bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Once-Daily Vancomycin against Methicillin-Resistant Staphylococcus aureus in a Hollow-Fiber Infection Model
Authors: Nicasio Anthony M. , Bulitta Jürgen B. , Lodise Thomas P. , D'Hondt Rebecca E. , Kulawy Robert , Louie Arnold , Drusano George L.
Published: November 2011

For methicillin-resistant
Staphylococcus aureus
(MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in an
in vitro
hollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 μg/ml) using an inoculum of ∼10
6
CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 μg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.
The Repeat-In-Toxin Family Member TosA Mediates Adherence of Uropathogenic Escherichia coli and Survival during Bacteremia
Authors: Vigil Patrick D. , Wiles Travis J. , Engstrom Michael D. , Prasov Lev , Mulvey Matthew A. , Mobley Harry L. T.
Published: November 2011

Uropathogenic
Escherichia coli
(UPEC) is responsible for the majority of uncomplicated urinary tract infections (UTI) and represents the most common bacterial infection in adults. UPEC utilizes a wide range of virulence factors to colonize the host, including the novel repeat-in-toxin (RTX) protein TosA, which is specifically expressed in the host urinary tract and contributes significantly to the virulence and survival of UPEC.
tosA
, found in strains within the B2 phylogenetic subgroup of
E. coli
, serves as a marker for strains that also contain a large number of well-characterized UPEC virulence factors. The presence of
tosA
in an
E. coli
isolate predicts successful colonization of the murine model of ascending UTI, regardless of the source of the isolate. Here, a detailed analysis of the function of
tosA
revealed that this gene is transcriptionally linked to genes encoding a conserved type 1 secretion system similar to other RTX family members. TosA localized to the cell surface and was found to mediate (i) adherence to host cells derived from the upper urinary tract and (ii) survival in disseminated infections and (iii) to enhance lethality during sepsis (as assessed in two different animal models of infection). An experimental vaccine, using purified TosA, protected vaccinated animals against urosepsis. From this work, it was concluded that TosA belongs to a novel group of RTX proteins that mediate adherence and host damage during UTI and urosepsis and could be a novel target for the development of therapeutics to treat ascending UTIs.
The Vsa Shield of Mycoplasma pulmonis Is Antiphagocytic
Authors: Shaw Brandon M. , Simmons Warren L. , Dybvig Kevin
Published: November 2011

The infection of mice with
Mycoplasma pulmonis
is a model for studying chronic mycoplasmal respiratory disease. Many
in vivo
and
in vitro
studies have used the organism to gain a better understanding of host-pathogen interactions in chronic respiratory infection. The organism's Vsa proteins contain an extensive tandem repeat region. The length of the tandem repeat unit varies from as few as 11 amino acids to as many as 19. The number of tandem repeats can be as high as 60. The number of repeats varies at a high frequency due to slipped-strand mispairing events that occur during DNA replication. When the number of repeats is high, e.g., 40, the mycoplasma is resistant to lysis by complement but does not form a robust biofilm. When the number of repeats is low, e.g., 5, the mycoplasma is killed by complement when the cells are dispersed but has the capacity to form a biofilm that resists complement. Here, we examine the role of the Vsa proteins in the avoidance of phagocytosis and find that cells producing a protein with many tandem repeats are relatively resistant to killing by macrophages. These results may be pertinent to understanding the functions of similar proteins that have extensive repeat regions in other microbes.
A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults
Authors: Minassian Angela M , Rowland Rosalind , Beveridge Natalie E R , Poulton Ian D , Satti Iman , Harris Stephanie , Poyntz Hazel , Hamill Matthew , Griffiths Kristin , Sander Clare R , Ambrozak David R , Price David A , Hill Brenna J , Casazza Joseph P , Douek Daniel C , Koup Richard A , Roederer Mario , Winston Alan , Ross Jonathan , Sherrard Jackie , Rooney Guy , Williams Nicola , Lawrie Alison M , Fletcher Helen A , Pathan Ansar A , McShane Helen
Published: November 2011

Objectives

Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults.

Design

This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis.

Results

MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable.

Conclusion

MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited.
Oral contraceptive use is associated with prostate cancer: an ecological study
Authors: Margel David , Fleshner Neil E
Published: November 2011

Background

Several recent studies have suggested that oestrogen exposure may increase the risk of prostate cancer (PCa).

Objectives

To examine associations between PCa incidence and mortality and population-based use of oral contraceptives (OCs). It was hypothesised that OC by-products may cause environmental contamination, leading to an increased low level oestrogen exposure and therefore higher PCa incidence and mortality.

