bluuebunny/crossref_metadata_2025 huggingface dataset:
Activating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis
Authors: Charles Roch-Philippe , Silva Jillian , Iezza Gioia , Phillips Wayne A. , McMahon Martin
Published: April 2014

Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer-related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3′-Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAFV600E, we previously developed a model of PTC. However, as in humans, BRAFV600E-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CAH1047R is unable to drive transformation on its own, when combined with BRAFV600E in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAFV600E cooperates with either PIK3CAH1074R or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma.

Implications: This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma. Mol Cancer Res; 12(7); 979–86. ©2014 AACR.
Evaluation of Clinical Criteria for the Identification of Lynch Syndrome among Unselected Patients with Endometrial Cancer
Authors: Bruegl Amanda S. , Djordjevic Bojana , Batte Brittany , Daniels Molly , Fellman Bryan , Urbauer Diana , Luthra Rajyalakshmi , Sun Charlotte , Lu Karen H. , Broaddus Russell R.
Published: April 2014

Clinical criteria, primarily young age of cancer onset and family history of signature cancers, have been developed to identify individuals at elevated risk for Lynch syndrome with the goals of early identification and cancer prevention. In 2007, the Society of Gynecologic Oncology (SGO)–codified criteria for women presenting with gynecologic cancers. These criteria have not been validated in a population-based setting. For 412 unselected endometrial cancers, immunohistochemical expression of DNA mismatch repair proteins and MLH1 methylation were assessed to classify tumors as sporadic or probable Lynch syndrome (PLS). In this cohort, 10.5% of patients were designated as PLS based on tumor testing. The sensitivity and specificity of the SGO criteria to identify these same cases were 32.6% [95% confidence interval (CI), 19.2–48.5] and 77% (95% CI, 72.7–81.8), respectively. With the exception of tumor location in the lower uterine segment, multivariate analysis of clinical features, family history, and pathologic variables failed to identify significant differences between the sporadic and PLS groups. A simplified cost-effectiveness analysis demonstrated that the SGO clinical criteria and universal tissue testing strategies had comparable costs per patient with PLS identified. In conclusion, the SGO criteria successfully identify PLS cases among women with endometrial cancer who are young or have significant family history of signature tumors. However, a larger proportion of patients with PLS who are older and have less significant family history are not detected by this screening strategy. Universal tissue testing may be necessary to capture more individuals at risk for having Lynch syndrome. Cancer Prev Res; 7(7); 686–97. ©2014 AACR.
A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors
Authors: Konieczkowski David J. , Johannessen Cory M. , Abudayyeh Omar , Kim Jong Wook , Cooper Zachary A. , Piris Adriano , Frederick Dennie T. , Barzily-Rokni Michal , Straussman Ravid , Haq Rizwan , Fisher David E. , Mesirov Jill P. , Hahn William C. , Flaherty Keith T. , Wargo Jennifer A. , Tamayo Pablo , Garraway Levi A.
Published: April 2014

Most melanomas harbor oncogenic BRAFV600 mutations, which constitutively activate the MAPK pathway. Although MAPK pathway inhibitors show clinical benefit in BRAFV600-mutant melanoma, it remains incompletely understood why 10% to 20% of patients fail to respond. Here, we show that RAF inhibitor–sensitive and inhibitor-resistant BRAFV600-mutant melanomas display distinct transcriptional profiles. Whereas most drug-sensitive cell lines and patient biopsies showed high expression and activity of the melanocytic lineage transcription factor MITF, intrinsically resistant cell lines and biopsies displayed low MITF expression but higher levels of NF-κB signaling and the receptor tyrosine kinase AXL. In vitro, these MITF-low/NF-κB–high melanomas were resistant to inhibition of RAF and MEK, singly or in combination, and ERK. Moreover, in cell lines, NF-κB activation antagonized MITF expression and induced both resistance marker genes and drug resistance. Thus, distinct cell states characterized by MITF or NF-κB activity may influence intrinsic resistance to MAPK pathway inhibitors in BRAFV600-mutant melanoma.

Significance: Although most BRAFV600-mutant melanomas are sensitive to RAF and/or MEK inhibitors, a subset fails to respond to such treatment. This study characterizes a transcriptional cell state distinction linked to MITF and NF-κB that may modulate intrinsic sensitivity of melanomas to MAPK pathway inhibitors. Cancer Discov; 4(7); 816–27. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 745
Low Serum Allopregnanolone Is Associated with Symptoms of Depression in Late Pregnancy
Authors: Hellgren Charlotte , Åkerud Helena , Skalkidou Alkistis , Bäckström Torbjörn , Sundström-Poromaa Inger
Published: April 2014

