bluuebunny/crossref_metadata_2025 huggingface dataset:
A Questionnaire-Based Survey on Screening for Gastric and Colorectal Cancer by Physicians in East Asian Countries in 2010
Authors: Naito Yuji , Uchiyama Kazuhiko , Kinoshita Yoshikazu , Fukudo Shin , Joh Takashi , Suzuki Hidekazu , Takahashi Shin’ichi , Ueno Fumiaki , Fujiwara Yasuhiro , Arakawa Tetsuo , Matsumoto Takayuki , Hahm Ki-Baik , Kachintorn Udom , Syam Ari Fahrial , Rani Abdul Aziz , Sollano Jose D. , Zhu Qi
Published: July 2012

Background: The incidence of gastric cancer (GC) is high, and colorectal cancer (CRC) has significantly increased in Asian countries. Aim: To examine the current screening for GC and CRC within East Asia by means of a questionnaire survey. Methods: Representative members of the Committee of the International Gastrointestinal Consensus Symposium provided a questionnaire to physicians in six East Asian countries. Results: A total of 449 physicians participated in this survey. In all countries, more than 70% of physicians started GC screening between 40 and 59 years. The most popular method to screen for GC was endoscopy (92.7%), but combination methods such as Helicobacter pylori (HP) antibody, barium X-ray, and tumor marker with endoscopy differed by country. For HP-positive individuals, most physicians screened every year by endoscopy, and for individuals post-HP eradication, about half of physicians (56.3%) thought there was a need to follow-up with GC screening. Among all physicians, the most common age to start CRC screening was in the 40s (39.8%) and 50s (40.9%). Based on the American Cancer Society Recommendations, a fecal occult blood test every year was the most popular method for CRC screening overall. However, among each country, this test was most popular in only Japan (76.9%) and Indonesia. In other countries, sigmoidoscopy every 5 years and total colonoscopy every 10 years were the most popular methods. Conclusion: There are similarities and differences in the screening of GC and CRC among East Asian countries.
Basal GLP-1 Levels in Morbidly Obese Patients following Biliopancreatic Diversion Surgery
Authors: de Luis Daniel , Pacheco D. , Conde Rosa , Primo David , Aller Rocio , Izaola Olatz
Published: July 2012

Background: Previous studies addressing the changes of glucagon-like peptide-1 (GLP-1) concentrations in morbidly obese patients after bariatric surgery have demonstrated conflicting results. The aim of the present study was to investigate the changes in serum GLP-1 levels 9 months after biliopancreatic diversion in morbidly obese patients without diabetes mellitus. Methods: A sample of 40 morbidly obese patients without diabetes mellitus was enrolled. Biochemical and anthropometrical evaluations were conducted at basal and 9 months after surgery. Results: The mean patient age was 46.6 ± 13.1 years, and the mean preoperative body mass index (BMI) was 47.1 ± 18.1. A significant decrease in BMI, weight, waist circumference, fat mass, glucose, LDL cholesterol, total cholesterol, and triglyceride levels was observed after 9 months. Serum basal GLP-1 levels did not change after surgery (0.65 ± 0.18 ng/ml vs. 0.66 ± 0.17 ng/ml; n.s.). Postsurgical correlation analysis showed a negative association between basal GLP-1 and HDL cholesterol (r = –0.57; p < 0.01). Conclusions: Fasting GLP-1 concentrations did not change after massive weight loss with biliopancreatic diversion in morbidly obese patients without diabetes mellitus.
Genetic Control of Ovarian Development
Authors: Tevosian S.G.
Published: July 2012

During embryonic development, ovarian somatic cells embark on a course that is separate from male somatic cells and from indifferent precursor cells. While the former aspect of ovarian development is well known, the latter has not received much attention until recently. This review attempts to integrate the most recent work regarding the differentiation of ovarian somatic cells. The discussion of the parallel development of the testis is limited to the key differences only. Similarly, germ cell development will be introduced only inasmuch as it becomes necessary to draw attention to a particular aspect of the somatic component differentiation. Finally, while postnatal ovarian development and folliculogenesis undoubtedly provide the ultimate morphological and functional fitness tests for the ovarian somatic cells, postnatal phenotypes will be only referred to when they have already been connected to genes that are expressed during embryogenesis.
Analysis of Four Genes Involved in the Neurodevelopment Shows Association of rs4307059 Polymorphism in the Cadherin 9/10 Region with Completed Suicide
Authors: Chojnicka Izabela , Strawa Katarzyna , Fudalej Sylwia , Fudalej Marcin , Pawlak Aleksandra , Kostrzewa Grażyna , Wojnar Marcin , Krajewski Paweł , Płoski Rafał
Published: July 2012

