bluuebunny/crossref_metadata_2025 huggingface dataset:
Invariant Points and ε‐Simultaneous Approximation
Authors: Chandok Sumit , Narang T. D.
Published: June 2011

We generalize and extend Brosowski‐Meinardus type results on invariant points from the set of best approximation to the set of ε‐simultaneous approximation. As a consequence some results on ε‐approximation and best approximation are also deduced. The results proved in this paper generalize and extend some of the known results on the subject.
Robust Adaptive Control for Nonlinear Uncertain Systems Using Type‐2 Fuzzy Neural Network System
Authors: Lee Ching-Hung , Lin Yu-Ching
Published: June 2011

This paper proposes a novel intelligent control scheme using type‐2 fuzzy neural network (type‐2 FNN) system. The control scheme is developed using a type‐2 FNN controller and an adaptive compensator. The type‐2 FNN combines the type‐2 fuzzy logic system (FLS), neural network, and its learning algorithm using the optimal learning algorithm. The properties of type‐1 FNN system parallel computation scheme and parameter convergence are easily extended to type‐2 FNN systems. In addition, a robust adaptive control scheme which combines the adaptive type‐2 FNN controller and compensated controller is proposed for nonlinear uncertain systems. Simulation results are presented to illustrate the effectiveness of our approach.
Preoperative Assessment of Anomalous Right Coronary Artery Arising from the Main Pulmonary Artery
Authors: Winner Marshall W. , Raman Subha V. , Sun Benjamin C. , Crestanello Juan A.
Published: May 2011

Anomalous origin of the right coronary artery from the pulmonary artery is a rare condition. Two cases are presented in this paper. One case was treated by ligation and coronary artery bypass. The other was treated by direct reimplantation of the anomalous coronary artery into the aorta.
TheInterleukin-6Gene Promoter Polymorphism -174 and Atherosclerotic Events in Overweight Transplanted Patients
Authors: Bamoulid Jamal , Courivaud Cécile , Deschamps Marina , Gaugler Béatrice , Tiberghien Pierre , Chalopin Jean-Marc , Saas Philippe , Ducloux Didier
Published: June 2011

Chronic inflammation plays a pivotal role in atherosclerosis. We hypothesized that combining overweight and a greater genetic capacity to produce IL-6 predicted byIL-6gene promoter polymorphism at position -174 (G→C) may allow to identify individuals exhibiting higher IL-6 and C-reactive protein (CRP) concentrations with a higher risk of atherosclerotic events (AE). The occurrence of AE was analyzed with respect to body mass index,IL-6gene promoter polymorphism at position -174 (G→C), and other relevant risk factors, retrospectively, in 217 renal transplant recipients and, prospectively, in 132. Circulating IL-6 concentrations were closely related to BMI (r=0.55,P=.0005). In overweight patients, serum IL-6 concentration was found to be significantly lower in C carriers than in GG patients (4.2 [1.0–5.1] versus 7.3 pg/mL [4.4–100];P=.025). The incidence of AE was higher in overweight GG patients (29.5% versus 10.1%;P=.0003). In multivariate analysis, overweight-GG had an increased risk to develop AE (HR 2.96 [95% CI 1.09–8.04],P=.034in the retrospective cohort, and HR 2.99 [95% CI 0.92–9.33],P=.069in the prospective cohort). All these data are consistent with a role for both genetic and environmental determinants of inflammation (white adipose tissue mass) in the development of AE in renal transplanted patients.
Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development
Authors: Khalil Feras , Läer Stephanie
Published: June 2011

The concept of physiologically based pharmacokinetic (PBPK) modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision‐making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.
Molecular-Beam Epitaxially Grown MgB2Thin Films and Superconducting Tunnel Junctions
Authors: Laloë Jean-Baptiste , Kim Tae Hee , Moodera Jagadeesh S.
Published: June 2011

Since the discovery of its superconducting properties in 2001, magnesium diboride has generated terrific scientific and engineering research interest around the world. With a of 39 K and two superconducting gaps, MgB2has great promise from the fundamental point of view, as well as immediate applications. Several techniques for thin film deposition and heterojunction formation have been established, each with its own advantages and drawbacks. Here, we will present a brief overview of research based on MgB2thin films grown by molecular beam epitaxy coevaporation of Mg and B. The films are smooth and highly crystalline, and the technique allows for virtually any heterostructure to be formed, including all-MgB2tunnel junctions. Such devices have been characterized, with both quasiparticle and Josephson tunneling reported. MgB2remains a material of great potential for a multitude of further characterization and exploration research projects and applications.
Detection of Promoter Hypermethylation in Salivary Rinses as a Biomarker for Head and Neck Squamous Cell Carcinoma Surveillance
Authors: Carvalho André Lopes , Henrique Rui , Jeronimo Carmen , Nayak Chetan S. , Reddy Ashok N. , Hoque Mohammad O. , Chang Steven , Brait Mariana , Jiang Wei-Wen , Kim Michael M. , Claybourne Quia , Goldenberg David , Khan Zubair , Khan Tanbir , Westra William H. , Sidransky David , Koch Wayne , Califano Joseph A.
Published: June 2011

Purpose: Hypermethylation of tumor suppressor gene promoters has been found in head and neck squamous carcinoma (HNSCC) and other solid tumors. We evaluated these alterations in pretreatment salivary rinses from HNSCC patients by using real-time quantitative methylation-specific PCR (Q-MSP).

