bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic c-Myc Quadruplex DNA Selectively Kills Leukemia
Authors: Sedoris Kara C. , Thomas Shelia D. , Clarkson Cortney R. , Muench David , Islam Ashraful , Singh Rajesh , Miller Donald M.
Published: November 2011

c-Myc, a key regulator of cell cycle and proliferation, is commonly overexpressed in leukemia and associated with poor prognosis. Conventional antisense oligonucleotides targeting c-myc may attenuate leukemic cell growth, however, are poorly taken into cells, rapidly degraded, and have unwanted effects on normal cells. The c-myc promoter contains a guanine-rich sequence (PU27) capable of forming quadruplex (four-stranded) DNA, which may negatively regulate c-myc transcription. However, its biological significance is unknown. We show that treatment of leukemia with an oligonucleotide encoding the genomic PU27 sequence induces cell-cycle arrest and death by oncotic necrosis due to PU27-mediated suppression of c-myc mRNA/protein expression. Furthermore, PU27 is abundantly taken into cells, localized in the cytoplasm/nucleus, inherently stable in serum and intracellularly, and has no effect on normal cells. Suppression of c-myc expression by PU27 caused significant DNA damage, cell and mitochondrial swelling, and membrane permeability characteristic of oncotic necrosis. Induction of oncosis caused mitochondrial dysfunction, depletion of cellular ATP levels, and enhanced oxidative stress. This novel antileukemic strategy addresses current concerns of oligonucleotide therapeutics including problems with uptake, stability, and unintentional effects on normal cells and is the first report of selective cancer cell killing by a genomic DNA sequence. Mol Cancer Ther; 11(1); 66–76. ©2011 AACR.
MK1775, a Selective Wee1 Inhibitor, Shows Single-Agent Antitumor Activity against Sarcoma Cells
Authors: Kreahling Jenny M. , Gemmer Jennifer Y. , Reed Damon , Letson Douglas , Bui Marilyn , Altiok Soner
Published: November 2011

Wee1 is a critical component of the G2–M cell-cycle checkpoint control and mediates cell-cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by a selective small molecule inhibitor MK1775 can abrogate G2–M checkpoint, resulting in premature mitotic entry and cell death. MK1775 has recently been tested in preclinical and clinical studies of human carcinoma to enhance the cytotoxic effect of DNA-damaging agents. However, its role in mesenchymal tumors, especially as a single agent, has not been explored. Here, we studied the cytotoxic effect of MK1775 in various sarcoma cell lines and patient-derived tumor explants ex vivo. Our data show that MK1775 treatment at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. In MK1775-treated cells, CDC2 activity was enhanced, as determined by decreased inhibitory phosphorylation of tyrosine-15 residue and increased expression of phosphorylated histone H3, a marker of mitotic entry. The cytotoxic effect of Wee1 inhibition on sarcoma cells seems to be independent of p53 status as all sarcoma cell lines with different p53 mutation were highly sensitive to MK1775 treatment. Finally, in patient-derived sarcoma samples, we showed that MK1775 as a single agent causes significant apoptotic cell death, suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas. Mol Cancer Ther; 11(1); 174–82. ©2011 AACR.
Targeted Mutations in the ATR Pathway Define Agent-Specific Requirements for Cancer Cell Growth and Survival
Authors: Wilsker Deborah , Chung Jon H. , Pradilla Ivan , Petermann Eva , Helleday Thomas , Bunz Fred
Published: November 2011

Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase–specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents. Mol Cancer Ther; 11(1); 98–107. ©2011 AACR.
Effective Targeting of Hedgehog Signaling in a Medulloblastoma Model with PF-5274857, a Potent and Selective Smoothened Antagonist That Penetrates the Blood–Brain Barrier
Authors: Rohner Allison , Spilker Mary E. , Lam Justine L. , Pascual Bernadette , Bartkowski Darian , Li Qing John , Yang Amy H. , Stevens Greg , Xu Meirong , Wells Peter A. , Planken Simon , Nair Sajiv , Sun Shaoxian
Published: November 2011

