bluuebunny/crossref_metadata_2025 huggingface dataset:
Inactivation of Junctional Adhesion Molecule-A Enhances Antitumoral Immune Response by Promoting Dendritic Cell and T Lymphocyte Infiltration
Authors: Murakami Masato , Francavilla Chiara , Torselli Ilaria , Corada Monica , Maddaluno Luigi , Sica Antonio , Matteoli Gianluca , Iliev Iliyan Dimitrov , Mantovani Alberto , Rescigno Maria , Cavallaro Ugo , Dejana Elisabetta
Published: February 2010

Junctional adhesion molecule-A (JAM-A)–null dendritic cells (DCs) are more motile and effective than their wild-type counterpart in promoting contact hypersensitivity reaction. Here, we show that the growth and aggressiveness of pancreatic islet cell carcinoma induced by SV40 T antigen expression in β cells (Rip1Tag2 mice) are significantly reduced in JAM-A–null mice. Because these tumor cells do not express JAM-A, we focused on changes in stroma reactivity. In the absence of JAM-A, tumors showed a small but significant reduction in angiogenesis and a marked increase in the immune reaction with enhanced infiltration of DCs (CD11c+ and MHC-II+) and CD4+ and CD8+ lymphocytes. In contrast, phagocyte number was not affected. DC capacity to produce cytokines was not significantly altered, but transmigration through JAM-A–null endothelial cells was increased as compared with JAM-A–positive endothelium. On adoptive transfer, JAM-A−/− DCs were recruited to tumors at slightly but significantly higher rate than JAM-A+/+ DCs. Ablation of CD4+ and CD8+ cells with specific antibodies abrogated the inhibitory effect of JAM-A deletion on tumor growth and angiogenesis. These findings support the idea that, in the Rip1Tag2 tumor model, abrogation of JAM-A reduces cancer development by increasing antitumor immune response. Cancer Res; 70(5); 1759–65
Loss of FOXA1/2 Is Essential for the Epithelial-to-Mesenchymal Transition in Pancreatic Cancer
Authors: Song Yan , Washington M. Kay , Crawford Howard C.
Published: February 2010

FOXA1 and FOXA2, members of the forkhead transcription factor family, are critical for epithelial differentiation in many endoderm-derived organs, including the pancreas. However, their role in tumor progression is largely unknown. Here, we identified FOXA1 and FOXA2 as important antagonists of the epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDA) through their positive regulation of E-cadherin and maintenance of the epithelial phenotype. In human PDA samples, FOXA1/2 are expressed in all epithelia from normal to well-differentiated cancer cells, but are lost in undifferentiated cancer cells. In PDA cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. Conversely, ectopic FOXA1/2 expression can potently neutralize several EMT-related E-cadherin repressive mechanisms. Finally, ectopic FOXA2 expression could reactivate E-cadherin expression in a PDA cell line with extensive promoter hypermethylation. In fact, demethylation-mediated reactivation of E-cadherin expression in these cells required concurrent reactivation of endogenous FOXA2 expression. We conclude that suppression of FOXA1/2 expression is both necessary and sufficient for EMT during PDA malignant progression. Cancer Res; 70(5); 2115–25
Vitamin D Deficiency Promotes Human Breast Cancer Growth in a Murine Model of Bone Metastasis
Authors: Ooi Li Laine , Zhou Hong , Kalak Robert , Zheng Yu , Conigrave Arthur D. , Seibel Markus J. , Dunstan Colin R.
Published: February 2010

Vitamin D exerts antiproliferative, prodifferentiation, and proapoptotic effects on nonclassic target tissues such as breast. Blood levels of 25-hydroxyvitamin D [25(OH)D], the most sensitive indicator of vitamin D status, are inversely correlated with breast cancer risk; however, a causal relationship between vitamin D deficiency and breast cancer growth in bone has not been assessed. We examined the effect of vitamin D deficiency on the intraskeletal growth of the human breast cancer cell line MDA-MB-231-TxSA in a murine model of malignant bone lesions. Subsets of mice were treated concurrently with osteoprotegerin (OPG) to abrogate bone resorption. Outcomes were assessed by repeated radiographic and end-point micro–computed tomography and histologic analyses. Mice weaned onto a vitamin D–free diet developed vitamin D deficiency within 4 weeks [mean ± SE serum 25(OH)D: 11.5 ± 0.5 nmol/L], which was sustained throughout the study and was associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D–deficient than in vitamin D–sufficient mice after 2 weeks (radiographic osteolysis: +121.5%; histologic tumor area: +314%; P < 0.05). Although OPG treatment reduced the size of radiographic osteolyses and tumor area in both groups, tumors remained larger in OPG-treated vitamin D–deficient compared with OPG-treated vitamin D–sufficient mice (0.53 ± 0.05 mm2 versus 0.19 ± 0.05 mm2; P < 0.05). We conclude that vitamin D deficiency promotes the growth of human breast cancer cells in the bones of nude mice. These effects are partly mediated through secondary changes in the bone microenvironment, along with direct effects of vitamin D on tumor growth. Cancer Res; 70(5); 1835–44
Celastrol Suppresses Angiogenesis-Mediated Tumor Growth through Inhibition of AKT/Mammalian Target of Rapamycin Pathway
Authors: Pang Xiufeng , Yi Zhengfang , Zhang Jing , Lu Binbin , Sung Bokyung , Qu Weijing , Aggarwal Bharat B. , Liu Mingyao
Published: February 2010

