bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraindividual Variation and Short-term Temporal Trend in DNA Methylation of Human Blood
Authors: Shvetsov Yurii B. , Song Min-Ae , Cai Qiuyin , Tiirikainen Maarit , Xiang Yong-Bing , Shu Xiao-Ou , Yu Herbert
Published: December 2014

Background: Between- and within-person variation in DNA methylation levels are important parameters to be considered in epigenome-wide association studies. Temporal change is one source of within-person variation in DNA methylation that has been linked to aging and disease.

Methods: We analyzed CpG-site–specific intraindividual variation and short-term temporal trend in leukocyte DNA methylation among 24 healthy Chinese women, with blood samples drawn at study entry and after 9 months. Illumina HumanMethylation450 BeadChip was used to measure methylation. Intraclass correlation coefficients (ICC) and trend estimates were summarized by genomic location and probe type.

Results: The median ICC was 0.36 across nonsex chromosomes and 0.80 on the X chromosome. There was little difference in ICC profiles by genomic region and probe type. Among CpG loci with high variability between participants, more than 99% had ICC > 0.8. Statistically significant trend was observed in 10.9% CpG loci before adjustment for cell-type composition and in 3.4% loci after adjustment.

Conclusions: For CpG loci differentially methylated across subjects, methylation levels can be reliably assessed with one blood sample. More samples per subject are needed for low-variability and unmethylated loci. Temporal changes are largely driven by changes in cell-type composition of blood samples, but temporal trend unrelated to cell types is detected in a small percentage of CpG sites.

Impact: This study shows that one measurement can reliably assess methylation of differentially methylated CpG loci. Cancer Epidemiol Biomarkers Prev; 24(3); 490–7. ©2014 AACR.
A Pooled Analysis of Cigarette Smoking and Risk of Multiple Myeloma from the International Multiple Myeloma Consortium
Authors: Andreotti Gabriella , Birmann Brenda M. , Cozen Wendy , De Roos Anneclaire J. , Chiu Brian C.H. , Costas Laura , de Sanjosé Silvia , Moysich Kirsten , Camp Nicola J. , Spinelli John J. , Pahwa Punam , Dosman James A. , McLaughlin John R. , Boffetta Paolo , Staines Anthony , Weisenburger Dennis , Benhaim-Luzon Véronique , Brennan Paul , Costantini Adele Seniori , Miligi Lucia , Campagna Marcello , Nieters Alexandra , Becker Nikolaus , Maynadié Marc , Foretová Lenka , Zheng Tongzhang , Tricot Guido , Milliken Kevin , Krzystan Joseph , Steplowski Emily , Baris Dalsu , Purdue Mark P.
Published: December 2014

Background: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association, we conducted a pooled analysis of nine case–control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates.

Methods: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (OR) and 95% confidence intervals (CI) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center.

Results: Neither ever smokers (OR, 0.95; 95% CI, 0.87–1.05), current smokers (OR, 0.82; 95% CI, 0.73–0.93), nor former smokers (OR, 1.03; 95% CI, 0.92–1.14) had increased risks of multiple myeloma compared with never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups.

Conclusion: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma.

Impact: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. Cancer Epidemiol Biomarkers Prev; 24(3); 631–4. ©2014 AACR.
Epigenetics Markers of Metastasis and HPV-Induced Tumorigenesis in Penile Cancer
Authors: Feber Andrew , Arya Manit , de Winter Patricia , Saqib Muhammad , Nigam Raj , Malone Peter R. , Tan Wei Shen , Rodney Simon , Lechner Matthias , Freeman Alex , Jameson Charles , Muneer Asif , Beck Stephan , Kelly John D.
Published: December 2014

Purpose: Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer.

Experimental Design: Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations.

Results: We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature–negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021–0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13–0.78], HPV epi-signature is a better predictor of survival than HPV status alone.

Conclusions: These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies. Clin Cancer Res; 21(5); 1196–206. ©2014 AACR.
Pathological Response and Circulating Tumor Cell Count Identifies Treated HER2+ Inflammatory Breast Cancer Patients with Excellent Prognosis: BEVERLY-2 Survival Data
Authors: Pierga Jean-Yves , Petit Thierry , Lévy Christelle , Ferrero Jean-Marc , Campone Mario , Gligorov Joseph , Lerebours Florence , Roché Henri , Bachelot Thomas , Charafe-Jauffret Emmanuelle , Bonneterre Jacques , Hernandez Juana , Bidard François-Clément , Viens Patrice
Published: December 2014

Purpose: The BEVERLY-2 single-arm phase II trial assessed the efficacy and safety of combining neoadjuvant chemotherapy with bevacizumab and trastuzumab for the treatment of HER2-positive inflammatory breast cancer (IBC). Here, we report the results of a preplanned survival analysis at 3 years of follow-up, along with the association between outcome and circulating biomarkers and pathologic complete response (pCR).