Inhibition of the Smoothened (Smo) represents a promising therapeutic strategy for treating malignant tumors that are dependent on the Hedgehog (Hh) signaling pathway. PF-5274857 is a novel Smo antagonist that specifically binds to Smo with a Ki of 4.6 ± 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC50 of 2.7 ± 1.4 nmol/L in cells. This Smo antagonist showed robust antitumor activity in a mouse model of medulloblastoma with an in vivo IC50 of 8.9 ± 2.6 nmol/L. The downregulation of Gli1 is closely linked to the tumor growth inhibition in patched+/− medulloblastoma mice. Mathematical analysis of the relationship between the drug's pharmacokinetics and Gli1 pharmacodynamics in patched+/− medulloblastoma tumor models yielded similar tumor and skin Gli1 IC50 values, suggesting that skin can be used as a surrogate tissue for the measurement of tumor Gli1 levels. In addition, PF-5274857 was found to effectively penetrate the blood–brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. The brain permeability of PF-5274857 was also confirmed and quantified in nontumor-bearing preclinical species with an intact blood–brain barrier. PF-5274857 was orally available and metabolically stable in vivo. These findings suggest that PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway. Mol Cancer Ther; 11(1); 57–65. ©2011 AACR.
Vascular Disruption in Combination with mTOR Inhibition in Renal Cell Carcinoma
Authors: Ellis Leigh , Shah Preeti , Hammers Hans , Lehet Kristin , Sotomayor Paula , Azabdaftari Gissou , Seshadri Mukund , Pili Roberto
Published: November 2011

Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, there has been an increased interest in the use of antiangiogenic agents for the management of RCC in patients. However, the activity of tumor-vascular disrupting agents (tumor-VDA) has not been extensively examined against RCC. In this study, we investigated the therapeutic efficacy of the tumor-VDA ASA404 (DMXAA, 5,6-dimethylxanthenone-4-acetic acid, or vadimezan) in combination with the mTOR inhibitor everolimus (RAD001) against RCC. In vitro studies were carried out using human umbilical vein endothelial cells and in vivo studies using orthotopic RENCA tumors and immunohistochemical patient tumor-derived RCC xenografts. MRI was used to characterize the vascular response of orthotopic RENCA xenografts to combination treatment. Therapeutic efficacy was determined by tumor growth measurements and histopathologic evaluation. ASA404/everolimus combination resulted in enhanced inhibition of endothelial cell sprouting in the 3-dimensional spheroid assay. MRI of orthotopic RENCA xenografts revealed an early increase in permeability 4 hours posttreatment with ASA404, but not with everolimus. Twenty-four hours after treatment, a significant reduction in blood volume was observed with combination treatment. Correlative CD31/NG2 staining of tumor sections confirmed marked vascular damage following combination therapy. Histologic sections showed extensive necrosis and a reduction in the viable rim following combination treatment compared with VDA treatment alone. These results show the potential of combining tumor-VDAs with mTOR inhibitors in RCC. Further investigation into this novel combination strategy is warranted. Mol Cancer Ther; 11(2); 383–92. ©2011 AACR.
Aspirin in the Chemoprevention of Colorectal Neoplasia: An Overview
Authors: Chan Andrew T. , Arber Nadir , Burn John , Chia Whay Kuang , Elwood Peter , Hull Mark A. , Logan Richard F. , Rothwell Peter M. , Schrör Karsten , Baron John A.
Published: November 2011

Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrial follow-up of nearly 14,000 patients from four randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about five years was associated with a 34% reduction in 20-year CRC mortality. A separate metaanalysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in four randomized adenoma prevention trials showed that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least two years, there was a 50% or more reduction in the risk of CRC commencing five years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation. Cancer Prev Res; 5(2); 164–78. ©2011 AACR.
Frequent and Widespread Vascular Abnormalities in Human Signal Transducer and Activator of Transcription 3 Deficiency
Authors: Chandesris Marie-Olivia , Azarine Arshid , Ong Kim-Thanh , Taleb Soraya , Boutouyrie Pierre , Mousseaux Elie , Romain Mélissa , Bozec Erwan , Laurent Stéphane , Boddaert Nathalie , Thumerelle Caroline , Tillie-Leblond Isabelle , Hoarau Cyrille , Lebranchu Yvon , Aladjidi Nathalie , Tron François , Barlogis Vincent , Body Gérard , Munzer Marine , Jaussaud Roland , Suarez Felipe , Clément Olivier , Hermine Olivier , Tedgui Alain , Lortholary Olivier , Picard Capucine , Mallat Ziad , Fischer Alain
Published: November 2011

Background—

Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described.

Methods and Results—

We prospectively screened 21 adult STAT3-deficient patients (median age, 26 years; range, 17–44 years) for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking–based imaging specifically for the carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models.

Conclusions—

Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.
Fetal Cells Traffic to Injured Maternal Myocardium and Undergo Cardiac Differentiation
Authors: Kara Rina J. , Bolli Paola , Karakikes Ioannis , Matsunaga Iwao , Tripodi Joseph , Tanweer Omar , Altman Perry , Shachter Neil S. , Nakano Austin , Najfeld Vesna , Chaudhry Hina W.
Published: November 2011

Rationale:

Fetal cells enter the maternal circulation during pregnancy and may persist in maternal tissue for decades as microchimeras.

Objective:

Based on clinical observations of peripartum cardiomyopathy patients and the high rate of recovery they experience from heart failure, our objective was to determine whether fetal cells can migrate to the maternal heart and differentiate to cardiac cells.

