bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of clenching on t2 and diffusion parameters of the masseter muscle
Authors: Chikui Toru , Shiraishi Tomoko , Ichihara Takahiro , Kawazu Toshiyuki , Hatakenaka Masamitsu , Kami Yukiko , Yuasa Kenji , Yoshiura Kazunori
Published: December 2009

Background: Persistent muscle contractions during clenching are considered to be one reason for temporomandibular disorders. However, no report has evaluated the effect of clenching on the masticatory muscles, as measured by magnetic resonance imaging (MRI).

Purpose: To investigate whether clenching has an effect on either T2 or the coefficients for diffusion of the masseter muscles (MM), and to evaluate the effect of the distribution of bite force on such indices.

Material and Methods: Twenty-three subjects were examined. Bite force was measured by a pressure-sensitive sheet, and the force of the right and the left sides was calculated. MRI was used to evaluate T2, the apparent diffusion coefficient (ADC), and the primary (λ1), secondary (λ2), and tertiary eigenvalues (λ3). These indices on the stronger side of the bite force were compared to those on the weaker side. Thereafter, the indices were compared between at rest and during clenching.

Results: There was no significant difference in any of the indices (T2, ADC, λ1, λ2, and λ3) between the side of stronger bite force and the side with weaker. T2 increased by clenching, and the difference was significant in the side with stronger bite force ( P = 0.006). ADC, λ1, λ2, and λ3 increased significantly by clenching ( P <0.01, P <0.01, P <0.01, and P <0.01, respectively) on both sides. The percentage of change of λ2 by clenching was 26.2±15.7% on the stronger side and 26.9±18.6% on the weaker side, which was significantly greater than either that of λ1 or λ3.

Conclusion: The coefficients for diffusion of the MM were sensitive to change by clenching, and λ2 was the most sensitive. Moreover, the relative distribution of the bite forces had no effect on any of the indices.
Magnetic resonance imaging signal reduction may precede volume loss in the pituitary gland of transfusion-dependent beta-thalassemic patients
Authors: Hekmatnia Ali , Radmard Amir Reza , Rahmani Ali Asghar , Adibi Atoosa , Khademi Hooman
Published: December 2009

Background: Pituitary iron overload in patients with transfusion-dependent beta-thalassemia may lead to delayed puberty. Magnetic resonance imaging (MRI) has the potential to estimate tissue iron concentration by detecting its paramagnetic effect and hypophyseal damage by measuring its dimensions indirectly.

Purpose: To investigate the association of pituitary MRI findings and pubertal status in thalassemic patients as well as to demonstrate any priority in appearance of them.

Material and Methods: Twenty-seven beta-thalassemic patients, aged 15–25 years, were divided into 13 with (group A) and 14 without hypogonadism (group B), matched by age, gender, duration of transfusion, and chelation therapy. Thirty-eight age- and sex-adjusted healthy control individuals were also included (group C). All participants underwent pituitary MRI using a 1.5T unit. Pituitary-to-fat signal intensity ratios (SIR) were calculated from coronal T2-weighted images. Estimated pituitary volumes were measured using pituitary height, width, and length on T1-weighted images.

Results: The mean values of pituitary-to-fat SIRs were significantly lower in group A as compared with group B ( P <0.001), and likewise group B had statistically lower values than group C ( P=0.03). The pituitary height and volume were significantly decreased in group A compared to group B (P = 0.006 and P = 0.002, respectively), while these differences did not demonstrate statistically significance between groups B and C.

Conclusion: Pituitary MRI findings such as signal intensity reduction and decrease in volume can be useful markers in estimating pituitary dysfunction in beta-thalassemic patients. Compared to healthy controls, lower values of pituitary-to-fat SIRs in thalassemic patients experiencing normal puberty, without marked decrease in volume, indicate that signal reduction may precede volume loss and could be expected first on MRI.
Randomized controlled non‐inferiority trial of a telehealth treatment for chronic stuttering: the Camperdown Program
Authors: Carey Brenda , O'Brian Sue , Onslow Mark , Block Susan , Jones Mark , Packman Ann
Published: December 2009

Background: Although there are treatments that can alleviate stuttering in adults for clinically significant periods, in Australia there are barriers to the accessibility and availability of best‐practice treatment.

Aims: This parallel group, non‐inferiority randomized controlled trial with multiple blinded outcome assessments investigated whether telehealth delivery of the Camperdown Program provides a non‐inferior alternative to face‐to‐face treatment for adults who stutter.

Methods & Procedures: Forty participants who presented to a university speech clinic were randomized: 20 to the telehealth arm and 20 to the face‐to‐face arm. Exclusion criteria were age younger than 18 years, frequency of stuttering less than 2% of syllables stuttered and previous speech‐restructuring treatment within the past 12 months. The Camperdown Program for adults who stutter was the intervention. Primary outcome measures were frequency of stuttering measured in per cent syllables stuttered (%SS) before treatment and at 9 months post‐randomization and efficiency, measured by counting the number of speech pathologist contact hours used by each participant. Intention to treat analysis was conducted using last observation carried forward. Secondary outcome measures were speech naturalness, self‐reported stuttering severity, and treatment satisfaction.

