bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of an integrated pancreatic disease service
Authors: Jupp James A , Johnson Colin D , Shek Fanny W , Fine David R
Published: January 2011

An integrated pancreatic disease unit needs to deliver high-quality care both to patients with malignant and non-malignant pancreatic disease. The regionalisation of pancreatic cancer services which followed the publication of policy frameworks by the Department of Health and NHS executive led to the development of disease-site-specialised high-volume multidisciplinary teams. As the majority of patients with pancreatic cancer are not suitable for surgery, partner hospitals within a region need to provide access to a wide range of non-surgical treatment. The implementation of such working may require pooling of local resources to create networks of equivalence to tertiary centres. The provision of care to non-malignant pancreatic disease can benefit from this type of working and services can be modelled on, and integrate with, cancer services. One way of achieving this is to establish working groups based upon diseases rather than traditional departments, which can deliver standardised and optimal care with a patient-centred approach. However, this poses a number of potential problems. This review examines how an integrated pancreatic unit may be developed in district general and larger hospitals, and also describes our experience in developing such a unit.
GRAVITY AND YANG–MILLS THEORY
Authors: ANANTH SUDARSHAN
Published: January 2011

Three of the four forces of Nature are described by quantum Yang–Mills theories with remarkable precision. The fourth force, gravity, is described classically by the Einstein–Hilbert theory. There appears to be an inherent incompatibility between quantum mechanics and the Einstein–Hilbert theory which prevents us from developing a consistent quantum theory of gravity. The Einstein–Hilbert theory is therefore believed to differ greatly from Yang–Mills theory (which does have a sensible quantum mechanical description). It is therefore very surprising that these two theories actually share close perturbative ties. This essay focuses on these ties between Yang–Mills theory and the Einstein–Hilbert theory. We discuss the origin of these ties and their implications for a quantum theory of gravity.
QUANTUM GRAVITY AND TURBULENCE
Authors: JEJJALA VISHNU , MINIC DJORDJE , NG Y. JACK , TZE CHIA-HSIUNG
Published: January 2011

We apply recent advances in quantum gravity to the problem of turbulence. Adopting the AdS/CFT approach we propose a string theory of turbulence that explains the Kolmogorov scaling in 3 + 1 dimensions and the Kraichnan and Kolmogorov scalings in 2 + 1 dimensions. In the gravitational context, turbulence is intimately related to the properties of space–time or quantum foam.
EQUIPARTITION OF MICROSCOPIC DEGREES OF FREEDOM, SPACE–TIME ENTROPY AND HOLOGRAPHY
Authors: PADMANABHAN T.
Published: January 2011

One can identify the number density of the microscopic space–time degrees of freedom in any diffeomorphism-invariant theory of gravity by using the principle of equipartition, applied to the area elements of a surface [Formula: see text] which are at the local Unruh temperature. The entropy associated with these degrees of freedom, which matches with the Wald entropy for the theory, can be used to obtain the field equations of the theory through an extremization priciple. When the microscopic degrees of freedom are in local thermal equilibrium, the entropy of a bulk region of space–time resides on its boundary. These facts support an emergent perspective of gravity.
A LASER GYROSCOPE SYSTEM TO DETECT THE GRAVITO-MAGNETIC EFFECT ON EARTH
Authors: DI VIRGILIO A. , SCHREIBER K. U. , GEBAUER A. , WELLS J.-P. R. , TARTAGLIA A. , BELFI J. , BEVERINI N. , ORTOLAN A.
Published: January 2011

Large scale square ring laser gyros with a length of four meters on each side are approaching a sensitivity of [Formula: see text]. This is approximately the regime required to measure the gravito-magnetic effect (Lense–Thirring) of the Earth. For an ensemble of linearly independent gyros each measurement signal depends upon the orientation of each single axis gyro with respect to the rotational axis of the Earth. Therefore at least three gyros are necessary to reconstruct the complete angular orientation of the apparatus. In general, the setup consists of several laser gyroscopes (we would prefer more than three for sufficient redundancy), rigidly referenced to each other. Adding more gyros for one plane of observation provides a cross-check against intra-system biases and furthermore has the advantage of improving the signal-to-noise ratio by the square root of the number of gyros. In this paper we analyze a system of two pairs of identical gyros (twins) with a slightly different orientation with respect to the Earth's axis. The twin-gyro configuration has several interesting properties. The relative angle can be controlled and provides a useful null measurement. A quadruple twin system could reach a 1% sensitivity after 3.2 years of data taking, provided each square ring has 6 m length on a side, the system is limited by shot noise and there is no source for 1/f-noise.
DARK ENERGY, WITH SIGNATURES
Authors: DUTTA SOURISH , SCHERRER ROBERT J. , HSU STEPHEN D. H.
Published: January 2011

We propose a class of simple dark energy models which predict a late-time dark radiation component and a distinctive time-dependent equation of state w(z) for redshift z < 3. The dark energy field can be coupled strongly enough to standard model particles to be detected in colliders, and the model requires only modest additional particle content and little or no fine-tuning other than a new energy scale of order milli-electron volts.
ON THE EFFECTIVE EQUATION OF STATE OF DARK ENERGY
Authors: SLOTH MARTIN S.
Published: January 2011

