bluuebunny/crossref_metadata_2025 huggingface dataset:
Antigen sensitization modulates alveolar macrophage functions in an asthma model
Authors: Careau Éric , Proulx Léa-Isabelle , Pouliot Philippe , Spahr Annie , Turmel Véronique , Bissonnette Élyse Y.
Published: April 2006

We have previously demonstrated that adoptive transfer of alveolar macrophages from allergy-resistant rats to alveolar macrophage-depleted allergic rats prevents airway hyperresponsiveness development, suggesting an important role for alveolar macrophages in asthma pathogenesis. Given that ovalbumin sensitization can modulate alveolar macrophage cytokine production, we investigated the role of sensitized and unsensitized alveolar macrophages in an asthma model. Alveolar macrophages from unsensitized or sensitized Brown Norway rats were transferred to alveolar macrophage-depleted sensitized rats 24 h before allergen challenge. Airway responsiveness to methacholine and airway inflammation were measured the following day. Methacholine concentration needed to increase lung resistance by 200% was significantly higher in alveolar macrophage-depleted sensitized rats that received unsensitized alveolar macrophages compared with alveolar macrophage-depleted sensitized rats that received sensitized alveolar macrophages. Tumor necrosis factor levels in bronchoalveolar lavage fluid of sensitized rats that received unsensitized alveolar macrophages were significantly lower compared with rats that received sensitized alveolar macrophages. Interestingly, alveolar macrophages of unsensitized animals showed higher phagocytosis activity compared with alveolar macrophages of sensitized rats, suggesting that sensitization modulates alveolar macrophage phagocytosis function. Our data suggest an important role of allergen sensitization on alveolar macrophage function in asthma pathogenesis.
Nitric oxide modulates elicitation of reflex swallowing from the pharynx in rats
Authors: Kijima Hiroshi , Shingai Tomio , Takahashi Yoshihiro , Kajii Yuka , Fukushima Shin-ichi , Taguchi Yo , Noda Tadashi , Yamada Yoshiaki
Published: April 2006

The pharynx is very important for elicitation of reflex swallowing. The region of the pharynx is innervated by the pharyngeal branch of the glossopharyngeal nerve (GPN-ph). Nitric oxide (NO) plays an important role in various physiological functions. The purpose of this study is to investigate the contribution of NO to reflex swallowing evoked by electrical stimulation of the GPN-ph. Swallowing was evoked in urethane-anesthetized rats by application of repetitive electrical stimulation (10- to 20-μA amplitude, 10- to 20-Hz frequency, 1.0-ms duration) to the central cut end of the GPN-ph or superior laryngeal nerve. Swallowing was identified by electromyographic activity of the mylohyoid muscle. Latency to the first swallow and the interval between swallows were measured. Intravenous administration of NG-nitro-l-arginine (l-NNA, 0.6 mg/kg), a nonselective inhibitor of NO synthase (NOS), extremely prolonged latency to the first swallow and the interval between swallows evoked by the GPN-ph. Intraperitoneal administration of 7-nitroindazole (5.0 mg/kg), a selective inhibitor of neuronal NOS, significantly prolonged latency to the first swallow and the interval between swallows evoked by the GPN-ph. Administration of l-arginine (an NO donor, 500 mg/kg) and sodium nitroprusside (an NO releaser, 0.6 mg/kg) restored the suppression of swallowing induced by the NOS inhibitor. Superior laryngeal nerve-evoked swallowing was suppressed by administration of a higher dose of l-NNA (6.0 mg/kg). Swallowing evoked by water stimulation of the pharynx was also suppressed by l-NNA (0.6 mg/kg). These results suggest that NO plays an important role in signal processing for initiation of reflex swallowing from the pharynx.
Central angiotensin II receptors mediate hemodynamic response variability to stressors
Authors: Rowe Kayla D. , Schwartz Julie A. , Lomax Lance L. , Knuepfer Mark M.
Published: April 2006

We examined whether ANG II receptors in the central nervous system mediate hemodynamic responses to pharmacological (cocaine) and behavioral (cold water) stressors. After administration of cocaine (5 mg/kg iv), rats were classified as vascular responders (VR) if their pressor response was due entirely to an increase in systemic vascular resistance (SVR) despite a decrease in cardiac output (CO). Cocaine elicited a pressor response in mixed responders (MR) that was dependent on small increases in both SVR and CO. ANG II (30 ng/5 μl icv, 5 min before cocaine) augmented the decrease in CO in VR and prevented the increase in CO in MR. Administration of [Sar1,Thr8]ANG II (20 μg/5 μl icv; sarthran) before cocaine attenuated the decrease in CO and the large increase in SVR in VR so that they were no longer different from MR. Losartan (20 μg icv) or captopril (50 μg icv) preceding cocaine administration also attenuated the decrease in CO and the large increase in SVR seen in VR only. The role of angiotensin was not specific for cocaine, because ANG II (icv) pretreatment before startle with cold water (1 cm deep) enhanced the decrease in CO and the increase in SVR in both MR and VR, whereas losartan (icv) pretreatment before startle attenuated the decrease in CO and the increase in SVR in VR so that they were no longer different from MR. These data suggest that central ANG II receptors mediate the greater vascular and cardiac responsiveness in vascular responders to acute pharmacological and behavioral stressors.
Objective evaluation of changes in left ventricular and atrial volumes during parabolic flight using real-time three-dimensional echocardiography
Authors: Caiani E. G. , Sugeng L. , Weinert L. , Capderou A. , Lang R. M. , Vaïda P.
Published: April 2006