Outcomes & Results: There was no statistically or clinically significant difference in %SS between the two groups at 9 months post‐randomization. Analysis of covariance adjusting for baseline %SS showed telehealth had 0.8% absolute lower per cent syllables stuttered than face‐to‐face. There were also no differences in %SS between groups immediately post‐treatment, or at 6 months and 12 months post‐treatment (p = 0.9). In the second primary outcome measure, the telehealth group used statistically less contact time (221 min) on average than the face‐to‐face group (95% confidence interval = − 387 to − 56 min, p = 0.01).

Conclusions & Implications: The results provide evidence to support the use of the Camperdown Program delivered by telehealth as an alternate to the face‐to‐face treatment delivery of this programme for adults who stutter. Such a model will increase accessibility to this evidence‐based treatment for adults currently isolated from treatment services.

Trial registration: Current Controlled Trials ISRCTN 48954432.
Project for a Film by Kafka
Authors: Guattari Félix
Published: December 2009

This short document, appearing for the first time in English translation, concerns the prospects of a made-for-television cultural mini-series inspired by select episodes in Kafka's works. A window is opened onto Guattari's curatorial ambitions, cinematic projects, and theory of minor cinema, bringing into focus how he translated theoretical preoccupations into the cultural sector with reference to diverse semiotic media.
Paris and its Doubles: Deleuze/Rivette
Authors: Dowd Garin
Published: December 2009

This essay sets out from the premise that the films of Jacques Rivette merit sustained reconsideration in the framework provided by Deleuze's Cinema 2: The Time-Image. In particular it explores the concepts of ‘the powers of the false’ and ‘fabulation’ as ways of engaging with Rivette's cinematic oeuvre, with a particular focus on his Paris-set films. On this basis the article seeks to add to the readings undertaken by Deleuze himself and, in the light of Rivette's cine-thinking, to examine in tandem both films to which Deleuze directly responded, such as Le Pont du nord, and later post-Deleuze renegotiations of the city such as Secret défense.
Deleuze, Bacon and the Challenge of the Contemporary
Authors: Conio Andrew
Published: December 2009

This paper tests the aesthetic theory presented in Francis Bacon: The Logic of Sensation against the Foucauldian Turn in art in the 1980s and Damien Hirst's early artworks, in order to ask if the concepts taken from the more general aesthetics to be found in A Thousand Plateaus and What is Philosophy? are better suited to an understanding of contemporary art, before returning to the question of whether there is something truly significant at work in this folie à deux between painter and philosopher.
Triptychs, Eternity and the Spirituality of the Body
Authors: Ambrose D. C.
Published: December 2009

This paper develops a detailed reading of Deleuze's philosophical study of Bacon's triptychs in Francis Bacon: The Logic of Sensation. It examines his claims regarding their apparent non-narrative status, and explores the capacity of the triptychs to embody and express a spiritual sensation of the eternity of time.
Pore Forming Properties of Cecropin-Melittin Hybrid Peptide in a Natural Membrane
Authors: Milani Alberto , Benedusi Mascia , Aquila Marco , Rispoli Giorgio
Published: December 2009

The pore forming properties of synthetic cecropin-melittin hybrid peptide (Acetyl-KWKLFKKIGAVLKVL-CONH2; CM15) were investigated by using photoreceptor rod outer segments (OS) isolated from frog retinae obtained by using the whole-cell configuration of the patch-clamp technique. CM15 was applied (and removed) to (from) the OS in ~50 ms with a computer-controlled microperfusion system. Once the main OS endogenous conductance was blocked with light, the OS membrane resistance was ≥1 GΩ, allowing high resolution, low-noise recordings. Different to alamethicines, CM15 produced voltage-independent membrane permeabilisation, repetitive peptide application caused a progressive permeabilisation increase, and no single-channel events were detected at low peptide concentrations. Collectively, these results indicate a toroidal mechanism of pore formation by CM15.
Symmetry in Infancy: Analysis of Motor Development in Autism Spectrum Disorders
Authors: Esposito Gianluca , Venuti Paola
Published: December 2009

Motor asymmetry, defined as the lack of symmetry in movements or postures, is often observed briefly in many typically developing children. However, if such asymmetry persists, it may be a sign of neurological disease. Recent studies have suggested that motor asymmetries may be an early symptom of Autism Spectrum Disorders (ASD). ASD involve a range of social, cognitive, and behavioral problems, at different degrees of functioning, which are thought to be the final common pathway of multiple etiological mechanisms. Furthermore, early identification of ASD has been recognized as a critical aspect for treatment. Our study aims to analyze symmetry in the motor milestones of infants with ASD compared with typically developing infants (TD) or infants with other developmental delay (DD) during the first year of life. Our results highlight that there are different patterns of motor symmetry in the groups. In particular, infants with ASD scored significantly poorer (higher levels of asymmetry) then the TD and DD infants. We also identified two subgroups of infants with ASD, one with a typical level and the other with a lower level of motor functioning. Implications of the study for diagnosis and treatment are described.
Exploring Health Information Technology Innovativeness and its Antecedents in Canadian Hospitals
Authors: Jaana M. , Sicotte C. , Paré G.
Published: December 2009

Objectives: The primary aim of this study was to assess the antecedents of health information technology (HIT) innovativeness in public hospitals. To do so, we built upon our own previous work to relate the level of HIT innovativeness to organizational capacity characteristics.

Methods: We conducted a survey of chief information officers (CIOs) in public hospitals in the two largest Canadian provinces to identify the level of HIT innovativeness in these settings and test nine research hypotheses derived from the proposed research model.