In an effective field theory model with an ultraviolet momentum cutoff, there is a relation between the effective equation-of-state of dark energy and the ultraviolet cutoff scale. It implies that a measure of the equation of state of dark energy different from minus one, ω ≠ -1, does not rule out vacuum energy as dark energy. It also indicates an interesting possibility that precise measurements of the infrared properties of dark energy can be used to probe the ultraviolet cutoff scale of effective quantum field theory coupled to gravity. In a toy model with a vacuum energy-dominated universe with a Planck scale cutoff, the dark energy effective equation of state is w eff ≈ -0.96.
GO WITH THE FLOW, AVERAGE HOLOGRAPHIC UNIVERSE
Authors: SMOOT GEORGE F.
Published: January 2011

Gravity is a macroscopic manifestation of a microscopic quantum theory of space–time, just as the theories of elasticity and hydrodynamics are the macroscopic manifestations of the underlying quantum theory of atoms. The connection between gravitation and thermodynamics is long and deep. The observation that space–time has a temperature for accelerating observers and horizons is direct evidence that there are underlying microscopic degrees of freedom. The equipartition of energy, the meaning of temperature, in these modes leads one to anticipate that there is also an entropy associated. When this entropy is maximized on a volume of space–time, then one retrieves the metric of space–time (i.e. the equations of gravity, e.g. general relativity). Since the metric satisfies the extremum in entropy on the volume, then the volume integral of the entropy can readily be converted to surface integral, via Gauss's Theorem. This surface integral is simply an integral of the macroscopic entropy flow producing the mean entropy holographic principle. This approach also has the added value that it naturally dispenses with the cosmological constant/vacuum energy problem in gravity except perhaps for second-order quantum effects on the mean surface entropy.
COSMOLOGY WITH MIRROR DARK MATTER
Authors: CIARCELLUTI PAOLO
Published: January 2011

Mirror matter is a stable self-collisional dark matter candidate. If parity is a conserved unbroken symmetry of nature, there could exist a parallel hidden (mirror) sector of the universe composed of particles with the same masses and obeying the same physical laws as our (visible) sector, except for the opposite-handedness of weak interactions. The two sectors interact predominantly via gravity, therefore mirror matter is naturally "dark". Here I review the cosmological signatures of mirror dark matter, concerning thermodynamics of the early universe, big bang nucleosynthesis, primordial structure formation and evolution, cosmic microwave background and large scale structure power spectra. Besides gravity, the effects on primordial nucleosynthesis of the kinetic mixing between photons and mirror photons are considered. Summarizing the present status of research and comparing theoretical results with observations/experiments, it emerges that mirror matter is not just a viable, but a promising dark matter candidate.
GRAVITY IN QUANTUM SPACE–TIME
Authors: AMELINO-CAMELIA GIOVANNI , LORET NICCOLÒ , MANDANICI GIANLUCA , MERCATI FLAVIO
Published: January 2011

The literature on quantum-gravity-inspired scenarios for the quantization of space–time has so far focused on particle-physics-like studies. This is partly justified by the present limitations of our understanding of quantum gravity theories, but we here argue that valuable insight can be gained through semi-heuristic analyses of the implications for gravitational phenomena of some results obtained in the quantum space–time literature. In particular, we show that the types of description of particle propagation that emerged in certain quantum space–time frameworks have striking implications for gravitational collapse and for the behavior of gravity at large distances.
THE DANGERS OF EXTREMES
Authors: MAROLF DONALD
Published: January 2011

While extreme black hole space–times with smooth horizons are known at the level of mathematics, we argue that the horizons of physical extreme black holes are effectively singular. Test particles encounter a singularity the moment they cross the horizon, and only objects with significant back-reaction can fall across a smooth (now non-extreme) horizon. As a result, classical interior solutions for extreme black holes are theoretical fictions that need not be reproduced by any quantum mechanical model. This observation suggests that significant quantum effects might be visible outside extreme or nearly extreme black holes. It also suggests that the microphysics of such black holes may be very different from that of their Schwarzschild cousins.
CONDITIONS FOR SPONTANEOUS HOMOGENIZATION OF THE UNIVERSE
Authors: BOLEJKO KRZYSZTOF , STOEGER WILLIAM R.
Published: January 2011

The present-day universe appears to be homogeneous on very-large scales. Yet when the casual structure of the early universe is considered, it becomes apparent that the early universe must have been highly inhomogeneous. The current paradigm attempts to answer this problem by postulating the inflation mechanism. However, inflation in order to start requires a homogeneous patch of at least the horizon size. This paper examines if dynamical processes of the early universe could lead to homogenization. In the past similar studies seem to imply that the set of initial conditions that leads to homogenization is of measure zero. This essay proves the contrary: a set of initial conditions for spontaneous homogenization of cosmological models can form a set of nonzero measure.
Effects of Tert-Butylhydroquinone on Intestinal Inflammatory Response and Apoptosis following Traumatic Brain Injury in Mice
Authors: Jin Wei , Ni Hongbin , Dai Yuxiang , Wang Handong , Lu Tianyu , Wu Jun , Jiang Jian , Liang Weibang
Published: January 2011