Experimental Design: Patients received fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1–4) and docetaxel, trastuzumab, and bevacizumab (cycles 5–8) before surgery, followed by trastuzumab and bevacizumab for 30 weeks after surgery. Circulating tumor cell (CTC) and endothelial cell (CEC) counts were assessed at baseline, cycle 5, preoperative, postoperative, and at 1 year.

Results: Fifty-two patients were included. The 3-year disease-free survival (DFS) rate was 68% and overall survival (OS) rate was 90%. pCR (centrally reviewed) was strongly associated with 3-year DFS [80% and 53% in patients with/without pCR, respectively (P = 0.03)]. CTC detection also independently predicted 3-year DFS [81% vs. 43% for patients with <1 vs. ≥1 CTC/7.5 mL at baseline (P = 0.01)]. Patients with no CTCs detected at baseline and with pCR had a high 3-year DFS (95%). CEC changes during treatment had no prognostic value.

Conclusions: Our study suggests that the prognosis of IBC relies on more than the achievement of pCR and highlights the role of early hematogenous tumor dissemination as assessed by CTCs. Combining these two prognostic factors isolates a subgroup of IBC with excellent survival when treated with bevacizumab- and trastuzumab-containing regimens. Clin Cancer Res; 21(6); 1298–304. ©2014 AACR.
Angiogenic Cytokines Are Antibody Targets During Graft-versus-Leukemia Reactions
Authors: Piesche Matthias , Ho Vincent T. , Kim Haesook , Nakazaki Yukoh , Nehil Michael , Yaghi Nasser K. , Kolodin Dmitriy , Weiser Jeremy , Altevogt Peter , Kiefel Helena , Alyea Edwin P. , Antin Joseph H. , Cutler Corey , Koreth John , Canning Christine , Ritz Jerome , Soiffer Robert J. , Dranoff Glenn
Published: December 2014

Purpose: The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed patients with advanced myelodysplasia (MDS) and acute myelogenous leukemia (AML) who received an autologous, granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT).

Experimental Design: A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were used to characterize sera obtained longitudinally from 15 patients with AML/MDS who were vaccinated early after allogeneic HSCT.

Results: A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival.

Conclusions: These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with natural killer cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias. Clin Cancer Res; 21(5); 1010–8. ©2014 AACR.
Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial
Authors: Choueiri Toni K. , Figueroa David J. , Fay André P. , Signoretti Sabina , Liu Yuan , Gagnon Robert , Deen Keith , Carpenter Christopher , Benson Peter , Ho Thai H. , Pandite Lini , de Souza Paul , Powles Thomas , Motzer Robert J.
Published: December 2014

Purpose: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy.

Experimental Design: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test.

Results: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results.

Conclusions: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC. Clin Cancer Res; 21(5); 1071–7. ©2014 AACR.
Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice
Authors: Shen Yi , Ma Jun , Yan Ruilan , Ling Hongyan , Li Xiaoning , Yang Wancai , Gao John , Huang Chenfei , Bu Yiwen , Cao Yu , He Yingchun , Wan Laxiang , Zu Xuyu , Liu Jianghua , Huang Mei Chris , Stenson William F. , Liao Duan-Fang , Cao Deliang
Published: December 2014

Purpose: Ulcerative colitis and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but downregulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in ulcerative colitis and CAC.

Experimental Design: Ulcerative colitis and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8−/−) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide exome sequencing was used to profile DNA damage in DSS-induced colitis and tumors.

Results: AKR1B10 expression was markedly diminished in over 90% of ulcerative colitis and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8−/− mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8−/− mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8−/− mice than in wild-type mice. Palpable masses were seen in the AKR1B8−/− mice only, not in wild-type.

Conclusions: AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of ulcerative colitis and CAC, being a new etiopathogenic factor of these diseases. Clin Cancer Res; 21(6); 1466–76. ©2014 AACR.
Systemic High-Dose Corticosteroid Treatment Does Not Improve the Outcome of Ipilimumab-Related Hypophysitis: A Retrospective Cohort Study
Authors: Min Le , Hodi Frank Stephen , Giobbie-Hurder Anita , Ott Patrick A. , Luke Jason J. , Donahue Hilary , Davis Meredith , Carroll Rona S. , Kaiser Ursula B.
Published: December 2014

Purpose: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS).

Experimental Design: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan–Meier.

Results: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5–36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms.

