bluuebunny/crossref_metadata_2025 huggingface dataset:
Network Meta-Analysis of Chinese Herbal Injections Plus the FOLFOX Regimen for the Treatment of Colorectal Cancer in China
Authors: Zhang Dan , Wu Jiarui , Duan Xiaojiao , Wang Kaihuan , Ni Mengwei , Liu Shuyu , Zhang Xiaomeng , Zhang Bing , Zhao Yi
Published: February 2019

Objective: The aim of the present network meta-analysis (NMA) was to explore the comparative effectiveness and safety of different Chinese herbal injections (CHIs) combined with the FOLFOX regimen versus FOLFOX alone for colorectal cancer (CRC). Methods: A comprehensive search for randomized controlled trials (RCTs) was performed with regard to different CHIs for treating CRC in several electronic databases up to July 2016. The quality assessment of the included RCTs was conducted according to the Cochrane risk of bias tool. Standard pair-wise and Bayesian NMA were designed to compare the effectiveness and safety of different CHIs combined with the FOLFOX regimen by utilizing WinBUGS 1.4.3 and Stata 13.1 software, simultaneously. Results: Initially, a total of 820 citations were retrieved through comprehensive searching, and 60 eligible articles involving 4849 participants and 14 CHIs were ultimately included. The results of the current evidence indicated that the FOLFOX regimen combined with Delisheng, Kanglaite, Shenqifuzheng, or Aidi injections were associated with the most favorable clinical efficacy compared with the FOLFOX regimen alone. Additionally, the FOLFOX regimen combined with Delisheng, Xiaoaiping, Lentinan, Kangai, Shenqifuzheng, or Aidi injections improved performance status among patients with CRC. Conclusions: The results of cluster analysis demonstrated that the combination of Compound matrine injection and FOLFOX regimen was associated with more preferable and beneficial outcomes than other CHIs groups. Nevertheless, the additional results from multicenter trials and high-quality studies will be pivotal for supporting our findings.
The Linear No-Threshold Model of Low-Dose Radiogenic Cancer: A Failed Fiction
Authors: Pennington Charles W. , Siegel Jeffry A.
Published: February 2019

The linear no-threshold (LNT) model for low-dose, radiogenic cancer has been a fixture of radiation protection and regulatory requirements for decades, but its validity has long been contested. This article finds, yet again, more questionable data and analyses purporting to support the model, this within the “gold-standard” data set for estimating radiation effects in humans. Herein is addressed a number of significant uncertainties in the Radiation Effects Research Foundation’s Life Span Study (LSS) cohort of atomic bomb survivors, especially in its latest update of 2017, showing that the study’s support of the LNT model is not evidence based. We find that its latest 2 analyses of solid cancer incidence ignore biology and do not support the LNT model. Additionally, we identify data inconsistencies and missing causalities in the LSS data and analyses that place reliance on uncertain, imputed data and apparently flawed modeling, further invalidating the LNT model. These observations lead to a most credible conclusion, one supporting a threshold model for the dose–response relationship between low-dose radiation exposure and radiogenic cancer in humans. Based upon these findings and those cited from others, it becomes apparent that the LNT model cannot be scientifically valid.
Comparative preclinical evaluation of a polymer-free sirolimus-eluting stent in porcine coronary arteries
Authors: Sperling Christian , Waliszewski Matthias W. , Kherad Behrouz , Krackhardt Florian
Published: February 2019

Background:

Polymer-free drug-eluting stents (DES) without permanent-polymer coating may be associated with rapid vessel healing, providing a rationale to reduce dual-antiplatelet therapy (DAPT). The aim of the current study was to compare vessel healing of a polymer-free sirolimus-eluting stent (PF-SES), its bare metal stent (BMS) analogue to a permanent polymer-based sirolimus-eluting stent (SES) with proven effectiveness in porcine coronary arteries.

Material and methods:

An ultrathin-strut cobalt–chromium PF-SES, its BMS analogue and an SES with a permanent polymer were used to study vessel healing and their antistenotic potential. Stents were implanted in porcine coronary arteries for histopathologic analysis at 7, 28 and 180 days. In an additional in vitro study, the thrombogenicity of PF-SES was compared with a fluoropolymer-coated everolimus-eluting stent (EES) which demonstrated low stent thrombosis rates in numerous studies.