Traumatic brain injury (TBI) can induce intestinal inflammatory response and mucosal injury. Antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown in our previous studies to prevent oxidative stress and inflammatory response in gut after TBI. The objective of this study was to test whether tert-butylhydroquinone (tBHQ), an Nrf2 inducer, can protect against TBI-induced intestinal inflammatory response and mucosal injury in mice. Adult male ICR mice were randomly divided into three groups: (1) sham + vehicle group, (2) TBI + vehicle group, and (3) TBI + tBHQ group (n=12per group). Closed head injury was adopted using Hall's weight-dropping method. Intestinal mucosa apoptosis and inflammatory-related factors, such as nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1), were investigated at 24 h after TBI. As a result, we found that oral treatment with 1% tBHQ prior to TBI for one week markedly decreased NF-κB activation, inflammatory cytokines production, and ICAM-1 expression in the gut. Administration of tBHQ also significantly attenuated TBI-induced intestinal mucosal apoptosis. The results of the present study suggest that tBHQ administration could suppress the intestinal inflammation and reduce the mucosal damage following TBI.
Using Bacterial Artificial Chromosomes in Leukemia Research: The Experience at the University Cytogenetics Laboratory in Brest,France
Authors: De Braekeleer Etienne , Douet-Guilbert Nathalie , Basinko Audrey , Morel Frédéric , Le Bris Marie-Josée , Férec Claude , De Braekeleer Marc
Published: January 2011

The development of the bacterial artificial chromosome (BAC) system was driven in part by the human genome project in order to construct genomic DNA libraries and physical maps for genomic sequencing. The availability of BAC clones has become a valuable tool for identifying cancer genes. We report here our experience in identifying genes located at breakpoints of chromosomal rearrangements and in defining the size and boundaries of deletions in hematological diseases. The methodology used in our laboratory consists of a three‐step approach using conventional cytogenetics followed by FISH with commercial probes, then BAC clones. One limitation to the BAC system is that it can only accommodate inserts of up to 300 kb. As a consequence, analyzing the extent of deletions requires a large amount of material. Array comparative genomic hybridization (array‐CGH) using a BAC/PAC system can be an alternative. However, this technique has limitations also, and it cannot be used to identify candidate genes at breakpoints of chromosomal rearrangements such as translocations, insertions, and inversions.
Phase I Dose-Escalation Study of the Pan-HER Inhibitor, PF299804, in Patients with Advanced Malignant Solid Tumors
Authors: Jänne Pasi A. , Boss David S. , Camidge D. Ross , Britten Carolyn D. , Engelman Jeffrey A. , Garon Edward B. , Guo Feng , Wong Steven , Liang Jane , Letrent Stephen , Millham Robert , Taylor Ian , Eckhardt S. Gail , Schellens Jan H.M.
Published: January 2011

Purpose: PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.

Experimental Design: PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non–small cell lung cancer (NSCLC) patients.

Results: 121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non–small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.

Conclusions: The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients. Clin Cancer Res; 17(5); 1131–9. ©2011 AACR.
Gefitinib or Placebo in Combination with Tamoxifen in Patients with Hormone Receptor–Positive Metastatic Breast Cancer: A Randomized Phase II Study
Authors: Osborne C. Kent , Neven Patrick , Dirix Luc Y. , Mackey John R. , Robert Jean , Underhill Craig , Schiff Rachel , Gutierrez Carolina , Migliaccio Ilenia , Anagnostou Valsamo K. , Rimm David L. , Magill Patrick , Sellers Mark
Published: January 2011

Purpose: Increased growth factor signaling may contribute to tamoxifen resistance. This randomized phase II trial assessed tamoxifen plus placebo or the epidermal growth factor receptor inhibitor gefitinib in estrogen receptor (ER)–positive metastatic breast cancer.

Experimental Design: Patients with newly metastatic disease or recurred after adjuvant tamoxifen (stratum 1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (stratum 2), were eligible. Primary variables were progression-free survival (PFS; stratum 1) and clinical benefit rate (CBR; stratum 2). A 5% or more improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor.

Results: In stratum 1 (n = 206), the PFS HR (gefitinib:placebo) was 0.84 (95% CI, 0.59–1.18; median PFS 10.9 versus 8.8 months). In the stratum 1 endocrine therapy–naïve subset (n = 158) the HR was 0.78 (95% CI, 0.52–1.15), and the prior endocrine-treated subgroup (n = 48) 1.47 (95% CI, 0.63–3.45). In stratum 1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In stratum 2 (n = 84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in stratum 1 there was greater benefit with gefitinib in patients who were ER-negative or had lower levels of ER protein.

Conclusions: In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy. In stratum 2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients. Clin Cancer Res; 17(5); 1147–59. ©2011 AACR.
Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models
Authors: Tan Nguyen , Malek Mehnaz , Zha Jiping , Yue Peng , Kassees Robert , Berry Leanne , Fairbrother Wayne J. , Sampath Deepak , Belmont Lisa D.
Published: January 2011

Purpose: To explore the potential of navitoclax in combination with taxane-based chemotherapy in the treatment of non–small cell lung cancer (NSCLC) by defining mechanism of synergy and identifying correlative biomarkers.

