bluuebunny/crossref_metadata_2025 huggingface dataset:
An LMI Approach to Stability for Linear Time‐Varying System with Nonlinear Perturbation on Time Scales
Authors: Mukdasai Kanit , Niamsup Piyapong
Published: July 2011

We consider Lyapunov stability theory of linear time‐varying system and derive sufficient conditions for uniform stability, uniform exponential stability, ψ‐uniform stability, and h‐stability for linear time‐varying system with nonlinear perturbation on time scales. We construct appropriate Lyapunov functions and derive several stability conditions. Numerical examples are presented to illustrate the effectiveness of the theoretical results.
Troublesome Tinnitus in Children: Epidemiology, Audiological Profile, and Preliminary Results of Treatment
Authors: Bartnik G. , Stępień A. , Raj-Koziak D. , Fabijańska A. , Niedziałek I. , Skarżyński H.
Published: July 2011

Introduction. Although tinnitus often has a significant impact on individual's life, there are still few reports relating to tinnitus in children. In our tinnitus clinic, children with distressing tinnitus constitute about 0,5% of all our patients.Objectives. The aim of this study was to analyse children with troublesome tinnitus as regards epidemiology, audiological profile, and preliminary effects of the therapy.Methods. A retrospective study was carried out involving the cases of 143 children consulted in our Tinnitus Clinic in 2009. The selected group with troublesome tinnitus was evaluated and classified for proper category of Tinnitus Retraining Therapy (TRT).Results. The study showed that 41.3% of the children suffered from bothersome tinnitus. In this group 44.1% of the patients demonstrated normal hearing. The success of the therapy after 6 months was estimated on 81.4% of significant improvement.Conclusions. It is recommended that a questionnaire include an inquiry about the presence of tinnitus during hearing screening tests.
Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells
Authors: Natoni Alessandro , Murillo Laura S. , Kliszczak Anna E. , Catherwood Mark A. , Montagnoli Alessia , Samali Afshin , O'Dwyer Michael , Santocanale Corrado
Published: July 2011

In chronic lymphocytic leukemia (CLL) the proliferation rate and resistance to drug-induced apoptosis are recognized as important factors in the outcome of treatment. In this study, we assess the activity and the mechanism of action of the prototype cell division cycle kinase 7 (Cdc7) inhibitor, PHA-767491, which inhibits the initiation of DNA replication but also has cyclin-dependent kinase 9 (Cdk9) inhibitory activity. We have studied the effects of this dual Cdc7/Cdk9 inhibitor in both quiescent CLL cells and CLL cells that have been induced to proliferate using a cellular coculture system that mimics the lymph node microenvironment. We find that this compound, originally developed as a DNA replication inhibitor, is particularly active in promoting mitochondrial dependent apoptosis in quiescent CLL cells purified from peripheral blood of patients regardless of recognized risk factors. In this setting, apoptosis is preceded by a decrease in the levels of Mcl-1 protein and transcript possibly due to inhibition of Cdk9. Following stimulation by CD154 and interleukin-4, CLL cells become highly chemoresistant, reenter into the cell cycle, reexpress Cdc7 kinase, a key molecular switch for the initiation of DNA replication, replicate their DNA, and undergo cell division. In this context, treatment with PHA-767491 abolished DNA synthesis by inhibiting Cdc7 but is less effective in triggering cell death, although Mcl-1 protein is no longer detectable. Thus, dual Cdc7/Cdk9 inhibition has the potential to target both the quiescent and actively proliferating CLL populations through two distinct mechanisms and may be a new therapeutic strategy in CLL. Mol Cancer Ther; 10(9); 1624–34. ©2011 AACR.
Hypoxia Induces Tumor Aggressiveness and the Expansion of CD133-Positive Cells in a Hypoxia-Inducible Factor-1α-Dependent Manner in Pancreatic Cancer Cells
Authors: Hashimoto Okito , Shimizu Kazuya , Semba Shuho , Chiba Sachie , Ku Yonson , Yokozaki Hiroshi , Hori Yuichi
Published: July 2011

Background: Intratumoral hypoxia is known to lead to increased aggressiveness and distant metastasis. However, the interplay underlying these actions is still unknown. Objective: We explored whether cancer cells might acquire a stem-like phenotype under hypoxia, consequently leading to an aggressive phenotype, including invasiveness and metastasis. Methods: Under normoxia (20% O2) or hypoxia (1% O2), the expression of CD133 (cancer stem cell marker), CXC chemokine receptor 4 (CXCR4) and hypoxia-inducible factor-1α (HIF-1α) was examined by RT-PCR and immunostaining using human pancreatic cancer cell lines. We also examined if hypoxia facilitates the invasiveness of CD133+ cancer cells. Furthermore, we transfected dominant active HIF-1α (HIF-1αΔODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo. Results: Compared with normoxia, hypoxia elevated the expression of CD133, CXCR4 and HIF-1α. Moreover, hypoxia facilitated the invasiveness of CD133+ pancreatic cancer cells. The behavior of HIF-1αΔODD-transfected cells under normoxia was compatible with that of the parent cells under hypoxia. Furthermore, a xenograft model of HIF-1αΔODD cells showed aggressiveness, including metastasis and highly tumorigenic ability. Conclusion: Hypoxia induces tumor aggressiveness associated with the expansion of CD133+ pancreatic cancer cells in a predominantly HIF-1α-dependent manner.
Disease-Free Survival of Colorectal Cancer Patients in Relation to CDw75 Antigen Expression
Authors: Villar-Portela Susana , Muinelo-Romay Laura , Cuevas Elisa , Gil-Martín Emilio , Fernández-Briera Almudena
Published: July 2011

