bluuebunny/crossref_metadata_2025 huggingface dataset:
Amino Acid-Derived 1,2-Benzisothiazolinone Derivatives as Novel Small-Molecule Antifungal Inhibitors: Identification of Potential Genetic Targets
Authors: Alex Deepu , Gay-Andrieu Francoise , May Jared , Thampi Linta , Dou Dengfeng , Mooney Aileen , Groutas William , Calderone Richard
Published: June 2012

We have identified four synthetic compounds (DFD-VI-15, BD-I-186, DFD-V-49, and DFD-V-66) from an amino acid-derived 1,2-benzisothiazolinone (BZT) scaffold that have reasonable MIC50values against a panel of fungal pathogens. These compounds have no structural similarity to existing antifungal drugs. Three of the four compounds have fungicidal activity againstCandidaspp.,Cryptococcus neoformans, and several dermatophytes, while one is fungicidal toAspergillus fumigatus. The kill rates of our compounds are equal to those in clinical usage. The BZT compounds remain active against azole-, polyene-, and micafungin-resistant strains ofCandidaspp. A genetics-based approach, along with phenotype analysis, was used to begin mode of action (MOA) studies of one of these compounds, DFD-VI-15. The genetics-based screen utilized a homozygous deletion collection of approximately 4,700Saccharomyces cerevisiaemutants. We identified mutants that are both hypersensitive and resistant. Using FunSpec, the hypersensitive mutants and a resistantace2mutant clustered within a category of genes related directly or indirectly to mitochondrial functions. InCandida albicans, the functions of the Ace2p transcription factor include the regulation of glycolysis. Our model is that DFD-VI-15 targets a respiratory pathway that limits energy production. Supporting this hypothesis are phenotypic data indicating that DFD-VI-15 causes increased cell-reactive oxidants (ROS) and a decrease in mitochondrial membrane potential. Also, the same compound has activity when cells are grown in a medium containing glycerol (mitochondrial substrate) but is much less active when cells are grown anaerobically.
Critical Role for MyD88-Mediated Neutrophil Recruitment during Clostridium difficile Colitis
Authors: Jarchum Irene , Liu Mingyu , Shi Chao , Equinda Michele , Pamer Eric G.
Published: June 2012

Clostridium difficilecan infect the large intestine and cause colitis when the normal intestinal microbiota is altered by antibiotic administration. Little is known about the innate immune signaling pathways that marshal inflammatory responses toC. difficileinfection and whether protective and pathogenic inflammatory responses can be dissociated. Toll-like receptors predominantly signal via the MyD88 adaptor protein and are important mediators of innate immune signaling in the intestinal mucosa. Here, we demonstrate that MyD88-mediated signals trigger neutrophil and CCR2-dependent Ly6Chimonocyte recruitment to the colonic lamina propria (cLP) during infection, which prevent dissemination of bystander bacteria to deeper tissues. Mortality is markedly increased in MyD88-deficient mice followingC. difficileinfection, as are parameters of mucosal tissue damage and inflammation. Antibody-mediated depletion of neutrophils markedly increases mortality, while attenuated recruitment of Ly6Chimonocytes in CCR2-deficient mice does not alter the course ofC. difficileinfection. Expression of CXCL1, a neutrophil-recruiting chemokine, is impaired in the cLP of MyD88−/−mice. Our studies suggest that MyD88-mediated signals promote neutrophil recruitment by inducing expression of CXCL1, thereby providing critical early defense againstC. difficile-mediated colitis.
MprA and DosR Coregulate a Mycobacterium tuberculosis Virulence Operon Encoding
Rv1813c
and
Rv1812c
Authors: Bretl Daniel J. , He Hongjun , Demetriadou Crystalla , White Mark J. , Penoske Renee M. , Salzman Nita H. , Zahrt Thomas C.
Published: June 2012

Mycobacterium tuberculosis
remains a significant global pathogen, causing extensive morbidity and mortality worldwide. This bacterium persists within granulomatous lesions in a poorly characterized, nonreplicating state. The two-component signal transduction systems MprAB and DosRS-DosT (DevRS-Rv2027c) are responsive to conditions likely to be present within granulomatous lesions and mediate aspects of
M. tuberculosis
persistence
in vitro
and
in vivo
. Here, we describe a previously uncharacterized locus,
Rv1813c-Rv1812c
, that is coregulated by both MprA and DosR. We demonstrate that MprA and DosR bind to adjacent and overlapping sequences within the promoter region of
Rv1813c
and direct transcription from an initiation site located several hundred base pairs upstream of the
Rv1813
translation start site. We further show that
Rv1813c
and
Rv1812c
are cotranscribed, and that the genomic organization of this operon is specific to
M. tuberculosis
and
Mycobacterium bovis
. Although
Rv1813c
is not required for survival of
M. tuberculosis
in vitro
, including under conditions in which MprAB and DosRST signaling are activated, an
M. tuberculosis
Δ
Rv1813c
mutant is attenuated in the low-dose aerosol model of murine tuberculosis, where it exhibits a lower bacterial burden, delayed time to death, and decreased ability to stimulate proinflammatory cytokines interleukin-1β (IL-1β) and IL-12. Interestingly, overcomplementation of these phenotypes is observed in the
M. tuberculosis
Δ
Rv1813c
mutant expressing both
Rv1813c
and
Rv1812c
, but not
Rv1813c
alone, in
trans
. Therefore, Rv1813c and Rv1812c may represent general stress-responsive elements that are necessary for aspects of
M. tuberculosis
virulence and the host immune response to infection.
Sequential Plasmodium chabaudi and Plasmodium berghei Infections Provide a Novel Model of Severe Malarial Anemia
Authors: Harris Juliana V. , Bohr Tiffany M. , Stracener Catherine , Landmesser Mary E. , Torres Vladimir , Mbugua Amos , Moratz Chantal , Stoute José A.
Published: June 2012