Background: We hypothesized that DNA variants affecting neurodevelopment such as rs4307059 (CDH10/CDH9), rs930752 (NRXN1), rs6265 (BDNF) or rs10868235 (NTRK2) may predispose to completed suicide. Methodology: We used a case-control two-stage approach based on a discovery cohort (557 cases and ∼550 controls) and replication cohort (159 cases and 186 controls). The suicides were ascertained as consecutive cases autopsied at the Department of Forensic Medicine, Medical University of Warsaw, Poland. Results: In the discovery cohort we found an association between suicide and the CC genotype in the rs4307059 polymorphism (OR 1.64, p = 0.012). The trend for an overrepresentation of the CC homozygotes among suicides was replicated in the second cohort (OR 1.97, p = 0.056). Analysis in the pooled cohorts showed that rs4307059 CC was associated with completed suicide (OR 1.71, p = 0.002) also after Bonferroni correction (pcor. = 0.024). In an exploratory search for genotype-phenotype correlation we found that males with the rs4307059 CC genotype committed suicide earlier than those with CT/TT genotypes (p = 0.049). Conclusions: The CC genotype of rs4307059 located in the region between CDH9 and CDH10 is associated with completed suicide in a Polish cohort.
Questionnaire-Based Survey Conducted in 2011 concerning Endoscopic Management of Barrett’s Esophagus in East Asian Countries
Authors: Ishimura Norihisa , Amano Yuji , Sollano Jose D. , Zhu Qi , Kachintorn Udom , Rani Abdul Aziz , Hahm Ki-Baik , Takahashi Shin’ichi , Arakawa Testuo , Joh Takashi , Matsumoto Takayuki , Naito Yuji , Suzuki Hidekazu , Ueno Fumiaki , Fukudo Shin , Fujiwara Yasuhiro , Kamiya Takeshi , Uchiyama Kazuhiko , Kinoshita Yoshikazu ,   The IGICS Study Group
Published: July 2012

Background/Aims: Endoscopic definitions and management of Barrett’s esophagus vary widely among countries. To examine the current situation regarding diagnosis, epidemiology, management and treatment of Barrett’s esophagus in East Asian countries using a questionnaire-based survey. Methods: Representative members of the Committee of the International Gastrointestinal Consensus Symposium developed and sent a questionnaire to major institutions in China, South Korea, Japan, Thailand, Indonesia, and the Philippines. Results: A total of 56 institutions in the 6 countries participated in the survey. We found that the presence of specialized columnar metaplasia is considered to be important for diagnosing Barrett’s esophagus in East Asian countries except for Japan. C&M criteria have not been well accepted in East Asia. The palisade vessels are mainly used as a landmark for the esophagogastric junction in Japan. The prevalence of long segment Barrett’s esophagus is extremely low in East Asia, while the prevalence of short segment Barrett’s esophagus is very high only in Japan, likely due to different diagnostic criteria. Conclusion: Among East Asian countries, we found both similarities and differences regarding diagnosis and management of Barrett’s esophagus. The findings in the present survey are helpful to understand the current situation of Barrett’s esophagus in East Asian countries.
Assessing the Bioequivalence of Topical Retinoid Products by Pharmacodynamic Assay
Authors: Lehman P.A. , Franz T.J.
Published: July 2012

Purpose: To develop a simple pharmacodynamic (PD) assay for the evaluation of the bioequivalence of topically applied retinoid products. Methods: Daily applications of products containing tretinoin or adapalene were made to the forearms of human subjects for up to 21 days. Percutaneous absorption was enhanced through the use of polyethylene film occlusion (5 h). Pharmacologic activity was assessed through the daily measurement of three cutaneous responses intimately linked to retinoid-induced changes in epidermal differentiation: (1) erythema; (2) exfoliation (scaling/peeling), and (3) increased transepidermal water loss. Results: The PD model exhibited the sensitivity and specificity required to function as a bioequivalence surrogate. It was possible to differentiate between: (1) three concentrations of tretinoin in a commercial cream product line; (2) two concentrations of tretinoin in a commercial gel product line; (3) different vehicles (gel vs. cream) containing the same concentration of tretinoin, and (4) tretinoin and adapalene at the same concentration. The applicability of this model for bioequivalence testing was established by showing that it had sufficient power to determine that three test tretinoin cream products and two approved generic tretinoin gel products were equivalent to their corresponding reference products. Conclusions: A surrogate PD model to assess retinoid bioequivalence has been developed.
Preservation of Blood Pressure Stability with Hypertonic Mannitol during Hemodialysis Initiation
Authors: Mc Causland Finnian R. , Prior Lisa M. , Heher Eliot , Waikar Sushrut S.
Published: July 2012

Background: Intradialytic hypotensive events are common among hemodialysis patients and are associated with a variety of patient- and procedure-related factors, including intradialytic decline in plasma osmolality. Prior studies and practice have suggested that administration of osmotically active drugs may ameliorate blood pressure decline during chronic hemodialysis. Methods: Clinical and treatment data were collected for 102 consecutive patients requiring initiation of renal replacement therapy in 2 major teaching hospitals. Routine administration of mannitol differed according to institutional protocols, allowing its examination as the primary exposure of interest. Generalized linear models were fit to estimate associations of mannitol use during dialysis initiation with intradialytic blood pressure, as assessed by: (1) intradialytic blood pressure decline; (2) nadir intradialytic blood pressure; (3) absolute systolic blood pressure <90 mm Hg or decline >20 mm Hg. Results: Mean age was 62 years (±16), 70% were male and 44% were diabetic. Mean predialysis and nadir systolic blood pressure were 142 mm Hg (±29) and 121 mm Hg (±26), respectively. Mannitol administration was associated with a lesser decline in intradialytic blood pressure, a higher nadir blood pressure and fewer hypotensive events requiring intervention. No effect modification was evident according to diabetes or acuity of kidney disease (chronic vs. acute). Conclusions: Mannitol administration appears to preserve hemodynamic stability during hemodialysis initiation. Randomized controlled trials are needed to confirm these findings and identify optimal management strategies to prevent intradialytic hypotension.
Branch Atheromatous Plaque: A Major Cause of Lacunar Infarction (High-Resolution MRI Study)
Authors: Chung Jong-Won , Kim Beom Joon , Sohn Chul Ho , Yoon Byung-Woo , Lee Seung-Hoon
Published: July 2012