Methods

The hypothesis was tested in an ecological study. Data from the International Agency for Research on Cancer were used to retrieve age-standardised rates of prostate cancer in 2007, and data from the United Nations World Contraceptive Use 2007 report were used to retrieve data on contraceptive use. A Pearson correlation and multivariable linear regression were used to associate the percentage of women using OCs, intrauterine devices, condoms or vaginal barriers to the age standardised prostate cancer incidence and mortality. These analyses were performed by individual nations and by continents worldwide.

Results

OC use was significantly associated with prostate cancer incidence and mortality in the individual nations worldwide (r=0.61 and r=0.53, respectively; p<0.05 for all). PCa incidence was also associated with OC use in Europe (r=0.545, p<0.05) and by continent (r=0.522, p<0.05). All other forms of contraceptives (ie, intra-uterine devices, condoms or vaginal barriers) were not correlated with prostate cancer incidence or mortality. On multivariable analysis the correlation with OC was independent of a nation's wealth.

Conclusion

A significant association between OCs and PCa has been shown. It is hypothesised that the OC effect may be mediated through environmental oestrogen levels; this novel concept is worth further investigation.
GAUGED ADS–MAXWELL ALGEBRA AND GRAVITY
Authors: DURKA R. , KOWALSKI-GLIKMAN J. , SZCZACHOR M.
Published: November 2011

We deform the anti-de Sitter algebra by adding additional generators [Formula: see text], forming in this way the negative cosmological constant counterpart of the Maxwell algebra. We gauge this algebra and construct a dynamical model with the help of a constrained BF theory. It turns out that the resulting theory is described by the Einstein–Cartan action with Holst term, and the gauge fields associated with the Maxwell generators [Formula: see text] appear only in topological terms that do not influence dynamical field equations. We briefly comment on the extension of this construction, which would lead to a nontrivial Maxwell fields dynamics.
Integrative Genomic Analyses of Sporadic Clear Cell Renal Cell Carcinoma Define Disease Subtypes and Potential New Therapeutic Targets
Authors: Dondeti Vijay R. , Wubbenhorst Bradley , Lal Priti , Gordan John D. , D'Andrea Kurt , Attiyeh Edward F. , Simon M. Celeste , Nathanson Katherine L.
Published: November 2011

Sporadic clear cell renal cell carcinoma (ccRCC), the most common type of adult kidney cancer, is often associated with genomic copy number aberrations on chromosomes 3p and 5q. Aberrations on chromosome 3p are associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), which activates the hypoxia-inducible factors HIF1α and HIF2α. In contrast, ccRCC genes on chromosome 5q remain to be defined. In this study, we conducted an integrated analysis of high-density copy number and gene expression data for 54 sporadic ccRCC tumors that identified the secreted glycoprotein STC2 (stanniocalcin 2) and the proteoglycan VCAN (versican) as potential 5q oncogenes in ccRCCs. In functional assays, STC2 and VCAN each promoted tumorigenesis by inhibiting cell death. Using the same approach, we also investigated the two VHL-deficient subtypes of ccRCC, which express both HIF1α and HIF2α (H1H2) or only HIF2α (H2). This analysis revealed a distinct pattern of genomic aberrations in each group, with the H1H2 group displaying, on average, a more aberrant genome than the H2 group. Together our findings provide a significant advance in understanding ccRCCs by offering a molecular definition of two subtypes with distinct characteristics as well as two potential chromosome 5q oncogenes, the overexpression of which is sufficient to promote tumorigenesis by limiting cell death. Cancer Res; 72(1); 112–21. ©2011 AACR.
Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1
Authors: Arnault Jean Philippe , Mateus Christine , Escudier Bernard , Tomasic Gorana , Wechsler Janine , Hollville Emilie , Soria Jean-Charles , Malka David , Sarasin Alain , Larcher Magalie , André Jocelyne , Kamsu-Kom Nyam , Boussemart Lise , Lacroix Ludovic , Spatz Alain , Eggermont Alexander M. , Druillennec Sabine , Vagner Stephan , Eychène Alain , Dumaz Nicolas , Robert Caroline
Published: November 2011

Purpose: The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.

Experimental Design: Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1, and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes.

Results: We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1, and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin.

Sorafenib induced BRAF–CRAF dimerization in cultured keratinocytes and activated CRAF with a dose-dependent effect on MAP-kinase pathway activation and on keratinocyte proliferation.