Conclusion: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given. Clin Cancer Res; 21(4); 749–55. ©2014 AACR.
Dynamic Epigenetic Regulation by Menin During Pancreatic Islet Tumor Formation
Authors: Lin Wenchu , Watanabe Hideo , Peng Shouyong , Francis Joshua M. , Kaplan Nathan , Pedamallu Chandra Sekhar , Ramachandran Aruna , Agoston Agoston , Bass Adam J. , Meyerson Matthew
Published: December 2014

The tumor suppressor gene MEN1 is frequently mutated in sporadic pancreatic neuroendocrine tumors (PanNET) and is responsible for the familial multiple endocrine neoplasia type 1 (MEN-1) cancer syndrome. Menin, the protein product of MEN1, associates with the histone methyltransferases (HMT) MLL1 (KMT2A) and MLL4 (KMT2B) to form menin–HMT complexes in both human and mouse model systems. To elucidate the role of methylation of histone H3 at lysine 4 (H3K4) mediated by menin–HMT complexes during PanNET formation, genome-wide histone H3 lysine 4 trimethylation (H3K4me3) signals were mapped in pancreatic islets using unbiased chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). Integrative analysis of gene expression profiles and histone H3K4me3 levels identified a number of transcripts and target genes dependent on menin. In the absence of Men1, histone H3K27me3 levels are enriched, with a concomitant decrease in H3K4me3 within the promoters of these target genes. In particular, expression of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) gene is subject to dynamic epigenetic regulation by Men1-dependent histone modification in a time-dependent manner. Decreased expression of IGF2BP2 in Men1-deficient hyperplastic pancreatic islets is partially reversed by ablation of RBP2 (KDM5A), a histone H3K4-specific demethylase of the jumonji, AT-rich interactive domain 1 (JARID1) family. Taken together, these data demonstrate that loss of Men1 in pancreatic islet cells alters the epigenetic landscape of its target genes.

Implications: Epigenetic profiling and gene expression analysis in Men1-deficient pancreatic islet cells reveals vital insight into the molecular events that occur during the progression of pancreatic islet tumorigenesis. Mol Cancer Res; 13(4); 689–98. ©2014 AACR.
CRISPR-Cas9 Genome Editing of a Single Regulatory Element Nearly Abolishes Target Gene Expression in Mice—Brief Report
Authors: Han Yu , Slivano Orazio J. , Christie Christine K. , Cheng Albert W. , Miano Joseph M.
Published: December 2014

Objective—

To ascertain the importance of a single regulatory element in the control of
Cnn1
expression using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) genome editing.

Approach and Results—

The CRISPR/Cas9 system was used to produce 3 of 18 founder mice carrying point mutations in an intronic CArG box of the smooth muscle cell–restricted
Cnn1
gene. Each founder was bred for germline transmission of the mutant CArG box and littermate interbreeding to generate homozygous mutant (
Cnn1
ΔCArG/ΔCArG
) mice. Quantitative reverse transcription polymerase chain reaction, Western blotting, and confocal immunofluorescence microscopy showed dramatic reductions in
Cnn1
mRNA and CNN1 protein expression in
Cnn1
ΔCArG/ΔCArG
mice with no change in other smooth muscle cell–restricted genes and little evidence of off-target edits elsewhere in the genome. In vivo chromatin immunoprecipitation assay revealed a sharp decrease in binding of serum response factor to the mutant CArG box. Loss of CNN1 expression was coincident with an increase in Ki-67 positive cells in the normal vessel wall.

Conclusions—

CRISPR/Cas9 genome editing of a single CArG box nearly abolishes
Cnn1
expression in vivo and evokes increases in smooth muscle cell DNA synthesis. This facile genome editing system paves the way for a new generation of studies designed to test the importance of individual regulatory elements in living animals, including regulatory variants in conserved sequence blocks linked to human disease.
Progress in Late Results Among Pediatric Cardiac Surgery Patients
Authors: Raissadati Alireza , Nieminen Heta , Jokinen Eero , Sairanen Heikki
Published: December 2014

Background—

Surgical treatment of congenital cardiac defects in Finland started >60 years ago. We analyzed the survival of all the pediatric cardiac surgery patients operated on before 2010.

