bluuebunny/crossref_metadata_2025 huggingface dataset:
Fabrication, Characterization, and Optimization of CdS and CdSe Quantum Dot-Sensitized Solar Cells with Quantum Dots Prepared by Successive Ionic Layer Adsorption and Reaction
Authors: Jun H. K. , Careem M. A. , Arof A. K.
Published: April 2014

CdS and CdSe quantum dot-sensitized solar cells (QDSSCs) were used for the study of determining the optimum preparation parameters that could yield the best solar cell performance. The quantum dots (QDs) were coated on the surface of mesoporous TiO2layer deposited on FTO substrate using the successive ionic layer adsorption and reaction (SILAR) method. In this method the QDs are allowed to grow on TiO2by dipping the TiO2electrode successively in two different solutions for predetermined times. This method allows the fabrication of QDs in a facile way. Three preparation parameters that control the QD fabrication were investigated: concentration of precursor solutions, number of dipping cycles (SILAR cycles), and dipping time in each solution. CdS based QDSSC showed optimum performance when the QDs were prepared from precursor solutions having the concentration of 0.10 M using 4 dipping cycles with the dipping time of 5 minutes in each solution. For CdSe QDSSC, the optimum performance was achieved with QDs prepared from 0.03 M precursor solutions using 7 dipping cycles with 30 s dipping time in each solution. The QDs deposited on TiO2surface were characterized using UV-vis absorption spectroscopy, FESEM, and TEM imaging.
Antibiotic Resistance Pattern and Evaluation of Metallo-Beta Lactamase Genes Includingbla-IMPandbla-VIMTypes inPseudomonas aeruginosaIsolated from Patients in Tehran Hospitals
Authors: Aghamiri Samira , Amirmozafari Nour , Fallah Mehrabadi Jalil , Fouladtan Babak , Samadi Kafil Hossein
Published: April 2014

Beta-lactamase producing strains ofPseudomonas aeruginosaare important etiological agents of hospital infections. Carbapenems are among the most effective antibiotics used againstPseudomonasinfections, but they can be rendered infective by group Bβ-lactamase, commonly called metallo-beta lactamase. In this study, the antimicrobial sensitivity patterns ofP. aeruginosastrains isolated from 9 different hospitals in Tehran, Iran, as well as the prevalence of MBLs genes (bla-VIMandbla-IMP) were determined. A total of 212 strains ofP. aeruginosarecovered from patients in hospitals in Tehran were confirmed by both biochemical methods and PCR. Their antimicrobial sensitivity patterns were determined by Kirby-Bauer disk diffusion method. Following MIC determination, imipenem resistant strains were selected by DDST method which was followed by PCR tests for determination of MBLs genes:bla-IMPandbla-VIM. The results indicated that, in the DDST phenotypic method, among the 100 imipenem resistant isolates, 75 strains were MBLs positive. The PCR test indicated that 70 strains (33%) carriedbla-VIMgene and 20 strains (9%) harboredbla-IMP. The results indicated that the extent of antibiotic resistance amongPseudomonas aeruginosais on the rise. This may be due to production of MBLs enzymes. Therefore, determination of antibiotic sensitivity patterns and MBLs production by these bacteria, can be important in control of clinicalPseudomonasinfection.
Mineral Element Contents in Commercially Valuable Fish Species in Spain
Authors: Rivas Ana , Peña-Rivas Luis , Ortega Eduardo , López-Martínez Concepción , Olea-Serrano Fátima , Lorenzo Maria Luisa
Published: April 2014

The aim of this study was to measure selected metal concentrations inTrachurus trachurus,Trachurus picturatus, andTrachurus mediterraneus, which are widely consumed in Spain. Principal component analysis suggested that the variable Cr was the main responsible variable for the identification ofT. trachurus, the variables As and Sn forT. mediterraneus, and the rest of variables forT. picturatus. This well-defined discrimination between fish species provided by mineral element allows us to distinguish them on the basis of their metal content. Based on the samples collected, and recognizing the inferential limitation of the sample size of this study, the metal concentrations found are below the proposed limit values for human consumption. However, it should be taken into consideration that there are other dietary sources of these metals. In conclusion, metal contents in the fish species analyzed are acceptable for human consumption from a nutritional and toxicity point of view.
Development and Performance Evaluation of Corrosion Resistance Self-Healing Coating
Authors: Guin Akshya Kumar , Nayak Suryakanta , Bhadu Manish Kumar , Singh Veena , Rout Tapan Kumar
Published: April 2014

Polymer based nanocapsule was developed using core-cell approach, where the core material was methyl diphenyl diisocyanate and the cell material was urea-formaldehyde. The synthesized capsules of 100 to 800 nm size were incorporated into sol-gel matrix to prepare a final coating for steel protection. This coating was found protecting the steel at the damage or crack locations in 3.5% NaCl solution. SEM micrographs confirmed healing of the coating at the damage or crack points.
Insulin, Estrogen, Inflammatory Markers, and Risk of Benign Proliferative Breast Disease
Authors: Catsburg Chelsea , Gunter Marc J. , Chen Chu , Cote Michele L. , Kabat Geoffrey C. , Nassir Rami , Tinker Lesley , Wactawski-Wende Jean , Page David L. , Rohan Thomas E.
Published: April 2014

