression Scale.

Methods

The study was an observational cross-sectional multi-centre study of prevalent cases of skin diseases in 13 countries in Europe. Consecutive patients were recruited in out-patient clinics and filled in questionnaires prior to clinical examination by a dermatologist who reported any diagnosis of skin disease and signs of mood disorders.

Results

Analysis of the 3635 consultations showed that the agreement between dermatologist and HADS was poor to fair (lower than 0.4) for all diagnose categories. The true positive rate (represented by the percentage of dermatologists recognizing signs of depression or anxiety in depressed or anxious patients defined by HADS-value >=11) was 44.0% for depression and 35.6% for anxiety. The true negative rate (represented by the percentage of dermatologists not detecting signs of depression or anxiety in non-depressed or non-anxious patients defined byHADS-value < 11) was 56.0% for depression and 64.4% for anxiety.

Conclusions

Dermatologists in Europe tend to underestimate mood disorders. The results point out that further training for dermatologists to improve their skills in diagnosing depression and anxiety might be appropriate. The psychological suffering of dermatological patients needs to be addressed when present.

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Symptom Signatures and Diagnostic Timeliness in Cancer Patients: A Review of Current Evidence

Publication date: February 2018
Source:Neoplasia, Volume 20, Issue 2
Author(s): Minjoung M. Koo, William Hamilton, Fiona M. Walter, Greg P. Rubin, Georgios Lyratzopoulos
Early diagnosis is an important aspect of contemporary cancer prevention and control strategies, as the majority of patients are diagnosed following symptomatic presentation. The nature of presenting symptoms can critically influence the length of the diagnostic intervals from symptom onset to presentation (the patient interval), and from first presentation to specialist referral (the primary care interval). Understanding which symptoms are associated with longer diagnostic intervals to help the targeting of early diagnosis initiatives is an area of emerging research. In this Review, we consider the methodological challenges in studying the presenting symptoms and intervals to diagnosis of cancer patients, and summarize current evidence on presenting symptoms associated with a range of common and rarer cancer sites. We propose a taxonomy of cancer sites considering their symptom signature and the predictive value of common presenting symptoms. Finally, we consider evidence on associations between symptomatic presentations and intervals to diagnosis before discussing implications for the design, implementation, and evaluation of public health or health system interventions to achieve the earlier detection of cancer.



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Prescription of DPP-4 Inhibitors to Type 2 Diabetes Mellitus Patients With Renal Impairment: A UK Primary Care Experience

Publication date: Available online 13 December 2017
Source:Clinical Therapeutics
Author(s): Dionysis Spanopoulos, Brendan Barrett, Michael Busse, Toni Roman, Chris Poole
Members of the dipeptidyl peptidase-4 inhibitor drug class are indicated for glycemic control in patients with type 2 diabetes mellitus and all, except linagliptin, require dose adjustment in renal impairment. A cross-sectional analysis of a cohort of type 2 diabetes mellitus patients treated with dipeptidyl peptidase-4 inhibitors identified in the Clinical Practice Research Datalink was conducted to explore compliance with the renal adjustment requirements of the Summaries of Product Characteristics. Approximately one third of type 2 diabetes mellitus patients with creatinine clearance <50 mL/min who were at risk of inappropriate prescribing, were initiated on a DPP-4 inhibitor at a higher dose than the specified in their respective Summary of Product Characteristics.



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Factors Influencing Norvancomycin Concentration in Plasma and Cerebrospinal Fluid in Patients After Craniotomy and Dosing Guideline: A Population Approach

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Publication date: Available online 8 December 2017
Source:Clinical Therapeutics
Author(s): Xingang Li, Yuanxing Wu, Shusen Sun, Qiang Wang, Zhigang Zhao
PurposeAntibacterial spectrum and activity of norvancomycin are comparable with vancomycin, and it has been widely used in China. Norvancomycin can penetrate into the cerebrospinal fluid (CSF) through the damaged blood–brain barrier in patients after craniotomy. Because higher inter-individual variability was observed, we aimed to identify factors related to drug concentration to guide clinicians with norvancomycin dosing.MethodsAfter craniotomy, patients with an indwelling catheter in the operational area/ventricle were intravenously administered norvancomycin. Venous blood and CSF specimens were collected at a scheduled time for measuring drug concentrations. Blood and CSF data were fitted simultaneously with the use of the nonlinear fixed-effects modeling method to develop the population pharmacokinetic model. Covariate analysis was applied to select candidate factors associated with pharmacokinetic parameters. A model-based simulation was performed to find optimized regimens for different subgroups of patients.FindingsA 3-compartmental model (central, peripheral, and CSF compartments) with 2 elimination pathways (drug elimination from the kidney and CSF outflow) was developed to characterize the in vivo process of norvancomycin. The covariate analysis identified that weight and drainage amount were strongly associated with the central volume and the drug clearance from CSF, respectively. Goodness-of-fit and model validation suggested that the proposed model was acceptable. A dosage regimen table was created for specific patient populations with different weights and drainage amounts to facilitate clinical application.ImplicationsWe identified 2 clinical markers associated with plasma and CSF concentrations. The proposed simulation may be useful to clinicians for norvancomycin dosing in this specific population with normal kidney function.



