bluuebunny/crossref_metadata_2025 huggingface dataset:
Turbidimeter Design and Analysis: A Review on Optical Fiber Sensors for the Measurement of Water Turbidity
Authors: Bin Omar Ahmad  Fairuz , Bin MatJafri Mohd  Zubir
Published: October 2009

Turbidimeters operate based on the optical phenomena that occur when incident light through water body is scattered by the existence of foreign particles which are suspended within it. This review paper elaborates on the standards and factors that may influence the measurement of turbidity. The discussion also focuses on the optical fiber sensor technologies that have been applied within the lab and field environment and have been implemented in the measurement of water turbidity and concentration of particles. This paper also discusses and compares results from three different turbidimeter designs that use various optical components. Mohd Zubir and Bashah and Daraigan have introduced a design which has simple configurations. Omar and MatJafri, on the other hand, have established a new turbidimeter design that makes use of optical fiber cable as the light transferring medium. The application of fiber optic cable to the turbidimeter will present a flexible measurement technique, allowing measurements to be made online. Scattered light measurement through optical fiber cable requires a highly sensitive detector to interpret the scattered light signal. This has made the optical fiber system have higher sensitivity in measuring turbidity compared to the other two simple turbidimeters presented in this paper. Fiber optic sensors provide the potential for increased sensitivity over large concentration ranges. However, many challenges must be examined to develop sensors that can collect reliable turbidity measurements in situ.
Identification of Mouse Cytomegalovirus Resistance Loci by ENU Mutagenesis
Authors: Crozat Karine , Georgel Philippe
Published: October 2009

Host resistance to infection depends on the efficiency with which innate immune responses keep the infectious agent in check. Innate immunity encompasses components with sensing, signaling and effector properties. These elements with nonredundant functions are encoded by a set of host genes, the resistome. Here, we review our findings concerning the resistome. We have screened randomly mutagenized mice for susceptibility to a natural opportunistic pathogen, the mouse cytomegalovirus. We found that some genes with initially no obvious functions in innate immunity may be critical for host survival to infections, falling into a newly defined category of genes of the resistome.
Operationalization of the Resource Investments Construct of Recreational Sport Event
Authors: Okayasu Isao , Nogawa Haruo , Morais Duarte B.
Published: October 2009

Research models should be grounded in sound theory. This applies to models attempting to elucidate why individuals participate in recreational sport event. Social phenomena have often been understood in terms of interpersonal behavior between individuals. Therefore, this article proposes
that resource theory, which has been used widely to explain interpersonal relationships, can help us understand participation in recreational sport events. This study develops an instrument to assess the resources that participants and organizers deploy as they participate in recreational
sport events. We detail a two-staged process of analysis. Initially, a pool of items is developed using six widely cited dimensions in resource theory: love, status, information, services, goods, and money. Second, each subscale is examined and modified so that it is appropriate for understanding
participation in recreational sport events. Results show that these items in particular and resource theory in general are useful in understanding participant–organizer relationships within recreational sport events.
Examining Visitor Mindfulness at a Cultural Event
Authors: Van Winkle Christine M. , Backman Kenneth
Published: October 2009

This study examined visitor mindfulness at a cultural festival. Mindfulness is considered a state of being that requires individuals to engage in active information processing, enabling them to be adaptive and responsive to information in their surroundings. Mindfulness is believed
to result in more learning, high satisfaction, greater understanding, and greater feeling of control over behavior. Event managers must find ways to enhance visitor satisfaction as well as minimize negative impacts that result from events, and encouraging visitor mindfulness could contribute
to these outcomes. This study took place over a 2-week period in July 2005 at the Winnipeg Fringe Theatre Festival in Winnipeg, Manitoba, Canada. Results presented demonstrate that the more interested visitors were in the festival the higher they scored on the mindfulness scale. Visitor level
of mindfulness was positively related to their satisfaction with the event and their feelings of control over their own contribution to impacts. Implications for event managers are discussed.
Circulating Leptin and Bone Mineral Density in Rheumatoid Arthritis
Authors: AGUILAR-CHAVEZ ERIKA A. , GAMEZ-NAVA JORGE I. , LOPEZ-OLIVO MARIA A. , GALVAN-MELENDRES SILVIA , CORONA-SANCHEZ ESTHER G. , LOAIZA-CARDENAS CARLOS A. , CELIS ALFREDO , CARDONA-MUÑOZ ERNESTO G. , GONZALEZ-LOPEZ LAURA
Published: October 2009

Objective.

To evaluate the association between circulating leptin and bone mineral density (BMD) in patients with rheumatoid arthritis (RA).

Methods.

One-hundred thirty postmenopausal women with RA were assessed for body mass index (BMI), disease characteristics, history of drug use, rheumatoid factor, and erythrocyte sedimentation rate (ESR). BMD (g/cm2) was determined in the hip and spine by DEXA. Serum leptin concentrations were measured by ELISA. Spearman’s correlation coefficients (rho) were determined between BMD and leptin and other variables. A multiple regression analysis was used to adjust for confounders.

Results.