Women with benign proliferative breast disease (BPBD) are at increased risk for developing breast cancer. Evidence suggests that accumulation of adipose tissue can influence breast cancer development via hyperinsulinemia, increased estrogen, and/or inflammation. However, there are limited data investigating these pathways with respect to risk of BPBD. We evaluated serologic markers from these pathways in a case–control study of postmenopausal women nested within the Women's Health Initiative Clinical Trial. Cases were the 667 women who developed BPBD during follow-up, and they were matched to 1,321 controls. Levels of insulin, estradiol, C-reactive protein (CRP), and adiponectin were measured in fasting serum collected at baseline. Conditional logistic regression models were used to estimate ORs for the association of each factor with BPBD risk. Among nonusers of hormone therapy, fasting serum insulin was associated with a statistically significant increase in risk of BPBD (OR for highest vs. lowest quartile = 1.80; 95% confidence interval, CI, 1.16–2.79; Ptrend = 0.003) as were levels of estradiol (OR for highest vs. lowest tertile = 1.89; 95% CI, 1.26–2.83; Ptrend = 0.02) and CRP (OR for highest vs. lowest quartile = 2.46; 95% CI, 1.59–3.80; Ptrend < 0.001). Baseline adiponectin level was inversely associated with BPBD risk (OR for highest vs. lowest quartile = 0.47; 95% CI, 0.31–0.71; Ptrend < 0.001). These associations persisted after mutual adjustment, but were not observed among users of either estrogen alone or of estrogen plus progestin hormone therapy. Our results indicate that serum levels of estrogen, insulin, CRP, and adiponectin are independent risk factors for BPBD and suggest that the estrogen, insulin, and inflammation pathways are associated with the early stages of breast cancer development. Cancer Res; 74(12); 3248–58. ©2014 AACR.
IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism
Authors: Grassian Alexandra R. , Parker Seth J. , Davidson Shawn M. , Divakaruni Ajit S. , Green Courtney R. , Zhang Xiamei , Slocum Kelly L. , Pu Minying , Lin Fallon , Vickers Chad , Joud-Caldwell Carol , Chung Franklin , Yin Hong , Handly Erika D. , Straub Christopher , Growney Joseph D. , Vander Heiden Matthew G. , Murphy Anne N. , Pagliarini Raymond , Metallo Christian M.
Published: April 2014

Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed 13C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. Cancer Res; 74(12); 3317–31. ©2014 AACR.
Molecular Pathways: Turning Proteasomal Protein Degradation into a Unique Treatment Approach
Authors: Stintzing Sebastian , Lenz Heinz-Josef
Published: April 2014

Cancer treatment regimens have evolved from single cytotoxic substances affecting all proliferative tissues toward antibodies and kinase inhibitors targeting tumor-specific pathways. Treatment efficacy and cancer survival have improved overall, and side effects have become less frequent. The ubiquitin-proteasome system–mediated proteasomal protein degradation is the most critical pathway to regulate the quantity of signal proteins involved in carcinogenesis and tumor progression. These processes are, as well as protein recycling, highly regulated and offer targets for biomarker and drug development. Unspecific proteasome inhibitors such as bortezomib and carfilzomib have shown clinical efficacy and are approved for clinical use. Inhibitors of more substrate-specific enzymes of degradation processes are being developed and are now in early clinical trials. The novel compounds focus on the degradation of key regulatory proteins such as p53, p27Kip1, and ß-catenin, and inhibitors specific for growth factor receptor kinase turnover are in preclinical testing. Clin Cancer Res; 20(12); 3064–70. ©2014 AACR.
Molecular Biomarkers of Residual Disease after Surgical Debulking of High-Grade Serous Ovarian Cancer
Authors: Tucker Susan L. , Gharpure Kshipra , Herbrich Shelley M. , Unruh Anna K. , Nick Alpa M. , Crane Erin K. , Coleman Robert L. , Guenthoer Jamie , Dalton Heather J. , Wu Sherry Y. , Rupaimoole Rajesha , Lopez-Berestein Gabriel , Ozpolat Bulent , Ivan Cristina , Hu Wei , Baggerly Keith A. , Sood Anil K.
Published: April 2014

Purpose: Residual disease following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of residual disease has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease.

Methods: We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with residual disease and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using quantitative RT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for residual disease. Predictive success was evaluated using a one-sided Fisher exact test.

Results: Forty-seven probe sets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold and had high expression levels associated with increased incidence of residual disease. In the validation cohort (n = 139), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a prespecified threshold, we found 30 of 35 cases of residual disease in the predicted high-risk group (positive predictive value = 86%) and 54 of 104 among the remaining patients (P = 0.0002; OR, 5.5).

