bluuebunny/crossref_metadata_2025_split huggingface dataset:
Obducted nappe sequence in the San Juan Islands – northwest Cascades thrust system, Washington and British Columbia
Authors: Brown E.H. 
Published: June 2012

The San Juan Islands – northwest Cascades thrust system in Washington and British Columbia is composed of previously accreted terranes now assembled as four broadly defined composite nappes stacked on a continental footwall of Wrangellia and the Coast Plutonic Complex. Emplacement ages of the nappe sequence are interpreted from zircon ages, field relations, and lithlogies, to young upward. The basal nappe was emplaced prior to early Turonian time (∼93 Ma), indicated by the occurrence of age-distinctive zircons from this nappe in the Sidney Island Formation of the Nanaimo Group. The emplacement age of the highest nappe in the thrust system postdates 87 Ma detrital zircons within the nappe. The nappes bear high-pressure – low-temperature (HP–LT) mineral assemblages indicative of deep burial in a thrust wedge; however, several features indicate that metamorphism occurred prior to nappe assembly: metamorphic discontinuities at nappe boundaries, absence of HP–LT assemblages in the footwall to the nappe pile, and absence of significant unroofing detritus in the Nanaimo Group. A synorogenic relationship of the thrust system to the Nanaimo Group is evident from mutually overlapping ages and by conglomerates of Nanaimo affinity that lie within the nappe pile. From the foregoing relations, and broader Cordilleran geology, the tectonic history of the nappe terranes is interpreted to involve initial accretion and subduction-zone metamorphism south of the present locality, uplift and exhumation, orogen-parallel northward transport of the nappes as part of a forearc sliver, and finally obduction at the present site over the truncated south end of Wrangellia and the Coast Plutonic Complex.
Bone-Derived IGF Mediates Crosstalk between Bone and Breast Cancer Cells in Bony Metastases
Authors: Hiraga Toru , Myoui Akira , Hashimoto Nobuyuki , Sasaki Akira , Hata Kenji , Morita Yoshihiro , Yoshikawa Hideki , Rosen Clifford J. , Mundy Gregory R. , Yoneda Toshiyuki 
Published: June 2012

Abstract
The continuous release of bone-stored growth factors after bone resorption promotes the colonization of circulating cancer cells. However, the precise role of each of the various growth factors remains unclear. In this study, we investigated the role of bone-derived insulin-like growth factor (IGF) in the development of bone metastases in an animal model of breast cancer. We found that local stimulation of calvarial bone resorption before cell inoculation stimulated subsequent bone metastases to that site in vivo, although inhibition of bone resorption inhibited bone metastases. Anchorage-independent growth of cancer cells was stimulated by the culture supernatants from resorbed bones, which contained elevated levels of IGF-I. This stimulation was blocked by IGF type I receptor (IGF-IR) neutralizing antibody, but not antibody targeting other bone-stored growth factors including TGF-β, fibroblast growth factors, and platelet-derived growth factors. Although recombinant human IGF-I caused IGF-IR tyrosine autophosphorylation, followed by activation of Akt and NF-κB in cancer cells, dominant-negative inhibition of IGF-IR, Akt, or NF-κB significantly reduced bone metastases with increased apoptosis and decreased mitosis in metastatic cells. Together, our findings suggest that bone-derived IGF-I bridges the crosstalk between bone and metastasized cancer cells via activation of the IGF-IR/Akt/NF-κB pathway. Disruption of this pathway therefore may represent a promising therapeutic intervention for bone metastasis. Cancer Res; 72(16); 4238–49. ©2012 AACR.
Heart healthy diet and risk of myocardial infarction and venous thromboembolism
Authors: Enga Kristin F. , Njølstad Inger , Hansen John-Bjarne , Braekkan Sigrid K. , Hansen-Krone Ida J. 
Published: June 2012