Results: A total of 106 completed questionnaires were received, which represents a response rate of 52%. Our findings indicate strong support for the research model. Seven out of nine hypotheses were supported indicating a significant relationship between HIT innovativeness and structural, financial, leadership, and knowledge sharing capacity characteristics. Results also reveal a moderate level of HIT innovativeness in the surveyed hospitals, with more emphasis on administrative systems and their integration than on clinical systems and emerging technologies.

Conclusions: This study demonstrates that organizational characteristics are related to HIT innovativeness; this relationship holds irrespective of the public or private nature of hospitals.
OmniSCOPE: Composing Universal Therapies
Authors: Carriço L. , de Sá M.
Published: December 2009

Objectives: This paper presents Omni SCOPE, an environment for the development of mobile pervasive therapy artifacts. OmniSCOPE builds on SCOPE, a tool for the support of mobile psychotherapy. It aims at providing therapists with means to adjust and compose new therapeutic artifacts to suit their patients’ needs and new therapeutic approaches.

Methods: Given the positive results that emerged through the development and utilization of SCOPE, a previous single therapy version of Omni SCOPE, extensions were developed in order to enhance the artifacts, the data collection by patients and its consequent analysis by therapists. These extend the usage possibilities to new situations and therapies also targeting a wider range of users and were developed following a user-centered design approach.

Results: As results, we detail the extensions and how they support new activities and therapies illustrated by two case studies in which they are being currently evaluated. Initial results from the involved therapists’ assessment and future trends and directions are also discussed.

Conclusions: The features and accessible artifacts that can be composed with Omni-SCOPE have provided therapists with the possibility to enhance their therapy procedures and to reach a wider audience of patients even while out of the office. Additionally, the data gathering options that can be included within the therapeutic artifacts provide much more detail which can clearly facilitate diagnosis and posterior therapy adjustments.
Studying the Place of Technology to Lower Financial Barriers for Dietary Change
Authors: Maitland J. , Siek K. A.
Published: December 2009

Background: Current dietary self-monitoring systems assume users have access to healthy foods and resources to effectively implement and monitor dietary behavioral change. Objectives: The purpose of this qualitative study is to understand the specific financial-related barriers that caregivers of low socioeconomic status encounter when attempting to make dietary behavior change.

Methods: In this qualitative study, we conducted a focus group and 14 in-person interviews with the primary caregivers of low socioeconomic families. Participants were recruited from a community considered to be ‘at risk’ through high levels of exposure to multiple modifiable risk factors for cardiovascular disease. All participants were English-speaking caregivers, who had children under

eight years old. The families lived in an urban, public housing community. The focus group and interviews were transcribed and coded during data analysis sessions, then analyzed for emergent themes.

Results: We abstracted three main themes from the data. The caregivers of 17 families: 1) feared trying healthier food alternatives because of possibly wasting the food; 2) planned meals only when they had enough time, space, and financial security; and 3) defined produce as luxury items and often could only afford staple food items, such as meat and grains.

Conclusion: We challenge the community to design technological interventions to lower the financial barriers presented with existing information and communication technology available to low socioeconomic populations. In addition, we encourage interventions to foster a community’s social capital to decrease feelings of isolation and increase opportunities for cooperation.
Decision Support for Teletraining of COPD Patients
Authors: Wolf K.-H. , Gietzelt M. , Al Scharaa O. , Tegtbur U. , Haux R. , Marschollek M. , Song B.
Published: December 2009

Background: Supervised physical training has been shown to promote rehabilitation of patients affected by chronic obstructive pulmonary disease (COPD). Currently, due to limited resources, not all COPD patients can be trained by an expert supervisor.

Objectives: The objective of our research is to construct a decision support system (DSS) which observes and controls physical ergometer training sessions of COPD patients.

Methods: A systematic literature review and expert interviews were carried out to build up the knowledge base for the DSS.

Results: Nine production rules were established and standardized by Drools and Arden Syntax. The developed software autonomously controls training sessions on a bicycle ergometer on the basis of vital signs data. Thus it offers a new way for the rehabilitation of COPD patients.

Conclusion: Evaluation with nine healthy subjects in a laboratory environment has confirmed its correct function, but the effects of its use for COPD patients’ rehabilitation and their quality of life have to be investigated in a further study.
An Evidence-Based Nurse Residency Program in Geropalliative Care
Authors: Lee Susan M. , Coakley Edward E. , Dahlin Constance , Carleton Penny Ford
Published: December 2009

As U.S. baby boomers age and the older population doubles by 2030, unprecedented numbers of older adults will need and benefit from nursing care that is evidence-based and tailored to their needs and preferences. To address this need, Massachusetts General Hospital developed the RN Residency: Transitioning to Geriatrics and Palliative Care program. Guided by two national curricula, the RN Residency program was designed to expand the disease model of geriatrics to a functional, emotional, and social perspective of aging, in which palliative care is an integral component. This article describes the RN Residency program, which was designed to improve the effectiveness of nursing assessment, interventions, and outcomes for older adults and their families.