Experimental Design: Pretreatment saliva DNA samples from HNSCC patients were evaluated for patterns of hypermethylation by using Q-MSP. Target tumor suppressor gene promoter regions were selected based on a previous study describing a screening panel for HNSCC in a high-risk population subjects. The selected genes were: DAPK, DCC, MINT-31, TIMP-3, p16, MGMT, CCNA1.

Results: We analyzed the panel in a cohort of 61 HNSCC patients. Thirty-three of the analyzed patients (54.1%) showed methylation of at least one of the selected genes in the saliva DNA. Pretreatment methylated saliva DNA was not significantly associated with tumor site (P = 0.209) nor clinical stage (P = 0.299). However, local disease control and overall survival were significantly lower in patients presenting hypermethylation in saliva rinses (P = 0.010 and P = 0.015, respectively). Multivariate analysis confirmed that this hypermethylation pattern remained as an independent prognostic factor for local recurrence (HR = 12.2; 95% CI = 1.8–80.6; P = 0.010) and overall survival (HR = 2.8; 95% CI = 1.2–6.5; P = 0.016).

Conclusions: We were able to confirm an elevated rate of promoter hypermethylation in HNSCC saliva of patients by using a panel of gene promoters previously described as methylated specifically in HNSCC. Detection of hypermethylation in pretreatment saliva DNA seems to be predictive of local recurrence and overall survival. This finding has potential to influence treatment and surveillance of HNSCC patients. Clin Cancer Res; 17(14); 4782–9. ©2011 AACR.
miRNA-223 Promotes Gastric Cancer Invasion and Metastasis by Targeting Tumor Suppressor EPB41L3
Authors: Li Xiaohua , Zhang Ying , Zhang Hongwei , Liu Xiaonan , Gong Taiqian , Li Mengbin , Sun Li , Ji Gang , Shi Yongquan , Han Zheyi , Han Shuang , Nie Yongzhang , Chen Xiong , Zhao Qinchuan , Ding Jie , Wu Kaichun , Daiming Fan
Published: June 2011

Traditional research modes aim to find cancer-specific single therapeutic target. Recently, emerging evidence suggested that some micro-RNAs (miRNA) can function as oncogenes or tumor suppressors. miRNAs are single-stranded, small noncoding RNA genes that can regulate hundreds of downstream target genes. In this study, we evaluated the miRNA expression patterns in gastric carcinoma and the specific role of miR-223 in gastric cancer metastasis. miRNA expression signature was first analyzed by real-time PCR on 10 paired gastric carcinomas and confirmed in another 20 paired gastric carcinoma tissues. With the 2-fold expression difference as a cutoff level, we identified 22 differential expressed mature miRNAs. Sixteen miRNAs were upregulated in gastric carcinoma, including miR-223, miR-21, miR-23b, miR-222, miR-25, miR-23a, miR-221, miR-107, miR-103, miR-99a, miR-100, miR-125b, miR-92, miR-146a, miR-214 and miR-191, and six miRNAs were downregulated in gastric carcinoma, including let-7a, miR-126, miR-210, miR-181b, miR-197, and miR-30aa-5p. After examining these miRNAs in several human gastric originated cell lines, we found that miR-223 is overexpressed only in metastatic gastric cancer cells and stimulated nonmetastatic gastric cancer cells migration and invasion. Mechanistically, miR-223, induced by the transcription factor Twist, posttranscriptionally downregulates EPB41L3 expression by directly targeting its 3′-untranslated regions. Significantly, overexpression of miR-223 in primary gastric carcinomas is associated with poor metastasis-free survival. These findings indicate a new regulatory mode, namely, specific miRNA, which is activated by its upstream transcription factor, could suppress its direct targets and lead to tumor invasion and metastasis. Mol Cancer Res; 9(7); 824–33. ©2011 AACR.
Motivational Intervention to Reduce Cannabis Use in Young People with Psychosis: A Randomized Controlled Trial
Authors: Bonsack Charles , Gibellini Manetti Silvia , Favrod Jérôme , Montagrin Yves , Besson Jacques , Bovet Pierre , Conus Philippe
Published: June 2011

Background: Cannabis use has a negative impact on psychosis. Studies are needed to explore the efficacy of psychological interventions to reduce cannabis use in psychosis. Our aim is to study the efficacy of a specific motivational intervention on young cannabis users suffering from psychosis. Methods: Participants (aged less than 35 years) were randomly assigned to treatment as usual (TAU) alone, or treatment as usual plus motivational intervention (MI + TAU). TAU was comprehensive and included case management, early intervention and mobile team when needed. Assessments were completed at baseline and at 3, 6 and12 months follow-up. Results: Sixty-two participants (32 TAU and 30 MI + TAU) were included in the study. Cannabis use decreased in both groups at follow-up. Participants who received MI in addition to TAU displayed both a greater reduction in number of joints smoked per week and greater confidence to change cannabis use at 3 and 6 months follow-up, but differences between groups were nonsignificant at 12 months. Conclusions: MI is well accepted by patients suffering from psychosis and has a short-term impact on cannabis use when added to standard care. However, the differential effect was not maintained at 1-year follow-up. MI appears to be a useful active component to reduce cannabis use which should be integrated in routine clinical practice.
Functional Characterization of Embryonic Stem Cell-Derived Endothelial Cells
Authors: Glaser Drew E. , Gower Robert M. , Lauer Nicholas E. , Tam Kayan , Blancas Alicia A. , Shih Albert J. , Simon Scott I. , McCloskey Kara E.
Published: June 2011