Results:

In the animal study, neointimal growth and injury scores were minimal and inflammation scores were low in the neointima and adventitia in all study groups. After 28 days, neointimal area was lowest in PF-SES when compared with SES and BMS (1.48 ± 0.55 mm² versus 2.43 ± 0.69 mm² versus 1.90 ± 0.85 mm², respectively, p < 0.05) and endothelialization of luminal surfaces was nearly complete in all groups, though SES show the least coverage with occasional adherent luminal inflammatory cells ( p > 0.05). At 180 days, neointimal area and thickness were most pronounced in SES ( p < 0.05) and comparable with BMS implantations, which were characterized by nearly completed vessel healing. PF-SES and BMS had complete endothelialization, absence of fibrin and sustained low inflammatory reaction when compared with the permanent polymer-based SES (inflammation score: PF-SES 0.41 ± 0.74 versus SES 2.52 ± 1.72 versus BMS 0.30 ± 0.65, respectively, p < 0.05 BMS versus SES). Granuloma formation and fibrin accumulation were most pronounced in SES but did not reach statistical significance, p > 0.05). In the in vitro thrombogenicity study, the PF-SES confirmed comparable antithrombogenic properties with regard to the parameters fibrin and platelet binding, and platelet aggregation when compared with the EES.

Conclusions:

As compared with BMS, the ultrathin-strut cobalt–chromium PF-SES showed similar endothelialization at 28 days and comparable healing characteristics at 180 days efficacious inhibition of neointimal proliferation in porcine coronary arteries with low inflammation responses and a BMS-like endothelialization at 180 days. In addition, in an in vitro model, the PF-SES also confirmed low thrombogenicity as compared with the EES.
Computer-assisted navigation as a diagnostic tool in revision total hip arthroplasty: A case report
Authors: Paprosky Wayne G , Vincent John , Sostak Jennifer R , Muir Jeffrey M
Published: February 2019

Revision total hip arthroplasty is a costly procedure accounting for approximately 14% of all hip arthroplasties. Compounding the cost considerations is the potential for serious injury to the patient when removing existing components. Such injury can result in not only increased morbidity but also dramatically increased costs. The use of computer-assisted navigation in revision total hip arthroplasty, while relatively uncommon, offers surgeons the ability to measure component position and orientation intraoperatively, thus allowing them the opportunity to modify their surgical plan, with the potential for decreasing both costs and iatrogenic injury. Here, we report a case of revision total hip arthroplasty where the use of computer-assisted navigation as a diagnostic tool allowed for intraoperative alterations in surgical plan and resulted in improved post-operative outcomes.
“. . . What Is Going On in the Lives of These People?”: Encouraging Community Engagement in Development Economics Studies
Authors: Claassen Carike , Blaauw Derick
Published: February 2019

To respond to the numerous socioeconomic challenges facing South Africa, universities must equip students to actively participate in economic development initiatives. Students from Economics and all disciplines in the Social Sciences have a pertinent role to play in this regard. This article presents an initiative to implement service learning as part of the curriculum for Development Economics students at undergraduate and postgraduate levels at a South African public university. Undergraduate and postgraduate students acted as fieldworkers who carried out survey research in the local informal economy in the university town of Potchefstroom in South Africa’s North West Province. The experiences of students and lecturers in these two complimenting projects are compared and contrasted. The enthusiasm for the project was a clear theme emerging form the pilot projects. Future endeavors must employ even more resources to enable even more reflection in the learning experience. The possibility and benefits of converting the complete curriculum of Development Economics into a service learning approach also emerged from the research.
Effective Professional Development for Teachers to Foster Students’ Academic Language Proficiency Across the Curriculum: A Systematic Review
Authors: Kalinowski Eva , Gronostaj Anna , Vock Miriam
Published: February 2019

This review summarizes features of professional development programs that aim to prepare in-service teachers to improve students’ academic language proficiency when teaching subject areas. The 38 studies reviewed suggest that all of the profiled interventions were effective to some extent. The programs share many characteristics considered important in successful teacher professional development across different subject areas. They also include some features that appear to be specific to teacher training in this particular domain. This review supports the idea that professional development helps change teachers’ thinking and practice and benefits students, if certain features are taken into consideration in its design and implementation.
Sociology, Demography, and Economics Presidential Ages and Sex over Time
Authors: Hauer Mathew E.
Published: February 2019

I provide a visualization of presidential ages and gender over time for three academic associations: the American Sociological Association (ASA), the Population Association of America (PAA), and the American Economic Association (AEA). The figure reveals important trends in the twentieth century concerning (1) the continued aging of association presidents, (2) the relatively recent increasing gender parity in association presidents of ASA and PAA but not AEA, and (3) the sharp increase in PAA presidential ages beginning near the turn of the twenty-first century.
Efficacy of Vitrectomy and Macular Hole Repair in Eyes With Dry Age-Related Macular Degeneration
Authors: Ismail Omar M. , Mason Lauren , Mason John O.
Published: February 2019

Purpose:

The purpose of this article is to examine the efficacy of macular hole repair in eyes with coexisting dry age-related macular degeneration (AMD).