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The Good and the Bad About the 2017 American College of Physicians Osteoporosis Guidelines

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Publication date: Available online 28 November 2017
Source:Clinical Therapeutics
Author(s): Violet Lagari, Tara Gavcovich, Silvina Levis
PurposeThe American College of Physicians (ACP) published a set of guidelines on how to prevent fractures in men and women with low bone density or osteoporosis. As the population ages, the overall risk of fractures increases, thus burdening the health care system. These guidelines review current evidence for osteoporosis management, providing an update to the previous 2008 ACP's guidelines.MethodsThe ACP put forth 6 recommendations addressing the complexities in osteoporosis management based on evidence available through October 2016 with a focus on bisphosphonates, calcium, vitamin D, and estrogen. Evidence was graded according to recommended strength by using the ACP standard methods.FindingsThe ACP recommends anti-osteoporosis therapy with 1 of 3 bisphosphonates (alendronate, risedronate, or zoledronic acid) or denosumab in patients with osteoporosis, while excluding anabolic therapies, and recommends against raloxifene. Although bisphosphonates are the mainstay of treatment, anabolic therapy and raloxifene may be used in specific situations. Pharmacologic therapy is recommended for 5 years, oversimplifying length of therapy and failing to promote an individualized patient-centered care approach. Moreover, abrupt discontinuation of denosumab is associated with a decline in bone mineral density (BMD), which must be addressed. Routine monitoring of BMD by dual x-ray absorptiometry is not endorsed during treatment, which leads to underrecognition of management issues. Pharmacologic treatment with bisphosphonates for male osteoporosis is recommended, although therapies such as denosumab and teriparatide are excluded. Finally, the ACP recommends treatment for women aged ≥65 years at high risk for fracture with osteopenia after a discussion of patient preferences, fracture risk profile, and medications.ImplicationsOsteoporosis management is complex. The 2017 ACP guidelines address challenges faced by clinicians but oversimplify more complex issues. These are among a number of guidelines that are available for osteoporosis management, which may be used in combination with other sources to assist clinicians with diagnostic and management strategies.



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Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-Treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized, Double-blind, and Placebo-controlled Trial

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Publication date: Available online 7 December 2017
Source:Clinical Therapeutics
Author(s): Chee Hae Kim, Kyung Ah Han, Jaemyung Yu, Sang Hak Lee, Hui Kyung Jeon, Sang Hyun Kim, Seok Yeon Kim, Ki Hoon Han, Kyungheon Won, Dong-Bin Kim, Kwang-Jae Lee, Kyungwan Min, Dong Won Byun, Sang-Wook Lim, Chul Woo Ahn, SeongHwan Kim, Young Joon Hong, Jidong Sung, Seung-Ho Hur, Soon Jun Hong, Hong-Seok Lim, Ie Byung Park, In Joo Kim, Hyoungwoo Lee, Hyo-Soo Kim
PurposeThe purpose of this study was to examine the efficacy and safety of adding ω-3 fatty acids to rosuvastatin in patients with residual hypertriglyceridemia despite statin treatment.MethodsThis study was a multicenter, randomized, double-blind, placebo-controlled study. After a 4-week run-in period of rosuvastatin treatment, the patients who had residual hypertriglyceridemia were randomized to receive rosuvastatin 20 mg/d plus ω-3 fatty acids 4 g/d (ROSUMEGA group) or rosuvastatin 20 mg/d (rosuvastatin group) with a 1:1 ratio and were prescribed each medication for 8 weeks.FindingsA total of 201 patients were analyzed (mean [SD] age, 58.1 [10.7] years; 62.7% male). After 8 weeks of treatment, the percentage change from baseline in triglycerides (TGs) and non–HDL-C was significantly greater in the ROSUMEGA group than in the rosuvastatin group (TGs: −26.3% vs −11.4%, P < 0.001; non–HDL-C: −10.7% vs −2.2%, P = 0.001). In the linear regression analysis, the lipid-lowering effect of ω-3 fatty acids was greater when baseline TG or non−HDL-C levels were high and body mass index was low. The incidence of adverse events was not significantly different between the 2 groups.ImplicationsIn patients with residual hypertriglyceridemia despite statin treatment, a combination of ω-3 fatty acids and rosuvastatin produced a greater reduction of TGs and non−HDL-C than rosuvastatin alone. Further study is needed to determine whether the advantages of this lipid profile of ω-3 fatty acids actually leads to the prevention of cardiovascular event. ClinicalTrials.gov identifier: NCT03026933.