Conclusion: High FABP4 and ADH1B expression is associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy. Clin Cancer Res; 20(12); 3280–8. ©2014 AACR.
A Pragmatic Definition of Therapeutic Synergy Suitable for Clinically Relevant In Vitro Multicompound Analyses
Authors: Kashif Muhammad , Andersson Claes , Åberg Magnus , Nygren Peter , Sjöblom Tobias , Hammerling Ulf , Larsson Rolf , Gustafsson Mats G.
Published: April 2014

For decades, the standard procedure when screening for candidate anticancer drug combinations has been to search for synergy, defined as any positive deviation from trivial cases like when the drugs are regarded as diluted versions of each other (Loewe additivity), independent actions (Bliss independence), or no interaction terms in a response surface model (no interaction). Here, we show that this kind of conventional synergy analysis may be completely misleading when the goal is to detect if there is a promising in vitro therapeutic window. Motivated by this result, and the fact that a drug combination offering a promising therapeutic window seldom is interesting if one of its constituent drugs can provide the same window alone, the largely overlooked concept of therapeutic synergy (TS) is reintroduced. In vitro TS is said to occur when the largest therapeutic window obtained by the best drug combination cannot be achieved by any single drug within the concentration range studied. Using this definition of TS, we introduce a procedure that enables its use in modern massively parallel experiments supported by a statistical omnibus test for TS designed to avoid the multiple testing problem. Finally, we suggest how one may perform TS analysis, via computational predictions of the reference cell responses, when only the target cell responses are available. In conclusion, the conventional error-prone search for promising drug combinations may be improved by replacing conventional (toxicology-rooted) synergy analysis with an analysis focused on (clinically motivated) TS. Mol Cancer Ther; 13(7); 1964–76. ©2014 AACR.
Influence of Parental Alcohol-Related Attitudes, Behavior and Parenting Styles on Alcohol Use in Late and Very Late Adolescence
Authors: Stafström Martin
Published: April 2014

Parents influence adolescent drinking behavior, but to what extent does this association diminish with age, however? The cross-sectional data was drawn from the Scania drug use survey 2007, consisting of 4,828 secondary education students in the 9th and 11th grade. The age- and gender-adjusted findings indicate that having parents who are consenting to alcohol use (OR 1.4), having been provided with alcohol by one's parents (OR 1.8), having parents with an authoritarian (OR 1.5) or neglectful (OR 2.1) parenting style, and having parents who both have a university degree (OR 1.3) were factors significantly associated with monthly heavy episodic drinking. These findings lead to the conclusion that parenting styles as well as parental attitudes and behaviors are important throughout the high school years. Thus, prevention targeting parents should emphasize both these domains.
Prevalence of Intracranial Atherosclerosis among Patients with Coronary Artery Disease: A 1-Year Hospital-Based Study
Authors: Abd-Allah Foad , Heshmat Kassem Hussien , Hashad Assem , Shamloul Reham Mohammed , Zaki Adel
Published: April 2014

Background: There are limited data on the prevalence of intracranial atherosclerotic disease (ICAD) in patients with coronary artery disease (CAD) worldwide and especially among Egyptians. The purpose of the present study was to determine the prevalence and correlates of ICAD in patients with CAD. Methods: From January 1, 2012 to January 1, 2013, we recruited 118 consecutive patients who had ischemic heart disease. All patients were assessed for vascular risk factors and the existence of stroke or transient ischemic attack (TIA) and were evaluated by extracranial and transcranial color-coded sonography. All patients underwent coronary angiography. Clinical, echocardiographic and angiographic variables were tested by univariate and multivariate analysis. Results: Out of 118 consecutive patients with CAD, intracranial disease was detected in 14 patients (11.9%). Eight patients (6.8%) had stenosis >50%, while 6 patients (5.1%) had stenosis <50%. The univariate analysis showed that the strongest variables associated with ICAD were the presence of recent or old stroke or TIA, followed by moderate or severe extracranial stenosis, and multivessel or left main CAD. Conclusion: We observed low prevalence (6.8%) of high-grade ICAD among Egyptian patients with CAD. Multivessel or left main CAD and moderate-to-severe extracranial carotid stenosis were the strongest predictors for the existence of ICAD among CAD patients.
Cardiopulmonary Exercise Testing to Detect Chronic Thromboembolic Pulmonary Hypertension in Patients with Normal Echocardiography
Authors: Held Matthias , Grün Maria , Holl Regina , Hübner Gudrun , Kaiser Ralf , Karl Sabine , Kolb Martin , Schäfers Hans Joachim , Wilkens Heinrike , Jany Berthold
Published: April 2014

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious complication of pulmonary embolism (PE). Taking into account the reported incidence of CTEPH after acute PE, the number of patients with undiagnosed CTEPH may be high. Objectives: We aimed to determine if cardiopulmonary exercise testing (CPET) could serve as complementary tool in the diagnosis of CTEPH and can detect CTEPH in patients with normal echocardiography. Methods: At diagnosis, we analyzed the data of CPET parameters in 42 patients with proven CTEPH and 51 controls, and evaluated the performance of two scores. Results: VE/VCO2 slope, EQO2, EQCO2, P(A-a)O2, end-tidal partial pressure of CO2 at anaerobic threshold (PETCO2) and capillary to end-tidal carbon dioxide gradient [P(c-ET)CO2] were significantly different between patients with CTEPH and controls (p < 0.001). P(c-ET)CO2 was the single parameter with the highest sensitivity (85.7%) and specificity (88.2%). A score combining VE/VCO2 slope, P(A-a)O2, P(c-ET)CO2, PETCO2 [4-parameter-CPET (4-P-CPET) score] reached a sensitivity of 83.3% and a specificity of 92.2% after cross-validation. In 42 patients with CTEPH, echocardiography identified PH in 29 patients (69%), but it was normal in 13 patients (31%). All patients with normal or unmeasurable right ventricular systolic pressure had a pathological CPET. Twelve of the 13 patients (92%) were detected by both CPET scores. Conclusion: CPET is a useful noninvasive diagnostic tool for the detection of CTEPH in patients with suspected PH but normal echocardiography. The 4-P-CPET score provides a high sensitivity with the highest specificity.
Optimal Method and Timing of Intrauterine Intervention in Twin Reversed Arterial Perfusion Sequence: Case Study and Meta-Analysis
Authors: Chaveeva Petya , Poon Leona C. , Sotiriadis Alexandros , Kosinski Przemek , Nicolaides Kypros H.
Published: April 2014