Methods:

A retrospective analysis was performed of charts of 25 patients (27 eyes) diagnosed with mild to moderate dry AMD who underwent macular hole repair via 25-gauge pars plana vitrectomy between 2014 and 2016. Data of interest included anatomic failure rates, complication rates, and best-corrected visual acuity (BCVA) preoperatively, and at 1 month, 3 months, 6 months, and 12 months postoperatively. When available, data at each patient’s most recent visit were also analyzed.

Results:

Macular hole repair resulted in a statistically significant ( P < .05) visual improvement postoperatively, with BCVA increasing from 20/141 preoperatively to 20/33 1 year postoperatively. Mean BCVA at most recent visit was 20/41. Mean duration of follow-up was 13 months (range, 1-39 months). One of 27 (3.7%) macular holes failed to close after vitrectomy. One of 27 eyes (3.7%) progressed from dry to wet AMD. Four of 27 additional eyes (18.5%) were noted to have worsening of their AMD on exam over the course of follow-up.

Conclusions:

Macular hole repair in patients with coexisting dry AMD leads to a significant improvement in visual performance and has a low risk of failure or complication.
Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma
Authors: Zhuang Junling , Shirazi Fazal , Singh Ram Kumar , Kuiatse Isere , Wang Hua , Lee Hans C. , Berkova Zuzana , Berger Allison , Hyer Marc , Chattopadhyay Nibedita , Syed Sakeena , Shi Judy Qiuju , Yu Jie , Shinde Vaishali , Tirrell Stephen , Jones Richard Julian , Wang Zhiqiang , Davis R. Eric , Orlowski Robert Z.
Published: February 2019

Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings; but drug resistance is an emerging challenge, prompting interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive target is the E1 ubiquitin-activating enzyme (UAE); we therefore evaluated the activity of TAK-243, a novel and specific UAE inhibitor. TAK-243 potently suppressed myeloma cell line growth, induced apoptosis, and activated caspases while decreasing the abundance of ubiquitin-protein conjugates. This was accompanied by stabilization of many short-lived proteins, including p53, myeloid cell leukemia 1 (MCL-1), and c-MYC, and activation of the activating transcription factor 6 (ATF-6), inositol-requiring enzyme 1 (IRE-1), and protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) arms of the ER stress response pathway, as well as oxidative stress. UAE inhibition showed comparable activity against otherwise isogenic cell lines with wild-type (WT) or deleted p53 despite induction of TP53 signaling in WT cells. Notably, TAK-243 overcame resistance to conventional drugs and novel agents in cell-line models, including bortezomib and carfilzomib resistance, and showed activity against primary cells from relapsed/refractory myeloma patients. In addition, TAK-243 showed strong synergy with a number of antimyeloma agents, including doxorubicin, melphalan, and panobinostat as measured by low combination indices. Finally, TAK-243 was active against a number of in vivo myeloma models in association with activation of ER stress. Taken together, the data support the conclusion that UAE inhibition could be an attractive strategy to move forward to the clinic for patients with relapsed and/or refractory multiple myeloma.
Irrigated agriculture
Authors: Кузнецова Елена , Kuznecova Elena , Закабунина Елена , Zakabunina Elena , Снипич Юрий , Snipich Yuriy , Дыцкова Елена , Dyckova Elena
Published: February 2019

In recent years, domestic and world science has come to the conclusion that it is necessary to introduce into agriculture ecological methods of cultivation of agricultural crops: irrigation, nutrition and care for the preservation of soil fertility. The training manual describes the main sprinkler machines for irrigation of agricultural crops; for the first time the materials for the study and calculations of water consumption of root crops, cereals, legumes when used in agriculture environmentally safe fine sprinkling. A new method of diagnosing irrigation time by temperature difference in the "sheet — air"system is presented.
Meets the requirements of the Federal state educational standards of higher education of the last generation.
It will be useful in the educational process for bachelors, undergraduates, graduate students and teachers, as well as specialists in the field of agriculture, land reclamation, soil science, ecology, physiology.
Life safety
Authors: Сычев Юрий , Sychev Yuriy
Published: February 2019

The textbook is designed to study the discipline "life Safety" in educational institutions of secondary vocational and higher education. The presented material is recommended for familiarization with the General population as instructions for action in emergency situations to preserve life and health.
Accounting technology of carrying out and registration of inventory
Authors: Качан Наталья , Kachan Natal'ya
Published: February 2019

The textbook "Accounting technology of carrying out and registration of inventory" is intended for preparation for practical and independent studies of students of the faculty of secondary professional education in the specialty "Economics and accounting (by industry)".
Vehicle Routing and Location Routing with Intermediate Stops: A Review
Authors: Schiffer Maximilian , Schneider Michael , Walther Grit , Laporte Gilbert
Published: February 2019