Conclusion: Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors. Clin Cancer Res; 18(1); 263–72. ©2011 AACR.
Vemurafenib and BRAF Inhibition: A New Class of Treatment for Metastatic Melanoma
Authors: Luke Jason J. , Hodi F. Stephen
Published: November 2011

The U.S. Food and Drug Administration recently approved vemurafenib for the treatment of BRAF valine in exon 15, at codon 600 (V600E) mutant metastatic melanoma. Vemurafenib is a competitive small-molecule serine–threonine kinase inhibitor that functions by binding to the ATP-binding domain of mutant BRAF. Compared with dacarbazine chemotherapy, vemurafenib significantly improved the 6-month overall survival of patients from 64% to 84% and exhibited a response rate of approximately 50%. Median progression-free survival was also significantly improved with vemurafenib as compared with dacarbazine (5.3 versus 1.6 months, respectively), and this was consistent among groups analyzed, including age, sex, geography, Eastern Cooperative Oncology Group status, disease stage, and serum lactate dehydrogenase. The success of targeting melanoma genomics has created a paradigm shift for future drug development. Currently, the elucidation of resistant mechanisms to vemurafenib therapy remains an important area of active investigation that will shape rational drug treatments for melanoma. The development of vemurafenib, the role of BRAF targeting, and the changing landscape of treatment for melanoma provide a new foundation for clinical investigation. Clin Cancer Res; 18(1); 9–14. ©2011 AACR.
Prognostic Significance of Plasma Osteopontin in Patients with Locoregionally Advanced Head and Neck Squamous Cell Carcinoma Treated on TROG 02.02 Phase III Trial
Authors: Lim Annette M. , Rischin Danny , Fisher Richard , Cao Hongbin , Kwok Kathleen , Truong Daniel , McArthur Grant A. , Young Richard J. , Giaccia Amato , Peters Lester , Le Quynh-Thu
Published: November 2011

Purpose: High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in head and neck squamous cell carcinomas (HNSCC), correlate with tumor hypoxia, and be predictive of benefit from hypoxia-targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial.

Experimental Design: Patients with stage III/IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). Eligibility criteria for this prospective substudy included plasma sample availability for OPN assay by ELISA and absence of major radiation therapy deviations (N = 578). OPN concentrations were analyzed for overall survival (OS) and time to locoregional failure (TTLRF), adjusting for known prognostic factors. Additional analysis was carried out in patients with available tumor p16INK4A staining status.

Results: The median OPN level was 544 ng/mL (range: 7–2,640). High OPN levels were not associated with worse OS (relative HR, 1.03 for highest tertile) or TTLRF (relative HR 0.91 for highest tertile). There was no interaction between OPN and treatment arm for OS or TTLRF (P = 0.93 for OS; P = 0.87 for TTLRF). For the highest tertile the 2-year OS was 66% on control arm and 67% on TPZ arm (HR = 1.11, P = 0.67). Similarly for p16INK4A negative patients in the highest tertile, the 2-year OS was 61% on control arm and 63% on TPZ arm (HR = 1.05, P = 0.86).

Conclusions: We found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy. Clin Cancer Res; 18(1); 301–7. ©2011 AACR.
Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo
Authors: Budhraja Amit , Gao Ning , Zhang Zhuo , Son Young-Ok , Cheng Senping , Wang Xin , Ding Songze , Hitron Andrew , Chen Gang , Luo Jia , Shi Xianglin
Published: November 2011

In this study, we investigated the functional role of Akt and c-jun-NH2-kinase (JNK) signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo. Apigenin induced apoptosis by inactivation of Akt with a concomitant activation of JNK, Mcl-1 and Bcl-2 downregulation, cytochrome c release from mitochondria, and activation of caspases. Constitutively active myristolated Akt prevented apigenin-induced JNK, caspase activation, and apoptosis. Conversely, LY294002 and a dominant-negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. Interruption of the JNK pathway showed marked reduction in apigenin-induced caspase activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin resulted in attenuation of tumor growth in U937 xenografts accompanied by inactivation of Akt and activation of JNK. Attenuation of tumor growth in U937 xenografts by apigenin raises the possibility that apigenin may have clinical implications and can be further tested for incorporating in leukemia treatment regimens. Mol Cancer Ther; 11(1); 132–42. ©2011 AACR.
Targeting Interleukin-4 Receptor α with Hybrid Peptide for Effective Cancer Therapy
Authors: Yang Liying , Horibe Tomohisa , Kohno Masayuki , Haramoto Mari , Ohara Koji , Puri Raj K. , Kawakami Koji
Published: November 2011

Interleukin-4 receptor α (IL-4Rα) chain is highly expressed on the surface of various human solid tumors. We designed a novel hybrid peptide termed IL-4Rα–lytic peptide that targets the IL-4Rα chain. The IL-4Rα–lytic peptide contains a target moiety to bind to IL-4Rα and a cellular toxic lytic peptide that selectively kills cancer cells. The anticancer activity of the IL-4Rα–lytic peptide was evaluated in vitro and in vivo. It was found that the IL-4Rα–lytic peptide has cytotoxic activity in cancer cell lines expressing IL-4Rα, determined by quantitative real-time PCR. The IC50 ratios of the lytic peptide to the IL-4Rα–lytic peptide correlated well with the expression levels of IL-4Rα on cancer cells (r = 0.80). In addition, IL-4Rα–lytic peptide administered either intratumoraly or intravenously significantly inhibited tumor growth in xenograft model of human pancreatic cancer (BXPC-3) in mice. These results indicate that the IL-4Rα–lytic peptide generated in this study has a potent and selective anticancer potential against IL-4Rα–positive solid cancers. Mol Cancer Ther; 11(1); 235–43. ©2011 AACR.
Induction of Vascular Progenitor Cells From Endothelial Cells Stimulates Coronary Collateral Growth
Authors: Yin Liya , Ohanyan Vahagn , Fen Pung Yuh , DeLucia Angelo , Bailey Erin , Enrick Molly , Stevanov Kelly , Kolz Christopher L. , Guarini Giacinta , Chilian William M.
Published: November 2011