Patients’ serum leptin levels varied widely (range 2–128 ng/ml). Thirty-three patients (25%) had osteoporosis. Higher levels of leptin correlated significantly with BMD in the lumbar spine (rho = 0.17, p = 0.04) and total hip (rho = 0.21, p = 0.01). The variables that were negatively correlated with BMD were age, duration of menopause, and ESR. After adjustment for confounders, leptin was no longer associated with BMD. In the multivariate model, factors that remained associated with BMD in the total hip were age (p = 0.021) and BMI (p = 0.003); and the factors that remained associated with BMD in the lumbar spine were BMI (p = 0.03) and ESR (p = 0.01).

Conclusion.

No relevant association was found between circulating leptin levels and BMD in patients with RA in this cross-sectional study. Followup studies are needed to evaluate whether abnormal leptin levels confer a risk for fractures due to osteoporosis.
Gout in the Axial Skeleton
Authors: KONATALAPALLI RUKMINI M. , DEMARCO PAUL J. , JELINEK JAMES S. , MURPHEY MARK , GIBSON MICHAEL , JENNINGS BRYAN , WEINSTEIN ARTHUR
Published: October 2009

Objective.

Gout typically affects the peripheral joints of the appendicular skeleton and rarely involves the axial joints. The literature on axial gout is limited to case reports and case series. This preliminary study was conducted to identify the frequency and characteristics of axial gout.

Methods.

Six hundred thirty medical records with ICD codes 274.0, 274.82, and 274.9 for peripheral gout were reviewed. Ninety-two patients had clinical or crystal-proven gout, of which 64 had prior computed tomography (CT) images of the spine performed for various medical reasons. These CT images were reviewed for features of axial gout, which include vertebral erosions mainly at the discovertebral junction and the facet joints, deposits of tophi, and erosions in the vertebral body, epidural space, ligamentum flavum and pars interarticularis.

Results.

Nine of the 64 patients had radiographic changes suggestive of axial gout. Lumbar vertebrae were most commonly involved, with facet joint erosions being the most common finding. Isolated involvement of the sacroiliac joints was seen in 2 patients. Axial gout had been diagnosed clinically in only one patient.

Conclusion.

Radiologic changes of axial gout were more common than recognized clinically, with a frequency of 14%. Since not all patients had CT images, it is possible that the frequency of axial involvement was even greater. A prospective study is needed to further define this process.
Increased Expression of Toll-like Receptors in Aseptic Loose Periprosthetic Tissues and Septic Synovial Membranes Around Total Hip Implants
Authors: TAMAKI YASUNOBU , TAKAKUBO YUYA , GOTO KAORU , HIRAYAMA TOMOYUKI , SASAKI KAN , KONTTINEN YRJÖ T. , GOODMAN STUART B. , TAKAGI MICHIAKI
Published: October 2009

Objective.

Toll-like receptors (TLR) are transmembrane proteins found in various cells. They recognize infectious and endogenous threats, so-called danger signals, that evoke inflammation and assist adaptive immune reactions. It has been suggested that TLR play a role in periprosthetic tissues and arthritic synovium. Our objective was to elucidate tissue localization and functional roles of TLR in periprosthetic tissues in 2 different pathologic conditions, aseptic and septic implant loosening.

Methods.

For immunohistochemistry studies, aseptic synovial-like membranes of periprosthetic connective tissues (n = 15) and septic synovial capsular tissues (n = 5) were obtained at revision surgery and from salvage of infected totally replaced hips, respectively. Osteoarthritic synovial tissues were used for comparison (n = 5). Samples were processed for immunohistopathologic analyses for tissue colocalization of TLR with CD68 and/or CD15 using theAlexa fluorescent system. Total RNA was isolated from frozen tissues and converted into cDNA, TLR 2, 4, 5 and 9 sequences were amplified, and the products were quantified using real-time polymerase chain reaction.

Results.

Immunofluorescent staining showed colocalization of TLR 2, 4, 5, and 9 with CD68 in the focal monocyte/macrophage aggregates in aseptic synovial-like membranes from loose total hip replacements. TLR 2, 4, 5, and 9 were also found colocalized with CD15+ polymorphonuclear leukocytes and CD68+ mononuclear cells of the synovial membranes from septic total hip replacements. In osteoarthritic synovial tissues, expression of TLR was found only in vascular cells and mononuclear cells, and the reactivity was weak. mRNA levels of TLR 2, 4, 5, and 9 were increased in both aseptic and septic periprosthetic tissues. TLR 2 and 5 were significantly higher than TLR 4 and 9 in aseptic and septic samples.

Conclusion.

Peri-implant tissues were well equipped with TLR in both aseptic and septic conditions. TLR 2- and TLR 5-mediated responses seemed to dominate. In aseptic loosening, monocytes/ macrophages were the main TLR-equipped cells apparently responsible for alarmin-induced responses. This could lead to production of inflammatory cytokines and extracellular matrix-degrading proteinases after phagocytosis of wear debris derived from an implant, but in septic cases they eventually respond to microbial components. Thus, inflammatory cells in both aseptic and septic tissues were equipped with TLR, providing them with responsiveness to both endogenous and exogenous TLR ligands.
Six and 12 Weeks Treatment Response Predicts Continuation of Tumor Necrosis Factor Blockade in Rheumatoid Arthritis: An Observational Cohort Study from Southern Sweden
Authors: GÜLFE ANDERS , KRISTENSEN LARS ERIK , GEBOREK PIERRE
Published: October 2009

Objective.

To investigate if treatment response predicts continuation of anti-tumor necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA).

Methods.