J Contin Educ Nurs
2009;40(12):536–542.
The Professional Portfolio: An Evidence-Based Assessment Method
Authors: Byrne Michelle , Schroeter Kathryn , Carter Shannon , Mower Julie
Published: December 2009

Competency assessment is critical for a myriad of disciplines, including medicine, law, education, and nursing. Many nurse managers and educators are responsible for nursing competency assessment, and assessment results are often used for annual reviews, promotions, and satisfying accrediting agencies' requirements. Credentialing bodies continually seek methods to measure and document the continuing competence of licensees or certificants. Many methods and frameworks for continued competency assessment exist. The portfolio process is one method to validate personal and professional accomplishments in an interactive, multidimensional manner. This article illustrates how portfolios can be used to assess competence. One specialty nursing certification board's process of creating an evidence-based portfolio for recertification or reactivation of a credential is used as an example. The theoretical background, development process, implementation, and future implications may serve as a template for other organizations in developing their own portfolio models.

J Contin Educ Nurs
2009;40(12):545–552.
Connecting the Dots of Evaluation
Authors: DeSilets Lynore D.
Published: December 2009

This column presents an overview of Kirkpatrick's four levels of evaluation that can be helpful to continuing nursing education providers when building evaluation into their provider units and activities.

J Contin Educ Nurs
2009;40(12):532–533.
Caregiver Burden or Caregiver Gain?: Respite for Family Caregivers
Authors: Cangelosi Pamela R.
Published: December 2009

Many caregivers of older family members do not realize the need for respite until their own health begins to deteriorate. The mental, emotional, and physical stress of caring for a family member can seem overwhelming. Creative options for respite care are emerging, but there are barriers to effective use of these programs. This article discusses these barriers and proposes suggestions for overcoming them.
Antihypoxic and antioxidant activity of Hibiscus esculentus seeds
Authors: Ebrahimzadeh Mohammad Ali , Nabavi Seyed Fazel , Nabavi Seyed Mohammad , Eslami Bahman
Published: December 2009

The antihypoxic and antioxidant activities of Hibiscus esculentus seeds were investigated employing eight in vitro assay systems. Antihypoxic activity was investigated in two models, haemic and circulatory. The effects were pronounced in both models of hypoxia. The antihypoxic effects were dose-dependent. The results indicated that the extracts have a protective effect against hypoxia induced lethality in mice. The extracts showed antioxidant activity in some models. IC50 for DPPH radical-scavenging activity was 234 ± 8.9 μg ml-1. The extracts showed weak nitric oxide-scavenging activity between 0.1 and 1.6 mg ml-1. The extracts showed weak Fe2+ chelating ability. IC50 were 150 ± 13 μg ml-1. The extracts also exhibited low antioxidant activity in the linoleic acid model but were capable of scavenging hydrogen peroxide in a concentration dependent manner. The total amount of phenolic compounds in each extract was determined as gallic acid equivalents and total flavonoid contents were calculated as quercetin equivalents from a calibration curve. Pharmacological effects may be attributed, at least in part, to the presence of phenols and flavonoids in the extracts.
Dry fermented buffalo sausage with sage oil extract: Safety and quality
Authors: Abu Salem Ferial M. , Ibrahim Hayam M.
Published: December 2009

Sage oil extract was added during the preparation of dry fermented buffalo meat sausage. Some chemical, microbial and sensory characteristics of sausages were evaluated during the ripening period. In particular, pH, lipid oxidation, biogenic amines and micro flora were analyzed. Results of this study pointed out that sage oil extract as natural antioxidant could be utilized in dry fermented sausage, prepared from buffalo meat, in order to obtain a final product within acceptable lipid oxidation and biogenic amine levels, as well as improved sensory quality.
Estimation of reference evapotranspiration in a mountainous mediterranean site using the Penman-Monteith equation with limited meteorological data
Authors: López-Moreno J. I. , Hess T. M. , White S. M.
Published: December 2009

En los últimos años, diferentes autores han adoptado el método de Penman-Monteith para estimar la evapotranspiración potencial mediante datos climáticos. El principal inconveniente de este método es que precisa de un gran número de variables para ser calculado: temperatura, radiación solar, humedad relativa y velocidad del viento. En el Pirineo español las bases de datos climáticas a menudo solamente muestran disponibilidad de datos térmicos y pluviométricos. Bajo estas carencias, algunos autores recomiendan el uso de métodos que precisan de menos datos, como es el caso de la ecuación empírica de Hargreaves. Otros autores sugieren que resulta preferible estimar los datos no disponibles necesarios para aplicar la ecuación de Penman –Monteith a partir de los datos disponibles de temperatura y velocidad del viento. Los resultados de ambos procedimientos han sido comparados con la información disponible en una estación del Pirineo central español (1999-2003) donde están disponibles los parámetros para aplicar la ecuación de Penman-Monteith. Se han comparado los resultados con el modelo de Hargreaves para valorar el método más apropiado de cálculo. Los resultados muestran errores estacionales muy diferentes mediante la fórmula de Penman-Monteith, sin embargo, este procedimiento muestra una aproximación mejor para obtener la evapotranspiración potencial que aplicando la fórmula de Hargreaves.
Historia paleoecológica y modelo de idoneidad de Abies Alba Mill. en la cordillera pirenaica.
Authors: Alba Sánchez F. , López Sáez J. A. , Benito De Pardo B. , López Merino L.
Published: December 2009