Rationale:

A well-developed coronary collateral circulation improves the morbidity and mortality of patients following an acute coronary occlusion. Although regenerative medicine has great potential in stimulating vascular growth in the heart, to date there have been mixed results, and the ideal cell type for this therapy has not been resolved.

Objective:

To generate induced vascular progenitor cells (iVPCs) from endothelial cells, which can differentiate into vascular smooth muscle cells (VSMCs) or endothelial cells (ECs), and test their capability to stimulate coronary collateral growth.

Methods and Results:

We reprogrammed rat ECs with the transcription factors Oct4, Klf4, Sox2, and c-Myc. A population of reprogrammed cells was derived that expressed pluripotent markers Oct4, SSEA-1, Rex1, and AP and hemangioblast markers CD133, Flk1, and c-kit. These cells were designated iVPCs because they remained committed to vascular lineage and could differentiate into vascular ECs and VSMCs in vitro. The iVPCs demonstrated better in vitro angiogenic potential (tube network on 2-dimensional culture, tube formation in growth factor reduced Matrigel) than native ECs. The risk of teratoma formation in iVPCs is also reduced in comparison with fully reprogrammed induced pluripotent stem cells (iPSCs). When iVPCs were implanted into myocardium, they engrafted into blood vessels and increased coronary collateral flow (microspheres) and improved cardiac function (echocardiography) better than iPSCs, mesenchymal stem cells, native ECs, and sham treatments.

Conclusions:

We conclude that iVPCs, generated by partially reprogramming ECs, are an ideal cell type for cell-based therapy designed to stimulate coronary collateral growth.
Acidosis Dilates Brain Parenchymal Arterioles by Conversion of Calcium Waves to Sparks to Activate BK Channels
Authors: Dabertrand Fabrice , Nelson Mark T. , Brayden Joseph E.
Published: November 2011

Rationale:

Acidosis is a powerful vasodilator signal in the brain circulation. However, the mechanisms by which this response occurs are not well understood, particularly in the cerebral microcirculation. One important mechanism to dilate cerebral (pial) arteries is by activation of large-conductance, calcium-sensitive potassium (BK
Ca
) channels by local Ca
2+
signals (Ca
2+
sparks) through ryanodine receptors (RyRs). However, the role of this pathway in the brain microcirculation is not known.

Objective:

The objectives of this study were to determine the mechanism by which acidosis dilates brain parenchymal arterioles (PAs) and to elucidate the roles of RyRs and BK
Ca
channels in this response.

Methods and Results:

Internal diameter and vascular smooth muscle cell Ca
2+
signals were measured in isolated pressurized murine PAs, using imaging techniques. In physiological pH (7.4), vascular smooth muscle cells exhibited primarily RyR-dependent Ca
2+
waves. Reducing external pH from 7.4 to 7.0 in both normocapnic and hypercapnic conditions decreased Ca
2+
wave activity, and dramatically increased Ca
2+
spark activity. Acidic pH caused a dilation of PAs which was inhibited by about 60% by BK
Ca
channel or RyR blockers, in a nonadditive manner. Similarly, dilator responses to acidosis were reduced by nearly 60% in arterioles from BK
Ca
channel knockout mice. Dilations induced by acidic pH were unaltered by inhibitors of K
ATP
channels or nitric oxide synthase.

Conclusions:

These results support the novel concept that acidification, by converting Ca
2+
waves to sparks, leads to the activation of BK
Ca
channels to induce dilation of cerebral PAs.
A Critical Role for the Protein Apoptosis Repressor With Caspase Recruitment Domain in Hypoxia-Induced Pulmonary Hypertension
Authors: Zaiman Ari L. , Damico Rachel , Thoms-Chesley Alan , Files D. Clark , Kesari Priya , Johnston Laura , Swaim Mara , Mozammel Shehzin , Myers Alan C. , Halushka Marc , El-Haddad Hazim , Shimoda Larissa A. , Peng Chang-Fu , Hassoun Paul M. , Champion Hunter C. , Kitsis Richard N. , Crow Michael T.
Published: November 2011

Background—

Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly upregulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH.

Methods and Results—

Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced downregulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease.