Experimental Design: We treated a panel of NSCLC lines with a dose matrix of paclitaxel and navitoclax (formerly ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w (1), and evaluated synergy. We next used time-lapse microscopy to explore mechanism of synergy. Finally, we developed an immunohistochemical assay and assessed prevalence of Bcl-xL in NSCLC tumor tissues.

Results: All cell lines exhibit greater than additive response to the combination of navitoclax and a taxane. These results were extended to mouse xenograft tumor models, in which the combination is more efficacious than either single-agent docetaxel or navitoclax. Addition of navitoclax to paclitaxel decreases the time from mitotic entry to cell death and changes cell fate from mitotic slippage to death during mitotic arrest. The relative levels of Bcl-xL and Mcl-1 correlate with the extent of synergy, suggesting that cancers with elevated levels of Bcl-xL will be relatively resistant to taxane-based therapy but could benefit from the addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit relatively high Bcl-xL levels.

Conclusions: The addition of navitoclax to taxane-based chemotherapy in NSCLC has the potential to increase efficacy, particularly in patients whose tumors express high levels of Bcl-xL. Clin Cancer Res; 17(6); 1394–404. ©2011 AACR.
Digital Transcript Profile Analysis with aRNA-LongSAGE Validates FERMT1 As a Potential Novel Prognostic Marker for Colon Cancer
Authors: Fan Junwei , Yan Dongwang , Teng Mujian , Tang Huamei , Zhou Chongzhi , Wang Xiaoliang , Li Dawei , Qiu Guoqiang , Peng Zhihai
Published: January 2011

Purpose: To use gene transcript profiling to identify cancer-associated gene expression.

Experimental Design: Methods included (i) marker discovery using laser capture microdissection (LCM)-assisted specimen preparation and antisense RNA-long serial analysis of gene expression (aRNA-LongSAGE) on matched colon cancer and uninvolved colon tissue specimens (n = 5). Candidate tumor-associated genes were selected by combining the LongSAGE libraries reported herein with our previous colon cancer LCM-microarray transcript profiling data; (ii) marker selection and validation by quantitative real-time PCR (n = 15) and immunohistochemistry (n = 31); and (iii) independent validation on multiple tissue microarray (n = 203).

Results: Among 30 upregulated and 73 downregulated genes, upregulation of fermitin family member 1 (FERMT1), adenosylhomocysteinase (AHCY), secernin 1 (SCRN1), and SAC3 domain-containing protein 1 (SAC3D1) expression and downregulation of IgJ and MALL expression in colon cancer were confirmed by quantitative PCR. FERMT1 and AHCY protein expression was also upregulated in colon cancer compared with uninvolved colon mucosa, and FERMT1 expression showed upregulation in colon adenoma. Patients with moderate/strong tumor FERMT1 protein expression (n = 122) showed significantly poorer overall survival (OS; P = 0.011) and disease-free survival (DFS; P = 0.005) than patients with negative/weak tumor FERMT1 protein expression (n = 81). Multivariate Cox regression analysis showed that FERMT1 protein expression was also an independent prognostic factor for OS (P = 0.018) and DFS (P = 0.009). In addition, upregulated FERMT1 protein expression appeared to have some specificity among alimentary tract tumors.

Conclusions: FERMT1 is a novel prognostic factor for colon carcinoma. Clin Cancer Res; 17(9); 2908–18. ©2011 AACR.
Surfactant Replacement Therapy in Preterm Infants: A European Survey
Authors: van Kaam Anton H. , De Jaegere Anne P. , Borensztajn Dorine , Rimensberger Peter C. ,   on behalf of the Neovent Study Group
Published: January 2011

Background: Exogenous surfactant is an undisputed treatment for neonatal respiratory distress syndrome but its efficacy is highly dependent on the treatment strategy. International guidelines have published recommendations on the optimal surfactant replacement strategy. Objective: To determine how evidence-based guidelines on surfactant replacement therapy are implemented in daily clinical practice. Methods: Data on surfactant replacement therapy, including preparation, dosing and timing, were collected in 173 European neonatal intensive care units (NICUs) by questionnaire and in a cohort of preterm infants mechanically ventilated on two separate predefined dates in these units. Results: All NICUs used animal-derived surfactant in the treatment of respiratory distress syndrome, with Poractant being most widely used (86%). The most frequently used first dose was 100 mg/kg (58%) and 200 mg/kg (39%) and all NICUs allowed for repeat dosing. 39% of the NICUs claimed to use prophylactic treatment (<15 min of life). Data on surfactant treatment were collected in 338 infants, with a median gestational age of 27 weeks and a birth weight of 860 g. All infants were treated with animal-derived surfactant. The median first dose was 168 mg/kg in the Poractant group compared with 100 mg/kg in the Beractant and Bovactant groups. Prophylactic treatment was used in 23% of the infants and 28% of the infants received surfactant >2 h after birth. 43% of the infants received multiple doses. Conclusions: With the exception of surfactant timing, guidelines on surfactant replacement therapy seem to be implemented in daily clinical practice in European NICUs.
The Renin Inhibitor Aliskiren Attenuates High-Glucose Induced Extracellular Matrix Synthesis and Prevents Apoptosis in Cultured Podocytes
Authors: Phillips Lynetta M. , Wang Ying , Dai Tiane , Feldman David L. , LaPage Janine , Adler Sharon G.
Published: January 2011

