bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombin-activatable fibrinolysis inhibitor in hypothyroidism and hyperthyroxinaemia
Authors: Verkleij Chantal , van Zaane Bregje , Squizzato Alessandro , Brandjes Dees , Büller Harry , Meijers Joost , Gerdes Victor , Stuijver Danka 
Published: November 2012

SummaryEndocrine disorders affect both the coagulation and fibrinolytic systems, and have been associated with the development of cardiovascular diseases. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a link between coagulation and the fibrinolytic system. The aim of this study was to determine the effect of thyroid hormone excess and deficiency on TAFI levels and function. The effect of hyperthyroxinemia on TAFI was studied in healthy volunteers who were randomised to receive levothyroxine or no medication for 14 days in a crossover design. The effect of hypothyroidism on TAFI was studied in a multicentre observational cohort study. Blood was drawn before treatment of patients with newly diagnosed hypothyroidism and when euthyroidism was achieved. Plasma clot-lysis times, activated TAFI (TAFIa)-dependent prolongation of clot-lysis and TAFI levels were measured. Thyroid hormone excess resulted in a hypofibrinolytic condition and in an enhanced TAFIa-dependent prolongation of clot lysis. A trend towards decreased plasma TAFI levels was observed in healthy volunteers who used levothyroxine. Hypothyroidism resulted in hyperfibrinolysis and a reduced TAFIa-dependent prolongation of clot lysis. In conclusion, alterations of TAFIa-dependent prolongation of clot lysis in patients with thyroid disorders may cause an impaired haemostatic balance. The disturbed haemostatic balance in patients with hyperthyroidism might make them prone to thrombosis, while the risk for bleeding may increase in patients with hypothyroidism.
Creating a genotype-based dosing algorithm for acenocoumarol steady dose
Authors: Cerezo-Manchado Juan J. , Rosafalco Mario , Antón Ana , Perez-Andreu Virginia , Garcia-Barberá Nuria , Martínez Ana B. , Corral Javier , Vicente Vincente , González-Conejero Rocio , Roldán Vanessa 
Published: November 2012

SummaryAcenocoumarol is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries. In counterpart of warfarin, there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation. The aim of this study was to develop an algorithm of prediction for acenocoumarol.The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2,683 patients. The best regression model to predict stable dosage in the Primary Cohort included clinical factors (age and body mass index, BSA) and genetic variants (VKORC1, CYP2C9* and CYP4F2 polymorphisms) and explained up to 50% of stable dose. In the validation study the clinical algorithm yielded an adjusted R2=0.15 (estimation´s standard error=4.5) and the genetic approach improved the dose forecast up to 30% (estimation´s standard error=4.6). Again, the best model combined clinical and genetic factors (R2= 0.48; estimation´s standard error=4) which provided the best results of doses estimates within 20% of the real dose in patients taking lower (≤7mg/week) or higher (≥25mg/week) acenocoumarol doses. In conclusion, we developed a prediction algorithm using clinical data and three polymorphisms in VKORC1, CYP2C9* and CYP4F2 genes that provided a steady acenocoumarol dose for about 50% of patients in the Validation Cohort. Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses, those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication.
Increased Dietary Intake of Vitamin A Promotes Aortic Valve Calcification In Vivo
Authors: Huk Danielle J. , Hammond Harriet L. , Kegechika Hiroyuki , Lincoln Joy 
Published: November 2012

Objective—

Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor
Sox9
. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro.

Methods and Results—

Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated
Sox9
repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors.

Conclusion—
Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.
Phosphorylation of Protein Inhibitor of Activated STAT1 (PIAS1) by MAPK-Activated Protein Kinase-2 Inhibits Endothelial Inflammation via Increasing Both PIAS1 Transrepression and SUMO E3 Ligase Activity
Authors: Heo Kyung-Sun , Chang Eugene , Takei Yuichiro , Le Nhat-Tu , Woo Chang-Hoon , Sullivan Mark A. , Morrell Craig , Fujiwara Keigi , Abe Jun-ichi 
Published: November 2012

Objective—
Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is known to function as small ubiquitin-like modifier (SUMO) E3 ligase as well as transrepressor. The aim of the study is to elucidate the regulatory mechanisms for these 2 different functions, especially with respect to endothelial inflammation.

