bluuebunny/crossref_metadata_2025 huggingface dataset:
Attitude Strength
Authors: Howe Lauren C. , Krosnick Jon A.
Published: September 2016

Attitude strength has been the focus of a huge volume of research in psychology and related sciences for decades. The insights offered by this literature have tremendous value for understanding attitude functioning and structure and for the effective application of the attitude concept in applied settings. This is the first Annual Review of Psychology article on the topic, and it offers a review of theory and evidence regarding one of the most researched strength-related attitude features: attitude importance. Personal importance is attached to an attitude when the attitude is perceived to be relevant to self-interest, social identification with reference groups or reference individuals, and values. Attaching personal importance to an attitude causes crystallizing of attitudes (via enhanced resistance to change), effortful gathering and processing of relevant information, accumulation of a large store of well-organized relevant information in long-term memory, enhanced attitude extremity and accessibility, enhanced attitude impact on the regulation of interpersonal attraction, energizing of emotional reactions, and enhanced impact of attitudes on behavioral intentions and action. Thus, important attitudes are real and consequential psychological forces, and their study offers opportunities for addressing behavioral change.
Reinforcement Learning and Episodic Memory in Humans and Animals: An Integrative Framework
Authors: Gershman Samuel J. , Daw Nathaniel D.
Published: September 2016

We review the psychology and neuroscience of reinforcement learning (RL), which has experienced significant progress in the past two decades, enabled by the comprehensive experimental study of simple learning and decision-making tasks. However, one challenge in the study of RL is computational: The simplicity of these tasks ignores important aspects of reinforcement learning in the real world: (a) State spaces are high-dimensional, continuous, and partially observable; this implies that (b) data are relatively sparse and, indeed, precisely the same situation may never be encountered twice; furthermore, (c) rewards depend on the long-term consequences of actions in ways that violate the classical assumptions that make RL tractable. A seemingly distinct challenge is that, cognitively, theories of RL have largely involved procedural and semantic memory, the way in which knowledge about action values or world models extracted gradually from many experiences can drive choice. This focus on semantic memory leaves out many aspects of memory, such as episodic memory, related to the traces of individual events. We suggest that these two challenges are related. The computational challenge can be dealt with, in part, by endowing RL systems with episodic memory, allowing them to (a) efficiently approximate value functions over complex state spaces, (b) learn with very little data, and (c) bridge long-term dependencies between actions and rewards. We review the computational theory underlying this proposal and the empirical evidence to support it. Our proposal suggests that the ubiquitous and diverse roles of memory in RL may function as part of an integrated learning system.
Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice
Authors: Charrier Alyssa , Wang Li , Stephenson Erin J. , Ghanta Siddharth V. , Ko Chih-wei , Croniger Colleen M. , Bridges Dave , Buchner David A.
Published: September 2016

The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is central to the pathophysiology and treatment of metabolic disease through the receptors' ability to regulate the expression of genes involved in glucose homeostasis, adipogenesis, and lipid metabolism. However, the mechanism by which PPAR is regulated remains incompletely understood. We generated a transgenic mouse strain (ZFP-TG) that overexpressed Zfp407 primarily in muscle and heart. Transcriptome analysis by RNA-Seq identified 1,300 differentially expressed genes in the muscle of ZFP-TG mice, among which PPAR target genes were significantly enriched. Among the physiologically important PPARγ target genes, Glucose transporter (Glut)-4 mRNA and protein levels were increased in heart and muscle. The increase in Glut4 and other transcriptional effects of Zfp407 overexpression together decreased body weight and lowered plasma glucose, insulin, and HOMA-IR scores relative to control littermates. When placed on high-fat diet, ZFP-TG mice remained more glucose tolerant than their wild-type counterparts. Cell-based assays demonstrated that Zfp407 synergistically increased the transcriptional activity of all PPAR subtypes, PPARα, PPARγ, and PPARδ. The increased PPAR activity was not associated with increased PPAR mRNA or protein levels, suggesting that Zfp407 posttranslationally regulates PPAR activity. Collectively, these results demonstrate that Zfp407 overexpression improved glucose homeostasis. Thus, Zfp407 represents a new drug target for treating metabolic disease.
Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration
Authors: Aamodt Kristie I. , Aramandla Radhika , Brown Judy J. , Fiaschi-Taesch Nathalie , Wang Peng , Stewart Andrew F. , Brissova Marcela , Powers Alvin C.
Published: September 2016

Numerous compounds stimulate rodent β-cell proliferation; however, translating these findings to human β-cells remains a challenge. To examine human β-cell proliferation in response to such compounds, we developed a medium-throughput in vitro method of quantifying adult human β-cell proliferation markers. This method is based on high-content imaging of dispersed islet cells seeded in 384-well plates and automated cell counting that identifies fluorescently labeled β-cells with high specificity using both nuclear and cytoplasmic markers. β-Cells from each donor were assessed for their function and ability to enter the cell cycle by cotransduction with adenoviruses encoding cell cycle regulators cdk6 and cyclin D3. Using this approach, we tested 12 previously identified mitogens, including neurotransmitters, hormones, growth factors, and molecules, involved in adenosine and Tgf-1β signaling. Each compound was tested in a wide concentration range either in the presence of basal (5 mM) or high (11 mM) glucose. Treatment with the control compound harmine, a Dyrk1a inhibitor, led to a significant increase in Ki-67+ β-cells, whereas treatment with other compounds had limited to no effect on human β-cell proliferation. This new scalable approach reduces the time and effort required for sensitive and specific evaluation of human β-cell proliferation, thus allowing for increased testing of candidate human β-cell mitogens.
Ccl22 Diverts T Regulatory Cells and Controls the Growth of Melanoma
Authors: Klarquist Jared , Tobin Kristen , Farhangi Oskuei Peyman , Henning Steven W. , Fernandez Manuel F. , Dellacecca Emilia R. , Navarro Flor C. , Eby Jonathan M. , Chatterjee Shilpak , Mehrotra Shikhar , Clark Joseph I. , Le Poole I. Caroline
Published: September 2016

