bluuebunny/crossref_metadata_2025 huggingface dataset:
Agreement between medical expert assessments in social medicine
Authors: Rudbeck M. , Fonager K.
Published: August 2011

Background and aims: Medical specialists in social medicine play an important role in description of work-related health problems of the individual citizen in the Municipalities, yet knowledge of the consistency in their medical assessment remains poor. However, we expect good agreement between medical specialists’ descriptions of health and work ability. The present paper aims to evaluate inter-rater differences between assessments issued by medical specialists in social medicine on health-related work ability in patients with musculoskeletal diseases and some lighter psychiatric diseases. Methods: A total of 11 medical specialists in social medicine from four departments across Denmark each described eight subjects’ health and health-related disability upon request from the municipal authorities. The resultant 88 written medical expert assessments were evaluated and scored independently by two medical specialists in social medicine with respect to functional impairment/ health-related work ability as intact, slightly reduced, much reduced, or extremely reduced. Kappa analysis described the inter-rater agreements. Results: The combined Kappa value for work ability was 0.33 (slight agreement). In the category ‘‘extremely reduced’’ work ability the Kappa value was 0.61 (good agreement), but mostly this result was due to one subject. One department had better intra-departmental agreement than the other departments. Agreement on the level of work ability was poorer in subjects with psychiatric diseases. Conclusions: The assessments from medical specialists in social medicine on work ability and thereby occupational possibilities show much variation. The results of the present study demonstrate that there is much room for improving agreement on these assessments.
Faith communities, communitarianism, social capital and youth civic engagement
Authors: Annette John
Published: August 2011

In this article I will examine the changing nature of faith-based community action in England and consider what evidence we have about the extent and diversity of such forms of community action. I will also analyse the current government policy toward faith-based community action and the continuum of policy initiatives from community cohesion to prevention of terrorism. Having done this I will look specifically at what we know about the role of youth civic engagement in relationship to faith identity and faith-based community politics. This will be seen in the context of a shift from encouraging youth volunteering, which followed from the Russell Commission Report, to the new emphasis on youth civic engagement and various proposals for a youth National Civic Service. Finally, in conclusion I will consider models of social capital being utilized in this policy development concerning faith communities and youth civic engagement.
Semi-automatic drawing of metabolic networks
Authors: Droste Peter , Wiechert Wolfgang , Nöh Katharina
Published: August 2011

In the living cell, biochemical reactions catalyzed by enzymes are the drivers for metabolic processes like growth, energy production, and replication. Metabolic networks are the representation of these processes describing the complex interactions of biochemical compounds. The large amount of manifold data concerning metabolic networks continually arising from current research activities in biotechnology leads to the great challenge of information visualization. Visualizing information in networks first of all requires appropriate network diagrams. In the context of metabolic networks, historical conventions regarding the network layout have been established. These layouts are not realizable by prevailing algorithms for automatic graph drawing. Hence, manual graph drawing is the predominating way to set up metabolic network diagrams. This is very time-consuming without software support, especially considering large networks with more than 500 nodes. We present a semi-automatic approach to drawing networks which relies on manual editing supported by two concepts of the interactive and automatic arrangement of nodes and edges. The first concept, called the layout pattern, uses an arbitrarily shaped skeleton as a backbone for the arrangement of nodes and edges. The second concept allows us to wrap a set of repeating drawing steps onto a so-called motif stamp, which can be appended to other parts of a diagram during the drawing process. Finally, a case study demonstrates that both semi-automatic drawing techniques diminish the time to be devoted for the manual network drawing process.
Lipid-altering efficacy of switching to ezetimibe/simvastatin 10/20 mg versus rosuvastatin 10 mg in high-risk patients with and without metabolic syndrome
Authors: Averna Maurizio , Missault Luc , Vaverkova Helena , Farnier Michel , Viigimaa Margus , Dong Qian , Shah Arvind , Johnson-Levonas Amy O , Taggart William , Brudi Philippe
Published: August 2011

Metabolic syndrome (MetS) is a clustering of atherosclerotic coronary heart disease risk factors. This post-hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg in a cohort of 618 high-risk hypercholesterolaemic patients with ( n=368) and without ( n=217) MetS who had previously been on statin monotherapy. Patients were randomised 1:1 to double-blind ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg for 6 weeks. Least squares mean percent change from baseline and 95% confidence intervals in lipid efficacy parameters were calculated for the population and within subgroups. Treatment with ezetimibe/simvastatin was significantly more effective than rosuvastatin at lowering low-density lipoprotein cholesterol, total cholesterol, non- high-density lipoprotein cholesterol, and apolipoprotein B (all p<0.001). No significant differences in treatment effects were seen between the presence and absence of MetS. In this post-hoc analysis of high-risk hypercholesterolaemic patients the lipid-reducing effects of ezetimibe/simvastatin or rosuvastatin were not altered significantly by the presence of MetS.
Developmental Evaluation
Authors: Fagen Michael C. , Redman Sarah Davis , Stacks Jonathan , Barrett Vivian , Thullen Benjamin , Altenor Sunyata , Neiger Brad L.
Published: August 2011