Methods and Results—

Data were obtained retrospectively from a pediatric cardiac surgery database. Patient status was received from the Finnish Population Registry. Survival was determined with the Kaplan–Meier method, and the survival rate was compared with a sex- and age-matched general population. Between 1953 and 2009, 13 876 cardiac operations were performed on 10 964 pediatric patients in Finland. Follow-up coverage was 98%. The 60-year survival for the entire study was 70% versus 86% for the general population. The number and proportion of severe cardiac defects increased in the 2000s. The long-term survival of patients with severe defects improved significantly across decades. For instance, the 22-year survival rate of patients with transposition of the great arteries operated on in 1953 to 1989 and in 1990 to 2009 improved from 71% to 93% (hazard ratio for death, 0.29; 95% confidence interval, 0.17–0.49;
P
<0.0001), respectively. The mean patient age at operation decreased from 8.9 to 2.2 years (95% confidence interval, 6.2–7.1;
P
<0.0001). The early mortality of patients decreased from a maximum of 7% in the 1970s to 3% in the 2000s (95% confidence interval, 0.05–0.08;
P
<0.0001).

Conclusions—

Patients are diagnosed and treated at an increasingly younger age. Advanced diagnostics, surgical methods, and postoperative intensive care have led to substantial improvements in both early and late results among pediatric cardiac surgery patients.
Achievements in Congenital Heart Defect Surgery
Authors: Erikssen Gunnar , Liestøl Knut , Seem Egil , Birkeland Sigurd , Saatvedt Kjell Johan , Hoel Tom Nilsen , Døhlen Gaute , Skulstad Helge , Svennevig Jan Ludvig , Thaulow Erik , Lindberg Harald Lauritz
Published: December 2014

Background—

This article presents an update of the results achieved by modern surgery in congenital heart defects (CHDs) over the past 40 years regarding survival and the need for reoperations, especially focusing on the results from the past 2 decades.

Methods and Results—

From 1971 to 2011, all 7038 patients <16 years of age undergoing surgical treatment for CHD at Rikshospitalet (Oslo, Norway) were enrolled prospectively. CHD diagnosis, date, and type of all operations were recorded, as was all-cause mortality until December 31, 2012. CHDs were classified as simple (3751/7038=53.2%), complex (2918/7038=41.5%), or miscellaneous (369/7037=5.2%). Parallel to a marked, sequential increase in operations for complex defects, median age at first operation decreased from 1.6 years in 1971 to 1979 to 0.19 years in 2000 to 2011. In total, 1033 died before January 1, 2013. Cumulative survival until 16 years of age in complex CHD operated on in 1971 to 1989 versus 1990 to 2011 was 62.4% versus 86.9% (
P
<0.0001). In the comparison of patients operated on in 2000 to 2004 versus 2005 to 2011, 1-year survival was 90.7% versus 96.5% (
P
=0.003), and 5-year cumulative survival was 88.8% versus 95.0% (
P
=0.0003). In simple versus complex defects, 434 (11.6%) versus 985 (33.8%) patients needed at least 1 reoperation before 16 years of age. In complex defects, 5-year cumulative freedom of reoperation among patients operated on in 1990 to 1999 versus 2000 to 2011 was 66% versus 73% (
P
=0.0001).

Conclusions—

Highly significant, sequential improvements in survival and reductions in reoperations after CHD surgery were seen. A future challenge is to find methods to reduce the need for reoperations and further reduce long-term mortality.
Gender Differences in Health Status and Adverse Outcomes Among Patients With Peripheral Arterial Disease
Authors: Dreyer Rachel P. , van Zitteren Moniek , Beltrame John F. , Fitridge Robert , Denollet Johan , Vriens Patrick W. , Spertus John A. , Smolderen Kim G.
Published: December 2014

Background

Few studies have examined gender differences in health status and cardiovascular outcomes in patients with peripheral artery disease (
PAD
). This study assessed (1) self‐reported health status at
PAD
diagnosis and 12‐months later, and explored (2) whether outcomes in women with
PAD
differ with regard to long‐term major adverse events.

Methods and Results

A total of 816 patients (285 women) with
PAD
were enrolled from 2 vascular clinics in the Netherlands. Baseline clinical data and subsequent adverse events were recorded and patients completed the Short Form‐12 (
SF
‐12, Physical Component Score [
PCS
] and Mental Component Score [
MCS
]) upon
PAD
diagnosis and 12‐months later. Women had similar ages and clinical characteristics, but poorer socio‐economic status and more depressive symptoms at initial diagnosis, as compared with men. Women also had poorer physical (
PCS
: 37±10 versus 40±10,
P
=0.004) and mental (
MCS
: 47±12 versus 49±11,
P
=0.005) health status at the time of presentation. At 12‐months, women still reported a poorer overall
PCS
score (41±12 versus 46±11,
P
=0.006) and
MCS
score (42±14 versus 49±12,
P
=0.002). Female gender was an independent determinant of a poorer baseline and 12‐month
PCS
and
MCS
scores. However, there were no significant differences by gender on either mortality (unadjusted hazard ratio [
HR
]=0.93, 95%
CI
0.60;1.44,
P
=0.74) or major adverse events (unadjusted
HR
=0.90, 95%
CI
0.63;1.29,
P
=0.57), after a median follow‐up of 3.2 years.