Understanding the molecular basis and target of traditional medicine is critical for drug development. Celastrol, derived from Trypterygium wilfordii Hook F. (“Thunder of God Vine”), a traditional Chinese medicine plant, has been assigned anticancer activities, but its mechanism is not well understood. Here, we investigated whether Celastrol could inhibit angiogenesis-mediated tumor growth and, if so, through what mechanism. When given s.c. to mice bearing human prostate cancer (PC-3 cell) xenografts, Celastrol (2 mg/kg/d) significantly reduced the volume and the weight of solid tumors and decreased tumor angiogenesis. We found that this agent inhibited vascular endothelial growth factor (VEGF)–induced proliferation, migration, invasion, and capillary-like structure formation by primary cultured human umbilical vascular endothelial cells (HUVEC) in a dose-dependent manner. Furthermore, Celastrol abrogated VEGF-induced sprouting of the vessels from aortic rings and inhibited vascular formation in the Matrigel plug assay in vivo. To understand the molecular mechanism of these activities, we next examined the signaling pathways in treated HUVECs and PC-3 tumor cells. Celastrol suppressed the VEGF-induced activation of AKT, mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (P70S6K). Additionally, we found that Celastrol inhibited the proliferation of prostate cancer cells and induced apoptosis, and these effects correlated with the extent of inhibition of AKT/mTOR/P70S6K signaling. Taken together, our results suggest that Celastrol targets the AKT/mTOR/P70S6K pathway, which leads to suppression of tumor growth and angiogenesis. Cancer Res; 70(5); 1951–9
Role of Secreted Frizzled-Related Protein 3 in Human Renal Cell Carcinoma
Authors: Hirata Hiroshi , Hinoda Yuji , Ueno Koji , Majid Shahana , Saini Sharanjot , Dahiya Rajvir
Published: February 2010

The secreted frizzled-related protein (sFRP) family plays an important role in the inhibition of the Wnt signaling pathway in various cancers. The functional significance of Wnt antagonist sFRP3 has not been investigated in renal cancer. We performed tissue microarray and found that the level of sFRP3 protein was high in normal kidney, low in primary renal cancer tissues, and high in metastatic renal cancer tissues. Therefore, we hypothesized that sFRP3 may play an important role in metastatic renal cancer. To test this hypothesis, we performed a series of experiments to determine the role of sFRP3 using primary and metastatic renal cancer cell lines. Functional analysis showed increased numbers of viable and invaded cells and tube formation and decreased numbers of apoptotic cells in the sFRP3-transfected renal cancer cell line A498. Promotion of tumor growth was also observed in nude mice injected with sFRP3-transfected A498 cells. In contrast, the number of viable cells and invasive cells was decreased in sFRP3 mRNA knockdown metastatic cells (ACHN and Hs891.T). To investigate the mechanism of sFRP3 function, we performed microarray analysis to see which genes were upregulated or downregulated by sFRP3 expression. Among these genes, MMP-3 and ANGPT1 were significantly upregulated in sFRP3-transfected cells. In conclusion, this is the first report to show that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells. Cancer Res; 70(5); 1896–905
Immunotherapeutic Suppression of Indoleamine 2,3-Dioxygenase and Tumor Growth with Ethyl Pyruvate
Authors: Muller Alexander J. , DuHadaway James B. , Jaller Daniel , Curtis Peter , Metz Richard , Prendergast George C.
Published: February 2010

Efforts to improve cancer care in the developing world will benefit from the identification of simple, inexpensive, and broadly applicable medical modalities based on emergent innovations in treatment, such as targeting mechanisms of tumoral immune tolerance. In this report, we offer preclinical evidence that the low-cost, anti-inflammatory agent ethyl pyruvate elicits a potent immune-based antitumor response through inhibition of indoleamine 2,3-dioxygenase (IDO), a key tolerogenic enzyme for many human tumors. Consistent with its reported ability to interfere with NF-κB function, ethyl pyruvate blocks IDO induction both in vitro and in vivo. Antitumor activity was achieved in mice with a noncytotoxic dosing regimen of ethyl pyruvate shown previously to protect against lethality from sepsis. Similar outcomes were obtained with the functional ethyl pyruvate analogue 2-acetamidoacrylate. Ethyl pyruvate was ineffective at suppressing tumor outgrowth in both athymic and Ido1-deficient mice, providing in vivo corroboration of the importance of T-cell–dependent immunity and IDO targeting for ethyl pyruvate to achieve antitumor efficacy. Although ethyl pyruvate has undergone early-phase clinical testing, this was done without consideration of its possible applicability to cancer. Our findings that IDO is effectively blocked by ethyl pyruvate treatment deepen emerging links between IDO and inflammatory processes. Further, these findings rationalize oncologic applications for this agent by providing a compelling basis to reposition ethyl pyruvate as a low-cost immunochemotherapy for clinical evaluation in cancer patients. Cancer Res; 70(5); 1845–53
Critical Role of Gα12 and Gα13 for Human Small Cell Lung Cancer Cell Proliferation In vitro and Tumor Growth In vivo
Authors: Grzelinski Marius , Pinkenburg Olaf , Büch Thomas , Gold Maike , Stohr Stefanie , Kalwa Hermann , Gudermann Thomas , Aigner Achim
Published: February 2010

Purpose: In small cell lung cancer cells (SCLC), various autocrine stimuli lead to the parallel activation of Gq/11 and G12/13 proteins. Although the contribution of the Gq/11-phospholipase C-β cascade to mitogenic effects in SCLC cells is well established, the relevance of G12/13 signaling is still elusive. In other tumor entities, G12/13 activation promotes invasiveness without affecting cellular proliferation. Here, we investigate the role of G12/13-dependent signaling in SCLC.