Developmental evaluation is an emerging approach to program evaluation that emphasizes innovation and learning. It is particularly well suited to evaluating innovative programs in their earliest stages of development and adapting existing programs to complex or changing environments. Key features of the developmental evaluation approach include a tight integration between evaluators and program staff and the use of data for continuous program improvement. This article presents developmental evaluation as a complementary approach to the traditional formative–summative evaluation cycle, especially when used for preformative evaluation. To illustrate this emerging approach, the article features a case example from the Illinois Caucus for Adolescent Health’s evaluation of its school board sexuality education policy change project. The article concludes by suggesting ways that developmental evaluation can be useful in health promotion practice.
A Case of Kaposi’s Sarcoma during Primary HIV-1 Infection
Authors: Grijsen Marlous L. , Cornelissen Marion , Prins Jan M.
Published: August 2011

The majority of cases of Kaposi’s sarcoma (KS) occur at low CD4 counts during chronic HIV-1 infection. We present a case of KS which was diagnosed during primary HIV-1 infection. This report aims to draw attention that KS may occur early in the course of HIV-1 infection and that primary HIV-1 infection may rapidly progress to AIDS.
Effect of temperature on the dynamic properties of soccer balls
Authors: Wiart N , Kelley J , James D , Allen T
Published: August 2011

Soccer is played over a wide range of temperatures. Previous research has shown that the dynamic properties of sports balls, such as squash balls, tennis balls, and baseballs are dependent on temperature. The aim of this research was to determine whether the dynamic properties of soccer balls are temperature dependent. Quasi-static tensile testing was conducted on samples of soccer ball material, at nominal temperatures of 0, 20, and 40 °C. Normal impact testing at speeds up to 22 m/s was undertaken at nominal ball temperatures of 0, 20, and 40 °C. The stiffness of the material decreased as the temperature increased. The coefficient of restitution, contact time, and maximum deformation of the ball all increased with temperature. The mean coefficient of restitution was 0.82 ± 0.03 at 40 °C in comparison to 0.73 ± 0.02 at 0 °C. A foot-to-ball impact model combined with a trajectory model was used to simulate a penalty kick directed at the top corner of the goal. The results showed that the time available to the goalkeeper was 7 per cent shorter at 40 °C in comparison to that at 0 °C. Therefore, the time available for a goalkeeper to prevent a goal decreases as temperature increases.
Juvenile idiopathic arthritis: management and therapeutic options
Authors: Ruth Natasha M. , Passo Murray H.
Published: August 2011

The goals of treatment for juvenile idiopathic arthritis (JIA) include: suppression of inflammation, achievement of remission, relief of pain, maintenance of function and doing so with minimal toxicity. Important discoveries over the past 10–15 years have led to more targeted treatments for children with JIA. The International League of Associations for Rheumatology (ILAR) classification system for childhood arthritides, better assessment tools for clinical response, improved definitions of remission, new imaging techniques and evidence in gene expression profiling have all contributed to the development of more targeted treatments. Nonsteroidal anti-inflammatory agents still have a role in mild disease and intra-articular steroid injections continue to be used most commonly in patients with oligoarticular JIA. Disease-modifying agents such as methotrexate have demonstrated efficacy and safety; however, in many patients, the disease remains active despite this treatment. These children now receive more targeted treatment including the tumor necrosis factor alpha (TNFα) inhibitors, interleukin-1 blockade, interleukin-6 blockade, selective costimulation modulators and selective B-cell blockade. The biologic targeted therapies have changed the strategy in which we treat our children with JIA; however, there remains much to be learned about the long-term effects and safety of these medicines.
Atypical femur fractures: a review of the evidence and its implication to clinical practice
Authors: Girgis Christian M. , Seibel Markus J.
Published: August 2011

Whilst bisphosphonates are an established modality in the treatment of osteoporosis, there have been increasing concerns regarding the risk of an unusual form of femur fracture amongst patients receiving bisphosphonates for prolonged periods. These fractures, referred to as ‘atypical’, have been characterized by a number of clinical and radiographic features that distinguish them from ‘typical’ osteoporotic fractures. The evidence base is currently split between a large number of case series demonstrating an association between the occurrence of atypical fractures and bisphosphonate use and several population-based studies that do not confirm such an association. Hence, a degree of uncertainty surrounds this important issue. In this review, we examine the emerging evidence on atypical femur fractures, assess hypotheses on their biomechanical evolution and discuss the wider clinical implications of this phenomenon.
Efficacy and safety of febuxostat in patients with hyperuricemia and gout
Authors: Garcia-Valladares Ignacio , Khan Tahir , Espinoza Luis R.
Published: August 2011

The past decade has witnessed an exponential increase of novel therapeutic modalities for a variety of rheumatic disorders, including gout. During the past few years two novel therapeutic agents have been approved by the US Food and Drug Administration for the treatment of hyperuricemia in patients with gout, one of them being febuxostat, a nonpurine selective inhibitor of xanthine oxidase. Review of its pharmacokinetics and pharmacodynamics, efficacy and safety profile, and use in gout patients with comorbid conditions reveals that age and gender have no clinically significant effect and dose adjustments based on age or gender are not required. In addition, febuxostat can be used in patients with mild-to-moderate renal or hepatic involvement. Its overall efficacy and safety profile is comparable and, in certain subsets such as gout patients with mild and moderate renal insufficiency, is superior to allopurinol.
Simplifying fibromyalgia assessment: the VASFIQ Brief Symptom Scale
Authors: Boomershine Chad S. , Emir Birol , Zlateva Gergana , Wang Yi
Published: August 2011

Objectives: We tested the ability of the VASFIQ, a seven-item scale composed of Fibromyalgia Impact Questionnaire (FIQ) visual analog scales (VASs), to quantify fibromyalgia global disease severity and identify fibromyalgia patients with significant symptoms of fatigue, poor sleep, depression or anxiety.