Introduction: The objective of this study was to define the optimal method and timing of intervention in twin reversed arterial perfusion (TRAP) sequence. Material and Methods: During a period of 20 years (1993-2013), we performed endoscopic laser coagulation of umbilical cord vessels or intrafetal laser in 67 pregnancies with TRAP sequence. These data were combined with those reported in the literature to determine the survival rate of the pump twin for different methods and timing of interventions. Results: A variety of techniques were used to interrupt the blood supply to the acardiac twin. Most procedures were performed at or after 16 weeks, and with most methods the survival rate of the pump twin was about 80%. Good results were also obtained for triplet pregnancies. In 18 of 30 cases (60%) diagnosed at 11-14 weeks, there was spontaneous cessation of flow in the acardiac twin before planned intervention at 16-18 weeks, and in 11 of these (61.1%) the pump twin died or suffered brain damage. In 103 pregnancies treated by intrafetal laser at 12-27 weeks, there was no correlation between gestational age at treatment and survival rate, but there was an inverse association between gestational age at treatment and gestational age at birth. Discussion: In TRAP sequence, survival may be improved by elective intervention at 12-14 weeks.
Clinical Severity of Gitelman Syndrome Determined by Serum Magnesium
Authors: Jiang Lanping , Chen Chen , Yuan Tao , Qin Yan , Hu Mingming , Li Xuemei , Xing Xiaoping , Lee Xuewang , Nie Min , Chen Limeng
Published: April 2014

Background/Aims: Normomagnesemia is considered atypical in Gitelman syndrome (GS). Here, we describe clinical, pathological and genetic characteristics in Chinese GS patients with or without hypomagnesemia in order to determine whether serum magnesium concentration indicates the severity of the disease. Methods: 7 normomagnesemic and 25 hypomagnesemic GS patients who were confirmed by direct sequencing of SLC12A3 gene were included. Clinical manifestation and laboratory tests were documented. Supine and upright plasma renin activity, angiotensin II and aldosterone were determined by radioimmunoassay. Transient receptor potential channel melastatin subtype 6 (TRPM6) was detected by immunohistochemistry in paraffin-embedded renal biopsy sections of 12 GS patients. 14 patients with glomerular minor lesion served as controls. The distribution of the mutations on the predicted NCC protein was analyzed and compared between two subgroups. Results: Clinical manifestations, electrolyte abnormalities, metabolic alkalosis and renin-angiotensin-aldosterone system activation were found to be milder in normomagnesemic compared with the hypomagnesemic group. Compared with glomerular minor lesion controls, the TRPM6-positive area was significantly decreased in hypomagnesemic patients (4.96 ± 1.88 vs. 8.63 ± 2.67%) while it was near normal (7.82 ± 5.23%) in 2 normomagnesemic GS patients. A higher percentage of intracellular mutations was observed in normomagnesemic patients than hypomagnesemic patients (92.31 vs. 56.52%, p = 0.02). Conclusions: Normomagnesemia is not rare in GS. Serum magnesium may indicate the severity of GS.
Effect of the FTO rs9930506 Polymorphism on the Main Comorbidities of the Cardiorenal Metabolic Syndrome in an Elderly Spanish Cohort
Authors: Coto Eliecer , Tavira Beatriz , Gómez Juan , Tranche Salvador , Díaz Corte Carmen
Published: April 2014

Background/Aim: Fat mass and obesity-associated (FTO) gene polymorphisms have been linked to the risk of obesity and diabetes, two well-recognized risk factors for renal disease. Our aim was to determine whether a common FTO polymorphism was associated with a reduced estimated glomerular filtration rate (eGFR) independently of body mass index (BMI) and type 2 diabetes mellitus (T2DM) in a cohort of elderly individuals from the region of Asturias (Northern Spain; RENASTUR cohort). Methods: A total of 544 Spanish Caucasians aged 55-85 years were genotyped for the FTO rs9930506 single-nucleotide polymorphism (SNP). Individuals with a previous diagnosis of renal disease were not eligible for the study. The eGFR was calculated with the Modification of Diet in Renal Disease formula, and individuals with an eGFR of <60 ml/min/1.73 m2 (n = 91) were considered as having impaired renal function. The effect of alleles and genotypes on BMI, hypertension, diabetes, eGFR and blood lipid values was statistically determined. Results: The rs9930506 GG genotype was significantly more common in the group with a BMI of >25 (p = 0.03; odds ratio = 2.43; 95% CI: 1.09-5.43). Age and T2DM were significant risk factors for a reduced eGFR, but neither obesity nor the FTO genotypes were associated with a reduced eGFR. Conclusion: The common FTO rs9930506 polymorphism was a risk factor for overweight and obesity in the RENASTUR cohort. However, this SNP was not associated with other comorbidities of the cardiorenal metabolic syndrome in this population.
Impact of Chronic Kidney Disease and Anemia on Physical Function in Patients with Chronic Heart Failure
Authors: Saitoh Masakazu , Itoh Haruki , Morotomi Nobuo , Ozawa Tetsuya , Ishii Noriko , Uewaki Reina , Hori Kentaro , Shiotani Yohei , Ando Miki , Nakashima Shogo , Kawai Kana , Ohno Azusa , Nagayama Masatoshi
Published: April 2014