Background/Aims: Altered extracellular matrix (ECM) remodeling and podocyte apoptosis are characteristic features of diabetic nephropathy (DN). Aliskiren (ALI) inhibits the renin-catalyzed conversion of angiotensinogen to angiotensin I. This study tested ALI’s effect on podocyte ECM accretion and survival in a high-glucose environment in vitro. Methods: Conditionally immortalized mouse podocytes were incubated in normal glucose (NG; 5.5 mM) or high glucose (HG; 40 mM) for 24–48 h with and without ALI (20 nM). Real-time RT-PCR was performed for fibronectin (FN), collagen α5(type IV) (Cola5IV), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), and tissue inhibitor of metalloproteinases 1 and 2 (TIMP1 and TIMP2). Western blots were performed for FN, Cola5IV, MMP2, MMP9, TIMP1 and cleaved (activated) caspase-3. Results: ALI significantly reduced the mRNA and protein levels of FN, Cola5IV and TIMP1, and the mRNA of TIMP2 and cleaved caspase-3. ALI had no effect on MMP2 mRNA or protein or MMP9 mRNA tested under HG conditions. Under NG conditions, ALI had no effect on FN, Cola5IV, MMP2, MMP9 and activated caspase-3 proteins. ALI decreased the activated caspase-3 protein and evidence of apoptosis by TUNEL staining observed in podocytes cultured under HG conditions. Conclusion: These results show for the first time that renin inhibition with ALI mitigates the profibrotic and apoptotic effects of HG in cultured podocytes. These data strengthen the therapeutic rationale for renin inhibition with ALI beyond its hemodynamic effects.
β-Arrestin 2-Mediated Immune Suppression Induced by Chronic Stress
Authors: Li Hui , Smalligan Dean Andrew , Xie Nanchang , Javer Avani , Zhang Yi , Hanley Gregory , Yin Deling
Published: January 2011

Objective: Stress, either physical or psychological, can modulate immune function. However, the mechanisms associated with stress-induced immune suppression remain to be elucidated. β-Arrestin 2 serves as adaptor, scaffold, and/or signal transducer. The role of β-arrestin 2 in stress-induced immune suppression is not known yet. Methods/Results: Here, we demonstrate that β-arrestin 2 deficiency in mice increases the sensitivity to the chronic stress-induced reduction in the number of splenocytes. Interestingly, the stress-induced suppression of T helper-type (Th) 1 cytokines and the increased production of Th2 cytokines were greatly enhanced in β-arrestin 2-deficient mice compared with wild-type mice. Moreover, inhibition of PI3K in β-arrestin 2-deficient mice exerts an additive effect on the stress-induced reduction in the number of splenocytes. Conclusion: Our study demonstrates that a deficiency in β-arrestin 2 augments stress-induced immune suppression.
Expression of Steroid Receptor Coactivator-1 Was Regulated by Postnatal Development but Not Ovariectomy in the Hippocampus of Rats
Authors: Zhang Dongmei , Guo Qiang , Bian Chen , Zhang Jiqiang , Cai Wenqin , Su Bingyin
Published: January 2011

Female steroids such as estrogens and progestins, through their nuclear receptors, play important roles in regulation of the structure and function of the hippocampus. Steroid receptor coactivator-1 (SRC-1) has been detected in embryonic and/or adult hippocampus of rodents, and SRC-1 null mice showed significantly longer escape latency in the Morris maze test, indicating a role of this coactivator in the regulation of hippocampus function. Whether this is regulated by development and circulating ovary hormones remains unclear. In this study, postnatal development and ovariectomy for regulation of hippocampal SRC-1 in female rats were investigated by Western blot and immunohistochemistry. The results showed that SRC-1-immunopositive materials were predominantly detected in the CA1 pyramidal cell layer and dentate gyrus granular cell layer. Very low levels of SRC-1 were detected at postnatal day 0, but they increased with development. The highest levels of SRC-1 were detected at postnatal day 14, then they decreased to adult levels from postnatal day 30; significantly lower levels of SRC-1 were detected in the middle-aged (18-month-old) hippocampus when compared with that of the adult. Western blot and immunohistochemistry demonstrated that hippocampal SRC-1 expression was unchanged after ovariectomy, no significant differences were noticed from day 3 to 8 weeks postsurgery when compared with sham animals. The above results showed that hippocampal SRC-1 is regulated by postnatal development but not ovariectomy, and that the exact role of SRC-1 in the estradiol regulation of hippocampus needs further investigation.
Statins for Secondary Prevention of Cardiovascular Disease: The Right Dose
Authors: Spector Reynold , Snapinn Steven M.
Published: January 2011