Conclusions—

These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome.
Status of Cardiovascular Health in US Adults
Authors: Shay Christina M. , Ning Hongyan , Allen Norrina B. , Carnethon Mercedes R. , Chiuve Stephanie E. , Greenlund Kurt J. , Daviglus Martha L. , Lloyd-Jones Donald M.
Published: November 2011

Background—

The American Heart Association's 2020 Strategic Impact Goals define a new concept, cardiovascular (CV) health; however, current prevalence estimates of the status of CV health in US adults according to age, sex, and race/ethnicity have not been published.

Methods and Results—

We included 14 515 adults (≥20 years of age) from the 2003 to 2008 National Health and Nutrition Examination Surveys. Participants were stratified by young (20–39 years), middle (40–64 years), and older (≥65 years) ages. CV health behaviors (diet, physical activity, body mass index, smoking) and CV health factors (blood pressure, total cholesterol, fasting blood glucose, smoking) were defined as poor, intermediate, or ideal. Fewer than 1% of adults exhibited ideal CV health for all 7 metrics. For CV health behaviors, nonsmoking was most prevalent (range, 60.2%–90.4%), whereas ideal Healthy Diet Score was least prevalent (range, 0.2%–2.6%) across groups. Prevalences of ideal body mass index (range, 36.5%–45.3%) and ideal physical activity levels (range, 50.2%–58.8%) were higher in young adults compared with middle or older ages. Ideal total cholesterol (range, 23.7%–36.2%), blood pressure (range, 11.9%–16.3%), and fasting blood glucose (range, 31.2%–42.9%) were lower in older adults compared with young and middle-aged adults. Prevalence of poor CV health factors was lowest in young age but higher at middle and older ages. Prevalence estimates by age and sex were consistent across race/ethnic groups.

Conclusions—

These prevalence estimates of CV health represent a starting point from which effectiveness of efforts to promote CV health and prevent CV disease can be monitored and compared in US adult populations.
Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy
Authors: Rosenberg Victor A. , Buhimschi Irina A. , Lockwood Charles J. , Paidas Michael J. , Dulay Antonette T. , Ramma Wenda , Abdel-Razeq Sonya S. , Zhao Guomao , Ahmad Shakil , Ahmed Asif , Buhimschi Catalin S.
Published: November 2011

Background—

Alterations in circulating levels of pro- and antiangiogenic factors have been associated with adverse pregnancy outcomes. Heparin is routinely administered to pregnant women, but without clear knowledge of its impact on these factors.

Methods and Results—

We conducted a longitudinal study of 42 pregnant women. Twenty-one women received prophylactic heparin anticoagulation, and 21 healthy pregnant women served as controls. Compared with gestational age-matched controls, heparin treatment was associated with increased circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1) in the third trimester (
P
<0.05), in the absence of preeclampsia, placental abruption, or fetal growth restriction. Heparin had no effect on circulating levels of vascular endothelial growth factor, placenta growth factor, or soluble endoglin as assessed by ELISA. In vitro, low-molecular weight and unfractionated heparins stimulated sFlt-1 release from placental villous explants, in a dose- and time-dependent manner. This effect was not due to placental apoptosis, necrosis, alteration in protein secretion, or increased transcription. Western blot analysis demonstrated that heparin induced shedding of the N-terminus of Flt-1 both in vivo and in vitro as indicated by a predominant band of 100–112 kDa. By using an in vitro angiogenesis assay, we demonstrated that serum of heparin-treated cases inhibited both basal and vascular endothelial growth factor-induced capillary-like tube formation.

Conclusions—

Heparin likely increases the maternal sFlt-1 through shedding of the extracellular domain of Flt-1 receptor. Our results imply that upregulation of circulating sFlt-1 immunoreactivity in pregnancy is not always associated with adverse outcomes, and that heparin's protective effects, if any, cannot be explained by promotion of angiogenesis.
Pathogenic Cycle Between the Endogenous Nitric Oxide Synthase Inhibitor Asymmetrical Dimethylarginine and the Leukocyte-Derived Hemoprotein Myeloperoxidase
Authors: von Leitner Eike-Christin , Klinke Anna , Atzler Dorothee , Slocum Jessica L. , Lund Natalie , Kielstein Jan T. , Maas Renke , Schmidt-Haupt Robin , Pekarova Michaela , Hellwinkel Olaf , Tsikas Dimitrios , D'Alecy Louis G. , Lau Denise , Willems Stephan , Kubala Lukas , Ehmke Heimo , Meinertz Thomas , Blankenberg Stefan , Schwedhelm Edzard , Gadegbeku Crystal A. , Böger Rainer H. , Baldus Stephan , Sydow Karsten
Published: November 2011

Background—

The nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) and the leukocyte-derived hemoprotein myeloperoxidase (MPO) are associated with cardiovascular diseases. Activation of monocytes and polymorphonuclear neutrophils (PMNs) with concomitant release of MPO is regulated in a nitric oxide–dependent fashion. The aim of the study was to investigate a potential 2-way interaction between ADMA and MPO.