Objective: CDw75 is an α(2,6)-sialylated antigen associated with a poor prognosis in gastric cancer. In the present study, we examined if CDw75 expression in colorectal cancer (CRC) predicts tumour recurrence.Besides, we evaluated CDw75 expression in different colorectal tissue specimens to clarify their role in tumour development and progression. Methods: We analyzed CDw75 expression in 34 specimens of healthy disease-free colorectal mucosa, 19 specimens of inflammatory colorectal mucosa, 73 colorectal adenomas, 35 specimens of healthy tissue and 101 specimens of tumoural tissue from CRC patients. Results: None of the healthy disease-free and inflammatory colorectal mucosa specimens showed the presence of the epitope. CDw75 was expressed in 26% of the colorectal adenomas. In healthy and tumoural tissue from CRC patients, CDw75 was detected in 22.9% and 82.2% of the specimens, respectively. CDw75 expression in tumoural tissue was correlated with growth pattern (p = 0.044), Dukes stage (p = 0.002), TNM stage (p = 0.020) and distant metastasis (p = 0.005). Survival analysis showed that CDw75 expression is not associated with tumour recurrence.Conclusion: CDw75 expression in CRC is not a prognostic factor for predicting disease-free survival. Nevertheless, CDw75 expression may be agood marker of tumour progressionand of the malignant potential of CRC.
High Prevalence of Multiple Human Papillomavirus Infection in Japanese Patients with Invasive Uterine Cervical Cancer
Authors: Watari Hidemichi , Michimata Rie , Yasuda Motoaki , Ishizu Akihiro , Tomaru Utano , Xiong Ying , Hassan Mohamed K. , Sakuragi Noriaki
Published: July 2011

Objective: Multiple human papillomavirus (HPV) infection of the uterine cervix has been suggested as a risk factor for persistent HPV infection, resulting in the development of invasive cervical cancer. The aim of this study was to reveal the actual state of multiple HPV infection in Japanese patients with invasive cervical cancer. Methods: Sixty fresh-frozen invasive cervical cancer tissues were examined for genotyping of HPV. The presence of HPV genotypes was determined with an HPV-DNA array, which can discriminate 25 different HPV genotypes with high sensitivity and specificity. Results: Among 60 samples, 59 (96.7%) were positive for HPV. The three common genotypes were HPV-16 (83.3%), HPV-18 (45.0%) and HPV-52 (28.3%). Multiple HPV infection was observed in 47 of 60 samples (78.3%), among which 42 were infected with more than one high-risk genotype (70.0%). Multiple high-risk HPV infection was significantly more prevalent in patients below 40 years old (14/15, 93.3%) than in patients 40 years of age and over (28/45, 62.2%). Conclusion: The HPV-DNA array is the preferred method to detect HPV genotypes. Multiple HPV infection in Japanese patients with invasive cervical cancer seemed to be more frequent than reported in the literature.
Frequent Upregulation of Cyclin D1 and p16INK4a Expression with Low Ki-67 Scores in Multinucleated Giant Cells
Authors: Choi Jung-Woo , Lee Ju-Han , Kim Young-Sik
Published: July 2011

Background/Aims: Multinucleated giant cells are formed from the fusion of macrophages and are classified into foreign body-type giant cells (FBGCs), osteoclast-type giant cells (OCGCs) and Langhans-type giant cells (LHGCs). OCGCs display upregulated cyclin D1 expression with low Ki-67 activity. However, little is known about the expression of cell cycle regulators in the other types of multinucleated giant cells. We aimed to investigate the cell cycle status of multinucleated giant cells. Methods: The immunohistochemical expressions of cyclin D1, p16INK4a and Ki-67 were analyzed in a total of 127 cases showing multinucleated giant cells. Results: Cyclin D1 was overexpressed in 45 (88%) of 51 FBGC cases, 25 (86%) of 29 OCGC cases and 22 (47%) of 47 LHGC cases. p16INK4a showed diffuse nuclear and/or cytoplasmic overexpression in 45 (88%) of 51 FBGC cases, 27 (93%) of 29 OCGC cases and 24 (51%) of 47 LHGC cases. Ki-67 immunostaining was negative in almost all FBGC, OCGC and LHGC cases. Conclusion: This study demonstrates that FBGCs and OCGCs frequently show upregulation of cyclin D1 and p16INK4a expression with low Ki-67 scores. This suggests that multinucleated giant cells are arrested in the G1/S cell cycle transition.
WT1 and Pax2 Re-Expression Is Required for Epithelial-Mesenchymal Transition in 5/6 Nephrectomized Rats and Cultured Kidney Tubular Epithelial Cells
Authors: Huang Bin , Pi Lei , Chen Cha , Yuan Fei , Zhou Qingsong , Teng Junqi , Jiang Tang
Published: July 2011