We investigated if treatment response and/or achieving a certain activity state at 6 weeks or 3 months predicts continuation of treatment in an observational cohort of 1789 anti-TNF-naive patients with established RA disease from southern Sweden.

Results.

Response to treatment at 6 weeks at overall/American College of Rheumatology (ACR20) or good/major level (except ACR70) significantly predicted drug continuation. Response according to all criteria sets at overall/ACR20 and at good/major/ACR70 level predicted drug continuation at 3 months, as did achieving low disease activity at 3 months irrespective of activity index applied. Remaining in a high disease activity state predicted drug discontinuation at both timepoints and according to all criteria sets.

Conclusion.

Response criteria may be useful aids in deciding on continuation of TNF blockade in RA as early as after 6 weeks of treatment. The various criteria sets perform similarly.
Patients with Moderate Rheumatoid Arthritis (RA) Achieve Better Disease Activity States with Etanercept Treatment Than Patients with Severe RA
Authors: KEYSTONE EDWARD , FREUNDLICH BRUCE , SCHIFF MICHAEL , LI JUAN , HOOPER MICHELE
Published: October 2009

Objective.

This analysis examined clinical and radiographic responses to methotrexate (MTX), etanercept (ETN), and combination ETN and MTX in patients with moderate versus severe rheumatoid arthritis (RA) in both early and late disease.

Methods.

Data from the Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes (TEMPO) and the Early Rheumatoid Arthritis trials were used. Patients were classified with moderate or severe RA based on Disease Activity Score including 28-joint count (DAS28). Outcomes included DAS28 remission, DAS28 low disease activity, Health Assessment Questionnaire (HAQ), American College of Rheumatology (ACR) scores, Total Sharp Score (TSS) progression, no radiographic progression (annualized change in TSS ≥ 0), change from baseline in TSS, and the change in TSS for patients who had radiographic progression (TSS > 0).

Results.

Patients with moderate disease generally achieved better clinical outcomes than patients with severe disease, including significant differences in DAS28 remission, low disease activity, and HAQ ≤0.5 at Month 12. Patients with baseline severe disease had higher ACR and DAS responses than patients with moderate disease.

Conclusion.

Patients with severe RA disease activity achieved substantial clinical improvement with high-dose MTX and/or ETN treatment, but patients with moderate disease were more likely to reach a lower disease activity state. These findings were independent of disease duration. The results support the opportunity for excellent clinical outcomes, particularly with combination therapy, in patients with moderate RA.
Is There an Urban-Rural Divide? Population Surveys of Rheumatic Musculoskeletal Disorders in the Pune Region of India Using the COPCORD Bhigwan Model
Authors: JOSHI VAIJAYANTI LAGU , CHOPRA ARVIND
Published: October 2009

Objective.

To estimate urban prevalence of rheumatic musculoskeletal (MSK) disorders and compare to an earlier rural regional study.

Methods.

We screened 8145 adults from a preselected urban locality in Pune, India, for MSK pain in a cross-sectional house-to-house survey (Stage I) over 20 weeks. The World Health Organization-International League of Associations for Rheumatology (WHO-ILAR) Community Oriented Program for Control of Rheumatic Diseases (COPCORD) Bhigwan model was used. Thirty trained community volunteers completed Phases I and II questionnaires, concurrent with rheumatology evaluation (Phase III). Clinical diagnosis was based on standard diagnosis/classification criteria. Point prevalence rates from our survey and the earlier Bhigwan village (Pune district) survey were standardized (adjusted age-sex to India population census 2001) and are reported for osteoarthritis (OA), rheumatoid arthritis (RA), seronegative spondyloarthritis (SSA), and inflammatory arthritis (IA).

Results.

One thousand one hundred fifty-two urban cases (65% women) were identified (14.1%, 95% confidence interval 13.4, 14.9). The self-reported pain sites (Phase II) were hip (0.4), knees (6.3), ankle (1.9), feet (0.7), shoulders (2), hands (1.3), wrist (1.2), neck (1.9), upper back (1.7), low back (5.5), thigh (1.5), calf (1.4), and sole (0.8); corresponding rural sites being hip (1.1), knees (13.7), ankle (7), feet (1.6), shoulders (7.9), hands (6.3), wrist (6.9), neck (6.8), upper back (8.4), low back (12.6), thigh (4.8), calf (7.1) and sole (2.2). OA disorders, soft tissue rheumatism (STR) and ill-defined aches and pains were predominant in both surveys; < 10% reported IA. The major disorders among urban cases were OA (4), STR (1.2), RA (0.2, ACR criteria 1988), undifferentiated IA (0.3), SSA (0.3), and gout (0.06); corresponding rates in Bhigwan were OA (6.3), STR (3.8), RA (0.5), undifferentiated IA (0.8), SSA (0.3), and gout (0.1). Infections were conspicuously absent.

Conclusion.