Objective: The aim of this study was to confirm the effects of chronic kidney disease (CKD) and anemia on physical function and to clarify whether the interaction between CKD and anemia has an additive effect. Design: Eligible subjects were chronic heart failure (HF) patients who were discharged between March 2007 and August 2009. A total of 102 chronic HF patients (33% females; mean age: 68 ± 14 years) were enrolled in the present study. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m2, and anemia was defined as a hemoglobin level of <12 g/dl in males and of <11 g/dl in females. The Short Physical Performance Battery (SPPB) was used to assess physical function. Results: The adjusted mean SPPB score was lower in patients with both CKD and anemia than in those with neither of the diseases or with either disease alone (p < 0.05). Conclusion: This study found that CKD and anemia are independently associated with reduced physical function.
Investigating Epigenetic Effects of Prenatal Exposure to Toxic Metals in Newborns: Challenges and Benefits
Authors: Nye Monica D. , Fry Rebecca C. , Hoyo Cathrine , Murphy Susan K.
Published: April 2014

Increasing evidence suggests that epigenetic alterations can have a great impact on human health, and that epigenetic mechanisms (DNA methylation, histone modifications, and microRNAs) may be particularly relevant in responding to environmental toxicant exposure early in life. The epigenome plays a vital role in embryonic development, tissue differentiation, and development of disease by controlling gene expression. In this review, we discuss what is currently known about epigenetic alterations in response to prenatal exposure to inorganic arsenic (iAs) and lead (Pb), focusing specifically on their effects on DNA methylation. We then describe how epigenetic alterations are studied in newborns as potential biomarkers of in utero environmental toxicant exposure, and the benefits and challenges of this approach. In summary, the studies highlighted herein indicate how epigenetic mechanisms have an impact on early-life exposure to iAs and Pb and the research that is being done to move towards an understanding of the relationships between toxicant-induced epigenetic alterations and disease development. Although much remains unknown, several groups are working to understand the correlative and causal effects of early-life toxic metal exposure on epigenetic changes and to find out how these may result in later disease development.
Neuroendocrine Tumors of the Bronchopulmonary System (Typical and Atypical Carcinoid Tumors): Current Strategies in Diagnosis and Treatment. Conclusions of an Expert Meeting February 2011 in Weimar, Germany
Authors: Hörsch Dieter , Schmid Kurt W. , Anlauf Martin , Darwiche Kaid , Denecke Tim , Baum Richard P. , Spitzweg Christine , Grohé Christian , Presselt Norbert , Stremmel Christian , Heigener David F. , Serke Monika , Kegel Thomas , Pavel Marianne , Waller Cornelius F. , Deppermann Karl-Matthias , Arnold Rudolf , Huber Rudolf M. , Weber Matthias M. , Hoffmann Hans
Published: April 2014

Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum markers and the use of functional imaging techniques are important additive tools to establish the diagnosis of a NET. The only curative option for lung NETs is complete surgical resection. Beyond that, the currently available interdisciplinary therapeutic options are local ablation, biotherapy (somatostatin analogues), or chemotherapy. New therapeutic options such as peptide receptor radionuclide therapy (PRRT) and molecularly targeted therapies achieve promising results and are under further evaluation. This report is a consensus summary of the interdisciplinary symposium ‘Neuroendocrine Tumors of the Lung and of the Gastroenteropancreatic System (GEP NET) - Expert Dialogue' held on February 25-26, 2011 in Weimar, Germany. At this conference, a panel of 23 German experts shared their knowledge and exchanged their thoughts about research, diagnosis, and clinical management of NETs, whereby special attention was paid to NETs of the respiratory tract.
An Atypical Case of Pityriasis Rosea Gigantea after Influenza Vaccination
Authors: Papakostas Dimitrios , Stavropoulos Panagiotis G. , Papafragkaki Dafni , Grigoraki Ekaterini , Avgerinou Georgia , Antoniou Christina
Published: April 2014

Pityriasis rosea is a common erythematosquamous eruption, typically presenting along the cleavage lines of the skin. A wide spectrum of atypical manifestations may challenge even the most experienced physician. Here we report a rare case of a suberythrodermic pityriasis rosea with gigantic plaques after an influenza vaccination, and we discuss the possible triggers of atypical manifestations of such a common dermatological disease in the setting of an altered immunity.
Association Between Down Syndrome and In-Hospital Death Among Children Undergoing Surgery for Congenital Heart Disease
Authors: Evans Jacqueline M. , Dharmar Madan , Meierhenry Erin , Marcin James P. , Raff Gary W.
Published: April 2014

Background—

The prevalence of Down syndrome (DS)–affected births has increased during the past 30 years; moreover, children with DS have a higher incidence of congenital heart disease compared with their peers. Whether children with DS have better or worse outcomes after repair of congenital heart disease is unclear. We sought to identify differences in in-hospital mortality after cardiac surgery in pediatric patients with and without DS using a large national database.