T regulatory cells (Treg) avert autoimmunity, but their increased levels in melanoma confer a poor prognosis. To explore the basis for Treg accumulation in melanoma, we evaluated chemokine expression in patients. A 5-fold increase was documented in the Treg chemoattractants CCL22 and CCL1 in melanoma-affected skin versus unaffected skin, as accompanied by infiltrating FoxP3+ T cells. In parallel, there was an approximately two-fold enhancement in expression of CCR4 in circulating Treg but not T effector cells. We hypothesized that redirecting Treg away from tumors might suppress autoimmune side effects caused by immune checkpoint therapeutics now used widely in the clinic. In assessing this hypothesis, we observed a marked increase in skin Treg in mice vaccinated with Ccl22, with repetitive vaccination sufficient to limit Treg accumulation and melanoma growth in the lungs of animals challenged by tumor cell injection, whether using a prevention or treatment protocol design. The observed change in Treg accumulation in this setting could not be explained by Treg conversion. Overall, our findings offered a preclinical proof of concept for the potential use of CCL22 delivered by local injection as a strategy to enhance the efficacious response to immune checkpoint therapy while suppressing its autoimmune side effects. Cancer Res; 76(21); 6230–40. ©2016 AACR.
Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma
Authors: Nguyen Phu Hung , Giraud Julie , Chambonnier Lucie , Dubus Pierre , Wittkop Linda , Belleannée Geneviève , Collet Denis , Soubeyran Isabelle , Evrard Serge , Rousseau Benoit , Senant-Dugot Nathalie , Mégraud Francis , Mazurier Frédéric , Varon Christine
Published: September 2016

Purpose: Gastric carcinomas are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemotherapy and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human gastric carcinoma of different histologic types.

Experimental Design: The primary tumors from 37 patients with intestinal- or diffuse-type noncardia gastric carcinoma were studied, and patient-derived tumor xenograft (PDX) models in immunodeficient mice were developed. The expressions of 10 putative cell surface markers of CSCs, as well as aldehyde dehydrogenase (ALDH) activity, were studied, and the tumorigenic properties of cells were evaluated by in vitro tumorsphere assays and in vivo xenografts by limiting dilution assays.

Results: We found that a subpopulation of gastric carcinoma cells expressing EPCAM, CD133, CD166, CD44, and a high ALDH activity presented the properties to generate new heterogeneous tumorspheres in vitro and tumors in vivo. CD44 and CD166 were coexpressed, representing 6.1% to 37.5% of the cells; ALDH activity was detected in 1.6% to 15.4% of the cells; and the ALDH+ cells represented a core within the CD44+/CD166+ subpopulation that contained the highest frequency of tumorigenic CSCs in vivo. The ALDH+ cells possessed drug efflux properties and were more resistant to standard chemotherapy than the ALDH− cells, a process that was partially reversed by verapamil treatment.

Conclusions: CD44 and ALDH are the most specific biomarkers to detect and isolate tumorigenic and chemoresistant gastric CSCs in noncardia gastric carcinomas independently of the histologic classification of the tumor. Clin Cancer Res; 23(6); 1586–97. ©2016 AACR.
Multilayer OMIC Data in Medullary Thyroid Carcinoma Identifies the STAT3 Pathway as a Potential Therapeutic Target in RETM918T Tumors
Authors: Mancikova Veronika , Montero-Conde Cristina , Perales-Paton Javier , Fernandez Agustin , Santacana María , Jodkowska Karolina , Inglada-Pérez Lucia , Castelblanco Esmeralda , Borrego Salud , Encinas Mario , Matias-Guiu Xavier , Fraga Mario , Robledo Mercedes
Published: September 2016

Purpose: Medullary thyroid carcinoma (MTC) is a rare disease with few genetic drivers, and the etiology specific to each known susceptibility mutation remains unknown. Exploiting multilayer genomic data, we focused our interest on the role of aberrant DNA methylation in MTC development.

Experimental Design: We performed genome-wide DNA methylation profiling assessing more than 27,000 CpGs in the largest MTC series reported to date, comprising 48 molecularly characterized tumors. mRNA and miRNA expression data were available for 33 and 31 tumors, respectively. Two human MTC cell lines and 101 paraffin-embedded MTCs were used for validation.

Results: The most distinctive methylome was observed for RETM918T-related tumors. Integration of methylation data with mRNA and miRNA expression data identified genes negatively regulated by promoter methylation. These in silico findings were confirmed in vitro for PLCB2, DKK4, MMP20, and miR-10a, -30a, and -200c. The mutation-specific aberrant methylation of PLCB2, DKK4, and MMP20 was validated in 25 independent MTCs by bisulfite pyrosequencing. The methylome and transcriptome data underscored JAK/Stat pathway involvement in RETM918T MTCs. Immunostaining [immunohistochemistry (IHC)] for the active form of signaling effector STAT3 was performed in a series of 101 MTCs. As expected, positive IHC was associated with RETM918T-bearing tumors (P < 0.02). Pharmacologic inhibition of STAT3 activity increased the sensitivity to vandetanib of the RETM918T-positive MTC cell line, MZ-CRC-1.