While similar in spectrum, standardized prevalence rates of self-reported pain sites and rheumatic MSK disorders were significantly lower in the urban (current Pune COPCORD surveys) versus rural (Bhigwan) community, and in both communities aches and pains that are poorly understood by modern science were predominant.
Bisphosphonate Associated Osteonecrosis of the Jaw
Authors: KHAN ALIYA A. , SÁNDOR GEORGE K.B. , DORE EDWARD , MORRISON ARCHIBALD D. , ALSAHLI MAZEN , AMIN FAIZAN , PETERS EDMUND , HANLEY DAVID A. , CHAUDRY SULTAN R. , LENTLE BRIAN , DEMPSTER DAVID W. , GLORIEUX FRANCIS H. , NEVILLE ALAN J. , TALWAR REENA M. , CLOKIE CAMERON M. , MARDINI MAJD AL , PAUL TERRI , KHOSLA SUNDEEP , JOSSE ROBERT G. , SUTHERLAND SUSAN , LAM DAVID K. , CARMICHAEL ROBERT P. , BLANAS NICK , KENDLER DAVID , PETAK STEVEN , STE-MARIE LOUIS GEORGES , BROWN JACQUES , EVANS A.WAYNE , RIOS LORENA , COMPSTON JULIET E.
Published: October 2009

In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%–12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.
Evaluation of a Web-based Teaching Module on Examination of the Hand
Authors: AVERNS HENRY , MARASCHIELLO MARK , van MELLE ELAINE , DAY ANDREW
Published: October 2009

Objective.

To evaluate the effectiveness of an online module in the development of medical students’ clinical hand examination skills.

Methods.

We developed a Web-based module to teach examination of the hand to first-year medical students (n = 99) to address the core skills expected in undergraduate medical training in Canada. The module was compared to the standard recommended text and tutor-led teaching using a validated objective structured clinical examination (OSCE) and a written knowledge test.

Results.

A total of 17 students completed the OSCE from the book-based learning group, 18 from the tutor-led group, and 26 from the online module group. The average total OSCE score was significantly higher for students in the online module group compared to the textbook group (73.2% and 60.5%, respectively; p = 0.003). There was no significant difference between students in the online module and tutor-led groups (73.2% and 69.0%, respectively; p = 0.31). The online module group had a significantly higher mean total knowledge score than the textbook group (8.4 and 5.7, respectively; p < 0.001; maximum score 10) and the tutor-led group (8.4 and 7.4, respectively; p = 0.04).

Conclusion.

Our study provides evidence that a well designed Web-based module, supported by sound educational theory, is an effective tool in the teaching of musculoskeletal examination skills, and provides some advantages over tutor-led teaching in terms of knowledge retention.
Interpersonal Psychotherapy: A Treatment for Late-life Depression
Authors: Hinrichsen Gregory A.
Published: October 2009

CME Educational Objectives

1.

Identify that interpersonally relevant stressors are a potential cause and consequence of depression in later life.

2.

Explain the basic structure of interpersonal psychotherapy (IPT) in the treatment of depression.

3.

Express that IPT has been found useful in the treatment of late life depression.
Psychotherapy as End-of-life Care: Special Considerations for the Older Patient
Authors: Scalmati Alessandra , Kennedy Gary J.
Published: October 2009

CME Educational Objectives

1.

List at least three presenting problems in the psychiatric consultation for older patients at the end of life.

2.

State the psychotherapeutic modalities studied in geriatric end-of-life care and describe their efficacy.

3.

Name at least two common conter-transference responses to working with aged patients at the end of life, and how to address them.
Family Therapy in Late Life
Authors: Qualls Sara H. , Anderson Lindsay N.
Published: October 2009

CME Educational Objectives

1.

Define challenges faced by caregivers for which mental health providers should be vigilant.

2.

List three common interventions that benefit caregivers.

3.

Name common factors in successful family interventions.
Survey of Expert Treatment Approaches for Children with Bipolar Disorder-Not Otherwise Specified and Bipolar-I Presentations
Authors: Post Robert M. , Wozniak Janet
Published: October 2009

The intrinsic difficulties in studying and treating children younger than 10 years who have bipolar affective disorders were highlighted in the article by Post (see page 879). Currently, there are virtually no Food and Drug Administration (FDA)-approved medications for children with pediatric onset bipolar disorder (PBD) who are younger than 10 years. This is in contrast to the nearly 20 FDA-approved medications for the treatment of attention-deficit/hyperactivity disorder (ADHD), an illness with onset before 7 years. Existing guidelines for PBD suggest that mood stabilization with lithium, anticonvulsants, or second-generation antipsychotics (SGA) in PBD is the first step in treating mania prior to the use of adjuvant stimulant medications to treat comorbid ADHD.
La formación en los colegios profesionales, el aprendizaje a lo largo de la vida, la acreditación profesional y la calidad de servicios a los usuarios
Authors: Chacón Fuertes Fernando
Published: October 2009

Los Colegios profesionales, corporaciones de derecho público, tienen como fines esenciales la ordenación del ejercicio de las profesiones, la representación exclusiva de las mismas, y la defensa de los intereses profesionales. El cambio social ha impulsado tres aspectos: la calidad del servicio, el necesario aprendizaje “a lo largo de la vida profesional” y su certificación. Ejemplos de acreditación profesional son los Abogados del Turno de Oficio, el EURO-PSY y el Certificado Europeo de Experto en Psicoterapia de la EFPA. Se describen el contenido y las fases del currículum, el Desarrollo Profesional Continuo (DPC) y el Certificado de Acreditación de Psicólogos Especialistas en Psicoterapia.
La metáfora teatral en la interacción social
Authors: Beltrán Villalva Miguel
Published: October 2009