SummaryPrudent dietary patterns are associated with reduced risk of arterial cardiovascular diseases (CVD). Limited data exist on the relation between diet and venous thromboembolism (VTE). The aim of our prospective, population based study was to investigate the association of a heart healthy diet on risk of myocardial infarction (MI) and VTE. Information on dietary habits was available in 18,062 subjects, aged 25–69, who participated in the fourth Tromsø study, 1994–1995. Dietary patterns were assessed by a slightly modified version of the validated SmartDiet score; a 13-item questionnaire producing a diet score based on the intakes of fat, fibre, fruit and vegetables. Incident events of MI (n=518) and VTE (n=172) were recorded to the end of follow-up December 31, 2005 (median follow-up 10.8 years). Cox-regression models were used to calculate hazard ratios (HR). A healthy diet score of >27 points (upper tertile) was associated with 17% reduced risk of MI (HR: 0.83, 95% confidence interval [CI]: 0.66–1.06), and no association with VTE (HR: 1.01; 95%CI: 0.66–1.56), compared to <24 points (lower tertile) in multivariable analysis. High intake of fish, fruit, vegetables and polyunsatured fat had a 23% reduced risk of MI (HR 0.77; 95%CI: 0.60–0.98), but no association with VTE (HR 0.95; 95%CI: 0.64–1.40). A heart healthy diet showed an even more favourable association with MI in obese subjects (HR: 0.62; 95%CI: 0.41–0.95), but not with VTE. Our findings suggest that a heart healthy dietary pattern is associated with moderately reduced risk of MI, but not related to risk of VTE.
Evidence that fibrinolytic changes in paediatric obesity translate into a hypofibrinolytic state
Authors: Semeraro Fabrizio , Giordano Paola , Faienza Maria F. , Cavallo Luciano , Semeraro Nicola , Colucci Mario 
Published: June 2012

SummaryPaediatric obesity, like adulthood obesity, is associated with an increase of fibrinolysis inhibitors. No study, however, has evaluated the impact of these changes on plasma fibrinolytic capacity. We investigated plasma fibrinolysis and the role therein of the fibrinolytic changes associated with obesity in 59 obese children (body mass index > 95th percentile) and 40 matched controls. Fibrinolysis was investigated by measuring 1) the plasma levels of relevant fibrinolytic factors; 2) the in vitro fibrinolytic capacity under different conditions, using a microplate plasma clot lysis assay; 3) the circulating levels of markers of clotting and fibrinolysis activation. Plasminogen activator inhibitor 1 (PAI-1), total thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen levels were higher in obese children as compared to controls (p<0.01). Plasma clots from obese children lysed significantly slower than control clots when exposed to exogenous plasminogen activator, indicating a greater resistance to fibrinolysis. By the use of a selective inhibitor of activated TAFI and by regression analyses we found that fibrinolysis resistance in obese samples was attributable to PAI-1 increase and to enhanced TAFI activation. The ratio between the circulating levels of D-dimer and thrombin-antithrombin complex, a marker of in vivo fibri-nolysis, was significantly lower in obese children, suggesting a reduced fibrinolytic efficiency. These data indicate that paediatric obesity is associated with a hypofibrinolytic state which might contribute to the increased thrombotic risk associated with this condition.
The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease
Authors: Jilma-Stohlawetz Petra , Knöbl Paul , Gilbert James C. , Jilma Bernd 
Published: June 2012

SummaryBlockade of hyperactive von Willebrand factor (VWF) by ARC1779 blunted the platelet drop induced by desmopressin in patients with type 2B von Willebrand disease (VWD). Thus, we hypothesised that ARC1779 may increase VWF levels and correct thrombocytopenia. Three thrombocytopenic patients suffering from type 2B VWD received a loading dose of 0.23 mg/kg ARC1779 followed by 4 μg/kg/min intravenously for 72 hours in a prospective clinical trial. ARC1779 was well tolerated and safe. Plasma concentrations of ARC1779 increased to 76 μg/ml (59–130) leading to an immediate decrease of free VWF A1 domains. VWF/FVIII levels increased as early as 12 h after start of infusion, peaked near the end of infusion, and returned to baseline at follow-up. VWF ristocetin cofactor activity (VWF:RCo) showed a median 10-fold increase 8 hours after end of infusion, while the median VWF-antigen and FVIII increase was less (5-fold and 4-fold, respectively). Most importantly inhibition of hyperactive VWF rapidly increased platelet counts from 40x109/l (38–58 x109/l) to a maximum of 146 x109/l (107–248 x109/l). In conclusion, ARC1779 markedly increases VWF/FVIII levels and most importantly improves or even corrects thrombocytopenia in VWD type 2B patients. This underscores the in vivo potency of ARC1779.
NT-pro-BNP levels in patients with acute pulmonary embolism are correlated to right but not left ventricular volume and function
Authors: Klok Frederikus A. , van der Bijl Noortje , de Roos Albert , Kroft Lucia J. M. , Huisman Menno V. , Pasha Sharif M. 
Published: June 2012