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Effects of Flibanserin on the Pharmacokinetics of a Combined Ethinylestradiol/Levonorgestrel Oral Contraceptive in Healthy Premenopausal Women: A Randomized Crossover Study

Publication date: Available online 2 December 2017
Source:Clinical Therapeutics
Author(s): Crista Johnson-Agbakwu, Louise Brown, James Yuan, Robert Kissling, David J. Greenblatt
PurposeThis study aimed to investigate the effect of steady-state exposure to flibanserin, a 5-HT1A agonist/5-HT2A antagonist approved for the treatment of hypoactive sexual desire disorder in premenopausal women, on the single-dose pharmacokinetics of the contraceptive steroids ethinylestradiol and levonorgestrel in healthy premenopausal women.MethodsHealthy female volunteers (N = 24) received 2 single doses of a combined oral contraceptive containing ethinylestradiol 30 μg and levonorgestrel 150 μg, either alone (reference) or preceded by treatment with flibanserin 100 mg once daily for 14 days (test). The 2 treatments were given in randomized order, with a 4-week washout period following the last administration of the first treatment. Plasma concentrations of ethinylestradiol and levonorgestrel were measured over 48 hours after dosing for the determination of pharmacokinetic parameters; the primary end points were Cmax and AUC0–∞ of ethinylestradiol and levonorgestrel.FindingsOf the 24 women enrolled (mean age, 38.0 years), 23 completed the study. Mean (SD) Cmax and AUC0–∞ values of ethinylestradiol were 66.7 (16.3) pg/mL and 693 (268) pg · h/mL, respectively, following the oral contraceptive alone, and 72.7 (25.5) pg/mL and 740 (235) pg · h/mL, respectively, when the oral contraceptive was preceded by flibanserin. In both cases, the 90% CIs of the reference/test ratios of Cmax and AUC0–∞ were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of ethinylestradiol. Similarly, the mean (SD) Cmax and AUC0–∞ values of levonorgestrel were 5.0 (1.6) ng/mL and 52.2 (18.7) ng · h/mL, respectively, with the oral contraceptive alone, and 5.0 (1.6) ng/mL and 53.3 (20.4) ng · h/mL, respectively, following flibanserin; again, in both cases, the 90% CIs of the reference/test ratios were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of levonorgestrel. All adverse events were mild to moderate in intensity (incidence: 12.5% and 70.8% with ethinylestradiol/levonorgestrel treatment alone and following administration of flibanserin, respectively).ImplicationsPretreatment with flibanserin 100 mg once daily for 2 weeks did not produce a clinically relevant change in oral contraceptive drug exposure following single-dose administration of ethinylestradiol/levonorgestrel. This finding is relevant to women with hypoactive sexual desire disorder who might prefer oral contraceptives to other forms of birth control. EudraCT No: 2006-006960-46.