Background: Lacunar infarctions account for up to 25% of all ischemic strokes and, thus, constitute a numerically important subgroup. It is important that the two pathogeneses of lacunar infarction, that is, small-vessel occlusion and branch atheromatous disease, be differentiated because prognoses and treatment strategies differ. The authors evaluated the presence of branch atheromatous plaque in parent arteries that supply lacunar infarcts by high-resolution magnetic resonance imaging (HR-MRI). Methods: HR-MRI was performed in 15 patients with (1) a clinical presentation consistent with classical lacunar syndromes; (2) an acute lacunar infarction by diffusion-weighted imaging, measuring ≤20 mm in maximal diameter; (3) a magnetic resonance angiography showing a normal middle cerebral artery or basilar artery supplying the ischemic lesion, and (4) no other obvious etiology for small-vessel distribution ischemic stroke. Results: The median time of vessel wall imaging after index events was 4 days (range, 2–15 days). Six of the 15 patients had a lacunar infarction in the middle cerebral artery territory, and 9 had a lesion in the basilar artery territory. HR-MRI detected underlying atheromatous plaques in 9 patients (60%) with a lacunar infarction. In these 9 patients, asymptomatic intracranial atherosclerotic stenosis was more frequent compared to patients without branch atheromatous plaque (55.6 vs. 16.7%). In pontine infarctions, ischemic lesions that extended to the pial base of the pons were more frequent in patients with branch atheromatous plaques (83.3 vs. 33.3%), and all the ischemic lesions and atheromatous plaques were on the same side (right, n = 2; left, n = 4). All plaques responsible for acute symptomatic lacunar infarction were enhanced in contrast-enhanced T1-weighted HR-MR images. Conclusions: HR-MRI results enabled underlying symptomatic branch atheromatous disease to be detected in lacunar infarction patients. The experience gained during this study indicates that HR-MRI better delineates intracranial arterial lesions, suggesting that its use will lead to a further understanding of the mechanisms involved in stroke.
Influence of Exclusive Resistance Training on Body Composition and Cardiovascular Risk Factors in Overweight or Obese Children: A Systematic Review
Authors: Dietz Pavel , Hoffmann Sascha , Lachtermann Ella , Simon Perikles
Published: July 2012

Objective: Since the last decade, a significant increase in the prevalence of overweight and obesity among children has been reported. Low aerobic fitness and a low compliance with endurance sports in such children are theoretical reasons to favor the use of resistance training in intervention studies, even though positive effects of resistance training on morbidity without accompanying dietary modifications are a matter of debate. In this review we summarize the studies that have shown the isolated effect of resistance training on body composition and cardiovascular risk factors in overweight and obese children. Method: We systematically reviewed interventional studies that exclusively applied resistance training to overweight and obese 3- to 18-year-old children. Outcome measurements were body composition or cardiovascular risk factors. Results: Only six studies passed the inclusion criteria. All studies preferred an individually planned and supervised whole-body resistance training of moderate to submaximal intensity during treatment. The mean compliance was 84%. Four studies reported significant changes in body composition, with an increase in fat free mass and BMI, along with a decrease in fat mass. Three studies analyzed the effect of resistance training on cardiovascular risk factors, and only one study reported a significant decrease in systolic blood pressure. Conclusion: An individually planned and supervised whole-body resistance training of moderate to submaximal intensity in children seems to be safe and tends to show positive effects on body composition. Similar to interventions based on endurance exercise alone or in combination with dietary modifications, the effects on cardiovascular risk factors cannot be substantiated. In consequence, we suggest to substantiate the effect of resistance training on cardiovascular risk factors in overweight and obese children in upcoming randomized controlled trials with high case numbers, applying both resistance training only and resistance training in combination with dietary intervention to get knowledge about whether resistance training alone is effectual in the treatment of overweight and obesity in youth or if a combination of resistance training and dietary interventions is actually needed.
European Stroke Science Workshop
Authors: Mattle Heinrich P. , Brainin Michael , Chamorro Angel , Diener Hans Christoph , Hacke Werner , Leys Didier , Norrving Bo , Ward Nick
Published: July 2012

The European Stroke Organisation held its first European Stroke Science Workshop in Garmisch-Partenkirchen, Germany (December 15–17, 2011). Stroke experts based in Europe were invited to present and discuss their current research. The scope of the workshop was to review the most recent findings of selected topics in stroke, to exchange ideas, to stimulate new research, and to enhance collaboration between European stroke research groups. Seven scientific sessions were held, each starting with a keynote lecture to review the state of the art of the given topic, followed by 4 or 5 short presentations by experts. They were asked to limit their presentations to 10 slides containing only recent information. The meeting was organized by the executive committee of the European Stroke Organisation (Heinrich Mattle, chairman, Michael Brainin, Angel Chamorro, Werner Hacke, Didier Leys) and supported by the European Stroke Conference (Michael Hennerici). The following sections summarize the content of the workshop.
Sleeping Habits Predict the Magnitude of Fat Loss in Adults Exposed to Moderate Caloric Restriction
Authors: Chaput Jean-Philippe , Tremblay Angelo
Published: July 2012