Endothelial cells (EC) derived from embryonic stem cells (ESC) require additional functional characterization before they are used as a cell therapy in order to enhance their potential for engraftment and proliferation. We explore several physiologically relevant functions of ESC-derived EC (ESC-EC), such as its capacity to produce nitric oxide (NO), regulate permeability, activate and express surface molecules for the recruitment of leukocytes in response to inflammatory stimuli, migrate and grow new blood vessels, lay down extracellular matrix, and take up low-density lipoproteins. We also examined the ESC-EC ability to upregulate NO in response to shear stress and downregulate NO in response to pro-inflammatory TNF-α activation. Functional responses of ESC-EC were compared with those of cultured mouse aortic ECs. The ESC-EC exhibit most aspects of functional endothelium, but interesting differences remain. The ESC-EC produced less NO on a per cell basis, but the same amount of NO if quantified based on the area of endothelial tissue. They also exhibit increased angiogenic sprouting and are more resistant to inflammatory signals. We further characterized the subphenotype of our ESC-EC and observed both venous and arterial markers on individual cells with a larger percentage of the cells exhibiting a venous phenotype. These data support the hypothesis that the developmental default pathway is toward a venous EC, and that refinement of methods for differentiation towards arterial EC is required to maintain a homogeneous population.
Cellular and Molecular Responses of the Basilar Terminus to Hemodynamics during Intracranial Aneurysm Initiation in a Rabbit Model
Authors: Kolega John , Gao Ling , Mandelbaum Max , Mocco J , Siddiqui Adnan H. , Natarajan Sabareesh K. , Meng Hui
Published: June 2011

Background/Aims: Hemodynamics constitute a critical factor in the formation of intracranial aneurysms. However, little is known about how intracranial arteries respond to hemodynamic insult and how that response contributes to aneurysm formation. We examined early cellular responses at rabbit basilar termini exposed to hemodynamic insult that initiates aneurysmal remodeling. Methods: Flow in the basilar artery was increased by bilateral carotid artery ligation. After 2 and 5 days, basilar terminus tissue was examined by immunohistochemistry and quantitative PCR. Results: Within 2 days of flow increase, internal elastic lamina (IEL) was lost in the periapical region of the bifurcation, which experienced high wall shear stress and positive wall shear stress gradient. Overlying endothelium was still largely present in this region. IEL loss was associated with localized apoptosis and elevated expression of matrix metalloproteinases (MMPs) 2 and 9. A small number of inflammatory cells were sporadically scattered in the bifurcation adventitia and were not concentrated in regions of IEL loss and MMP elevation. Elevated MMP expression colocalized with smooth muscle α-actin in the media. Conclusion: The initial vascular response to aneurysm-initiating hemodynamic insult includes localized matrix degradation and cell apoptosis. Such destructive remodeling arises from intrinsic mural cells, rather than through inflammatory cell infiltration.
Characterization of Human Late Outgrowth Endothelial Progenitor-Derived Cells under Various Flow Conditions
Authors: Mazzolai Lucia , Bouzourene Karima , Hayoz Daniel , Dignat-George Françoise , Liu Jia Wei , Bounameaux Henri , Dunoyer-Geindre Sylvie , Kruithof Egbert K.O.
Published: June 2011

Background: Endothelial progenitor-derived cells (EPC) are a cell therapy tool in peripheral arterial disease and for re-endothelialization of bypasses and stents. Objective: To assess EPC behavior under flow conditions normally found in vivo. Results: EPC were isolated from human cord blood, cultured on compliant tubes and exposed in an in vitro flow system mimicking hemodynamic environments normally found in medium and large arteries. EPC exposed for 24 h to unidirectional (0.3 ± 0.1 or 6 ± 3 dynes/cm2) shear stress oriented along flow direction, while those exposed to bidirectional shear stress (0.3 ± 3 dynes/cm2) or static conditions had random orientation. Under bidirectional flow, tissue factor (TF) activity and mRNA expression were significantly increased (2.5- and 7.0-fold) compared to static conditions. Under low shear unidirectional flow TF mRNA increased 4.9 ± 0.5-fold. Similar flow-induced increases were observed for TF in mature umbilical vein-derived endothelial cells. Expression of tissue-type plasminogen activator (t-PA), urokinase (u-PA) and monocyte chemotactic protein 1 (MCP1) were reduced by 40–60% in late outgrowth endothelial progenitor-derived cells (LO-EPC) exposed to any flow environment, while MCP1, but not t-PA or u-PA, was decreased in HUVEC. Conclusions: Flow, in particular bidirectional, modifies the hemostatic balance in LO-EPC with increased TF and decreased plasminogen activator expression.
Isolation and Characterization of Murine Mandibular Condylar Cartilage Cell Populations
Authors: Chen J. , Utreja A. , Kalajzic Z. , Sobue T. , Rowe D. , Wadhwa S.
Published: June 2011