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Editorial Board

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12





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Efficacy and Tolerability of Telmisartan/Amlodipine + Hydrochlorothiazide Versus Telmisartan/Amlodipine Combination Therapy for Essential Hypertension Uncontrolled With Telmisartan/Amlodipine: The Phase III, Multicenter, Randomized, Double-Blind TAHYTI Study

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Publication date: Available online 14 December 2017
Source:Clinical Therapeutics
Author(s): Ki-Chul Sung, Yong-Seog Oh, Dong-Hun Cha, Soon-Jun Hong, Kyung-Heon Won, Ki-Dong Yoo, Seung-Woon Rha, Young-Keun Ahn, Jeong-Cheon Ahn, Ji-Yong Jang, Tack-Jong Hong, Sang-Kyoon Cho, Sang-Ho Park, Min-Su Hyon, Chang-Wook Nam, In-Ho Chae, Byung-Su Yoo, Jong-Min Song, Jin-Ok Jeong, Young Won Yoon, Byung-Soo Kim, Tae-Hyun Yang, Deok-Kyu Cho, Sang-Hyun Kim, Yu-Jeong Choi, Ji-Hun Ahn, Dong-Woon Jeon, Hyo-Soo Kim
PurposeThis 8-week study in Korea aimed to evaluate the efficacy and tolerability of a telmisartan/amlodipine + hydrochlorothiazide (TAH) combination versus telmisartan/amlodipine (TA) combination in patients with essential hypertension that did not respond appropriately to 4-week treatment with TA.MethodsAll patients who met the inclusion criteria received TA (40/5 mg) during a 4-week run-in period (period 1). Patients who met the criteria for essential hypertension (mean sitting systolic blood pressure [MSSBP], ≥140 and <200 mm Hg, or ≥130 and<200 mm Hg in those with diabetes mellitus or chronic kidney disease) after period 1 were randomly assigned to receive TA 40/5 mg + hydrochlorothiazide 12.5 mg (test group) or TA only (control group). The test and control drugs were administered in each group for 2 weeks (period 2). Patients who completed period 2 underwent 6-week treatment (period 3) with a TAH and TA dose twice that in period 2. The primary end point was the change in MSSBP at week 8 of treatment. Secondary end points were the change in MSSBP at week 2 and MS diastolic BP, BP control rate, and BP response rate at weeks 2 and 8. Treatment tolerability was assessed based on adverse events (AEs), laboratory evaluations (chemistry, hematology, and urinalysis), 12-lead ECG, and physical examination including vital sign measurements.FindingsWe randomized 310 patients to the treatment groups. The mean (SD) ages of the TAH and TA groups were 62.0 (10.8) and 63.4 (10.4) years, respectively. The least squares mean change in MSSBP was significantly greater in the TAH group than in the TA group after 8 weeks (–18.7 vs –12.2 mm Hg; P < 0.001). Similar results were obtained on changes in MSSBP after 2 weeks and changes in sitting diastolic BP, BP control rate, and BP response rate at weeks 2 and 8 compared with the respective baseline values. The prevalences of treatment-emergent AEs (29.0% vs 16.3%; P = 0.008) and adverse drug reactions (20.0% vs 10.5%; P = 0.020) were significantly greater in the TAH group than in the TA group. Most treatment-emergent AEs were mild or moderate; none were severe. The most frequently reported AEs were dizziness and headache.ImplicationTAH triple therapy was more effective than was TA double therapy in reducing BP in these patients in Korea with essential hypertension that did not adequately respond to TA. ClinicalTrials.gov identifier: NCT02738632.



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Table of Contents

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12





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Scholar : ΦΩΝΗΤΙΚΕΣ ΧΟΡΔΕΣ - νέα αποτελέσματα

[PDF] Το μοιρολόι του Πόντου. Βιβλιογραφία & ηχογραφήσεις.

Γ Αμπερίδης - 2017
Page 1. ΤΕΙ ΗΠΕΙΡΟΥ ΣΧΟΛΗ ΚΑΛΛΙΤΕΧΝΙΚΩΝ ΣΠΟΥΔΩΝ ΤΜΗΜΑ ΛΑΪΚΗΣ ΚΑΙ ΠΑΡΑΔΟΣΙΑΚΗΣ
ΜΟΥΣΙΚΗΣ ΠΤΥΧΙΑΚΗ ΕΡΓΑΣΙΑ ΤΟ ΜΟΙΡΟΛΟΙ ΤΟΥ ΠΟΝΤΟΥ ΒΙΒΛΙΟΓΡΑΦΙΑ & ΗΧΟΓΡΑΦΗΣΕΙΣ
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ΙΣ Αγγελινάς - 2017
Page 1. ΤΕΙ ΗΠΕΙΡΟΥ ΣΧΟΛΗ ΜΟΥΣΙΚΗΣ ΤΕΧΝΟΛΟΓΙΑΣ ΤΜΗΜΑ ΛΑΙΚΗΣ ΚΑΙ
ΠΑΡΑΔΟΣΙΑΚΗΣ ΜΟΥΣΙΚΗΣ ΠΤΥΧΙΑΚΗ ΕΡΓΑΣΙΑ ΘΕΜΑ Ιορδάνης Τσομίδης: ένας
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Table of Contents