Experimental Design: We used small hairpin RNA–mediated targeting of Gα12, Gα13, or both in H69 and H209 cells and analyzed the effects of Gα12 and/or Gα13 knockdown on tumor cells in vitro, tumor growth in vivo, and mitogen-activated protein kinase (MAPK) activation.

Results: Lentiviral expression of small hairpin RNAs resulted in robust and specific Gα12 and Gα13 knockdown as well as markedly inhibited proliferation, colony formation, and bradykinin-promoted stimulation of cell growth. Analyzing the activation status of all three major MAPK families revealed nonredundant functions of Gα12 and Gα13 in SCLC and a marked p42/p44 activation upon Gα12/Gα13 knockdown. In a s.c. tumor xenograft mouse model, Gα12 or Gα13 downregulation led to decreased tumor growth due to reduced tumor cell proliferation. More importantly, Gα12/Gα13 double knockdown completely abolished H69 tumorigenicity in mice.

Conclusions: Gα12 and Gα13 exert a complex pattern of nonredundant effects in SCLC, and in contrast to other tumor types, SCLC cell proliferation in vitro and tumorigenicity in vivo critically depend on G12/13 signaling. Due to the complete abolishment of tumorgenicity in our study, RNAi-mediated double knockdown may provide a promising new avenue in SCLC treatment. Clin Cancer Res; 16(5); 1402–15
An Escherichia coli-Based Cell-Free System for Large-Scale Production of Functional Mammalian Membrane Proteins Suitable for X-Ray Crystallography
Authors: Nguyen Tuan A. , Lieu Samantha S. , Chang Geoffrey
Published: February 2010

A cell-free expression system using an Escherichia coli extract was adapted for large-scale expression and purification of mammalian membrane proteins. The system was tested with a set of human membrane proteins of different sizes, numbers of transmembrane domains, oligomeric arrangements, and native membrane locations. Tens of milligrams of protein were readily expressed and purified from an overnight cell-free reaction. Both reaction ‘mode A’ (proteins were expressed as precipitant) and ‘mode B’ (proteins were expressed in the presence of mild detergents to keep them soluble) were investigated. The combination of ‘mode B’ and the right detergents, used in the subsequent extraction and purification steps, is critical for obtaining properly folded proteins (CX32 and VDAC1) that can be crystallized and diffracted (VDAC1). The E. coli cell-free system is capable of efficient expression of many mammalian membrane proteins. However, fine-tuning of the system, especially to facilitate proper protein folding, will be required for each specific target.
Physical Changes in Human Meibum with Age as Measured by Infrared Spectroscopy
Authors: Borchman Douglas , Foulks Gary N. , Yappert Marta C. , Kakar Shelly , Podoll Nathan , Rychwalski Paul , Schwietz Eric
Published: February 2010

Both lipids and mucins contribute to the stability of the tear film and lipids may inhibit tears from evaporating. Younger people have lower lipid viscosity, higher lipid volume, and a lower rate of tear evaporation. Since age-related changes in human meibum composition and conformation have never been investigated, as a basis for the study of lipid-associated changes with meibomian gland dysfunction, we used the power of infrared spectroscopy to characterize hydrocarbon chain conformation and packing in meibum from humans without dry eye symptoms in relation to age and sex. Meibum from normal human donors ranging in age from 3 to 88 years was studied. Meibum phase transitions were quantified by fitting them to a 4-parameter 2-state sigmoidal equation. Human meibum order and phase transition temperatures decrease with age and this trend may be attributed to lipid compositional changes. If meibum has the same thermodynamic properties on the surface of the tears as it does on the lid margin, a decrease in lipid-lipid interaction strength with increasing age could decrease the stability of tears since lipid-lipid interactions on the tear surface must be broken for the tear film to break up. This study also serves as a foundation to examine meibum conformational differences in meibum from people with meibomian gland dysfunction.
Interrelationship of Cytokines, Hypothalamic-Pituitary-Adrenal Axis Hormones, and Psychosocial Variables in the Prediction of Preterm Birth
Authors: Pearce B.D. , Grove J. , Bonney E.A. , Bliwise N. , Dudley D.J. , Schendel D.E. , Thorsen P.
Published: February 2010

Background/Aims: To examine the relationship of biological mediators (cytokines, stress hormones), psychosocial, obstetric history, and demographic factors in the early prediction of preterm birth (PTB) using a comprehensive logistic regression model incorporating diverse risk factors. Methods: In this prospective case-control study, maternal serum biomarkers were quantified at 9–23 weeks’ gestation in 60 women delivering at <37 weeks compared to 123 women delivering at term. Biomarker data were combined with maternal sociodemographic factors and stress data into regression models encompassing 22 preterm risk factors and 1st-order interactions. Results: Among individual biomarkers, we found that macrophage migration inhibitory factor (MIF), interleukin-10, C-reactive protein (CRP), and tumor necrosis factor-α were statistically significant predictors of PTB at all cutoff levels tested (75th, 85th, and 90th percentiles). We fit multifactor models for PTB prediction at each biomarker cutoff. Our best models revealed that MIF, CRP, risk-taking behavior, and low educational attainment were consistent predictors of PTB at all biomarker cutoffs. The 75th percentile cutoff yielded the best predicting model with an area under the ROC curve of 0.808 (95% CI 0.743–0.874). Conclusion: Our comprehensive models highlight the prominence of behavioral risk factors for PTB and point to MIF as a possible psychobiological mediator.
Curcumin Inhibits Transforming Growth Factor-β Activity via Inhibition of Smad Signaling in HK-2 Cells
Authors: Hu Ying , Liang Hua , Du Yong , Zhu Yongliang , Wang Xuanding
Published: February 2010