This paper reviews the literature on vehicle routing problems and location routing problems with intermediate stops. We classify publications into different categories from both an application-based perspective and a methodological perspective. In addition, we analyze the papers with respect to the algorithms and benchmark instances they present. Furthermore, we provide an overview of trends in the literature and identify promising areas for further research.
Traditional Versus Instructing Standard Guidelines of Preoperative Fasting Times on Associated Discomforts in Patients undergoing Elective Cesarean Section: Orotta Maternity National Referral and Teaching Hospital and Sembel Hospital, Eritrea
Authors: Beraki Michael , Yohannes Yosief , Geldner Goetz , McDonough John
Published: February 2019

AbstractIntroduction: Preoperative fasting is vital in preventing pulmonary aspiration, regurgitation and vomiting during the induction of anesthesia. Every patient scheduled for surgery including pregnant mothers need to be on fasting for certain period of time. Women undergoing cesarean section need full energy for themselves and the fetus to overcome the stress of birth. However, fasting time in Eritrea is generally longer than is recommended by American Society of Anesthesiologists. Prolonged fasting time has undesirable effects including, nausea, vomiting, dizziness, thirst, hunger etc. Objectives: This study compared the associated discomforts between traditional versus instructing standard guidelines of fasting times among mothers undergoing elective cesarean section. Methods: A non-randomized clinical trials among 106 mothers was conducted. Two groups for comparisons in two different hospitals were selected. One group received instructions of preoperative fasting according to the American Society of Anesthesiologists Task Force guidelines and the other group followed through the traditional approaches, i.e. â€œnothing by mouth after mid-nightâ€. Results: Mild to moderate degrees of discomforts was seen in the study participants. Feelings of thirst and hunger were the serious discomforts experienced. The associated discomforts were not determined to be significantly different (p=0.256) among the two groups of comparison. Conclusion: The study concluded that the associated discomforts were not statistically different between the traditional and standard groups. There was mild to moderate degrees of discomforts in both groups of study. Though the finding shows similar magnitude of discomforts between the two comparison groups, postoperative discomforts appear to worsen as the timing of fasting increases.
Fundamentos de ecología integral
Authors: Amo Usanos Rafael
Published: February 2019

Este artículo pretende explorar la arquitectura interna de Laudato si’ en busca de las raíces de los principios fundamentales de la ecología integral. En este trabajo, una vez estudiados y considerados los principios «todo está conectado» y el «todo es superior a la parte» como los fundamentos de la encíclica, se aborda la teología de la creación de corte trinitario y la filosofía de la biología de los sistemas abiertos que se consideran los lugares donde echan las raíces los principios citados. Ahora bien, esta investigación también saca a la luz el ángulo muerto de la ecología integral: el puesto del hombre en el cosmos y su derivada ética. Por último, se propone la distinción entre vida y sujeto de la vida como ayuda para superar el reduccionismo que se puede filtrar desde el paradigma sistémico a la ecología integral.
La comprensión de la voluntad de Dios en la obra «Camino Espiritual» del P. Luis de La Palma
Authors: Vargas Cano de Santayana Manuel
Published: February 2019

El artículo comienza recordando la actualidad que tiene la cuestión de la voluntad de Dios y explica que es posible distinguir una comprensión deontotónica y otra agapetónica de la misma. Nos acerca a la comprensión de la voluntad divina en la obra Camino Espiritual del P. Luis de la Palma (1559-1641), ofrece algunos párrafos escogidos y profundiza en la denominación de voluntad de Dios como agrado de Dios. En la segunda parte, cita a otros autores que comparten esta perspectiva: jesuitas del inicio, como Ignacio, Fabro, Javier, Nadal y Borja; y otros contemporáneos a La Palma como Canisio, Alonso Rodríguez, La Puente y Claver. El artículo ofrece las siguientes conclusiones: Cristo vive y se comunica, importancia de cumplir la voluntad divina, relación entre mandamientos y agrado de Dios, luz que esto aporta al fin de los ejercicios y el tesoro espiritual que todavía esconde Luis de La Palma.
La «educación» recibida y pensada por el joven Giovanni B. Montini
Authors: Martínez-Carbonell López Alfonso
Published: February 2019