Mature tubular epithelial cells in the adult kidney can undergo epithelial-mesenchymal transition (EMT), a phenotypic change that is linked to the pathogenesis of renal interstitial fibrosis. EMT may be considered the reverse of mesenchymal-epithelial transition, which occurs during normal kidney development. The Wilms’ tumor suppressor gene WT1 and the paired box 2 gene Pax2 are needed to induce mesenchymal-epithelial transition and play key roles in the progression of nephrogenesis. However, until now, WT1 and Pax2 have not been tested for their direct involvement in the process of renal tubular EMT. In this study, we explored the potential roles of WT1 and Pax2 in EMT that is induced in the remnant kidney of rats following 5/6 nephrectomy. We also examined WT1 and Pax2 in cultured renal tubular epithelial (NRK52E) cells treated with interleukin-1α and investigated the effects of blocking EMT using RNA interference. We showed that WT1 and Pax2 were re-expressed in the EMT models, and these were accompanied by decreased expression of E-cadherin and increased expression of vimentin, Snail and α-smooth muscle actin. Silencing WT1 and Pax2 by RNA interference blocked the interleukin-1α-induced EMT in the NRK52E cells, as reflected in the suppression of α-SMA and Snail expression, the restoration of E-cadherin expression and normal cell morphology. Our experiments suggested that the re-expression of WT1 and Pax2 in the tubular epithelial cells plays important roles in the promotion of EMT, and there may be therapeutic value in silencing Pax2 and WT1 to prevent or reverse renal fibrosis.
Recombinant Encapsulated Cells Overexpressing Alpha-L-Iduronidase Correct Enzyme Deficiency in Human Mucopolysaccharidosis Type I Cells
Authors: Baldo Guilherme , Quoos Mayer Fabiana , Burin Maira , Carrillo-Farga Joaquín , Matte Ursula , Giugliani Roberto
Published: July 2011

Mucopolysaccharidosis I (MPS I) is an autosomal recessive lysosomal storage disease due to deficient α-L-iduronidase (IDUA) activity. It results in the accumulation of the glycosaminoglycans (GAGs) heparan and dermatan sulfate and leads to several clinical manifestations. Available treatments are limited in their efficacy to treat some aspects of the disease. Thus, new approaches have been studied for the treatment of MPS I. Here, we tested the ability of recombinant baby hamster kidney cells transfected with human IDUA cDNA in correcting skin fibroblasts from MPS I patients in vitro. Our results showed an increase in IDUA activity in MPS I fibroblasts after 15, 30 and 45 days of coculture with the capsules. Cytological analysis showed a marked reduction in GAG storage within MPS I cells. Enzyme uptake by the fibroblasts was blocked in a dose-dependent manner with mannose-6-phosphate (M6P), indicating that cells use the M6P receptor to internalize the recombinant enzyme. Capsules were effective in correcting MPS I cells even after a 12-month period of cryopreservation. Taken together, our results indicate that cell encapsulation is a potential approach for treatment of MPS I. This approach becomes particularly interesting as a complementary approach, since the capsules could be implanted in sites which current treatments available are not able to reach. Future studies will focus on the efficacy of this approach in vivo.
Serum Paraoxonase/Arylesterase Activity Affects Outcome in Ischemic Stroke Patients
Authors: Michalak Slawomir , Kazmierski Radoslaw , Hellmann Agnieszka , Wysocka Ewa , Kocialkowska-Adamczewska Dagmara , Wencel-Warot Agnieszka , Nowinski Wiesław L.
Published: July 2011

Background: The severity of neurological deficits arising from ischemic stroke may be related to serum redox homeostasis. The aim of this study was to estimate the effect of serum paraoxonase (PON), arylesterase (ARE) activities and conjugated dienes (CD) on patient outcome during a 1-year follow-up period. Methods: The study included 468 consecutive ischemic stroke patients (251 males, 217 females) with an average age of 67.5 ± 12.4 years. Clinical evaluation was based on vital signs, National Institutes of Health Stroke Scale (NIHSS) scored at the time of admission and on the 7th day after stroke, as well as modified Rankin scale (mRS) and Barthel index (BI) scored at 30, 90, 180 and 360 days after stroke onset. Serum PON, ARE activities and CD concentration were measured with the use of spectrophotometric methods. Results: Serum PON activity alone correlated directly with a favorable outcome during a 3-month observation period. Serum ARE activity correlated directly only with the mRS score in a 1-year observation. PON/ARE ratio showed the strongest direct correlation with favorable stroke outcome expressed by BI and inverse correlation with mRS as compared to serum PON or ARE activities assessed alone. PON/ARE affected the NIHSS score on admission (rS = –0.119, p = 0.014) and on the 7th day after stroke (rS = 0.120, p = 0.015); it also showed an association with the BI and mRS on the 30th (rS = 0.145, p = 0.007 and rS = –0.098, p = 0.049, respectively), 90th (rS = 0.147, p = 0.009, rS = –0.133, p = 0.008, respectively), as well as 180th, and 360th day after stroke. We did not find correlations between the serum CD concentration and stroke outcome. Conclusion: The PON/ARE ratio is an important predictor of ischemic stroke outcome and can be used in clinical practice rather than evaluating either PON or ARE activity alone.
Experimentally Induced Hyperthyroidism Disrupts Hippocampal Long-Term Potentiation in Adult Rats
Authors: Taşkın Eylem , Artis A. Seda , Bitiktas Soner , Dolu Nazan , Liman Narin , Süer Cem
Published: July 2011