Lack of an adequate animal model ofPlasmodium falciparumsevere malarial anemia (SMA) has hampered the understanding of this highly lethal condition. We developed a model of SMA by infecting C57BL/6 mice withP. chabaudifollowed after recovery byP. bergheiinfection.P. chabaudi/P. berghei-infected mice had an initial 9- to 10-day phase of relatively low parasitemia and severe anemia, followed by a second phase of hyperparasitemia, more profound anemia, reticulocytosis, and death 14 to 21 days after infection.P. chabaudi/P. berghei-infected animals had more intense splenic hematopoiesis, higher interleukin-10 (IL-10)/tumor necrosis factor alpha and IL-12/gamma interferon (IFN-γ) ratios, and higher antibody levels againstP. bergheiandP. chabaudiantigens thanP. berghei-infected orP. chabaudi-recovered animals. Early treatment with chloroquine or artesunate did not prevent the anemia, suggesting that the bulk of red cell destruction was not due to the parasite. Red cells fromP. chabaudi/P. berghei-infected animals had increased surface IgG and C3 by flow cytometry. However, C3−/−mice still developed anemia. Tracking of red cells labeledex vivoandin vivoand analysis of frozen tissue sections by immunofluorescence microscopy showed that red cells fromP. chabaudi/P. berghei-infected animals were removed at an accelerated rate in the liver by erythrophagocytosis. This model is practical and reproducible, and its similarities withP. falciparumSMA in humans makes it an appealing system with which to study the pathogenesis of this condition and explore potential immunomodulatory interventions.
The association of dental plaque with cancer mortality in Sweden. A longitudinal study
Authors: Söder Birgitta , Yakob Maha , Meurman Jukka H , Andersson Leif C , Söder Per-Östen
Published: June 2012

Objectives

To study whether the amount of dental plaque, which indicates poor oral hygiene and is potential source of oral infections, associates with premature death from cancer.

Design

Prospective cohort study.

Participants

1390 randomly selected healthy young Swedes followed up from 1985 to 2009. All subjects underwent oral clinical examination and answered a questionnaire assessing background variables such as socioeconomic status and smoking.

Outcome measures

Causes of death were recorded from national statistics and classified according to the WHO International Classification of Diseases. Unpaired t test, χ2tests and multiple logistic regressions were used.

Results

Of the 1390 participants, 4.2% had died during the follow-up. Women had died at a mean age of 61.0 (±2.6 SD) years and men at the age of 60.2 (±2.9 SD) years. The amount of dental plaque between those who had died versus survived was statistically significant (p<0.001). In multiple logistic regression analysis, dental plaque appeared to be a significant independent predictor associated with 1.79 times the OR of death (p<0.05). Age increased the risk with an OR of 1.98 (p<0.05) and gender (men) with an OR of 1.91 (p<0.05). The malignancies were more widely scattered in men, while breast cancer was the most frequent cause of death in women.

Conclusions

This study hypothesis was confirmed by showing that poor oral hygiene, as reflected in the amount of dental plaque, was associated with increased cancer mortality.
Increasing cotton genome coverage with polymorphic SSRs as revealed by SSCP
Authors: Li Ximei , Yuan Daojun , Wang Hantao , Chen Xuemei , Wang Bin , Lin Zhongxu , Zhang Xianlong
Published: June 2012

Simple sequence repeat (SSR) markers are widely used in plant genetics and breeding. However, there are many SSR markers that do not reveal polymorphism in cotton. Traditional SSR genotyping methods only provide information on product sizes. This leaves many marker polymorphism undetected, thus, lowering the utility of SSRs. In the present study, monomorphic SSRs between two mapping parents, ‘Emian22’ and 3-79, were subjected to single-strand conformation polymorphism (SSCP) analysis to reveal polymorphism. Of the 4194 monomorphic SSR primer pairs, 158 pairs (3.77%) showed polymorphism and revealed 174 polymorphic loci. Sequence analysis showed that the differences in PCR products between the mapping parents were solely due to base transition or transversion, which was in agreement with SSCP principles. SSCP also revealed SSRs with motifs of AT/TA and GAA/CTT were more polymorphic in dinucleotides and trinucleotides, respectively. Genetic mapping integrated 160 loci into our interspecific BC1 linkage map, 5 of which associated with QTLs related to cotton fiber quality. The technique discussed in the present study enables us to detect polymorphism of monomorphic SSRs, and increase the utilization efficiency of the existing SSR primers.
The Computational Complexity of Nash Equilibria in Concisely Represented Games
Authors: Schoenebeck Grant R. , Vadhan Salil
Published: June 2012