Presentamos una aproximación fitogeográfica de Abies alba Mill. en la vertiente española de la cordillera pirenaica, basada en “Modelos de Distribución de Especies” (MDEs) y una revisión del registro fósil paleopalinológico cuaternario más sobresaliente de los Pirineos. Articulando los resultados derivados del MDEs (perspectiva topoclimática), y una revisión del registro fósil palinológico cuaternario de los Pirineos (enfoque climático y antrópico), intentaremos realizar una interpretación histórica de la dinámica de estos bosques. El modelo presentado revela que los abetales españoles ocupan en la actualidad el 30% de su potencial geográfico óptimo y ofrece pruebas suficientes que demuestran que A. alba podría haber vivido en un gradiente altitudinal más amplio que el actual. Este trabajo sugiere el empleo de los MDEs para reforzar hipótesis acerca de la distribución cuaternaria de A. alba en la península Iberica, así como para ubicar geográficamente refugios que permitan la pervivencia a largo plazo de esta especie.
IL-1R1/MyD88 Signaling Is Critical for Elastase-Induced Lung Inflammation and Emphysema
Authors: Couillin Isabelle , Vasseur Virginie , Charron Sabine , Gasse Pamela , Tavernier Marie , Guillet Julien , Lagente Vincent , Fick Lizette , Jacobs Muazzam , Coelho Fernando Rodrigues , Moser René , Ryffel Bernhard
Published: December 2009

Lung emphysema and fibrosis are severe complications of chronic obstructive pulmonary disease, and uncontrolled protease activation may be involved in the pathogenesis. Using experimental elastase-induced acute inflammation, we demonstrate here that inflammation and development of emphysema is IL-1R1 and Toll/IL-1R signal transduction adaptor MyD88 dependent; however, TLR recognition is dispensable in this model. Elastase induces IL-1β, TNF-α, keratinocyte-derived chemokine, and IL-6 secretion and neutrophil recruitment in the lung, which is drastically reduced in the absence of IL-1R1 or MyD88. Further, tissue destruction with emphysema and fibrosis is attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Specific blockade of IL-1 by IL-1R antagonist diminishes acute inflammation and emphysema. Finally, IL-1β production and inflammation are reduced in mice deficient for the NALP3 inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and we identified uric acid, which is produced upon elastase-induced lung injury, as an activator of the NALP3/ASC inflammasome. In conclusion, elastase-mediated lung pathology depends on inflammasome activation with IL-1β production. IL-1β therefore represents a critical mediator and a possible therapeutic target of lung inflammation leading to emphysema.
Antigen Specificity Determines the Pro- or Antitumoral Nature of CD8+ T Cells
Authors: Cuff Simone , Dolton Garry , Matthews R. James , Gallimore Awen
Published: December 2009

Although CD8+ T cells are usually considered antitumoral, several recent studies report that the cells can also promote tumor progression. Using the melanoma cell line B16 as a murine model of pulmonary metastasis, we examined whether the pro- versus antitumoral effects of CD8+ T cells relate to their Ag specificity. Results of the study indicate that although CD8+ T cells specific for tumor Ags promote tumor rejection, CD8+ T cells specific for unrelated Ags promote tumor progression. We found the effect to be partly attributable to CD8+ T cells dampening effective antitumor NK cell responses. Notably, activation of CD8+ T cell responses by an unrelated stimulus, in this case infection with influenza virus, increased the number of pulmonary tumor nodules. These data provide a rationale for previously unexplained data identifying contrasting roles for CD8+ T cells in tumor progression.
Helicobacter pyloriInduces MAPK Phosphorylation and AP-1 Activation via a NOD1-Dependent Mechanism
Authors: Allison Cody C. , Kufer Thomas A. , Kremmer Elisabeth , Kaparakis Maria , Ferrero Richard L.
Published: December 2009

Helicobacter pylori rapidly activates MAPKs and transcription factors, NF-κB and AP-1, in gastric epithelial cells following host attachment. Activation of these signal transducers is largely dependent on the cag pathogenicity island (cagPAI)-encoded Type IV Secretion System. H. pylori was shown to translocate peptidoglycan through the Type IV Secretion System, which is recognized by the pathogen recognition molecule, NOD1, thus resulting in NF-κB activation. The mechanisms of H. pylori-induced MAPK and AP-1 activation, however, are less well defined and therefore, we assessed the contribution of NOD1 to their activation. For this, we used gastric epithelial cell lines, stably expressing siRNA to either NOD1 or a control gene. In siNOD1-expressing cells stimulated with cagPAI+ H. pylori, we observed significant reductions in p38 and ERK phosphorylation (p < 0.05), whereas the levels of Jnk phosphorylation remained unchanged. Consistent with a previous report, however, we were able to demonstrate NOD1-dependent Jnk phosphorylation by the invasive pathogen Shigella flexneri, highlighting pathogen-specific host responses to infection. We also show that NOD1 was essential for H. pylori induction of not only NF-κB, but also AP-1 activation, implying that NOD1 induces robust proinflammatory responses, in an attempt to rapidly control infection. Pharmacological inhibition of p38 and ERK activity significantly reduced IL-8 production in response to H. pylori, further emphasizing the importance of MAPKs in innate immune responses to the pathogen. Thus, for the first time we have shown the important role for NOD1 in MAPK and AP-1 activation in response to cagPAI+ H. pylori.
Novel Role for Aldose Reductase in Mediating Acute Inflammatory Responses in the Lung
Authors: Ravindranath Thyyar M. , Mong Phyllus Y. , Ananthakrishnan Radha , Li Qing , Quadri Nosirudeen , Schmidt Ann Marie , Ramasamy Ravichandran , Wang Qin
Published: December 2009