La educación fue una constante preocupación en Pablo VI. Nos centramos aquí en su pensamiento educativo expresado en sus escritos juveniles hasta 1922, en la revista estudiantil La Fionda, en los que trata los principales problemas educativos de su tiempo como son la cuestión escolar y la necesidad de una reforma educativa, el papel revitalizador del estudiante en el periodo de posguerra, la libertad de enseñanza en el contexto de la Italia liberal posterior a la unión, la importancia de una enseñanza religiosa de calidad y la dimensión social de la educación y su apertura a los problemas sociales del tiempo. Toda esta concepción nace de una experiencia vital educativa que Montini vivió en su familia, en la escuela, en el oratorio juvenil y en el movimiento católico bresciano que son la fuente donde se forjó su honda preocupación y extraordinario interés por la educación.
El director escolar en Argentina: Un actor clave pero (aún) invisible. Un estudio sobre las normas, condiciones laborales y formación de los directores escolares de escuelas públicas
Authors: Romero Claudia , Krichesky Gabriela
Published: February 2019

El liderazgo directivo es un tema estratégico de política educativa. Las investigaciones especializadas han generado, durante la última década, evidencias fuertes sobre la centralidad de la función directiva en la mejora de los procesos de enseñanza y el logro de buenos resultados de aprendizaje; ésta se define incluso como el “segundo factor intra-escolar de importancia”. Sin embargo, en América Latina en general y en Argentina en particular, esto contrasta con la falta de investigación sistemática sobre el tema y con iniciativas aisladas de políticas focalizadas en fortalecer el liderazgo directivo.  Este artículo recoge aspectos centrales de un estudio cuyo objetivo es producir y analizar información relevante sobre los directores escolares en la Argentina en tres dimensiones: (a) la normativa que regula las funciones y competencias de los directores, (b) las condiciones de trabajo y contratación a las que están sujetos,  y (c) la oferta de formación existente para este colectivo. Aún con las limitaciones del caso, ya que el estudio se basa exclusivamente en el sector público que representa aproximadamente el 70% de la oferta educativa, este trabajo ofrece información clave para comprender la situación actual de los directores escolares en el país y pretende ser una contribución a ulteriores análisis regionales comparados y a la producción de políticas destinadas al desarrollo, fortalecimiento y profesionalización de la función directiva como factor de mejora escolar.
O vírus-cinema: cinema queer e VIH/sida
Authors: Colins Alfredo Taunay
Published: February 2019

Recensão do livro O vírus-cinema: cinema queer e VIH/sida, organizado por António Fernando Cascais e João Ferreira.
Ao ritmo a que a luz se perde. Em visita à exposição A Serenidade da Loucura de Apichatpong Weerasethakul
Authors: Marques Sabrina D.
Published: February 2019

Em visita à Exposição ''A Serenidade da Loucura'' de Apichatpong Weerasethakul no Núcleo de Arte Oliva, Portugal, 2018.
Séries de Televisão: Estética, Visionamento Atento e Escrita Crítica
Authors: Branco Sérgio Dias
Published: February 2019

Introdução ao dossier temático, “O Visionamento e a Crítica de Séries de Televisão”, editado por Sérgio Dias Branco.
Personalising library services in higher education: the boutique approach, red. Andy Priestner, Elizabeth Tilley, Farnham, Burlington: Ashgate 2012, s. XIV, 229. ISBN 9781409431800
Authors: Andruszko Hanna
Published: February 2019

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Andrzej Zaremba (1938–2018)
Authors: Nowakowski Andrzej
Published: February 2019

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Kazimierz Twardowski. Dzienniki młodzieńcze (1881–1887), wydała A. Brożek, Warszawa 2013 ss. 210
Authors: Szulakiewicz Władysława
Published: February 2019

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Wzorce wychowania do życia w rodzinie przekazywane dziewczętom w szkołach klasztornych (XVII–XIX w.)
Authors: Szylar Anna
Published: February 2019

Patterns of education for family life for girls in convent schools (XVII – half of XIXth century) The paper aims to analyse the education and upbringing of girls in schools run by nuns in the period from the seventeenth to the mid-nineteenth century. It shows the elements of upbringing and education that shaped the attitudes and values considered the most important in family life. It discusses issues related to the education of girls in how to run and manage a household, how to do household work, how to manage the household expenditure. On the basis of school curricula the range of intellectual education, the development of personal standards (attitudes, behaviours and features of character) of women in this period will be shown. These issues will be presented against a changing historical context, and will focus on girls from different social backgrounds.
Elevated Uncertainty during the Financial Crisis: Do Effects on Subjective Well-Being Differ across European Countries?
Authors: Tonzer Lena
Published: February 2019

This paper focuses on the effect of uncertainty as reflected by financial market variables on subjective well-being. The analysis is based on Eurobarometer surveys, covering 18 countries over the period 2000–2013. Individuals report lower levels of life satisfaction in times of higher uncertainty approximated by stock market volatility. This effect is heterogeneous across respondents: the probability of being unsatisfied is higher for respondents who are older, unemployed, less educated, and live in one of the GIIPS countries of the Euro area. Furthermore, higher uncertainty in combination with a financial crisis increases the probability of reporting low values of life satisfaction.
Differential Impact of Appropriate Use Criteria on the Association between Age and Abnormal Stress Myocardial Perfusion SPECT
Authors: Malhotra Saurabh , Doukky Rami
Published: February 2019

Background: The diagnostic and prognostic value of appropriate use criteria (AUC) for coronary artery disease (CAD) is well established. Whether the diagnostic yield of AUC for predicting CAD is preserved among the elderly is not known.