SummaryN-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) is primarily secreted by left ventricular (LV) stretch and wall tension. Notably, NT-pro-BNP is a prognostic marker in acute pulmonary embolism (PE), which primarily stresses the right ventricle (RV). We sought to evaluate the relative contribution of the RV to NT-pro-BNP levels during PE. A posthoc analysis of an observational prospective outcome study in 113 consecutive patients with computed tomography (CT)-proven PE and 226 patients in whom PE was clinically suspected but ruled out by CT. In all patients RV and LV function was established by assessing ECG-triggered-CT measured ventricular end-diastolic-volumes and ejection fraction (EF). NT-pro-BNP was assessed in all patients. The correlation between RV and LV end-diastolic-volumes and systolic function was evaluated by multiple linear regression corrected for known con-founders. In the PE cohort increased RVEF (β-coefficient (95% confidence interval [CI]) –0.044 (± –0.011); p<0.001) and higher RV enddiastolic-volume (β-coefficient 0.005 (± 0.001); p<0.001) were significantly correlated to NT-pro-BNP, while no correlation was found with LVEF ( β-coefficient 0.005 (± 0.010); p=0.587) and LV end-diastolic-volume (β-coefficient –0.003 (± 0.002); p=0.074). In control patients without PE we found a strong correlation between NT-pro-BNP levels and LVEF ( β-coefficient –0.027 (± –0.006); p<0.001) although not LV enddiastolic-volume (β-coefficient 0.001 (± 0.001); p=0.418). RVEF (β-co-efficient –0.002 (± –0.006); p=0.802) and RV end-diastolic-volume (β-coefficient <0.001 (± 0.001); p=0.730) were not correlated in patients without PE. In PE patients, lower RVEF and higher RV end-diastolic-volume were significantly correlated to NT-pro-BNP levels as compared to control patients without PE. These observations provide patho-physiological ground for the well-known prognostic value of NT-pro-BNP in acute PE.
Red blood cell distribution width is associated with poor clinical outcome in acute cerebral infarction
Authors: Kim Jinkwon , Kim Young , Song Tae-Jin , Park Ji , Lee Hye , Nam Chung , Nam Hyo , Heo Ji 
Published: June 2012

SummaryIncreased red blood cell distribution width (RDW), which is a marker of anisocytosis, is associated with mortality and cardiovascular events in the general population and in patients with heart failure or coronary heart disease. We investigated whether RDW in acute cerebral infarction is predictive of functional outcome and mortality. A total of 847 consecutive patients with first-ever acute cerebral infarction who presented to the emergency department within seven days of symptom onset were enrolled in this study. We investigated the association of RDW with poor functional outcome (modified Rankin Scale >2) and all-cause mortality at three months, as well as survival time for one year after stroke onset. Multivariate logistic regression revealed that higher RDW was independently associated with poor functional outcome (adjusted odds ratio [OR], 1.222 per 1% increment in RDW, 95% confidence interval [CI] 1.059–1.409, p=0.006) and all-cause death (adjusted OR, 1.395 per 1% increment in RDW, 95% CI 1.168–1.665, p<0.001) at three months after stroke onset. RDW was an independent predictor of survival in multivariate Cox-proportional regression model (adjusted hazard ratio, 1.328 per 1% increment in RDW, 95%CI 1.178–1.498, p<0.001). The addition of RDW to a survival model significantly increased predictability for survival across the entire follow-up period (weighted average of the area-under the curves, 0.858 vs. 0.841, p<0.05). In conclusion, higher RDW measured in cases of acute stage cerebral infarction was associated with poor functional outcome and mortality. RDW may be used as a biomarker for the prediction of long-term outcomes in patients with acute cerebral infarction.
Long-Term Survival and Recurrence After Acute Myocardial Infarction in England, 2004 to 2010
Authors: Smolina Kate , Wright F. Lucy , Rayner Mike , Goldacre Michael J. 
Published: June 2012

Background—
There are limited population-based national data on prognosis in survivors of acute myocardial infarction (AMI), particularly on long-term survival and the risk of recurrence.