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Publication date: November 2017
Source:Clinical Therapeutics, Volume 39, Issue 11





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Note of Thanks

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12





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Forgotten Influences and Reflections on Exercise and on the End of the Year 2017

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12
Author(s): Richard I. Shader




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Budgetary Impact of Telotristat Ethyl, a Novel Treatment for Patients with Carcinoid Syndrome Diarrhea: A US Health Plan Perspective

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12
Author(s): Vijay N. Joish, Feride Frech, Pablo Lapuerta
PurposeTelotristat ethyl (TE) was recently approved for carcinoid syndrome diarrhea (CSD) in patients not adequately controlled with somatostatin analog long-acting release (SSA LAR) therapy alone. A budget impact model was developed to determine the short-term affordability of reimbursing TE in a US health plan.MethodsA budget impact model compared health care costs when CSD is managed per current treatment patterns (SSA LAR, reference drug scenario) versus when TE is incorporated in the treatment algorithm (SSA LAR + TE, new drug scenario). Prevalence of CSD, proportion of patients not adequately controlled on SSA LAR, monthly treatment costs (pharmacy and medical), and treatment efficacy were derived from the literature. In the reference drug scenario, an escalated monthly dose of SSA LAR therapy of 40 mg was assumed to treat patients with CSD not adequately controlled on the labeled dose of SSA LAR. In the new drug scenario, TE was added to the maximum labeled monthly dose of SSA LAR therapy of 30 mg. The incremental budget impact was calculated based on an assumed TE market uptake of 28%, 42%, and 55% during Years 1, 2, and 3, respectively. One-way sensitivity analyses were conducted to test model assumptions.FindingsA hypothetical health plan of 1 million members was estimated to have 42 prevalent CSD patients of whom 17 would be inadequately controlled on SSA LAR therapy. The monthly medical cost per patient not adequately controlled on SSA LAR in addition to pharmacotherapy was estimated to be $3946 based on the literature. Based on the observed treatment response in a clinical trial of 20% and 44% for the base case reference and new drug scenarios, total per patient per month costs were estimated to be $7563 and $11,205, respectively. Total annual costs in the new drug scenario were estimated to be $2.3 to $2.5 million during the first 3 years. The overall incremental annual costs were estimated to be $154,000 in Year 1, $231,000 in Year 2, and $302,000 in Year 3. This translated to an incremental per patient per month cost of $0.013, $0.019, and $0.025 for Years 1, 2, and 3. These results remained robust in 1-way sensitivity analyses.ImplicationsThe availability of TE for patients not adequately controlled on SSA LAR therapy provides a novel treatment option for CSD. This model showed that providing access to this first-in-class oral agent would have a minimal budget impact to a US health plan.



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Comparative Bioavailability of Hydroxyprogesterone Caproate Administered via Intramuscular Injection or Subcutaneous Autoinjector in Healthy Postmenopausal Women: A Randomized, Parallel Group, Open-label Study

Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12
Author(s): Julie Krop, William G. Kramer
PurposeThe purpose of this study was to evaluate the bioavailability of hydroxyprogesterone caproate (HPC) administered as a subcutaneous injection in the back of the upper arm using a prefilled autoinjector syringe with a 27-gauge needle compared with standard intramuscular injection in the gluteus maximus using a 21-gauge needle.MethodsHealthy postmenopausal women 50 to 75 years old were randomized in a parallel group design to receive a single SC injection of 1.1 mL (275-mg total dose) of preservative-free HPC administered using an autoinjector in the back of the upper arm or a single IM injection of 1 mL (250-mg total dose) of preservative-free HPC administered in the gluteus maximus. Blood samples were collected through 1008 hours (42 days) after injection. The primary measures were the Cmax, AUC0–t, and AUC0–∞. Secondary measures were Tmax, ke, t½, and injection site reactions captured as a treatment-emergent adverse event.FindingsThe pharmacokinetic population consisted of 90 individuals; 45 received subcutaneous administration and 45 received intramuscular administration. Geometric mean whole blood concentrations of HPC were comparable between administration regimens. Subcutaneous administration resulted in a higher geometric mean Cmax than intramuscular administration (7.88 vs 6.91 ng/mL), but median Tmax values were comparable (48.1 vs 49.7 hours). The least square geometric mean ratios for AUC0–168), AUC0–t, and AUC0–∞ were 102.89%, 110.25%, and 113.51%, respectively, with all 90% CIs within the 80.0% to 125.0% window that defined bioequivalence. The ratio for Cmax was 113.95% with a 90% CI of 91.94% to 141.23% but with substantial overlap of individual values between administration regimens. The geometric mean t½ of HPC was 212 hours for the subcutaneous administration and 188 hours for the intramuscular administration. The most common treatment-emergent adverse event was injection site pain (subcutaneous, 37.3%; intramuscular, 8.2%), described as mild (85%) to moderate (15%).ImplicationsAdministration of HPC by SC injection of 1.1 mL (275 mg) via autoinjector is bioequivalent to IM injection of 1.0 mL (250 mg). ClinicalTrials.gov identifier: NCT02940522.