Background: Curcumin, a polyphenolic compound derived from rhizomes of Curcuma spp., has been shown to possess potent anti-fibrotic properties. Here, we investigate the role of curcumin in modulating the profibrotic action of TGF-β in human proximal tubule cells (HK-2) and its underlying mechanisms. Methods: HK-2 cells were stimulated with 5 ng/ml TGF-β1. The effects of curcumin on TGF-β1-regulated gene expression and Smad phosphorylation were analyzed by RT-PCR, ELISA and Western blotting. Results:Curcumin inhibited TGF-β1-induced plasminogen activator inhibitor-1 (PAI-1), α-smooth muscle actin (α-SMA) mRNA and protein expression. Curcumin suppressed not only TGF-β1-induced Smad2 phosphorylation in a dose- and time-dependent manner, but also the nuclear accumulation of receptor-regulated Smads (R-Smad), Smad2 and Smad3. A serine/threonine protein phosphatase inhibitor (microcystin) could partly reverse the inhibitory effect of curcumin on Smad phosphorylation. Conclusions: Curcumin blocks the profibrotic actions of TGF-β on HK-2 cells through the down-regulation of the Smad signaling pathway, and curcumin may have some similar effect as serine/threonine protein phosphatases. Our findings suggest curcumin as a potential candidate for treatment of tubulointerstitial fibrosis.
Curcumin Inhibits the Growth, Induces Apoptosis and Modulates the Function of Pituitary Folliculostellate Cells
Authors: Schaaf Christian , Shan Bing , Onofri Chiara , Stalla Günter K. , Arzt Eduardo , Schilling Tobias , Perone Marcelo J. , Renner Ulrich
Published: February 2010

The polyphenol curcumin (diferuloylmethane) is the active componenet of the spice plant Curcuma longa and has been shown to exert multiple actions on mammalian cells. We have studied its effect on folliculostellate (FS) TtT/GF mouse pituitary cells, representative of a multifunctional, endocrine inactive cell type of the anterior pituitary. Proliferation of TtT/GF cells was inhibited by curcumin in a monolayer cell culture and in the colony formation assay in soft agar. Fluorescence-activated cell-sorting (FACS) analysis demonstrated curcumin-induced cell cycle arrest at G2/M accompanied by inhibition of cyclin D1 protein expression. Curcumin had a small effect on necrosis of TtT/GF cells, but it mainly stimulated apoptosis as demonstrated by FACS analysis (Annexin V-fluorescein isothiocyannate/7-aminoactinomycin D staining). Curcumin-induced apoptosis involved suppression of Bcl-2, stimulation of cleaved caspase-3 and induction of DNA fragmentation. Functional studies on FS cell-derived compounds showed that curcumin inhibited mRNA synthesis and release of angiogenic vascular endothelial growth factor-A (VEGF-A). Immune-like functions of FS cells were impaired since curcumin downregulated Toll-like receptor 4, reduced nuclear factor-ĸB expression and suppressed bacterial endotoxin-induced interleukin-6 (IL-6) secretion. The inhibitory action of curcumin on VEGF-A and IL-6 production was also found in primary rat pituitary cell cultures, in which FS cells are the only source of these proteins. The observed effects of curcumin on FS cell growth, apoptosis and functions may have therapeutic consequences for the intrapituitary regulation of hormone production and release as well as for pituitary tumor pathogenesis.
Performance of a New Leadless Implantable Cardiac Monitor in Detecting and Quantifying Atrial Fibrillation Results of the XPECT Trial
Authors: Hindricks Gerhard , Pokushalov Evgueny , Urban Lubos , Taborsky Milos , Kuck Karl-Heinz , Lebedev Dmitry , Rieger Guido , Pürerfellner Helmut
Published: February 2010

Background—

Current methods for detecting atrial fibrillation (AF) have limited diagnostic yield. Continuous monitoring with automatic arrhythmia detection and classification may improve detection of symptomatic and asymptomatic AF and subsequent patient treatment. The study purpose was to quantify the performance of the first implantable leadless cardiac monitor (ICM) with dedicated AF detection capabilities.

Methods and Results—

Patients (n=247) with an implanted ICM (Reveal XT, Medtronic Inc, Minneapolis, Minn) who were likely to present with paroxysmal AF were selected. A special Holter device stored 46 hours of subcutaneously recorded ECG, ICM markers, and 2 surface ECG leads. The ICM automatic arrhythmia classification was compared with the core laboratory classification of the surface ECG. Of the 206 analyzable Holter recordings collected, 76 (37%) contained at least 1 episode of core laboratory classified AF. The sensitivity, specificity, positive predictive value, and negative predictive value for identifying patients with any AF were 96.1%, 85.4%, 79.3%, and 97.4%, respectively. The AF burden measured with the ICM was very well correlated with the reference value derived from the Holter (Pearson coefficient=0.97). The overall accuracy of the ICM for detecting AF was 98.5%.

Conclusions—

In this ICM validation study, the dedicated AF detection algorithm reliably detected the presence or absence of AF and the AF burden was accurately quantified. The ICM is a promising new diagnostic and monitoring tool for the clinician to treat AF patients independently of symptoms. Long-term studies are needed to evaluate the clinical benefits of the technology.