Methods and Results—
The mitogen-activated protein kinase (MAPK)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates PIAS1 at the Ser522 residue. Activation of MAPK-activated protein kinase-2 enhances p53-SUMOylation, but a PIAS1 phosphorylation mutant, PIAS1-S522A, abolished this p53-SUMOylation, suggesting a critical role for PIAS1-S522 phosphorylation in its SUMO ligase activity. Because nuclear p53 can inhibit Kruppel-like factor 2 promoter activity, we investigated the roles for PIAS1 phosphorylation and p53-SUMOylation in the Kruppel-like factor 2 and endothelial NO synthase expression. Both MAPK-activated protein kinase-2 and PIAS1 overexpression increased Kruppel-like factor 2 promoter activity and endothelial NO synthase expression, which were inhibited by expressing a p53-SUMOylation defective mutant, p53-K386R, and PIAS1-S522A. PIAS1-S522A also abolished the anti-inflammatory effect of wild-type PIAS1 in vitro and also in vivo, which was examined by leukocyte rolling in microvessels of skin grafts transduced by adenovirus encoding PIAS1-WT or - S522A mutant.

Conclusion—
Our study has identified a novel negative feedback regulatory pathway through which MAPK-activated protein kinase-2 limits endothelial inflammation via the PIAS1 S522 phosphorylation-mediated increase in PIAS1 transrepression and SUMO ligase activity.
Reference Values for and Determinants of Right Atrial Area in Healthy Adults by 2-Dimensional Echocardiography
Authors: Grünig Ekkehard , Henn Philipp , D’Andrea Antonello , Claussen Martin , Ehlken Nicola , Maier Felicitas , Naeije Robert , Nagel Christian , Prange Felix , Weidenhammer Johannes , Fischer Christine , Bossone Eduardo 
Published: November 2012

Background—
Right atrial (RA) size is important in screening, diagnosis, and follow-up assessment in patients with pulmonary hypertension. The objective of this study was to define normal reference values for RA area by echocardiography in a large population of athletic versus sedentary healthy subjects.

Methods and Results—

In the first part of the study, 880 healthy adult subjects (mean age, 28±6 years; 38% women; 395 top-level endurance athletes, 255 strength athletes, and 230 nonathletes) were prospectively assessed. In the second part, we performed a pooled analysis of all studies published between 1976 and 2011 describing RA area in healthy subjects (n=624). Statistical analysis included the calculation of 95% quantiles for defining cutoff values. Mean RA area in the 880 subjects was significantly larger in endurance athletes compared with the strength athletes and nonathletes. RA area correlated significantly with age, sex, body surface, and endurance training. In a synopsis of both data sets, 95% quantiles for RA area in strength atheletes and nonathletes were 15.2 cm
2
(95% confidence interval, 14.7–15.7) in women and 16.2 cm
2
(95% confidence interval, 15.8–16.6) in men.

Conclusions—

To the best of our knowledge, this is the largest data set to describe RA size in adult healthy subjects (age <50 years). Cutoff values for RA area were significantly different in women (15 cm
2
) and men (16 cm
2
). Age, sex, body surface area, and high-level endurance training were determinants of RA area.
Familial Intracranial Aneurysms
Authors: Mackey Jason , Brown Robert D. , Moomaw Charles J. , Hornung Richard , Sauerbeck Laura , Woo Daniel , Foroud Tatiana , Gandhi Dheeraj , Kleindorfer Dawn , Flaherty Matthew L. , Meissner Irene , Anderson Craig , Rouleau Guy , Connolly E. Sander , Deka Ranjan , Koller Daniel L. , Abruzzo Todd , Huston John , Broderick Joseph P. ,   For the FIA Investigators
Published: November 2012

Background and Purpose—
Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study.