Conclusions: Multilayer OMIC data analysis uncovered methylation hallmarks in genetically defined MTCs and revealed JAK/Stat signaling effector STAT3 as a potential therapeutic target for the treatment of RETM918T MTCs. Clin Cancer Res; 23(5); 1334–45. ©2016 AACR.
Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer
Authors: George Julie , Saito Motonobu , Tsuta Koji , Iwakawa Reika , Shiraishi Kouya , Scheel Andreas H. , Uchida Shinsuke , Watanabe Shun-ichi , Nishikawa Ryo , Noguchi Masayuki , Peifer Martin , Jang Se Jin , Petersen Iver , Büttner Reinhard , Harris Curtis C. , Yokota Jun , Thomas Roman K. , Kohno Takashi
Published: September 2016

Purpose: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether CD274 is a target of recurrent genomic alterations.

Experimental Design: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining.

Results: By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where CD274 resides) and focal, high-level amplification of CD274. We found evidence for genomic targeting of CD274, suggesting selection during oncogenic transformation. CD274 amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased CD274 transcripts and high level expression of PD-L1.

Conclusions: A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of CD274. Such tumors may be particularly susceptible to immune checkpoint blockade. Clin Cancer Res; 23(5); 1220–6. ©2016 AACR.
Intraarterielle Chemotherapie des Retinoblastoms: Eine monozentrische Untersuchung
Authors: Bertelmann Eckart
Published: September 2016

Hintergrund: In den letzten Jahren durchgeführte Untersuchungen zur Behandlung des Retinoblastoms haben vielversprechende Ergebnisse für die intraarterielle Anwendung von Melphalan erbracht. In dieser Studie berichten wir über die Ergebnisse der intraarteriellen Chemotherapie (IACT) mit Melphalan in der Behandlung von Patienten mit neu diagnostiziertem oder rezidivierendem/therapierefraktärem Retinoblastom an der Klinik für Pädiatrische Onkologie der Universität Hacettepe, Ankara, Türkei. Material und Methoden: Es handelt sich um eine retrospektive Studie zu Patienten mit intraokulärem Retinoblastom, die zwischen Dezember 2011 und Mai 2014 mit einer IACT behandelt wurden. Insgesamt 56 Augen von 46 konsekutiven Patienten (30 männlich und 16 weiblich) wurden in die Studie eingeschlossen. 44 Augen waren im Anschluss an die Diagnosestellung mit einer systemischen Chemotherapie behandelt worden (systemische Chemotherapie-Gruppe, SCG), bei 12 Augen war die Diagnose neu (primäre intraarterielle Melphalan-Gruppe, PIAG). Die Bemessung der IACT-Dosis richtete sich nach dem Lebensalter. Tumorkontrolle und Bulbuserhalt unter IACT wurden analysiert. 7 Tage nach der IACT erfolgte eine Untersuchung auf systemische Toxizität anhand eines vollständigen Blutbilds. Okuläre Nebenwirkungen, z.B. Exophthalmus, Ödembildung des Augenlids, okuläre Motilität sowie Retina- und Optikusatrophie wurden durch einen Spezialisten für okuläre Onkologie mittels regelmäßiger augenärztlicher Untersuchungen beurteilt. Ergebnisse: Eine Enukleation konnte insgesamt bei 66% der Augen (37/56) vermieden werden - 75% (9/12) in der PIAG und 64% (28/44) in der SCG. Die enukleationsfreie Überlebensrate nach einem Jahr betrug 56,7%, bei einer medianen Nachbeobachtungsdauer von 11,9 Monaten (Spannweite 0,27-27,6). Die IACT wurde über insgesamt 124 Zyklen verabreicht (je 1-7 Zyklen; im Mittel 2,3). Die Patienten sprachen wie folgt auf die Behandlung an: Regression des Netzhauttumors in 27 Augen und Verbesserung der Glaskörperaussaat in 5 von 15 Augen. Folgende weitere Behandlungsschritte wurden nach der IACT noch erforderlich: Enukleation in 19 Augen (10 mit Glaskörperaussaat), Strahlentherapie in 3 Augen, systemische Chemotherapie in einem Auge und lokale Therapie in einem Auge. Es traten keine schwerwiegenden systemischen Nebenwirkungen auf. Zu verzeichnen waren transitorische Schwellungen der Augenlider (22 Patienten), Bindehautchemose (12 Patienten), Ptosis des oberen Augenlids (5 Patienten), Hautrötung in der Stirnregion (3 Patienten), Einschränkung der okulären Motilität (3 Patienten) sowie geringfügiger Exophthalmus (ein Patient). Veränderungen des retinalen Pigmentepithels (30 Patienten) und Optikusatrophie (3 Patienten) traten in der späteren Nachbeobachtung auf. Schlussfolgerungen: Eine IACT kann die Erhaltung des Augapfels und Vermeidung einer Strahlentherapie bei begrenzter Toxizität ermöglichen. Die Behandlung ist wirksam, reproduzierbar und sicher. Übersetzung aus Ophthalmologica 2015;234:227-232 (DOI:10.1159/000439357)
Impact of ATG Dose on the Outcome of Patients Undergoing Reduced Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies
Authors: Cornillon Jérôme , Balsat Marie , Cabrespine Aurélie , Tavernier-Tardy Emmanuelle , Hermet Eric , Mulliez Aurélien , Augeul-Meunier Karine , Guyotat Denis , Bay Jacques-Olivier
Published: September 2016