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Effects of Exercise on Non-Motor Symptoms in Parkinson’s Disease

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Publication date: Available online 1 December 2017
Source:Clinical Therapeutics
Author(s): Amy W. Amara, Adeel A. Memon
Patients with Parkinson's disease experience disabling non-motor symptoms, including autonomic dysfunction, cognitive decline, and sleep disorders. Pharmacologic treatments for these symptoms are often ineffective or have intolerable side effects. Therefore, non-pharmacologic interventions are an attractive alternative. Exercise in particular has the potential to alleviate the progressive impairment related to these non-motor symptoms. In this commentary, we explore available research that addresses the impact of exercise and physical activity on autonomic dysfunction, cognitive impairment, and sleep disorders in Parkinson's disease and suggest areas in need of further study. Many gaps remain in our understanding of the most effective exercise intervention for these symptoms, the mechanisms underlying exercise-induced changes, and the best way to monitor response to therapy. However, available research suggests that exercise is a promising approach to improve non-motor symptoms in patients with Parkinson's disease.



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Cost-effectiveness of Paclitaxel + Ramucirumab Combination Therapy for Advanced Gastric Cancer Progressing After First-line Chemotherapy in Japan

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12
Author(s): Shota Saito, Yusuke Muneoka, Takashi Ishikawa, Kouhei Akazawa
PurposeThe combination of paclitaxel + ramucirumab is a standard second-line treatment in patients with advanced gastric cancer. This therapy has been associated with increased median overall survival and progression-free survival compared with those with paclitaxel monotherapy. We evaluated the cost-effectiveness of paclitaxel + ramucirumab combination therapy in patients with advanced gastric cancer, from the perspective of health care payers in Japan.MethodsWe constructed a Markov model to compare, over a time horizon of 3 years, the costs and effectiveness of the combination of paclitaxel + ramucirumab and paclitaxel alone as second-line therapies for advanced gastric cancer in Japan. Health outcomes were measured in life-years (LYs) and quality-adjusted (QA) LYs gained. Costs were calculated using year-2016 Japanese yen (¥1 = US $17.79) according to the social insurance reimbursement schedule and drug tariff of the fee-for-service system in Japan. Model robustness was addressed through 1-way and probabilistic sensitivity analyses. The costs and QALYs were discounted at a rate of 2% per year. The willingness-to-pay threshold was set at the World Health Organization's criterion of ¥12 million, because no consensus exists regarding the threshold for acceptable cost per QALY ratios in Japan's health policy.FindingsPaclitaxel + ramucirumab combination therapy was estimated to provide an additional 0.09 QALYs (0.10 LYs) at a cost of ¥3,870,077, resulting in an incremental cost-effectiveness ratio of ¥43,010,248/QALY. The incremental cost-effectiveness ratio for the combination therapy was >¥12 million/QALY in all of the 1-way and probabilistic sensitivity analyses.ImplicationsAdding ramucirumab to a regimen of paclitaxel in the second-line treatment of advanced gastric cancer is expected to provide a minimal incremental benefit at a high incremental cost per QALY. Based on our findings, adjustments in the price of ramucirumab, as well as improves in other clinical parameters such as survival time and adverse event in advanced gastric cancer therapy, are needed.