Since the publication of the 4S trial in 1994, there has emerged a consensus that statins save lives and decrease myocardial infarctions and strokes in coronary artery disease (CAD) patients irrespective of baseline serum cholesterol. However, there is controversy over the correct dose and the utility of the treatment-to-goal (cholesterol, low-density lipoprotein) approach. To answer remaining questions about the optimal statin dose in CAD patients, we have performed simple and meta-analyses of 3 large long-term (approx. 5 years) dose-clinical response studies (TNT, IDEAL, and SEARCH) and compared the results with older data including long-term safety data. The results show that raising the dose of simvastatin or atorvastatin to 80 mg confers no mortality advantage, an increase in adverse reactions and only a slight decrease in myocardial infarctions and stroke versus a lower dose. These results suggest a cost-effective approach of a single safe dose (40 mg of inexpensive generic simvastatin or atorvastatin) for almost all CAD patients and makes treatment-to-goal and cholesterol monitoring (except to check for medication compliance) unnecessary; moreover, it is likely to improve the weakness in statin use – medication compliance.
Incidence and Predictors of Early and Late Mortality After Transcatheter Aortic Valve Implantation in 663 Patients With Severe Aortic Stenosis
Authors: Tamburino Corrado , Capodanno Davide , Ramondo Angelo , Petronio Anna Sonia , Ettori Federica , Santoro Gennaro , Klugmann Silvio , Bedogni Francesco , Maisano Francesco , Marzocchi Antonio , Poli Arnaldo , Antoniucci David , Napodano Massimo , De Carlo Marco , Fiorina Claudia , Ussia Gian Paolo
Published: January 2011

Background—

There is a lack of information on the incidence and predictors of early mortality at 30 days and late mortality between 30 days and 1 year after transcatheter aortic valve implantation (TAVI) with the self-expanding CoreValve Revalving prosthesis.

Methods and Results—

A total of 663 consecutive patients (mean age 81.0±7.3 years) underwent TAVI with the third generation 18-Fr CoreValve device in 14 centers. Procedural success and intraprocedural mortality were 98% and 0.9%, respectively. The cumulative incidences of mortality were 5.4% at 30 days, 12.2% at 6 months, and 15.0% at 1 year. The incidence density of mortality was 12.3 per 100 person-year of observation. Clinical and hemodynamic benefits observed acutely after TAVI were sustained at 1 year. Paravalvular leakages were trace to mild in the majority of cases. Conversion to open heart surgery (odds ratio [OR] 38.68), cardiac tamponade (OR 10.97), major access site complications (OR 8.47), left ventricular ejection fraction <40% (OR 3.51), prior balloon valvuloplasty (OR 2.87), and diabetes mellitus (OR 2.66) were independent predictors of mortality at 30 days, whereas prior stroke (hazard ratio [HR] 5.47), postprocedural paravalvular leak ≥2+ (HR 3.79), prior acute pulmonary edema (HR 2.70), and chronic kidney disease (HR 2.53) were independent predictors of mortality between 30 days and 1 year.

Conclusions—

Benefit of TAVI with the CoreValve Revalving System is maintained over time up to 1 year, with acceptable mortality rates at various time points. Although procedural complications are strongly associated with early mortality at 30 days, comorbidities and postprocedural paravalvular aortic regurgitation ≥2+ mainly impact late outcomes between 30 days and 1 year.
Deregulation of microRNA-503 Contributes to Diabetes Mellitus–Induced Impairment of Endothelial Function and Reparative Angiogenesis After Limb Ischemia
Authors: Caporali Andrea , Meloni Marco , Völlenkle Christine , Bonci Desiree , Sala-Newby Graciela B. , Addis Roberta , Spinetti Gaia , Losa Sergio , Masson Rachel , Baker Andrew H. , Agami Reuven , le Sage Carlos , Condorelli Gianluigi , Madeddu Paolo , Martelli Fabio , Emanueli Costanza
Published: January 2011

Background—

Diabetes mellitus impairs endothelial cell (EC) function and postischemic reparative neovascularization by molecular mechanisms that are not fully understood. microRNAs negatively regulate the expression of target genes mainly by interaction in their 3′ untranslated region.

Methods and Results—

We found that microRNA-503 (miR-503) expression in ECs is upregulated in culture conditions mimicking diabetes mellitus (high D-glucose) and ischemia-associated starvation (low growth factors). Under normal culture conditions, lentivirus-mediated miR-503–forced expression inhibited EC proliferation, migration, and network formation on Matrigel (comparisons versus
lentivirus.GFP
control). Conversely, blocking miR-503 activity by either adenovirus-mediated transfer of a miR-503 decoy (
Ad.decoymiR-503
) or by antimiR-503 (antisense oligonucleotide) improved the functional capacities of ECs cultured under high D-glucose/low growth factors. We identified CCNE1 and cdc25A as direct miR-503 targets which are downregulated by high glucose/low growth factors in ECs. Next, we obtained evidence that miR-503 expression is increased in ischemic limb muscles of streptozotocin-diabetic mice and in ECs enriched from these muscles. Moreover,
Ad.decoymiR-503
delivery to the ischemic adductor of diabetic mice corrected diabetes mellitus–induced impairment of postischemic angiogenesis and blood flow recovery. We finally investigated miR-503 and target gene expression in muscular specimens from the amputated ischemic legs of diabetic patients. As controls, calf biopsies of nondiabetic and nonischemic patients undergoing saphenous vein stripping were used. In diabetic muscles, miR-503 expression was remarkably higher, and it inversely correlated with cdc25 protein expression. Plasma miR-503 levels were also elevated in the diabetic individuals.