Methods: Spearman rank correlations were used to compare global VASFIQ, FIQ and Patient Global Impression of Change (PGIC) scores and individual FIQ VAS scores with full-length, validated questionnaire scores for fatigue (Multidimensional Assessment of Fatigue–Global Fatigue Index [MAF-GFI]), poor sleep (Medical Outcomes Study Sleep Problems Index [SPI]) and depression and anxiety (Hospital Anxiety and Depression Scale [HADS]). Patient scores used in the analyses were derived from 2229 patients enrolled in three pregabalin fibromyalgia trials. Receiver operating characteristic analyses determined VASFIQ cutoff scores identifying patients with clinically significant symptom levels using full-length, validated symptom questionnaires to define cases.

Results: Global VASFIQ and FIQ scores correlated highly at baseline and study endpoints (ρ = 0.94 and 0.97, respectively; both p < 0.0001). Change in global VASFIQ and FIQ scores correlated similarly to PGIC scores at study endpoints (ρ = 0.58 and 0.61, respectively; both p < 0.0001). Individual FIQ VAS scores correlated with corresponding full-length symptom questionnaire scores at baseline and study endpoints (VASfatigue with MAF-GFI, ρ = 0.64 and 0.76; VASsleep with SPI, ρ = 0.50 and 0.67; VASdepression with HADS-D, ρ = 0.43 and 0.62; VASanxiety with HADS-A, ρ = 0.47 and 0.67, respectively; p < 0.0001 for all). Patients with significant symptoms of fatigue were identified by VASfatigue >7.5, poor sleep by VASsleep >7.9, depression by VASdepression >5.8 and anxiety by VASanxiety >6.0. VASFIQ global scores ≥31.4 and ≥45.0 identified patients with moderate and severe global fibromyalgia symptoms, respectively.

Conclusions: The VASFIQ scale accurately quantifies global fibromyalgia severity and identifies patients with significant symptoms of fatigue, poor sleep, depression or anxiety with brevity, enabling rapid patient assessment and informing treatment decisions in busy clinics.
An empirical model for predicting energy consumption of manufacturing processes: a case of turning process
Authors: Li W , Kara S
Published: August 2011

Optimizing the energy efficiency of processes has become a priority in the manufacturing sector; driven by soaring energy costs and the environmental impact caused by high energy consumption levels. The energy consumed by a machine tool performing a turning process consists of not only the energy required by the tool tip for material removal but also the energy used for auxiliary functions. Traditionally, the energy required for the cutting process is estimated based on cutting force prediction equations. However, this estimation is limited to the energy consumption of the tool tip. Thus, the aim of this paper is to develop a reliable method to predict the total energy consumption of a selected machine tool performing a turning operation. In order to compare the energy consumption under different cutting conditions, the specific energy consumption is defined as a functional unit: the energy consumed to remove 1 cm3 of material. An empirical model is obtained based on power measurements under various cutting conditions, and it is able to provide a reliable prediction of energy consumption for given process parameters. Additional investigations are conducted in order to understand and explain each coefficient in the energy consumption model.
An endocrine perspective of nonalcoholic fatty liver disease (NAFLD)
Authors: Lomonaco Romina , Chen Janet , Cusi Kenneth
Published: August 2011

Endocrinologists are encountering patients with obesity-related complications such as metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) on a daily basis. Nonalcoholic fatty liver disease (NAFLD) is a liver condition characterized by insulin resistance, hepatic steatosis and frequently T2DM. This is now the most common chronic liver condition in adults and is present in the majority of obese subjects. Liver fat accumulation may range from simple steatosis to severe steatohepatitis with hepatocyte necroinflammation (or nonalcoholic steatohepatitis [NASH]). Although the natural history is incompletely understood, NAFLD may lead to serious medical consequences ranging from cirrhosis and hepatocellular carcinoma to earlier onset of T2DM and cardiovascular disease (CVD). The diagnosis of NAFLD may be challenging because signs and symptoms are frequently absent or nonspecific, and thus easily missed. Liver aminotransferases may be helpful if elevated, but most times are normal in the presence of the disease. Liver imaging may assist in the diagnosis (ultrasound or MRI and spectroscopy) but a definitive diagnosis of NASH still requires a liver biopsy. This may change in the near future as novel biomarkers become available. Treatment of NAFLD includes aggressive management of associated cardiovascular risk factors and many times control of T2DM. Pioglitazone and vitamin E appear promising for patients with NASH, although long-term studies are unavailable. In summary, this review hopes to address the common clinical dilemmas that endocrinologists face in the diagnosis and management of NAFLD and increase awareness of a potentially serious medical condition.
Pseudothrombosis of the Subclavian Vein
Authors: Washko Patrick A. , Smith S. Wayne , Reese Savannah , Stull Brian , Rimmer Susan
Published: August 2011