Exaggerated inflammatory responses and the resultant increases in alveolar-capillary permeability underlie the pathogenesis of acute lung injury during sepsis. This study examined the functions of aldose reductase (AR) in mediating acute lung inflammation. Transgenic mice expressing human AR (ARTg) were used to study the functions of AR since mice have low intrinsic AR activity. In a mild cecal ligation and puncture model, ARTg mice demonstrated an enhanced AR activity and a greater inflammatory response as evaluated by circulating cytokine levels, neutrophil accumulation in the lungs, and activation of Rho kinase in lung endothelial cells (ECs). Compared with WT lung cells, ARTg lung cells produced more IL-6 and showed augmented JNK activation in response to LPS stimulation ex vivo. In human neutrophils, AR activity was required for fMLP-included CD11b activation and up-regulation, respiratory burst, and shape changes. In human pulmonary microvascular ECs, AR activity was required for TNF-α-induced activation of the Rho kinase/MKK4/JNK pathway and IL-6 production, but not p38 activation or ICAM-1 expression. Importantly, AR activity in both human neutrophils and ECs was required for neutrophil adhesion to TNF-α-stimulated ECs. These data demonstrate a novel role for AR in regulating the signaling pathways leading to neutrophil-EC adhesion during acute lung inflammation.
DcR3 Protects Islet β Cells from Apoptosis through ModulatingAdcyap1andBank1Expression
Authors: Han Bing , Wu Jiangping
Published: December 2009

The islet primary nonfunction (PNF) is a serious problem in islet transplantation. In this study, we investigated whether DcR3-secreting transgenic (Tg) islets could reduce PNF. We generated Tg mice expressing human DcR3. The transgenically expressed DcR3 protected islets from IFN-γ plus IL-1β- or TNF-α plus IL-1β-induced dysfunction and apoptosis in vitro. The Tg islets presented significantly reduced PNF after transplantation. Mechanistically, in addition to the known FasL apoptotic pathway, components of two other apoptosis pathways, that is, HVEM/LTβR for the LIGHT pathway and DR3 for the TL1A pathway, were found to be expressed in islets. Recombinant LIGHT- and TL1A-induced islet apoptosis in the absence of the FasL/Fas pathway, as well as DcR3, could block such induction. These results for the first time demonstrated that LIGHT and TL1A were capable of inducing islet apoptosis in addition to FasL, while DcR3 protected the islets by blocking all three apoptosis pathways. By DNA microarray analysis, we discovered that Adcyap was up-regulated >700-fold and Bank1 was down-regulated 50-fold in the cytokine-assaulted Tg islets, compared with WT islets. Forced overexpression of Adcyap1 by plasmid transfection or knockdown of Bank1 expression by small interfering RNA in insulinoma NIT-1 cells protected them from cytokine-triggered apoptosis, indicating that indeed DcR3 protects β cells via the action of these two downstream molecules. This study has revealed novel mechanisms by which DcR3 protects islet survival, and it has identified new therapeutic targets of diabetes.
Ectopic Activation of Mycobacterium tuberculosis-Specific CD4+ T Cells in Lungs of CCR7−/− Mice
Authors: Olmos Sofia , Stukes Sabriya , Ernst Joel D.
Published: December 2009

Initiation of an adaptive cellular immune response depends on intimate interactions with APCs and naive T lymphocytes. We previously reported that activation of naive Mycobacterium tuberculosis-specific CD4+ T cells depends on dendritic cell (DC) transport of live bacteria from the lungs to the mediastinal lymph node (MDLN). Because the migratory paths of DCs are largely governed by the chemokine receptor CCR7, which is expressed on DCs upon maturation by proinflammatory stimuli, we examined the quantitative contribution of CCR7-dependent DC migration in the context of tuberculosis. We found that early trafficking of DCs from the lungs to the MDLN depended on CCR7-mediated signaling, but alternative mechanism(s) are used later in infection. Impaired migration of DCs in CCR7−/− mice resulted in delayed dissemination of bacteria to MDLN and spleen and in delayed kinetics of activation of adoptively transferred Ag85B-specific CD4+ T cells. Furthermore, in contrast to control mice, we found that naive Ag85B-specific CD4+ T cells are activated to proliferate in the lungs of CCR7−/− mice and, when infected with higher doses of bacteria, resistance to M. tuberculosis infection in CCR7−/− mice is compromised compared with wild-type mice.
Pronounced Phenotype in Activated Regulatory T Cells during a Chronic Helminth Infection
Authors: Layland Laura E. , Mages Jörg , Loddenkemper Christoph , Hoerauf Achim , Wagner Hermann , Lang Roland , Prazeres da Costa Clarissa U.
Published: December 2009