En la descripción científica de ciertos fenómenos es usual utilizar metáforas que faciliten su investigación y comprensión. La teoría sociológica utiliza la de rol o “papel social” para identificar las expectativas compartidas de conducta en la interacción social. Esta metáfora teatral, o “dramatúrgica”, permite construir una noción de homo sociologicus con la que percibir regularidades sociales que pueden ser calificadas de rituales, dotando así a la idea de drama ritual de una potente capacidad heurística. Capacidad que debe tener en cuenta el riesgo epistemológico de suponer que nuestro conocimiento de la realidad social la refleja literal y fielmente, olvidando la ambigüedad y la contingencia que la caracterizan.
1,25-Dihydroxyvitamin D3 and IL-2 Combine to Inhibit T Cell Production of Inflammatory Cytokines and Promote Development of Regulatory T Cells Expressing CTLA-4 and FoxP3
Authors: Jeffery Louisa E. , Burke Fiona , Mura Manuela , Zheng Yong , Qureshi Omar S. , Hewison Martin , Walker Lucy S. K. , Lammas David A. , Raza Karim , Sansom David M.
Published: October 2009

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has potent immunomodulatory properties that have promoted its potential use in the prevention and treatment of infectious disease and autoimmune conditions. A variety of immune cells, including macrophages, dendritic cells, and activated T cells express the intracellular vitamin D receptor and are responsive to 1,25(OH)2D3. Despite this, how 1,25(OH)2D3 regulates adaptive immunity remains unclear and may involve both direct and indirect effects on the proliferation and function of T cells. To further clarify this issue, we have assessed the effects of 1,25(OH)2D3 on human CD4+CD25− T cells. We observed that stimulation of CD4+CD25− T cells in the presence of 1,25(OH)2D3 inhibited production of proinflammatory cytokines including IFN- γ, IL-17, and IL-21 but did not substantially affect T cell division. In contrast to its inhibitory effects on inflammatory cytokines, 1,25(OH)2D3 stimulated expression of high levels of CTLA-4 as well as FoxP3, the latter requiring the presence of IL-2. T cells treated with 1,25(OH)2D3 could suppress proliferation of normally responsive T cells, indicating that they possessed characteristics of adaptive regulatory T cells. Our results suggest that 1,25(OH)2D3 and IL-2 have direct synergistic effects on activated T cells, acting as potent anti-inflammatory agents and physiologic inducers of adaptive regulatory T cells.
Analysis of the Role of Tripeptidyl Peptidase II in MHC Class I Antigen Presentation In Vivo
Authors: Kawahara Masahiro , York Ian A. , Hearn Arron , Farfan Diego , Rock Kenneth L.
Published: October 2009

Previous experiments using enzyme inhibitors and RNA interference in cell lysates and cultured cells have suggested that tripeptidyl peptidase II (TPPII) plays a role in creating and destroying MHC class I-presented peptides. However, its precise contribution to these processes has been controversial. To elucidate the importance of TPPII in MHC class I Ag presentation, we analyzed TPPII-deficient gene-trapped mice and cell lines from these animals. In these mice, the expression level of TPPII was reduced by >90% compared with wild-type mice. Thymocytes from TPPII gene-trapped mice displayed more MHC class I on the cell surface, suggesting that TPPII normally limits Ag presentation by destroying peptides overall. TPPII gene-trapped mice responded as well as did wild-type mice to four epitopes from lymphocytic choriomeningitis virus. The processing and presentation of peptide precursors with long N-terminal extensions in TPPII gene-trapped embryonic fibroblasts was modestly reduced, but in vivo immunization with recombinant lentiviral or vaccinia virus vectors revealed that such peptide precursors induced an equivalent CD8 T cell response in wild-type and TPPII-deficient mice. These data indicate that while TPPII contributes to the trimming of peptides with very long N-terminal extensions, TPPII is not essential for generating most MHC class I-presented peptides or for stimulating CTL responses to several Ags in vivo.
CD4+ T Cells and Lactobacillus casei Control Relapsing Colitis Mediated by CD8+ T Cells
Authors: Hacini-Rachinel Feriel , Nancey Stephane , Boschetti Gilles , Sardi Fatima , Doucet-Ladevèze Remi , Durand Pierre-Yves , Flourié Bernard , Kaiserlian Dominique
Published: October 2009

Evidence that CD4+ regulatory T cells can control Ag-specific CD8+ T cell-mediated colitis in immunocompetent mice is poorly documented. To examine the potential of CD4+ T cells to control colitis, we used our model of CD8+ T cell-mediated colitis induced by intracolonic sensitization followed by challenge with the hapten 2,4-dinitrobenzene sulfonic acid. The defect of CD4+ T cells in MHC class II-deficient (Aβ°/°) mice allowed priming of 2,4-dinitrobenzene sulfonic acid-specific IFN-γ-producing CD8 colitogenic effectors and development of colitis in the otherwise resistant C57BL/6 strain. Cotransfer experiments in RAG2°/° mice and ex vivo studies showed that CD4+CD25+ T cells completely prevented CD8+ T cell-mediated colitis and controlled CD8+ T cell activation, respectively. In the susceptible BALB/c strain, Ab depletion revealed that lack of CD4+ regulatory T cells resulted in 1) acute colitis elicited by a suboptimal dose of hapten challenge and 2) more severe relapsing episodes of colitis induced by effector/memory CD8+ T cell-mediated colitis at an optimal dose of hapten challenge, even when CD4 depletion was performed just before the second challenge. Oral administration of the probiotic strain Lactobacillus casei DN-114 001 alleviated colitis and increased the suppressive function of Foxp3+CD4+ regulatory T cells of colon lamina propria. These data demonstrate that CD4+ regulatory T cells exert a protective effect on colitis by controlling colitogenic effector/memory CD8+ T cells during the effector (symptomatic) phase of acute and relapsing colitis, respectively. Probiotics with natural adjuvant effects on mucosal regulatory T cells may represent a valuable approach to alleviate the colitogenic effect of Tc1-type CD8+ effectors.
Protein Kinase B/Akt Signals Impair Th17 Differentiation and Support Natural Regulatory T Cell Function and Induced Regulatory T Cell Formation
Authors: Pierau Mandy , Engelmann Swen , Reinhold Dirk , Lapp Thabo , Schraven Burkhart , Bommhardt Ursula H.
Published: October 2009