Objective: To verify whether sleep quantity and quality at baseline predict the magnitude of fat loss in adults subjected to moderate caloric restriction. Methods: A total of 123 overweight and obese men and women (age, 41.1 ± 6.0 years; BMI, 33.2 ± 3.6 kg/m2 (mean ± SD)) underwent a weight loss intervention consisting of a targeted 600–700 kcal/day decrease in energy intake supervised by a dietician. The length of the intervention varied between 15 and 24 weeks. Body fat mass (dual-energy X-ray absorptiometry), sleep quality (total Pittsburgh Sleep Quality Index score) and sleep duration (h/night, self-reported from the Pittsburgh Sleep Quality Index) were assessed at both baseline and at the end of the weight loss program. Results: The mean weight loss over the dietary intervention was 4.5 ± 3.9 kg, 76% of which came from fat stores. Using a multiple linear regression analysis, we observed a significant positive relationship between sleep duration and the loss of body fat, both in absolute (adjusted β = 0.72 kg/h; p < 0.05) as well as in relative terms (adjusted β = 0.77%/h; p < 0.01), after adjusting for age, sex, baseline BMI, length of the intervention, and change in total energy intake. Furthermore, we observed that a better sleep quality at baseline was associated with greater fat mass loss. Conclusion: This study provides evidence that sleeping habits can influence the success of a weight loss intervention and should be taken into consideration when one decides to start a diet.
Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation
Authors: Borgman Mark P. , Pendleton Robert C. , McMillin Gwendolyn A. , Reynolds Kristen K. , Vazquez Sara , Freeman Andrew , Wilson Andrew , Valdes Roland , Linder Mark W.
Published: July 2012

We performed a randomised pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 hours of enrolment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patient’s genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilised INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S-warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/l. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management.

Clinical Trials Registration identifier: NCT00993200
Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines
Authors: Pagel Judith I. , Tschernatsch Marlene , Sperandio Markus , Preissner Klaus T. , Fischer Silvia , Grantzow Tobias , Deindl Elisabeth
Published: July 2012

Extracellular RNA (eRNA), released from cells under conditions of injury or vascular disease, acts as potent prothrombotic factor and promotes vascular hyperpermeability related to oedema formation in vivo. In this study, we aimed to investigate the mechanism by which eRNA triggers inflammatory processes, particularly associated with different steps of leukocyte recruitment. Using intravital microscopy of murine cremaster muscle venules, eRNA (but not DNA) significantly induced leukocyte adhesion and transmigration in vivo, which was comparable in its effects to the function of tumour-necrosis-factor-α (TNF-α). In vitro, eRNA promoted adhesion and transmigration of monocytic cells on and across endothelial cell monolayers. eRNA-induced monocyte adhesion in vitro was mediated by activation of the vascular endothelial growth factor (VEGF)/VEGF-receptor-2 system and was abolished by neutralising antibodies against intercellular adhesion molecule-1 or the p2-inte-grin Mac-1. Additionally, eRNA induced the release of TNF-α from monocytic cells in a time- and concentration-dependent manner, which involved activation of TNF- α -converting enzyme (TACE) as well as the nuclear factor kB signalling machinery. In vivo, inhibiton of TACE significantly reduced eRNA-induced leukocyte adhesion. Our findings present evidence that eRNA in connection with tissue/vascular damage provokes a potent inflammatory response by inducing leukocyte recruitment and by mobilising proinflammatory cytokines from monocytes.
Platelets directly enhance neutrophil transmigration in response to oxidised low-density lipoprotein
Authors: Badrnya Sigrun , Butler Lynn M. , Söderberg-Naucler Cecilia , Volf Ivo , Assinger Alice
Published: July 2012

Beyond their primary role in haemostasis and tissue repair, platelets are causally involved in the onset of inflammatory reactions, cell proliferation and immune response. Platelet activation and platelet binding to the endothelium result in release of chemokines and increased expression of adhesion molecules, which promote the recruitment of leukocytes that will eventually migrate across the endothelium into the tissue. Here, we provide the first evidence that platelets stimulated with oxidised low-density lipoprotein (oxLDL) directly enhance recruitment and transmigration of neutrophils, via cell-cell interaction. OxLDL immediately activates platelets, which then rapidly bind to neutrophils, foster their activation and facilitate transmigration through an endothelial monolayer. The observed effects of oxLDL on platelet-neutrophil aggregate (PNA) formation depend on incubation time, lipoprotein concentration and the degree of oxidative modification of LDL. PNA form within minutes following stimulation by oxLDL and remain for up to 1 h post stimulation, while native LDL is unable to induce platelet-neutrophil interactions. In the presence of acetylsalicylic acid the formation of PNA in response to oxLDL is virtually absent, and platelets fail to further enhance oxLDL-induced neutrophil transmigration. P2Y1 and P2Y12 inhibitors have less pronounced effects on PNA formation in response to oxLDL. Furthermore, we demonstrate that the PI3K pathway is essential for efficient neutrophil transmigration induced by oxLDL. Consequently, platelets enhance neutrophil transmigration in response to oxLDL and might thereby contribute essentially to the amplification of inflammatory processes within the vessel wall, which fosters the development of atherosclerosis.
Venous thromboembolism in cancer patients – Risk scores and recent randomised controlled trials
Authors: Ay Cihan , Pabinger Ingrid , Thaler Johannes
Published: July 2012