Background: Allopregnanolone (3α-hydroxy-5α-pregnan-20-one) is a neurosteroid which has an inhibitory function through interaction with the GABAA receptor. This progesterone metabolite has strong sedative and anxiolytic properties, and low endogenous levels have been associated with depressed mood. This study aimed to investigate whether the very high serum allopregnanolone levels in late pregnancy covary with concurrent self-rated symptoms of depression and anxiety. Methods: Ninety-six women in pregnancy weeks 37-40 rated symptoms of depression and anxiety with the Montgomery-Åsberg Depression Rating Scale (MADRS-S) and Spielberger State-Trait Anxiety Inventory. Their serum allopregnanolone was analyzed by Celite chromatography and radioimmunoassay. Results: Ten women had elevated depression scores (MADRS-S ≥13), and this group had significantly lower allopregnanolone levels compared to women with MADRS-S scores in the normal range (39.0 ± 17.9 vs. 54.6 ± 18.7 nmol/l, p = 0.014). A significant negative correlation was found between self-rated depression scores and allopregnanolone concentrations (Pearson's correlation coefficient = -0.220, p = 0.031). The linear association between self-rated depression scores and allopregnanolone serum concentrations remained significant when adjusted for gestational length, progesterone levels, and parity. Self-rated anxiety, however, was not associated with allopregnanolone serum concentrations during pregnancy. Conclusion: High allopregnanolone serum concentrations may protect against depressed mood during pregnancy.
Dose of Hemodialysis and Survival: A Marginal Structural Model Analysis
Authors: Lertdumrongluk Paungpaga , Streja Elani , Rhee Connie M. , Park Jongha , Arah Onyebuchi A. , Brunelli Steven M. , Nissenson Allen R. , Gillen Daniel , Kalantar-Zadeh Kamyar
Published: April 2014

Background: Observational studies have consistently demonstrated the survival benefits of a greater dialysis dose in maintenance hemodialysis (MHD) patients, whereas randomized controlled trials have shown conflicting results. The possible causal impact of dialysis dose on mortality needs to be investigated using rich cohort data analyzed with novel statistical methods such as marginal structural models (MSMs) that account for time-varying confounding and exposure. Methods: We quantified the effect of delivered dose of hemodialysis (HD) [single-pool Kt/V (spKt/V)] on mortality risk in a contemporary cohort of 68,110 patients undergoing HD 3 times weekly (7/2001-9/2005). We compared conventional Cox proportional hazard and MSM survival analyses, accounting for time-varying confounding by applying longitudinally modeled inverse-probability-of-dialysis-dose weights to each observation. Results: In conventional Cox models, baseline spKt/V showed a weak negative association with mortality, while higher time-averaged spKt/V was strongly associated with lower mortality risk. In MSM analyses, compared to a spKt/V range of 1.2-<1.4, a spKt/V range of <1.2 was associated with a higher risk of mortality [HR (95% CI) 1.67 (1.54-1.80)], whereas mortality risks were significantly lower with higher spKt/V [HRs (95% CI): 0.74 (0.70-0.78), 0.63 (0.59-0.66), 0.56 (0.52-0.60), and 0.56 (0.52-0.61) for spKt/V ranges of 1.4-<1.6, 1.6-<1.8, 1.8-<2.0, and ≥2.0, respectively]. Thus, MSM analyses showed that the greatest survival advantage of a higher dialysis dose was observed for a spKt/V range of 1.8-<2.0, and the dialysis dose-mortality relationship was robust in almost all subgroups of patients. Conclusions: Higher HD doses were robustly associated with greater survival in MSM analyses that more fully and appropriately accounted for time-varying confounding.
Effect of the Restitution Properties of Cardiac Tissue on the Repeatability of Entrainment Mapping Response
Authors: Derejko Paweł , Podziemski Piotr , Żebrowski Jan Jacek , Walczak Franciszek , Szumowski Łukasz Jan
Published: April 2014

Background—

The difference between the postpacing interval (PPI) and the tachycardia cycle length (TCL; PPI−TCL) is a useful tool in mapping macro-reentrant tachycardias. However, entrainment pacing causes some perturbation of the conduction velocity within the tachycardia circuit, which may affect the repeatability and consequently the accuracy of the measurement of PPI−TCL. The aim of this study was to assess PPI−TCL repeatability both in vivo and in silico.

Methods and Results—

In the experimental part, entrainment pacing was performed twice at each of the 124 tested sites for 30 patients undergoing radiofrequency ablation of atrial and ventricular re-entrant arrhythmias. A similar protocol was used in a simplified computer model of the cardiac tachycardia circuit in a 2-dimensional tissue strip using a Fenton–Karma model of cardiac tissue. In vivo, in the case of fast tachycardias (<350 ms), PPI−TCL variability observed was doubled compared with slow tachycardias (>350 ms; 95% Limits of Agreement ranged from −21.4 to 21.6 ms for TCL<350 ms and from −10.8 to 11.5 ms for TCL>350 ms). Simulations show that this increase of variability may be because of the oscillations of the conduction velocity inside the tachycardia circuits. The effect of the restitution properties of cardiac tissue on the outcome of entrainment pacing is discussed.

Conclusions—

PPI−TCL is characterized by a high repeatability with the differences between the results for individual stimulations of ≤20 ms. The variability of this parameter is significantly lower in the case of slow tachycardias.
Prevalence and Prognostic Value of Concealed Structural Abnormalities in Patients With Apparently Idiopathic Ventricular Arrhythmias of Left Versus Right Ventricular Origin
Authors: Nucifora Gaetano , Muser Daniele , Masci Pier Giorgio , Barison Andrea , Rebellato Luca , Piccoli Gianluca , Daleffe Elisabetta , Toniolo Mauro , Zanuttini Davide , Facchin Domenico , Lombardi Massimo , Proclemer Alessandro
Published: April 2014

Background—

Routine diagnostic work-up occasionally does not identify any abnormality among patients with monomorphic ventricular arrhythmias (VAs) of left ventricular (LV) origin. Aim of this study was to investigate the value of cardiac MRI (cMRI) for the diagnostic work-up and prognostication of these patients.