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often proposed for patients with comorbidities. To enhance engraftment and limit graft-versus-host disease (GVHD), antithymoglobulin (ATG) is usually used. However, the dose needed remains unclear unlike myeloablative conditioning. In order to clarify this point, we conducted a retrospective study on patients who received a reduced intensity conditioning allo-HSCT based on a 2-day fludarabine and busulfan treatment with either 1 or 2 days of ATG treatment. One hundred and eight patients received 2.5 mg/kg (ATG2.5) and another 60 patients 5 mg/kg (ATG5). The median follow-up was 36 months. The median overall survival was 39 months and the median disease-free survival 45 months. In multivariate analysis, overall nonrelapse mortality (NRM) was independently influenced by the acute GVHD grade III-IV (p < 0.001) and ATG dose (30 vs. 21% for ATG5; p = 0.008). Despite heterogeneity of populations, using proportional-hazard assumptions, we have been able to observe in multivariate analysis a lower NRM in the ATG5 group. This leads to a statistically higher overall survival for the ATG5 group. In conclusion, 2 days of ATG decrease NRM independently without increasing the risk of relapse or infectious disease.
Emixustat und Lampalizumab: Potenzielle neue Therapieoptionen bei geographischer Atrophie
Authors: Jack Loren S. , Sadiq Mohammad Ali , Do Diana V. , Nguyen Quan Dong
Published: September 2016

Zwei neuartige Wirkstoffklassen werden derzeit umfassend für die Behandlung der trockenen altersbedingten Makuladegeneration (AMD) untersucht. Emixustat, ein oral einzunehmender Sehzyklus-Inhibitor, und Lampalizumab, ein intravitreal zu verabreichendes monoklonales Antikörperfragment gegen Komplementfaktor D, haben in klinischen Studien der Phase 2 zur Behandlung der nichtneovaskulären (trockenen) AMD vielversprechende Ergebnisse gezeigt. Lampalizumab wird derzeit in einer großen multizentrischen klinischen Studie der Phase 3 zur trockenen AMD/geographischen Atrophie untersucht.
Charles-Bonnet-Syndrom bei Patienten mit Netzhauterkrankung
Authors: Rohrschneider Klaus
Published: September 2016

Ziel: Ziel dieser Studie ist die Untersuchung der Prävalenz und der klinischen Merkmale des Charles-Bonnet-Syndroms (CBS) bei einer Gruppe türkischer Patienten mit verschiedenen Netzhauterkrankungen. Methoden: 264 Patienten mit einem bestkorrigierten Visus von ≤20/40 im besseren Auge wurden mit einer standardisierten Frage nach dem Vorliegen von CBS-Symptomen befragt. Bei positiver Antwort wurde ein Fragebogen mündlich erhoben, um mehr über die Beschwerden im Einzelnen zu erfahren. Ergebnisse: An der Studie nahmen 125 (47,3%) Frauen und 139 (52,7%) Männer im mittleren Alter von 72,1 Jahren (Spannweite: 31-90 Jahre) teil. Bei 17 Patienten (6,4%) wurde ein CBS diagnostiziert. 3 Patienten (17,7%) hatten nichtkomplexe Halluzinationen, 14 (82,3%) hatten komplexe Halluzinationen. Schlussfolgerung: CBS ist bei Patienten mit einer Netzhauterkrankung und beeinträchtigtem Sehvermögen nicht ungewöhnlich. Kliniker, die Patienten mit beeinträchtigtem Sehvermögen behandeln, sollten an CBS denken. Übersetzung aus Ophthalmologica (DOI:10.1159/000446295)
Onychomycosis: Practical Approaches to Minimize Relapse and Recurrence
Authors: Tosti Antonella , Elewski Boni E.
Published: September 2016

Introduction: Toenail onychomycosis is a common disease in which treatment options are limited and treatment failures and disease recurrence are frequently encountered. It usually requires many months of treatment, and recurrence may occur in more than half of the patients within 1 year or more after the infection has been eradicated. Data on long-term treatment, follow-up and recurrence are limited. Objective: Our objective is to interpret these data and recommend practical approaches that should minimize recurrence based on our clinical experience. Results: Several factors have been suggested to play a role in the high incidence of recurrence, but only the extent of nail involvement and co-existing diabetes mellitus have been shown to have a significant impact. Conclusion: The use of topical antifungals to prevent recurrences after complete cure was achieved has been suggested by various workers and used successfully in our practice. However, it has never been validated through clinical studies. Topical prophylaxis once weekly or twice monthly would seem appropriate in those patients most at risk. Prompt treatment of tinea pedis is essential, as is ensuring family members are free from disease. Patient education and pharmacologic intervention are equally important, and there are a number of simple strategies patients can employ. Managing onychomycosis is a significant long-term commitment for any patient, and minimizing recurrence is critical to meet their expectations.
Tyrosine Kinase Inhibitors in the Treatment of Choroidal Metastases from Non-Small-Cell Lung Cancer: A Case Report and Review of Literature
Authors: Nair Akshay Gopinathan , Asnani Haresh T. , Mehta Vinod C. , Mehta Siddharth V. , Pathak Rima S. , Palkar Amit H. , Gopinathan Indumati
Published: September 2016