Cancer patients are at increased risk of developing venous thromboembolism (VTE). Guidelines recommend routine thromboprophylaxis in hospitalised acutely ill cancer patients and in myeloma patients receiving combination treatments including thalidomide or lenalidomide. Currently, thromboprophylaxis is not recommended in cancer out-patients. It is the aim of this review to give an overview of studies that applied scores for the risk assessment of cancer-related VTE. We will also discuss randomised controlled trials (RCTs) that investigated primary thromboprophylaxis in cancer patients. Recently, Khorana et al. published a practical and reproducible risk assessment score that includes clinical and laboratory parameters for the stratification of cancer patients according to their propensity to develop VTE. Patients assigned to the high-risk group are likely to benefit most from primary thromboprophylaxis. This score was validated in prospective and retrospective observational studies. In the Vienna Cancer and Thrombosis Study (CATS) the score was expanded by adding two biomarkers, and the prediction of VTE was considerably improved. In recent RCTs including cancer patients with different malignancies it was shown that thromboprophylaxis is safe and effective. However, VTE incidence rates were low. To date, no data is available from interventional studies applying thromboprophylaxis in cancer patients categorised into high-risk groups on the basis of risk assessment with scores. From the available literature we conclude that risk assessment for VTE is feasible in cancer patients;however, interventional studies to investigate the safety and efficacy of thromboprophylaxis in a high risk cancer population have yet to be performed.
Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: Detoxifying mechanisms and potential therapeutic options
Authors: Madrigal-Matute Julio , Martinez-Pinna Roxana , Ramos-Mozo Priscila , Blanco-Colio Luis , Moreno Juan , Tarin Carlos , Burillo Elena , Fernandez-Garcia Carlos , Egido Jesus , Meilhac Olivier , Michel Jean-Baptiste , Martin-Ventura Jose
Published: July 2012

Oxidative stress is involved in the chronic pathological vascular remodelling of both abdominal aortic aneurysm and occlusive atherosclerosis. Red blood cells (RBCs), leukocytes and platelets present in both, aneurysmal intraluminal thrombus and intraplaque haemorraghes, could be involved in the redox imbalance inside diseased arterial tissues. RBCs haemolysis may release the pro-oxidant haemoglobin (Hb), which transfers heme to tissue and low-density lipoproteins. Heme-iron potentiates molecular, cell and tissue toxicity mediated by leukocytes and other sources of reactive oxygen species (ROS). Polymorphonuclear neutrophils release myeloperoxidase and, along with activated platelets, produce superoxide mediated by NADPH oxidase, causing oxidative damage. In response to this pro-oxidant milieu, several anti-oxidant molecules of plasma or cell origin can prevent ROS production. Free Hb binds to haptoglobin (Hp) and once Hp-Hb complex is endocytosed by CD163, liberated heme is converted into less toxic compounds by heme oxygenase-1. Iron homeostasis is mainly regulated by transferrin, which transports ferric ions to other cells. Transferrin-bound iron is internalised via endocytosis mediated by transferrin receptor. Once inside the cell, iron is mainly stored by ferritin. Other non hemo-iron related antioxidant enzymes (e.g. superoxide dismutase, catalase, thioredoxin and peroxiredoxin) are also involved in redox modulation in vascular remodelling. Oxidative stress is a main determinant of chronic pathological remodelling of the arterial wall, partially linked to the presence of RBCs, leukocytes, platelets and oxidised fibrin within tissue and to the imbalance between pro-/anti-oxidant molecules. Understanding the complex mechanisms underlying redox imbalance could help to define novel potential targets to decrease atherothrombotic risk.
A novel regulatory element between the human FGA and FGG genes
Authors: Fish Richard J. , Neerman-Arbez Marguerite
Published: July 2012

High circulating fibrinogen levels correlate with cardiovascular disease (CVD) risk. Fibrinogen levels vary between people and also change in response to physiological and environmental stimuli. A modest proportion of the variation in fibrinogen levels can be explained by genotype, inferring that variation in genomic sequences that regulate the fibri-nogen genes (FGA, FGB and FGG) may affect hepatic fibrinogen production and perhaps CVD risk. We previously identified a conserved liver enhancer in the fibrinogen gene cluster (CNC12), between FGB and FGA. Genome-wide Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that transcription factors which bind fibrinogen gene promoters also interact with CNC12, as well as two potential fibrinogen enhancers (PFE), between FGA and FGG. Here we show that one of the PFE sequences has potent hepatocyte enhancer activity. Using a luciferase reporter gene system, we found that PFE2 enhances minimal promoter- and FGA promoter-driven gene expression in hepatoma cells, regardless of its orientation with respect to the promoters. A region within PFE2 bears a short series of conserved nucleotides which maintain enhancer activity without flanking sequence. We also demonstrate that PFE2 is a liver enhancer in vivo, driving enhanced green fluorescent protein expression in transgenic zebrafish larval livers. Our study shows that combining public domain ChIP-seq data with in vitro and in vivo functional tests can identify novel fibrinogen gene cluster regulatory sequences. Variation in such elements could affect fibrinogen production and influence CVD risk.
Circulating microparticles in carriers of factor V Leiden with and without a history of venous thrombosis
Authors: Campello Elena , Spiezia Luca , Radu Claudia M. , Bon Maria , Gavasso Sabrina , Zerbinati Patrizia , Woodhams Barry , Tormene Daniela , Prandoni Paolo , Simioni Paolo
Published: July 2012