Methods and Results:

We report that fetal cells selectively home to injured maternal hearts and undergo differentiation into diverse cardiac lineages. Using enhanced green fluorescent protein (eGFP)-tagged fetuses, we demonstrate engraftment of multipotent fetal cells in injury zones of maternal hearts. In vivo, eGFP+ fetal cells form endothelial cells, smooth muscle cells, and cardiomyocytes. In vitro, fetal cells isolated from maternal hearts recapitulate these differentiation pathways, additionally forming vascular tubes and beating cardiomyocytes in a fusion-independent manner; ≈40% of fetal cells in the maternal heart express Caudal-related homeobox2 (Cdx2), previously associated with trophoblast stem cells, thought to solely form placenta.

Conclusions:

Fetal maternal stem cell transfer appears to be a critical mechanism in the maternal response to cardiac injury. Furthermore, we have identified Cdx2 cells as a novel cell type for potential use in cardiovascular regenerative therapy.
Pak1 as a Novel Therapeutic Target for Antihypertrophic Treatment in the Heart
Authors: Liu Wei , Zi Min , Naumann Ronald , Ulm Susanne , Jin Jiawei , Taglieri Domenico M. , Prehar Sukhpal , Gui Junhong , Tsui Hoyee , Xiao Rui-Ping , Neyses Ludwig , Solaro R. John , Ke Yunbo , Cartwright Elizabeth J. , Lei Ming , Wang Xin
Published: November 2011

Background—

Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy.

Methods and Results—

Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1
cko
). When subjected to 2 weeks of pressure overload, Pak1
cko
mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1
cko
mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1
cko
mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation.

Conclusions—

These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.
Predictive Value of the High-Sensitivity Troponin T Assay and the Simplified Pulmonary Embolism Severity Index in Hemodynamically Stable Patients With Acute Pulmonary Embolism
Authors: Lankeit Mareike , Jiménez David , Kostrubiec Maciej , Dellas Claudia , Hasenfuss Gerd , Pruszczyk Piotr , Konstantinides Stavros
Published: November 2011

Background—

The new, high-sensitivity troponin T (hsTnT) assay may improve risk stratification of normotensive patients with acute pulmonary embolism (PE). We externally validated the prognostic value of hsTnT, and of the simplified Pulmonary Embolism Severity Index (sPESI), in a large multicenter cohort.

Methods and Results—

We prospectively examined 526 normotensive patients with acute PE; of those, 31 (5.9%) had an adverse 30-day outcome. The predefined hsTnT cutoff value of 14 pg/mL was associated with a high prognostic sensitivity and negative predictive value, comparable to those of the sPESI. Both hsTnT ≥14 pg/mL (OR, 4.97 [95% CI, 1.71–14.43];
P
=0.003) and sPESI ≥1 point(s) (OR, 9.51 [2.24–40.29];
P
=0.002) emerged, besides renal insufficiency (OR, 2.97 [1.42–6.22];
P
=0.004), as predictors of early death or complications; in a multivariable model, they remained independent predictors of outcome (
P
=0.044 and 0.012, respectively). A total of 127 patients (24.1%) were identified as low risk by a sPESI of 0 and hsTnT <14 pg/mL; none of them had an adverse 30-day outcome. During 6-month follow-up, 52 patients (9.9%) died. Kaplan-Meier analysis illustrated that patients with hsTnT ≥14 pg/mL (
P
=0.001) and those with sPESI ≥1 (
P
<0.001) had a decreased probability of 6-month survival. Patients with sPESI of 0 and hsTnT <14 pg/mL at baseline had a 42% reduction in the risk of dying (hazard ratio, 0.58 [0.01–0.42];
P
=0.005).

Conclusions—

The hsTnT assay and the sPESI improve risk stratification of acute PE. Combination of both modalities may yield additive prognostic information and particularly identify possible candidates for out-of-hospital treatment.
Circulation
Editors' Picks
Authors:   The Editors
Published: November 2011

The following articles are being highlighted as part of
Circulation
's Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in
Circulation
and the
Circulation
subspecialty journals. The studies included in this article represent the most read manuscripts published on the topic of epidemiology and prevention in 2009 and 2010.
Efficacy and Safety of Celivarone, With Amiodarone as Calibrator, in Patients With an Implantable Cardioverter-Defibrillator for Prevention of Implantable Cardioverter-Defibrillator Interventions or Death
Authors: Kowey Peter R. , Crijns Harry J.G.M. , Aliot Etienne M. , Capucci Alessandro , Kulakowski Piotr , Radzik David , Roy Denis , Connolly Stuart J. , Hohnloser Stefan H.
Published: November 2011

Background—

Celivarone is a new antiarrhythmic agent developed for the treatment of ventricular arrhythmias. This study investigated the efficacy and safety of celivarone in preventing implantable cardioverter-defibrillator (ICD) interventions or death.