Methods and Results—
Record linkage of hospital and mortality data identified 387 452 individuals in England who were admitted to hospital with a main diagnosis of AMI between 2004 and 2010 and who survived for at least 30 days. Seven years after an AMI, the risk of death from any cause in survivors of first or recurrent AMI was, respectively, 2 and 3 times higher than that in the English general population of equivalent age. For all survivors of a first AMI, the risk of a second AMI was highest during the first year and the cumulative risk increased more gradually thereafter. For men, 1- and 7-year cumulative risks were 5.6% (95% confidence interval [CI], 5.5–5.7) and 13.9% (95% CI, 13.7–14.1); for women, they were 7.2% (95% CI, 7.1–7.4) and 16.2% (95% CI, 16.0–16.5). Older age, higher deprivation, no revascularization procedures, and presence of comorbidities were associated with higher recurrence risk.

Conclusions—
Survivors of both first and recurrent AMI remained at a significantly higher risk of death compared with the general population for at least 7 years after the event. For survivors of first AMI, the influence of predisposing factors for second AMI lessened with time after the initial event. The results reinforce the importance of acute clinical care and secondary prevention in improving long-term prognosis of hospitalized AMI patients.
Clinical Evidence, Practice Guidelines, and β-Blocker Utilization Before Major Noncardiac Surgery
Authors: Wijeysundera Duminda N. , Mamdani Muhammad , Laupacis Andreas , Fleisher Lee A. , Beattie W. Scott , Johnson Sindhu R. , Kolstad Jonathan , Neuman Mark D. 
Published: June 2012

Background—
Largely on the basis of 2 randomized trials published in the 1990s, β-blockers were initially promoted as an evidence-based intervention for preventing cardiac complications of noncardiac surgery. However, subsequent studies raised concerns about a widespread use of perioperative β-blockade. Little is known regarding how this changing evidence influenced the use of perioperative β-blockers in clinical practice.

Methods and Results—

We conducted a population-based, time-series analysis (April 1999 to March 2010) among residents of Ontario, Canada (age 66 years and older), to evaluate the influence of research publications and practice guidelines on rates of new β-blocker prescriptions before major elective noncardiac surgery. In an analysis of 249 828 procedures, the rate of new β-blocker prescriptions increased from 26.3 per 1000 procedures in April 1999 to 62.7 per 1000 procedures in the first quarter of 2005, after which it decreased to 19.7 per 1000 procedures by March 2010. We observed a marked decrease in prescriptions (
P
=0.004) during early 2005, without any preceding publications that raised concerns about perioperative β-blockade. There was no change (
P
=0.98) in prescription rates after the May 2008 publication of a multicenter, randomized trial that showed increased mortality from perioperative β-blockade. Prescribing trends remain unchanged after revisions of related practice guidelines in 2002 (
P
=0.28) and 2006 (
P
=0.53).

Conclusions—
After a period characterized by increasing adoption of preoperative β-blockade between 1999 and 2005, prescriptions rates subsequently fell from 2005 to 2010. Further research is needed to understand the basis for these changes, which are only partially explained by evidence of potential harm.
Antenatal Factors Associated With Perinatal Arterial Ischemic Stroke
Authors: Darmency-Stamboul Véronique , Chantegret Corinne , Ferdynus Cyril , Mejean Nathalie , Durand Christine , Sagot Paul , Giroud Maurice , Bejot Yannick , Gouyon Jean Bernard 
Published: June 2012

Background and Purpose—
Perinatal arterial ischemic stroke (PAIS) is a common cause of hemiplegic cerebral palsy in children. The diagnosis of PAIS is based on cerebral imaging. The objective of our study was to determine prenatal risk factors associated with PAIS.

Methods—
A retrospective case–control study was nested in the whole population of Burgundy, France, from January 2000 to December 2007. Case patients were confirmed by review of brain imaging and medical records. Three control subjects per case were randomly selected from the study population by sex, term, place, and year of birth.

Results—

PAIS was confirmed in 32 patients and its incidence was one per 4400 live births. In comparison to control subjects, clinical conditions significantly associated to cases were gestational diabetes (16.1% versus 4.2%;
P
=0.04), fetal heart rate abnormalities (35.5% versus 10.9%;
P
=0.001), and meconium-stained liquor (40% versus 12%;
P
<0.001). At the limit of statistical significance were found maternal smoking before (39.3% versus 22.9%;
P
=0.08) and during pregnancy (32.1% versus 16.7%;
P
=0.07), cord abnormalities (29% versus 14.1%;
P
=0.06), and cesarean delivery (28.1% versus 14.6%;
P
=0.08). In the multivariate analysis, maternal smoking during pregnancy (OR, 3.1; 95% CI, 1.1–8.8;
P
=0.04) was the only risk factor significantly associated with PAIS.