Background: Choroidal metastases being the sole presenting feature of lung cancer is rare. Erlotinib, a tyrosine kinase inhibitor (TKI), is used in the treatment of lung adenocarcinoma where tumor cells exhibit epidermal growth factor receptor (EGFR) mutations. We report a case of metastatic non-small-cell lung cancer (NSCLC) with choroidal metastasis, which was the sole presenting feature and which responded to erlotinib. Methods: We performed a retrospective case review. Case: A 78-year-old man presented with a choroidal mass which was found to be the presenting feature of metastatic NSCLC. Our patient, a nonsmoker, had disseminated bony metastases, and therefore was advised to undergo palliative chemotherapy, which he refused. He was therefore instituted on oral erlotinib. Results: Tumor cells expressing EGFR mutations are known to be susceptible to TKIs. Even though the tumor in our case showed no mutation, i.e. was classified as ‘wild-type', our patient showed a dramatic response to erlotinib. At 1 year, the choroidal lesion had regressed and visual acuity had recovered. Conclusions: TKIs may be beneficial in patients with choroidal metastases from NSCLC, especially those in which an EGFR mutation is noted. Even in the absence of such mutations, choroidal metastases may show a favorable effect in response to TKIs, such as erlotinib.
Hypothermia and Rewarming Activate a Macroglial Unfolded Protein Response Independent of Hypoxic-Ischemic Brain Injury in Neonatal Piglets
Authors: Lee Jennifer K. , Wang Bing , Reyes Michael , Armstrong Jillian S. , Kulikowicz Ewa , Santos Polan T. , Lee Jeong-Hoo , Koehler Raymond C. , Martin Lee J.
Published: September 2016

Therapeutic hypothermia provides incomplete neuroprotection after hypoxia-ischemia (HI)-induced brain injury in neonates. We previously showed that cortical neuron and white matter apoptosis are promoted by hypothermia and early rewarming in a piglet model of HI. The unfolded protein response (UPR) may be one of the potential mediators of this cell death. Here, neonatal piglets underwent HI or sham surgery followed by 29 h of normothermia, 2 h of normothermia + 27 h of hypothermia or 18 h of hypothermia + rewarming. Piglets recovered for 29 h. Immunohistochemistry for endoplasmic reticulum to nucleus signaling-1 protein (ERN1), a marker of UPR activation, was used to determine the ratios of ERN1+ macroglia and neurons in the motor subcortical white matter and cerebral cortex. The ERN1+ macroglia were immunophenotyped as oligodendrocytes and astrocytes by immunofluorescent colabeling. Temperature (p = 0.046) and HI (p < 0.001) independently affected the ratio of ERN1+ macroglia. In sham piglets, sustained hypothermia (p = 0.011) and rewarming (p = 0.004) increased the ERN1+ macroglia ratio above that in normothermia. HI prior to hypothermia diminished the UPR. Ratios of ERN1+ macroglia correlated with white matter apoptotic profile counts in shams (r = 0.472; p = 0.026), thereby associating UPR activation with white matter apoptosis during hypothermia and rewarming. Accordingly, macroglial cell counts decreased in shams that received sustained hypothermia (p = 0.009) or rewarming (p = 0.007) compared to those in normothermic shams. HI prior to hypothermia neutralized the macroglial cell loss. Neither HI nor temperature affected ERN1+ neuron ratios. In summary, delayed hypothermia and rewarming activate the macroglial UPR, which is associated with white matter apoptosis. HI may decrease the macroglial endoplasmic reticulum stress response after hypothermia and rewarming.
Acute Hemorrhagic Retinopathy following Intravitreal Melphalan Injection for Retinoblastoma: A Report of Two Cases and Technical Modifications to Enhance the Prevention of Retinal Toxicity
Authors: Aziz Hassan A. , Kim Jonathan W. , Munier Francis L. , Berry Jesse L.
Published: September 2016

Aims: To report the occurrence of acute hemorrhagic retinopathy following intravitreal melphalan injection for retinoblastoma. Methods: This is a retrospective case series of 2 patients with retinoblastoma treated with intravitreal melphalan for vitreous seeding who developed acute hemorrhagic retinopathy. Results: Patient 1 is a 6-month-old female with bilateral retinoblastoma (Group D right eye and Group B left eye) treated with 4 cycles of systemic chemotherapy and 2 intravitreal melphalan injections in each eye. Patient 2 is a 10-month-old male with unilateral Group D retinoblastoma treated with 6 cycles of systemic chemotherapy and 2 injections of intravitreal melphalan. At the 1-week follow-up after the second injection, both patients had an acute hemorrhagic retinopathy that resulted in chorioretinal toxicity with a sharp demarcation line between the normal and abnormal retina. At the last follow-up (22 and 12 months, respectively), there was total tumor control and resolution of vitreous seeding in both patients. Conclusions: Although intravitreal melphalan injection is effective for vitreous seeding in eyes with retinoblastoma, acute hemorrhagic retinopathy and diffuse chorioretinal atrophy is a possible complication of this treatment modality. Given the clinical findings observed in these patients, the development of this retinal toxicity most likely results from a retrohyaloid overdose. Consequently we suggest preventive measures aimed at limiting the risk of retrohyaloid injection.
Cl-Amidine Prevents Histone 3 Citrullination and Neutrophil Extracellular Trap Formation, and Improves Survival in a Murine Sepsis Model
Authors: Biron Bethany M. , Chung Chun-Shiang , O'Brien Xian M. , Chen Yaping , Reichner Jonathan S. , Ayala Alfred
Published: September 2016