A woman in her late 20s presented one week after an abdominoplasty surgical procedure to the emergency room complaining of shortness of breath and chest pain. A chest computed tomography angiogram (CTA) pulmonary embolism protocol (PE) was ordered to rule out acute PE. The CTA study was negative for PE, but an incidental finding of complete obstruction of the right subclavian vein was noted.
Autoreactive CD1b-restricted T cells: a new innate-like T-cell population that contributes to immunity against infection
Authors: Li Sha , Choi Hak-Jong , Felio Kyrie , Wang Chyung-Ru
Published: August 2011

Group 1 CD1 (CD1a, -b, and -c) presents self and foreign lipid antigens to multiple T-cell subsets in humans. However, in the absence of a suitable animal model, the specific functions and developmental requirements of these T cells remain unknown. To study group 1 CD1-restricted T cells in vivo, we generated double transgenic mice (HJ1Tg/hCD1Tg) that express group 1 CD1 molecules in a similar pattern to that observed in humans (hCD1Tg) as well as a TCR derived from a CD1b-autoreactive T-cell line (HJ1Tg). Using this model, we found that similar to CD1d-restricted NKT cells, HJ1 T cells exhibit an activated phenotype (CD44hiCD69+CD122+) and a subset of HJ1 T cells expresses NK1.1 and is selected by CD1b-expressing hematopoietic cells. HJ1 T cells secrete proinflammatory cytokines in response to stimulation with CD1b-expressing dendritic cells derived from humans as well as hCD1Tg mice, suggesting that they recognize species conserved self-lipid antigen(s). Importantly, this basal autoreactivity is enhanced by TLR-mediated signaling and HJ1 T cells can be activated and confer protection against Listeria infection. Taken together, our data indicate that CD1b-autoreactive T cells, unlike mycobacterial lipid antigen-specific T cells, are innate-like T cells that may contribute to early anti-microbial host defense.
Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone
Authors: Kumar Shaji K. , Uno Hajime , Jacobus Susanna J. , Wier Scott A. Van , Ahmann Greg J. , Henderson Kimberly J. , Callander Natalie S. , Haug Jessica L. , Siegel David S. , Greipp Philip R. , Fonseca Rafael , Rajkumar S. Vincent
Published: August 2011

Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma; however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of 2 GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%), respectively, were high-risk using the GEP70 and GEP15 signatures. The median overall survival for the GEP70 high-risk group was 19 months versus not reached for the rest (hazard ratio = 14.1). Although the medians were not reached, the GEP15 also predicted a poor outcome among the high-risk patients. The C-statistic for the GEP70, GEP15, and FISH based risk stratification systems was 0.74, 0.7, and 0.7, respectively. Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475.
Targeting DC-SIGN via its neck region leads to prolonged antigen residence in early endosomes, delayed lysosomal degradation, and cross-presentation
Authors: Tacken Paul J. , Ginter Wiebke , Berod Luciana , Cruz Luis J. , Joosten Ben , Sparwasser Tim , Figdor Carl G. , Cambi Alessandra
Published: August 2011

Targeting antigens to dendritic cell (DC)–specific receptors, such as DC-SIGN, induces potent T cell-mediated immune responses. DC-SIGN is a transmembrane C-type lectin receptor with a long extracellular neck region and a carbohydrate recognition domain (CRD). Thus far, only antibodies binding the CRD have been used to target antigens to DC-SIGN. We evaluated the endocytic pathway triggered by antineck antibodies as well as their intracellular routing and ability to induce CD8+ T-cell activation. In contrast to anti-CRD antibodies, antineck antibodies induced a clathrin-independent mode of DC-SIGN internalization, as demonstrated by the lack of colocalization with clathrin and the observation that silencing clathrin did not affect antibody internalization in human DCs. Interestingly, we observed that anti-neck and anti-CRD antibodies were differentially routed within DCs. Whereas anti-CRD antibodies were mainly routed to late endosomal compartments, anti-neck antibodies remained associated with early endosomal compartments positive for EEA-1 and MHC class I for up to 2 hours after internalization. Finally, cross-presentation of protein antigen conjugated to antineck antibodies was approximately 1000-fold more effective than nonconjugated antigen. Our studies demonstrate that anti-neck antibodies trigger a distinct mode of DC-SIGN internalization that shows potential for targeted vaccination strategies.
TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms
Authors: Fleischman Angela G. , Aichberger Karl J. , Luty Samuel B. , Bumm Thomas G. , Petersen Curtis L. , Doratotaj Shirin , Vasudevan Kavin B. , LaTocha Dorian H. , Yang Fei , Press Richard D. , Loriaux Marc M. , Pahl Heike L. , Silver Richard T. , Agarwal Anupriya , O'Hare Thomas , Druker Brian J. , Bagby Grover C. , Deininger Michael W.
Published: August 2011

Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2V617F expressing cells in MPN. We show that JAK2V617F kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2V617F allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2V617F-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2V617F expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2V617F-positive MPN. Altogether our data are consistent with a model where JAK2V617F promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.
IL-36R ligands are potent regulators of dendritic and T cells
Authors: Vigne Solenne , Palmer Gaby , Lamacchia Céline , Martin Praxedis , Talabot-Ayer Dominique , Rodriguez Emiliana , Ronchi Francesca , Sallusto Federica , Dinh Huyen , Sims John E. , Gabay Cem
Published: August 2011

IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) are members of the IL-1 family of cytokines. These cytokines bind to IL-36R (IL-1Rrp2) and IL-1RAcP, activating similar intracellular signals as IL-1, whereas IL-36Ra (IL-1F5) acts as an IL-36R antagonist (IL-36Ra). In this study, we show that both murine bone marrow-derived dendritic cells (BMDCs) and CD4+ T lymphocytes constitutively express IL-36R and respond to IL-36α, IL-36β, and IL-36γ. IL-36 induced the production of proinflammatory cytokines, including IL-12, IL-1β, IL-6, TNF-α, and IL-23 by BMDCs with a more potent stimulatory effect than that of other IL-1 cytokines. In addition, IL-36β enhanced the expression of CD80, CD86, and MHC class II by BMDCs. IL-36 also induced the production of IFN-γ, IL-4, and IL-17 by CD4+ T cells and cultured splenocytes. These stimulatory effects were antagonized by IL-36Ra when used in 100- to 1000-fold molar excess. The immunization of mice with IL-36β significantly and specifically promoted Th1 responses. Our data thus indicate a critical role of IL-36R ligands in the interface between innate and adaptive immunity, leading to the stimulation of T helper responses.
Serological identification of HSP105 as a novel non-Hodgkin lymphoma therapeutic target
Authors: Zappasodi Roberta , Bongarzone Italia , Ghedini Gaia C. , Castagnoli Lorenzo , Cabras Antonello D. , Messina Antonella , Tortoreto Monica , Tripodo Claudio , Magni Michele , Carlo-Stella Carmelo , Gianni Alessandro M. , Pupa Serenella M. , Di Nicola Massimo
Published: August 2011

We reported that the clinical efficacy of dendritic cell–based vaccination is strongly associated with immunologic responses in relapsed B-cell non-Hodgkin lymphoma (B-NHL) patients. We have now investigated whether postvaccination antibodies from responders recognize novel shared NHL-restricted antigens. Immunohistochemistry and flow cytometry showed that they cross-react with allogeneic B-NHLs at significantly higher levels than their matched prevaccination samples or nonresponders' antibodies. Western blot analysis of DOHH-2 lymphoma proteome revealed a sharp band migrating at approximately 100 to 110 kDa only with postvaccine repertoires from responders. Mass spectrometry identified heat shock protein-105 (HSP105) in that molecular weight interval. Flow cytometry and immunohistochemistry disclosed HSP105 on the cell membrane and in the cytoplasm of B-NHL cell lines and 97 diagnostic specimens. A direct correlation between HSP105 expression and lymphoma aggressiveness was also apparent. Treatment of aggressive human B-NHL cell lines with an anti-HSP105 antibody had no direct effects on cell cycle or apoptosis but significantly reduced the tumor burden in xenotransplanted immunodeficient mice. In vivo antilymphoma activity of HSP105 engagement was associated with a significant local increase of Granzyme B+ killer cells that very likely contributed to the tumor-restricted necrosis. Our study adds HSP105 to the list of nononcogenes that can be exploited as antilymphoma targets.
Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome
Authors: Shao Bojing , Wahrenbrock Mark G. , Yao Longbiao , David Tovo , Coughlin Shaun R. , Xia Lijun , Varki Ajit , McEver Rodger P.
Published: August 2011

Trousseau syndrome is classically defined as migratory, heparin-sensitive but warfarin-resistant microthrombi in patients with occult, mucinous adenocarcinomas. Injecting carcinoma mucins into mice generates platelet-rich microthrombi dependent on P- and L-selectin but not thrombin. Heparin prevents mucin binding to P- and L-selectin and mucin-induced microthrombi. This model of Trousseau syndrome explains resistance to warfarin, which inhibits fluid-phase coagulation but not selectins. Here we found that carcinoma mucins do not generate microthrombi in mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), the leukocyte ligand for P- and L-selectin. Furthermore, mucins did not activate platelets in blood from PSGL-1–deficient mice. Mucins induced microthrombi in radiation chimeras lacking endothelial P-selectin but not in chimeras lacking platelet P-selectin. Mucins caused leukocytes to release cathepsin G, but only if platelets were present. Mucins failed to generate microthrombi in cathepsin G-deficient mice. Mucins did not activate platelets in blood from mice lacking cathepsin G or protease-activated receptor-4 (PAR4), indicating that cathepsin G activates platelets through PAR4. Using knockout mice and blocking antibodies, we found that mucin-triggered cathepsin G release requires L-selectin and PSGL-1 on neutrophils, P-selectin on platelets, and Src family kinases in both cell types. Thus, carcinoma mucins promote thrombosis through adhesion-dependent, bidirectional signaling in neutrophils and platelets.
BMP-2 gene-fibronectin-apatite composite layer enhances bone formation
Authors: Zhang Wei , Tsurushima Hideo , Oyane Ayako , Yazaki Yushin , Sogo Yu , Ito Atsuo , Matsumura Akira
Published: August 2011

Background

Safe and efficient gene transfer systems are needed for tissue engineering. We have developed an apatite composite layer including the bone morphogenetic protein-2 (BMP-2) gene and fibronectin (FB), and we evaluated its ability to induce bone formation.