Games may be represented in many different ways, and different representations of games affect the complexity of problems associated with games, such as finding a Nash equilibrium. The traditional method of representing a game is to explicitly list all the payoffs, but this incurs an exponential blowup as the number of agents grows. We study two models of concisely represented games:
circuit games
, where the payoffs are computed by a given boolean circuit, and
graph games
, where each agent’s payoff is a function of only the strategies played by its neighbors in a given graph. For these two models, we study the complexity of four questions: determining if a given strategy is a Nash equilibrium, finding a Nash equilibrium, determining if there exists a pure Nash equilibrium, and determining if there exists a Nash equilibrium in which the payoffs to a player meet some given guarantees. In many cases, we obtain tight results, showing that the problems are complete for various complexity classes.
Crosscorrelation of Earthquake Data Using Stationary Phase Evaluation: Insight into Reflection Structures of Oceanic Crust Surface in the Nankai Trough
Authors: Minato Shohei , Tsuji Takeshi , Matsuoka Toshifumi , Obana Koichiro
Published: June 2012

Seismic interferometry (SI) has been recently employed to retrieve the reflection response from natural earthquakes. We perform experimental study to apply SI to Ocean Bottom Seismogram (OBS) records in the Nankai Trough, southwest Japan in order to reveal the relatively shallow geological boundaries including surface of oceanic crust. Although the local earthquakes with short raypath we use to retrieve reflection response are expected to contain the higher-frequency components to detect fine-scale structures by SI, they cannot be assumed as plane waves and are inhomogeneously distributed. Since the condition of inhomogeneous source distribution violates the assumption of SI, the conventional processing yields to the deteriorated subsurface images. Here we adopt the raypath calculation for stationary phase evaluation of SI in order to overcome this problem. To find stationary phase, we estimate the raypaths of two reflections: (1) sea-surfaceP-wave reflection and (2) sea-surface multipleP-wave reflection. From the estimated raypath, we choose the crosscorrelation traces which are expected to produce objective reflections considering the stationary phase points. We use the numerical-modeling data and field data with 6 localized earthquakes and show that choosing the crosscorrelation traces by stationary phase evaluation improves the quality of the reflections of the oceanic crust surface.
Reducing Noises and Artifacts Simultaneously of Low‐Dosed X‐Ray Computed Tomography Using Bilateral Filter Weighted by Gaussian Filtered Sinogram
Authors: Hu Shaoxiang , Liao Zhiwu , Chen Wufan
Published: June 2012

Existing sinogram restoration methods cannot handle noises and nonstationary artifacts simultaneously. Although bilateral filter provides an efficient way to preserve image details while denoising, its performance in sinogram restoration for low‐dosed X‐ray computed tomography (LDCT) is unsatisfied. The main reason for this situation is that the range filter of the bilateral filter measures similarity by sinogram values, which are polluted seriously by noises and nonstationary artifacts of LDCT. In this paper, we propose a simple method to obtain satisfied restoration results for sinogram of LDCT. That is, the range filter weighs the similarity by Gaussian smoothed sinogram. Since smoothed sinogram can reduce the influence of both noises and nonstationary artifacts for similarity measurement greatly, our new method can provide more satisfied denoising results for sinogram restoration of LDCT. Experimental results show that our method has good visual quality and can preserve anatomy details in sinogram restoration even in both noises and non‐stationary artifacts.
Postextraction Alveolar Ridge Preservation: Biological Basis and Treatments
Authors: Pagni Giorgio , Pellegrini Gaia , Giannobile William V. , Rasperini Giulio
Published: June 2012

Following tooth extraction, the alveolar ridge undergoes an inevitable remodeling process that influences implant therapy of the edentulous area. Socket grafting is a commonly adopted therapy for the preservation of alveolar bone structures in combination or not with immediate implant placement although the biological bases lying behind this treatment modality are not fully understood and often misinterpreted. This review is intended to clarify the literature support to socket grafting in order to provide practitioners with valid tools to make a conscious decision of when and why to recommend this therapy.
Single Feed Aperture-Coupled Wideband Dielectric Resonator Antenna with Circular Polarization for Ku-Band Applications
Authors: Patin Joshua M. , Sharma Satish K.
Published: June 2012

A novel single feed aperture-coupled wideband dielectric resonator antenna (DRA) exhibiting righ-handed circular polarization (RHCP) operating in the Ku-band frequency range is presented. The aperture-coupled single feed design utilizes back-side microstrip excitation through a novel bow-tie-shaped cross-slots in the ground plane. Extensive simulation parametric studies resulted in a 3 dB axial ratio (AR) bandwidth of 17.24% at a center frequency of 13 GHz, where the dielectric resonator is excited in its HEM11δresonant mode. A prototype DRA was fabricated with some limitations and experimentally verified for the impedance matching and radiation patterns showing circular polarization.
Isolated Pancreatic Tuberculosis Mimicking Malignancy in an Immunocompetent Host
Authors: Raghavan Pooja , Rajan Dhyan
Published: June 2012

Despite the high prevalence of tuberculosis (TB) worldwide, pancreatic TB is rare. When present, pancreatic TB is frequently associated with miliary TB, often in immunocompromised hosts. Pancreatic TB may present as a pancreatic abscess, acute or chronic pancreatitis, and cystic or solid pancreatic masses. We present a case of an immunocompetent patient who presented with two discrete pancreatic masses and was subsequently diagnosed with isolated pancreatic TB. This case suggests that clinicians should have a heightened suspicion of pancreatic TB when faced with discrete pancreatic lesions, especially in patients from areas where the infection is endemic. Such recognition may lead to appropriate diagnostic testing, and possible resolution of pancreatic lesions with antituberculin therapy.
Clinical Data Mining of Phenotypic Network in Angina Pectoris of Coronary Heart Disease
Authors: Chen Jianxin , Lu Peng , Zuo Xiaohan , Shi Qi , Zhao Huihui , Luo Liangtao , Yi Jianqiang , Zheng Chenglong , Yang Yi , Wang Wei
Published: June 2012