Conclusions—
This study is the first to identify maternal smoking during pregnancy as an independent prenatal risk factor of PAIS. Additional prospective studies are needed to confirm this result and to investigate the role of maternal smoking in fetal and neonatal thrombogenesis.
Telmisartan on Top of Antihypertensive Treatment Does Not Prevent Progression of Cerebral White Matter Lesions in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) MRI Substudy
Authors: Weber Ralph , Weimar Christian , Blatchford Jon , Hermansson Karin , Wanke Isabel , Möller-Hartmann Claudia , Gizewski Elke R. , Forsting Michael , Demchuk Andrew M. , Sacco Ralph L. , Saver Jeffrey L. , Warach Steven , Diener Hans-Christoph , Diehl Anke ,   for the PRoFESS Imaging Substudy Group
Published: June 2012

Background and Purpose—
High blood pressure is one of the main risk factors for cerebral white matter lesions (WMLs). There is limited evidence from one randomized trial that blood pressure-lowering is able to slow WML progression. We investigated whether telmisartan prevents WML progression in the imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

Methods—
This predefined substudy comprised 771 patients (mean age, 65 years) with recent ischemic stroke of noncardioembolic origin who received telmisartan or placebo during a mean follow-up of 27.9 (SD, 7.6) months and had 2 evaluable MRI examinations after index stroke and at study closeout. All MRI scans were centrally adjudicated for progression of periventricular and subcortical WML by 2 neuroradiologists blinded to treatment allocation.

Results—

Mean blood pressure was 3.0/1.3 mm Hg lower with telmisartan compared with placebo at follow-up MRI. There was no statistically significant difference in progression of the mean periventricular WML score (least squares mean difference, 0.14; 95% CI, −0.12 to 0.39;
P
=0.29) and mean subcortical WML diameter (least squares mean difference, −0.35 mm; 95% CI, −1.00 to 0.31 mm;
P
=0.30) during follow-up between patients on telmisartan and placebo.

Conclusions—
Treatment with telmisartan on top of existing antihypertensive medication did not result in significant blood pressure-lowering and did not prevent the progression of WML in patients with a recent ischemic stroke in this patient cohort. Our analysis is limited by the relatively short follow-up period.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique Identifier: NCT00153062.
Quaternary structures of recombinant, cellular, and serum forms of Thymidine Kinase 1 from dogs and humans
Authors: Hanan Sharif , Jagarlamudi Kiran Kumar , Liya Wang , Ellen He , Staffan Eriksson 
Published: June 2012

Abstract

Background
Thymidine kinase 1 (TK1) is a salvage enzyme involved in DNA precursor synthesis, and its expression is proliferation dependent. A serum form of TK1 has been used as a biomarker in human medicine for many years and more recently to monitor canine lymphoma. Canine TK1 has not been cloned and studied. Therefore, dog and human TK1 cDNA were cloned and expressed, and the recombinant enzymes characterized. The serum and cellular forms of canine and human TK1 were studied by size-exclusion chromatography and the level of TK1 protein was determined using polyclonal and monoclonal anti-TK1 antibodies.

Results
Canine TK1 phosphorylated the thymidine (dThd) analog 3'-azido-thymidine (AZT) as efficiently as it did dThd, whereas AZT phosphorylation by human TK1 was less efficient than that of dThd. Dog TK1 was also more thermostable and pH tolerant than the human enzyme. Oligomeric forms were observed with both enzymes in addition to the tetrameric and dimeric forms. Cellular TK1 was predominantly seen in dimeric and tetrameric forms, in the case of both dog TK1 from MDCK cells and human TK1 from CEM cells. Active serum TK1 was found mainly in a high molecular weight form, and treatment with a reducing agent shifted the high molecular weight complex to lower molecular weight forms with reduced total activity. Western blot analysis demonstrated a polypeptide of 26 kDa (dog) and 25 kDa (human) for cellular and serum TK1. There was no direct correlation between serum TK1 activity and protein level. It appears that a substantial fraction of serum TK1 is not enzymatically active.

Conclusions
These results suggest that the serum TK1 protein differs from cellular or recombinant forms, is more active in high molecular weight complexes, and is sensitive to reducing agents. The results presented here provide important information for the future development and use of serum TK1 as a diagnostic biomarker in human and veterinary medicine.