Methods and Results—

Children aged <18 years who underwent surgical intervention for congenital heart disease were identified using the Kids’ Inpatient Database (2000, 2003, 2006, and 2009). Patients were stratified using the Risk Adjustment for Congenital Heart Surgery algorithm. A total of 4231 (8.2%) of the 51 309 patients studied had a diagnosis of DS. In-hospital death for patients with DS was significantly lower than that for patients without DS overall (1.9% versus 4.3%;
P
<0.05) as well as within risk categories 2 (1.0% versus 1.8%;
P
<0.05) and 3 (2.3% versus 5.1%;
P
<0.05). Multivariable logistic regression showed a lower odds of death among children with DS (odds ratio=0.60; 95% confidence interval, 0.47–0.76;
P
<0.05) after adjusting for Risk Adjustment for Congenital Heart Surgery risk category, premature birth, major noncardiac structural anomaly, and age.

Conclusions—

In this large national study, children with DS who underwent repair of congenital heart disease were more likely to survive to discharge than children without DS. Future work is needed to better understand the factors underlying these differences.
Hemodynamic Disturbed Flow Induces Differential DNA Methylation of Endothelial Kruppel-Like Factor 4 Promoter In Vitro and In Vivo
Authors: Jiang Yi-Zhou , Jiménez Juan M. , Ou Kristy , McCormick Margaret E. , Zhang Ling-Di , Davies Peter F.
Published: April 2014

Rationale
:

Hemodynamic disturbed flow (DF) is associated with susceptibility to atherosclerosis. Endothelial Kruppel-Like Factor 4 (KLF4) is an important anti-inflammatory atheroprotective transcription factor that is suppressed in regions of DF.

Objective
:

The plasticity of epigenomic KLF4 transcriptional regulation by flow-mediated DNA methylation was investigated in vitro and in arterial tissue.

Methods and Results
:

To recapitulate dominant flow characteristics of atheroprotected and atherosusceptible arteries, human aortic endothelial cells were subjected to pulsatile undisturbed flow or oscillatory DF containing a flow-reversing phase. Differential CpG site methylation was measured by methylation-specific polymerase chain reaction, bisulfite pyrosequencing, and restriction enzyme-polymerase chain reaction. The methylation profiles of endothelium from disturbed and undisturbed flow sites of adult swine aortas were also investigated. In vitro, DF increased DNA methylation of CpG islands within the KLF4 promoter that significantly contributed to suppression of KLF4 transcription; the effects were mitigated by DNA methyltransferase (DNMT) inhibitors and knockdown of DNMT3A. Contributory mechanisms included DF-induced increase of DNMT3A protein (1.7-fold), DNMT3A enrichment (11-fold) on the KLF4 promoter, and competitive blocking of a myocyte enhancer factor-2 binding site in the KLF4 promoter near the transcription start site. DF also induced DNMT-sensitive propathological expression of downstream KLF4 transcription targets nitric oxide synthase 3, thrombomodulin, and monocyte chemoattractant protein-1. In support of the in vitro findings, swine aortic endothelium isolated from DF regions expressed significantly lower KLF4 and nitric oxide synthase 3, and bisulfite sequencing of KLF4 promoter identified a hypermethylated myocyte enhancer factor-2 binding site.

Conclusions
:

Hemodynamics influence endothelial KLF4 expression through DNMT enrichment/myocyte enhancer factor-2 inhibition mechanisms of KLF4 promoter CpG methylation with regional consequences for atherosusceptibility.
Accelerated Degeneration of a Bovine Pericardial Bioprosthetic Aortic Valve in Children and Young Adults
Authors: Saleeb Susan F. , Newburger Jane W. , Geva Tal , Baird Christopher W. , Gauvreau Kimberlee , Padera Robert F. , del Nido Pedro J. , Borisuk Michele J. , Sanders Stephen P. , Mayer John E.
Published: April 2014

Background—

Experience with aortic valve replacement (AVR) with current-generation pericardial bioprostheses in young patients is limited. The death of a child with accelerated bioprosthetic aortic stenosis prompted enhanced surveillance of all such patients at our institution.

Methods and Results—

We reviewed records of 27 patients who had undergone AVR (median follow-up, 13.7 months) with a bovine pericardial bioprosthesis at ≤30 years of age. In the Mitroflow LXA valve group (n=15), freedom from valve failure was 100% at 1 year, 53% (95% confidence interval, 12–82) at 2 years, and 18% (95% confidence interval, 1–53) at 3 years. No Magna/Magna Ease valves (n=12) failed by 3 years. Among valve failure patients, median age at AVR was 12 years (range, 10–21 years). Life-threatening prosthetic aortic stenosis was detected at a median of 6 months after prior echocardiograms showing mild or less gradients. Patients with Mitroflow LXA compared with Magna/Magna Ease valves were smaller (median body surface area, 1.42 versus 1.93 m
2
;
P
=0.002) and younger (median age, 13.0 versus 20.9 years;
P
=0.02) at AVR. Pathology demonstrated diffuse intrinsic leaflet calcification, not associated with inflammation or infection, and virtually immobile leaflets in closed position.