Conclusions

Women's physical and mental health status is compromised both at initial
PAD
diagnosis and at 12‐month follow‐up, despite experiencing a similar magnitude of change in their health scores throughout the first 12‐months after diagnosis.
Alberta Stroke Program Early Computed Tomographic Scoring Performance in a Series of Patients Undergoing Computed Tomography and MRI
Authors: McTaggart Ryan A. , Jovin Tudor G. , Lansberg Maarten G. , Mlynash Michael , Jayaraman Mahesh V. , Choudhri Omar A. , Inoue Manabu , Marks Michael P. , Albers Gregory W.
Published: December 2014

Background and Purpose—

In this study, we compare the performance of pretreatment Alberta Stroke Program Early Computed Tomographic scoring (ASPECTS) using noncontrast CT (NCCT) and MRI in a large endovascular therapy cohort.

Methods—

Prospectively enrolled patients underwent baseline NCCT and MRI and started endovascular therapy within 12 hours of stroke onset. Inclusion criteria for this analysis were evaluable pretreatment NCCT, diffusion-weighted MRI (DWI), and 90-day modified Rankin Scale scores. Two expert readers graded ischemic change on NCCT and DWI using the ASPECTS. ASPECTS scores were analyzed with the full scale or were trichotomized (0–4 versus 5–7 versus 8–10) or dichotomized (0–7 versus 8–10). Good functional outcome was defined as a 90-day modified Rankin Scale score of 0 to 2.

Results—

Seventy-four patients fulfilled our study criteria. The full-scale inter-rater agreement for CT-ASPECTS and DWI-ASPECTS was 0.579 and 0.867, respectively. DWI-ASPECTS correlated with functional outcome (
P
=0.004), whereas CT-ASPECTS did not (
P
=0.534). Both DWI-ASPECTS and CT-ASPECTS correlated with DWI volume. The receiver operating characteristic analysis revealed that DWI-ASPECTS outperformed both CT-ASPECTS and the time interval between symptom onset and start of the procedure for predicting good functional outcome (modified Rankin Scale score, ≤2) and DWI volume ≥70 mL.

Conclusion—

Inter-rater agreement for DWI-ASPECTS was superior to that for CT-ASPECTS. DWI-ASPECTS outperformed NCCT ASPECTS for predicting functional outcome at 90 days.
Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development
Authors: Lee Seyoung , Chu Hannah X. , Kim Hyun Ah , Real Nicola C. , Sharif Saeed , Fleming Stephen B. , Mercer Andrew A. , Wise Lyn M. , Drummond Grant R. , Sobey Christopher G.
Published: December 2014

Background and Purpose—

Expression of numerous chemokine-related genes is increased in the brain after ischemic stroke. Here, we tested whether post-stroke administration of a chemokine-binding protein (CBP), derived from the parapoxvirus bovine papular stomatitis virus, might reduce infiltration of leukocytes into the brain and consequently limit infarct development.

Methods—

The binding spectrum of the CBP was evaluated in chemokine ELISAs, and binding affinity was determined using surface plasmon resonance. Focal stroke was induced in C57Bl/6 mice by middle cerebral artery occlusion for 1 hour followed by reperfusion for 23 or 47 hours. Mice were treated intravenously with either bovine serum albumin (10 μg) or CBP (10 μg) at the commencement of reperfusion. At 24 or 48 hours, we assessed plasma levels of the chemokines CCL2/MCP-1 and CXCL2/MIP-2, as well as neurological deficit, brain leukocyte infiltration, and infarct volume.

Results—

The CBP interacted with a broad spectrum of CC, CXC, and XC chemokines and bound CCL2/MCP-1 and CXCL2/MIP-2 with high affinity (pM range). Stroke markedly increased plasma levels of CCL2/MCP-1 and CXCL2/MIP-2, as well as numbers of microglia and infiltrating leukocytes in the brain. Increases in plasma chemokines were blocked in mice treated with CBP, in which there was reduced neurological deficit, fewer brain-infiltrating leukocytes, and ≈50% smaller infarcts at 24 hours compared with bovine serum albumin–treated mice. However, CBP treatment was no longer protective at 48 hours.

Conclusions—

Post-stroke administration of CBP can reduce plasma chemokine levels in association with temporary atten uation of brain inflammation and infarct volume development.
Chronic Ischemia Alters Brain Microstructural Integrity and Cognitive Performance in Adult Moyamoya Disease
Authors: Kazumata Ken , Tha Khin Khin , Narita Hisashi , Kusumi Ichiro , Shichinohe Hideo , Ito Masaki , Nakayama Naoki , Houkin Kiyohiro
Published: December 2014

Background and Purpose—

The mechanisms underlying frontal lobe dysfunction in moyamoya disease (MMD) are unknown. We aimed to determine whether chronic ischemia induces subtle microstructural brain changes in adult MMD and evaluated the association of changes with neuropsychological performance.