Methods and Results—

Forty-six consecutive patients (65% males; mean age, 44±15 years) with monomorphic VAs of LV origin and negative routine diagnostic work-up were included. Seventy-four consecutive patients (60% males; mean age, 40±17 years) with apparently idiopathic monomorphic VAs of right ventricular origin served as control group. Both groups underwent comprehensive cMRI study and were followed-up for a median of 14 months (25th–75th percentiles, 7–37 months). The outcome event was an arrhythmic composite end point of sudden cardiac death or nonfatal episode of ventricular fibrillation or sustained ventricular tachycardia requiring external cardioversion or appropriate implantable cardioverter defibrillator therapy. The 2 groups of patients did not differ in age (
P
=0.14) and sex (
P
=0.57). No significant difference was observed between patients with VAs of LV origin and VAs of right ventricular origin about biventricular volumes and systolic function. cMRI demonstrated myocardial structural abnormalities in 19 (41%) patients with VAs of LV origin versus 4 (5%) patients with VAs of right ventricular origin (
P
<0.001). The outcome event occurred in 9 patients; myocardial structural abnormalities on cMRI were significantly related to the outcome event (hazard ratio, 41.6; 95% confidence interval, 5.2–225.0;
P
<0.001).

Conclusions—

Myocardial structural changes are detected by cMRI in a non-negligible proportion of patients with apparently idiopathic monomorphic VAs of LV origin and are associated with worse outcome.
Real-Time Magnetic Resonance Assessment of Septal Curvature Accurately Tracks Acute Hemodynamic Changes in Pediatric Pulmonary Hypertension
Authors: Pandya Bejal , Quail Michael A. , Steeden Jennifer A. , McKee Andrea , Odille Freddy , Taylor Andrew M. , Schulze-Neick Ingram , Derrick Graham , Moledina Shahin , Muthurangu Vivek
Published: April 2014

Background—

This study assesses the relationship between septal curvature and mean pulmonary artery pressure and indexed pulmonary vascular resistance in children with pulmonary hypertension. We hypothesized that septal curvature could be used to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics.

Methods and Results—

Fifty patients with a median age of 6.7 years (range, 0.45–16.5 years) underwent combined cardiac catheterization and cardiovascular magnetic resonance. The majority had idiopathic pulmonary arterial hypertension (n=30); the remaining patients had pulmonary hypertension associated with repaired congenital heart disease (n=17) or lung disease (n=3). Mean pulmonary artery pressure and pulmonary vascular resistance were acquired at baseline and during vasodilation. Septal curvature was measured using real-time cardiovascular magnetic resonance. There was a strong correlation between mean pulmonary artery pressure and
SC
min
at baseline and during vasodilator testing (
r
=–0.81 and –0.85, respectively;
P
<0.01). A strong linear relationship also existed between pulmonary vascular resistance and minimum septal curvature indexed to cardiac output both at baseline and during vasodilator testing (
r
=–0.88 and –0.87, respectively;
P
<0.01). Change in septal curvature metrics moderately correlated with absolute change in mean pulmonary artery pressure and pulmonary vascular resistance, respectively (
r
=0.58 and –0.74;
P
<0.01). Septal curvature metrics were able to identify vasoresponders with a sensitivity of 83% (95% confidence interval, 0.36–0.99) and a specificity of 91% (95% confidence interval, 0.77–0.97), using the Sitbon criteria. Idiopathic pulmonary arterial hypertension subgroup analysis revealed 3 responders with Δ
SC
min
values of 0.523, 0.551, and 0.568. If the middle value of 0.551 is taken as a cutoff, the approximate sensitivity would be 67% and the specificity would be 93%.

Conclusions—

Septal curvature metrics are able to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics during vasodilator testing. This suggests that septal curvature could be used for continuing assessment of load in pulmonary hypertension.
Nuclear Localization of α1A‐Adrenergic Receptors Is Required for Signaling in Cardiac Myocytes: An “Inside‐Out” α1‐AR Signaling Pathway
Authors: Wu Steven C. , Dahl Erika F. , Wright Casey D. , Cypher Andrew L. , Healy Chastity L. , O'Connell Timothy D.
Published: April 2014

Background

Recent studies indicate that α1‐adrenergic receptors (α1‐ARs) are cardioprotective by preventing cardiac myocyte death and augmenting contractility in heart failure. Although G‐protein‐coupled receptors are assumed to localize to and signal at the plasma membrane, we previously demonstrated that endogenous α1‐ARs localize to the nuclei in adult cardiac myocytes. However, the functional consequence of this nuclear localization remains unclear. Here, we attempted to reconcile nuclear localization of α1‐ARs with their physiologic function by examining α1‐AR‐induced contractility in adult cardiac myocytes.

Methods and Results

By measuring shortening in unloaded, cultured adult cardiac myocytes, we found that the α1A‐subtype regulated contractility through phosphorylation of cardiac troponin I (cTnI) at the protein kinase C (PKC) site, threonine 144. Reconstitution of an α1A‐subtype nuclear localization mutant in cardiac myocytes lacking α1‐ARs failed to rescue nuclear α1A‐mediated phosphorylation of cTnI and myocyte contractility. Leptomycin B, the nuclear export inhibitor, also blocked α1A‐mediated phosphorylation of cTnI. These data indicate that α1‐AR signaling originates in the nucleus. Consistent with these observations, we localized the α1A‐subtype to the inner nuclear membrane, identified PKCα, δ, and ε in the nucleus, and found that α1‐ARs activate PKCδ in nuclei isolated from adult cardiac myocytes. Finally, we found that a PKCδ nuclear localization mutant blunted α1‐induced phosphorylation of cTnI.