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Editorial Board

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Publication date: November 2017
Source:Clinical Therapeutics, Volume 39, Issue 11





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Pharmacokinetics of a New Amphetamine Extended-release Oral Liquid Suspension Under Fasted and Fed Conditions in Healthy Adults: A Randomized, Open-label, Single-dose, 3-treatment Study

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12
Author(s): Carolyn Sikes, Jeffrey G. Stark, Russ McMahen, Dorothy Engelking
PurposeA new amphetamine extended-release liquid formulation (AMP XR-OS), intended for the treatment of attention-deficit/hyperactivity disorder, has been developed. This study was performed to determine if administration with food affected the rate of absorption or bioavailability of AMP XR-OS. The formulation was also compared with an equivalent dose of an extended-release mixed amphetamine salts reference product (30 mg) under fed conditions.MethodsThirty adult volunteers participated in this single-dose, open-label, randomized, 3-period, 3-treatment crossover study. Each participant received a single 15-mL dose of AMP XR-OS (equivalent to 30 mg of the reference drug) under fasted conditions, a single 15-mL dose of AMP XR-OS under fed conditions, and a single dose of the reference drug under fed conditions. A 7-day washout separated the 3 treatment periods. Blood samples were collected at predetermined time points and analyzed for d- and l-amphetamine. Pharmacokinetic parameters reported are AUC0–5, AUC0–last, AUC5–last, and AUC0–∞; Cmax; elimination t1/2; and Tmax. The geometric mean ratios and 90% CIs of Cmax, AUC0–last, and AUC0–∞were determined for the comparison of AMP XR-OS fed and fasted, and Cmax, AUC0–5, AUC5–last, and AUC0–∞ were calculated for AMP XR-OS compared with the reference drug under fed conditions. Safety was also assessed.FindingsTwenty-nine subjects completed the study. Subjects were mostly male, white, and of Hispanic/Latino ethnicity with a mean age of 35.83 years and a mean BMI of 25.36kg/m2. The 90% CIs of Cmax, AUC0–last, and AUC0–∞ for AMP XR-OS fasted versus fed were within the accepted 80% to 125% range, indicating lack of a food effect. In the comparison of AMP XR-OS fed versus the reference product, Cmax, AUC5–last, and AUC0–∞ were within the range to establish bioequivalence; however, AUC0–5 was significantly higher for AMP XR-OS compared with that of the reference drug. This difference between products was likely due to the known delay of Tmax and decreased exposure when the extended-release mixed amphetamine salts reference product is administered with food. A total of 36 mild or moderate adverse events were reported; 1 subject withdrew due to an adverse event, and no deaths occurred. These adverse events were consistent with the known pharmacodynamic effects of amphetamine.ImplicationsThe absence of a food effect may allow for AMP XR-OS to be administered with or without a meal.



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Characteristics Associated with the Choice of First Injectable Therapy Among US Patients With Type 2 Diabetes

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12
Author(s): Maria Yu, Reema Mody, Laura Fernández Landó, Amy Shui, Lee Kallenbach, Lukas Slipski, Carolina Piras de Oliveira
PurposeThe objective of this retrospective observational study was to describe and identify clinical and demographic characteristics associated with the choice of first injectable therapy (glucagon-like peptide-1 receptor agonist [GLP-1-RA] or basal insulin) among patients with type 2 diabetes mellitus (T2DM).MethodsThis analysis included adults naive to injectable therapy with T2DM who initiated a GLP-1-RA or basal insulin (index date) between November 2014 and February 2016 using data from the Practice Fusion Electronic Health Record database. Patients with T2DM, ≥1 office visit between 6 and 18 months before the index date, and with ≥1 glycosylated hemoglobin (HbA1c) result in the 6-month preindex (baseline) period were included. A generalized boosted regression model was used to determine the patient characteristics most influential in the selection of a GLP-1-RA or basal insulin as first injectable therapy. Sensitivity analysis was performed by using bootstrapped logistic regression.FindingsThe study included 3546 and 7507 GLP-1-RA and basal insulin initiators, respectively. At baseline, GLP-1-RA initiators were significantly younger (mean, 58 vs 63 years), had lower HbA1c values (mean, 8.2% vs 9.1%), lower Diabetes Complications Severity Index (DCSI) scores (mean, 1.0 vs 1.7), and a higher body mass index (BMI) (mean, 36 vs 33 kg/m2) compared with basal insulin initiators. Variables selected by using the generalized boosted regression model with the highest relative importance (≥5%) in the selection of GLP-1-RA or basal insulin were HbA1c level (20.43%), BMI (17.73%), age (12.21%), prior prescription of a sodium-glucose cotransporter-2 inhibitor (9.17%), and DCSI score (8.39%). The same variables, as well as race, were selected by using stepwise logistic regression in all the bootstrapped samples. Patients who were older (adjusted odds ratio [OR], 0.975 [95% CI, 0.971–0.979]) and had higher HbA1c values (OR, 0.741 [95% CI, 0.721–0.761]) and DCSI scores (OR, 0.870 [95% CI, 0.848–0.892]) were significantly less likely to be prescribed a GLP-1-RA compared with basal insulin. Patients with higher BMI (OR, 1.046 [95% CI, 1.040–1.053]) and previous prescription of sodium-glucose cotransporter-2 inhibitors (OR, 2.633 [95% CI, 2.224–2.982]) were significantly more likely to be prescribed a GLP-1-RA.ImplicationsThe clinically relevant differences observed between the 2 patient populations suggest that GLP-1-RAs and basal insulin are prescribed to different types of patients with T2DM. Examining patients' demographic and clinical characteristics may be important in assisting physicians in the choice of patient-centered injectable treatment regimens.