Protein kinase B (PKB)/Akt signals control T cell proliferation and differentiation but their effect on the generation and function of regulatory T cells (Treg) and Th17 cells is not well understood. In this study, we show that elevated PKB signals antagonize the immunosuppressive effect of TGF-β1 on cell size, CD25 and CD98 expression, and proliferation of CD3-stimulated naive CD4+ T cells from wild-type and CD28-deficient mice. Conventional CD4+ T cells expressing active PKB are less susceptible to suppression by natural regulatory T cells. Although PKB signals do not affect the development of natural regulatory T cells, they enhance their suppressor capacity. Upon TCR triggering and TGF-β1 costimulation, wild-type and CD28-deficient CD4+ T cells transgenic for PKB readily express Foxp3, thereby acquiring suppressor capacity. These effects of elevated PKB signals on T cell function involve a marked and sustained activation of STAT5 and Foxp3 and reduction in nuclear NFATc1 levels. In contrast, PKB signals impair TGF-β1/IL-6-mediated differentiation of naive CD4+ T cells into the Th17 lineage. This correlates with an increased signaling of ERK, STAT5, and STAT6. Finally, elevated PKB signals reduced the severity of experimental autoimmune encephalomyelitis in wild-type mice but induced experimental autoimmune encephalomyelitis in mice deficient for CD28. Altogether, these data indicate an important role of PKB signals on control of TGF-β1-mediated T cell responses and, thereby, on tolerizing and inflammatory immune processes.
Phenotypical Characterization of Human Th17 Cells Unambiguously Identified by Surface IL-17A Expression
Authors: Brucklacher-Waldert Verena , Steinbach Karin , Lioznov Michael , Kolster Manuela , Hölscher Christoph , Tolosa Eva
Published: October 2009

Th17 cells are involved in the defense against bacteria and fungi and play a prominent role in the pathogenesis of autoimmune diseases, but research on human Th17 cells is hindered due to the lack of a surface marker. In this study, we report that a subset of human and mouse CD4+ T cells as well as human Th17 T cell clones express IL-17A on their surface upon stimulation. Correlation of surface IL-17A expression with intracellular IL-17A production and with RORγt mRNA expression identified surface IL-17A as a specific marker for human and mouse Th17 cells. Phenotype characterization of ex vivo CD4+ IL-17A+ cells showed that the chemokines CCR6 and CCR4, costimulatory molecules, as well as CD2 and CD49d were more prominently expressed on these cells than in surface IL-17A− cells, supporting the concept of Th17 cells as a potent inflammatory effector subtype. In addition, we generated human Th1, Th1/17 (producing both IFN-γ and IL-17A), and Th17 T cell clones based on single cell sorting of surface IL-17A−, IL-17Aint, and IL-17Ahigh CD4+ T cells, respectively, and showed the plasticity of the double producing clones to the cytokine milieu. The identification of surface IL-17A as a marker for Th17 cells should facilitate research on this subset.
Responsiveness of Stromal Fibroblasts to IFN-γ Blocks Tumor Growth via Angiostasis
Authors: Lu Yu , Yang Wei , Qin Chuan , Zhang Lianfeng , Deng Jingjing , Liu Shubai , Qin Zhihai
Published: October 2009

The importance of stromal cells for tumor is akin to soil for seed. However, the interaction among these cells is far from understood. In this study, we show that stromal fibroblasts exist not only during tumor progression but also during regression stage, together with immune effector cells. Coinjection of stromal fibroblasts with tumor cells often promotes tumor growth. However, the presence of IFN-γ significantly impairs the ability of these cells to promote tumor growth due to a reduced angiogenesis. The mechanism relies mainly on the IFN-γ-mediated down-regulation of vascular endothelial growth factor production by fibroblasts. The results reveal a novel link between immune cells and nonbone marrow-derived stromal cells, and define stromal fibroblasts as the main targets of IFN-γ in tumor immunity.
The Activation Threshold of CD4+ T Cells Is Defined by TCR/Peptide-MHC Class II Interactions in the Thymic Medulla
Authors: Stephen Tom Li , Tikhonova Anastasia , Riberdy Janice M. , Laufer Terri M.
Published: October 2009

Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4+ single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4+ T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.
A NUP98-HOXD13 Fusion Gene Impairs Differentiation of B and T Lymphocytes and Leads to Expansion of Thymocytes with Partial TCRB Gene Rearrangement
Authors: Choi Chul Won , Chung Yang Jo , Slape Christopher , Aplan Peter D.
Published: October 2009