Conclusions

Together, our data identify a novel, “inside‐out” nuclear α1A‐subtype/PKCδ/cTnI‐signaling pathway that regulates contractile function in adult cardiac myocytes. Importantly, these data help resolve the discrepancy between nuclear localization of α1‐ARs and α1‐AR‐mediated physiologic function.
The Association of Albuminuria With Tubular Reabsorption of Uric Acid: Results From a General Population Cohort
Authors: Scheven Lieneke , Joosten Michel M. , de Jong Paul E. , Bakker Stephan J. L. , Gansevoort Ron T. ,   For the PREVEND study group
Published: April 2014

Background

Elevated albuminuria as well as an increased serum uric acid concentration is associated with poor cardiovascular outcome. We questioned whether these 2 variables (albuminuria and serum uric concentration) may be interrelated via tubular uric acid reabsorption.

Methods and Results

Included were 7688 participants of the
PREVEND
Study, an observational, general population‐based cohort study. Linear regression analyses were used to test associations of baseline albuminuria with baseline serum uric acid concentration and tubular uric acid reabsorption (calculated as [100−fractional uric acid excretion]%). Cox regression analyses were used to study the association of baseline serum uric acid and albuminuria with incident cardiovascular morbidity and mortality. In cross‐sectional analyses, albuminuria was associated positively with serum uric acid concentration, both crude and after adjustment for potential confounders (both
P
<0.001). Albuminuria was found to be associated positively with tubular uric acid reabsorption, again both crude and after adjustment for potential confounders (both
P
<0.001). In longitudinal analyses during a median follow‐up of 10.5 years, 702 cardiovascular events occurred. After adjusting for cardiovascular risk factors, both albuminuria and serum uric acid were associated with incident cardiovascular events (Hazard Ratios 1.09 [1.03 to 1.17],
P
=0.01 and 1.19 [1.09 to 1.30],
P
<0.001, respectively). A significant interaction between these variables was present (
P
<0.001), consistent with high serum uric acid being less predictive for cardiovascular morbidity and mortality in the presence of high albuminuria and vice versa.

Conclusions

Albuminuria is strongly associated with tubular uric acid reabsorption, and consequently with serum uric acid concentration. This phenomenon may explain in part why albuminuria is associated with cardiovascular outcome.
The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Observational Follow‐Up Study: Benefits of RAS Blockade With Olmesartan Treatment Are Sustained After Study Discontinuation
Authors: Menne Jan , Ritz Eberhard , Ruilope Luis M. , Chatzikyrkou Christos , Viberti Giancarlo , Haller Hermann
Published: April 2014

Background

The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study showed that 40 mg Olmesartan medoxomil (
OM
) versus placebo delayed microalbuminuria onset in patients with type 2 diabetes and normoalbuminuria.

Methods and Results

One thousand seven hundred and fifty‐eight
ROADMAP
patients (placebo arm: 877;
OM
arm: 881) participated in the observational follow up (
OFU
) with an average of 3.3 years. They received standard medical care and micro‐ and macrovascular events were documented. During observational follow‐up 62.9% and 60.1% in the former
OM
and placebo group, respectively, received treatment with a
RAS
blocking agent. During the
OFU
period the systolic blood pressure (
SBP
) increased to mean values of 135 mm Hg in both groups. Patients who had developed microalbuminuria during
ROADMAP
had a higher incidence of cardio‐ and cerebrovascular events (
OR
1.77,
CI
1.03 to 3.03,
P
=0.039) during the
OFU
period compared with patients in whom this was not the case. Diabetic retinopathy was significantly reduced in the former
OM
group (8 [0.9%] versus 23 [2.6%],
OR
: 0.34,
CI
0.15 to 0.78,
P
=0.011) and the rate of microalbuminuria was numerically reduced. Congestive heart failure requiring hospitalization (3 [0.3%] versus 12 [1.4%],
OR
: 0.23,
CI
0.06 to 0.85,
P
=0.027) was reduced and there was a trend of reduced cardio‐/cerebrovascular events (
OM
versus Pb: 73 [8.3%] versus 86 [9.8%] patients). Seven (0.8%) deaths (including 2
CV
events) were reported in former placebo patients versus 3 (0.3%) (non‐
CV
events) in former
OM
patients.

Conclusions

Development of microalbuminuria is a valid marker for future
CV
events.
RAS
blockade with Olmesartan might cause sustained reduction (legacy effect) of micro‐ and macrovascular events.
Door‐to‐Puncture: A Practical Metric for Capturing and Enhancing System Processes Associated With Endovascular Stroke Care, Preliminary Results From the Rapid Reperfusion Registry
Authors: Sun Chung‐Huan J. , Ribo Marc , Goyal Mayank , Yoo Albert J. , Jovin Tudor , Cronin Carolyn A. , Zaidat Osama , Nogueira Raul , Nguyen Thanh , Hussain M. Shazam , Menon Bijoy K. , Mehta Brijesh , Jindal Gaurav , Horev Anat , Norbash Alexander , Leslie‐Mazwi Thabele , Wisco Dolora , Gupta Rishi
Published: April 2014

Background

In 2011, the Brain Attack Coalition proposed door‐to‐treatment times of 2 hours as a benchmark for patients undergoing intra‐arterial therapy (
IAT
). We designed the Rapid Reperfusion Registry to capture the percentage of stroke patients who meet the target and its impact on outcomes.