Methods: We analyzed a multisite prospective cohort of 1511 consecutive patients (age 59±13 years, 57% males) who underwent outpatient, community-based single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Appropriateness of the studies was determined on the basis of the 2013 multimodality AUC for detection and risk assessment of stable ischemic heart disease. Abnormal SPECT MPI was defined by either a summed stress score of 4 or greater or a summed difference score of 2 or greater.

Results: Abnormal SPECT MPI was present in 190 patients (12.5%), while ischemia on MPI alone was present in 122 patients (8%). In multivariate logistic regression analysis, age of 60 years or greater, male sex, hypertension, diabetes mellitus, and known CAD were independent predictors of abnormal SPET MPI, while appropriate indication for testing was not. Age of 60 years or greater was also an independent predictor of inducible myocardial ischemia, while appropriate indication for testing was not. Among the elderly (≥60 years), regardless of appropriateness of testing, there was no difference in the prevalence of abnormal SPECT (19 vs. 14%, P=0.14) or prevalence of SPECT ischemia (11 vs. 11%, P=1.00). Among younger patients, however, appropriate testing predicted a greater prevalence of abnormal SPECT (12 vs. 7%, P=0.013).

Conclusion: In this multisite cohort, testing based on AUC did not discriminate the risk of abnormal SPECT MPI among the elderly. Caution is advised when relying on AUC for referral of elderly patients for SPECT MPI.
Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity
Authors: Ruhl Douglas , Du Ting-Ting , Wagner Elizabeth L. , Choi Jeong Hwan , Li Sihan , Reed Robert , Kim Kitae , Freeman Michael , Hashisaki George , Lukens John R. , Shin Jung-Bum
Published: February 2019

Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinase (RIPK) 1 and RIPK3. In this study, we used pharmacological and genetic interventions in the mouse to test the relative contributions of necroptosis and caspase-8-mediated apoptosis toward cisplatin and aminoglycoside ototoxicity. We find thatex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, whilein vivo, necroptosis as well as apoptosis are involved in both sexes. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity.

SIGNIFICANCE STATEMENTThe clinical application of cisplatin and aminoglycosides is limited due to ototoxic side effects. Here, using pharmaceutical and genetic intervention, we present evidence that two types of programmed cell death, apoptosis and necroptosis, contribute to aminoglycoside and cisplatin ototoxicity. Key molecular factors mediating necroptosis are well characterized and druggable, presenting new avenues for pharmaceutical intervention.
Rod Photoresponse Kinetics Limit Temporal Contrast Sensitivity in Mesopic Vision
Authors: Umino Yumiko , Guo Ying , Chen Ching-Kang , Pasquale Rose , Solessio Eduardo
Published: February 2019

The mammalian visual system operates over an extended range of ambient light levels by switching between rod and cone photoreceptors. Rod-driven vision is sluggish, highly sensitive, and operates in dim or scotopic lights, whereas cone-driven vision is brisk, less sensitive, and operates in bright or photopic lights. At intermediate or mesopic lights, vision transitions seamlessly from rod-driven to cone-driven, despite the profound differences in rod and cone response dynamics. The neural mechanisms underlying such a smooth handoff are not understood. Using an operant behavior assay, electrophysiological recordings, and mathematical modeling we examined the neural underpinnings of the mesopic visual transition in mice of either sex. We found that rods, but not cones, drive visual sensitivity to temporal light variations over much of the mesopic range. Surprisingly, speeding up rod photoresponse recovery kinetics in transgenic mice improved visual sensitivity to slow temporal variations, in the range where perceptual sensitivity is governed by Weber's law of sensation. In contrast, physiological processes acting downstream from phototransduction limit sensitivity to high frequencies and temporal resolution. We traced the paradoxical control of visual temporal sensitivity to rod photoresponses themselves. A scenario emerges where perceptual sensitivity is limited by: (1) the kinetics of neural processes acting downstream from phototransduction in scotopic lights, (2) rod response kinetics in mesopic lights, and (3) cone response kinetics as light levels rise into the photopic range.