Expression of a NUP98-HOXD13 (NHD13) fusion gene leads to myelodysplastic syndrome in mice. In addition to ineffective hematopoiesis, we observed that NHD13 mice were lymphopenic; the lymphopenia was due to a decrease in both T and B lymphocytes. Although the pro-B cell (B220+/CD43+) populations from the NHD13 and wild-type mice were similar, the NHD13 mice showed decreased pre-B cells (B220+/CD43−), indicating impaired differentiation at the pro-B to pre-B stage. Thymi from NHD13 mice were smaller and overexpressed Hoxa cluster genes, including Hoxa7, Hoxa9, and Hoxa10. In addition, the NHD13 thymi contained fewer thymocytes, with an increased percentage of CD4−/CD8− (double-negative (DN)) cells and a decreased percentage of CD4+/CD8+ (double-positive) cells; the DN1/DN2 population was increased and the DN3/DN4 population was decreased, suggesting a partial block at the DN2 to DN3 transition. To determine clonality of the thymocytes, we used degenerate RT-PCR to identify clonal Tcrb gene rearrangements. Five of six NHD13 thymi showed an unusual Tcrb gene rearrangement pattern with common, clonal DJ rearrangements, but distinct V-D junctions, suggesting a marked clonal expansion of thymocytes that had undergone a DJ rearrangement, but not completed a VDJ rearrangement. Taken together, these findings demonstrate that expression of the NHD13 transgene inhibits lymphoid as well as myeloid and erythroid differentiation, results in overexpression of Hoxa cluster genes, and leads to a precursor T cell lymphoblastic leukemia/lymphoma.
A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments
Authors: Ohta Akio , Ohta Akiko , Madasu Manasa , Kini Radhika , Subramanian Meenakshi , Goel Nipun , Sitkovsky Michail
Published: October 2009

Immunosuppressive signaling via the A2A adenosine receptor (A2AR) provokes a mechanism that protects inflamed tissues from excessive damage by immune cells. This mechanism is desirable not only for preventing uncontrolled tissue destruction by overactive immune responses, but also for protecting tumor tissues from antitumor immune responses. In aforementioned circumstances, T cell priming may occur in an environment containing high concentrations of extracellular adenosine. To examine qualitative changes in T cells activated in the presence of adenosine, we asked whether different functional responses of T cells are equally susceptible to A2AR agonists. In this study, we demonstrate that A2AR signaling during T cell activation strongly inhibited development of cytotoxicity and cytokine-producing activity in T cells, whereas the inhibition of T cell proliferation was only marginal. Both CD8+ and CD4+ T cells proliferated well in the presence of A2AR agonists, but their IFN-γ-producing activities were susceptible to inhibition by cAMP-elevating A2AR. Importantly, the impaired effector functions were maintained in T cells even after removal of the A2AR agonist, reflecting T cell memory of the immunoregulatory effect of adenosine. Thus, although the adenosine-rich environment may allow for the expansion of T cells, the functional activation of T cells may be critically impaired. This physiological mechanism could explain the inefficiency of antitumor T cells in the tumor microenvironment.
IL-27 Directly Restrains Lung Tumorigenicity by Suppressing Cyclooxygenase-2-Mediated Activities
Authors: Ho Ming-Yi , Leu Shr-Jeng Jim , Sun Guang-Huan , Tao Mi-Hua , Tang Shye-Jye , Sun Kuang-Hui
Published: October 2009

Gene transfer of IL-27 to tumor cells has been proven to inhibit tumor growth in vivo by antiproliferation, antiangiogenesis, and stimulation of immunoprotection. To investigate the nonimmune mechanism of IL-27 that suppresses lung cancer growth, we have established a single-chain IL-27-transduced murine Lewis lung carcinoma (LLC-1) cell line (LLC-1/scIL-27) to evaluate its tumorigenic potential in vivo. Mice inoculated with LLC/scIL-27 displayed retardation of tumor growth. Production of IL-12, IFN-γ, and cytotoxic T cell activity against LLC-1 was manifest in LLC/scIL-27-injected mice. Of note, LLC-1/scIL-27 exhibited decreased expression of cyclooxygenase-2 (COX-2) and PGE2. On the cellular level, the LLC/scIL-27 transfectants had reduced malignancy, including down-regulation of vimentin expression and reduction of cellular migration and invasion. The suppression of tumorigenesis by IL-27 on lung cancer cells was further confirmed by the treatment with rIL-27 on the murine LLC-1 and human non-small cell lung carcinoma (NSCLC) cell lines. PGE2-induced vimentin expression, movement, and invasiveness were also suppressed by the treatment with rIL-27. Our data show that IL-27 not only suppresses expression of COX-2 and PGE2 but also decreases the levels of vimentin and the abilities of cellular migration and invasion. Furthermore, inoculation of LLC/scIL-27 into immunodeficient NOD/SCID mice also exhibited reduced tumor growth. Our data indicate that IL-27-induced nonimmune responses can contribute to significant antitumor effects. Taken together, the results suggest that IL-27 may serve as an effective agent for lung cancer therapy in the future.
IDO Mediates TLR9-Driven Protection from Experimental Autoimmune Diabetes
Authors: Fallarino Francesca , Volpi Claudia , Zelante Teresa , Vacca Carmine , Calvitti Mario , Fioretti Maria C. , Puccetti Paolo , Romani Luigina , Grohmann Ursula
Published: October 2009

