bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise-Induced Neuroprotection of Hippocampus in APP/PS1 Transgenic Mice via Upregulation of Mitochondrial 8-Oxoguanine DNA Glycosylase
Authors: Bo Hai , Kang Weimin , Jiang Ning , Wang Xun , Zhang Yong , Ji Li Li
Published: November 2014

Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-β(Aβ) load and to modify the progression of Alzheimer’s disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Aβ-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration.
Intrinsic Apoptosis Pathway in Fallopian Tube Epithelial Cells Induced by Cladribine
Authors: Wawryk-Gawda Ewelina , Chylińska-Wrzos Patrycja , Lis-Sochocka Marta , Bulak Kamila , Jodłowska-Jędrych Barbara
Published: November 2014

Cladribine is a purine nucleoside analog which initiates the apoptotic mechanism within cells. Moreover, the available data confirms that cladribine, with the participation of the p53 protein, as well as the proapoptotic proteins from the Bcl-2 family, also induces the activation of the intrinsic apoptosis pathway. However, while there has been a lot of research devoted to the effect of cladribine on lymphatic system cells, little is known about the impact of cladribine on the reproductive system. The aim of our study was to evaluate apoptosis in oviduct epithelial cells sourced from 15 different female rats. In so doing, the sections were stained with caspases 3, 9, and 8. Results suggest that cladribine also induces apoptosis in the oviduct epithelial cells by way of the intrinsic pathway. Indeed, the discontinuing of the administration of cladribine leads to a reduction in the amount of apoptotic cells in the oviduct epithelium.
Fuzzy Temporal Logic Based Railway Passenger Flow Forecast Model
Authors: Dou Fei , Jia Limin , Wang Li , Xu Jie , Huang Yakun
Published: November 2014

Passenger flow forecast is of essential importance to the organization of railway transportation and is one of the most important basics for the decision-making on transportation pattern and train operation planning. Passenger flow of high-speed railway features the quasi-periodic variations in a short time and complex nonlinear fluctuation because of existence of many influencing factors. In this study, a fuzzy temporal logic based passenger flow forecast model (FTLPFFM) is presented based on fuzzy logic relationship recognition techniques that predicts the short-term passenger flow for high-speed railway, and the forecast accuracy is also significantly improved. An applied case that uses the real-world data illustrates the precision and accuracy of FTLPFFM. For this applied case, the proposed model performs better than thek-nearest neighbor (KNN) and autoregressive integrated moving average (ARIMA) models.
Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis
Authors: Couvé Sophie , Ladroue Charline , Laine Elodie , Mahtouk Karène , Guégan Justine , Gad Sophie , Le Jeune Hélène , Le Gentil Marion , Nuel Gregory , Kim William Y. , Lecomte Bernard , Pagès Jean-Christophe , Collin Christine , Lasne Françoise , Benusiglio Patrick R. , Bressac-de Paillerets Brigitte , Feunteun Jean , Lazar Vladimir , Gimenez-Roqueplo Anne-Paule , Mazure Nathalie M. , Dessen Philippe , Tchertanov Luba , Mole David R. , Kaelin William , Ratcliffe Peter , Richard Stéphane , Gardie Betty
Published: November 2014

The classic model of tumor suppression implies that malignant transformation requires full “two-hit” inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a “continuum” model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the “continuum” model of tumor suppression. Cancer Res; 74(22); 6554–64. ©2014 AACR.
A Genome-wide View of Microsatellite Instability: Old Stories of Cancer Mutations Revisited with New Sequencing Technologies
Authors: Kim Tae-Min , Park Peter J.
Published: November 2014

Microsatellites are simple tandem repeats that are present at millions of loci in the human genome. Microsatellite instability (MSI) refers to DNA slippage events on microsatellites that occur frequently in cancer genomes when there is a defect in the DNA-mismatch repair system. These somatic mutations can result in inactivation of tumor-suppressor genes or disrupt other noncoding regulatory sequences, thereby playing a role in carcinogenesis. Here, we will discuss the ways in which high-throughput sequencing data can facilitate genome- or exome-wide discovery and more detailed investigation of MSI events in microsatellite-unstable cancer genomes. We will address the methodologic aspects of this approach and highlight insights from recent analyses of colorectal and endometrial cancer genomes from The Cancer Genome Atlas project. These include identification of novel MSI targets within and across tumor types and the relationship between the likelihood of MSI events to chromatin structure. Given the increasing popularity of exome and genome sequencing of cancer genomes, a comprehensive characterization of MSI may serve as a valuable marker of cancer evolution and aid in a search for therapeutic targets. Cancer Res; 74(22); 6377–82. ©2014 AACR.
Chimeric Antigen Receptor T-cell Therapy to Target Hematologic Malignancies
Authors: Kenderian Saad Sirop , Ruella Marco , Gill Saar , Kalos Michael
Published: November 2014