Conclusions—

Young patients undergoing AVR with Mitroflow LXA pericardial valves are at high risk for rapid progression from mild or less to severe aortic stenosis over months, highlighting their need for heightened echocardiographic surveillance and suggesting that this aortic bioprosthesis should not be implanted in the young. Current data are insufficient to assess the safety of AVR with other pericardial bioprostheses in children and the youngest adults.
Outcomes of Out‐of‐Hospital Cardiac Arrest by Public Location in the Public‐Access Defibrillation Era
Authors: Murakami Yukiko , Iwami Taku , Kitamura Tetsuhisa , Nishiyama Chika , Nishiuchi Tatsuya , Hayashi Yasuyuki , Kawamura Takashi ,   the Utstein Osaka Project
Published: April 2014

Background

The strategy to place public‐access automated external defibrillators (
AED
s) has not yet been established in real settings.

Methods and Results

This, prospective, population‐based observational study in Osaka, Japan, included consecutive out‐of‐hospital cardiac arrest (
OHCA
) patients with resuscitation attempts during 7 years, from January 2005 through December 2011. The trends in the proportion of public‐access
AED
use and 1‐month survival with neurologically favorable outcome were evaluated by location. Factors associated with neurologically favorable outcome (defined as cerebral performance category 1 or 2) after ventricular fibrillation were also assessed using multiple logistic regression analysis. A total of 9453 bystander‐witnessed
OHCA
s of cardiac origin were documented and 894 (9.5%) of them occurred at public places. The proportion of public‐access
AED
use significantly increased from 0.0% (0/20) in 2005 to 41.2% (7/17) in 2011 at railway stations and from 0.0% (0/7) to 56.5% (13/23) at sports facilities. Mean time from collapse to shock was 5.0 minutes among those who received shocks with public‐access
AED
s. The proportion of neurologically favorable outcome was 28.0% (33/118) at railway stations, 51.6% (48/93) at sports facilities, 23.3% (20/86) in public buildings, and 41.9% (13/31) in schools. In multivariate analysis, early defibrillation, irrespective of bystander or emergency medical service (EMS) personnel, was significantly associated with neurologically favorable outcome (adjusted odds ratio for 1‐minute increment, 0.89; 95% confidence interval, 0.87 to 0.92).

Conclusions

This large, population‐based
OHCA
registry demonstrated that earlier shock, irrespective the shock provider (bystander or
EMS
personnel), contributed to improving outcome, and a public‐access defibrillation program was successfully implemented so that shocks with public‐access
AED
s were delivered to over 40% of bystander‐witnessed
OHCA
s and time to shock was shortened in some kinds of public places.
Association of Physical Activity in Childhood and Early Adulthood With Carotid Artery Elasticity 21 Years Later: The Cardiovascular Risk in Young Finns Study
Authors: Pälve Kristiina S. , Pahkala Katja , Magnussen Costan G. , Koivistoinen Teemu , Juonala Markus , Kähönen Mika , Lehtimäki Terho , Rönnemaa Tapani , Viikari Jorma S. A. , Raitakari Olli T.
Published: April 2014

Background

Decreased arterial elasticity is a risk factor for several cardiovascular outcomes. Longitudinal data on the effect of physical activity in youth on adult arterial elasticity are limited. The aim of this study was to determine the long‐term effects of physical activity in children and young adults on carotid artery elasticity after 21 years of follow‐up.

Methods and Results

Participants were 1417 children (aged 9 to 15 years) and 999 young adults (aged 18 to 24 years) from the prospective Cardiovascular Risk in Young Finns Study. Participants had questionnaire measures of leisure‐time physical activity available from 1986 and ultrasound‐derived indices of carotid artery elasticity measured in 2007. Carotid artery elasticity indices were distensibility (%/10 mm Hg), Young's elastic modulus (kPa), and stiffness index (unitless). Physical activity at age 18 to 24 years was directly associated with distensibility (β=0.068,
P
=0.014) and inversely with Young's elastic modulus (β=−0.057,
P
=0.0037) and indirectly with stiffness index (β=−0.050,
P
=0.0028) 21 years later in males and females. The associations remained after adjustment for age, sex, body mass index, smoking, systolic blood pressure, serum lipids and insulin, and 21‐year change in physical activity. At age 9 to 15 years, the favorable association, remaining after adjustment, was found in males (distensibility [β=0.097,
P
=0.010], Young's elastic modulus [β=−0.060,
P
=0.028], and stiffness index [β=−0.062,
P
=0.007]) but not in females (
P
=0.70,
P
=0.85, and
P
=0.91, respectively).

Conclusions

Leisure‐time physical activity in boys and young adults is associated with carotid artery elasticity later in life, suggesting that higher levels of physical activity in youth may benefit future cardiovascular health.
Risk Factors and Outcome of Fontan‐Associated Plastic Bronchitis: A Case‐Control Study
Authors: Schumacher Kurt R. , Singh Tajinder P. , Kuebler Joseph , Aprile Kayla , O'Brien Molly , Blume Elizabeth D.
Published: April 2014

Background

The onset of plastic bronchitis (
PB
) can be debilitating in survivors of Fontan surgery. The rarity of this complication makes designing studies to understand risk factors for
PB
challenging. This 2‐center case‐control study aimed to describe patient outcomes and to assess the association of antecedent patient factors with
PB
development.