Clinical Trial Registration—

clinicaltrials.gov Identifier NCT00680927.
Changes in Left and Right Ventricular Mechanics During the Mueller Maneuver in Healthy Adults
Authors: Koshino Yuki , Villarraga Hector R. , Orban Marek , Bruce Charles J. , Pressman Gregg S. , Leinveber Pavel , Saleh Haydar K. , Konecny Tomas , Kara Tomas , Somers Virend K. , Lopez-Jimenez Francisco
Published: February 2010

Background—

Obstructive sleep apnea is highly prevalent in patients with cardiovascular disease and has detrimental effects on systolic and diastolic function of the ventricles. In this research, the changes in strain (S) and strain rate (SR) during the performance of the Mueller maneuver (MM) in an effort to better understand how negative intrathoracic pressures affect ventricular mechanics.

Methods and Results—

The MM was performed to maintain a target intrathoracic pressure of −40 mm Hg. Echocardiography was used to measure various parameters of cardiac structure and function. Myocardial deformation measurements were performed using tissue speckle tracking. Twenty-four healthy subjects (9 women; mean age, 30�6 years) were studied. Global left ventricular longitudinal S in systole and SR in early filling were significantly decreased during the MM (S: baseline, −17.0�1.6%; MM, −14.5�2.2%;
P
<0.0001, SR: baseline, 1.09�0.20 s
−1
; MM, 0.92�0.21 s
−1
;
P
=0.01). Global right ventricular longitudinal S was also significantly decreased during the MM (baseline, −22.0�3.1%; MM, −17.2�2.5%;
P
<0.0001), as was global right ventricular longitudinal systolic SR (baseline, −1.34�0.35 s
−1
; MM, −1.02�0.21 s
−1
;
P
=0.0006).

Conclusions—

Left ventricular and right ventricular longitudinal deformation are significantly reduced during the MM. These results suggest that negative intrathoracic pressure during apnea may contribute to changes in myocardial mechanics. These results could help explain the observed changes in left ventricular and right ventricular mechanics in patients with obstructive sleep apnea.
The Role of Social Support in Health Status and Depressive Symptoms After Acute Myocardial Infarction
Authors: Leifheit-Limson Erica C. , Reid Kimberly J. , Kasl Stanislav V. , Lin Haiqun , Jones Philip G. , Buchanan Donna M. , Parashar Susmita , Peterson Pamela N. , Spertus John A. , Lichtman Judith H.
Published: February 2010

Background—

Prior studies have associated low social support (SS) with increased rehospitalization and mortality after acute myocardial infarction. However, relatively little is known about whether similar patterns exist for other outcomes, such as health status and depressive symptoms, and whether these patterns vary by sex.

Methods and Results—

Using data from 2411 English- or Spanish-speaking patients with acute myocardial infarction enrolled in a 19-center prospective study, we examined the association of SS (low, moderate, high) with health status (angina, disease-specific quality of life, general physical and mental functioning) and depressive symptoms over the first year of recovery. Overall and sex-stratified associations were evaluated using mixed-effects Poisson and linear regression, adjusting for site, baseline health status, baseline depressive symptoms, and demographic and clinical factors. Patients with the lowest SS (relative to those with the highest) had increased risk of angina (relative risk, 1.27; 95% confidence interval [CI], 1.10, 1.48); lower disease-specific quality of life (mean difference [β]=−3.33; 95% CI, −5.25, −1.41), lower mental functioning (β=−1.72; 95% CI, −2.65, −0.79), and more depressive symptoms (β=0.94; 95% CI, 0.51, 1.38). A nonsignificant trend toward lower physical functioning (β=−0.87; 95% CI, −1.95, 0.20) was observed. In sex-stratified analyses, the relationship between SS and outcomes was stronger for women than for men, with a significant SS-by-sex interaction for disease-specific quality of life, physical functioning, and depressive symptoms (all
P
<0.02).

Conclusions—

Lower SS is associated with worse health status and more depressive symptoms over the first year of acute myocardial infarction recovery, particularly for women.
Representation of Women in Randomized Clinical Trials of Cardiovascular Disease Prevention
Authors: Melloni Chiara , Berger Jeffrey S. , Wang Tracy Y. , Gunes Funda , Stebbins Amanda , Pieper Karen S. , Dolor Rowena J. , Douglas Pamela S. , Mark Daniel B. , Newby L. Kristin
Published: February 2010

Background—

The 2007 American Heart Association guidelines for cardiovascular disease prevention in women drew heavily on results from randomized clinical trials; however, representation of women in trials of cardiovascular disease prevention has not been systematically assessed.

Methods and Results—

We abstracted 156 randomized clinical trials cited by the 2007 women’s prevention guidelines to determine female representation over time and by clinical indication, prevention type, location of trial conduct, and funding source. Both women and men were represented in 135 of 156 (86.5%) trials; 20 trials enrolled only men; 1 enrolled only women. Among all trials, the proportion of women increased significantly over time, from 9% in 1970 to 41% in 2006. Considering only trials that enrolled both women and men, female enrollment was 18% in 1970 and increased to 34% in 2006. Female representation was higher in international versus United States–only trials (32.7% versus 26.7%) and primary versus secondary prevention trials (42.6% versus 26.6%). Female enrollment was comparable in government/foundation-funded versus industry-funded trials (31.9% versus 31.5%). Representation of women was highest among trials in hypertension (44%), diabetes (40%), and stroke (38%) and lowest for heart failure (29%), coronary artery disease (25%), and hyperlipidemia (28%). By contrast, women accounted for 53% of all individuals with hypertension, 50% with diabetes, 51% with heart failure, 49% with hyperlipidemia, and 46% with coronary artery disease. Sex-specific results were discussed in only 31% of primary trial publications.