Several decades of humoral immunotherapy using monoclonal antibodies and cellular immunotherapy using hematopoietic cell transplantation have recently culminated in a successful merger: the development and clinical application of genetically engineered antibody–T cell chimeras. Also known as chimeric antigen receptor T cells (CAR T cells), these entities combine the exquisite antigen specificity of antibodies with the polyfunctionality and potency of cellular immunity and are a prime example of the potential for synthetic biology to treat disease. CAR T cells overcome several of the biologic obstacles that have historically hampered immunotherapy while providing fundamental mechanistic insights into cellular immunology and revealing new challenges in genetic engineering and target selection. Results from early-phase CAR T-cell–based clinical trials demonstrate the significant potential for this approach to affect dramatic and complete clinical responses while revealing novel toxicities associated with activation of potent and specific antitumor immunity. Cancer Res; 74(22); 6383–9. ©2014 AACR.
Association of Prostate Cancer Risk Variants with Gene Expression in Normal and Tumor Tissue
Authors: Penney Kathryn L. , Sinnott Jennifer A. , Tyekucheva Svitlana , Gerke Travis , Shui Irene M. , Kraft Peter , Sesso Howard D. , Freedman Matthew L. , Loda Massimo , Mucci Lorelei A. , Stampfer Meir J.
Published: November 2014

Background: Numerous germline genetic variants are associated with prostate cancer risk, but their biologic role is not well understood. One possibility is that these variants influence gene expression in prostate tissue. We therefore examined the association of prostate cancer risk variants with the expression of genes nearby and genome-wide.

Methods: We generated mRNA expression data for 20,254 genes with the Affymetrix GeneChip Human Gene 1.0 ST microarray from normal prostate (N = 160) and prostate tumor (N = 264) tissue from participants of the Physicians' Health Study and Health Professionals Follow-up Study. With linear models, we tested the association of 39 risk variants with nearby genes and all genes, and the association of each variant with canonical pathways using a global test.

Results: In addition to confirming previously reported associations, we detected several new significant (P < 0.05) associations of variants with the expression of nearby genes including C2orf43, ITGA6, MLPH, CHMP2B, BMPR1B, and MTL5. Genome-wide, five genes (MSMB, NUDT11, RBPMS2, NEFM, and KLHL33) were significantly associated after accounting for multiple comparisons for each SNP (P < 2.5 × 10−6). Many more genes had an FDR <10%, including SRD5A1 and PSCA, and we observed significant associations with pathways in tumor tissue.

Conclusions: The risk variants were associated with several genes, including promising prostate cancer candidates and lipid metabolism pathways, suggesting mechanisms for their impact on disease. These genes should be further explored in biologic and epidemiologic studies.

Impact: Determining the biologic role of these variants can lead to improved understanding of prostate cancer etiology and identify new targets for chemoprevention. Cancer Epidemiol Biomarkers Prev; 24(1); 255–60. ©2014 AACR.
Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study
Authors: Flanagan James M. , Brook Mark N. , Orr Nick , Tomczyk Katarzyna , Coulson Penny , Fletcher Olivia , Jones Michael E. , Schoemaker Minouk J. , Ashworth Alan , Swerdlow Anthony , Brown Robert , Garcia-Closas Montserrat
Published: November 2014

Background: Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. We aimed to identify stable variable methylated probes (VMP), i.e., markers that are variable in the population, yet stable over time.

Methods: We estimated the intraclass correlation coefficient (ICC) for each probe on the Illumina 450K methylation array in paired samples collected approximately 6 years apart from 92 participants in the Breakthrough Generations Study. We also evaluated relationships with age, reproductive and hormonal history, weight, alcohol intake, and smoking.

Results: Approximately 17% of probes had an ICC > 0.50 and were considered stable VMPs (stable-VMPs). Stable-VMPs were enriched for probes located in “shores” bordering CpG islands, and at approximately 1.3 kb downstream from the transcription start site in the transition between the unmethylated promoter and methylated gene body. Both cross-sectional and longitudinal data analyses provided strong evidence for associations between changes in methylation levels and aging. Smoking-related probes at 2q37.1 and AHRR were stable-VMPs and related to time since quitting. We also observed associations between methylation and weight changes.

Conclusion: Our results provide support for the use of white blood cell DNA methylation as a biomarker of exposure in EWAS.

Impact: Larger studies, preferably with repeated measures over time, will be required to establish associations between specific probes and exposures. Cancer Epidemiol Biomarkers Prev; 24(1); 221–9. ©2014 AACR.
Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer
Authors: Ring Alistair , Wheatley Duncan , Hatcher Helen , Laing Robert , Plummer Ruth , Uttenreuther-Fischer Martina , Temple Graham , Pelling Katy , Schnell David
Published: November 2014

Purpose: The HER2 mAb, trastuzumab, is a standard therapy for patients with HER2-positive breast cancer before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive breast cancer.

Experimental Design: This phase I study used a 3+3 dose escalation to determine the MTD of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/wk thereafter). Adult women with confirmed advanced/metastatic HER2-positive breast cancer were eligible.

Results: Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall, pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall, objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0–274.0).

Conclusions: The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1 of 6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose-expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug–drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive breast cancer, suggesting further investigation with optimal diarrhea management is warranted. Clin Cancer Res; 21(12); 2737–44. ©2014 AACR.