Background: Manipulating thyroid hormones has been shown to influence learning and memory. Although a large body of literature is available on the effects of thyroid hormone deficiency on learning and memory functions during developmental or adult-onset hypothyroidism, electrophysiological findings are limited. This limitation is especially notable with respect to thyroxine administration in adult, normothyroid animals. Methods: Experiments were carried out on 12 adult male Wistar rats, each 9–10 months of age. Rats were randomly divided into hyperthyroid (0.2 mg/kg/day intraperitoneal thyroxine injection, for 21 days) and control groups (n = 6 animals in each group). Following spatial learning performance tests on hyperthyroid and control groups, rats were anesthetized with urethane and placed in a stereotaxic frame. A bipolar, tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted within the granule cell layer of the ipsilateral dentate gyrus to record field excitatory postsynaptic potentials (fEPSP). Following a 15-min baseline recording of fEPSPs, long-term potentiation (LTP) was induced by four sets of tetanic pulse trains. Results: Thyroxine-treated rats showed significantly worse performance in the spatial memory task and attenuated input-output relationships in the electrophysiological analyses. Treated rats also showed a lower efficacy of LTP induction when compared with controls. Conclusion: The present study provides clear in vivo evidence for the action of L-thyroxine in the impairment of synaptic plasticity and in inducing spatial memory task deficits in adult rats. These findings may explain the complaints of cognitive function reductions in hyperthyroid patients.
Blood Biomarkers for the Diagnosis of Acute Cerebrovascular Diseases: A Prospective Cohort Study
Authors: Whiteley William , Wardlaw Joanna , Dennis Martin , Lowe Gordon , Rumley Ann , Sattar Naveed , Welsh Paul , Green Alison , Andrews Mary , Graham Catriona , Sandercock Peter
Published: July 2011

Background: The diagnosis of stroke or TIA in the emergency department is difficult, though important for early treatment. Circulating biomarkers might improve upon clinical assessment at admission. Methods: We recruited symptomatic patients with suspected stroke or TIA and drew blood soon after admission. Each patient was assessed with the Face Arm Speech Test (FAST). We measured a panel of 15 circulating inflammatory, thrombotic, cardiac, and cerebral tissue damage biomarkers. Improvement in diagnostic performance was assessed by adding biomarkers to the FAST in logistic regression models to predict a final diagnosis of stroke or TIA (verified by expert review and imaging). Results: 405 patients had suspected stroke: 285 with TIA or stroke (230 definite or probable ischemic stroke, 40 TIA, 15 hemorrhagic stroke) and 120 with other diagnoses. Only the markers t-PA and NT-proBNP were associated positively and significantly (p < 0.01) with a diagnosis of TIA or stroke. The FAST had a sensitivity of 82% (95% CI 78–87) and specificity of 38% (95% CI 29–46) for the diagnosis of TIA or stroke. No biomarker individually improved the sensitivity or specificity of the FAST. A model containing the FAST, age, systolic blood pressure, NT-proBNP and t-PA had a better sensitivity (88%, p < 0.006) and a better specificity (48%, p = 0.04) than the FAST test alone. Conclusions: No single blood marker improved the diagnostic performance of a validated clinical stroke scale. Panels of biomarkers may marginally improve diagnosis, but their practicability is uncertain, and requires further study.
Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH)
Authors: Arnold Suzanne V. , Chan Paul S. , Jones Philip G. , Decker Carole , Buchanan Donna M. , Krumholz Harlan M. , Ho P. Michael , Spertus John A. ,   for the Cardiovascular Outcomes Research Consortium
Published: July 2011

Background—

Black patients with myocardial infarction (MI) have worse outcomes than white patients, including higher mortality rates, more angina, and worse quality of life. The Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) study was designed to examine whether racial differences in socioeconomic, clinical, genetic, metabolic, biomarker, or treatment characteristics mediate observed disparities in outcomes.

Methods and Results—

Between April 11, 2005, and December 31, 2008, 31 567 patients with MI were prospectively screened; 6152 had an eligible MI, and 4340 (71%) were enrolled from 24 US centers. Consenting patients had detailed chart abstractions of their medical history and processes of inpatient care, supplemented with a detailed baseline interview. Detailed genetic and metabolic data were obtained at hospital discharge in 2979 (69%) and 3013 patients (69%), respectively. In a subset of patients, blood and urine samples were obtained at 1 month (obtained in 27% of survivors) and blood samples at 6 months (obtained in 19% of survivors). Centralized follow-up interviews sought to quantify patients' postdischarge care and outcomes, with a focus on their health status (symptoms, function, and quality of life). At 1, 6, and 12 months, 23%, 27%, and 24%, respectively, were lost to follow-up. Vital status was available for 99% of patients at 12 months.

Conclusions—

TRIUMPH is a novel MI registry with detailed information on patients' sociodemographic, clinical, treatment, health status, metabolic, and genetic characteristics. The wealth of patient data collected in TRIUMPH will provide unique opportunities to examine factors that may mediate racial differences in mortality and health status after MI and the complex interactions between genetic and environmental determinants of post-MI outcomes.
Effect of Dietary Protein Supplementation on Blood Pressure
Authors: He Jiang , Wofford Marion R. , Reynolds Kristi , Chen Jing , Chen Chung-Shiuan , Myers Leann , Minor Deborah L. , Elmer Patricia J. , Jones Daniel W. , Whelton Paul K.
Published: July 2011

Background—

Observational studies have reported an inverse association between dietary protein intake and blood pressure (BP). We compared the effect of soy protein, milk protein, and carbohydrate supplementation on BP among healthy adults.