Objectives: The mandibular condylar cartilage is a heterogeneous tissue containing cells at various stages of chondrocyte maturation organized into 4 zones: superficial, polymorphic, flattened, and hypertrophic. The goal of this study was to use transgenic mice containing chondrocyte maturation markers fused to fluorescent protein transgenes to isolate and characterize homogenous cell populations of the mandibular condylar cartilage. Methods: Fluorescent reporter expression in the mandibular condylar cartilage of transgenic mice containing the 3.6-kb fragment of the rat collagen type 1 promoter fused to a topaz-fluorescent protein (Col3.6-tpz), collagen type 2 promoter fused to a cyan-fluorescent protein (Col2-cyan), and/or collagen type 10 promoter fused to cherry-fluorescent protein (Col10-cherry) was examined. Mandibular condylar cartilage cells were analyzed by fluorescence-activated cell sorting (FACS) and either used for gene expression analysis or plated in cell cultures and exposed to adipogenic, osteogenic, or chondrogenic conditions. To determine cell fate, transgenic mice containing the Col3.6-cre recombinase were bred with cre reporter mice. Results: Localization and analysis of gene expression revealed that Col3.6-tpz-positive cells corresponded to the polymorphic/flattened zones and Col2-cyan-positive cells corresponded to the flattened/hypertrophic zones of the mandibular condylar cartilage. Mandibular condylar cartilage FACS-sorted Col3.6-tpz-positive cells have the potential to differentiate into bone, cartilage, and fat. Cell fate mapping revealed that Col3.6 cells are precursors of some of the hypertrophic chondrocytes in the mandibular condylar cartilage. Conclusion: Col3.6-tpz cells represent an earlier stage of the mandibular condylar cartilage maturation pathway.
Methods for the Measurement and Characterization of Erosion in Enamel and Dentine
Authors: Schlueter N. , Hara A. , Shellis R.P. , Ganss C.
Published: June 2011

The advantages, limitations and potential applications of available methods for studying erosion of enamel and dentine are reviewed. Special emphasis is placed on the influence of histological differences between the dental hard tissue and the stage of the erosive lesion. No method is suitable for all stages of the lesion. Factors determining the applicability of the methods are: surface condition of the specimen, type of the experimental model, nature of the lesion, need for longitudinal measurements and type of outcome. The most suitable and most widely used methods are: chemical analyses of mineral release and enamel surface hardness for early erosion, and surface profilometry and microradiography for advanced erosion. Morphological changes in eroded dental tissue have usually been characterised by scanning electron microscopy. Novel methods have also been used, but little is known of their potential and limitations. Therefore, there is a need for their further development, evaluation, consolidation and, in particular, validation.
Qualitative Evaluation of Adjuvant Activities and Its Application to Th2/17 Diseases
Authors: Matsushita Sho , Takagi Rie , Hashimoto Kumiko , Higashi Takehiro
Published: June 2011

Dendritic cells (DCs) are antigen-presenting cells specialized to activate naive T lymphocytes and initiate primary immune responses. The different classes of specific immune responses are driven by the biased development of antigen-specific helper T cell subsets – that is, Th1, Th2, and Th17 cells – that activate different components of cellular and humoral immunity. DCs reside in an immature state in many nonlymphoid tissues such as the skin or airway mucosa which are highly exposed to allergens, pathogens, and chemicals. T cell receptor stimulation with costimulation allows naive Th cells to develop into effector cells, normally accompanied by high-level expression of selective sets of cytokines. The balance of these cytokines and the resulting class of immune responses depend on the conditions under which DCs are primed. Immunomodulators such as lipopolysaccharides/forskolin/curdlan change the nature of DCs to induce Th1/Th2/Th17 cells thereby designated Th1/Th2/Th17 adjuvants. We have recently found that such activities can be scrutinized by using mixed lymphocyte reaction, cAMP, and differential expression of Notch ligand isoforms. Application of these methods for the analyses of atopic dermatitis and experimental autoimmune encephalomyelitis will be discussed.
Combined Administration of Kanamycin and Furosemide Does Not Result in Loss of Vestibular Function in Guinea Pigs
Authors: Bremer Hendrik G. , de Groot John C.M.J. , Versnel Huib , Klis Sjaak F.L.
Published: June 2011

Aminoglycoside antibiotics are known to damage the vestibular and auditory sensory epithelia. Although loop diuretics enhance the cochleotoxic effect of aminoglycosides, it is not known whether concomitant administration of an aminoglycoside and a loop diuretic affects the vestibular system. The aim of our study was to investigate the effect of co-administration of kanamycin and furosemide upon the otolith organs and to compare it to the known vestibulotoxic effect of gentamicin. Five guinea pigs were injected with a single dose of both kanamycin (400 mg/kg, s.c.) and furosemide (100 mg/kg, i.v.), 5 animals received gentamicin (100 mg/kg, i.p.) for 10 days, and 5 untreated animals served as controls. After 7 days, vestibular function was assessed by measuring vestibular short-latency evoked potentials (VsEPs) to linear acceleration stimuli and cochlear function by auditory brainstem responses (ABRs) to clicks. Hair cell densities were determined in phalloidin-stained whole mounts of the utricles and saccules, and in midmodiolar sections of resin-embedded cochleae. Co-administration of kanamycin and furosemide had no significant effect on VsEPs and hair cell densities in the utricles and saccules were not reduced. ABR thresholds were increased to a great extent (by ∼60 dB), and histologically a severe loss of cochlear hair cells was observed. The effect of gentamicin, both on vestibular and cochlear function, was just the opposite. VsEP thresholds to horizontal stimulation were elevated and suprathreshold amplitudes showed a decrease, whereas cochlear function was not reduced. With this protocol, we have a tool to selectively induce cochlear or vestibular damage, which may be of interest to researchers and clinicians alike.
Zinc Finger Protein, Multitype 1, Suppresses Human Th2 Development via Downregulation of IL-4
Authors: Kitamura Noriko , Mori Akio , Tatsumi Hideki , Nemoto Soichi , Hiroi Takachika , Kaminuma Osamu
Published: June 2011