Although several markers have been associated with the characterization of regulatory T cells (Tregs) and their function, no studies have investigated the dynamics of their phenotype during infection. Since the necessity of Tregs to control immunopathology has been demonstrated, we used the chronic helminth infection model Schistosoma mansoni to address the impact on the Treg gene repertoire. Before gene expression profiling, we first studied the localization and Ag-specific suppressive nature of classically defined Tregs during infection. The presence of Foxp3+ cells was predominantly found in the periphery of granulomas and isolated CD4+CD25hiFoxp3+ Tregs from infected mice and blocked IFN-γ and IL-10 cytokine secretion from infected CD4+CD25− effector T cells. Furthermore, the gene expression patterns of Tregs and effector T cells showed that 474 genes were significantly regulated during schistosomiasis. After k-means clustering, we identified genes exclusively regulated in all four populations, including Foxp3, CD103, GITR, OX40, and CTLA-4—classic Treg markers. During infection, however, several nonclassical genes were upregulated solely within the Treg population, such as Slpi, Gzmb, Mt1, Fabp5, Nfil3, Socs2, Gpr177, and Klrg1. Using RT-PCR, we confirmed aspects of the microarray data and also showed that the expression profile of Tregs from S. mansoni-infected mice is simultaneously unique and comparable with Tregs derived from other infections.
Decreased Levels of Secretory Leucoprotease Inhibitor in the Pseudomonas-Infected Cystic Fibrosis Lung Are Due to Neutrophil Elastase Degradation
Authors: Weldon Sinéad , McNally Paul , McElvaney Noel G. , Elborn J. Stuart , McAuley Danny F. , Wartelle Julien , Belaaouaj Abderrazzaq , Levine Rodney L. , Taggart Clifford C.
Published: December 2009

Secretory leucoprotease inhibitor (SLPI) is a neutrophil serine protease inhibitor constitutively expressed at many mucosal surfaces, including that of the lung. Originally identified as a serine protease inhibitor, it is now evident that SLPI also has antimicrobial and anti-inflammatory functions, and therefore plays an important role in host defense. Previous work has shown that some host defense proteins such as SLPI and elafin are susceptible to proteolytic degradation. Consequently, we investigated the status of SLPI in the cystic fibrosis (CF) lung. A major factor that contributes to the high mortality rate among CF patients is Pseudomonas aeruginosa infection. In this study, we report that P. aeruginosa-positive CF bronchoalveolar lavage fluid, which contains lower SLPI levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective at cleaving recombinant human SLPI. Additionally, we found that only NE inhibitors were able to prevent SLPI cleavage, thereby implicating NE in this process. NE in excess was found to cleave recombinant SLPI at two novel sites in the NH2-terminal region and abrogate its ability to bind LPS and NF-κB consensus binding sites but not its ability to inhibit activity of the serine protease cathepsin G. In conclusion, this study provides evidence that SLPI is cleaved and inactivated by NE present in P. aeruginosa-positive CF lung secretions and that P. aeruginosa infection contributes to inactivation of the host defense screen in the CF lung.
IFN Regulatory Factor 5 Is Required for Disease Development in the FcγRIIB−/−Yaa and FcγRIIB−/− Mouse Models of Systemic Lupus Erythematosus
Authors: Richez Christophe , Yasuda Kei , Bonegio Ramon G. , Watkins Amanda A. , Aprahamian Tamar , Busto Patricia , Richards Rocco J. , Liu Chih Long , Cheung Regina , Utz Paul J. , Marshak-Rothstein Ann , Rifkin Ian R.
Published: December 2009

Polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis has not previously been tested in an animal model. In this study, we show that IRF5 is absolutely required for disease development in the FcγRIIB−/−Yaa and FcγRIIB−/− lupus models. In contrast to IRF5-sufficient FcγRIIB−/−Yaa mice, IRF5-deficient FcγRIIB−/−Yaa mice do not develop lupus manifestations and have a phenotype comparable to wild-type mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5 heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I IFN, IFN-α, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcγRIIB−/−Yaa mice lacking the type I IFN receptor subunit 1. Unlike the IRF5-deficient and IRF5-heterozygous FcγRIIB−/−Yaa mice, type I IFN receptor subunit 1-deficient FcγRIIB−/−Yaa mice maintained a substantial level of residual disease. Furthermore, in FcγRIIB−/− mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcγRIIB−/−Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I IFN production.
In Vivo Induction of Type 1-Like Regulatory T Cells Using Genetically Modified B Cells Confers Long-Term IL-10-Dependent Antigen-Specific Unresponsiveness
Authors: Ahangarani Roxana Roohi , Janssens Wim , VanderElst Luc , Carlier Vincent , VandenDriessche Thierry , Chuah Marinee , Weynand Birgit , Vanoirbeek Jeroen A. J. , Jacquemin Marc , Saint-Remy Jean-Marie
Published: December 2009

Regulatory T cells (Tregs) hold much promise for the therapy of allergy and autoimmunity, but their use is hampered by lack of Ag specificity (natural Tregs) and difficulty to expand in vitro or in vivo (adaptive Tregs). We designed a method for in vivo induction of Ag-specific Tregs, in BALB/c H-2d, that share characteristics with type 1 Tregs (Tr1). A retroviral vector was constructed encoding a major T cell epitope of a common allergen, Der p 2, fused to an endosomal targeting sequence (gp75) for efficient MHC class II presentation. B cells transduced with such construct were adoptively transferred to BALB/c mice before or after peptide immunization. Long-lasting Ag-specific immune tolerance was achieved in both cases. Genetically modified B cells constitutively expressed the transgene for at least 3 mo. B cells from IL-10−/− mice were unable to induce tolerance. Upon transfer, B cells induced Foxp3−CD4+ T cells showing phenotypic and functional characteristics comparable to Tr1-cells, including production of IL-10 but not of TGF-β, and high expression of CTLA-4. Adoptive transfer of such T cells conferred unresponsiveness to allergen immunization and prevented the development of Der p 2-induced asthma. Functional Tr1-like cells can therefore be induced in vivo using retrovirally transduced B cells.
The Anti-Inflammatory and Proresolving Mediator Resolvin E1 Protects Mice from Bacterial Pneumonia and Acute Lung Injury
Authors: Seki Hiroyuki , Fukunaga Koichi , Arita Makoto , Arai Hiroyuki , Nakanishi Hiroki , Taguchi Ryo , Miyasho Taku , Takamiya Rina , Asano Koichiro , Ishizaka Akitoshi , Takeda Junzo , Levy Bruce D.
Published: December 2009