Methods and Results—

We conducted a randomized, double-blind crossover trial with 3 intervention phases among 352 adults with prehypertension or stage 1 hypertension in New Orleans, LA, and Jackson, MS, from September 2003 to April 2008. The trial participants were assigned to take 40 g/d soy protein, milk protein, or carbohydrate supplementation each for 8 weeks in a random order. A 3-week washout period was implemented between the interventions. Three BPs were measured at 2 baseline and 2 termination visits during each of 3 intervention phases with a random-zero sphygmomanometer. Compared with carbohydrate controls, soy protein and milk protein supplementations were significantly associated with −2.0 mm Hg (95% confidence interval −3.2 to −0.7 mm Hg,
P
=0.002) and −2.3 mm Hg (−3.7 to −1.0 mm Hg,
P
=0.0007) net changes in systolic BP, respectively. Diastolic BP was also reduced, but this change did not reach statistical significance. There was no significant difference in the BP reductions achieved between soy or milk protein supplementation.

Conclusions—

The results from this randomized, controlled trial indicate that both soy and milk protein intake reduce systolic BP compared with a high-glycemic-index refined carbohydrate among patients with prehypertension and stage 1 hypertension. Furthermore, these findings suggest that partially replacing carbohydrate with soy or milk protein might be an important component of nutrition intervention strategies for the prevention and treatment of hypertension.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00107744.
Profibrinolytic, Antithrombotic, and Antiinflammatory Effects of an Insulin-Sensitizing Strategy in Patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
Authors: Sobel Burton E. , Hardison Regina M. , Genuth Saul , Brooks Maria M. , McBane Robert D. , Schneider David J. , Pratley Richard E. , Huber Kurt , Wolk Robert , Krishnaswami Ashok , Frye Robert L. ,   for the BARI 2D Investigators
Published: July 2011

Background—

Effects were compared in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of 2 mechanistically different strategies for treatment of hyperglycemia, insulin-sensitizing and insulin-providing strategies, on biomarker profiles reflecting the balance between fibrinolysis and thrombosis and the intensity of inflammation implicated in diabetic vasculopathy.

Methods and Results—

A total of 2368 patients with type 2 diabetes mellitus and clinically stable, angiographically documented coronary artery disease were randomized to treatment with 1 of the 2 strategies and followed for an average of 5 years. Plasminogen activator inhibitor type 1 antigen and activity, tissue plasminogen activator antigen, fibrinogen, D-dimer, C-reactive protein, insulin, and hemoglobin A
1c
were assayed in blood samples acquired at baseline and at 12 regular intervals throughout the follow-up interval. Higher baseline D-dimer, fibrinogen, and C-reactive protein portended a poor prognosis in patients in both groups. In contrast to the insulin-providing strategy, the insulin-sensitizing strategy led to (1) lower plasma insulin; (2) lower plasminogen activator inhibitor type 1 antigen and activity and lower tissue plasminogen activator antigen (known to track with plasminogen activator inhibitor type 1); and (3) lower C-reactive protein and fibrinogen at all intervals after baseline (
P
<0.001 for each).

Conclusions—

The insulin-sensitizing treatment strategy led to changes in biomarker profiles indicative of decreased insulin resistance, an altered balance between thrombosis and fibrinolysis favoring fibrinolysis, and diminished intensity of the systemic inflammatory state, factors that have been associated with cardiovascular risk.

Clinical Trial Registration—

http://www.clinicaltrials.gov
. Unique identifier: NCT00006305.
Mutation-Linked Defective Interdomain Interactions Within Ryanodine Receptor Cause Aberrant Ca
2+
Release Leading to Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Suetomi Takeshi , Yano Masafumi , Uchinoumi Hitoshi , Fukuda Masakazu , Hino Akihiro , Ono Makoto , Xu Xiaojuan , Tateishi Hiroki , Okuda Shinichi , Doi Masahiro , Kobayashi Shigeki , Ikeda Yasuhiro , Yamamoto Takeshi , Ikemoto Noriaki , Matsuzaki Masunori
Published: July 2011

Background—

The molecular mechanism by which catecholaminergic polymorphic ventricular tachycardia is induced by single amino acid mutations within the cardiac ryanodine receptor (RyR2) remains elusive. In the present study, we investigated mutation-induced conformational defects of RyR2 using a knockin mouse model expressing the human catecholaminergic polymorphic ventricular tachycardia–associated RyR2 mutant (S2246L; serine to leucine mutation at the residue 2246).

Methods and Results—

All knockin mice we examined produced ventricular tachycardia after exercise on a treadmill. cAMP-dependent increase in the frequency of Ca
2+
sparks was more pronounced in saponin-permeabilized knockin cardiomyocytes than in wild-type cardiomyocytes. Site-directed fluorescent labeling and quartz microbalance assays of the specific binding of DP2246 (a peptide corresponding to the 2232 to 2266 region: the 2246 domain) showed that DP2246 binds with the K201-binding sequence of RyR2 (1741 to 2270). Introduction of S2246L mutation into the DP2246 increased the affinity of peptide binding. Fluorescence quench assays of interdomain interactions within RyR2 showed that tight interaction of the 2246 domain/K201-binding domain is coupled with domain unzipping of the N-terminal (1 to 600)/central (2000 to 2500) domain pair in an allosteric manner. Dantrolene corrected the mutation-caused domain unzipping of the domain switch and stopped the exercise-induced ventricular tachycardia.