SIGNIFICANCE STATEMENTOur ability to detect flickering lights is constrained by the dynamics of the slowest step in the visual pathway. Cone photoresponse kinetics limit visual temporal sensitivity in bright (photopic) lights, whereas mechanisms in the inner retina limit sensitivity in dim (scotopic) lights. The neural mechanisms underlying the transition between scotopic and photopic vision in mesopic lights, when both rods are cones are active, are unknown. This study provides a missing link in this mechanism by establishing that rod photoresponse kinetics limit temporal sensitivity during the mesopic transition. Surprisingly, this range is where Weber's Law of Sensation governs temporal contrast sensitivity in mouse. Our results will help guide future studies of complex and dynamic interactions between rod–cone signals in the mesopic retina.
Luring the Motor System: Impact of Performance-Contingent Incentives on Pre-Movement Beta-Band Activity and Motor Performance
Authors: Savoie Félix-Antoine , Hamel Raphaël , Lacroix Angélina , Thénault François , Whittingstall Kevin , Bernier Pierre-Michel
Published: February 2019

It has been shown that when incentives are provided during movement preparation, activity in parieto-frontal regions reflects both expected value and motivational salience. Yet behavioral work suggests that the processing of rewards is faster than for punishments, raising the possibility that expected value and motivational salience manifest at different latencies during movement planning. Given the role of beta oscillations (13–30 Hz) in movement preparation and in communication within the reward circuit, this study investigated how beta activity is modulated by positive and negative monetary incentives during reach planning, and in particular whether it reflects expected value and motivational salience at different latencies. Electroencephalography was recorded while male and female humans performed a reaching task in which reward or punishment delivery depended on movement accuracy. Before a preparatory delay period, participants were informed of the consequences of hitting or missing the target, according to four experimental conditions: Neutral (hit/miss:+0/−0¢), Reward (hit/miss:+5/−0¢), Punish (hit/miss:+0/−5¢) and Mixed (hit/miss:+5/−5¢). Results revealed that beta power over parieto-frontal regions was strongly modulated by incentives during the delay period, with power positively correlating with movement times. Interestingly, beta power was selectively sensitive to potential rewards early in the delay period, after which it came to reflect motivational salience as movement onset neared. These results demonstrate that beta activity reflects expected value and motivational salience on different time scales during reach planning. They also provide support for models that link beta activity with basal ganglia and dopamine for the allocation of neural resources according to behavioral salience.

SIGNIFICANCE STATEMENTThe present work demonstrates that pre-movement parieto-frontal beta power is modulated by monetary incentives in a goal-directed reaching task. Specifically, beta power transiently scaled with the availability of rewards early in movement planning, before reflecting motivational salience as movement onset neared. Moreover, pre-movement beta activity correlated with the vigor of the upcoming movement. These findings suggest that beta oscillations reflect neural processes that mediate the invigorating effect of incentives on motor performance, possibly through dopamine-mediated interactions with the basal ganglia.
Disruption of RAB-5 Increases EFF-1 Fusogen Availability at the Cell Surface and Promotes the Regenerative Axonal Fusion Capacity of the Neuron
Authors: Linton Casey , Riyadh M. Asrafuzzaman , Ho Xue Yan , Neumann Brent , Giordano-Santini Rosina , Hilliard Massimo A.
Published: February 2019

Following a transection injury to the axon, neurons from a number of species have the ability to undergo spontaneous repair via fusion of the two separated axonal fragments. In the nematodeCaenorhabditis elegans, this highly efficient regenerative axonal fusion is mediated by epithelial fusion failure-1 (EFF-1), a fusogenic protein that functions at the membrane to merge the two axonal fragments. Identifying modulators of axonal fusion and EFF-1 is an important step toward a better understanding of this repair process. Here, we present evidence that the small GTPase RAB-5 acts to inhibit axonal fusion, a function achieved via endocytosis of EFF-1 within the injured neuron. Therefore, we find that perturbing RAB-5 activity is sufficient to restore axonal fusion in mutant animals with decreased axonal fusion capacity. This is accompanied by enhanced membranous localization of EFF-1 and the production of extracellular EFF-1-containing vesicles. These findings identify RAB-5 as a novel regulator of axonal fusion inC. eleganshermaphrodites and the first regulator of EFF-1 in neurons.