Methods

An apatite composite layer was evaluated to determine the efficiency of gene transfer to cells cultured on it. Cells were cultured on a composite layer including theBMP-2gene and FB, andBMP-2gene expression,BMP-2protein concentrations, alkaline phosphatase (ALP) activity, and osteocalcin (OC) concentrations were measured. A bone defect on the cranium of rats was treated with hydroxyapatite (HAP)-coated ceramic buttons with the apatite composite layer including theBMP-2gene and FB (HAP-BMP-FB). The tissue concentration of BMP-2, bone formation, and the expression levels of theBMP-2, ALP, andOCgenes were all quantified.

Results

The apatite composite layer provided more efficient gene transfer for the cultured cells than an apatite composite layer without FB. The BMP-2 concentration was approximately 100~600 pg/mL in the cell-culture medium. Culturing the cells on the apatite composite layer for 27 days increased ALP activity and OC concentrations. In animal experiments, the tissue concentrations of BMP-2 were over 100 pg/mg in the HAP-BMP-FB group and approximately 50 pg/mg in the control groups. Eight weeks later, bone formation was more enhanced in the HAP-BMP-FB group than in the control groups. In the tissues surrounding the HAP button, the gene expression levels of ALP and OC increased.

Conclusion

TheBMP-2gene-FB-apatite composite layer might be useful for bone engineering.
Dextromethorphan attenuated the higher vulnerability to inflammatory thermal hyperalgesia caused by prenatal morphine exposure in rat offspring
Authors: Tao Pao-Luh , Chen Chien-Fang , Huang Eagle Yi-Kung
Published: August 2011

Background

Co-administration of dextromethorphan (DM) with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on inflammatory hyperalgesia in morphine-exposed offspring. Therefore, we attempt to investigate the possible effect of prenatal morphine exposure on the vulnerability to hyperalgesia and the possible therapeutic effect of DM in the present study.

Methods

Fifty μl of carrageenan (20 mg/ml) was injected subcutaneously into the plantar surface of the right hind paw in p18 rats to induce hyperalgesia. Mean paw withdrawal latency was measured in the plantar test to index the severity of hyperalgesia. Using Western blotting and RT-PCR, the quantitative analyses of NMDA receptor NR1 and NR2B subunits were performed in spinal cords from different groups of animals.

Results

In the carrageenan-induced hyperalgesia model, rat offspring passively exposed to morphine developed a severe hyperalgesia on postnatal day 18 (p18), which also had a more rapid time course than those in the controls. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Western blot and RT-PCR analysis showed that the levels of protein and mRNA of NMDA receptor NR1 and NR2B subunits were significantly higher in the lumbar spinal cords of rats (p14) exposed to prenatal morphine; the co-administration of DM could reverse the effect of morphine on NR1 and attenuate the effect on NR2B.

Conclusions

Thus, DM may have a great potential in the prevention of higher vulnerability to inflammatory thermal hyperalgesia in the offspring of morphine-addicted mothers.
Differential toll-like receptor 3 (TLR3) expression and apoptotic response to TLR3 agonist in human neuroblastoma cells
Authors: Chuang Jiin-Haur , Chuang Hui-Ching , Huang Chao-Cheng , Wu Chia-Ling , Du Yung-Ying , Kung Mei-Lang , Chen Chih-Hao , Chen San-Cher , Tai Ming-Hong
Published: August 2011

Background

Toll-like receptor-3 (TLR-3) is a critical component of innate immune system against dsRNA viruses and is expressed in the central nervous system. However, it remains unknown whether TLR3 may serve as a therapeutic target in human neuroblastoma (NB).

Methods

TLR3 expression in human NB samples was examined by immunohistochemical analysis. Quantitative RT-PCR and western blot was used to determine TLR3 expression in three human NB cell lines. The effect of TLR3 agonist, polyinosinic-polycytidylic acid (poly(I:C)), on the growth of human NB cells was evaluated by WST-1 cell proliferation assay, flow cytometry analysis, and immunoblot analysis. Blockade of TLR3 signaling was achieved using TLR3 neutralizing antibody, small interference RNA, and 2-aminopurine (2-AP), an inhibitor of protein kinase R (PKR), an interferon-induced, double-stranded RNA-activated protein kinase.

Results

In immunohistochemical studies, TLR3 mainly expressed in the cytoplasm of ganglion cells and in some neuroblastic cells, but not in the stromal cells in human NB tissues. Among three human NB cell lines analyzed, TLR3 was significantly up-regulated in SK-N-AS cells at mRNA and protein level compared with other two low TLR3- expressing NB cells. Treatment with poly(I:C) elicited significant growth inhibition and apoptosis only in high TLR3-expressing SK-N-AS cells, but not in low TLR3-expressing SK-N-FI and SK-N-DZ cells. Moreover, poly(I:C) treatment significantly stimulated the activities of PKR, interferon regulatory factor 3 (IRF-3) and caspase-3 in SK-N-AS cells. Application of TLR3 neutralizing antibody or small interference RNA (siRNA) reduced the poly(I:C)-induced inhibition of cell proliferation and apoptosis in SK-N-AS cells. On the contrary, ectopic TLR3 expression enhanced the sensitivity of low TLR3-expressing NB cells to poly(I:C). Finally, application of 2-AP attenuated the poly(I:C)-induced IRF-3 and caspase-3 activation in SK-N-AS cells.