Methods and Results—

Ex vivo, ADMA uptake by isolated human PMNs, the principal source of MPO in humans, significantly impaired nitric oxide synthase activity determined by gas chromatography–mass spectrometry. In humans, short-term ADMA infusion (0.0125 mg · kg
−1
· min
−1
) significantly increased MPO plasma concentrations. Functionally, PMN exposure to ADMA enhanced leukocyte adhesion to endothelial cells, augmented NADPH oxidase activity, and stimulated PMN degranulation, resulting in release of MPO. In vivo, a 28-day ADMA infusion (250 μmol · kg
−1
· d
−1
) in C57Bl/6 mice significantly increased plasma MPO concentrations, whereas this ADMA effect on MPO was attenuated by human dimethylarginine dimethylaminohydrolase1 (hDDAH1) overexpression. Moreover, the MPO-derived reactive molecule hypochlorous acid impaired recombinant hDDAH1 activity in vitro. In MPO
−/−
mice, the lipopolysaccharide-induced increase in systemic ADMA concentrations was abrogated.

Conclusions—

ADMA profoundly impairs nitric oxide synthesis of PMNs, resulting in increased PMN adhesion to endothelial cells, superoxide generation, and release of MPO. In addition, MPO impairs DDAH1 activity. Our data reveal an ADMA-induced cycle of PMN activation, enhanced MPO release, and subsequent impairment of DDAH1 activity. These findings not only highlight so far unrecognized cytokine-like properties of ADMA but also identify MPO as a regulatory switch for ADMA bioavailability under inflammatory conditions.
Atrial Fibrillation Catheter Ablation Versus Surgical Ablation Treatment (FAST)
Authors: Boersma Lucas V.A. , Castella Manuel , van Boven WimJan , Berruezo Antonio , Yilmaz Alaaddin , Nadal Mercedes , Sandoval Elena , Calvo Naiara , Brugada Josep , Kelder Johannes , Wijffels Maurits , Mont Lluís
Published: November 2011

Background—

Catheter ablation (CA) and minimally invasive surgical ablation (SA) have become accepted therapy for antiarrhythmic drug–refractory atrial fibrillation. This study describes the first randomized clinical trial comparing their efficacy and safety during a 12-month follow-up.

Methods and Results—

One hundred twenty-four patients with antiarrhythmic drug–refractory atrial fibrillation with left atrial dilatation and hypertension (42 patients, 33%) or failed prior CA (82 patients, 67%) were randomized to CA (63 patients) or SA (61 patients). CA consisted of linear antral pulmonary vein isolation and optional additional lines. SA consisted of bipolar radiofrequency isolation of the bilateral pulmonary vein, ganglionated plexi ablation, and left atrial appendage excision with optional additional lines. Follow-up at 6 and 12 months was performed by ECG and 7-day Holter recording. The primary end point, freedom from left atrial arrhythmia >30 seconds without antiarrhythmic drugs after 12 months, was 36.5% for CA and 65.6% for SA (
P
=0.0022). There was no difference in effect for subgroups, which was consistent at both sites. The primary safety end point of significant adverse events during the 12-month follow-up was significantly higher for SA than for CA (n=21 [34.4%] versus n=10 [15.9%];
P
=0.027), driven mainly by procedural complications such as pneumothorax, major bleeding, and the need for pacemaker. In the CA group, 1 patient died at 1 month of subarachnoid hemorrhage.

Conclusion—

In atrial fibrillation patients with dilated left atrium and hypertension or failed prior atrial fibrillation CA, SA is superior to CA in achieving freedom from left atrial arrhythmias after 12 months of follow-up, although the procedural adverse event rate is significantly higher for SA than for CA.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00662701.
New Theatrology and Performance Studies: Starting Points Towards a Dialogue
Authors: De Marinis Marco
Published: November 2011

New theatrology is a field of research not in two dimensions (theory-practice) but in three: theory-history-practice. “Theory” can refer to two genetically different metadiscourses: the theory of the theatre that artists create through their work; and the theory about the theatre made by scholars and critics. New theatrology attempts to account for both. While new theatrology and performance studies share several presuppositions, the notion of performance needs to be better defined, especially from a historical point of view.
The Performance of Time in Fluxus Intermedia
Authors: Lushetich Natasha
Published: November 2011

Can time be performed? Departing from the “processualist” view in which time is the expressive activity of any given thing, being, or phenomenon, the processes of pervasive temporalization and musicalization—characteristic of Fluxus intermedia—converge to produce concrete, lived time and perpetuate the dialectical interplay of continuity and discontinuity.
Brian Jungen's Verfremdungseffekt: Strange Comfort at the National Museum for the American Indian
Authors: Schweitzer Marlis
Published: November 2011