Methods and Results—

Celivarone (50, 100, or 300 mg/d) was assessed compared with placebo in this randomized, double-blind, placebo-controlled, parallel-group study. Amiodarone (200 mg/d after loading dose of 600 mg/d for 10 days) was used as a calibrator. A total of 486 patients with a left ventricular ejection fraction ≤40% and at least 1 ICD intervention for ventricular tachycardia or ventricular fibrillation in the previous month or ICD implantation in the previous month for documented ventricular tachycardia/ventricular fibrillation were randomized. Median treatment duration was 9 months. The primary efficacy end point was occurrence of ventricular tachycardia/ventricular fibrillation–triggered ICD interventions (shocks or antitachycardia pacing) or sudden death. The proportion of patients experiencing an appropriate ICD intervention or sudden death was 61.5% in the placebo group; 67.0%, 58.8%, and 54.9% in the celivarone 50-, 100-, and 300-mg groups, respectively; and 45.3% in the amiodarone group. Hazard ratios versus placebo for the primary end point ranged from 0.860 for celivarone 300 mg to 1.199 for celivarone 50 mg. None of the comparisons versus placebo were statistically significant. Celivarone had an acceptable safety profile.

Conclusions—

Celivarone was not effective for the prevention of ICD interventions or sudden death.

Clinical Trial Registration—

http://www.clinicaltrials.gov
. Unique identifier: NCT00993382.
Ambulatory Versus Home Versus Clinic Blood Pressure
Authors: Hara Azusa , Tanaka Kazushi , Ohkubo Takayoshi , Kondo Takeo , Kikuya Masahiro , Metoki Hirohito , Hashimoto Takanao , Satoh Michihiro , Inoue Ryusuke , Asayama Kei , Obara Taku , Hirose Takuo , Izumi Shin-Ichi , Satoh Hiroshi , Imai Yutaka
Published: November 2011

The usefulness of ambulatory, home, and casual/clinic blood pressure measurements to predict subclinical cerebrovascular diseases (silent cerebrovascular lesions and carotid atherosclerosis) was compared in a general population. Data on ambulatory, home, and casual/clinic blood pressures and brain MRI to detect silent cerebrovascular lesions were obtained in 1007 subjects aged ≥55 years in a general population of Ohasama, Japan. Of the 1007 subjects, 583 underwent evaluation of the extent of carotid atherosclerosis. Twenty-four–hour, daytime, and nighttime ambulatory and home blood pressure levels were closely associated with the risk of silent cerebrovascular lesions and carotid atherosclerosis (all
P
<0.05). When home and one of the ambulatory blood pressure values were simultaneously included in the same regression model, each of the ambulatory blood pressure values remained a significant predictor of silent cerebrovascular lesions, whereas home blood pressure lost its predictive value. Of the ambulatory blood pressure values, nighttime blood pressure was the strongest predictor of silent cerebrovascular lesions. The home blood pressure value was more closely associated with the risk of carotid atherosclerosis than any of the ambulatory blood pressure values when home and one of the ambulatory blood pressure values were simultaneously included in the same regression model. The casual/clinic blood pressure value had no significant association with the risk of subclinical cerebrovascular diseases. Although the clinical indications for ambulatory blood pressure monitoring and home blood pressure measurements may overlap, the clinical significance of each method for predicting target organ damage may differ for different target organs.
A New Presentation of the Chimeric CYP11B1/CYP11B2 Gene With Low Prevalence of Primary Aldosteronism and Atypical Gene Segregation Pattern
Authors: Carvajal Cristian A. , Campino Carmen , Martinez-Aguayo Alejandro , Tichauer Juan E. , Bancalari Rodrigo , Valdivia Carolina , Trejo Pamela , Aglony Marlene , Baudrand René , Lagos Carlos F. , Mellado Cecilia , Garcia Hernán , Fardella Carlos E.
Published: November 2011