Sepsis refers to the presence of a serious infection that correlates with systemic and uncontrolled immune activation. Posttranslational histone modification plays an important role in chromatin decondensation, which is regulated by citrullination. Citrullinated histone H3 (H3cit) has been identified as a component of neutrophil extracellular traps (NETs), which are released into the extracellular space as part of the neutrophil response to infection. The conversion of arginine to citrulline residues on histones is catalyzed by peptidylarginine deiminase 4 (PAD4). This study's goals were to characterize the presence of PAD4-catalyzed H3cit and NET formation during the onset of sepsis and elucidate the effects on the immune response when this mechanism of action is blocked. Adult C57BL/6 male mice were treated with Cl-amidine, an inhibitor of PAD4, 1 h prior to sepsis induced by cecal ligation and puncture (CLP). Twenty-four hours after CLP, cytokine levels, H3cit protein expression, neutrophil counts, and NET production were evaluated in the peritoneal cavity. Survival studies were also performed. Here we demonstrate that Cl-amidine treatment prior to CLP improves overall survival in sepsis and the abrogation of PAD4 has minimal effects on the proinflammatory immune response to sepsis, while it has no effect on overall neutrophil migration to the peritoneum.
Fever within 2 Weeks of Sorafenib Therapy Predicts Favorable Treatment Efficacy in Patients with Advanced Hepatocellular Carcinoma
Authors: Kuzuya Teiji , Ishigami Masatoshi , Ishizu Yoji , Honda Takashi , Hayashi Kazuhiko , Ishikawa Tetsuya , Nakano Isao , Goto Hidemi , Hirooka Yoshiki
Published: September 2016

Objectives: The aim of this study was to investigate the relationship between fever within 2 weeks after the start of sorafenib therapy and treatment efficacy in patients with advanced hepatocellular carcinoma (HCC). Methods: One hundred and two patients with advanced HCC were enrolled in this study. We retrospectively compared patients with fever (more than 38°C) within 2 weeks after the start of sorafenib therapy (fever group, n = 34) and patients without fever (non-fever group, n = 68) in terms of survival, best antitumor response, and change in intratumor blood on contrast-enhanced computed tomography (CE-CT) after 2 weeks of sorafenib therapy. Results: Fever was the only significant and independent predictor of better outcomes (hazard ratio, 0.517; 95% confidence interval, 0.319-0.838; p = 0.0071). In the fever group, the partial response rate, the disease control rate, and the rate of disappearance of arterial tumor enhancement on CE-CT after 2 weeks of sorafenib therapy were significantly higher than those in the non-fever group (38.2 vs. 5.9%, respectively, p = 0.0001; 85.3 vs. 60.3%, respectively, p = 0.0103; 76.5 vs. 35.3%, respectively, p < 0.0001). Conclusions: Fever within 2 weeks after the start of sorafenib therapy may be a useful predictor of a favorable treatment response in patients with advanced HCC.
Occult Fungal Scleritis
Authors: Jeang Lauren J. , Davis Aaron , Madow Brian , Espana Edgar M. , Margo Curtis E.
Published: September 2016

Purpose: To heighten awareness of occult fungal scleritis. Method: Case report and review of the literature. Results: A 73-year-old woman with diabetes mellitus was diagnosed for 3 months with immune-mediated scleritis and subsequently treated with corticosteroids. On referral, the patient had a scleral nodule with contiguous corneal infiltrate and hypopyon. Culture grew Fusarium species not further classified. The infection could not be controlled with antifungal therapy, and the eye was removed. No exogenous or endogenous source for the infection could be identified by clinical history or examination. Conclusion: Fungal scleritis can develop in persons without a history of foreign body injury, minor trauma, or evidence of endogenous fungemia. A high index of suspicion for infectious scleritis must be maintained in persons with presumed immune-mediated scleritis who fail to respond to conventional therapy, particularly if they present with decreased visual acuity.
Bilateral Choroidal Metastases from Lung Adenocarcinoma: A Case Report
Authors: Ergenc Hasan , Onmez Attila , Oymak Ezgi , Tanriseven Ramiser , Celik Erkan , Onmez Funda Ebru , Tamer Ali , Baykara Meltem
Published: September 2016

The most common malignancy of the eye is metastatic tumors, with choroidal metastases being the majority of them. In women, breast cancer is the most common cause of orbital metastases, and in men, it is lung cancer. Despite the fact that there are efficient treatment options for orbital metastases, the benefit of procedures to detect choroidal metastases is debatable due to the quick progression and poor prognosis of lung cancer. In choroidal metastases resulting from lung cancer, patients are usually presented with decreased sight. Defects in the field of vision, flashes of light and floating bodies generally follow. Treatment options of choroidal metastases include many methods including laser photocoagulation, cryotherapy, chemotherapy, radiotherapy, surgical resection, enucleation and photodynamic therapy. There are reports emphasizing radiotherapy as the most efficient treatment option. In this case report, we sum up the case of a male patient presenting with blurry vision in both eyes, who was subsequently detected to have bilateral choroidal metastatic tumor and was diagnosed with primary lung adenocarcinoma.
Deep Surgical Site Infections after Open Radical Cystectomy and Urinary Diversion Significantly Increase Hospitalisation Time and Total Treatment Costs
Authors: Wolters Mathias , Oelke Matthias , Lutze Bettina , Weingart Markus , Kuczyk Markus A. , Chaberny Iris F. , Graf Karolin
Published: September 2016