Methods—

We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family’s proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and
P
values from the 1001 logistic regression analyses were used to represent the final results of the analysis.

Results—

There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04–2.27];
P
=0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22–3.22];
P
=0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05–8.24],
P
=0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34–2.46];
P
<0.001).

Conclusions—
In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.
MR-DWI–Positive Lesions and Symptomatic Ischemic Complications After Coiling of Unruptured Intracranial Aneurysms
Authors: Kang Dong-Hun , Kim Byung Moon , Kim Dong Joon , Suh Sang Hyun , Kim Dong Ik , Kim Yong-Sun , Huh Seung Kon , Park Jaechan , Lee Jae Whan , Kim Yong Bae 
Published: November 2012

Background and Purpose—
The aims of this study are to evaluate the risk factors for symptomatic ischemic complication (symptomatic ischemic complication [SIC], transient ischemic attack, or stroke) and microembolisms detected as MR diffusion-weighted imaging (MR-DWI)–positive (DWI(+)) lesions, and the relationship between DWI(+) and SIC after coiling of unruptured intracranial aneurysm.

Methods—
Between March 2009 and November 2011, 382 unruptured intracranial aneurysms in 343 patients underwent both coiling and posttreatment MR-DWI. The incidence of and risk factors for SIC and DWI(+), and the relationship between DWI(+) and SIC were retrospectively analyzed.

Results—

The incidence of SIC was 4.1%. The incidence of DWI(+) was 54.5%. The number of DWI(+) lesions was significantly larger in the SIC group, than in the asymptomatic one (12.1±10.4 versus 5.0±8.7,
P
<0.00). The cutoff value of DWI(+) for predicting SIC was ≥6 (sensitivity 85.7%, specificity 70.7%). The patients with DWI(+) ≥6 was 28.6%. Of the patients with SIC, the patients with DWI(+) ≥6 was 78.6%. Patients aged≥65 years had a trend for SIC, and it was the only independent risk factor for DWI(+) ≥cutoff (n=6; 95%CI, 1.167–3.083).

Conclusions—
The number of DWI(+) lesions was significantly larger in the SIC group than in the asymptomatic one after coiling of unruptured intracranial aneurysm. Patients aged≥65 had a trend for SIC, and it was the only independent risk factor for the number of DWI(+) ≥cutoff value (n=6) for predicting SIC.
Symptomatic Recurrence of Intracranial Arterial Dissections
Authors: Ono Hideaki , Nakatomi Hirofumi , Tsutsumi Kazuo , Inoue Tomohiro , Teraoka Akira , Yoshimoto Yuhei , Ide Takafumi , Kitanaka Chifumi , Ueki Keisuke , Imai Hideaki , Saito Nobuhito 
Published: November 2012

Background and Purpose—
The frequency and pattern of symptomatic recurrence of spontaneous intracranial arterial dissection (IAD) are unknown.

Methods—
A follow-up study of 143 patients (85 men, 58 women; mean age, 50.7 [7–83] years) with spontaneous IADs at The University of Tokyo and affiliated hospitals from 1980 to 2000 was conducted. Tissue samples of IAD vessels obtained from 13 patients at various intervals from onset were also examined histologically.

Results—
With a mean follow-up of 8.2 years, symptomatic recurrence occurred in 47 patients (33%). Of 37 cases initially presenting with hemorrhage, 35 developed hemorrhagic recurrence with a mean interval of 4.8 days, and 2 developed nonhemorrhagic recurrences after 21 and 85 months, respectively. Of 10 patients initially presenting with nonhemorrhagic symptoms, 1 developed hemorrhagic recurrence 4 days later, and 9 developed nonhemorrhagic recurrences with a mean interval of 8.6 months. Histopathologically, the affected vessels in the acute stage of hemorrhage (days 0–6) demonstrated insufficient granulation formation within the pseudolumen, followed by marked intimal thickening around the pseudolumen and recanalizing vessel formation in the late stage (>day 30). In the late stage of brain ischemia, subintimal and subadventitial hemorrhage accompanied with intimal thickening was observed.