Familial hyperaldosteronism type I is caused by an unequal crossover of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, giving rise to a chimeric CYP11B1/CYP11B2 gene (CG). We describe a family carrying a CG with high levels of free 18-hydroxycortisol but low prevalence of primary aldosteronism (PA) and an atypical CG inheritance pattern in a family of 4 generations with 16 adults and 13 children, we measured the arterial blood pressure, serum aldosterone, and plasma renin activity and then calculated the serum aldosterone:plasma renin activity ratio and urinary free 18-hydroxycortisol. We identified the CG by long-extension PCR and predicted its inheritance pattern. The CG was found in 24 of 29 subjects (10 children and 14 adults). In CG+ patients, hypertension and high 18-hydroxycortisol were prevalent (83% and 100%, respectively). High serum aldosterone:plasma renin activity ratio was more frequent in pediatric than adult patients (80% versus 36%;
P
<0.001). An inverse association between serum aldosterone:plasma renin activity ratio and age was observed (
r
=−0.48;
P
=0.018). Sequence analysis identified the CYP11B1/CYP11B2 crossover in a 50-bp region spanning intron 3 of CYP11B1 and exon 4 of CYP11B2. The CG segregation differs from an autosomal disease, showing 100% of CG penetrance in generations II and III. Statistical analysis suggests that inheritance pattern was not attributed to random segregation (
P
<0.001). In conclusion, we describe a family with an atypical CYP11B1/CYP11B2 gene inheritance pattern and variable phenotypic expression, where the majority of pediatric patients have primary aldosteronism. Most adults have normal aldosterone and renin levels, which could mask them as essential hypertensives.
Peroxisome Proliferator-Activated Receptor-γ Regulates Inflammation and Renin-Angiotensin System Activity in the Hypothalamic Paraventricular Nucleus and Ameliorates Peripheral Manifestations of Heart Failure
Authors: Yu Yang , Zhang Zhi-Hua , Wei Shun-Guang , Weiss Robert M. , Felder Robert B.
Published: November 2011

Activation of peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, has been shown to inhibit the production of proinflammatory cytokines and, in peripheral tissues, to downregulate the renin-angiotensin system. PPAR-γ is expressed in key brain areas involved in cardiovascular and autonomic regulation. We hypothesized that activation of central PPAR-γ would reduce sympathetic excitation and ameliorate peripheral manifestations of heart failure (HF) by inhibiting central inflammation and brain renin-angiotensin system activity. Two weeks after coronary artery ligation, HF rats received an intracerebroventricular infusion of the PPAR-γ agonist pioglitazone or vehicle for another 2 weeks. PPAR-γ expression in the paraventricular nucleus of hypothalamus, an important cardiovascular region, was unchanged in HF compared with sham-operated rats. However, PPAR-γ DNA binding activity was reduced, nuclear factor-κB activity was increased, and expression of proinflammatory cytokines and angiotensin II type-1 receptor was augmented in the HF rats. Mean blood pressure response to ganglionic blockade was greater; plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased; and maximal left ventricular dP/dt was decreased. All of these findings were ameliorated in HF rats treated with intracerebroventricular pioglitazone, which increased PPAR-γ expression and DNA binding activity in the paraventricular nucleus of hypothalamus. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after myocardial infarction can be modulated by activation of PPAR-γ in the brain. Central PPAR-γ may be a novel target for treatment of sympathetic excitation in myocardial infarction–induced HF.
Sympathoexcitation by Brain Oxidative Stress Mediates Arterial Pressure Elevation in Salt-Induced Chronic Kidney Disease
Authors: Fujita Megumi , Ando Katsuyuki , Kawarazaki Hiroo , Kawarasaki Chiaki , Muraoka Kazuhiko , Ohtsu Hiroshi , Shimizu Hideki , Fujita Toshiro
Published: November 2011

Hypertension is very prevalent in chronic kidney disease and critical for its prognosis. Sympathoexcitation and oxidative stress have been demonstrated to be involved in chronic kidney disease. We have shown previously that sympathoexcitation by brain oxidative stress mediates arterial pressure elevation in the salt-sensitive hypertension model, Dahl salt-sensitive rats. Thus, we investigated whether sympathoexcitation by excessive brain oxidative stress could contribute to arterial pressure elevation in salt-induced chronic kidney disease model rats. Young (3-week–old) male Sprague-Dawley rats were randomly assigned to a uninephrectomy or sham operation and then subjected to either a normal salt (0.5%) or high-salt (8.0%) diet for 4 weeks. The young salt-loaded uninephrectomized rats exhibited sympathoexcitation, hypertension, and renal injury, proteinuria and global glomerulosclerosis together with tubulointerstitial damage. Under urethane anesthesia and artificial ventilation, renal sympathetic nerve activity, arterial pressure, and heart rate decreased to a greater degree in the salt-loaded uninephrectomized rats than in the nonsalt-loaded uninephrectomized rats and the salt-loaded or nonsalt-loaded sham-operated rats, when Tempol, a membrane-permeable superoxide dismutase mimetic, was infused acutely into the lateral cerebral ventricle. Oxidative stress in the hypothalamus, measured by lucigenin chemiluminescence, was also significantly greater. Furthermore, in the salt-loaded uninephrectomized rats, antioxidant treatment with chronic intracerebroventricular Tempol decreased sympathetic nerve activity and arterial pressure, which, in turn, led to a decrease in renal damage. Similar effects were elicited by treatment with oral moxonidine, the central sympatholytic agent. In conclusion, sympathoexcitation by brain oxidative stress may mediate arterial pressure elevation in salt-induced chronic kidney disease.
Skill of 2-m Temperature Seasonal Forecasts over Europe in ECMWF and RegCM Models
Authors: Patarčić Mirta , Branković Čedo
Published: November 2011