Methods and Results

Using center registries,
PB
patients (n=25) were matched 1:2 to non‐
PB
Fontans (n=43) by date of Fontan surgery and center. The groups were compared for baseline characteristics. Association of patient characteristics with
PB
was assessed using logistic regression and of potential risk factors with onset of
PB
using time‐to‐event analyses. The median time from Fontan to
PB
diagnosis was 2.5 years. Overall, 12/25
PB
patients died or underwent heart transplant; the median transplant‐free survival was 8.3 years after diagnosis. Factors associated with developing
PB
included post‐surgical chylothorax (44%
PB
versus 10% control; odds ratio [
OR
] 7.3;
P
=0.003), chest tube (
CT
) duration at stage 2 (
P
=0.04) and Fontan (
P
=0.004), and postoperative ascites (36%
PB
versus 12% control;
OR
4.2;
P
=0.003).
CT
drainage >13 days at Fontan was associated with earlier
PB
onset (
P
=0.04). Early‐onset
PB
was associated with an increased risk of death (
OR
5.0;
P
=0.002).

Conclusions

PB
is a life‐threatening disorder. A longer duration of
CT
drainage after surgery, chylothorax, and development of ascites are all associated with developing
PB
. Understanding the pathophysiology of peri‐operative complications in individual patients and using targeted interventions may delay the onset of the
PB
phenotype.
Geomagnetic Storms Can Trigger Stroke
Authors: Feigin Valery L. , Parmar Priya G. , Barker-Collo Suzanne , Bennett Derrick A. , Anderson Craig S. , Thrift Amanda G. , Stegmayr Birgitta , Rothwell Peter M. , Giroud Maurice , Bejot Yannick , Carvil Phillip , Krishnamurthi Rita , Kasabov Nikola
Published: April 2014

Background and Purpose—

Although the research linking cardiovascular disorders to geomagnetic activity is accumulating, robust evidence for the impact of geomagnetic activity on stroke occurrence is limited and controversial.

Methods—

We used a time-stratified case-crossover study design to analyze individual participant and daily geomagnetic activity (as measured by Ap Index) data from several large population-based stroke incidence studies (with information on 11 453 patients with stroke collected during 16 031 764 person-years of observation) in New Zealand, Australia, United Kingdom, France, and Sweden conducted between 1981 and 2004. Hazard ratios and corresponding 95% confidence intervals (CIs) were calculated.

Results—

Overall, geomagnetic storms (Ap Index 60+) were associated with 19% increase in the risk of stroke occurrence (95% CI, 11%–27%). The triggering effect of geomagnetic storms was most evident across the combined group of all strokes in those aged <65 years, increasing stroke risk by >50%: moderate geomagnetic storms (60–99 Ap Index) were associated with a 27% (95% CI, 8%–48%) increased risk of stroke occurrence, strong geomagnetic storms (100–149 Ap Index) with a 52% (95% CI, 19%–92%) increased risk, and severe/extreme geomagnetic storms (Ap Index 150+) with a 52% (95% CI, 19%–94%) increased risk (test for trend,
P
<2×10
−16
).

Conclusions—

Geomagnetic storms are associated with increased risk of stroke and should be considered along with other established risk factors. Our findings provide a framework to advance stroke prevention through future investigation of the contribution of geomagnetic factors to the risk of stroke occurrence and pathogenesis.
N-Terminal Pro–B-type Natriuretic Peptide and Stroke Risk
Authors: Cushman Mary , Judd Suzanne E. , Howard Virginia J. , Kissela Brett , Gutiérrez Orlando M. , Jenny Nancy S. , Ahmed Ali , Thacker Evan L. , Zakai Neil A.
Published: April 2014

Background and Purpose—

Improved identification of those at risk of stroke might improve prevention. We evaluated the association of the cardiac function biomarker N-terminal pro–B-type natriuretic peptide (NT-proBNP) with stroke risk in the 30 239 black and white participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.

Methods—

During 5.4 years of follow-up after enrollment in 2003 to 2007, NT-proBNP was measured in baseline blood samples of 546 subjects with incident ischemic stroke and 956 without stroke.

Results—

NT-proBNP was higher with older age and in those with heart disease, kidney disease, atrial fibrillation, and lower low-density lipoprotein-cholesterol. Adjusting for age, race, sex, income, education, and traditional stroke risk factors, there was an increased risk of stroke across quartiles of NT-proBNP; participants with NT-proBNP in the top versus the bottom quartile had a hazard ratio of 2.9 (95% confidence interval, 1.9–4.5). There was no impact of added adjustment for kidney function and heart failure. Among pathogenetic stroke subtypes, the association was largest for cardioembolic stroke, with a hazard ratio of 9.1 (95% confidence interval, 2.9–29.2). Associations did not differ by age, sex, or race, or after excluding those with baseline heart failure or atrial fibrillation. Predicted stroke risk was more accurate in 27% of participants if NT-proBNP was considered after traditional stroke risk factors (
P
<0.001).

Conclusions—

NT-proBNP was a major independent risk marker for stroke. Considering this and other data for stroke, coronary disease, and atrial fibrillation, the clinical use of NT-proBNP measurement in primary prevention settings should be considered.