Conclusions—

Enrollment of women in randomized clinical trials has increased over time but remains low relative to their overall representation in disease populations. Efforts are needed to reach a level of representation that is adequate to ensure evidence-based sex-specific recommendations.
Hemodynamic Support by Left Ventricular Assist Devices Reduces Cardiomyocyte DNA Content in the Failing Human Heart
Authors: Wohlschlaeger Jeremias , Levkau Bodo , Brockhoff Gero , Schmitz Klaus Jürgen , von Winterfeld Moritz , Takeda Atsushi , Takeda Nobuakira , Stypmann Jörg , Vahlhaus Christian , Schmid Christof , Pomjanski Natalia , Böcking Alfred , Baba Hideo Andreas
Published: February 2010

Background—

Whether adult cardiomyocytes have the capacity to regenerate in response to injury and, if so, to what extent are still issues of intense debate. In human heart failure, cardiomyocytes harbor a polyploid genome. A unique opportunity to study the mechanism of polyploidization is provided through the setting of hemodynamic support by left ventricular assist devices. Hence, the cardiomyocyte DNA content, nuclear morphology, and number of nuclei per cell were assessed before and after left ventricular assist device support.

Methods and Results—

In 23 paired myocardial samples, cardiomyocyte ploidy was investigated by DNA image cytometry, flow cytometry, and in situ hybridization. Nuclear cross-sectional area and perimeters were measured morphometrically, and the binucleated cardiomyocytes were counted. The median of the cardiomyocyte DNA content and the number of polyploid cardiomyocytes both declined significantly from 6.79 c to 4.7 c and 40.2% to 23%, whereas a significant increase in diploid cardiomyocytes from 33.4% to 50.3% and in binucleated cardiomyocytes from 4.5% to 10% after unloading was observed.

Conclusions—

The decrease in polyploidy and increase in diploidy after left ventricular assist device suggest a numeric increase in diploid cardiomyocytes (eg, through cell cycle progression with completion of mitosis or by increased stem cells). The cardiac regeneration that follows may serve as a morphological correlate of the recovery observed in some patients after unloading.
Frail Patients Are at Increased Risk for Mortality and Prolonged Institutional Care After Cardiac Surgery
Authors: Lee Dana H. , Buth Karen J. , Martin Billie-Jean , Yip Alexandra M. , Hirsch Gregory M.
Published: February 2010

Background—

Frailty is an emerging concept in medicine yet to be explored as a risk factor in cardiac surgery. Where elderly patients are increasingly referred for cardiac surgery, the prevalence of a frail group among these is also on the rise. We assessed frailty as a risk factor for adverse outcomes after cardiac surgery.

Methods and Results—

Functional measures of frailty and clinical data were collected prospectively for all cardiac surgery patients at a single center. Frailty was defined as any impairment in activities of daily living (Katz index), ambulation, or a documented history of dementia. Of 3826 patients, 157 (4.1%) were frail. Frail patients were older, were more likely to be female, and had risk factors for adverse surgical outcomes. By logistic regression, frailty was an independent predictor of in-hospital mortality (odds ratio 1.8, 95% CI 1.1 to 3.0), as well as institutional discharge (odds ratio 6.3, 95% CI 4.2 to 9.4). Frailty was an independent predictor of reduced midterm survival (hazard ratio 1.5, 95% CI 1.1 to 2.2).

Conclusions—

Frailty is a risk for postoperative complications and an independent predictor of in-hospital mortality, institutional discharge, and reduced midterm survival. Frailty screening improves risk assessment in cardiac surgery patients and may identify a subgroup of patients who may benefit from innovative processes of care.
Passive Stiffness of Myocardium From Congenital Heart Disease and Implications for Diastole
Authors: Chaturvedi Rajiv R. , Herron Todd , Simmons Robert , Shore Darryl , Kumar Pankaj , Sethia Babulal , Chua Felix , Vassiliadis Efstathios , Kentish Jonathan C.
Published: February 2010

Background—

In ventricular dilatation or hypertrophy, an elevated end-diastolic pressure is often assumed to be secondary to increased myocardial stiffness, but stiffness is rarely measured in vivo because of difficulty. We measured in vitro passive stiffness of volume- or pressure-overloaded myocardium mainly from congenital heart disease.

Methods and Results—

Endocardial ventricular biopsies were obtained at open heart surgery (n=61; pressure overload, 36; volume-overload, 19; dilated cardiomyopathy, 4; normal donors, 2). In vitro passive force-extension curves and the stiffness modulus were measured in skinned tissue: muscle strips, strips with myofilaments extracted (mainly extracellular matrix), and myocytes. Collagen content (n=38) and titin isoforms (n=16) were determined. End-diastolic pressure was measured at cardiac catheterization (n=14). Pressure-overloaded tissue (strips, extracellular matrix, myocytes) had a 2.6- to 7.0-fold greater force and stiffness modulus than volume-overloaded tissue. Myocyte force and stiffness modulus at short stretches (0.05 resting length, L
0
) was pressure-overloaded >normal≈volume-overloaded>dilated cardiomyopathy. Titin N2B:N2BA isoform ratio varied little between conditions. The extracellular matrix contributed more to force at 0.05 L
0
in pressure-overloaded (35.1%) and volume-overloaded (17.4%) strips than normal myocardium. Stiffness modulus increased with collagen content in pressure-overloaded but not volume-overloaded strips. In vitro stiffness modulus at 0.05 L
0
was a good predictor of in vivo end-diastolic pressure for pressure-overloaded but not volume-overloaded ventricles and estimated normal end-diastolic pressure as 5 to 7 mm Hg.