Coronary heart disease (CHD) is the leading causes of morbidity and mortality in China. The diagnosis of CHD in Traditional Chinese Medicine (TCM) was mainly based on experience in the past. In this paper, we proposed four MI-based association algorithms to analyze phenotype networks of CHD, and established scale of syndromes to automatically generate the diagnosis of patients based on their phenotypes. We also compared the change of core syndromes that CHD were combined with other diseases, and presented the different phenotype spectra.
Spatiotemporal Dysfunction of the Vascular Permeability Barrier in Transgenic Mice with Sickle Cell Disease
Authors: Ghosh Samit , Tan Fang , Ofori-Acquah Solomon F.
Published: June 2012

Sickle cell disease (SCD) is characterized by chronic intravascular hemolysis that generates excess cell-free hemoglobin in the blood circulation. Hemoglobin causes multiple endothelial dysfunctions including increased vascular permeability, impaired reactivity to vasoactive agonists, and increased adhesion of leukocytes to the endothelium. While the adhesive and vasomotor defects of SCD associated with cell-free hemoglobin are well defined, the vascular permeability phenotype remains poorly appreciated. We addressed this issue in two widely used and clinically relevant mouse models of SCD. We discovered that the endothelial barrier is normal in most organs in the young but deteriorates with aging particularly in the lung. Indeed, middle-aged sickle mice developed pulmonary edema revealing for the first time similarities in the chronic permeability phenotypes of the lung in mice and humans with SCD. Intravenous administration of lysed red blood cells into the circulation of sickle mice increased vascular permeability significantly in the lung without impacting permeability in other organs. Thus, increased vascular permeability is an endothelial dysfunction of SCD with the barrier in the lung likely the most vulnerable to acute inflammation.
Baroreflex Activation Therapy for the Treatment of Drug-Resistant Hypertension: New Developments
Authors: Alnima Teba , de Leeuw Peter W. , Kroon Abraham A.
Published: June 2012

In the past few years, novel accomplishments have been obtained in carotid baroreflex activation therapy (BAT) for the treatment of resistant hypertension. In addition, this field is still evolving with promising results in the reduction of blood pressure and heart rate. This overview addresses the latest developments in BAT for the treatment of drug-resistant hypertension. Although not totally understood considering the working mechanisms of BAT, it appeared to be possible to achieve at least as much efficacy of single-sided as bilateral stimulation. Therefore unlike the first-generation Rheos system, the second-generation Barostimneooperates by unilateral baroreflex activation, using a completely different carotid electrode. Also significant improvements in several cardiac parameters have been shown by BAT in hypertensive patients, which set the basis for further research to evaluate BAT as a therapy for systolic heart failure. Yet important uncertainties need to be clarified to guarantee beneficial effects; hence not all participants seem to respond to BAT.
Intragastric and Intranasal Administration ofLactobacillus paracaseiNCC2461 Modulates Allergic Airway Inflammation in Mice
Authors: Pellaton Céline , Nutten Sophie , Thierry Anne-Christine , Boudousquié Caroline , Barbier Nathalie , Blanchard Carine , Corthésy Blaise , Mercenier Annick , Spertini François
Published: June 2012

Introduction. Preclinical and clinical evidences for a role of oral probiotics in the management of allergic diseases are emerging.Aim. We aimed at testing the immunomodulatory effects of intranasalversusintragastric administration ofLactobacillus paracaseiNCC2461 in a mouse model of allergic airway inflammation and the specificity of different probiotics by comparingL. paracaseiNCC2461 toLactobacillus plantarumNCC1107.Methods.L. paracaseiNCC2461 orL. plantarumNCC1107 strains were administered either intragastrically (NCC2461) or intranasally (NCC2461 or NCC1107) to OVA-sensitized mice challenged with OVA aerosols. Inflammatory cell recruitment into BALF, eotaxin and IL-5 production in the lungs were measured.Results. IntranasalL. paracaseiNCC2461 efficiently protected sensitized mice upon exposure to OVA aerosols in a dose-dependent manner as compared to control mice. Inflammatory cell number, eotaxin and IL-5 were significantly reduced in BALF. Intranasal supplementation ofL. paracaseiNCC2461 was more potent than intragastric application in limiting the allergic response and possibly linked to an increase in T regulatory cells in the lungs. Finally, intranasalL. plantarumNCC1107 reduced total and eosinophilic lung inflammation, but increased neutrophilia and macrophages infiltration.Conclusion. A concerted selection of intervention schedule, doses, and administration routes (intranasal versus intragastric) may markedly contribute to modulate airway inflammation in a probiotic strain-specific manner.
Diminished Expression of Complement Regulatory Proteins on Peripheral Blood Cells from Systemic Lupus Erythematosus Patients
Authors: Alegretti Ana Paula , Schneider Laiana , Piccoli Amanda Kirchner , Monticielo Odirlei Andre , Lora Priscila Schmidt , Brenol João Carlos Tavares , Xavier Ricardo Machado
Published: June 2012