Background: Among several GATA family transcription factor-associating proteins, zinc finger protein, multitype 1 (ZFPM1), at least that of murine origin, has been shown to modulate the activity of GATA-3. However, the functional role of human ZFPM1 in the immune system has not been elucidated. Therefore, we here investigated the contribution of ZFPM1 to human Th1/Th2 differentiation. Methods: The cDNA of ZFPM1 was cloned and introduced into human cord blood CD4+ T cells by a lentiviral transduction system. Then, the expression of IL-4 and IFN-γ mRNA was determined by quantitative real-time RT-PCR. The effect of ZFPM1 on the promoter activity of IL-4 and IFN-γ in Jurkat cells was also investigated. Results: Stimulation-induced expression of IL-4 and IFN-γ in human CD4+ T cells was suppressed and enhanced, respectively, by the introduction of ZFPM1. The transcriptional activity of IL-4 was also diminished by ZFPM1, whereas that of IFN-γ was not affected. Conclusion: ZFPM1 that facilitates human Th1 differentiation via the downregulation of IL-4 is a potential target for the treatment of allergic diseases.
Inhibition of Eosinophil Activation Mediated by a Toll-Like Receptor 7 Ligand with a Combination of Procaterol and Budesonide
Authors: Hiraguchi Yukiko , Tanida Hisashi , Hosoki Koa , Nagao Mizuho , Tokuda Reiko , Fujisawa Takao
Published: June 2011

Background: Viral respiratory tract infections play an important role in the inception and exacerbation of asthma. Eosinophils, major effector cells in asthma, often accumulate in the airways during viral infections and are possibly activated by respiratory RNA viruses through Toll-like receptor (TLR) 7. We investigated the effect of a β2-agonist, i.e. procaterol, and a corticosteroid, i.e. budesonide, that are commonly used for viral-induced asthma, on TLR7 ligand-induced activation of eosinophils in vitro. Methods: Purified peripheral blood eosinophils were incubated with procaterol and/or budesonide and stimulated with a TLR7 ligand, i.e. R-837. Expression of CD11b was analyzed by flow cytometry. Superoxide generation was measured via the cytochrome C reduction method. IL-8 in the supernatants was assayed by ELISA. Results: Although procaterol or budesonide alone did not inhibit R-837-induced CD11b expression, combinations of the 2 drugs significantly inhibited CD11b. Likewise, the combinations significantly inhibited O2– generation at low concentrations. Budesonide significantly inhibited R-837-induced IL-8 production in a concentration-dependent manner, and procaterol potentiated inhibition by budesonide although single-agent procaterol had no effect. Conclusion: A combination of procaterol and budesonide inhibits the TLR7-mediated effector function of eosinophils, indicating their possible anti-inflammatory effect for virus-induced asthma.
Utility of the Peripheral Blood Basophil Histamine Release Test in the Diagnosis of Hen’s Egg, Cow’s Milk, and Wheat Allergy in Children
Authors: Sato Sakura , Tachimoto Hiroshi , Shukuya Akinori , Ogata Mika , Komata Takatsugu , Imai Takanori , Tomikawa Morimitsu , Ebisawa Motohiro
Published: June 2011

Background: The diagnosis of food allergy (FA) is made by oral food challenge tests (OFCs) that occasionally produce serious symptoms in patients; therefore, whether to perform OFCs should be carefully considered. The utility of the histamine release test (HRT) in the diagnosis of childhood FA has not been fully examined. Methods: Sixty-four subjects with suspected hen’s egg allergy, cow’s milk allergy (CMA), and wheat allergy (WA) were enrolled. The diagnosis of FA was made based on the outcomes of OFCs or a convincing history of symptoms after food ingestion within 6 months before or after sample collection. HRT was performed using an HRT Shionogi kit. The threshold of histamine release (HRT threshold), which was defined as the minimum concentration of food antigen to induce a 10% net histamine release, was analyzed in association with FA diagnosis. Results: Receiver operating characteristic analysis showed that the HRT threshold was useful in the diagnosis of heated egg allergy (HEA), raw egg allergy (REA), CMA, and WA. We were able to determine the cutoff value for the HRT threshold in relation to outcomes of OFCs. The cutoff value was 6 ng/ml of egg white antigen in HEA and REA (p < 0.01), 40 ng/ml of milk antigen in CMA (p < 0.01), and 500 ng/ml of wheat antigen in WA (p < 0.05). The efficiency was 70.3% for HEA, 78.0% for REA, 77.6% for CMA, and 70.7% for WA. Conclusions: We conclude that the HRT threshold measurement for egg white, milk, and wheat antigen is related to outcomes of OFCs and is useful in determining when OFCs should be performed.
Comparative Analysis of Steroid Sensitivity of T Helper Cells in vitro and in vivo
Authors: Abe Akemi , Ohtomo Takayuki , Koyama Satoshi , Kitamura Noriko , Kaminuma Osamu , Mori Akio
Published: June 2011