See related commentary by Sledge and Pegram, p. 2663
Phenotypic and Genotypic Diversity of Multidrug-Resistant Pseudomonas aeruginosa Isolates from Bloodstream Infections Recovered in the Hospitals of Belo Horizonte, Brazil
Authors: Inacio Hanoch S.M. , Bomfim Maria Rosa Q. , França Rafaela O. , Farias Luiz M. , Carvalho Maria Auxiliadora R. , Serufo José Carlos , Santos Simone Gonçalves
Published: November 2014

Background: Pseudomonas aeruginosa commonly causes nosocomial bloodstream infections and the emergence of a variety of β-lactamases (BLs) is worrying. In 5 hospitals in Belo Horizonte, Brazil, the presence of phenotypes encoding BL genes was established and the genetic diversity of the P. aeruginosa strains recovered from bloodstream infections was analyzed. Materials and Methods: The isolates were investigated using a disk diffusion (DD) method and the Etest®, for encoding metallo-β-lactamases (MBLs), oxacillinases and cephalosporinases. Genes and genetic diversity were evaluated by random amplified polymorphic DNA (RAPD) genotyping and enterobacterial repetitive intergenic consensus (ERIC)-PCR. Results: Twelve strains (30%) were positive for MBLs by Etest and DD, 15 were cephalosporinase-positive and 87.5% were positive for blaSPM-1 and blaVIM-1. Twenty-three strains (57.5%) were grouped into profile A, 32.5% into profile B and 10% into profile C by RAPD genotyping. ERIC-PCR revealed a varying degree of similarity between strains, ranging from 45 to 100%. Conclusions: The results suggest distinct clonal populations in the 5 hospitals studied, indicating a potentially problematic epidemiological situation in Belo Horizonte, Brazil.
Subsets of a Large Cognitive Battery Better Power Clinical Trials on Early Stage Alzheimer's Disease
Authors: Xiong Chengjie , Weng Hua , Bennett David A. , Boyle Patricia A. , Shah Raj C. , Fague Scot , Hall Charles B. , Lipton Richard B. , Morris John C.
Published: November 2014

Background/Aims: Cognitive batteries routinely used by the Alzheimer's disease (AD) research community may contain items that are uninformative for tracking disease progression to power clinical trials on early stage AD. We aim to identify the subsets of the most informative items from an existing cognitive battery to better power clinical trials on early AD. Methods: Longitudinal change in item scores from the battery was associated with the onset of mild cognitive impairment (MCI) in 1,513 elderly individuals. Items whose longitudinal changes were correlated with the onset of MCI were selected as informative for tracking the early cognitive progression. Results: 226 items in the battery were annually assessed over a follow-up of up to 13 years. Changes of item scores over time from 187 items were significantly correlated with the onset of MCI. For clinical trials on preclinical AD and on MCI, informative items permit smaller or similar sample sizes as compared to the entire battery, whereas uninformative items require much larger sample sizes. Conclusions: Longitudinal changes in item scores from about 17% of items in the cognitive battery are uninformative for tracking early disease progression. Clinical trials on early AD can be better powered using informative items rather than the entire battery.
Incidence Rates of Cranial Tremors in Essential Tremor: A Prospective, Longitudinal Study
Authors: Michalec Monika , Gillman Art , Louis Elan D.
Published: November 2014

Background: Cranial (head, jaw) tremors develop in a sizable number of essential tremor (ET) patients. They are particularly important because they are a significant source of embarrassment and are especially resistant to treatment. There are no data on the rate at which ET patients develop these cranial tremors. Our aim was to estimate the incidence rate of head and jaw tremors in ET. Methods: Cases, enrolled in a prospective, longitudinal study, were evaluated at baseline and one follow-up visit. The in-person evaluation included questionnaires and a videotaped neurological examination, which was reviewed by a senior movement disorder neurologist for the presence/absence of head and jaw tremors. The mean time between baseline and follow-up assessments was 6.3 ± 2.4 (median = 6.0; range = 1.5-12.4 years). Results: Five (6.3%) of 79 cases developed head tremor by follow-up (incidence rate = 1,012 per 100,000 person years; 95% confidence interval [CI] = 0-3,219). Twelve (10.6%) of 113 cases developed jaw tremor by follow-up (incidence rate = 1,692 per 100,000 person years; 95% CI = 0-1,692). Conclusion: These epidemiological data were designed to assist physicians in counseling ET patients when they ask about their risks of developing cranial tremors.
The Intron 4 Polymorphism in the Calcium-Sensing Receptor Gene in Diabetes Mellitus and its Chronic Complications, Diabetic Nephropathy and Non-Diabetic Renal Disease
Authors: Železníková Viera , Vedralová Marcela , Kotrbová-Kozak Anna , Zoubková Hana , Černá Marie , Rychlík Ivan
Published: November 2014