Methods—

MRI, including 3-dimensional T1-weighted imaging and diffusion tensor imaging, was performed in 23 adult patients with MMD and 23 age-matched controls and gray matter density and major diffusion tensor imaging indices were compared between them; any alterations in the patients were tested for associations with age, ischemic symptoms, hemodynamic compromise, and neuropsychological performance.

Results—

Decrease in gray matter density, associated with hemodynamic compromise (
P
<0.05), was observed in the posterior cingulate cortex of patients with MMD. Widespread reduction in fractional anisotropy and increases in radial diffusivity and mean diffusivity in some areas were also observed in bilateral cerebral white matter. The fractional anisotropy (
r
=0.54;
P
<0.0001) and radial diffusivity (
r
=−0.41;
P
<0.01) of white matter significantly associated with gray matter density of the cingulate cortex. The mean fractional anisotropy of the white matter tracts of the lateral prefrontal, cingulate, and inferior parietal regions were significantly associated with processing speed, executive function/attention, and working memory.

Conclusions—

In adult MMD, there were more white matter abnormalities than gray matter changes. Disruption of white matter may play a pivotal role in the development of cognitive dysfunction.
Reliability and Limitations of Automated Arrhythmia Detection in Telemetric Monitoring After Stroke
Authors: Kurka Natalia , Bobinger Tobias , Kallmünzer Bernd , Koehn Julia , Schellinger Peter D. , Schwab Stefan , Köhrmann Martin
Published: December 2014

Background and Purpose—

Guidelines recommend continuous ECG monitoring in patients with cerebrovascular events. Studies on intensive care units (ICU) demonstrated high sensitivity but high rates of false alarms of monitoring systems resulting in desensitization of medical personnel potentially endangering patient safety. Data on patients with acute stroke are lacking.

Methods—

One-hundred fifty-one consecutive patients with acute cerebrovascular events were prospectively included. Automatically identified arrhythmia events were analyzed by manual ECG analysis. Muting of alarms was registered. Sensitivity was evaluated by beat-to-beat analysis of the entire recorded ECG data in a subset of patients. Ethics approval was obtained by University of Erlangen-Nuremberg.

Results—

A total of 4809.5 hours of ECG registration and 22 509 alarms were analyzed. The automated detection algorithm missed no events but the overall rate of false alarms was 27.4%. Only 0.6% of all alarms indicated acute life-threatening events and 91.4% of these alarms were incorrect. Transient muting of acoustic alarms was observed in 20.5% patients.

Conclusions—

Continuous ECG monitoring using automated arrhythmia detection is highly sensitive in acute stroke. However, high rates of false alarms and alarms without direct therapeutic consequence cause desensitization of personnel. Therefore, acoustic alarms may be limited to life-threatening events but standardized manual evaluation of all alarms should complement automated systems to identify clinically relevant arrhythmias.
Common and Unique Representations in pFC for Face and Place Attractiveness
Authors: Pegors Teresa K. , Kable Joseph W. , Chatterjee Anjan , Epstein Russell A.
Published: December 2014

Although previous neuroimaging research has identified overlapping correlates of subjective value across different reward types in the ventromedial pFC (vmPFC), it is not clear whether this “common currency” evaluative signal extends to the aesthetic domain. To examine this issue, we scanned human participants with fMRI while they made attractiveness judgments of faces and places—two stimulus categories that are associated with different underlying rewards, have very different visual properties, and are rarely compared with each other. We found overlapping signals for face and place attractiveness in the vmPFC, consistent with the idea that this region codes a signal for value that applies across disparate reward types and across both economic and aesthetic judgments. However, we also identified a subregion of vmPFC within which activity patterns for face and place attractiveness were distinguishable, suggesting that some category-specific attractiveness information is retained in this region. Finally, we observed two separate functional regions in lateral OFC: one region that exhibited a category-unique response to face attractiveness and another region that responded strongly to faces but was insensitive to their value. Our results suggest that vmPFC supports a common mechanism for reward evaluation while also retaining a degree of category-specific information, whereas lateral OFC may be involved in basic reward processing that is specific to only some stimulus categories.
Spoils of the Sign: Group Material's Americana, 1985
Authors: Grace Claire
Published: December 2014