Various measures of forecast quality are analyzed for 2-m temperature seasonal forecasts over Europe from global and regional model ensembles for winter and summer seasons during the period 1991 to 2001. The 50-km Regional Climate Model (RegCM3) is used to dynamically downscale nine-member ensembles of ECMWF global experimental seasonal forecasts. Three sets of RegCM3 experiments with different soil moisture initializations are performed: the RegCM3 default initial soil moisture, initial soil moisture taken from ECMWF seasonal forecasts, and initial soil moisture obtained from RegCM3 ECMWF interim Re-Analysis (ERA-Interim)-driven integrations (RegCM3 climatology). Both deterministic and probabilistic skill metrics are estimated.

The better-resolved spatial scales in near-surface temperature by RegCM3 do not necessarily lead to the improved regional model skill in the regions where systematic errors are large. The impact of initial soil moisture on RegCM3 forecast skill is seen in summer in the southern part of the integration domain. When regional model soil moisture was initialized from ECMWF seasonal forecasts, systematic errors were reduced and deterministic skill was enhanced relative to the other RegCM3 experiments. The Brier skill score for rare cold anomalies in this experiment is comparable to that of the global model, whereas in other experiments it is significantly smaller than in global model.

There is no major impact of soil moisture initialization on forecast skill in winter. However, some significant improvements in RegCM3 probabilistic skill scores for positive anomalies in winter are found in the central part of the domain where RegCM3 systematic errors are smaller than in global model.
Large-Scale Characteristics and Probability of Rapidly Intensifying Tropical Cyclones in the Western North Pacific Basin
Authors: Shu Shoujuan , Ming Jie , Chi Peng
Published: November 2011

The China Meteorological Administration (CMA) and the National Centers for Environmental Prediction (NCEP) reanalysis datasets are employed to examine the large-scale characteristics of rapidly intensifying western North Pacific tropical cyclones (TCs). The results show that of all 27 581 samples for the period 1970–2007, 85%, 65%, and 47% of all tropical depressions (TDs), tropical storms (TSs), and typhoons (TYs), respectively, intensify. Of the 1214 TCs, 18%, 70%, 30%, and 10% of all tropical cyclones, supertyphoons, severe typhoons, and typhoons, respectively, underwent rapid intensification (RI) at least once during their lifetime. Three kinds of cases—RI, slow change in intensity (SC), and rapid decay (RD)—during the period 1982–2007 are used to analyze the large-scale conditions associated with them. The comparison shows that the RI cases tend to occur farther south and east than the non-RI cases. In addition, the RI cases have a more westerly component of motion and intensify more during the preceding 12 h than do the non-RI cases. For the non-RI cases, the SC cases tend to have a lower initial intensity and a lower speed of motion than do the RD cases. Also, the RI cases are farther from their maximum potential intensity and develop in warmer water, lower vertical shear, and more easterly upper-tropospheric flow than do the non-RI cases. The probability of RI for TCs is estimated by using the rapid intensify index (RII) developed in this study for the western North Pacific basin. The verification based upon the cross validation shows that the RII is skillful relative to climatology.
Frame Adoption in Referendum Campaigns
Authors: Wettstein Martin
Published: November 2011

Answering the call for nonexperimental framing effects research, this article analyzes the effects of news frames on citizens’ political cognitions using data derived from a campaign on the naturalization of immigrants. A content analysis of TV and newspaper coverage was combined at the individual level with answers to open- and closed-ended panel survey questions. The results largely confirm prior experimental framing effects research. Media frames had a strong impact on their public salience. Prior to the campaign, however, audience members interpreted the issue in different ways. Individual media exposure was found to affect frame adoption for all respondents (and all frames investigated), irrespective of the initial attitudes of respondents and the frames’ origin. The implications of these findings for experimental and nonexperimental framing effects research are discussed.
Taking the pain out of waiting
Authors: Cashmore Aaron W , Noller Jennifer , Johnson Bronwyn , Ritchie Jan , Blinkhorn Anthony S
Published: November 2011

Objective: The Tooth Smart Programme is a hospital-based parent-counselling programme established to stabilize existing carious lesions and prevent new caries in children. The purpose of this qualitative study was to: explore participating parents’ experiences of and views about parent counselling; identify and describe factors that influence the uptake of oral health advice; and uncover any unanticipated outcomes of parent counselling.

Methods: A purposively selected group of parents were invited to participate in, face-to-face, semi-structured interviews. Interviews were audio-recorded and transcribed. Transcripts were analyzed by qualitative thematic analysis.