Background/Aims: Calcium-Sensing Receptor (CaSR) significantly affects calcium-phosphate metabolism in kidneys, and it is implicated in the pathogenesis of diabetes mellitus (DM) due to its expression in pancreatic F-cells. The role of CaSR as one of the players in pathogenesis of chronic kidney disease (CKD) has been speculated. Methods: 158 Type 2 diabetic patients divided into three groups according to occurrence and type of kidney complications, 66 nondiabetic patients CKD, and 93 healthy subjects were enrolled into the study to analyze the role of two CaSR polymorphisms (in the codon 990 and in the intron 4) in ethiopathogenesis of DM and CKD. The Type 2 diabetic groups consisted of 48 patients without any kidney abnormalities, 58 patients with diabetic nephropathy (DN), and 52 patients with nondiabetic renal disease (NDRD). The distribution of genotype and allele frequencies was studied using PCR with the TaqMan Discrimination Assay or followed by the Restriction Fragment Length Polymorphism method, respectively. Results: We have found that the intron 4 polymorphism is a risk factor for the development of DM and CKD, except DN, while the codon 990 does not show any disease association. Conclusion: We conclude that CaSR is a general factor in pancreas and kidney pathologies. i 2014 S. Karger AG, Basel
Culprit Vessel Versus Multivessel Intervention at the Time of Primary Percutaneous Coronary Intervention in Patients With ST-Segment–Elevation Myocardial Infarction and Multivessel Disease
Authors: Iqbal M. Bilal , Ilsley Charles , Kabir Tito , Smith Robert , Lane Rebecca , Mason Mark , Clifford Piers , Crake Tom , Firoozi Sam , Kalra Sundeep , Knight Charles , Lim Pitt , Malik Iqbal S. , Mathur Anthony , Meier Pascal , Rakhit Roby D. , Redwood Simon , Whitbread Mark , Bromage Dan , Rathod Krishna , MacCarthy Philip , Dalby Miles
Published: November 2014

Background—

It is estimated that up to two thirds of patients presenting with ST-segment–elevation myocardial infarction have multivessel disease. The optimal strategy for treating nonculprit disease is currently under debate. This study provides a real-world analysis comparing a strategy of culprit-vessel intervention (CVI) versus multivessel intervention at the time of primary percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction.

Methods and Results—

We compared CVI versus multivessel intervention in 3984 patients with multivessel disease undergoing primary percutaneous coronary intervention between 2004 and 2011 at all 8 tertiary cardiac centers in London. Multivariable-adjusted models were built to determine independent predictors for in-hospital major adverse cardiovascular events (MACEs) and all-cause mortality at 1 year. To reduce confounding and bias, propensity score methods were used. CVI was associated with reduced in-hospital MACE (4.6% versus 7.2%;
P
=0.010) and mortality at 1 year (7.4% versus 10.1%;
P
=0.031). CVI was an independent predictor for reduced in-hospital MACE (odds ratio, 0.49; 95% confidence interval [CI], 0.32–0.75;
P
<0.001) and survival at 1 year (hazard ratio, 0.65; 95% CI, 0.47–0.91;
P
=0.011) in the complete cohort; and in 2821 patients in propensity-matched cohort (in-hospital MACE: odds ratio, 0.49; 95% CI, 0.32–0.76;
P
=0.002; and 1-year survival: hazard ratio, 0.64; 95% CI, 0.45–0.90;
P
=0.010). Inverse probability treatment weighted analyses also confirmed CVI as an independent predictor for reduced in-hospital MACE (odds ratio, 0.38; 95% CI, 0.15–0.96;
P
=0.040) and survival at 1 year (hazard ratio, 0.44; 95% CI, 0.21–0.93;
P
=0.033).

Conclusions—

In this observational analysis of patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, CVI was associated with increased survival at 1 year. Acknowledging the limitations with observational analyses, our findings support current recommended practice guidelines.
Endovascular Treatment of Mycotic Aortic Aneurysms
Authors: Sörelius Karl , Mani Kevin , Björck Martin , Sedivy Petr , Wahlgren Carl-Magnus , Taylor Peter , Clough Rachel E. , Lyons Oliver , Thompson Matt , Brownrigg Jack , Ivancev Krassi , Davis Meryl , Jenkins Michael P. , Jaffer Usman , Bown Matt , Rancic Zoran , Mayer Dieter , Brunkwall Jan , Gawenda Michael , Kölbel Tilo , Jean-Baptiste Elixène , Moll Frans , Berger Paul , Liapis Christos D. , Moulakakis Konstantinos G. , Langenskiöld Marcus , Roos Håkan , Larzon Thomas , Pirouzram Artai , Wanhainen Anders
Published: November 2014

Background—

Mycotic aortic aneurysm (MAA) is a rare and life-threatening disease. The aim of this European multicenter collaboration was to study the durability of endovascular aortic repair (EVAR) of MAA, by assessing late infection–related complications and long-term survival.