A motley grid of things set against clashing bands of homely wallpaper: The dense array was far from comfortable. This was Americana, Group Material's site-specific exhibition project for the 1985 Whitney Biennial in which it took over the museum's lobby gallery. Facing the entrance hung Laurie Simmons's Tourism: Las Vegas (1984), a large-format cibachrome print whose appropriated, rephotographed imagery bet on surface and illusion: A trio of plastic figurines strut toward the rear-projected neon glow of Vegas, wagering class aspiration in all its gendered trappings against the highs and lows of American consumer capitalism. A few paces to the left, five loaves of packaged sliced bread posed a strange rejoinder: Wonder, Arnold, Pepperidge Farm, pinned by their cellophane crests to form a graduated queue, brought out marginal differences in color scheme and logo design. (At left, Peter Nagy's depiction of a Pepperidge Farm industrial plant underscored the point.) Pop lurked; Andy Warhol's 1960s soup cans belabored brand to similar effect, registering the outstripping of substance by signs at the most intimate level of bodily nourishment.
Diurnally Modulated Cumulus Moistening in the Preonset Stage of the Madden–Julian Oscillation during DYNAMO*
Authors: Ruppert James H. , Johnson Richard H.
Published: December 2014

Atmospheric soundings, radar, and air–sea flux measurements collected during Dynamics of the Madden–Julian Oscillation (DYNAMO) are employed to study MJO convective onset (i.e., the transition from shallow to deep convection) in the tropical Indian Ocean. The findings indicate that moistening of the low–midtroposphere during the preonset stage of the MJO is achieved by simultaneous changes in the convective cloud population and large-scale circulation. Namely, cumuliform clouds deepen and grow in areal coverage as the drying by large-scale subsidence and horizontal (westerly) advection wane. The reduction of large-scale subsidence is tied to the reduction of column radiative cooling during the preonset stage, which ultimately links back to the evolving cloud population. While net column moistening in the preonset stage is tied to large-scale circulation changes, a new finding of this study is the high degree to which the locally driven diurnal cycle invigorates convective clouds and cumulus moistening each day. This diurnal cycle is manifest in a daytime growth of cumulus clouds (in both depth and areal coverage) in response to oceanic diurnal warm layers, which drive a daytime increase of the air–sea fluxes of heat and moisture. This diurnally modulated convective cloud field exhibits prominent mesoscale organization in the form of open cells and horizontal convective rolls. It is hypothesized that the diurnal cycle and mesoscale cloud organization characteristic of the preonset stage of the MJO represent two manners in which local processes promote more vigorous daily-mean column moistening than would otherwise occur.
Precipitable Water from GPS over the Continental United States: Diurnal Cycle, Intercomparisons with NARR, and Link with Convective Initiation
Authors: Radhakrishna Basivi , Fabry Frédéric , Braun John J. , Van Hove Teresa
Published: December 2014

The variation of precipitable water vapor (PW) over the continental United States is examined at various time scales using spatial maps of a column-averaged mixing ratio (CAMR) that is derived from integrated column PW from both observations and reanalysis data. CAMR spatial maps are generated utilizing PW measurements obtained from a network of ground-based global positioning system (GPS) receivers and the North American Regional Reanalysis (NARR) over a time span of 4 yr (February 2009–January 2013). The effect of topography on PW is mitigated by vertically averaging the mixing ratio instead of integrating the absolute humidity. An ordinary kriging interpolation technique is used to generate spatial maps of CAMR. The observed and predicted PW derived by GPS and NARR correlate well with each other at annual and monthly scales. When focusing on its diurnal cycle, moisture peaks in the late afternoon over the Great Plains and late night over the Rockies. It is also found that atmospheric moisture within NARR generally increases in the second half of the UTC day and is adjusted significantly lower when external observations, such as radiosondes, are assimilated into the analysis system. These adjustments in the analysis introduce nonphysical offsets that are not present within the GPS-derived moisture fields. At meso-β and meso-α scales, GPS PW fields can be used as a precursor to forecast convection up to 3 h prior to initiation. As stated previously, the correlation between GPS and NARR is high (>0.98) at monthly and seasonal time scales, but there is poor correlation at time scales less than a day. This indicates that the water budget within NARR is not in proper balance over these short-term time scales. Over the continental United States, daily cycles of PW and precipitation are coupled differently in different areas.
From disaster relief to development assistance: Why simple solutions don’t work
Authors: Audet François
Published: December 2014

The emergency–development continuum, also known as “linking relief, rehabilitation, and development” (LRRD), has been a conceptual, institutional, and programmatic preoccupation for aid organizations and humanitarian policymakers for well over two decades. The objective of this short paper is to introduce the idea of the emergency–development continuum and, only partly ironically, to advance the notion that we should not bother with it: operationally, it has done more harm than good, driving the work of humanitarian organizations in directions that run counter to the interests of the people they are trying to serve.
Asserting a leading role for the European Union in international aviation: When aspirations meet reality
Authors: Charokopos Michael
Published: December 2014