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Management of Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs): A Review

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Publication date: November 2017
Source:Clinical Therapeutics, Volume 39, Issue 11
Author(s): Gurleen Pasricha, Parikshit Padhi, Nour Daboul, Dulabh K. Monga
PurposeNeuroendocrine tumors (NETs) are heterogeneous tumors that arise from the neuroendocrine cells of the digestive tract and other organs, such as the lung, ovary, and thyroid glands. They can be well differentiated or poorly differentiated, and management of these tumors differs for each histologic subtype. We have performed a review of NETs and focused on management of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEPNETs) and carcinoid syndrome.MethodsA PubMed search was performed to obtain articles on the management of well-differentiated NETs. Using the key words neuroendocrine tumors, carcinoid, pNET, octreotide, somatostatin analogues, and radiolabeled therapy, we reviewed Phase II and III trials that were published over the past 30 years. We also reviewed guidelines from the European Neuroendocrine Tumor Society, North America Neuroendocrine Tumor Society, and National Comprehensive Cancer Network in our search.FindingsNETs are usually slow-growing tumors that remain asymptomatic for a long duration and can be either nonfunctioning or functioning. Surgical resection is recommended for locoregional disease, impending obstruction, symptom control, and advanced disease. Nonsurgical treatment options include somatostatin analogues (SSAs), multikinase inhibitors, targeted therapy, chemotherapy, and radiolabeled SSAs. Carcinoid syndrome is mainly treated with SSAs.ImplicationsAlthough GEPNETs are slow-growing tumors, most patients are diagnosed with metastatic disease, and therefore it is important that the management of each patient be discussed in a multidisciplinary setting to optimize the treatment strategy. Patients should be considered for clinical trials and refractory cases referred to a specialty center.



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Integrins: Integrating the Biology and Therapy of Cell–cell Interactions

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Publication date: December 2017
Source:Clinical Therapeutics, Volume 39, Issue 12
Author(s): Franco Pandolfi, Laura Franza, Simona Altamura, Claudia Mandolini, Rossella Cianci, Aftab Ansari, James T. Kurnick
PurposeAlthough the role of integrins has been described in a variety of diseases, these roles seem to be distinct. To date, no study has attempted to provide links to the various pathways by which such integrins can be involved in these diverse disease settings. The purpose of this review was to address this gap in our knowledge with the hypothesis that there is, in fact, a common pathway by which integrins may function.MethodsThis article provides an in-depth perspective on the discovery, development, and design of therapeutics that modulate cellular function by targeting integrin:ligand interactions by reviewing the literature on this subject; the review included the most recent results of clinical and subclinical studies. A MEDLINE search was conducted for articles pertaining to the various issues related to integrins, and the most relevant articles are discussed (ie, not only those published in journals with a higher impact factor).FindingsIt seems that the ligation of the integrins with their cognate ligands plays a major role in translating membrane dialogue into biological function. In addition, they also seem to play a major regulatory role that can enhance or inhibit biological function depending on the context within which such receptor:ligand interactions occur and the organ and tissues at which interactions occurs and is manipulated. Those studies that used statistical analyses have been included where appropriate.ImplicationsOur findings show that anti-integrin treatment has the potential to become a valid coadjuvant in the treatment of several diseases including cancer, inflammatory diseases, HIv infection and cardiovascular diseases.



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