Methods and Results

This is a retrospective analysis of anterior circulation patients treated with
IAT
within 9 hours of symptom onset. Data was collected from December 31, 2011 to December 31, 2012 at 2 centers and from July 1, 2012 to December 31, 2012 at 7 centers. Short “Door‐to‐Puncture” (D2P) time was hypothesized to be associated with good patient outcomes. A total of 478 patients with a mean age of 68±14 years and median National Institutes of Health Stroke Scale (NIHSS) of 18 (
IQR
14 to 21) were analyzed. The median times for
IAT
delivery were 234 minutes (
IQR
163 to 304) for “last known normal‐to‐groin puncture” time (
LKN
‐to‐
GP
) and 112 minutes (
IQR
68 to 176) for D2P time. The overall good outcome rate was 39.7% for the entire cohort. In a multivariable model adjusting for age,
NIHSS
, hypertension, diabetes, reperfusion status, and symptomatic hemorrhage, both short
LKN
‐to‐
GP
(
OR
0.996; 95%
CI
[0.993 to 0.998];
P
<0.001) and short D2P times (
OR
0.993, 95%
CI
[0.990 to 0.996];
P
<0.001) were associated with good outcomes. Only 52% of all patients in the registry achieved the targeted D2P time of 2 hours.

Conclusions

The time interval of D2P presents a clinically relevant time frame by which system processes can be targeted to streamline the delivery of
IAT
care nationally. At present, there is much opportunity to enhance outcomes through reducing D2P.
Evaluation of Carotid Angioplasty and Stenting for Radiation-Induced Carotid Stenosis
Authors: Yu Simon C.H. , Zou Winnie X.Y. , Soo Yannie O.Y. , Wang Lily , Hui Joyce Wai Yi , Chan Anne Y.Y. , Lee Kwok Tung , Ip Vincent H.L. , Fan Florence S.Y. , Chan Annie L.C. , Wong Lawrence K.S. , Leung Thomas W.
Published: April 2014

Background and Purpose—

We aimed to evaluate the procedural safety, clinical, and angiographic outcome of carotid angioplasty and stenting for high-grade (≥70%) radiation-induced carotid stenosis (RIS) using atherosclerotic stenosis (AS) as a control.

Methods—

In this 6-year prospective nonrandomized study, we compared the carotid angioplasty and stenting outcome of 65 consecutive patients (84 vessels) with RIS with that of a control group of 129 consecutive patients (150 vessels) with AS. Study end points were 30-day periprocedural stroke or death, ipsilateral ischemic stroke, technical success, procedural characteristics, instent restenosis (ISR; ≥50%) and symptomatic ISR.

Results—

The median follow-up was 47.3 months (95% confidence interval, 26.9–61.6). Imaging assessment was available in 74 vessels (RIS) and 120 vessels (AS) in 2 years. Comparing RIS group with AS group, the rates of periprocedural stroke or death were 1.5% (1/65) versus 1.6% (2/129;
P
=1); ipsilateral ischemic stroke rates were 4.6% (3/65) versus 4.7% (6/129;
P
=1); the annual risks of ipsilateral ischemic stroke were 1.2% (3 patient/254.7 patient year) versus 1.2% (6 patient/494.2 patient year;
P
=0.89); technical success rates were both 100%. Stenting of common carotid artery and the use of multiple stents was more common in the RIS group (
P
=0 in both cases); ISR rates were 25.7% (19/74) versus 4.2% (5/120;
P
<0.001); symptomatic ISR rates were 6.8% (5/74) versus 0.8% (1/120;
P
=0.031).

Conclusions—

The safety, effectiveness, and technical difficulty of carotid angioplasty and stenting for RIS are comparable with that for AS although it is associated with a higher rate of ISR.

Clinical Trial Registration—

This trial was not registered as enrollment started in 2006.
Clinical Investigation of the Protective Effects of Palm Vitamin E Tocotrienols on Brain White Matter
Authors: Gopalan Yogheswaran , Shuaib Ibrahim Lutfi , Magosso Enrico , Ansari Mukhtar Alam , Abu Bakar Mohd Rizal , Wong Jia Woei , Khan Nurzalina Abdul Karim , Liong Wei Chuen , Sundram Kalyana , Ng Bee Hong , Karuthan Chinna , Yuen Kah Hay
Published: April 2014

Background and Purpose—

Previous cell-based and animal studies showed mixed tocotrienols are neuroprotective, but the effect is yet to be proven in humans. Thus, the present study aimed to evaluate the protective activity of mixed tocotrienols in humans with white matter lesions (WMLs). WMLs are regarded as manifestations of cerebral small vessel disease, reflecting varying degrees of neurodegeneration and tissue damage with potential as a surrogate end point in clinical trials.

Methods—

A total of 121 volunteers aged ≥35 years with cardiovascular risk factors and MRI-confirmed WMLs were randomized to receive 200 mg mixed tocotrienols or placebo twice a day for 2 years. The WML volumes were measured from MRI images taken at baseline, 1 year, and 2 years using a validated software and were compared. Fasting blood samples were collected for full blood chemistry investigation.