SIGNIFICANCE STATEMENTPeripheral and central nerve injuries cause life-long disabilities due to the fact that repair rarely leads to reinnervation of the target tissue. In the nematodeCaenorhabditis elegans, axonal regeneration can proceed through axonal fusion, whereby a regrowing axon reconnects and fuses with its own separated distal fragment, restoring the original axonal tract. We have characterized axonal fusion and established that the fusogen epithelial fusion failure-1 (EFF-1) is a key element for fusing the two separated axonal fragments back together. Here, we show that the small GTPase RAB-5 is a key cell-intrinsic regulator of the fusogen EFF-1 and can in turn regulate axonal fusion. Our findings expand the possibility for this process to be controlled and exploited to facilitate axonal repair in medical applications.
Dopaminergic Mechanisms Underlying Normal Variation in Trait Anxiety
Authors: Berry Anne S. , White Robert L. , Furman Daniella J. , Naskolnakorn Jenna R. , Shah Vyoma D. , D'Esposito Mark , Jagust William J.
Published: February 2019

Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term “chemical imbalance” to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining interindividual variability in dopamine release at rest using [11C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans. To measure endogenous dopamine release, we collected two [11C]raclopride PET scans per participant. We contrasted baseline [11C]raclopride D2/3 receptor binding and D2/3 receptor binding following oral methylphenidate administration. Methylphenidate blocks the dopamine transporter, which increases extracellular dopamine and leads to reduced [11C]raclopride D2/3 receptor binding via competitive displacement. We found that individuals with higher dopamine release in the amygdala and rACC self-reported lower trait anxiety. Lower trait anxiety was also associated with reduced rACC–amygdala functional connectivity at baseline. Further, functional connectivity showed a modest negative relationship with dopamine release such that reduced rACC–amygdala functional connectivity was accompanied by higher levels of dopamine release in these regions. Together, these findings contribute to hypodopaminergic models of anxiety and support the utility of combining fMRI and PET measures of neurochemical function to advance our understanding of basic affective processes in humans.

SIGNIFICANCE STATEMENTIt is common wisdom that individuals vary in their baseline levels of anxiety. We all have a friend or colleague we know to be more “tightly wound” than others, or, perhaps, we are the ones marveling at others' ability to “just go with the flow.” Although such observations about individual differences within nonclinical populations are commonplace, the neural mechanisms underlying normal variation in trait anxiety have not been established. Using multimodal brain imaging in humans, this study takes initial steps in linking intrinsic measures of neuromodulator release and functional connectivity within regions implicated in anxiety disorders. Our findings suggest that in healthy adults, higher levels of trait anxiety may arise, at least in part, from reduced dopamine neurotransmission.
Learning Critical Qualitative Research
Authors: Hsiung Ping-Chun
Published: February 2019

This Special Issue focuses on the learning of qualitative research as a legitimate and productive site of inquiry with the potential to illuminate and advance pedagogical practices. Its three objectives were (1) empowering and giving voice to new generations of qualitative research practitioners, (2) facilitating dialogue across the divide between the teaching and learning of critical qualitative research, and (3) mapping out a space of knowledge production and accumulation in critical qualitative research. The Issue includes five articles written by junior scholars or graduate students with or under the supervision of their mentors/supervisors. From different angle and to varying degrees, they touch on the role of teacher in the teaching/learning, the emotional aspect of learning, and the institutional context within which the learning takes place.
Learning through a Reunion of Mind-Body-Emotion-Spirits
Authors: Nobe-Ghelani Chizuru
Published: February 2019

While reflexivity has been taken up as an important concept in critical qualitative research, there are few texts that illustrate explicit approaches to practicing reflexivity. Drawing on my doctoral research experience, this article fills this gap and explores how the practice of mindfulness may guide us to a rich engagement with reflexivity during the critical qualitative research process, in particular within the context of interactions with research participants. More specifically, mindfulness is put forth as a practice to invite an embodied and holistic form of learning that goes beyond cognitive knowing. I argue that a mindfulness-based reflexivity has the potential to open up a space to learn from the messiness and discomfort experienced in the research process and deepen our understanding about the operation of power relations in critical qualitative research and beyond.
Learning through Doing
Authors: Dias Lisa V. , Janjua Martyna A.
Published: February 2019

In this article, we discuss our experiences learning how to do Foucauldian discourse analysis as doctoral students situated in a school of public health. We mobilize language of “learning through doing” as we reflect on the struggles of conducting doctoral dissertation research. While challenging, these struggles have been productive because they have resulted in epistemological shifts. We explore the following pivotal learning moments that have been central to producing changes in our epistemological positions: (1) realizing there are no predetermined methodological templates, (2) letting go of positivist notions of bias and representativeness, (3) recognizing the iterative nature of the qualitative research process, and (4) experiencing the centrality of writing to qualitative inquiry. Our article recognizes the profound relevance of “doing” within the process of learning critical and interpretive approaches to qualitative research and in unlearning positivist ideas about the production of knowledge that dominate the field of public health.
Bifocal germinoma in a patient with 16p11.2 microdeletion syndrome
Authors: Ventura Mara , Gomes Leonor , Rosmaninho-Salgado Joana , Barros Luísa , Paiva Isabel , Melo Miguel , Oliveira Diana , Carrilho Francisco
Published: February 2019

Intracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background.

Learning points:

Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism.

The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation.

Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology.

16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders.

Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion.

Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.