Methods and Results—

All EVAR treated MAAs, between 1999 and 2013 at 16 European centers, were retrospectively reviewed. One hundred twenty-three patients with 130 MAAs were identified. Mean age was 69 years (range 39–86), 87 (71%) were men, 58 (47%) had immunodeficiency, and 47 (38%) presented with rupture. Anatomic locations were ascending/arch (n=4), descending (n=34), paravisceral (n=15), infrarenal aorta (n=63), and multiple (n=7). Treatments were thoracic EVAR (n=43), fenestrated/branched EVAR (n=9), and infrarenal EVAR (n=71). Antibiotic was administered for mean 30 weeks. Mean follow-up was 35 months (range 1 week to 149 months). Six patients (5%) were converted to open repair during follow-up. Survival was 91% (95% confidence interval, 86% to 96%), 75% (67% to 83%), 55% (44% to 66%), and 41% (28% to 54%) after 1, 12, 60, and 120 months, respectively. Infection-related death occurred in 23 patients (19%), 9 after discontinuation of antibiotic treatment. A Cox regression analysis demonstrated non-Salmonella–positive culture as predictors for late infection–related death.

Conclusions—

Endovascular treatment of MAA is feasible and for most patients a durable treatment option. Late infections do occur, are often lethal, and warrant long-term antibiotic treatment and follow-up. Patients with non-Salmonella–positive blood cultures were more likely to die from late infection.
Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca
2+
/Calmodulin-Dependent Protein Kinase II Signaling
Authors: Bisserier Malik , Berthouze-Duquesnes Magali , Breckler Magali , Tortosa Florence , Fazal Loubina , de Régibus Annélie , Laurent Anne-Coline , Varin Audrey , Lucas Alexandre , Branchereau Maxime , Marck Pauline , Schickel Jean-Nicolas , Deloménie Claudine , Cazorla Olivier , Soulas-Sprauel Pauline , Crozatier Bertrand , Morel Eric , Heymes Christophe , Lezoualc’h Frank
Published: November 2014

Background—

Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood.

Methods and Results—

Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin
−/−
) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice;
P
<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constriction–induced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice;
P
<0.0001). Carabin also conferred protection against adrenergic receptor–induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase–activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca
2+
/calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras–GTPase–activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin.

Conclusions—

Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca
2+
/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure.
Renal Dysfunction Is Associated With a Reduced Contribution of Nitric Oxide and Enhanced Vasoconstriction After a Congenital Renal Mass Reduction in Sheep
Authors: Lankadeva Yugeesh R. , Singh Reetu R. , Moritz Karen M. , Parkington Helena C. , Denton Kate M. , Tare Marianne
Published: November 2014

Background—

Children born with reduced congenital renal mass have an increased risk of hypertension and chronic kidney disease in adulthood, although the mechanisms are poorly understood. Similar sequelae occur after fetal uninephrectomy (uni-x) in sheep, leading to a 30% nephron deficit. We hypothesized that renal dysfunction is underpinned by a reduced contribution of nitric oxide (NO) and vascular dysfunction in uni-x sheep.

Methods and Results—

In 5-year-old female uni-x and sham sheep, mean arterial pressure, glomerular filtration rate, and renal blood flow were measured before and during NO inhibition (
N
ω
-nitro-
l
-arginine methyl ester [L-NAME]). Reactivity was assessed in resistance arteries, including renal lobar and arcuate arteries. Basal mean arterial pressure was 15 mm Hg higher and glomerular filtration rate and renal blood flow were ≈30% lower (
P
<0.001) in uni-x animals. L-NAME increased mean arterial pressure by ≈17 mm Hg in both groups, whereas glomerular filtration rate and renal blood flow were decreased less in uni-x sheep (
P
Interaction
<0.01). Endothelial NO synthase and Ser-1177–phosphorylated endothelial NO synthase protein levels were upregulated in renal cortex of uni-x sheep (
P
<0.05). Lobar arteries of uni-x sheep had enhanced responsiveness to phenylephrine and nitrotyrosine staining and reduced sensitivity to endothelial stimulation. Vasodilator prostanoid contribution to endothelium-dependent relaxation was reduced in lobar arteries of uni-x sheep, accompanied by reduced cyclooxygenase-1 and -2 gene expression (
P
<0.05). Neurovascular constriction was enhanced ≈1.5-fold in renal arteries of uni-x sheep (
P
<0.05).

Conclusions—

Renal dysfunction after congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in renal blood flow and glomerular filtration rate are underpinned by impaired basal NO contribution, endothelial dysfunction, and enhanced vascular responsiveness to sympathetic nerve stimulation.
Off-Hours Admission and Acute Stroke Care Quality
Authors: Kristiansen Nina Sahlertz , Mainz Jan , Nørgård Bente Mertz , Bartels Paul D. , Andersen Grethe , Johnsen Søren Paaske
Published: November 2014

Background and Purpose—

Studies have reported higher risks of death and other adverse outcomes in acute stroke patients admitted off-hours; however, little is known about the underlying mechanisms. According to time of admission, our aim was to examine compliance with performance measures for acute stroke care processes, including the effect of a systematic quality improvement program, and to examine 30 days case-fatality.