Introduction: Deep surgical site infections (DSSI) usually require secondary treatments. The aim of this study was to compare the total length of hospitalisation (LOH), intensive care unit (ICU) duration, and total treatment costs in patients with DSSI versus without DSSI after open radical cystectomy (ORC) and urinary diversion. Material and Methods: Prospective case-control study in a tertiary care hospital in patients after ORC with urinary diversion during April 2008 to July 2012. DSSI was defined based on Centers for Disease Control and Prevention criteria. Matched-pair analysis for patients with versus without DSSI was done in 1:2 ratios. Patients with superficial surgical site infections (SSI) were excluded from analysis. Results: In total, 189 operations were performed. Thirty-eight patients (20.1%) developed SSI of which 28 patients (14.8%) had DSSI. Out of 28 patients, 27 (96.4%) were with DSSI and required surgical re-intervention. Due to insufficient matching criteria, 11 patients with DSSI were excluded from analyses. Consequently, 17 patients with DSSI were matched with 34 patients without DSSI. Significant differences were seen for median overall LOH (30 vs. 18 days, p < 0.001), median ICU duration (p = 0.024), and median overall treatment costs (€17,030 vs. €11,402, p = 0.011). Conclusions: DSSI significantly increases LOH (67%) and treatment costs (49%), adding up to a financial loss for the hospital of approximately €5,500 in patients with DSSI.
Histological and Histometric Characterization of Myocardial Fibrosis in End-Stage Hypertrophic Cardiomyopathy
Authors: Galati Giuseppe , Leone Ornella , Pasquale Ferdinando , Olivotto Iacopo , Biagini Elena , Grigioni Francesco , Pilato Emanuele , Lorenzini Massimiliano , Corti Barbara , Foà Alberto , Agostini Valentina , Cecchi Franco , Rapezzi Claudio
Published: September 2016

Background—

Although noninvasively detected myocardial fibrosis (MF) has clinical implications in hypertrophic cardiomyopathy, the extent, type, and distribution of ventricular MF have never been extensively pathologically characterized. We assessed the overall amount, apex-to-base, circumferential, epicardial–endocardial distribution, pattern, and type of MF in 30 transplanted hearts of end-stage, hypertrophic cardiomyopathy.

Methods and Results—

Visual and morphometric histological analyses at basal, midventricular, and apical levels were performed. Overall MF ranged from 23.1% to 55.9% (mean=37.3±8.4%). Prevalent types of MF were as follows: replacement in 53.3%, interstitial-perimyocyte in 13.3%, and mixed in 33.3%. Considering left ventricular base-to-apex distribution, MF was 31.9%, 43%, and 46.2% at basal, midventricular, and apical level, respectively (
P
<0.001). Circumferential distributions (mean percentage of MF within the section) were as follows: anterior 11.9%, anterolateral 15.8%, inferolateral 7.0%, inferior 24.3%, anteroseptal 11%, midseptal 10.7%, and posteroseptal 11.4%; circumferential distributions for anterior and inferior right ventricular walls were 3.4% and 4.5%, respectively. Epicardial–endocardial distributions were as follows: trabecular 26.1% and subendocardial 20.2%, midwall 33.4%, and subepicardial 20.3%. Main patterns identified were as follows: midwall in 33.3% of the hearts, transmural in 23.3%, midwall–subepicardial in 23.3%, and midwall-subendocardial in 20%.

Conclusions—

In end-stage, hypertrophic cardiomyopathy patients undergoing transplantation, more than one-third of the left ventricular myocardium was replaced by fibrosis, mainly of replacement type. MF preferentially involved the left ventricular apex and the midwall. Inferior and anterior walls and septum were maximally involved, whereas inferolateral and right ventricular were usually spared. These observations reflect the complex pathophysiology of hypertrophic cardiomyopathy and may provide clues for the timely recognition of disease progression by imaging techniques capable of quantifying MF.
Effects of Sacubitril/Valsartan in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) According to Background Therapy
Authors: Okumura Naoki , Jhund Pardeep S. , Gong Jianjian , Lefkowitz Martin P. , Rizkala Adel R. , Rouleau Jean L. , Shi Victor C. , Swedberg Karl , Zile Michael R. , Solomon Scott D. , Packer Milton , McMurray John J.V.
Published: September 2016

Background—

In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan was more effective than the angiotensin-converting enzyme inhibitor enalapril in patients with heart failure and reduced ejection fraction. We examined whether this benefit was consistent irrespective of background therapy.

Methods and Results—

We examined the effect of study treatment in the following subgroups: diuretics (yes/no), digitalis glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no), and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization. We analyzed the primary composite end point of cardiovascular death or heart failure hospitalization, as well as cardiovascular death. Most randomized patients (n=8399) were treated with a diuretic (80%) and β-blocker (93%); 47% of those taking a β-blocker were treated with ≥50% of the recommended dose. In addition, 4671 (56%) were treated with a mineralocorticoid receptor antagonist, 2539 (30%) with digoxin, and 1243 (15%) had a defibrillating device; 2640 (31%) had undergone coronary revascularization. Overall, the sacubitril/valsartan versus enalapril hazard ratio for the primary composite end point was 0.80 (95% confidence interval, 0.73–0.87;
P
<0.001) and for cardiovascular death was 0.80 (0.71–0.89;
P
<0.001). The effect of sacubitril/valsartan was consistent across all subgroups examined. The hazard ratio for primary end point ranged from 0.74 to 0.85 and for cardiovascular death ranged from 0.75 to 0.89, with no treatment-by-subgroup interaction.

Conclusions—

The benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previous coronary revascularization or β-blocker dose.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01035255.
Afro-Caribbean Heart Failure in the United Kingdom
Authors: Dungu Jason N. , Papadopoulou Sofia A. , Wykes Katharine , Mahmood Ihtisham , Marshall Joseph , Valencia Oswaldo , Fontana Marianna , Whelan Carol J. , Gillmore Julian D. , Hawkins Philip N. , Anderson Lisa J.
Published: September 2016

Background—

It has been reported that subjects of African descent present with heart failure at a younger age and because of different causes than whites. We present contemporary data from UK Afro-Caribbean patients in London.