Conclusion

The present study demonstrates that TLR3 is expressed in a subset of NB cells. Besides, TLR3/PKR/IRF-3/capase-3 pathway is implicated in the selective cytotoxicity of TLR3 agonist towards high TLR3-expressing NB cells.
RETRACTED ARTICLE: Identification of one critical amino acid that determines a conformational neutralizing epitope in the capsid protein of porcine circovirus type 2
Authors: Huang Li P , Lu Yue H , Wei Yan W , Guo Long J , Liu Chang M
Published: August 2011

Background

Porcine circovirus type 2 (PCV2) is associated with post-weaning multisystemic wasting syndrome (PMWS) in pigs. Currently, there is considerable interest in the immunology of PCV2; in particular, the immunological properties of the capsid protein. This protein is involved in PCV2 immunogenicity and is a potential target for vaccine development. In this study, we identified one critical amino acid that determines a conformational neutralizing epitope in the capsid protein of PCV2.

Results

One monoclonal antibody (mAb; 8E4), against the capsid protein of PCV2, was generated and characterized in this study. 8E4 reacted with the genotype PCV2a (CL, LG and JF2) strains but not PCV2b (YJ, SH and JF) strains by an immunoperoxidase monolayer assay (IPMA) and a capture ELISA. Furthermore, the mAb had the capacity to neutralize PCV2a (CL, LG and JF2) strains but not PCV2b (YJ, SH and JF) strains. One critical amino acid that determined a conformational neutralizing epitope was identified using mAb 8E4 and PCV2 infectious clone technique. Amino acid residues 47-72 in the capsid protein of PCV2a/CL were replaced with the corresponding region of PCV2b/YJ, and the reactivity of mAb 8E4 was lost. Further experiments demonstrated that one amino acid substitution, the alanine for arginine at position 59 (A59R) in the capsid protein of PCV2a (CL, LG and JF2) strains, inhibited completely the immunoreactivity of three PCV2a strains with mAb 8E4.

Conclusions

It is concluded that the alanine at position 59 in the capsid protein of PCV2a (CL, LG and JF2) strains is a critical amino acid, which determines one neutralizing epitope of PCV2a (CL, LG and JF2) strains. This study provides valuable information for further in-depth mapping of the conformational neutralizing epitope, understanding antigenic difference among PCV2 strains, and development of a useful vaccine for control of PCV2-associated disease.
A single amino acid change within the R2 domain of the VvMYB5b transcription factor modulates affinity for protein partners and target promoters selectivity
Authors: Hichri Imène , Deluc Laurent , Barrieu François , Bogs Jochen , Mahjoub Ali , Regad Farid , Gallois Bernard , Granier Thierry , Trossat-Magnin Claudine , Gomès Eric , Lauvergeat Virginie
Published: August 2011

Background

Flavonoid pathway is spatially and temporally controlled during plant development and the transcriptional regulation of the structural genes is mostly orchestrated by a ternary protein complex that involves three classes of transcription factors (R2-R3-MYB, bHLH and WDR). In grapevine (Vitis vinifera L.), several MYB transcription factors have been identified but the interactions with their putative bHLH partners to regulate specific branches of the flavonoid pathway are still poorly understood.

Results

In this work, we describe the effects of a single amino acid substitution (R69L) located in the R2 domain of VvMYB5b and predicted to affect the formation of a salt bridge within the protein. The activity of the mutated protein (name VvMYB5bL, the native protein being referred as VvMYB5bR) was assessed in different in vivo systems: yeast, grape cell suspensions, and tobacco. In the first two systems, VvMYB5bL exhibited a modified trans-activation capability. Moreover, using yeast two-hybrid assay, we demonstrated that modification of VvMYB5b transcriptional properties impaired its ability to correctly interact with VvMYC1, a grape bHLH protein. These results were further substantiated by overexpression of VvMYB5b

R
and VvMYB5b

L
genes in tobacco. Flowers from 35S::VvMYB5b

L
transgenic plants showed a distinct phenotype in comparison with 35S::VvMYB5b

R
and the control plants. Finally, significant differences in transcript abundance of flavonoid metabolism genes were observed along with variations in pigments accumulation.

Conclusions

Taken together, our findings indicate that VvMYB5bL is still able to bind DNA but the structural consequences linked to the mutation affect the capacity of the protein to activate the transcription of some flavonoid genes by modifying the interaction with its co-partner(s). In addition, this study underlines the importance of an internal salt bridge for protein conformation and thus for the establishment of protein-protein interactions between MYB and bHLH transcription factors. Mechanisms underlying these interactions are discussed and a model is proposed to explain the transcriptional activity of VvMYB5L observed in the tobacco model.
Essential role of caspase-8 in p53/p73-dependent apoptosis induced by etoposide in head and neck carcinoma cells
Authors: Liu Juan , Uematsu Hiroshi , Tsuchida Nobuo , Ikeda Masa-Aki
Published: August 2011

Background

Caspase-8 is a key upstream mediator in death receptor-mediated apoptosis and also participates in mitochondria-mediated apoptosis via cleavage of proapoptotic Bid. However, the role of caspase-8 in p53- and p73-dependent apoptosis induced by genotoxic drugs remains unclear. We recently reported that the reconstitution of procaspase-8 is sufficient for sensitizing cisplatin- but not etoposide-induced apoptosis, in chemoresistant and caspase-8 deficient HOC313 head and neck squamous cell carcinoma (HNSCC) cells.