Canadian artist Brian Jungen has achieved international fame for taking mass-produced goods—plastic chairs, gas cans, basketball sneakers—and transforming them into intricately wrought pieces that resemble First Nations art objects. Displayed in the Smithsonian's National Museum of the American Indian, Jungen's pieces produced a Brechtian Verfremdungseffekt.
Intercomparison of Four Commercial Analyzers for Water Vapor Isotope Measurement
Authors: Wen Xue-Fa , Lee Xuhui , Sun Xiao-Min , Wang Jian-Lin , Tang Ya-Kun , Li Sheng-Gong , Yu Gui-Rui
Published: November 2011

The δ18O and δD of atmospheric water vapor are important tracers in hydrological and ecological studies. Isotope ratio infrared spectroscopy (IRIS) provides an in situ technology for measuring δ18O and δD in ambient conditions. An intercomparison experiment was carried out with four commercial IRIS analyzers to characterize their performance and transferability of calibration methods. Over a 15-day atmospheric measurement, during which the water vapor concentration ranged from 14 to 27 mol mol−1 and the isotopic ratios spanned about 90‰ and 13‰ for δD and δ18O, respectively, these analyzers tracked the natural variability in ambient conditions very well and achieved an average difference between one another within 2‰ for δD and within 0.1‰ for δ18O after calibration at appropriate frequencies. Two of the calibration methods (discrete liquid water injection and continuous dripping) agreed with each other within the tolerance thresholds of 2‰ for δD and 0.1‰ for δ18O. The Rayleigh distillation technique appeared to be acceptable as a calibration standard for δD but not for δ18O. The δD measurements were less prone to concentration dependence errors than the δ18O measurements. The concentration dependence underscores the importance of using a calibration procedure at multiple mixing ratios to bracket the range of natural variability.
Assessing Stability of CERES-FM3 Daytime Longwave Unfiltered Radiance with AIRS Radiances
Authors: Huang Xianglei , Loeb Norman G. , Chuang Huiwen
Published: November 2011

Clouds and the Earth’s Radiant Energy System (CERES) daytime longwave (LW) radiances are determined from the difference between a total (TOT) channel (0.3–200 μm) measurement and a shortwave (SW) channel (0.3–5 μm) measurement, while nighttime LW radiances are obtained directly from the TOT channel. This means that a drift in the SW channel or the SW portion of the TOT channel could impact the daytime longwave radiances, but not the nighttime ones. This study evaluates daytime and nighttime CERES LW radiances for a possible secular drift in CERES LW observations using spectral radiances observed by Atmospheric Infrared Sounder (AIRS). By examining the coincidental AIRS and CERES Flight Model 3 (FM3) measurements over the tropical clear-sky oceans for all of January and July months since 2005, a secular drift of about −0.11% yr−1 in the daytime CERES-FM3 longwave unfiltered radiance can be identified in the CERES Single Scanner Footprint (SSF) Edition 2 product. This provides an upper-bound estimation for the drift in daytime outgoing longwave radiation, which is approximately −0.323 W m−2 yr−1. This estimation is consistent with the independent assessment concluded by the CERES calibration team. Such secular drift has been greatly reduced in the latest CERES SSF Edition 3 product. Comparisons are conducted for the CERES window channel as well, and it shows essentially no drift. This study serves as a practical example illustrating how the measurements of spectrally resolved radiances can be used to help evaluate data products from other narrowband or broadband measurements.
Indian General Elections 2009: The Myth of the ‘National’ Verdict
Authors: Mazumdar Arijit
Published: November 2011

This article argues that the results of the Indian General Elections, 2009, emphasize continuity more than change. Regional political parties, local-level issues and identity-based politics remain significant. The verdict represents a confirmation of established patterns of electoral politics in India and not a break with the recent past.
Viral Gene Transfer to Developing Mouse Salivary Glands
Authors: Hsu J.C. , Di Pasquale G. , Harunaga J.S. , Onodera T. , Hoffman M.P. , Chiorini J.A. , Yamada K.M.
Published: November 2011