Background: Glucocorticoid (GC) action on asthma has been partly explained by the inhibition of T cell activation. We analyzed the steroid sensitivity of ovalbumin (OVA) reactive helper T (Th) cell clones both in vitro and in vivo. Method: For in vitro experiments, Th clones were cultured with antigen-presenting cells, OVA, and various concentrations of dexamethasone (DEX). The proliferative response of each Th clone was measured by 3H-thymidine uptake. For in vivo experiments, unprimed BALB/c mice were transferred with Th clones, challenged with OVA, and administered DEX subcutaneously. The number of infiltrating cells in bronchoalveolar lavage fluid (BALF) was measured. Results: Six Th clones were classified as steroid-sensitive or steroid-resistant clones in terms of the effects of GC on the proliferative responses analyzedin vitro. Airway infiltration of eosinophils and lymphocytes of mice transferred with steroid-sensitive clones were effectively inhibited by the administration of DEX. In contrast, those of mice transferred with steroid-resistant clones were not significantly inhibited by DEX; the number of eosinophils in the BALF of mice transferred with 1 steroid-resistant clone, i.e. T5-1, was only partially reduced. Conclusion: The steroid sensitivity of Th clones measured in vitro was consistent with that of an adoptively transferred asthma model measuredin vivo. Steroid-sensitive and resistant asthma models seem valuable for understanding the mechanisms of steroid resistance in severe asthma.
An 8-Year-Old Boy with Hypereosinophilic Syndrome
Authors: Hosoki Koa , Nagao Mizuho , Iguchi Kosei , Ihara Toshiaki , Yamada Yoshiyuki , Higashigawa Masamune , Kephart Gail M. , Kita Hirohito , Fujisawa Takao
Published: June 2011

Hypereosinophilic syndrome (HES) is a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia and tissue eosinophilia, resulting in a wide variety of clinical manifestations. We present the case of an 8-year-old boy with HES. He complained of recurrent abdominal pain, general fatigue, and diarrhea. Laboratory data showed marked eosinophilia, elevated total IgE with positive specific IgE antibodies to common inhalant and food allergens, and elevated serum CCL17/TARC. A chest CT scan revealed central bronchiectasis, bronchial wall thickening, a mosaic attenuation pattern, and multiple small nodules in lung parenchyma; abdominal CT showed a thickened bladder wall. Gastrointestinal endoscopy revealed scarring in the gastric mucosa and mucosal erosion in the duodenum. Immunohistochemical examination demonstrated numerous eosinophil infiltrations with extensive extracellular eosinophil major basic protein deposition in the gastric mucosa. Only high-dose oral steroid was effective and cyclosporine appeared to have a steroid-sparing effect. HES is extraordinary rare in children and the long-term prognosis in pediatric HES is not well known. Comprehensive diagnostic procedures are vital for the early detection and management of complications in pediatric HES.
Cockroach Induces Inflammatory Responses through Protease-Dependent Pathways
Authors: Wada Kota , Matsuwaki Yoshinori , Moriyama Hiroshi , Kita Hirohito
Published: June 2011

Exposure to cockroaches is a major risk factor for asthma. Products from cockroaches may contain proteases and ligands for pattern recognition receptors. These molecules may activate airway inflammatory cells, such as eosinophils, that are involved in asthma. Among inner-city children, cockroach allergens play an especially important role in increasing asthma morbidity. The molecular mechanism for this association between cockroach exposure and asthma is not fully understood. Enzymatic activities from cockroaches activate inflammatory cells in the airways and may also exacerbate certain human airway diseases, such as asthma. We recently reported that cockroach extracts contain pepstatin A-sensitive proteases that activate PAR-2 and induce activation and degranulation of human eosinophils. This review focuses on the effects of cockroach on various inflammatory cells, including eosinophils, epithelial cells, fibroblasts, dendritic cells, and T cells, in allergic reactions.
Premature Atherosclerosis in Non-Transfusion-Dependent β-Thalassemia Intermedia
Authors: Hahalis George , Kalogeropoulos Andreas , Terzis George , Tselepis Alexandros D. , Kourakli Alexandra , Mylona Panagiota , Grapsas Nikos , Alexopoulos Dimitrios
Published: June 2011

Objectives: β-Thalassemias are inherited hemolytic anemias with a broad phenotype and an increased rate of vascular complications despite a near absence of coronary artery disease. Methods: We investigated the presence of endothelial dysfunction and subclinical atherosclerosis in non-transfusion-dependent patients with β-thalassemia intermedia (β-TI) by means of flow-mediated (FMD) and flow-independent (FID) brachial artery dilatation and carotid artery intima-media thickness. Results: In 20 nondiabetic young adults with β-TI, FMD (6.6 ± 3.7 vs. 10.3 ± 3.1%; p = 0.002) and FID (14.0 ± 4.7 vs. 18.0 ± 5.6%; p = 0.02) were both lower relative to the values in 20 matched control subjects, whereas the intima-media thickness was increased (0.51 ± 0.09 vs. 0.46 ± 0.07 mm; p = 0.049). Fibrin generation, soluble endothelial activation markers, and proinflammatory proteins were higher in the patient group, while the plasma cholesterol level was lower. Conclusions: These findings indicate premature atherosclerosis among patients with β-TI; this is in accord with the high incidence of noncoronary vascular episodes in β-TI.
4-Chloro-7-Trifluoromethyl-10H- Benzo[4,5]furo[3,2-b]Indole-1-Carboxylic Acid (TBIC), a Putative BKCa Channel Opener with Uterine Relaxant Activities
Authors: Ahn Hyung Seok , dela Peña Ike , Kim Yong Chul , Cheong Jae Hoon
Published: June 2011