Methods—

A population-based historical cohort study, including patients admitted to Danish hospitals with a first ever acute stroke (January 1, 2003, to December 31, 2011; N=64 975). Off-hours were weekends and evening and nighttime shifts on weekdays. Compliance with performance measures was compared using general linear modeling, and odds ratios for 30 days case-fatality were obtained using multivariable logistic regression.

Results—

Patients admitted off-hours had a lower chance of compliance with 8 out of 10 performance measures; however, these differences diminished over time. Unadjusted odds ratio for 30 days case-fatality, for patients admitted off-hours compared with patients admitted on-hours, was 1.15 (95% confidence interval, 1.09–1.21). Adjusting for patient characteristics (in particular, stroke severity) decreased the odds ratio to 1.03 (95% confidence interval, 0.97–1.10). Additional adjustment for hospital characteristics and compliance with performance measures had no effect on the odds ratio.

Conclusion—

Patients admitted off-hours received a poorer quality of care. However, the admission time–related differences in care were substantially reduced over time, and the differences in 30 days case-fatality appeared primarily to be explained by differences in stroke severity.
18FDG-PET-CT
Authors: Müller Hubertus Fritz Georg , Viaccoz Aurélien , Fisch Loraine , Bonvin Christophe , Lovblad Karl-Olof , Ratib Osman , Lalive Patrice , Pagano Sabrina , Vuilleumier Nicolas , Willi Jean-Pierre , Sztajzel Roman
Published: November 2014

Background and Purpose—

We investigated whether uptake of
18
fluoro-2-deoxy-d-glucose (18FDG) positron emission tomography–computed tomography (PET-CT) correlated to clinical symptoms and presence of microembolic signals (MES) detected by transcranial Doppler in patients with carotid stenosis.

Methods—

18FDG-PET-CT and MES detection was performed in consecutive patients with 50% to 99% symptomatic or asymptomatic carotid stenoses. Uptake index was defined by a target to background ratio (TBR) between maximum standardized uptake value of the carotid plaque and the mean standardized uptake value of the jugular veins. End points for analysis were presence of symptoms and presence of MES.

Results—

We included 123 stenosis derived from 110 patients, 60 symptomatic and 63 asymptomatic. MES positive (+) lesions were found in 16%. TBR values were higher in symptomatic compared with asymptomatic (median 2.07 versus 1.78;
P
<0.0018) and in MES+ compared with MES− plaques (median 2.14 versus 1.86;
P
<0.008). TBR values were also higher in asymptomatic MES+ compared with MES− plaques (median 1.97 versus 1.76;
P
<0.03). The best TBR threshold value for symptomatic versus asymptomatic, for MES+ versus MES−, for symptomatic MES+ versus symptomatic or asymptomatic MES−, and for asymptomatic MES+ versus asymptomatic MES− plaques was 1.9. Sensitivity/specificity were, respectively, 56/77%, 73/63%, 79/64%, and 80/77%. We found a strong correlation between number of MES and TBR values (
ρ
0.26;
P
=0.0043).

Conclusions—

18FDG-PET-CT accurately detected high-risk carotid plaques. Also given its strong correlation to MES, 18FDG-PET-CT may be a useful tool in clinical practice.
Intraluminal Cell Transplantation Prevents Growth and Rupture in a Model of Rupture-Prone Saccular Aneurysms
Authors: Marbacher Serge , Frösén Juhana , Marjamaa Johan , Anisimov Andrey , Honkanen Petri , von Gunten Michael , Abo-Ramadan Usama , Hernesniemi Juha , Niemelä Mika
Published: November 2014

Background and Purpose—

Aneurysm occlusion by intraluminal thrombus formation is the desired effect of all endovascular treatments. Intraluminal thrombus may, however, recanalize and be absorbed, unless it is infiltrated by cells that turn it into fibrous tissue (neointima). Because ruptured aneurysm walls are characterized by loss of smooth muscle cells, we assessed the impact of mural cell loss on wall remodeling of thrombosed aneurysms and investigated whether neointima formation could be enhanced by direct transplantation of cells into the thrombus.

Methods—

Sidewall aneurysms were microsurgically created in rats (n=81). Certain aneurysms were decellularized. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil–labeled smooth muscle cells were injected into 25 of 46 fibrin embolized aneurysms. Recanalization and aneurysm growth were monitored with magnetic resonance angiography. Endoscopy, optical projection tomography, histology, and immunohistochemistry were used to study the fate of transplanted cells, thrombus organization, and neointima formation.

Results—

Decellularized embolized aneurysms demonstrated higher angiographic recurrence compared with decellularized embolized aneurysms with transplanted cells (
P
=0.037). Local cell replacement at the time of thrombosis resulted in better histological neointima formation than both nondecellularized embolized aneurysms (
P
<0.001) and decellularized embolized aneurysms (
P
=0.002). Aneurysm growth and rupture were observed exclusively in decellularized embolized aneurysms.