Although factor V Leiden (FVL) is a major determinant of thrombotic risk, the reason why less than 10% of carriers eventually develop venous thromboembolic (VTE) events is unknown. Recent observations suggest that circulating levels of microparticles (MP) may contribute to the thrombogenic profile of FVL carriers. We measured the plasma level of annexin V-MP (AMP) platelet-MP (PMP), endothelial-MP (EMP), leukocyte-MP (LMP) and tissue factor-bearing MP (TF+MP), and the MP procoagulant activity (PPL) in 142 carriers of FVL (of these 30 homozygous and 49 with prior VTE), and in 142 age and gender-matched healthy individuals. The mean (± SD) level of AMP was 2,802 ± 853 MP/ μl in carriers and 1,682 ± 897 in controls (p<0.0001). A statistically significant difference between homozygous and heterozygous carriers of FVL was seen in the level of PMP, EMP and LMP, but not in that of the remaining parameters. When the analysis was confined to carriers with and without a VTE history, the mean level of AMP was 3,110 ± 791 MP/ μl in the former, and 2,615 ± 839 MP/μl in the latter (p<0.005). The mean level of all subtypes of circulating MP showed a similar pattern. The PPL clotting time was 39 ± 9 seconds (sec) in carriers, and 52 ± 15 sec in controls (p=0.003); and was 35 ± 8 sec in carriers with prior thrombosis, and 41 ± 10 sec in thrombosis-free carriers (p<0.005). Our study results suggest that circulating MP may contribute to the development of thrombosis in carriers of FVL mutation.
Atrial fibrillation in pigs induces left atrial endocardial transcriptional remodelling
Authors: Cerveró Jorge , Segura Víctor , Macías Alfonso , Gavira Juan , Montes Ramón , Hermida José
Published: July 2012

The leading cause of cardioembolic stroke is atrial fibrillation (AF), which predisposes to atrial thrombus formation. Although rheological alterations promote a hypercoagulable environment, as yet undefined factors contribute to thrombogenesis. The role of the endocardium has barely been explored. To approach this topic, rapid atrial pacing (RAP) was applied in four pigs to mimic A F. Left and right endocardial cells were isolated separately and their gene expression pattern was compared with that of four control pigs. The AF-characteristic rhythm disorders and endothelial nitric oxide synthase down-regulation were successfully reproduced, and validated RAP to mimic A F. A change was observed in the transcriptomic endocardial profile after RAP: the expression of 364 genes was significantly altered (p<0.01), 29 of them having passed the B>0 criteria. The left atrial endocardium [325 genes (7 genes, B>0)] was largely responsible for such alterations. Blood coagulation, blood vessel morphogenesis and inflammatory response are among the most significant altered functions, and help to explain the activation of coagulation observed after RAP: D-dimer, 0.49 (1.63) vs. 0.23 (0.24) mg/l [median (interquartile range)] in controls, p=0.02. Furthermore, three genes directly related to thrombotic processes were differentially expressed after RAP: FGL2 [fold change (FC)=0.85; p=0.007], APLP2 (FC=-0.47; p=0.005) and ADAMTS-18 (FC=-0.69; p=0.004). We demonstrate for the first time that AF induces a global expression change in the left atrial endocardium associated with an activation of blood coagulation. The nature of some of the altered functions and genes provides clues to identify new therapeutic targets.
Psychometric properties of the 8-item Morisky Medication Adherence Scale in patients taking warfarin
Authors: Wang Ye , Kong Ming , Ko Yu
Published: July 2012

There is no patient-reported medication adherence measure that has been validated in Singapore. This study aimed to validate the 8-item Morisky Medication Adherence Scale (MMAS) in patients taking warfarin in Singapore. A cross-sectional survey was conducted in a convenience sample of 151 patients taking warfarin at an anticoagulation clinic in 2011. Respondents completed the MMAS in English or Chinese depending on their preference. The MMAS had a Cronbach′s alpha of 0.56 and good criterion-related validity as the scale scores were associated with warfarin refill rates (p = 0.04). Respondents with higher MMAS scores were found to have a higher percentage of International Normalised Ratios (INRs) within the therapeutic range (p = 0.01), higher adherence to diet recommendations (p = 0.02), and less perceived difficulty in taking all medications (p < 0.001); they were also more likely to take warfarin at the same time every day (p < 0.001). Confirmatory factor analysis showed that the eight items loaded onto one factor (RMSEA = 0.03). The sensitivity, specificity, positive predictive value and negative predictive value of the MMAS for identifying patients with poor INR control were 73.0%, 35.6%, 49.5% and 60.5%, respectively, using the time in the therapeutic INR range as the gold standard. This study shows that the 8-item MMAS has good validity and moderate reliability in patients taking warfarin. Future research is needed to investigate the scale′s psychometric properties in other patient populations and clinical settings.
Sphingosine-1-Phosphate Receptor-1 Controls Venous Endothelial Barrier Integrity in Zebrafish
Authors: Tobia Chiara , Chiodelli Paola , Nicoli Stefania , Dell’Era Patrizia , Buraschi Simone , Mitola Stefania , Foglia Efrem , van Loenen Pieter B. , Alewijnse Astrid E. , Presta Marco
Published: July 2012