In the present study, we examined the uterine relaxant activity of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), a putative opener of the large conductance Ca2+-activated K+ (BKCa) channel. TBIC concentration-dependently inhibited spontaneous uterine contractions (EC50 = 4.63 µmol/l; Emax = 94.85 ± 1.85%; 100 µmol/l, n = 6). It also reduced contractions induced by oxytocin (EC50 = 4.10 µmol/l; Emax = 84.3 ± 3.83%; 100 µmol/l, n = 6), prostaglandin F2α (EC50 = 2.14 µmol/l; Emax = 73.70 ± 5.21%; 100 µmol/l, n = 6) and acetylcholine (EC50 = 4.37 µmol/l; Emax = 83.67 ± 4.82; 100 µmol/l, n = 6). TBIC decreased KCl (20 mmol/l) -induced contractions (EC50 = 3.04 µmol/l; Emax = 94.0 ± 3.12%; 100 µmol/l, n = 6) indicating its K+ channel opening activity. BKCa channel blockers penitrem A (100 nmol/l) and tetraethylammonium chloride (1 mmol/l) attenuated the inhibitory activities of TBIC (p < 0.001) but not other K+ channel blockers such as barium chloride and glibenclamide (KIR and KATP channel blockers, respectively). These results demonstrate the uterine relaxant effects of TBIC in a mechanism of action largely referable to the potentiation of the BKCa channels. We have provided evidence for the potential use of TBIC as a tocolytic agent and support for the utility of BKCa channel openers in pathophysiologic conditions involving smooth muscle hyperactivity.
Prognostic Relevance of Circulating Tumor Cells in Metastatic Uveal Melanoma
Authors: Schuster R. , Bechrakis N.E. , Stroux A. , Busse A. , Schmittel A. , Thiel E. , Foerster M.H. , Keilholz U.
Published: June 2011

Objective: Uveal melanoma primarily metastasizes hematogenously with metastases often confined to the liver. The aim of this study was to investigate the presence of circulating tumor cells (CTC) in patients with metastatic disease as a marker for systemic disease and to determine their prognostic relevance. Methods: Blood samples from 68 patients were collected at the time of initial treatment of metastases. mRNA expression of tyrosinase and MelanA/MART1 as a surrogate marker for the presence of CTC was analyzed by real-time RT-PCR and compared with patient characteristics. Results: CTC were detected in 63% of all patients and in 67% of the 48 patients with only liver metastases. Univariate and multivariate analyses revealed PCR results and serum lactate dehydrogenase as independent prognostic factors for progression-free (hazard ratios 2.2/3.5) and overall survival (hazard ratios 4.0/6.5). Combination of PCR and lactate dehydrogenase divided the patient cohort into 3 groups with distinct prognosis. Conclusion: CTC as evidence for systemic disease can be found in the majority of patients with metastatic uveal melanoma, including patients with visible disease confined to the liver. Detection of CTC-specific mRNA transcripts for tyrosinase and MelanA/MART1 by PCR is a poor prognostic factor for progression-free and overall survival. Characterization of CTC could improve the understanding of their biology.
Clinical Performance of Two Fluorescence-Based Methods in Detecting Occlusal Caries Lesions in Primary Teeth
Authors: Matos R. , Novaes T.F. , Braga M.M. , Siqueira W.L. , Duarte D.A. , Mendes F.M.
Published: June 2011

This in vivo study aimed to evaluate the performance of 2 fluorescence-based methods in detecting occlusal caries lesions in primary teeth, compared with the performance of visual inspection and radiographic methods, and to propose a mathematic correction of the diagnostic parameters due to the imperfect reference standard method used in the study. Two examiners assessed the occlusal surfaces of 407 primary teeth (62 children) using visual inspection (ICDAS), radiographic, DIAGNOdent pen (pen type laser fluorescence; LFpen), and fluorescence camera (FC) methods. At the noncavitated threshold (NC) the reference standard method was the results of ICDAS, and at the dentine caries threshold (D3) teeth diagnosed with dentine caries by ICDAS or radiographic methods were subjected to operative treatment to confirm the presence of lesion. Reproducibility, sensitivity, specificity, accuracy, and the area under the ROC curve were calculated for the methods at both thresholds. At the NC threshold, LFpen had a slightly better performance compared to the FC and radiographic methods. However, at the D3 threshold, both fluorescence-based methods performed similarly. Visual inspection and radiographic methods presented higher specificities but lower sensitivities than fluorescence methods. After corrections, there was a significant decrease in some parameters. In conclusion, both fluorescence-based methods presented similar performance in detecting occlusal dentine caries lesions in primary teeth, but they usually gave more false-positive results than did the visual and radiographic methods. The correction proposed shows that the performance of the methods can be overestimated, and the correction should be validated and considered in further studies that use an imprecise reference standard method.
Risk of Recurrent Cardiac Events After Onset of Menopause in Women With Congenital Long-QT Syndrome Types 1 and 2
Authors: Buber Jonathan , Mathew Jehu , Moss Arthur J. , Hall W. Jackson , Barsheshet Alon , McNitt Scott , Robinson Jennifer L. , Zareba Wojciech , Ackerman Michael J. , Kaufman Elizabeth S. , Luria David , Eldar Michael , Towbin Jeffrey A. , Vincent Michael , Goldenberg Ilan
Published: June 2011

Background—

Women with congenital long-QT syndrome experience an increased risk for cardiac events after the onset of adolescence that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population.

Methods and Results—

We used a repeated-events analysis to evaluate the risk for recurrent syncope during the menopause transition and postmenopausal periods (5 years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the Long-QT Syndrome Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause transition (hazard ratio, 3.38;
P
=0.005) and the postmenopausal period (hazard ratio, 8.10;
P
<0.001) compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women, the onset of menopause was associated with a reduction in the risk for recurrent syncope (hazard ratio, 0.19;
P
=0.05;
P
=0.02 for genotype-by-menopause interaction). Only 22 women (8%) experienced aborted cardiac arrest or sudden cardiac death during follow-up. The frequency of aborted cardiac arrest/sudden cardiac death showed a similar genotype-specific association with the onset of menopause.