Results: Participants liked the programme sessions occurring in a hospital dental clinic. This approach was valued because it allowed a dental assessment to accompany the preventive advice. Most felt that they had been successful in increasing the frequency and quality of their child’s tooth-brushing. Some reported that increased brushing reduced their child’s dental pain. Conversely, most had found it hard to control their child’s snacking on sugary foods and drinks.

Conclusion: Future development of programmes should consider participants’ expressed need for parent counselling to be provided in patient-centred sessions.
Organizational commitment, organization-based self-esteem, emotional exhaustion and turnover: A conservation of resources perspective
Authors: Lapointe Émilie , Vandenberghe Christian , Panaccio Alexandra
Published: November 2011

We examined the relationship of four commitment dimensions (affective, normative, continuance-perceived sacrifices and continuance-lack of alternatives) to emotional exhaustion over time under the lens of conservation of resources theory. Using data from 260 employees, Time 1 lack of alternatives and normative commitment contributed positively to Time 2 emotional exhaustion, controlling for Time 1 emotional exhaustion. Organization-based self-esteem (OBSE) moderated the relationship of lack of alternatives commitment to emotional exhaustion such that the relationship was stronger when OBSE was high. We further theorized that the resource drain engendered by emotional exhaustion would cause the latter to be positively related to turnover, controlling for commitment dimensions. Results supported this prediction. The implications of these findings for future research on commitment, emotional exhaustion and turnover are discussed.
Does gender bias against female leaders persist? Quantitative and qualitative data from a large-scale survey
Authors: Elsesser Kim M , Lever Janet
Published: November 2011

The present study of 60,470 women and men examined evaluations of participants’ current managers as well as their preferences for male and female managers, in general. A cross-sex bias emerged in the ratings of one’s current boss, where men judged their female bosses more favorably and women judged male bosses more favorably. The quality of relationships between subordinates and managers were the same for competent male and female managers. A small majority (54%) of participants claimed to have no preference for the gender of their boss, but the remaining participants reported preferring male over female bosses by more than a 2:1 ratio. Qualitative analysis of the participants’ justifications for this preference are presented, and results are discussed within the framework of role congruity theory.
Entangled strands: A process perspective on the evolution of careers in the context of personal, family, work, and community life
Authors: Lee Mary Dean , Kossek Ellen Ernst , Hall Douglas T , Litrico Jean-Baptiste
Published: November 2011

The goal of this study is to develop a theoretical framework to illuminate the process of careers unfolding over time in an overall life context. We draw on data from a qualitative field study of the career paths of 81 professionals who pursued working on a reduced-load basis as a strategy for sustaining commitment to both their careers and family lives. Using multiple methods to analyze what happened between two interviews approximately six years apart, we identify five distinct career narratives and present a model of the evolution of careers. The model suggests that individuals construct careers over time through their own sensemaking of constantly shifting entangled strands of their personal, family, work, and community lives and three key dynamics that are ongoing: external events, gradual developments, and individual actions.
Multiparty Elections and Party Support in Tanzania
Authors: Babeiya Edwin
Published: November 2011

Multiparty elections in Tanzania have been characterized by the dominance of the ruling party and the erratic rise and fall of opposition parties. This trend has been largely influenced by, among others, such factors as institutionalization, age, personality sex, history and low level of civic competence. However, the results of the 2010 general elections suggest a new development that challenges the eminence of the aforementioned factors, which have for almost two decades favoured the ruling party. This new development is reflected in the 2010 elections that witnessed some of the areas that were an enclave of the incumbent party offering a relatively strong support to opposition parties, particularly Chama Cha Demokrasia na Maendeleo (CHADEMA). The 2010 general elections’ results prompt a need for an enquiry to establish whether or not this is the beginning of a new chapter in which both the ruling party and opposition parties stand an equal chance of winning the elections.
Freedom Hill Is Not for Sale—and Neither Is the Lower Ninth Ward
Authors: Phillips Brenda , Stukes Patricia Ann , Jenkins Pamela
Published: November 2011

In 1999, a series of flood and rain events inundated Princeville, North Carolina. This historic community, the first town in the United States founded by African Americans, chose to stay in place rather than to relocate. This article presents the relocation decision within the contexts of history, place attachment, and community connections. Interview, observation, and documentary data reveal themes that led to the decision to remain in place. A Discussion section ties the decision to place attachments and recommends that future research should move beyond the individual level of analysis. Recommendations for policy and practice are included. In particular, how residents are attached to their communities and the ways in which they negotiate the environment relative to that place must be linked to mitigation efforts such as relocation buyouts. Immediately after Hurricane Katrina in 2005, discourse surrounded areas in New Orleans regarding the future of a location similar in many ways to Princeville, particularly, the Lower Ninth Ward. The article concludes with an examination of that discourse and updates reconstruction progress in both Princeville and New Orleans.
Concentration or Diffusion? The Changing Geography of Ethnic Minority Pupils in English Secondary Schools, 1999–2009
Authors: Hamnett Chris
Published: November 2011