Originally predicated on the recognition of an increasing prevalence of allergy, the hygiene hypothesis was later found to accommodate the contrasting epidemiologic trends in developed countries for infectious vs autoimmune diseases. Experimentally, reduced exposure to infections will increase the risk of disease in several models of experimental autoimmunity. Although TLRs were initially considered as stimulatory molecules capable of activating early defense mechanisms against invading pathogens, emerging data suggest that they can also exert a regulatory function. In the present study, we evaluated whether TLR3 and TLR9, recognizing microbial dsDNA and CpG-containing DNA sequences, respectively, play a role in the protection from experimental autoimmune diabetes induced in C57BL/6 mice by streptozotocin. In wild-type animals, the disease was accompanied by up-regulation of IDO in pancreatic lymph nodes and would be greatly exacerbated by in vivo administration of an IDO inhibitor. Conversely, administration of a CpG-containing oligodeoxynucleotide greatly attenuated the disease in an IDO-dependent fashion. TLR9-, but not TLR3-deficient mice developed a more robust disease, an event accompanied by lack of IDO induction in pancreatic lymph nodes. Thus, our data suggest that the TLR9-IDO axis may represent a valuable target in the prevention/therapy of type 1 diabetes.
In Vitro Responses to Avian Influenza H5 by Human CD4 T Cells
Authors: Cusick Matthew F. , Wang Shuping , Eckels David D.
Published: October 2009

To address the question of whether human T cells are capable of recognizing novel isolates of influenza virus, in vitro responses to recombinant Ags and synthetic peptides derived from the sequences of H1, H3, and H5 were examined in a cohort of 64 individuals selected from a healthy blood donor population. Humans respond in vitro to H1 and H3 following exposure through natural infection and vaccination. Responses to H5 were well correlated with those to H1 or H3, and thus, a significant repertoire of H5-responsive T cells is present in many individuals; clear nonresponders to H1, H3, and H5, however, do exist. Differences were observed in the cytokine responses to H1, H3, and H5, whereas both IL-2 and IFN-γ production characteristic of memory responses were observed for H1 and H3, and H5-specific responses elicited primarily IL-2 and little or no IFN-γ, consistent with a naive T cell phenotype. Responses to all influenza HA were restricted by HLA-DR molecules. To address the structural basis for T cell recognition of H1 and H5, overlapping synthetic peptides were used to identify epitopes and to determine whether recognition of H5 was limited to homologous sequences in H1, the most closely related HA phylogenetically. Although responses were generally correlated, no complete structural overlap was observed. These results suggest that helper T cell cross reactivity between different influenza strains may impart cross-protection to H5N1 strain of influenza.
Activation-Induced CD154 Expression Abrogates Tolerance Induced by Apoptotic Cells
Authors: Gurung Prajwal , Kucaba Tamara A. , Ferguson Thomas A. , Griffith Thomas S.
Published: October 2009

The decision to generate a productive immune response or tolerance often depends on the context in which T cells first see Ag. Using a classical system of tolerance induction, we examined the immunological consequence of Ag encountered in the presence of naive or activated apoptotic cells. Naive apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a key role for CD154, as tolerance resulted after i.v. injection of either naive or activated apoptotic CD154−/− T cells, while coinjection of an agonistic anti-CD40 mAb with naive apoptotic T cells induced robust immunity. Dendritic cells fed activated apoptotic T cells in vitro produced IL-12p40 in a CD154-dependent manner, and the use of IL-12p40−/− mice or mAb-mediated neutralization of IL-12 revealed a link between CD154, IL-12, and the ability of activated apoptotic T cells to induce immunity rather than tolerance. Collectively, these results show that CD154 expression on apoptotic T cells can determine the outcome of an immune response to Ag recognized within the context of the apoptotic cells and suggest that the balance between naive and activated apoptotic T cells may dictate whether a productive immune response is encouraged.
Antibodies to the Desmoglein 1 Precursor Proprotein but Not to the Mature Cell Surface Protein Cloned from Individuals without Pemphigus
Authors: Yamagami Jun , Kacir Stephen , Ishii Ken , Payne Aimee S. , Siegel Don L. , Stanley John R.
Published: October 2009

In pemphigus foliaceus (PF), autoantibodies against desmoglein 1 (Dsg1) cause blisters. Using Ab phage display, we have cloned mAbs from a PF patient. These mAbs, like those from a previous patient, were directed against mature Dsg1 (matDsg1) on the cell surface of keratinocytes and precursor Dsg1 (preDsg1) in the cytoplasm. To determine whether individuals without pemphigus have B cell tolerance to Dsg1, we cloned mAbs from two patients with thrombotic thrombocytopenic purpura and a healthy person. We found mAbs against preDsg1, but not matDsg1. All but 1 of the 23 anti-preDsg1 mAbs from PF patients and those without PF used the VH3-09 (or closely related VH3-20) H chain gene, whereas no PF anti-matDsg1 used these genes. VH cDNA encoding anti-preDsg1 had significantly fewer somatic mutations than did anti-matDsg1 cDNA, consistent with chronic Ag-driven hypermutation of the latter compared with the former. These data indicate that individuals without PF do not have B cell tolerance to preDsg1 and that loss of tolerance to matDsg1 is not due to epitope shifting of anti-preDsg1 B cells (because of different VH gene usage). However, presentation of peptides from Dsg1 by preDsg1-specific B cells may be one step in developing autoimmunity in PF.