CD55, CD59, CD46, and CD35 are proteins with complement regulatory (Creg) properties that ensure cell and tissue integrity when this system is activated. The aim of this study was to evaluate the Creg expression on peripheral blood cells from SLE patients and its association with cytopenia and disease activity. Flow cytometric analyses were performed on blood cells from 100 SLE patients and 61 healthy controls. Compared with healthy controls, we observed in SLE patients with lymphopenia and neutropenia decreased expression of CD55, CD59, and CD46 (). In SLE patients with anemia, CD59 and CD35 were decreased on red blood cells. Furthermore, there was a negative correlation between CD55 and CD59 on neutrophils and the disease activity. The results suggest there is an altered pattern of Creg expression on the peripheral blood cells of SLE patients, and the expression is correlated with disease activity and/or with activation of the complement system.
Oxidative DNA Damage in Neurons: Implication of Ku in Neuronal Homeostasis and Survival
Authors: De Zio Daniela , Bordi Matteo , Cecconi Francesco
Published: June 2012

Oxidative DNA damage is produced by reactive oxygen species (ROS) which are generated by exogenous and endogenous sources and continuously challenge the cell. One of the most severe DNA lesions is the double-strand break (DSB), which is mainly repaired by nonhomologous end joining (NHEJ) pathway in mammals. NHEJ directly joins the broken ends, without using the homologous template. Ku70/86 heterodimer, also known as Ku, is the first component of NHEJ as it directly binds DNA and recruits other NHEJ factors to promote the repair of the broken ends. Neurons are particularly metabolically active, displaying high rates of transcription and translation, which are associated with high metabolic and mitochondrial activity as well as oxygen consumption. In such a way, excessive oxygen radicals can be generated and constantly attack DNA, thereby producing several lesions. This condition, together with defective DNA repair systems, can lead to a high accumulation of DNA damage resulting in neurodegenerative processes and defects in neurodevelopment. In light of recent findings, in this paper, we will discuss the possible implication of Ku in neurodevelopment and in mediating the DNA repair dysfunction observed in certain neurodegenerations.
Herbal Formula, PM014, Attenuates Lung Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease
Authors: Lee Hyojung , Kim Youngeun , Kim Hye Jin , Park Soojin , Jang Young Pyo , Jung Sungki , Jung Heejae , Bae Hyunsu
Published: June 2012

Chronic obstructive pulmonary disease (COPD), which is characterized by airway obstruction, leads to, as the two major forms of COPD, chronic bronchitis and emphysema. This study was conducted to evaluate the effects of herbal formula, PM014, in a murine model of COPD. Balb/c mice were treated once with each herb extract in PM014 or PM014 mixture via an oral injection. Lipopolysaccharide (LPS) or elastase/LPS were administrated to the mice to induce a disease that resembles COPD. PM014 treatment significantly attenuated the increased accumulation of immune cells in bronchoalveolar lavage fluid (BALF) compared to control mice. In addition, the TNF-αand IL-6 levels in BALF were decreased in the PM014 mice. Furthermore, histological analysis demonstrated that PM014 attenuated the hazardous effects of lung inflammation. These data suggest that PM014 exerts beneficial effects against forms of COPD such as lung inflammation.
Weight Gain Prevention for College Freshmen: Comparing Two Social Cognitive Theory-Based Interventions with and without Explicit Self-Regulation Training
Authors: Dennis Elizabeth A. , Potter Kerry L. , Estabrooks Paul A. , Davy Brenda M.
Published: June 2012

The college transition represents a critical period for maintaining a healthy weight, yet intervention participation and retention represent significant challenges. The objective of this investigation was to evaluate the preliminary efficacy and acceptability of two interventions to prevent freshman weight gain. One intervention provided opportunities to improve outcome expectations and self-efficacy within a social cognitive theory framework (SCT), while the other targeted the same variables but focused on explicit training in self-regulation skills (SCTSR).Methods.Freshmen (n=45) aged >18 years were randomized to a 14-week intervention, SCT or SCTSR; both included online modules and in-class meetings. Of the 45 students randomized, 5 withdrew before the classes began and 39 completed pre- and posttesting. Primary outcomes included body weight/composition, health behaviors, and program acceptability. Analyses included independent samplet-tests, repeated measures ANOVA, and bivariate correlational analyses.Results.Body weight increased over the 14-week period, but there was no group difference. Percent body fat increased in SCTSR but not SCT (mean difference: SCTSR, +1.63 ± 0.52%; SCT, −0.25 ± 0.45%;P=0.01). Class attendance was 100% (SCTSR) and 98% (SCT); SCTSR students (>50%) remarked that the online tracking required “too much time.”Conclusions.The intervention was well received, although there were no improvements in weight outcomes.
HIV Assembly and Budding: Ca2+ Signaling and Non-ESCRT Proteins Set the Stage
Authors: Ehrlich Lorna S. , Carter Carol A.
Published: June 2012

More than a decade has elapsed since the link between the endosomal sorting complex required for transport (ESCRT) machinery and HIV-1 protein trafficking and budding was first identified. L domains in HIV-1 Gag mediate recruitment of ESCRT which function in bud abscission releasing the viral particle from the host cell. Beyond virus budding, the ESCRT machinery is also involved in the endocytic pathway, cytokinesis, and autophagy. In the past few years, the number of non-ESCRT host proteins shown to be required in the assembly process has also grown. In this paper, we highlight the role of recently identified cellular factors that link ESCRT machinery to calcium signaling machinery and we suggest that this liaison contributes to setting the stage for productive ESCRT recruitment and mediation of abscission. Parallel paradigms for non-ESCRT roles in virus budding and cytokinesis will be discussed.
Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment
Authors: Tanida Satoshi , Mizoshita Tsutomu , Ozeki Keiji , Tsukamoto Hironobu , Kamiya Takeshi , Kataoka Hiromi , Sakamuro Daitoku , Joh Takashi
Published: June 2012

Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway. In addition, a new mechanism has recently been revealed, in which the oncoprotein c-Myc suppresses bridging integrator 1 (BIN1), thereby releasing poly(ADP-ribose)polymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance. The present paper focuses on the molecular mechanisms of cisplatin-induced apoptosis and of cisplatin resistance, in particular on the involvement of BIN1 in the maintenance of cisplatin sensitivity.
Flow-simulated thrombin generation profiles as a predictor of thrombotic risk among pre-menopausal women
Authors: Jordan Sumanas W. , Corriere Matthew A. , Vossen Carla Y. , Rosendaal Frits R. , Chaikof Elliot L.
Published: June 2012

A large number of individuals are at risk for deep venous thrombosis (DVT) due to alterations in multiple coagulation factors and inhibitors secondary to malignancy, drug interactions, or other general medical conditions. Traditional metrics of haemostasis such as prothrombin time, partial thromboplastin time, and bleeding time, generally estimate anticoagulation status and bleeding risk rather than thrombosis risk. The objective of this study was to correlate a novel, systems-based metric of clotting potential to risk of DVT from a database derived from the Leiden Thrombophilia Study (LETS). We utilised a computational model of blood coagulation, which addresses the interplay between biochemical factors, blood flow, and physiologic surface initiation of coagulation, to calculate an individualised, systems-based metric of clotting potential, termed the flow-simulated thrombin generation (FSTG), for 210 pre-menopausal women in LETS. Both DVT and oral contraceptive (OC) use were associated with higher values of FSTG. We demonstrated a nearly three-fold increased risk of DVT for each standard deviation increase above the mean in FSTG determined under venous flow conditions, which remained highly predictive after adjustment for age and OC status (adjusted odds ratio 2.66; 95% confidence interval 1.69–4.19; p<0.0001). In conclusion, a systems-based screening approach that integrates biochemical factors and flow haemodynamics identifies small subgroups of patients at risk of thrombosis that may benefit from oral anticoagulants.
In Vivo Human Brachial Artery Elastic Mechanics
Authors: Bank Alan J. , Kaiser Daniel R. , Rajala Scott , Cheng Anthony
Published: June 2012

Background
—–The effects of smooth muscle relaxation on arterial wall mechanics are controversial. We used a new, in vivo, noninvasive technique to measure brachial artery wall mechanics under baseline conditions and following smooth muscle relaxation with nitroglycerin (NTG).

Methods and Results
—Eight healthy, normal subjects (6 male, 2 female; age 30±3.1 years) participated in the study. The nondominant brachial artery was imaged through a water-filled blood pressure cuff using an external ultrasound wall-tracking system at baseline and following 0.4 mg sublingual NTG. Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Brachial artery area, unstressed area, compliance, stress, strain, incremental elastic modulus (E
inc
), and pulse wave velocity (PWV) were measured over a TP range from 0 to 100 mm Hg. Baseline area versus TP curves generated 30 minutes apart were not significantly different. NTG significantly shifted area versus TP (
P
<0.0001) and compliance versus TP (
P
<0.001) curves upward, whereas the E
inc
versus TP (
P
<0.05) and PWV versus TP (
P
<0.01) curves were shifted downward. NTG also significantly shifted stress versus strain (
P
<0.01) and E
inc
versus strain (
P
<0.01) curves to the right.

Conclusions
—We conclude that brachial artery elastic mechanics can be reproducibly measured over a wide range of TP and smooth muscle tone using a new noninvasive ultrasound technique. Smooth muscle relaxation with NTG increases isobaric compliance and decreases isobaric E
inc
and PWV in the human brachial artery.
Prolonged Diastolic Time Fraction Protects Myocardial Perfusion When Coronary Blood Flow Is Reduced
Authors: Merkus Daphne , Kajiya Fumihiko , Vink Hans , Vergroesen Isabelle , Dankelman Jenny , Goto Masami , Spaan Jos A. E.
Published: June 2012

Background
—Because coronary blood flow is impeded during systole, the duration of diastole is an important determinant of myocardial perfusion. The aim of this study was to show that coronary flow modulates the duration of diastole at constant heart rate.

Methods and Results
—In anesthetized, open-chest dogs, diastolic time fraction (DTF) increased significantly when coronary flow was reduced by lowering perfusion pressure from 100 to 70, 55, and 40 mm Hg. On average, DTF increased from 0.47±0.04 to 0.55±0.03 after a pressure step from 100 to 40 mm Hg in control, from 0.42±0.04 to 0.47±0.04 after administration of adenosine, and from 0.46±0.07 to 0.55±0.06 after L-NMMA (mean±SD, 6 dogs for control and adenosine, 4 dogs for L-NMMA, all
P
<0.05). Flow normalized to its value at full dilation and pressure of 90 mm Hg (375±25 mL/min) increased during the period of reduced pressure at 40 mm Hg; control, from 0.005±63 (2 seconds after pressure step) to 0.09±0.06 (15 seconds after pressure step); with adenosine, from 0.19±0.06 to 0.22±0.06; and with L-NMMA, from 0.013±0.007 to 0.12±0.02 (all
P
<0.05). The increase in DTF at low pressure may be explained by a decrease in interstitial volume at low pressure, which either decreases the preload of the myocytes or reduces the buffer capacity for ions determining repolarization, thereby causing an earlier onset of relaxation.