Conclusions—

The catecholaminergic polymorphic ventricular tachycardia–linked mutation of RyR2, S2246L, causes an abnormally tight local subdomain-subdomain interaction within the central domain involving the mutation site, which induces defective interaction between the N-terminal and central domains. This results in an erroneous activation of Ca
2+
channel in a diastolic state reflecting on the increased Ca
2+
spark frequency, which then leads to lethal arrhythmia.
WNK1 Regulates Vasoconstriction and Blood Pressure Response to α
1
-Adrenergic Stimulation in Mice
Authors: Bergaya Sonia , Faure Sébastien , Baudrie Véronique , Rio Marc , Escoubet Brigitte , Bonnin Philippe , Henrion Daniel , Loirand Gervaise , Achard Jean-Michel , Jeunemaitre Xavier , Hadchouel Juliette
Published: July 2011

Gain-of-function mutations in the human
WNK1
(
with-no-lysine[K]1
) gene are responsible for a monogenic form of arterial hypertension, and
WNK1
polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now.
WNK1
complete inactivation in the mouse is embryonically lethal. We, thus, examined in

Wnk1
+/−

haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation.

Wnk1
+/−

mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following α
1
-adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in

Wnk1
+/−

arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na
+
-K
+
-2Cl
−
cotransporter 1) in

Wnk1
+/−

arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to α
1
-adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α
1
-adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension.
Parental History of Hypertension Is Associated With Narrower Retinal Arteriolar Caliber in Young Girls
Authors: Gopinath Bamini , Baur Louise A. , Hardy Louise L. , Wang Jie Jin , Teber Erdahl , Wong Tien Y. , Mitchell Paul
Published: July 2011

We aimed to assess the associations between parental history of hypertension and indicators of cardiovascular risk (retinal vessel diameter, presence of obesity, and elevated blood pressure) in prepubertal children. There were 1739 (77.7% of those eligible) 6-year–old students (863 girls and 876 boys) who were examined from a random cluster sample of 34 Sydney schools. Parents completed questionnaires about their medical conditions, including whether they have/had hypertension. Retinal images were taken with a digital fundus camera, and retinal vessel caliber was quantified using computer software. Anthropometric (height, weight, percentage of body fat, and body mass index) and blood pressure measures were collected. There were 160 children (9.2%) with a positive parental history of hypertension (either biological mother and/or father). Children with a positive versus negative parental history of hypertension had significantly higher body mass index (16.8 versus 16.5 kg/m
2
;
P
=0.04) and systolic blood pressure (101.3 versus 99.8 mm Hg;
P
=0.01). Girls with positive versus negative parental history of hypertension had significantly higher diastolic blood pressure (≈3.1 mm Hg;
P
=0.01) and narrower retinal arteriolar caliber (≈4.3 μm;
P
=0.0004). Positive parental history of hypertension was not associated with mean retinal vascular caliber among boys. We show that a positive parental history of hypertension in healthy prepubertal girls, but not boys, is associated with narrower retinal arteriolar vessels, likely conveying a predisposition to develop hypertension later in life. These findings may indicate the need for cardiovascular disease prevention measures starting early in life among offspring of hypertensive parents.
Effect of Angiotensin II Type 2 Receptor Deletion in Hematopoietic Cells on Brain Ischemia-Reperfusion Injury
Authors: Iwanami Jun , Mogi Masaki , Tsukuda Kana , Min Li-Juan , Sakata Akiko , Jing Fei , Ohshima Kousei , Horiuchi Masatsugu
Published: July 2011

The angiotensin II type 2 (AT
2
) receptor is expressed in bone marrow cells and may affect cell differentiation. We previously reported a beneficial role of the AT
2
receptor in ischemic brain damage. Here, we investigated the effect of AT
2
receptor stimulation in hematopoietic cells on ischemic brain injury using chimeric mice. Chimeric mice were generated by bone marrow transplantation into wild-type mice after irradiation. Bone marrow cells were prepared from wild-type (
Agtr2
+
) or AT
2
receptor-deficient mice (
Agtr2
−
). Six weeks after bone marrow transplantation, these chimeric mice were subjected to ischemia/reperfusion injury. Both
Agtr2
+
and
Agtr2
−
chimeric mice did not show a significant change in systolic and diastolic blood pressures, whereas body weight decreased in
Agtr2
−
chimera. Twenty-four hours after ischemia/reperfusion injury, ischemic brain damage in
Agtr2
−
chimera was exaggerated compared with that in
Agtr2
+
chimera. Moreover, cerebral blood flow in the peripheral region before and after ischemia/reperfusion injury was decreased in
Agtr2
−
chimera. The inflammatory response in the ipsilateral hemisphere was not significantly different, whereas tumor necrosis factor-α and monocyte chemoattractant protein 1 expressions tended to increase in the
Agtr2
−
chimeric brain. Expression of methylmethane sulfonate 2, which has a neuroprotective effect, was lower in the brain of

Agtr2
−

chimera. These results indicate that deletion of AT
2
receptor in blood cells has a harmful effect on ischemic brain injury.
Impact of a Reduced Arctic Sea Ice Cover on Ocean and Atmospheric Properties
Authors: Sedláček Jan , Knutti Reto , Martius Olivia , Beyerle Urs
Published: July 2011