Whereas pneumonia is the most common cause of death and disability worldwide, most cases of pneumonia spontaneously resolve. Mechanisms that promote pneumonia resolution remain to be determined. Resolvin E1 (RvE1) is an endogenous mediator that displays proresolving actions in sterile inflammation. In this study, we developed a new model of aspiration pneumonia to evaluate the effect of RvE1 on acute lung injury caused by acid aspiration and subsequent bacterial challenge. Mice received hydrochloric acid into the left lung followed by the enteric pathogen Escherichia coli. I.v. administration of RvE1 (∼0.005 mg/kg) prior to acid injury selectively decreased lung neutrophil accumulation by 55% and enhanced clearance of E. coli. RvE1 significantly decreased lung tissue levels of several proinflammatory chemokines and cytokines, including IL-1β, IL-6, HMGB-1, MIP-1α, MIP-1β, keratinocyte-derived chemokine, and MCP-1, in a manner independent of the anti-inflammatory mediators IL-10 and lipoxin A4. In addition, animals treated with RvE1 had a marked improvement in survival. These findings in experimental aspiration pneumonia have uncovered protective roles for RvE1 in pathogen-mediated inflammation that are both anti-inflammatory for neutrophils and protective for host defense, suggesting that RvE1 represents the first candidate for a novel therapeutic strategy for acute lung injury and pneumonia that harnesses natural resolution mechanisms.
Mycobacterium bovis Bacillus Calmette-Guérin Killed by Extended Freeze-Drying Targets Plasmacytoid Dendritic Cells To Regulate Lung Inflammation
Authors: Lagranderie Micheline , Abolhassani Mohammad , Vanoirbeek Jeroen A. J. , Lima Carla , Balazuc Anne-Marie , Vargaftig B. Boris , Marchal Gilles
Published: December 2009

We have previously shown that bacillus Calmette-Guérin (BCG) inactivated by extended freeze-drying (EFD) reduces airway hyperresponsiveness, whereas live and heat-killed BCG fail to do so. However, the cells involved in the protective effect and the signaling and transcriptional networks that could reprogram T cell commitment after EFD BCG treatment remained to be elucidated. We investigated whether EFD BCG targets plasmacytoid dendritic cells (pDCs) potentially involved in the polarization of regulatory T cells (Tregs) and the transcriptional factors that regulate allergic inflammation. OVA-sensitized mice were s.c. injected with EFD, live, or heat-killed BCG. We analyzed after the injection of the various BCG preparations: 1) pDCs recruited in the draining lymph nodes (day 4); 2) transcription factors involved in inflammation and T cell commitment in spleen and lungs after OVA challenge (day 28). Airway hyperresponsiveness and transcription factors were determined after in vivo depletion of pDCs or Tregs in EFD BCG-treated and OVA-challenged mice. EFD BCG reduced inflammation via the recruitment of pDCs polarizing the differentiation of naive CD4+ T lymphocytes into Tregs. In vivo, pDC or Treg depletion at the time of EFD BCG treatment abrogated the protection against inflammation. EFD BCG treatment upregulated Forkhead-winged helix transcription factor (Treg signature) and downregulated GATA-3 and RORγt (Th2 and Th17 signatures) more efficiently than live and heat-killed BCG. Moreover, only EFD BCG enhanced peroxisome proliferator-activated receptor γ expression and blocked NF-κB activation, cyclooxygenase expression, and p38 MAPK phosphorylation. EFD BCG reduced allergic inflammation by recruiting pDCs that promoted Tregs; EFD BCG acted as a peroxisome proliferator-activated receptor γ agonist and thus could be used in asthma and other inflammatory diseases.
Peptide-MHC Class II Complex Stability Governs CD4 T Cell Clonal Selection
Authors: Baumgartner Christina K. , Ferrante Andrea , Nagaoka Mika , Gorski Jack , Malherbe Laurent P.
Published: December 2009

The clonal composition of the T cell response can affect its ability to mediate infection control or to induce autoimmunity, but the mechanisms regulating the responding TCR repertoire remain poorly defined. In this study, we immunized mice with wild-type or mutated peptides displaying varying binding half-lives with MHC class II molecules to measure the impact of peptide-MHC class II stability on the clonal composition of the CD4 T cell response. We found that, although all peptides elicited similar T cell response size on immunization, the clonotypic diversity of the CD4 T cell response correlated directly with the half-life of the immunizing peptide. Peptides with short half-lives focused CD4 T cell response toward high-affinity clonotypes expressing restricted public TCR, whereas peptides with longer half-lives broadened CD4 T cell response by recruiting lower-affinity clonotypes expressing more diverse TCR. Peptides with longer half-lives did not cause the elimination of high-affinity clonotypes, and at a low dose, they also skewed CD4 T cell response toward higher-affinity clonotypes. Taken collectively, our results suggest the half-life of peptide-MHC class II complexes is the primary parameter that dictates the clonotypic diversity of the responding CD4 T cell compartment.