Conclusions—

Our data suggest miR-503 as a possible therapeutic target in diabetic patients with critical limb ischemia.
Heart Rate Response During Exercise and Pregnancy Outcome in Women With Congenital Heart Disease
Authors: Lui George K. , Silversides Candice K. , Khairy Paul , Fernandes Sue M. , Valente Anne Marie , Nickolaus Michelle J. , Earing Michael G. , Aboulhosn Jamil A. , Rosenbaum Marlon S. , Cook Stephen , Kay Joseph D. , Jin Zhezhen , Gersony Deborah R. ,   for the Alliance for Adult Research in Congenital Cardiology (AARCC)
Published: January 2011

Background—

Cardiopulmonary exercise testing is often used to evaluate exercise capacity in adults with congenital heart disease including women who are considering pregnancy. The relationship between cardiopulmonary exercise testing parameters and pregnancy outcome has not been defined.

Methods and Results—

We conducted a multicenter retrospective observational study of women with congenital heart disease who had undergone cardiopulmonary exercise testing within 2 years of pregnancy or during the first trimester. Cardiopulmonary exercise testing variables included peak oxygen consumption and measures of chronotropic response: peak heart rate, percentage of maximum age predicted heart rate, heart rate reserve (peak heart rate−resting heart rate), and chronotropic index [(peak heart rate−resting heart rate)/(220−age−resting heart rate)]. We identified 89 pregnancies in 83 women. There were 4 spontaneous abortions and 1 termination. One or more adverse cardiac events occurred in 18%; congestive heart failure in 14%, and sustained arrhythmia in 7%. Peak heart rate (odds ratio [OR] 0.71; 95% confidence interval [CI] [0.53, 0.94];
P
=0.02), percentage of maximum age predicted heart rate (OR 0.93; 95% CI [0.88, 0.98];
P
=0.01), and chronotropic index (OR 0.65; 95% CI [0.47, 0.90];
P
=0.01) were associated with a cardiac event. Neonatal events occurred in 20%. Peak heart rate (OR 0.75; 95% CI [0.58, 0.98];
P
=0.04), percentage of maximum age predicted heart rate (OR 0.94; 95% CI [0.89, 0.99];
P
=0.02), heart rate reserve (OR 0.8; 95% CI [0.64, 0.99];
P
=0.04), and chronotropic index (OR 0.73; 95% CI [0.54, 0.98];
P
=0.04) correlated with a neonatal event. Peak oxygen consumption was not associated with an adverse pregnancy outcome.

Conclusions—

Abnormal chronotropic response correlates with adverse pregnancy outcomes in women with congenital heart disease and should be considered in refining risk stratification schemes.
Strut Coverage and Late Malapposition With Paclitaxel-Eluting Stents Compared With Bare Metal Stents in Acute Myocardial Infarction
Authors: Guagliumi Giulio , Costa Marco A. , Sirbu Vasile , Musumeci Giuseppe , Bezerra Hiram G. , Suzuki Nobuaki , Matiashvili Aleksandre , Lortkipanidze Nikoloz , Mihalcsik Laurian , Trivisonno Antonio , Valsecchi Orazio , Mintz Gary S. , Dressler Ovidiu , Parise Helen , Maehara Akiko , Cristea Ecaterina , Lansky Alexandra J. , Mehran Roxana , Stone Gregg W.
Published: January 2011

Background—

The safety of drug-eluting stents in ST-segment elevation myocardial infarction (STEMI) continues to be debated. Pathological studies have demonstrated an association between uncovered struts and subsequent stent thrombosis. Optical coherence tomography can detect stent strut coverage in vivo on a micron-scale level. We therefore used optical coherence tomography to examine strut coverage in patients with STEMI treated with paclitaxel-eluting stents (PES) and bare metal stents (BMS).

Methods and Results—

In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients with STEMI were randomized 3:1 to PES or BMS implantation. In a formal substudy, optical coherence tomography at 13 months was performed in 118 consecutive randomized patients (89 PES, 29 BMS) in whom 188 stents were assessed (146 PES and 42 BMS). A total of 44 139 stent struts were analyzed by an independent core laboratory blinded to stent assignment. The primary prespecified end point, the percentage of uncovered stent struts per lesion at follow-up, was 1.1±2.5% in BMS lesions versus 5.7±7.0% in PES lesions (
P
<0.0001). Malapposed struts were observed in 0.1±0.2% of BMS lesions versus 0.9±2.1% of PES lesions (
P
=0.0003). Percentage net volume obstruction was 36.0±15.4% with BMS and 19.2±11.3% with PES (
P
<0.0001).

Conclusions—

In patients with STEMI undergoing primary percutaneous coronary intervention, implantation of PES as compared with BMS significantly reduces neointimal hyperplasia but results in higher rates of uncovered and malapposed stent struts as assessed by optical coherence tomography at 13-month follow-up. Further studies are required to determine the clinical significance of these findings.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00433966.
Consumption of Added Sugars and Indicators of Cardiovascular Disease Risk Among US Adolescents
Authors: Welsh Jean A. , Sharma Andrea , Cunningham Solveig A. , Vos Miriam B.
Published: January 2011

Background—

Whereas increased carbohydrate and sugar consumption has been associated with higher cardiovascular disease risk among adults, little is known about the impact of high consumption of added sugars (caloric sweeteners) among US adolescents.