The Arctic sea ice cover declined over the last few decades and reached a record minimum in 2007, with a slight recovery thereafter. Inspired by this the authors investigate the response of atmospheric and oceanic properties to a 1-yr period of reduced sea ice cover. Two ensembles of equilibrium and transient simulations are produced with the Community Climate System Model. A sea ice change is induced through an albedo change of 1 yr. The sea ice area and thickness recover in both ensembles after 3 and 5 yr, respectively. The sea ice anomaly leads to changes in ocean temperature and salinity to a depth of about 200 m in the Arctic Basin. Further, the salinity and temperature changes in the surface layer trigger a “Great Salinity Anomaly” in the North Atlantic that takes roughly 8 yr to travel across the North Atlantic back to high latitudes. In the atmosphere the changes induced by the sea ice anomaly do not last as long as in the ocean. The response in the transient and equilibrium simulations, while similar overall, differs in specific regional and temporal details. The surface air temperature increases over the Arctic Basin and the anomaly extends through the whole atmospheric column, changing the geopotential height fields and thus the storm tracks. The patterns of warming and thus the position of the geopotential height changes vary in the two ensembles. While the equilibrium simulation shifts the storm tracks to the south over the eastern North Atlantic and Europe, the transient simulation shifts the storm tracks south over the western North Atlantic and North America. The authors propose that the overall reduction in sea ice cover is important for producing ocean anomalies; however, for atmospheric anomalies the regional location of the sea ice anomalies is more important.

While observed trends in Arctic sea ice are large and exceed those simulated by comprehensive climate models, there is little evidence based on this particular model that the seasonal loss of sea ice (e.g., as occurred in 2007) would constitute a threshold after which the Arctic would exhibit nonlinear, irreversible, or strongly accelerated sea ice loss. Caution should be exerted when extrapolating short-term trends to future sea ice behavior.
Precipitation Reproducibility over Tropical Oceans and Its Relationship to the Double ITCZ Problem in CMIP3 and MIROC5 Climate Models
Authors: Hirota Nagio , Takayabu Yukari N. , Watanabe Masahiro , Kimoto Masahide
Published: July 2011

Precipitation reproducibility over the tropical oceans in climate models is examined. Models participating in phase 3 of the Coupled Model Intercomparison Project (CMIP3) and the current (fifth) version Model for Interdisciplinary Research on Climate (MIROC5) developed by the Atmosphere and Ocean Research Institute, National Institute for Environmental Studies, and Research Institute for Global Change (AORI/NIES/RIGC) are analyzed. Scores of a pattern similarity between precipitation in the models and that in observations are evaluated. The low score models (LSMs) overestimate (underestimate) precipitation over large-scale subsidence (ascending) regions compared to the high score models (HSMs). The sensitivity of deep convection to sea surface temperature (SST) and large-scale subsidence is examined; analysis suggests that dynamical suppression of deep convection by the entrainment of environmental dry air over the subsidence region is very weak, and deep convection follows SST closely in LSMs. For example, deep convective activity is identified over the southeastern Pacific in LSMs, which corresponds to the double intertropical convergence zone (ITCZ) problem. It is suggested that the double ITCZ is associated not only with the local SST but also with the precipitation schemes that control deep convection over the entire tropical oceans. The current version, MIROC5, reproduces precipitation distributions significantly better than the older versions. Precipitation in MIROC5 has a weaker correlation with SST and a stronger correlation with environmental humidity than that in LSMs. The realistic representation of entrainment in regions with dynamical suppression is suggested to be a key factor for better reproducibility of precipitation distributions.
Precise Calculations of the Existence of Multiple AMOC Equilibria in Coupled Climate Models. Part I: Equilibrium States
Authors: Sijp Willem P. , England Matthew H. , Gregory Jonathan M.
Published: July 2011

This study examines criteria for the existence of two stable states of the Atlantic Meridional Overturning Circulation (AMOC) using a combination of theory and simulations from a numerical coupled atmosphere–ocean climate model. By formulating a simple collection of state parameters and their relationships, the authors reconstruct the North Atlantic Deep Water (NADW) OFF state behavior under a varying external salt-flux forcing. This part (Part I) of the paper examines the steady-state solution, which gives insight into the mechanisms that sustain the NADW OFF state in this coupled model; Part II deals with the transient behavior predicted by the evolution equation. The nonlinear behavior of the Antarctic Intermediate Water (AAIW) reverse cell is critical to the OFF state. Higher Atlantic salinity leads both to a reduced AAIW reverse cell and to a greater vertical salinity gradient in the South Atlantic. The former tends to reduce Atlantic salt export to the Southern Ocean, while the latter tends to increases it. These competing effects produce a nonlinear response of Atlantic salinity and salt export to salt forcing, and the existence of maxima in these quantities. Thus the authors obtain a natural and accurate analytical saddle-node condition for the maximal surface salt flux for which a NADW OFF state exists. By contrast, the bistability indicator proposed by De Vries and Weber does not generally work in this model. It is applicable only when the effect of the AAIW reverse cell on the Atlantic salt budget is weak.
Effects of Inversion Height and Surface Heat Flux on Downslope Windstorms
Authors: Smith Craig M. , Skyllingstad Eric D.
Published: July 2011

Simulations are presented focusing on the role of temperature inversions in controlling the formation and strength of downslope wind storms. Three mechanisms are examined depending on the relative height of the inversion with respect to the mountain and the stability of vertically propagating mountain waves. For low-level inversions, flows are generated that closely resemble a reduced gravity shallow water hydraulic response with a large vertical displacement of the inversion on the lee side of the mountain. For higher-level inversion cases, simulated flows more closely followed a stratified hydraulic behavior with the inversion acting as a rigid reflective lid. In the third mechanism, downslope winds were forced by a self-induced critical layer located below the inversion height. The presence of the inversion in this case had little effect on the resulting downslope winds.