Objective—

Endothelial sphingosine-1-phosphate (S1P) receptor-1 (S1P
1
) affects different vascular functions, including blood vessel maturation and permeability. Here, we characterized the role of the
zS1P

1

ortholog in vascular development in zebrafish.

Methods and Results—

zS1P

1

is expressed in dorsal aorta and posterior cardinal vein of zebrafish embryos at 24 to 30 hours postfertilization.
zS1P

1

downregulation by antisense morpholino oligonucleotide injection causes early pericardial edema, lack of blood circulation, alterations of posterior cardinal vein structure, and late generalized edema. Also,
zS1P

1

morphants are characterized by downregulation of vascular endothelial cadherin (
VE-cadherin
) and Eph receptor
EphB4a
expression and by disorganization of zonula occludens 1 junctions in posterior cardinal vein endothelium, with no alterations of dorsal aorta endothelium.
VE-cadherin
knockdown results in similar vascular alterations, whereas
VE-cadherin
overexpression is sufficient to rescue venous vascular integrity defects and
EphB4a
downregulation in
zS1P

1

morphants. Finally,
S1P

1

small interfering RNA transfection and the S1P
1
antagonist (R)-3-amino-(3-hexylphenylamino)-4-oxobutylphosphonic acid (W146) cause EPHB4 receptor down-modulation in human umbilical vein endothelial cells and the assembly of zonula occludens 1 intercellular contacts is prevented by the EPHB4 antagonist TNYL-RAW peptide in these cells.

Conclusion—

The data demonstrate a nonredundant role of
zS1P

1

in the regulation of venous endothelial barrier in zebrafish and identify a
S1P

1

/
VE-cadherin
/
EphB4a
genetic pathway that controls venous vascular integrity.
Myocardial Notch Signaling Reprograms Cardiomyocytes to a Conduction-Like Phenotype
Authors: Rentschler Stacey , Yen Alberta H. , Lu Jia , Petrenko Nataliya B. , Lu Min Min , Manderfield Lauren J. , Patel Vickas V. , Fishman Glenn I. , Epstein Jonathan A.
Published: July 2012

Background—

Notch signaling has previously been shown to play an essential role in regulating cell fate decisions and differentiation during cardiogenesis in many systems including
Drosophila
,
Xenopus
, and mammals. We hypothesized that Notch may also be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells.

Methods and Results—

In hearts where Notch signaling is activated within the myocardium from early development onward, Notch promotes a conduction-like phenotype based on ectopic expression of conduction system–specific genes and cell autonomous changes in electrophysiology. With the use of an in vitro assay to activate Notch in newborn cardiomyocytes, we observed global changes in the transcriptome, and in action potential characteristics, consistent with reprogramming to a conduction-like phenotype.

Conclusions—

Notch can instruct the differentiation of chamber cardiac progenitors into specialized conduction-like cells. Plasticity remains in late-stage cardiomyocytes, which has potential implications for engineering of specialized cardiovascular tissues.
Statistics of Solar Cycle–La Niña Connection: Correlation of Two Autocorrelated Time Series
Authors: Haam Eddie , Tung Ka-Kit
Published: July 2012

Both the 11-yr solar cycle and the El Niño–Southern Oscillation (ENSO) phenomena are quasi periodic, with periods of 9–11 and 3–4 yr, respectively. There have been claims that the two are correlated, with the sun at its peak in sunspot number presumably forcing a cold event in the equatorial Pacific. However, both phenomena are also highly autocorrelated. Caution should be exercised when testing for the statistical significance of the correlation of two autocorrelated time series. The solar peak years can coincide with cold ENSO by chance, even if the two time series are independent, and the coincidence then persists for many cycles due to their autocorrelation, before drifting apart. This study demonstrates that this is indeed the case using the Quinn El Niño index (1525–1987), which is a chronicle of observations of El Niño–related events, and the sunspot number (SSN) series going back to 1750. Appropriate statistical tests are suggested that can test for correlation, taking into account autocorrelation applicable to the shorter instrumental records. There is so far no solar peak–La Niña connection found that is statistically significant.
The North Atlantic Oscillation and the North Atlantic Jet Variability: Precursors to NAO Regimes and Transitions
Authors: Luo Dehai , Cha Jing
Published: July 2012

In this paper, precursors to the North Atlantic Oscillation (NAO) and its transitions are investigated to understand the dynamical cause of the interdecadal NAO variability from dominant negative (NAO−) events during 1950–77 (P1) to dominant positive (NAO+) events during 1978–2010 (P2). It is found that the phase of the NAO event depends strongly on the latitudinal position of the North Atlantic jet (NAJ) prior to the NAO onset. The NAO− (NAO+) events occur frequently when the NAJ core prior to the NAO onset is displaced southward (northward), as the situation within P1 (P2). Thus, the northward (southward) shift of the NAJ from its mean position is a precursor to the NAO+ (NAO−) event.