Methods and Results—

All patients with heart failure presenting to St George’s Hospital Heart Failure clinic between 2005 and 2012 were included (n=1392). Patients were predominantly white (71%) and male (67%), and median age at presentation was 73 years (range, 18–100 years). In 211 Afro-Caribbean patients, the most common cause of heart failure was nonischemic dilated cardiomyopathy in 27.5% (whites, 19.9%;
P
<0.001). Lower rates of ischemic cardiomyopathy were observed (13% versus 41%;
P
<0.001). The fourth most common cause of heart failure in Afro-Caribbeans was cardiac amyloidosis (11.4%). The prevalence may have been even higher as not all patients were tested for amyloidosis. Patients with ATTR V122I had the worst prognosis compared with other causes of Afro-Caribbean heart failure and white patients. To better understand this condition, we analyzed data from the largest international cohort of ATTR V122I patients, followed up at the UK National Amyloidosis Center (n=72). Patients presented with cardiac failure (median age, 75 [range, 59–90] years). Median survival was 2.6 years from diagnosis.

Conclusions—

In London, the cause of heart failure varies depending on ethnicity and affects age of presentation and outcomes. In Afro-Caribbean patients, ATTR V122I is an underappreciated cause of heart failure, and cardiomyopathy is often misattributed to hypertension. As promising TTR therapies are in development, increased awareness and proactive detection are needed.
The Holy Spirit and Eschatology – with Implications for Ministry and the Doctrine of Spirit Baptism
Authors: Gabriel Andrew K.
Published: September 2016

The coming of the Spirit at Pentecost represents both fulfillment and anticipation of eschatological expectations in as much as Pentecost both fulfills previous expectations regarding the coming of the Spirit and represents a promise of the future consummation of the work of God. This already/not yet reality of the eschaton is evident throughout pneumatology and carries implications for ministry and Christian living and for the doctrine of Spirit baptism. Believers should minister in the power of the Spirit with the aim of the kingdom of God that is already present while longing with Spirit-inspired hope for the future eschatological work of the Spirit that has not yet taken place. Furthermore, Spirit baptism is eschatological in as much as Pentecost fulfills and anticipates numerous eschatological expectations regarding the coming of the Spirit, including not only power for witness, but also a new heart, obedience, new life, and eventually resurrection.
VARIATIONS IN CELL WALL ULTRASTRUCTURE AND CHEMISTRY IN CELL TYPES OF EARLYWOOD AND LATEWOOD IN ENGLISH OAK (QUERCUS ROBUR)
Authors: Kim Jong Sik , Daniel Geoffrey
Published: September 2016

Although there is considerable information on anatomy and gross chemistry of oak wood, little is known on the ultrastructure and chemistry at the individual cell wall level. In particular, differences in ultrastructure and chemistry within the same cell type between earlywood (EW) and latewood (LW) are poorly understood. This study investigated the ultrastructure and chemistry of (vasicentric) tracheids, vessels, (libriform) fibers and axial/ray parenchyma cells of English oak xylem (Quercus robur L.) using light-, fluorescence- and transmission electron microscopy combined with histo/cytochemistry and immunohisto/ cytochemistry. EW tracheids showed several differences from LW tracheids including thinner cell walls, wider middle lamella cell corner (MLcc) regions and lesser amounts of mannan epitopes. Fibers showed thicker cell walls and higher amounts of mannan epitopes than tracheids. EW vessels were rich in guaiacyl (G) lignin with a characteristic non-layered cell wall organization (absence of S1–3 layers), whereas LW vessels were rich in syringyl (S) lignin with a three layered cell wall structure (S1–3 layers). Formation of a highly lignified and wide protective layer (PL) inside axial/ray parenchyma cells was detected only in EW. Distribution of mannan epitopes varied greatly between cell types and between EW and LW, whereas distribution of xylan epitopes was almost identical in all cell types within a growth ring. Together, this study demonstrates that there are great variations in ultrastructure and chemistry of cell walls within a single growth ring of English oak xylem.
NIRS IDENTIFICATION OF SWIETENIA MACROPHYLLA IS ROBUST ACROSS SPECIMENS FROM 27 COUNTRIES
Authors: Bergo Maria C.J. , Pastore Tereza C.M. , Coradin Vera T.R. , Wiedenhoeft Alex C. , Braga Jez W.B.
Published: September 2016

Big-leaf mahogany is the world’s most valuable widely traded tropical timber species and Near Infrared Spectroscopy (NIRS) has been applied as a tool for discriminating its wood from similar species using multivariate analysis. In this study four look-alike timbers of Swietenia macrophylla (mahogany or big-leaf mahogany), Carapa guianensis (crabwood), Cedrela odorata (cedar or cedro) and Micropholis melinoniana (curupixá) have been successfully discriminated using NIRS and Partial Least Squares for Discriminant Analysis using solid block and milled samples. Species identification models identified 155 samples of S. macrophylla from 27 countries with a correct classification rate higher than 96.8%. For these specimens, the NIRS spectrum variation was more powerful for species identification than for determining provenance of S. macrophylla at the country level.
INCIDENT LIGHT MICROPHOTOGRAPHY AT HIGH DEPTH OF FOCUS
Authors: Cerre Jean-Claude
Published: September 2016

A new method for stacked microphotography of 3D wood structures is described and illustrated with a practical protocol for visualizing the multiple perforation plates of Goupia glabra as seen in transverse surfaces.