Branching morphogenesis is essential for the formation of salivary glands, kidneys, lungs, and many other organs during development, but the mechanisms underlying this process are not adequately understood. Microarray and other gene expression methods have been powerful approaches for identifying candidate genes that potentially regulate branching morphogenesis. However, functional validation of the proposed roles for these genes has been severely hampered by the absence of efficient techniques to genetically manipulate cells within embryonic organs. Using ex vivo cultured embryonic mouse submandibular glands (SMGs) as models to study branching morphogenesis, we have identified new vectors for viral gene transfer with high efficiency and cell-type specificity to developing SMGs. We screened adenovirus, lentivirus, and 11 types of adeno-associated viruses (AAV) for their ability to transduce embryonic day 12 or 13 SMGs. We identified two AAV types, AAV2 and bovine AAV (BAAV), that are selective in targeting expression differentially to SMG epithelial and mesenchymal cell populations, respectively. Transduction of SMG epithelia with self-complementary (sc) AAV2 expressing fibroblast growth factor 7 (Fgf7) supported gland survival and enhanced SMG branching morphogenesis. Our findings represent, to our knowledge, the first successful selective gene targeting to epithelial vs. mesenchymal cells in an organ undergoing branching morphogenesis.
An X-ray Microtomographic Study of Natural White-spot Enamel Lesions
Authors: Cochrane N.J. , Anderson P. , Davis G.R. , Adams G.G. , Stacey M.A. , Reynolds E.C.
Published: November 2011

White-spot enamel lesions are an early presentation of dental caries and are ideally managed by non-invasive procedures. The aim of this study was to characterize white-spot enamel lesions by x-ray microtomography. In particular, mineral content across the lesion from the surface to the base of the lesion was measured and surface layers defined. Molars with long buccal white-spot enamel lesions were collected, photographed, and each sectioned to produce 3 500-µm-thick sections. The sections were mounted and imaged by quantitative x-ray microtomography at a 15-µm voxel size. We analyzed line profiles through the middle of each 3D image to determine mineral content and depth. The surface layer thickness of the lesions ranged from 35 to 130 µm, with the maximum mineral content in this layer being 74% to 100% of that of sound enamel. The average mineral content across the lesions ranged from 1.73 to 2.48 g/cm3. No significant differences could be found between lesions clinically categorized as active and those categorized as inactive. However, for depth-matched active and inactive lesions, the active lesions exhibited a more porous surface layer than the inactive lesions. White-spot enamel lesions are highly variable, with surface layers of considerable thickness.
(De-)Accentuation and the Processing of Information Status: Evidence from Event-Related Brain Potentials
Authors: Baumann Stefan , Schumacher Petra B.
Published: November 2011

The paper reports on a perception experiment in German that investigated the neuro-cognitive processing of information structural concepts and their prosodic marking using event-related brain potentials (ERPs). Experimental conditions controlled the information status (given vs. new) of referring and non-referring target expressions (nouns vs. adjectives) and were elicited via context sentences, which did not – unlike most previous ERP studies in the field – trigger an explicit focus expectation. Target utterances displayed prosodic realizations of the critical words which differed in accent position and accent type. Electrophysiological results showed an effect of information status, maximally distributed over posterior sites, displaying a biphasic N400 - Late Positivity pattern for new information. We claim that this pattern reflects increased processing demands associated with new information, with the N400 indicating enhanced costs from linking information with the previous discourse and the Late Positivity indicating the listener’s effort to update his/her discourse model. The prosodic manipulation registered more pronounced effects over anterior regions and revealed an enhanced negativity followed by a Late Positivity for deaccentuation, probably also reflecting costs from discourse linking and updating respectively. The data further lend indirect support for the idea that givenness applies not only to referents but also to non-referential expressions (‘lexical givenness’).
Toward an Agenda of High-Priority Tourism Research
Authors: Williams Peter W. , Stewart Kent , Larsen Donna
Published: November 2011

The Travel and Tourism Research Association (TTRA) creates networking opportunities to share perspectives on research issues related to the planning and marketing of travel and tourism. While its publications offer numerous suggestions for case- and context-specific research, rarely have attempts been made to develop a membership-wide agenda of priority topics. In an age of increasing resource scarcity and calls for accountability, the need for such an agenda is growing. This study prioritizes management- and method-related research topics deemed by TTRA members to be critical to travel and tourism decision makers over the next decade. It describes the member-based process used to establish these priorities, and suggests specific directions for investigations associated with each of them. It calls for greater dialogue around the relative priority placed on these topics by practitioners and academics within TTRA, as well as extending the discussion to other influential industry and professional travel and tourism organizations.
Modeling and Compensatory Processes Underlying Involvement in Child Care Among Kibbutz-Reared Fathers
Authors: Gaunt Ruth , Bassi Liat
Published: November 2011

This study examined modeling and compensatory processes underlying the effects of an early paternal model on father involvement in child care. Drawing on social learning theory, it was hypothesized that father–son relationships would moderate the association between a father’s involvement and his own father’s involvement. A sample of 136 kibbutz father–son dyads completed extensive questionnaires. Findings provided evidence for modeling effects on the socioemotional care dimension, whereas imitation of highly involved fathers occurred simultaneously with compensation for relatively uninvolved fathers on the physical care and responsibility dimensions. As predicted, imitation was more likely in close father–son relationships. These findings shed light on the role of paternal model and attest to the importance of differentiating various forms of involvement.