This finding is further supported by results obtained from a weakly nonlinear model. Furthermore, the model results show that, when the Atlantic mean zonal wind exceeds a critical strength under which the dipole anomaly prior to the NAO onset is stationary, in situ NAO− (NAO+) events, which are events not preceded by opposite events, can occur frequently during P1 (P2) when the Atlantic storm track is not too strong. This mean zonal wind condition is easily satisfied during P1 and P2. However, when the Atlantic storm track (mean zonal wind) prior to the NAO onset is markedly intensified (weakened), the NAO event can undergo a transition from one phase to another, especially in a relatively strong background westerly wind, the Atlantic storm track has to be strong enough to produce a phase transition.
Robust Identification of Global Greening Phase Patterns from Remote Sensing Vegetation Products
Authors: Dahlke Carola , Loew Alexander , Reick Christian
Published: July 2012

The fraction of absorbed photosynthetically active radiation (fAPAR) is an essential diagnostic variable to investigate the temporal and spatial dynamics of the terrestrial biosphere. The present study provides a new method to assess global vegetation greening phase dynamics, derived from fAPAR time series from four different remote sensing products. A robust algorithm is developed to detect intra-annual greening phase patterns and derive seasonality patterns of vegetation dynamics at the global scale. The comparison of four independent remote sensing datasets shows significantly consistent global spatiotemporal patterns at the 95% confidence level. Regions where the remote sensing datasets show consistent results, as well as regions where at least one of the used remote sensing datasets deviates, can be identified. The derived global greening phase dataset and analysis method provides a solid framework for the evaluation of global vegetation models.
Comments on “Changes to the North Atlantic Subtropical High and Its Role in the Intensification of Summer Rainfall Variability in the Southeastern United States”
Authors: Diem Jeremy E.
Published: July 2012

In a recent article, Li et al. examined changes in the summer-season location of the western ridge of the North Atlantic subtropical high from 1948 to 2007 because there has been an increase in interannual summer rainfall variability in the southeastern United States. The following major conclusions by Li et al. are incorrect: the western ridge has undergone a significant westward trend since the late 1970s; the western ridge had increased meridional movement during 1978–2007 compared to 1948–1977; and global warming appears to be contributing to the westward expansion of the western ridge. Results presented in this paper reveal that the western ridge has been moving eastward over the past three decades, there was no change in latitudinal variance, and a westward movement of the western ridge should not be linked to global warming.
Importance of Ocean Dynamics for the Skewness of the Indian Ocean Dipole Mode
Authors: Ogata Tomomichi , Xie Shang-Ping , Lan Jian , Zheng Xiaotong
Published: July 2012

Interannual anomalies of sea surface temperature (SST), wind, and cloudiness in the southeastern tropical Indian Ocean (SE-TIO) show negative skewness. In this research, asymmetry between warm and cold episodes in the SE-TIO and the importance of ocean dynamics are investigated. A coupled model simulation and observations show an asymmetric relationship between SST and the thermocline depth in the SE-TIO where SST is more sensitive to an anomalous shoaling than to deepening of the thermocline. This asymmetric thermocline feedback on SST is a result of a deep mean thermocline. Sensitivity experiments with an ocean general circulation model (OGCM) show that a negative SST skewness arises in response to sinusoidal zonal wind variations that are symmetric between the westerly and easterly phases. Heat budget analysis with an OGCM hindcast also supports the importance of ocean dynamics for SST skewness off Sumatra and Java.
AMO-Forced Regional Processes Affecting Summertime Precipitation Variations in the Central United States
Authors: Veres Michael C. , Hu Qi
Published: July 2012

Numerous previous studies have provided insight into the influence of the Atlantic multidecadal oscillation (AMO) on North American precipitation. However, these studies focused on large-scale processes, and additional studies are needed to gain understanding of local and regional processes that develop in different phases of the AMO and substantiate its influences on precipitation. In this study, the Weather Research and Forecasting (WRF) regional model is used to examine AMO-forced local and regional processes and how they have affected summertime precipitation variation in the central United States.

While moisture transport and convergence by the Great Plains low-level jet have been recognized as necessary conditions for summer precipitation, model simulations show similar low-level moisture flux convergence in the central United States between the cold and warm phases of the AMO. However, there was a strong moistening in the lower troposphere during the AMO cold phase, making the atmosphere more unstable for convection and precipitation. The source of the moisture was found to be a strong positive surface evaporation–precipitation feedback initiated and sustained by increased relative vorticity along a frontal zone. Along the frontal zone, isentropic stretching of the upper-level atmosphere and cyclonic circulation anomalies increased the relative vorticity during the AMO cold phase, providing the dynamic support needed to release the low-level moist instability and produce the increased precipitation. These results indicate that the dynamics of the circulation in the AMO cold phase played key roles to organize regional vorticity processes that further sustained a coupling of precipitation and the surface evaporation and perpetuated the precipitation.