Methods and Results—

In a cross-sectional study of 2157 US adolescents in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004, dietary data from one 24-hour recall were merged with added sugar content data from the US Department of Agriculture MyPyramid Equivalents databases. Measures of cardiovascular disease risk were estimated by added sugar consumption level (<10%, 10 to <15%, 15 to <20%, 20 to <25%, 25 to <30%, and ≥30% of total energy). Multivariable means were weighted to be representative of US adolescents and variances adjusted for the complex sampling methods. Daily consumption of added sugars averaged 21.4% of total energy. Added sugars intake was inversely correlated with mean high-density lipoprotein cholesterol levels (mmol/L) which were 1.40 (95% confidence interval [CI] 1.36 to 1.44) among the lowest consumers and 1.28 (95% CI 1.23 to 1.33) among the highest (
P
trend =0.001). Added sugars were positively correlated with low-density lipoproteins (
P
trend =0.01) and geometric mean triglycerides (
P
trend =0.05). Among the lowest and highest consumers, respectively, low-density lipoproteins (mmol/L) were 2.24 (95% CI 2.12 to 2.37) and 2.44 (95% CI 2.34 to 2.53), and triglycerides (mmol/L) were 0.81 (95% CI 0.74, 0.88) and 0.89 (95% CI 0.83 to 0.96). Among those overweight/obese (≥85th percentile body-mass-index), added sugars were positively correlated with the homeostasis model assessment (
P
linear trend =0.004).

Conclusion—

Consumption of added sugars among US adolescents is positively associated with multiple measures known to increase cardiovascular disease risk.
C-Reactive Protein Overexpression Exacerbates Pressure Overload–Induced Cardiac Remodeling Through Enhanced Inflammatory Response
Authors: Nagai Toshiyuki , Anzai Toshihisa , Kaneko Hidehiro , Mano Yoshinori , Anzai Atsushi , Maekawa Yuichiro , Takahashi Toshiyuki , Meguro Tomomi , Yoshikawa Tsutomu , Fukuda Keiichi
Published: January 2011

Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload–induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa α-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47
phox
), and collagen-I, the number of infiltrating Mac-2–positive macrophages, nuclear localization of phosphorylated NF-κB/p65 (p-p65) in cardiomyocytes, nuclear NF-κB-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, IL-6, GPx3, p47
phox
, collagen-I, and transforming growth factor (TGF)-β1, the protein level of TGF-β1, and the numbers of Mac-2–positive macrophages and p-p65–positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload–induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress.
Peroxisome Proliferator-Activated Receptor β/δ Activation in Adult Hearts Facilitates Mitochondrial Function and Cardiac Performance Under Pressure-Overload Condition
Authors: Liu Jian , Wang Peiyong , Luo Jinwen , Huang Yao , He Lan , Yang Huan , Li Qingbao , Wu Sijie , Zhelyabovska Olga , Yang Qinglin
Published: January 2011

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPARβ/δ activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPARβ/δ in adult mice using a tamoxifen-inducible transgenic approach with Cre-LoxP recombination. The expression of PPARβ/δ mRNA and protein in cardiomyocytes of adult mice was substantially increased after short-term induction. In these mice, the cardiac expression of key factors involved in mitochondrial biogenesis, such as PPARγ coactivator-1, endogenous antioxidants Cu/Zn superoxide dismutase, and catalase, fatty acid, and glucose metabolism, such as carnitine palmitoyltransferase Ib, carnitine palmitoyltransferase II, and glucose transporter 4, were upregulated. Subsequently, myocardial oxidative metabolism was elevated concomitant with an increased mitochondrial DNA copy number and an enhanced cardiac performance. Moreover, activation of PPARβ/δ in the adult heart improved cardiac function and resisted progression to pathological development in mechanical stress condition. We conclude that PPARβ/δ activation in the adult heart will promote cardiac performance along with transcriptional upregulation of mitochondrial biogenesis and defense, as well as oxidative metabolism at basal and pressure-overload conditions.
An Infomax Algorithm Can Perform Both Familiarity Discrimination and Feature Extraction in a Single Network
Authors: Lulham Andrew , Bogacz Rafal , Vogt Simon , Brown Malcolm W.
Published: January 2011

Psychological experiments have shown that the capacity of the brain for discriminating visual stimuli as novel or familiar is almost limitless. Neurobiological studies have established that the perirhinal cortex is critically involved in both familiarity discrimination and feature extraction. However, opinion is divided as to whether these two processes are performed by the same neurons. Previously proposed models have been unable to simultaneously extract features and discriminate familiarity for large numbers of stimuli. We show that a well-known model of visual feature extraction, Infomax, can simultaneously perform familiarity discrimination and feature extraction efficiently. This model has a significantly larger capacity than previously proposed models combining these two processes, particularly when correlation exists between inputs, as is the case in the perirhinal cortex. Furthermore, we show that once the model fully extracts features, its ability to perform familiarity discrimination increases markedly.