Conclusions
—Because the largest increase in DTF occurs at pressures below the autoregulatory range when blood flow to the subendocardium is closely related to DTF, modulation of DTF by coronary blood flow can provide an important regulatory mechanism to match supply and demand of the myocardium when vasodilatory reserve is exhausted.
Effect of Metoprolol Administration on Renal Sodium Handling in Experimental Congestive Heart Failure
Authors: DiBona Gerald F. , Sawin Linda L.
Published: June 2012

Background
—Long-term metoprolol therapy improves cardiac performance and decreases mortality in patients with chronic congestive heart failure (CHF). This study examined the effect of long-term metoprolol therapy on renal sodium handling in an experimental rat model of CHF.

Methods and Results
—Rats with left coronary ligation and myocardial infarction–induced CHF were treated with metoprolol (1.5 mg · kg
−1
· h
−1
) or vehicle for 3 weeks by osmotic minipump. They were then evaluated for their ability to excrete a short-term sodium load (5% body weight isotonic saline infusion over 30 minutes) and a long-term sodium load (change from low- to high-sodium diet over 8 days). All CHF rats had left ventricular end-diastolic pressure >10 mm Hg, and heart weight/body weight ratios averaged 0.68±0.02% (versus control of ≈0.40%). Compared with vehicle CHF rats (n=19), metoprolol CHF rats (n=18) had lower basal values of mean arterial pressure (122±3 versus 112±3 mm Hg) and heart rate (373±14 versus 315±9 bpm) and decreased heart rate responses to intravenous doses of isoproterenol. During short-term isotonic saline volume loading, metoprolol CHF rats excreted 54±4% more of the sodium load than vehicle CHF rats. During long-term dietary sodium loading, metoprolol CHF rats retained 28±3% less sodium than vehicle CHF rats.

Conclusions
—Metoprolol treatment of rats with CHF results in an improved ability to excrete both short- and long-term sodium loads.
Effects of Walking on Coronary Heart Disease in Elderly Men
Authors: Hakim Amy A. , Curb J. David , Petrovitch Helen , Rodriguez Beatriz L. , Yano Katsuhiko , Ross G. Webster , White Lon R. , Abbott Robert D.
Published: June 2012

Background
—Effects of walking on the risk of coronary heart disease morbidity and mortality have not been identified in the elderly. The purpose of this study was to determine whether walking is associated with a reduced risk of coronary heart disease in a sample of elderly men.

Methods and Results
—For this study, distance walked (mile/d) was examined at a baseline examination that occurred from 1991 to 1993 in the Honolulu Heart Program. Incident coronary heart disease from all causes was observed over a 2- to 4-year follow-up period. Subjects followed up were 2678 physically capable elderly men aged 71 to 93 years. During the course of follow-up, 109 men developed coronary heart disease. Men who walked <0.25 mile/d had a 2-fold increased risk of coronary heart disease versus those who walked >1.5 mile/d (5.1% versus 2.5%;
P
<0.01). Men who walked 0.25 to 1.5 mile/d were also at a significantly higher risk of coronary heart disease than men who walked longer distances (4.5% versus 2.5%;
P
<0.05). Adjustment for age and other risk factors failed to alter these findings.

Conclusions
—Findings from the Honolulu Heart Program, which targeted physically capable elderly men, suggest that the risk of coronary heart disease is reduced with increases in distance walked. Combined with evidence that suggests that an active lifestyle reduces the risk of cardiovascular disease in younger and more diverse groups, this suggests that important health benefits could be derived by encouraging the elderly to walk.
Unhealthy Effects of Atmospheric Temperature and Pressure on the Occurrence of Myocardial Infarction and Coronary Deaths
Authors: Danet Sandrine , Richard Florence , Montaye Michèle , Beauchant Stephanette , Lemaire Brigitte , Graux Catherine , Cottel Dominique , Marécaux Nadine , Amouyel Philippe
Published: June 2012

Background
—Associations between an increase in coronary heart disease occurrence and low atmospheric temperatures have been reported from mortality data and hospital admission registries. However, concomitant increases in noncardiovascular case fatality rates and selection bias of hospital cases may weaken this observation. In this study, we addressed the question of the relationships between fatal and nonfatal coronary diseases and meteorological variables in 10-year data (1985 to 1994) collected in a morbidity registry (Lille-WHO MONICA Project) monitoring 257 000 men from 25 to 64 years of age.

Methods and Results
—The impacts of atmospheric temperature (in Celsius) and pressure (in millibars) on daily rates of myocardial infarction (MI) and coronary deaths were studied. Percentages of variation of event rates according to meteorological variations were derived from the relative risks estimated with a Poisson regression model. During the 10-year longitudinal survey, 3616 events occurred. Rates of events decreased linearly with increasing atmospheric temperature. For atmospheric pressure, we detected a V-shaped relationship, with a minimum of daily event rates at 1016 mbar. A 10°C decrease was associated with a 13% increase in event rates (
P
<0.0001); a 10-mbar decrease <1016 mbar and a 10-mbar increase >1016 mbar were associated with a 12% increase (
P
=0.001) and an 11% increase (
P
=0.01) in event rates, respectively. These effects were independent and influenced both coronary morbidity and mortality rates, with stronger effects in older age groups and for recurrent events.

Conclusions
—This longitudinal study is the first to estimate the attributable effect of meteorological variables on MI morbidity in population and strongly argues for a systematic fight against cold in cardiovascular disease prevention, particularly in older ages and after a first MI.
Splicing Mutations in
KCNQ1
Authors: Murray A. , Donger C. , Fenske C. , Spillman I. , Richard P. , Dong Y. B. , Neyroud N. , Chevalier P. , Denjoy I. , Carter N. , Syrris P. , Afzal A. R. , Patton M. A. , Guicheney P. , Jeffery S.
Published: June 2012

Background
—Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene
KCNQ1
, previously named
KVLQT1
, on chromosome 11p15.5 is one of these.