Conclusions—

An elevated end-diastolic pressure in pressure-overloaded, but not volume-overloaded, ventricles was related to increased myocardial stiffness. The greater stiffness of pressure-overloaded compared with volume-overloaded myocardium was due to the higher stiffness of both the extracellular matrix and myocytes. The transition from normal to very-low stiffness myocytes may mark irreversible dilatation.
Mechanisms by Which Adenosine Restores Conduction in Dormant Canine Pulmonary Veins
Authors: Datino Tomás , Macle Laurent , Qi Xiao-Yan , Maguy Ange , Comtois Philippe , Chartier Denis , Guerra Peter G. , Arenal Angel , Fernández-Avilés Francisco , Nattel Stanley
Published: February 2010

Background—

Adenosine acutely reconnects pulmonary veins (PVs) after radiofrequency application, revealing “dormant conduction” and identifying PVs at risk of reconnection, but the underlying mechanisms are unknown.

Methods and Results—

Canine PV and left-atrial (LA) action potentials were recorded with standard microelectrodes and ionic currents with whole-cell patch clamp before and after adenosine perfusion. PVs were isolated with radiofrequency current application in coronary-perfused LA-PV preparations. Adenosine abbreviated action potential duration similarly in PV and LA but significantly hyperpolarized resting potential (by 3.9±0.5%;
P
<0.05) and increased dV/dt
max
(by 34±10%) only in PV. Increased dV/dt
max
was not due to direct effects on I
Na
, which was reduced similarly by adenosine in LA and PV but correlated with resting-potential hyperpolarization (
r
=0.80). Adenosine induced larger inward rectifier K
+
current (I
KAdo
) in PV (eg, −2.28±0.04 pA/pF; −100 mV) versus LA (−1.28±0.16 pA/pF). Radiofrequency ablation isolated PVs by depolarizing resting potential to voltages positive to −60 mV. Adenosine restored conduction in 5 dormant PVs, which had significantly more negative resting potentials (−57±6 mV) versus nondormant (−46±5 mV, n=6;
P
<0.001) before adenosine. Adenosine hyperpolarized both, but more negative resting-potential values after adenosine in dormant PVs (−66±6 mV versus −56±6 mV in nondormant;
P
<0.001) were sufficient to restore excitability. Adenosine effects on resting potential and conduction reversed on washout. Spontaneous recovery of conduction occurring in dormant PVs after 30 to 60 minutes was predicted by the adenosine response.

Conclusions—

Adenosine selectively hyperpolarizes canine PVs by increasing I
KAdo
. PVs with dormant conduction show less radiofrequency-induced depolarization than nondormant veins, allowing adenosine-induced hyperpolarization to restore excitability by removing voltage-dependent I
Na
inactivation and explaining the restoration of conduction in dormant PVs.
Vascular Inflammation in Obesity and Sleep Apnea
Authors: Jelic Sanja , Lederer David J. , Adams Tessa , Padeletti Margherita , Colombo Paolo C. , Factor Phillip H. , Le Jemtel Thierry H.
Published: February 2010

Background—

Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. We investigated directly whether the endothelial alterations that are attributed commonly to obesity are in fact related to OSA.

Methods and Results—

Seventy-one subjects with a body mass index ranging from normal to obese underwent attended polysomnography. To assess vascular inflammation and oxidative stress directly, we quantified the expression of nuclear factor-κB and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified the expression of endothelial NO synthase (eNOS) and phosphorylated eNOS. Vascular reactivity was measured by brachial artery flow-mediated dilation. Expression of eNOS and phosphorylated eNOS and flow-mediated dilation were significantly lower, whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of nuclear factor-κB was greater in obese OSA patients than in obese OSA-free subjects (
P
=0.004). Protein expression and flow-mediated dilation were not significantly affected by increasing body mass index or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-κB significantly decreased in OSA patients who adhered to continuous positive airway pressure ≥4 hours daily.

Conclusions—

Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients.
Gemeinschaft und Gesellschaft
Authors: Bond Niall
Published: February 2010

Ferdinand Tönnies's oeuvre Gemeinschaft und Gesellschaft, published in 1887, has been seminal for the social and human sciences in general, and is no less interesting for intellectual historians and theoreticians of concept formation in particular. Tönnies subscribed to the belief that terms could be rendered less ambiguous, defining the words Gemeinschaft and Gesellschaft more narrowly than their contemporary usage. In so doing, he sought to reconcile a heterogeneous agenda initially consisting in offering a diagnosis of vast historical developments and later consisting in providing heuristic tools to analyze individual relationships. This article examines the origins of the concepts and their politicized transformation prior to and subsequent to the publication of his work. As such, it takes on the transformation of Gemeinschaft during the romantic era and its revival by Germany's nationalist right wing and contrasts it with its appropriation by left-leaning communitarian movements in the English-speaking world. The polysemy of the terms in the German language accounts for their semantic evolution, for amalgamations of meanings within Tönnies's conceptual system, and for conundrums in translating the work into English or French. Although the terms were erroneously supposed to have been immediately applicable as ideal types, their adaptation, inter alia by Max Weber or by Talcott Parsons in the form of pattern variables, has been important in the reception of Tönnies's work in the social sciences.
Representing the Enemy
Authors: Campos Pérez Lara
Published: February 2010