Conclusions—
These data indicate that IAD is a disease carrying a relatively high risk of symptomatic recurrence, apparently occurring in 3 phases and patterns: early hemorrhagic recurrence, late nonhemorrhagic recurrence, and chronic fusiform aneurysm transformation. Knowledge of this triphasic recurrence and corresponding histopathological characteristics help determine the treatment and follow-up strategy for IAD patients.
The Neurorestorative Benefit of GW3965 Treatment of Stroke in Mice
Authors: Cui Xu , Chopp Michael , Zacharek Alex , Cui Yisheng , Roberts Cynthia , Chen Jieli 
Published: November 2012

Background and Purpose—
GW3965, a synthetic liver X receptor agonist, elevates high-density lipoprotein cholesterol and has antiatherosclerosis and anti-inflammation properties. We tested the hypothesis that GW3965 treatment of stroke increases vascular remodeling, promotes synaptic protein expression and axonal growth in the ischemic brain, and improves functional outcome in mice.

Methods—
Mice were subjected to transient middle cerebral artery occlusion and treated without or with different doses of GW3965 (5, 10, or 20 mg/kg) starting 24 hours after middle cerebral artery occlusion daily for 14 days. Neurological functional tests, blood high-density lipoprotein cholesterol measurement, and immunostaining were performed. Mouse brain endothelial cells, primary cultured artery explants, and primary cortical neurons cultures were also used in vitro.

Results—

GW3965 treatment of stroke significantly increased blood high-density lipoprotein cholesterol level, synaptic protein expression, axonal density, angiogenesis and arteriogenesis, and Angiopoietin1, Tie2, and occludin expression in the ischemic brain and improved functional outcome compared with middle cerebral artery occlusion control animals (n=10;
P
<0.05). In vitro, GW3965 and high-density lipoprotein cholesterol also significantly increased capillary-like tube formation and artery explant cell migration as well as neurite outgrowth. Inhibition of Angiopoietin-1 attenuated GW3965-induced tube-formation, artery cell migration, and neurite outgrowth (n=6 per group;
P
<0.05).

Conclusions—
These data indicate, for the first time, that GW3965 promotes synaptic protein expression and axonal growth and increases vascular remodeling, which may contribute to improvement of functional outcome after stroke. Increasing Angiopoietin-1/Tie2 signaling activity may play an important role in GW3965-induced brain plasticity and neurological recovery from stroke.
Estimating Central Equatorial Pacific SST Variability over the Past Millennium. Part I: Methodology and Validation
Authors: Emile-Geay Julien , Cobb Kimberly M. , Mann Michael E. , Wittenberg Andrew T. 
Published: November 2012