Methods and Results
—We initially analyzed one family using microsatellite markers and found linkage to
KCNQ1
. Mutation detection showed a G to C change in the last base of exon 6 (1032 G→C) that does not alter the coded alanine. Restriction digest analysis in the family showed that only affected individuals carried the mutation. A previous report suggested that a G to A substitution at the same position may act as a splice mutation in
KCNQ1
, but no data was given to support this hypothesis nor was the transcription product identified. We have shown by reverse-transcription polymerase chain reaction that 2 smaller bands were produced for the
KCNQ1
gene transcripts in addition to the normal-sized transcripts when lymphocytes of affected individuals were analyzed. Sequencing these transcripts showed a loss of exon 7 in one and exons 6 and 7 in the other, but an in-frame transcript was left in each instance. We examined other families in whom long-QT syndrome was diagnosed and found another unreported splice-site mutation, 922-1 G→C, in the acceptor site of intron 5, and 2 of the previously reported 1032 G→A mutations. All these showed a loss of exons 6 and 7 in the mutant transcripts, validating the proposal that a consensus sequence is affected in the exonic mutations and that the integrity of the base at position 1032 is essential for correct processing of the transcript.

Conclusions
—The 6 cases already reported in the literature with the 1032 G→A transition, the novel 1032 G→C transversion, and a recent G→T transversion at the same base show that codon 344 is the second most frequently mutated after codon 341, suggesting at least two hotspots for mutations in
KCNQ1
.
Endothelial Dysfunction and Collagen Accumulation
Authors: Lafont Antoine , Durand Eric , Samuel Jane L. , Besse Bruno , Addad Faouzi , Lévy Bernard I. , Desnos Michel , Guérot Claude , Boulanger Chantal M.
Published: June 2012

Background
—Constrictive remodeling plays a prominent role in restenosis after balloon angioplasty, but its regulation remains unclear. Because endothelial dysfunction and changes in extracellular matrix have been reported after angioplasty, this study was designed to simultaneously evaluate endothelial function and collagen and elastin changes after restenosis and arterial remodeling.

Methods and Results
—Atherosclerosis was induced in femoral arteries of 22 New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed. Histomorphometry and in vitro assessment of endothelial function were performed 4 weeks after angioplasty. Restenosis correlated with constrictive remodeling (
r
=0.60,
P
=0.01) but not with neointimal growth (
r
=−0.06,
P
=0.79). Restenosis correlated with an impaired relaxation to acetylcholine (ACh;
r
=0.61,
P
=0.02) but not with the response to the endothelium-independent vasodilator sodium nitroprusside (
r
=−0.25,
P
=0.40). Restenosis correlated positively with collagen accumulation (
r
=0.69,
P
=0.004) and inversely with elastin density (
r
=−0.48,
P
=0.05). Relaxations to ACh were significantly more decreased in arteries with constrictive remodeling than in those with enlargement remodeling (3.7±7.9% versus 35.5±15.0%,
P
=0.04). Neointimal collagen density was significantly higher in arteries with constrictive remodeling than in those with enlargement remodeling (34.5±4.5% versus 18.2±4.7%,
P
=0.03). Endothelial function and collagen and elastin density were independent predictors of restenosis in the study.

Conclusions
—These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.
Pharmacokinetics and Pharmacodynamic Effects of a New Antibody Glycoprotein IIb/IIIa Inhibitor (YM337) in Healthy Subjects
Authors: Harder Sebastian , Kirchmaier Carl M. , Krzywanek Hans Jürgen , Westrup Dagmar , Bae Jin-Woo , Breddin Hans Klaus
Published: June 2012

Background
—This study describes the first administration of YM337, the Fab fragment of a humanized monoclonal antibody against the fibrinogen GP IIb/IIIa receptor, in healthy male humans.

Methods and Results
—Platelet aggregation (20 μmol/L ADP), platelet adhesion, fibrinogen binding, bleeding time, and YM337 concentrations in plasma were studied in substudy 1 after single boluses of 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg YM337 and in substudy 2 after a bolus (0.35 mg/kg) plus 6 hours of infusion at different dose levels of YM337 (0.5, 0.75, 1.0, 1.5 μg · kg
−1
· min
−1
), with abciximab as reference drug (n=5 or 6 subjects per group). After the 0.2-mg/kg and 0.4-mg/kg boluses, fibrinogen binding was reduced by >80% and bleeding time was prolonged to ≈60 minutes. Bolus followed by infusion of 1.0 and 1.5 μg · kg
−1
· min
−1
YM337 maintained inhibition of platelet aggregation >80%. Aggregation and bleeding time returned to normal within 24 hours. A bolus of 0.25 mg/kg of abciximab followed by an infusion of 0.125 μg · kg
−1
· min
−1
showed effects similar to those observed with the 0.5- and 0.75-μg · kg
−1
· min
−1
infusion of YM337. In 53 subjects exposed to YM337, 1 case of transient thrombocytopenia and 3 minor bleeding events occurred. No human anti-chimeric antibodies were detected 2 weeks and 2 months after administration.

Conclusions
—YM337 effectively inhibits IIb/IIIa-mediated platelet aggregation and adhesion in humans. The results of this phase 1 study will give rise to further clinical evaluation of YM337.