Conclusions—

Lack of smooth muscle cells in the aneurysm wall promotes wall degradation, aneurysm growth and rupture, even if the aneurysm is occluded by luminal thrombus. Transplantation of smooth muscle cells into the luminal thrombus can reduce this degenerative remodeling.
Effect of Alteplase Within 6 Hours of Acute Ischemic Stroke on All-Cause Mortality (Third International Stroke Trial)
Authors: Whiteley William N. , Thompson Douglas , Murray Gordon , Cohen Geoff , Lindley Richard I. , Wardlaw Joanna , Sandercock Peter
Published: November 2014

Background and Purpose—

Prompt thrombolytic therapy with intravenous alteplase reduces disability after acute ischemic stroke. In an exploratory analysis, we examined whether long-term survival varied by baseline characteristics after alteplase.

Methods—

In this open-treatment, international, randomized, controlled trial, ischemic stroke patients were randomly allocated <6 hours of onset to intravenous alteplase (0.9 mg/kg) plus standard care (n=1515) or standard care alone (n=1520). We followed patients to death, censoring when last known to be alive. We grouped patients by delay to randomization, and good or poor predicted prognosis (calculated from baseline National Institutes of Health Stroke Scale [NIHSS] score and age). We present absolute mortality differences between treated and control groups at 7 days, 6 months, and 18 months poststroke.

Results—

Alteplase was not associated with a significant increase in mortality within 18 months (0.6% [95% confidence interval (CI), −2.9% to +4.2]
P
=0.72] in all patients with complete vital status (99.9%, 3034/3035). In patients randomized <3 hours of stroke, 18-month mortality was lower in the alteplase-treated group than the control group (40.6% [95% CI, 42.6–52.7] versus 47.8% [95% CI, 35.5–45.3];
P
=0.0434]. The difference in 18-month mortality between alteplase-treated and control patients was greater in patients who were randomized early (<3 hours) compared with late (3–6 hours; +9% [95% CI, 1–17];
P
=0.0317). Alteplase led to a greater improvement in 18-month survival in patients with a poor prognosis than in patients with a good prognosis (+8% [95% CI, 2–14];
P
=0.0091).

Conclusions—

These exploratory analyses of the third International Stroke Trial (IST-3) trial support improving acute stroke patients’ access to earlier alteplase treatment, treatment of patients with poor prognosis, and further randomized controlled trials in minor stroke to replicate these findings.

Clinical Trial Registration—

URL:
http://www.controlled-trials.com
. Unique identifier: ISRCTN25765518.
Incremental Predictive Value of Carotid Inflammation in Acute Ischemic Stroke
Authors: Toutouzas Konstantinos , Benetos Georgios , Drakopoulou Maria , Deligianni Christina , Spengos Konstantinos , Stefanadis Christodoulos , Siores Elias , Tousoulis Dimitrios
Published: November 2014

Background and Purpose—

Microwave Radiometry (MWR) allows in vivo noninvasive assessment of internal temperature of tissues. The aim of the present study was to evaluate in patients with ischemic stroke and bilateral carotid plaques (1) whether ipsilateral carotid arteries exhibit higher temperature differences (Δ
T
), as assessed by MWR; (2) the predictive accuracy of MWR in symptomatic carotid artery identification.

Methods—

Consecutive patients with recent acute anterior circulation ischemic stroke because of large artery atherosclerosis were included in the study. Carotid arteries of all patients were evaluated by carotid ultrasound and MWR.

Results—

In total, 50 patients were included in the study. Culprit carotid arteries had higher Δ
T
compared with nonculprit (0.93±0.58 versus 0.58±0.35°C;
P
<0.001). The addition of Δ
T
to a risk prediction model based only on ultrasound plaque characteristics increased its predictive accuracy significantly (c-statistic: 0.691 versus 0.768;
P
dif
=0.05).

Conclusions—

Culprit carotid arteries show higher thermal heterogeneity compared with nonculprit carotid arteries in patients with acute ischemic stroke and bilateral carotid plaques. MWR has incremental value in culprit carotid artery discrimination.
From the Analytical to the Artistic: A Review of Literature on Information Visualization
Authors: Gough Phillip
Published: November 2014

Engaging a general audience with scientific research can be effectively assisted by visualization. Visualization art has the potential to engage users with data in a way that gives the audience deep and reflective insights into information. This article reviews relevant literature on different methods and practices of visualization from the analytical to artistic. The literature shows that beautiful presentations of data, in a clarified context, can help an audience with little understanding of the data domain gain deep, meaningful insights into information.
Natural Gradient Learning Algorithms for RBF Networks
Authors: Zhao Junsheng , Wei Haikun , Zhang Chi , Li Weiling , Guo Weili , Zhang Kanjian
Published: November 2014