AbstractConstraining the low-frequency (LF) behavior of general circulation models (GCMs) requires reliable observational estimates of LF variability. This two-part paper presents multiproxy reconstructions of Niño-3.4 sea surface temperature over the last millennium, applying two techniques [composite plus scale (CPS) and hybrid regularized expectation maximization (RegEM) truncated total least squares (TTLS)] to a network of tropical, high-resolution proxy records. This first part presents the data and methodology before evaluating their predictive skill using frozen network analysis (FNA) and pseudoproxy experiments. The FNA results suggest that about half of the Niño-3.4 variance can be reconstructed back to A.D. 1000, but they show little LF skill during certain intervals. More variance can be reconstructed in the interannual band where climate signals are strongest, but this band is affected by dating uncertainties (which are not formally addressed here). The CPS reliably estimates interannual variability, while LF fluctuations are more faithfully reconstructed with RegEM, albeit with inevitable variance loss. The RegEM approach is also tested on representative pseudoproxy networks derived from two millennium-long integrations of a coupled GCM. The pseudoproxy study confirms that reconstruction skill is significant in both the interannual and LF bands, provided that sufficient variance is exhibited in the target Niño-3.4 index. It also suggests that FNA severely underestimates LF skill, even when LF variability is strong, resulting in overly pessimistic performance assessments. The centennial-scale variance of the historical Niño-3.4 index falls somewhere between the two model simulations, suggesting that the network and methodology presented here would be able to capture the leading LF variations in Niño-3.4 for much of the past millennium, with the caveats noted above.
Kinematic and Thermodynamic Structures of Sierra Barrier Jets and Overrunning Atmospheric Rivers during a Landfalling Winter Storm in Northern California
Authors: Kingsmill David E. , Neiman Paul J. , Moore Benjamin J. , Abel Mimi R. , Yuter Sandra E. , Ralph F. Martin 
Published: November 2012

AbstractThis study characterizes kinematic and thermodynamic structures of Sierra barrier jets (SBJs), atmospheric rivers (ARs), and their interaction over the period 14–16 February 2011 when a winter storm made landfall in northern California. A suite of scanning and profiling Doppler radars, rawinsondes, and GPS receivers is used to document these structures across the Central Valley and up the western Sierra slope to the crest along an ~200-km segment of the Sierra. The winter storm is grouped into two episodes, each having an AR that made landfall. Low-level winds in the SBJ observed during episode 1 were southeasterly and embedded in a stably stratified air mass. Along-barrier wind speeds U340 reached maximum values of 25–30 m s−1, as low as ~0.2 km MSL over the Central Valley, and as high as ~1.5 km MSL over the western Sierra slope. Southwesterly winds associated with the AR overlaid the SBJ along an interface that sloped upward from southwest to northeast with a southwestern extent at the western edge of the Central Valley. In contrast, low-level winds in the SBJ observed during episode 2 were more southerly and embedded in a less stable air mass. The U340 reached maximum values that were slightly weaker (~20–25 m s−1) and spread over a thicker layer that extended to higher levels over the western Sierra (~2.5 km MSL). Southwesterly winds associated with the AR overlaying the SBJ tilted upward from southwest to northeast with a steeper slope but did not extend as far southwest.
Migraine is a risk factor for sudden sensorineural hearing loss: A nationwide population-based study
Authors: Chu Chia-Huei , Liu Chia-Jen , Fuh Jong-Ling , Shiao An-Suey , Chen Tzeng-Ji , Wang Shuu-Jiun 
Published: November 2012

Background The pathophysiology of idiopathic sudden sensorineural hearing loss (SSNHL) is poorly understood. Few case reports have proposed a possible link between migraine and SSNHL. Objectives This study aimed to explore the risk of idiopathic SSNHL in patients with migraine in a nationwide, population-based cohort study. Methods We identified patients with migraine from the Taiwan National Health Insurance Research Database (NHIRD) between 2000 and 2009. Each migraine patient was matched with four randomly selected subjects without migraine for age, sex, and comorbidities. Both cohorts were followed up until the end of 2009. We compared the incidence rates of SSNHL in the two cohorts and identified the risk factors. Results A total of 10,280 migraine patients and 41,120 matched controls were enrolled with a median follow-up of five years. The migraine cohort had a greater risk of developing SSNHL than the matched cohort (81.6 vs. 45.7 per 100,000 person-years, incidence rate ratio (IRR) = 1.8; 95% confidence interval (CI) 1.22–2.61, p = 0.002). The Cox proportional hazards analysis revealed that among migraine subjects, comorbidity with hypertension was associated with a trend of developing SSNHL (hazard ratio (HR) = 1.92, 95% CI 0.97–3.79, p = 0.06). Conclusions This population-based study demonstrates that migraine is associated with an increased risk of idiopathic SSNHL, which, however, is a rare condition.