Results—

According to per-protocol (88 volunteers) and intention-to-treat (121 volunteers) analyses, the mean WML volume of the placebo group increased after 2 years, whereas that of the tocotrienol-supplemented group remained essentially unchanged. The mean WML volume change between the 2 groups was not significantly different (
P
=0.150) at the end of 1 year but was significant at the end of 2 years for both per-protocol and intention-to-treat analyses (
P
=0.019 and
P
=0.018). No significant difference was observed in the blood chemistry parameters between the 2 groups.

Conclusions—

Mixed tocotrienols were found to attenuate the progression of WMLs.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00753532.
A new lizard of the Phymaturus genus (Squamata: Liolaemidae) from Sierra Grande, northeastern Patagonia, Argentina
Authors: Avila Luciano Javier , PÉREZ CRISTIAN hERNÁN FULVIO , MINOLI IGNACIO , Morando Mariana
Published: April 2014

A new species of lizard of the saxicolous and viviparous genus Phymaturus from Patagonia is described. The new species is a member of the Phymaturus patagonicus species group distributed on volcanic plateaus, mountains or rocky outcrops of southern Argentina. Phymaturus yachanana sp. nov. differs from the other members of the patagonicus group by a dorsal pattern of small and medium-sized white spots on a brown background, the number of scales around the midbody, genetic differences in mitochondrial and nuclear markers, and allopatric geographic distribution in an isolated group of hills. As other species of the group, the new species is viviparous and herbivorous.
Two new species of Seira Lubbock (Collembola, Entomobryidae, Seirini) from South Brazil
Authors: CIPOLA NIKOLAS GIOIA , DE MORAIS JOSÉ WELLINGTON , BELLINI BRUNO CAVALCANTE
Published: April 2014

Two new species of Seira, Seira tinguira sp. nov. and Seira paulae sp. nov. from Atlantic Rainforest Phytogeographic Domain in Paraná State, southern Brazil, are described and illustrated, with dorsal chaetotaxy labeled in detail. The general morphology of S. tinguira sp. nov. resembles S. frater (Bonet) and S. oceanica Yosii, however differs by chaeta Pa4 present in head, three extra macrochaetae (m1i2, p1i2 and one extranumerary) in mesothorax; four (a3, p2e, p2ea and a4) in metathorax; one (m3ep) in the second abdominal segment , among other morphological features. Seira paulae sp. nov. is similar to S. atrolutea (Arlé) in body colour, however dorsal chaetoxy resembles S. mendoncea Bellini & Zeppelini and S. ritae Bellini & Zeppelini. On the other hand, the new species clearly differs from other similar taxa by the presence of cephalic macrochaeta M2; three macrochaetae (M2, M1 and M2i) in mesothorax and p2p as microchaeta; one extra macrochaeta (p1i) in metathorax and two (a1 and p2ea) as macro or microchaetae; macrochaeta m3ep missing in the second abdominal segment; macrochaeta am6 present in the third abdominal segment among other features. Seira tinguira sp. nov. was found in different habitats of Paraná State while S. paulae sp. nov. was recorded only in its type locality. A distribution map is provided for both species. With the presented description there are now four recorded species of Seira from south Brazil.
Evaluation of WRF Parameterizations for Dynamical Downscaling in the Canary Islands
Authors: Pérez J. C. , Díaz J. P. , González A. , Expósito J. , Rivera-López F. , Taima D.
Published: April 2014

The ability of the Weather Research and Forecasting (WRF) Model simulations to perform climate regionalization studies in an orographically complex region, the Canary Islands, is analyzed. Six different 5-yr simulations were carried out to investigate the sensitivity to several parameterization schemes and to uncertainties in sea surface temperature (SST). The simulated maximum and minimum temperatures, together with the daily rainfall, were compared with observational data. To take into account the climatic differences in this archipelago, observational sites were grouped using a geographical regionalization based on principal component analysis and a clustering technique to group the stations according to their climatic characteristics. The analysis showed that both the microphysics and the boundary layer schemes have a large impact on the simulated precipitation. However, the largest differences were observed when the cumulus parameterization, in the coarser domains, was changed. An analysis of the vertical profiles of the simulated hydrometeors was performed to study the differences revealed by the different simulations. Although the cumulus scheme was not applied in the innermost domain, the total amount of water available in the atmospheric column is modified. Moreover, an average increase of 0.7°C in SST, estimated from phase 5 of the Coupled Model Intercomparison Project (CMIP5) variability, produces changes of the same order as those those obtained with different parameterizations. Temperatures are similarly simulated by the different configurations, except for the case in which an SST increment was introduced. Two configurations (CTRL and LSM-PX) were able to correctly reproduce the studied variables in the Canary Islands, improving the Interim ECMWF Re-Analysis (ERA-Interim) data and showing their abilities for regional-scale climate studies in this archipelago.
Combining Datasets of Satellite-Retrieved Products. Part I: Methodology and Water Budget Closure
Authors: Aires Filipe
Published: April 2014