Radial basis function (RBF) networks are one of the most widely used models for function approximation and classification. There are many strange behaviors in the learning process of RBF networks, such as slow learning speed and the existence of the plateaus. The natural gradient learning method can overcome these disadvantages effectively. It can accelerate the dynamics of learning and avoid plateaus. In this letter, we assume that the probability density function (pdf) of the input and the activation function are gaussian. First, we introduce natural gradient learning to the RBF networks and give the explicit forms of the Fisher information matrix and its inverse. Second, since it is difficult to calculate the Fisher information matrix and its inverse when the numbers of the hidden units and the dimensions of the input are large, we introduce the adaptive method to the natural gradient learning algorithms. Finally, we give an explicit form of the adaptive natural gradient learning algorithm and compare it to the conventional gradient descent method. Simulations show that the proposed adaptive natural gradient method, which can avoid the plateaus effectively, has a good performance when RBF networks are used for nonlinear functions approximation.
Description of the first larval stage of Pontonia simplex (Decapoda, Caridea, Palaemonidae) from the eastern tropical Pacific
Authors: Ayón-Parente Manuel , Hendrickx Michel E. , Galván-Villa Cristian M. , Ríos-Jara Eduardo
Published: November 2014

The first stage ofPontonia simplexHolthuis, 1951 collected on the coast of Jalisco, Mexico, is described and compared with that ofP. pinnophylax(Otto, 1821) andAscidonia flavomaculata(Heller, 1864).
Notes on the distributions and taxonomy of two species of freshwater crabs of the genus Isolapotamon Bott, 1968 (Decapoda, Brachyura, Potamidae) from Sarawak, Malaysia
Authors: Grinang J. , Ng P. K. L. , Das I.
Published: November 2014

Of the seven species of potamid freshwater crabs of the genus Isolapotamon Bott, 1968, known from Sarawak, the type localities of two species, I. borneense Ng & Tan, 1998, and I. grusophallus Ng & Yang, 1986, are not known with accuracy. Through extensive collections in Sarawak, the provenances of these localities are now determined. Isolapotamon borneense is found in the upper parts of the Baram River in northern Sarawak; while I. grusophallus occurs in Gunung Penrissen and adjacent areas in central Sarawak. The taxonomy of these two species is also discussed.
On a collection of leucosiid crabs from the southeast coast of Taiwan
Authors: Lin C.-W. , Lai J. C. Y. , Galil B. S.
Published: November 2014

Two new species of leucosiid crabs of the genusUrnalanaGalil, 2005, are described from Taiwan.Urnalana erytheman. sp. is distinguished from the superficially similarU. angulata(Rathbun, 1911) in the shape of the apical process of the male first gonopod, which is beak-shaped and curved ventrally in the former, but sickle-shaped in the latter.Urnalana hirsutan. sp. differs from the superficially similarU. elatulaGalil, 2005 in its setose carapace and the shape of the apical process of the male first gonopod, which is club-like in the former, vs. dagger-shaped and curved in the latter. Two species are recorded for the first time from Taiwan:Raylilia uenoi(Takeda, 1995), and the recently describedCoralliocryptus caementaKomai & Ng, 2012. Three additional species,Arcania sagamiensisSakai, 1969,Urnalana purarensis(Ovaere, 1987) andOreotlos latus(Borradaile, 1903) are recorded for the second time. Diagnostic characters, colour photos and distributional information of these species are presented in this paper.
Decapod community structure in a subtropical mountain stream in Taiwan before and after a catastrophic typhoon
Authors: Siong Tew Kwee , Han Chiao-Chuan , Glover David C. , Chen Yu-Kang
Published: November 2014

Extreme events (typhoons, floods, and mudflows) can influence the abundance and community structure of aquatic organisms. In this study, we compare freshwater decapod abundance and community structure in main channel and tributary sites in a subtropical area of Taiwan before and after the typhoon Tembin. The results indicate that the physical conditions, decapod abundance and the Shannon diversity index were significantly different between the main channel and tributary sites, but were not significantly affected by the typhoon. The decapod community structure also showed significant differences spatially, but not temporally. The results of this study suggest that decapod communities are highly resilient to the acute effects of typhoons.
A new species of Cymbasoma (Copepoda, Monstrilloida) from the northern coast of Turkey (Black Sea) with comments on the C. longispinosum species-group
Authors: Üstün F. , Terbiyik Kurt T. , Suárez-Morales E.
Published: November 2014

Cymbasoma sinopense sp. nov. is described from an adult female collected off the Sinop coast, in the southern Black Sea, Turkey. This is the first species of this genus recorded from the Black Sea coast of Turkey. The new species is a member of the widespread Cymbasoma longispinosum species-group, and it closely resembles C. chelemense Suárez-Morales & Escamilla, 1997 from the Yucatan Peninsula and C. californiense Suárez-Morales & Palomares-García, 1999 from the Gulf of California. This species can be distinguished by a combination of subtle characters, including the body proportions, the structure and armature of the fifth legs, the ornamentation of the genital somite, and the relative length of the ovigerous spines. A previous report of C. longispinosum from the northern Black Sea probably represented a misidentified record of C. sinopense sp. nov. The Mediterranean reports refer to a species that is different from the one of the Black Sea. Comparative comments and data including the main taxonomic characters of members of the Cymbasoma longispinosum species-group are presented. Overall, it is confirmed that records of this species from different geographic areas should be revised carefully because they could represent undescribed species. A key for the identification of the females of the currently known species assigned to the Cymbasoma longispinosum species-group is included.