This article takes a close look at the iconographic construction of the so-called “otherness” in Spain between 1936 and 1945. During this three year period of civil unrest, the Franco regime set out to cast the defeated half of the war as an inimical “other.” In this process of building an impression of the “other,” the “New State,” created after April 1, 1939, played an important role, since in many ways the existence of this enemy “other” could favour unity between the rest, or “us.” The State used mandatory education as an efficient socialization tool in this process. The text looks at the different ways in which the image of the “other” was used in books that taught History, Civic Education and Patriotic Education in primary school.
Equatorial Mountain Torques and Cold Surge Preconditioning
Authors: Mailler Sylvain , Lott François
Published: February 2010

The evolution of the two components of the equatorial mountain torque (EMT) applied by mountains on the atmosphere is analyzed in the NCEP reanalysis. A strong lagged relationship between the EMT component along the Greenwich axis TM1 and the EMT component along the 90°E axis TM2 is found, with a pronounced signal on TM1 followed by a signal of opposite sign on TM2. It is shown that this result holds for the major massifs (Antarctica, the Tibetan Plateau, the Rockies, and the Andes) if a suitable axis system is used for each of them. For the midlatitude mountains, this relationship is in part associated with the development of cold surges.

Following these results, two hypotheses are made: (i) the mountain forcing on the atmosphere is well measured by the regional EMTs and (ii) this forcing partly drives the cold surges. To support these, a purely dynamical linear model is proposed: it is written on the sphere, uses an f-plane quasigeostrophic approximation, and includes the mountain forcings. In this model, a positive (negative) peak in TM1 produced by a mountain massif in the Northern (Southern) Hemisphere is due to a large-scale high surface pressure anomaly poleward of the massif. At a later stage, high pressure and low temperature anomalies develop in the lower troposphere east of the mountain, explaining the signal on TM2 and providing the favorable conditions for the cold surge development.

It is concluded that the EMT is a good measure of the dynamical forcing of the atmospheric flow by the mountains and that the poleward forces exerted by mountains on the atmosphere are substantial drivers of the cold surges, at least in their early stage. Therefore, the EMT time series can be an important diagnostic to assess the representation of mountains in general circulation models.
A Gaussian Mixture Model Approach to Forecast Verification
Authors: Lakshmanan Valliappa , Kain John S.
Published: February 2010

Verification methods for high-resolution forecasts have been based either on filtering or on objects created by thresholding the images. The filtering methods do not easily permit the use of deformation while identifying objects based on thresholds can be problematic. In this paper, a new approach is introduced in which the observed and forecast fields are broken down into a mixture of Gaussians, and the parameters of the Gaussian mixture model fit are examined to identify translation, rotation, and scaling errors. The advantages of this method are discussed in terms of the traditional filtering or object-based methods and the resulting scores are interpreted on a standard verification dataset.
Effects of Tobacco and P. gingivalis on Gingival Fibroblasts
Authors: Zhang W. , Song F. , Windsor L.J.
Published: February 2010

Cigarette smoke condensate (CSC) is the particulate matter of cigarette smoke. Porphyromonas gingivalis ( P. gingivalis) is an opportunistic pathogen involved in periodontitis. It was hypothesized that the combination of CSC and P. gingivalis would increase the collagen-degrading ability of human gingival fibroblasts (HGFs). In this study, HGFs were exposed to CSC, P. gingivalis supernatant, and CSC plus P. gingivalis supernatant. The collagen-degrading ability and protein/mRNA levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) of HGFs were examined. The combined treatment increased collagen degradation, protein levels of active forms of MMP-1, MMP-2, MMP-3, and MMP-14 in conditioned media, and the low-molecular-weight fragment of MMP-14 in membrane extracts, as well as mRNA levels of MMP-1, MMP-2, and MMP-14. In conclusion, the combined effects of CSC and P. gingivalis increased HGF-mediated collagen degradation by destroying the balance between MMPs and TIMPs at multiple levels.
Influence of CYP3A5 and MDR1 Genetic Polymorphisms on Urinary 6β‐Hydroxycortisol/Cortisol Ratio After Grapefruit Juice Intake in Healthy Chinese
Authors: Li Dan , Abudula Aziguli , Abulahake Muhutar , Zhu An‐Ping , Lou Ya‐Qing , Zhang Guo‐Liang
Published: February 2010

Interindividual variability of cytochrome P450 (CYP) 3A inhibition by grapefruit juice was investigated in relation to CYP3A5 and multidrug resistance gene (MDR) 1 genetic polymorphisms in Chinese Han, Uygur, and Kazakh healthy subjects. The measurement of urinary 6β‐hydroxycortisol/cortisol ratio was used to evaluate CYP3A activity in vivo by high‐performance liquid chromatography. CYP3A5*3 and MDR1 C1236T, G2677T/A, and C3435T polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism. After grapefruit juice intake, urinary ratios significantly decreased in 3 Chinese ethnic groups (P < .001). Kazakh had a larger decrease of urinary ratio compared to that of Han (P < .05), and the latter had similar decrease with Uygur. Furthermore, Chinese healthy subjects carrying CYP3A5*3/*3 and MDR11236‐2677‐3435T‐T‐T/T‐T‐T genotypes were found to have the largest reduction of urinary ratio (mean, 61.4%; 95% confidence interval, 53.4%‐69.5%), whereas *1/*3 subjects carrying MDR11236‐2677‐3435C‐G‐C/C‐G‐C genotypes had the lowest reduction (mean, 25.9%; 95% confidence interval, 3.1%‐48.8%; P < .01). In conclusion, both CYP3A5*3 and MDR1 variants influenced the extent of CYP3A inhibition by grapefruit juice in Chinese healthy subjects. The genetic variations influencing the CYP3A inhibitive phenotype might be helpful to explain the individual variability of grapefruit juice—drug interactions.