This study addresses in general terms the problem of the optimal combination of multiple observation datasets. Only satellite-retrieved geophysical parameter datasets are considered here (not the raw satellite observations). This study focuses on the terrestrial water cycle and presents methodologies to obtain a coherent dataset of four water cycle key components: precipitation, evapotranspiration, runoff, and terrestrial water storage. Various innovative “integration” methodologies are introduced: simple weighting (SW), constrained linear (CL), optimal interpolation (OI), and neural networks (NN). The term “integration” will be used here, not “assimilation,” as no model will be included in the data fusion process. A simple postprocessing filtering (PF) step can be used to impose the water cycle budget closure after the integration method. It is shown that this constraint actually improves the estimation of the water cycle components. The integration techniques are tested using real observation data over the Mississippi and Niger basins from satellite and in situ measurements. A Monte Carlo experiment with a synthetic uncertainty perturbation model is used to measure the ability of the SW, OI, and NN, with or without the PF step, to retrieve the four water cycle components. Once the PF closure constraint is added, the methodologies have equivalent accuracies. The need for these types of methodologies should increase in the future since multiple observation datasets are now available and the climate community needs to combine them into a unique, optimal, and coherent dataset of multiple parameters. A companion paper will test these methodologies on satellite observation datasets at the basin and global scales.
Using Reanalysis and Remotely Sensed Temperature and Precipitation Data for Hydrological Modeling in Monsoon Climate: Mekong River Case Study
Authors: Lauri H. , Räsänen T. A. , Kummu M.
Published: April 2014

Many large basins in the “Monsoon Asia” region have sparse surface observation networks of the hydrometeorological parameters needed for hydrological modeling. These models are often used in water resources–related planning, impact assessments, and flood forecasting, which sets strict requirements for model accuracy and reliability. The aim of this study was to assess the performance of several publicly available reanalyses and remotely sensed datasets when used in modeling of discharges in the Mekong River basin. Tested precipitations were extracted from Tropical Rainfall Measuring Mission (TRMM) 3B42, versions 6 and 7; Asian Precipitation–Highly-Resolved Observational Data Integration Towards Evaluation of Water Resources (APHRODITE); Climate Forecast System Reanalysis (CFSR); and Interim ECMWF Re-Analysis (ERA-Interim) datasets. Temperature data were extracted from CFSR and ERA-Interim datasets. The model results obtained using these datasets were compared to measured discharges and modeled values based on daily surface observations. It was found that using TRMM, version 7, and APHRODITE precipitation datasets together with CFSR temperature data resulted in similar accuracy of computed discharges in the Mekong main stem as using surface observation data. This indicates that these gridded datasets might support well the modeling efforts in monsoon-driven large river basins in Monsoon Asia.
Multiple Equilibria and Hysteresis of Two Unequal-Transport Western Boundary Currents Colliding at a Gap
Authors: Wang Zheng , Yuan Dongliang
Published: April 2014

The nonlinear collision of two western boundary currents (WBCs) of Munk thickness LM colliding near a gap of width 2a is studied using a 1.5-layer, reduced-gravity, quasigeostrophic ocean model. The work is a continuation of our recent study on nonlinear collision of two equal-strength WBCs at a wide gap. It is found that, for narrow gaps, a < 5.7LM, and both of the WBCs fail to penetrate into the western basin due to the restriction of friction; for intermediate size gaps, 5.7LM ≤ a < 9.6LM, and multiple equilibrium states exist for the colliding WBCs: the penetrating state, the choking state, and the eddy-shedding state. The current system transits between them through a hysteresis procedure, with transitions at different Reynolds numbers from those in the equal-transport case. The stronger WBC tends to intrude more deeply into the western basin than the weaker WBC; for wide gaps, a > 9.6LM, and only penetrating and eddy-shedding states exist. No choking state is identified for either WBC. It is found that the critical gap width for the disappearance of the choking state decreases with the asymmetry of the WBC system. The theory is used to explain some of the circulation features at the entrance of the Indonesian Throughflow in the western Pacific Ocean recently observed with satellite-tracked surface drifters.
3D Turbulence Measurements Using Three Synchronous Wind Lidars: Validation against Sonic Anemometry
Authors: Fuertes Fernando Carbajo , Iungo Giacomo Valerio , Porté-Agel Fernando
Published: April 2014

This paper presents a technique to measure the time series of the three components of the wind vector at a point in space from synchronous measurements of three scanning Doppler wind lidars. Knowing the position of each lidar on the ground and the orientation of each laser beam allows for reconstructing the three components of the wind velocity vector. The laser beams must intersect at the desired point in space and their directions must be noncoplanar, so that trigonometric relationships allow the reconstruction of the velocity vector in any coordinate system.

This technique has been tested during a measurement campaign carried out at Cabauw’s Experimental Site for Atmospheric Research (CESAR) in the Netherlands and compared against measurements from sonic anemometers installed in a meteorological mast. The spatial resolutions of both measurement techniques differ by one order of magnitude. Therefore, in order to properly compare the results, a pseudospatial filter that mimics the attenuation induced by the lidar technology at small scales of turbulence has been applied to the velocity time series provided by the sonic anemometer.