Results

We show that p53/p73-dependent caspase-8 activation is required for sensitizing etoposide-induced apoptosis by utilizing HOC313 cells carrying a temperature-sensitive p53G285K mutant. Restoration of wild-type p53 function under the permissive conditions, together with etoposide treatment, led to substantial transcriptional activation of proapoptotic Noxa and PUMA, but failed to induce apoptosis. In addition to p53 restoration, caspase-8 reconstitution was needed for sensitization to etoposide-induced apoptosis, mitochondria depolarization, and cleavage of the procaspases-3, and -9. In etoposide-sensitive Ca9-22 cells carrying a temperature-insensitive mutant p53, siRNA-based p73 knockdown blocked etoposide-induced apoptosis and procaspase-8 cleavage. However, induction of p73 protein and up-regulation of Noxa and PUMA, although observed in Ca9-22 cells, were hardly detected in etoposide-treated HOC313 cells under non-permissive conditions, suggesting a contribution of p73 reduction to etoposide resistance in HOC313 cells. Finally, the caspase-9 inhibitor Ac-LEHD-CHO or caspase-9 siRNA blocked etoposide-induced caspase-8 activation, Bid cleavage, and apoptosis in both cell lines, indicating that p53/p73-dependent caspase-8 activation lies downstream of mitochondria.

Conclusions

we conclude that p53 and p73 can act as upstream regulators of caspase-8, and that caspase-8 is an essential mediator of the p53/p73-dependent apoptosis induced by etoposide in HNSCC cells. Our data suggest the importance of caspase-8-mediated positive feedback amplification in the p53/p73-dependent apoptosis induced by etoposide in HNSCC cells.
In vitro cytotoxicity of two novel oral formulations of Amphotericin B (iCo-009 and iCo-010) against Candida albicans, human monocytic and kidney cell lines
Authors: Leon Carlos G , Lee Jinkyung , Bartlett Karen , Gershkovich Pavel , Wasan Ellen K , Zhao Jinying , Clement John G , Wasan Kishor M
Published: August 2011

Background

Invasive fungal infections such as candidiasis constitute an increasingly important medical problem. Drugs currently used for the treatment of candidiasis include polyenes (such as Amphotericin B) and azoles. Amphotericin B (AmpB) presents several limitations such as its nephrotoxicity and limited solubility. We have developed two novel lipid-based AmpB formulations which in vivo show less nephrotoxicity and enhanced solubility compared to Fungizone™ a commercial AmpB formulation.

The purpose of this study was to determine the cytotoxicity of Fungizone™, Ambisome™ and two novel AmpB formulations (iCo-009 and iCo-010) against Candida albicans, human kidney (293T) cells and monocytic (THP1) cells.

Methods

Cell cytotoxicity to the AmpB formulations was evaluated by MTS and LDH assays. In vitro anti-Candida albicans activity was assessed after a 48 h drug incubation.

Results

None of the AmpB formulations tested showed cytotoxicity against 293T cells. In the case of THP1 cells only Fungizone™ and Ambisome™ showed cytotoxicity at 500 μg/L (n = 4-10, p < 0.05).

The calculated EC50 to Candida albicans for the different formulations was as follows: 26.8 ± 2.9 for iCo-010, 74.6 ± 8.9 for iCo-009, 109 ± 31 for Ambisome™ and 87.1 ± 22 for Fungizone™ (μg of AmpB/L, n = 6-12, p < 0.05).

Conclusions

The AmpB formulations analyzed were not cytotoxic to 293T cells. Cytotoxicity in THP1 cells was observed for Fungizone™ and Ambisome™, but not with the novel AmpB formulations. iCo-010 had higher efficacy compared to other three AmpB formulations in the Candida albicans model.

The absence of cytotoxicity as well as its higher efficacy for the Candida model compared to Fungizone™ and Ambisome™ suggest that iCo-010 has potential in treating candidiasis.
Multivisceral resection of pancreatic neuroendocrine tumours: a report of two cases
Authors: Gundara Justin S , Alvarado-Bachmann Raul , Williams Nicholas , Gananadha Sivakumar , Gill Anthony , Hugh Thomas J , Samra Jaswinder S
Published: August 2011

Pancreatic neuroendocrine tumours (pNETs) are rare and surgical resection offers the only possibility of cure for localised disease. The role of surgery in the setting of locally advanced and metastatic disease is more controversial. Emerging data suggests that synchronous surgical resection of pancreas and liver may be associated with increased survival. We report two cases of synchronous, one stage multivisceral resections for pNET and associated reconstruction. We highlight the technical issues involved in such extensive resections and demonstrate that one stage multivisceral operations can be achieved safely.
Some Suzuki-type fixed point theorems for generalized multivalued mappings and applications
Authors: Đorić Dragan , Lazović Rade
Published: August 2011

In this article we obtain a Suzuki-type generalization of a fixed point theorem for generalized multivalued mappings of Ćirić (Matematićki Vesnik, 9(24), 265-272, 1972). The obtained results extend furthermore the recently developed Kikkawa-Suzuki-type contractions. Applications to certain functional equations arising in dynamic programming are also considered.