Britain has seen a significant increase in the size of its ethnic minority population over the past 20 years. Because of the relatively youthful age structure of the ethnic minority population, the percentage of ethnic minorities in the school age-groups is much higher than its share of the overall population. Given the very uneven geographical distribution of ethnic minorities, this has raised concerns over the extent of school ethnic segregation. This paper examines the changing distribution of ethnic minority secondary school pupils in England over the period 1999–2009. It shows that, while there have been big increases in the percentage of ethnic minorities in those local authorities with existing concentrations, with ethnic minorities comprising over 50 per cent of pupils in 24 urban authorities in 2009, the dominant trend has been one of an increase in the percentage of ethnic minority pupils across the board combined with the increasing diffusion of ethnic minorities across all local authorities, rather than increasing concentration in a small number of authorities.
‘Latino Gentrification’?: Focusing on Physical and Socioeconomic Patterns of Change in Latin American Inner Cities
Authors: Inzulza-Contardo Jorge
Published: November 2011

Although gentrification is an accepted process nowadays around the globe, little debate is found in the Latin American context—particularly, when considering that 70 per cent of this continent is urbanised and that major physical and socioeconomic changes have been observed in its historical neighbourhoods in the past 20 years. This paper focuses on the continuity and change that Santiago, Chile, has shown in recent decades. Empirical data are provided to reflect both the physical and socioeconomic patterns of change that have modified the urban morphology and the social capital of Santiago’s inner city. Furthermore, by selecting Bellavista—one of the oldest inner-city neighbourhoods of Santiago—this paper draws conclusions about how specific urban regeneration strategies can promote gentrification and then links them with wider patterns of ‘Latino gentrification’.
Semantic and Pragmatic Motivations for Constructional Preferences
Authors: De Clerck Bernard , Delorge Martine , Simon-Vandenbergen Anne-Marie
Published: November 2011

A select group of transfer verbs can enter into four different constructions: the ditransitive construction ( He provided John the money), the prepositional-dative construction ( He provided the money to John), a construction with a prepositional theme ( He provided John with the money), and a construction with a recipient realized by a for-phrase ( He provided the money for John). In this article, the authors take a close look at three such verbs: provide, supply, and present. Corpus analysis shows that these three verbs display different structural preferences with respect to the for-, to-, and with-patterns. To explain these preferences, the study investigates pragmatic principles (following Mukherjee on provide) and the role played by semantic factors. An examination of the semantics of the verbs and the lexically motivated constructional semantics of the to, for, and with-patterns shows (a) that the three constructions are not interchangeable and (b) that the preferential differences among the three verbs find an explanation in the compatibility between lexical and constructional semantics. The description is mainly based on data from the British National Corpus.
Gendering the Self
Authors: Knobloch-Westerwick Silvia , Hoplamazian Gregory J.
Published: November 2011

Based on gender schema theory, social role theory, and social-cognitive theory, this study investigated whether biological sex and gender conformity (femininity and masculinity) predict selective exposure to gender-typed magazines and whether this exposure, in turn, reinforces gender conformity. Participants browsed full issues—three women’s magazines, three associated with male readers, and three news magazines—while being taped. Before and after browsing, participants indicated their femininity and masculinity. Results show a strong impact of biological sex on selective magazine reading, resulting in gender-typed media use. However, gender conformity also influenced exposure. Moreover, mediation analyses showed that selective exposure to gender-typed magazines had a reinforcing effect on the gendered self-concept.
Forgiveness Results From Integrating Information About Relationship Value and Exploitation Risk
Authors: Burnette Jeni L. , McCullough Michael E. , Van Tongeren Daryl R. , Davis Don E.
Published: November 2011

Exploitation is a fact of life for social organisms, and natural selection gives rise to revenge mechanisms that are designed to deter such exploitations. However, humans may also possess cognitive forgiveness mechanisms designed to promote the restoration of valuable social relationships following exploitation. In the current article, the authors test the hypothesis that decisions about forgiveness result from a computational system that combines information about relationship value and exploitation risk to produce decisions about whom to forgive following interpersonal offenses. The authors examined the independent and interactive effects of relationship value and exploitation risk across two studies. In Study 1, controlling for other constructs related to forgiveness, the authors assessed relationship value and exploitation risk. In Study 2, participants experienced experimental manipulations of relationship value and exploitation risk. Across studies, using hypothetical and actual offenses and varied forgiveness measures, the combination of low exploitation risk and high relationship value predicted the greatest forgiveness.