Good agreement between both measurement systems is found in terms of the measured instantaneous velocity vector, turbulence statistics, Reynolds stresses, and the spectra of the three components of the velocity and the turbulent kinetic energy. These results provide a successful validation of the proposed technique.
Origin and Maintenance of the Long-Lasting, Outer Mesoscale Convective System in Typhoon Fengshen (2008)
Authors: Chen Buo-Fu , Elsberry Russell L. , Lee Cheng-Shang
Published: April 2014

Outer mesoscale convective systems (OMCSs) are long-lasting, heavy rainfall events separate from the inner-core rainfall that have previously been shown to occur in 22% of western North Pacific tropical cyclones (TCs). Environmental conditions accompanying the development of 62 OMCSs are contrasted with the conditions in TCs that do not include an OMCS. The development, kinematic structure, and maintenance mechanisms of an OMCS that occurred to the southwest of Typhoon Fengshen (2008) are studied with Weather Research and Forecasting Model simulations. Quick Scatterometer (QuikSCAT) observations and the simulations indicate the low-level TC circulation was deflected around the Luzon terrain and caused an elongated, north–south moisture band to be displaced to the west such that the OMCS develops in the outer region of Fengshen rather than spiraling into the center. Strong northeasterly vertical wind shear contributed to frictional convergence in the boundary layer, and then the large moisture flux convergence in this moisture band led to the downstream development of the OMCS when the band interacted with the monsoon flow. As the OMCS developed in the region of low-level monsoon westerlies and midlevel northerlies associated with the outer circulation of Fengshen, the characteristic structure of a rear-fed inflow with a leading stratiform rain area in the cross-line direction (toward the south) was established. A cold pool (Δθ < −3 K) associated with the large stratiform precipitation region led to continuous formation of new cells at the leading edge of the cold pool, which contributed to the long duration of the OMCS.
How Do Laypeople Evaluate the Degree of Certainty in a Weather Report? A Case Study of the Use of the Web Service yr.no
Authors: Sivle Anders D. , Kolstø Stein Dankert , Kirkeby Hansen Pål J. , Kristiansen Jørn
Published: April 2014

Many people depend on and use weather forecasts to plan their schedules. In so doing, ordinary people with no expertise in meteorology are frequently called upon to interpret uncertainty with respect to weather forecasts. With this in mind, this study addresses two main questions: 1) How do laypeople interpret online weather reports with respect to their degree of certainty and how is previous knowledge drawn upon in this interpretation? and 2) How do laypeople integrate information in weather reports to determine their degree of certainty? This qualitative study is based on semistructured interviews with 21 Norwegians. The results show the following: (a) only a portion of uncertainty information was used, (b) symbols were sometimes ascribed different meanings than intended, and (c) interpretations were affected by local experiences with wind direction and forecast quality. The informants’ prior knowledge was found to prevail in the event of a conflict with forecast information, and an expected range of uncertainty was often inferred into single-valued forecasts. Additionally, (d) interpretations were affected by the integration of information used to predict the time and location of precipitation. Informants typically interpreted the degree of certainty differently (more or less uncertain) than was intended. Clearer presentation of uncertainty information, a clear intent of all nuances in information, a thorough use of multimodal information, and consideration of users’ needs can help improve communication of forecast uncertainty. The diversity of user approaches makes forecast uncertainty more difficult to communicate and provides possible explanations for why communicating uncertainty is challenging.
A review on the flow structure and pollutant dispersion in urban street canyons for urban planning strategies
Authors: Yazid Afiq Witri Muhammad , Sidik Nor Azwadi Che , Salim Salim Mohamed , Saqr Khalid M
Published: April 2014

As a result of rapid urbanization in numerous cities around the world, the demand for transportation has increased rapidly, resulting in emission of high levels of exhaust pollutants into the atmosphere. This is a major cause of deterioration in the local air quality, with consequent escalating risk of adverse health conditions amongst urban inhabitants. Understanding dispersion of pollutants in street canyons, local urban configurations, meteorological processes, and other physical factors are essential for predicting and assessing air quality. This article presents a comprehensive review of the state-of-the-art research works relevant to the investigation of flow structures and pollutant dispersion phenomena in urban street canyons. Various factors, including building geometries, local atmospheric conditions, static and dynamic obstructions, as well as chemical reactions of exhaust pollutants, are critically discussed by taking into account field measurements, wind tunnel experiments, operational modeling techniques, and computational fluid dynamics (CFD). The most critical pollutant levels in street canyons under several physical circumstances are identified. Elements leading to discrepancies and resulting in inconsistencies of different research methods are briefly addressed and suggestions for future research are offered.
Ruptured ectopic pregnancy: the long and tortuous journey to the theatre
Authors: Ugboma Henry AA , Oputa Victory OA , Ugboma EW
Published: April 2014

Ectopic pregnancy is a common gynaecological emergency in Nigeria, West Africa. Here we present a case that brings to light some of the problems facing the health sector in reducing the high maternal mortality rate.
Putting the Freeze on Priming
Authors: Jia Lile , Hirt Edward R. , Evans Douglas N.
Published: April 2014

Past research has indicated that individuals with a high need for cognitive closure (NFCC) are more susceptible to priming effects in norm-absent contexts. We proposed that in norm-present contexts, whereby normative information competes with priming in affecting individuals’ understanding of the social environment, the opposite pattern would occur. In Study 1, low- rather than high-NFCC individuals showed greater prime-consistent behavior in a context with a strong norm to comply. In Study 2, when both priming and normative information were manipulated, priming dictated low-NFCC individuals’ behaviors, whereas norms guided high-NFCC individuals’ behavior. In Study 3, the effect of a single priming manipulation was observed in two consecutive contexts. While high-NFCC individuals, compared with low-NFCC ones, were less prime-consistent in the norm-present context, they were more influenced by the same priming manipulation in the norm-absent context. Our findings underscore the importance of NFCC in people’s selection of environmental cues to guide self-regulation.