More than a decade after the European Court of Justice’s “open skies” judgments, is the European Union (EU) now capable of asserting a leading role in the international aviation regime? This article approaches the EU’s external aviation policy through the lenses of role theory and, more precisely, through the threefold connotation of the concept of role: role conceptions, role expectations, and role performance. It finds that there is a converging tendency between the three dimensions and that the gap between external expectations and actual policy behaviour on the one hand, and the EU’s aspiration for a leading role in international aviation on the other, is diminishing. Over time, then, the EU could indeed transform from a regional trendsetter into a leading player in the international aviation regime.
Blake and Nietzsche on self-slaughter and the moral law: A reading of Jerusalem
Authors: Cauchi Francesca
Published: December 2014

Both Blake and Nietzsche deemed the perversion of energy or will by the architects and enforcers of the Judeo-Christian moral law to be the most cataclysmic event in the history of man. Coerced by a false dichotomy of good and evil, man’s primordial flux is not only stymied but vitiated through the self-mutilations of bad conscience. This essay examines the specific mechanism of moral coercion – a process of sublimation and condensation whereby the agonistic contraries within man are fixed into negating absolutes – and the extent to which such a process shapes the symbolic landscape of Blake’s final prophetic work, Jerusalem. At the heart of this landscape, an emblematic network of trees, rocks, nets and sacrificial altars, stands Vala, the virgin-whore of Babylon. Presiding remorselessly and remorsefully over the moral law’s slaughter of innocence, Vala is revealed as bad conscience personified and vilified.
The composition of Christine Brooke-Rose’s Thru: An afterlife of May ’68
Authors: Darlington Joseph
Published: December 2014

Christine Brooke-Rose’s 1975 novel Thru stands as one of the quintessential texts of postmodernism, both in its incomparable metatextual complexity and its reputation for conceptual excess. This paper traces the turbulent history of the novel’s construction. Fleeing from a collapsing marriage, illness and a dismissive literary establishment, Brooke-Rose left Britain to undertake a lecturing position at the University of Paris VIII, Vincennes, a hotbed of post-May ’68 student insurrection. Militantly a-political, Brooke-Rose remained detached from the situation, writing Thru as a satire of poststructuralist theory, until, in 1974, her own position was threatened by political machinations. The resulting disillusionment makes its way into the final text of Thru which, in turn, spells the end of her fiction writing career for nine years. This paper aims to place Thru in its historical context; a context not only resonant in terms of Brooke-Rose’s works, but for postmodernism in general.
The archite(x/c)ture of cinematic Milan
Authors: Melnikova Irina
Published: December 2014

The paper focuses on the issue of cinematic representation of Milan. The approach is based on Henri Lefebvre’s well-known argument regarding the importance of the textual nature of the city per se applicable to the analysis of the cinematic city. The analysis considers the ways in which Italian filmmakers represent Milan. It attempts to outline the ‘classical map’ of textual Milan created in Italian cinema and examines its changes in Luca Guadagnino’s recent film Io sono l’amore ( I Am Love, 2009). The analysis of the configuration of the diegetic city-space together with the exploration of the narrative devices in the representation of the city in Guadagnino’s film help to delineate the significance of a new cityscape and evaluate the changes to the ‘classical map’ of cinematic Milan.
Exploring Bergsonian time in Sadeq Hedayat’s The Blind Owl
Authors: Farahbakhsh Alireza , Haghshenas Saleh
Published: December 2014

This article aims to explore Henri Bergson’s notions of durée and simultaneity in Sadeq Hedayat’s The Blind Owl (1937), a prominent Modernist narrative in contemporary Iranian literature. Bergson refutes the logical and linear sequence of time and regards it as an indivisible whole that simultaneously posits the past, the present and the future on the same plane – the eternal present. Likewise, for Bergson, consciousness is characterized by flux and continuity as it processes all previous memories and experiences synchronously, as if they were all parts of a unified and organic whole. This article argues that certain features of the narrative structure of The Blind Owl, in particular the relativity and subjectivity of time and place and the constant intersection of memories and experiences, can be aligned with Bergson’s interpretation of temporality and consciousness. In the nameless narrator’s stream of consciousness and interrelated visions and reminiscences, characters, settings and incidents – which drive the narrative into a timeless and placeless context – constantly melt into and echo one another and ultimately become irreducible and radically interrelated constituents of an organic totality that resists temporal, spatial and cognitive divisibility.