Conclusions—

The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.
Blood Pressure Targets in Subjects With Type 2 Diabetes Mellitus/Impaired Fasting Glucose
Authors: Bangalore Sripal , Kumar Sunil , Lobach Iryna , Messerli Franz H.
Published: June 2011

Background—

Most guidelines for treatment of hypertension recommend a blood pressure (BP) goal of <140/90 mm Hg, and a more aggressive goal of <130/80 mm Hg for patients with diabetes mellitus. However, in the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, a lower BP was not beneficial. The optimal BP target in subjects with diabetes mellitus or those with impaired fasting glucose/glucose tolerance is therefore not well defined.

Methods and Results—

We performed PUBMED, EMBASE, and CENTRAL searches for randomized clinical trials from 1965 through October 2010 of antihypertensive therapy in patients with type 2 diabetes mellitus or impaired fasting glucose/impaired glucose tolerance that enrolled at least 100 patients with achieved systolic BP of ≤135 mm Hg in the intensive BP control group and ≤140 mm Hg in the standard BP control group, had a follow-up of at least 1 year, and evaluated macrovascular or microvascular events. We identified 13 randomized clinical trials enrolling 37 736 participants. Intensive BP control was associated with a 10% reduction in all-cause mortality (odds ratio, 0.90; 95% confidence interval, 0.83 to 0.98), a 17% reduction in stroke, and a 20% increase in serious adverse effects, but with similar outcomes for other macrovascular and microvascular (cardiac, renal, and retinal) events compared with standard BP control. The results were similar in a sensitivity analysis using a bayesian random-effects model. More intensive BP control (≤130 mm Hg) was associated with a greater reduction in stroke, but did not reduce other events. Meta–regression analysis showed continued risk reduction for stroke to a systolic BP of <120 mm Hg. However, at levels <130 mm Hg, there was a 40% increase in serious adverse events with no benefit for other outcomes.

Conclusions—

The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mm Hg is acceptable. However, with more aggressive goals (<130 mm Hg), we observed target organ heterogeneity in that the risk of stroke continued to fall, but there was no benefit regarding the risk of other macrovascular or microvascular (cardiac, renal and retinal) events, and the risk of serious adverse events even increased.
Differences in Admitting Hospital Characteristics for Black and White Medicare Beneficiaries With Acute Myocardial Infarction
Authors: Popescu Ioana , Cram Peter , Vaughan-Sarrazin Mary S.
Published: June 2011

Background—

Racial disparities in acute myocardial infarction treatment may be due to differences in admitting hospitals. Little is known about factors associated with hospital selection for black and white acute myocardial infarction patients.

Methods and Results—

We identified black and white Medicare beneficiaries with acute myocardial infarction in 63 hospital referral regions with at least 50 black admissions during 2005 (n=65 633). We calculated distance from patient home to hospital referral region hospitals using ZIP code centroids. We assessed hospital quality using a composite score made up of hospital risk-adjusted 30-day mortality and acute myocardial infarction performance measures. Hospitals with a score in the top 20% were categorized as high quality, and those in the lowest 20% as low quality. We used conditional multinomial logit models to examine differences in hospital selection for blacks and whites. On average, blacks lived closer to revascularization hospitals (mean, 3.8 versus 6.8 miles;
P
<0.001) and to high-quality hospitals (mean, 5.6 versus 9.7 miles;
P
<0.001). After distance was accounted for, blacks were relatively less likely (
P
<0.001) to be admitted to revascularization hospitals (risk ratio [RR], 0.87; 95% confidence interval [CI], 0.80 to 0.95) and to high-quality hospitals (RR, 0.88; 95% CI, 0.801 to 0.95) but more likely (
P
<0.001) to be admitted to low-quality hospitals (RR, 1.17; 95% CI, 1.05 to 1.29). In analyses matched by home ZIP code, differences in admissions to revascularization (RR, 0.92; 95% CI, 0.80 to 1.05), high-quality (RR, 0.94; 95% CI, 0.81 to 1.07), and low-quality (RR, 1.15; 95% CI, 0.94 to 1.35) hospitals were not significant.

Conclusions—

Differences in admissions to revascularization and high-quality hospitals may contribute to disparities in acute myocardial infarction care. These differences may be due in part to residential ZIP code characteristics.
Nonvestibular Motion Cueing in a Fixed-Base Driving Simulator: Effects on Driver Braking and Cornering Performance
Authors: de Groot S. , Mulder M. , Wieringa P. A.
Published: May 2011

Motion platforms can be used to provide vestibular cues in a driving simulator, and have been shown to reduce driving speed and acceleration. However, motion platforms are expensive devices, and alternatives for providing motion cues need to be investigated. In independent experiments, the following eight low-cost nonvestibular motion cueing systems were tested by comparing driver performance to control groups driving with the cueing system disengaged: (1) seat belt tensioning system, (2) vibrating steering wheel, (3) motion seat, (4) screeching tire sound, (5) beeping sound, (6) road noise, (7) vibrating seat, and (8) pressure seat. The results showed that these systems are beneficial in reducing speed and acceleration and that they improve lane-keeping and/or stopping accuracy. The seat belt tensioning system had a particularly large influence on driver braking performance. This system reduced driving speed, increased stopping distance, reduced maximum deceleration, and increased stopping accuracy. It is concluded that low-cost nonvestibular motion cueing may be a welcome alternative for improving in-simulator performance so that it better matches real-world driving performance.