Observations made on the Falkland Islands show that downslope windstorms may preferentially occur in early morning even without synoptic-scale changes in atmospheric structure. Most windstorms on the Falkland Islands generally have a short jet length; rare, longer jet length storms typically occur in conjunction with a strong low-level inversion. Idealized numerical experiments tend to produce a similar response depending on the presence of strong low-level inversion and surface cooling. Results suggest that surface heating can have significant control on the flow response by reducing the low-level inversion strength, or by changing the stratification and wind velocity below the inversion, thereby preventing a strong downslope windstorm.
The Relative Humidity in an Isentropic Advection–Condensation Model: Limited Poleward Influence and Properties of Subtropical Minima
Authors: O’Gorman Paul A. , Lamquin Nicolas , Schneider Tapio , Singh Martin S.
Published: July 2011

An idealized model of advection and condensation of water vapor is considered as a representation of processes influencing the humidity distribution along isentropic surfaces in the free troposphere. Results are presented for how the mean relative humidity distribution varies in response to changes in the distribution of saturation specific humidity and in the amplitude of a tropical moisture source. Changes in the tropical moisture source are found to have little effect on the relative humidity poleward of the subtropical minima, suggesting a lack of poleward influence despite much greater water vapor concentrations at lower latitudes. The subtropical minima in relative humidity are found to be located just equatorward of the inflection points of the saturation specific humidity profile along the isentropic surface. The degree of mean subsaturation is found to vary with the magnitude of the meridional gradient of saturation specific humidity when other parameters are held fixed.

The atmospheric relevance of these results is investigated by comparison with the positions of the relative humidity minima in reanalysis data and by examining poleward influence of relative humidity in simulations with an idealized general circulation model. It is suggested that the limited poleward influence of relative humidity may constrain the propagation of errors in simulated humidity fields.
On the Patterns of Wind-Power Input to the Ocean Circulation
Authors: Roquet Fabien , Wunsch Carl , Madec Gurvan
Published: July 2011

Pathways of wind-power input into the ocean general circulation are analyzed using Ekman theory. Direct rates of wind work can be calculated through the wind stress acting on the surface geostrophic flow. However, because that energy is transported laterally in the Ekman layer, the injection into the geostrophic interior is actually controlled by Ekman pumping, with a pattern determined by the wind curl rather than the wind itself. Regions of power injection into the geostrophic interior are thus generally shifted poleward compared to regions of direct wind-power input, most notably in the Southern Ocean, where on average energy enters the interior 10° south of the Antarctic Circumpolar Current core. An interpretation of the wind-power input to the interior is proposed, expressed as a downward flux of pressure work. This energy flux is a measure of the work done by the Ekman pumping against the surface elevation pressure, helping to maintain the observed anomaly of sea surface height relative to the global-mean sea level.
On the Probability and Spatial Distribution of Ocean Surface Currents
Authors: Ashkenazy Yosef , Gildor Hezi
Published: July 2011

Insights into the probability distribution of ocean currents are important for various applications such as the chance to encounter extreme events, which may affect, for example, marine construction, and for estimating the energy that can be extracted from the ocean. In addition, for devising better parameterizations for submesoscale mixing, which present climate models cannot resolve, one should understand the velocity distribution and its relation to the various forcing of surface ocean circulation. Here, the authors investigate the probability distribution of surface currents from the Gulf of Eilat/Aqaba measured by high-frequency radar. Their results show that the distribution of ocean current speeds can be approximated by a Weibull distribution. Moreover, the authors demonstrate the existence of spatial variations of the scale and shape parameters of the Weibull distribution over a relatively small region of only a few kilometers. They use a simple surface Ekman layer model to investigate this spatial variability. They find that, when forced by local winds, this model does not reproduce the observations. The addition of Gaussian noise to the zonal and meridional components of the bottom geostrophic currents has only a slight effect on the surface current distribution. However, noise added to the components of the local wind (mimicking wind gusts) has a much greater effect on the distribution of surface currents, suggesting that wind spatial and temporal variability underlay the observed spatial variability of the parameters of the Weibull distribution.
Multiscale Evaluation of Extreme Rainfall Event Predictions Using Severity Diagrams
Authors: Ceresetti Davide , Anquetin Sandrine , Molinié Gilles , Leblois Etienne , Creutin Jean-Dominique
Published: July 2011

Observations and simulations of rainfall events are usually compared by analyzing (i) the total rainfall depth produced by the event and (ii) the location of the rainfall maximum. A different approach is proposed here that compares the mesoscale simulated rainfall fields with the ground rainfall observations within the multiscale framework of maximum intensity diagrams and severity diagrams. While the first simply displays the maximum rainfall intensity of an event at a number of scales, the second gives the frequency of occurrence of the maximum rainfall intensities as a function of the spatial and temporal aggregation scales, highlighting the space–time scales of the event severity. For use in a region featuring complex relief, severity diagrams have been generalized to incorporate the regional behavior of heavy rainfall events. To assess simulation outputs from a meteorological mesoscale model, three major storms that have occurred in the last decade over a mountainous Mediterranean region of southern France are analyzed. The severity diagrams detect the critical space–time scales of the rainfall events for comparison with those predicted by the simulation. This validation approach is adapted to evaluate the ability of the mesoscale model to predict various types of storms with different regional climatologies.