We tested the feasibility of real-time three-dimensional (3D) echocardiographic (RT3DE) imaging to measure left heart volumes at different gravity during parabolic flight and studied the effects of lower body negative pressure (LBNP) as a countermeasure. Weightlessness-related changes in cardiac function have been previously studied during spaceflights using both 2D and 3D echocardiography. Several technical factors, such as inability to provide real-time analysis and the need for laborious endocardial definition, have limited its usefulness. RT3DE imaging overcomes these limitations by acquiring real-time pyramidal data sets encompassing the entire ventricle. RT3DE data sets were obtained (Philips 7500, X3) during breath hold in 16 unmedicated normal subjects in upright standing position at different gravity phases during parabolic flight (normogravity, 1 Gz; hypergravity, 1.8 Gz; microgravity, 0 Gz), with LBNP applied (−50 mmHg) at 0 Gz in selected parabolas. RT3DE imaging during parabolic flight was feasible in 14 of 16 subjects. Data were analyzed (Tomtec) to quantify left ventricular (LV) and atrial (LA) volumes at end diastole and end systole, which significantly decreased at 1.8 Gz and increased at 0 Gz. While ejection fraction did not change with gravity, stroke volume was reduced by 16% at 1.8 Gz and increased by 20% at 0 Gz, but it was not significantly different from 1 Gz values with LBNP. RT3DE during parabolic flight is feasible and provides the basis for accurate quantification of LV and LA volume changes with gravity. As LBNP counteracted the increase of LV and LA volumes caused by changes in venous return, it may be effectively used for preventing cardiac dilatation during 0 Gz.
Vital capacity, respiratory muscle strength, and pulmonary gas exchange during long-duration exposure to microgravity
Authors: Prisk G. Kim , Fine Janelle M. , Cooper Trevor K. , West John B.
Published: April 2006

Extended exposure to microgravity (μG) is known to reduce strength in weight-bearing muscles and was also reported to reduce respiratory muscle strength. Short- duration exposure to μG reduces vital capacity (VC), a surrogate measure for respiratory muscle strength, for the first few days, with little change in O2uptake, ventilation, or end-tidal partial pressures. Accordingly we measured VC, maximum inspiratory and expiratory pressures, and indexes of pulmonary gas exchange in 10 normal subjects (9 men, 1 woman, 39–52 yr) who lived on the International Space Station for 130–196 days in a normoxic, normobaric atmosphere. Subjects were studied four times in the standing and supine postures preflight at sea level at 1 G, approximately monthly in μG, and multiple times postflight. VC in μG was essentially unchanged compared with preflight standing [5.28 ± 0.08 liters (mean ± SE), n = 187; 5.24 ± 0.09, n = 117, respectively; P = 0.03] and considerably greater than that measured supine in 1G (4.96 ± 0.10, n = 114, P < 0.001). There was a trend for VC to decrease after the first 2 mo of μG, but there were no changes postflight. Maximum respiratory pressures in μG were generally intermediate to those standing and supine in 1G, and importantly they showed no decrease with time spent in μG. O2uptake and CO2production were reduced (∼12%) in extended μG, but inhomogeneity in the lung was not different compared with short-duration exposure to μG. The results show that VC is essentially unchanged and respiratory muscle strength is maintained during extended exposure to μG, and metabolic rate is reduced.
A Novel Role of DNA Polymerase η in Modulating Cellular Sensitivity to Chemotherapeutic Agents
Authors: Chen Yih-wen , Cleaver James E. , Hanaoka Fumio , Chang Ching-fang , Chou Kai-ming
Published: April 2006

Genetic defects in polymerase η (pol η; hRad30a gene) result in xeroderma pigmentosum variant syndrome (XP-V), and XP-V patients are sensitive to sunlight and highly prone to cancer development. Here, we show that pol η plays a significant role in modulating cellular sensitivity to DNA-targeting anticancer agents. When compared with normal human fibroblast cells, pol η–deficient cells derived from XP-V patients were 3-fold more sensitive to β-d-arabinofuranosylcytosine, gemcitabine, or cis-diamminedichloroplatinum (cisplatin) single-agent treatments and at least 10-fold more sensitive to the gemcitabine/cisplatin combination treatment, a commonly used clinical regimen for treating a wide spectrum of cancers. Cellular and biochemical analyses strongly suggested that the higher sensitivity of XP-V cells to these agents was due to the inability of pol η–deficient cells to help resume the DNA replication process paused by the gemcitabine/cisplatin-introduced DNA lesions. These results indicated that pol η can play an important role in determining the cellular sensitivity to therapeutic agents. The findings not only illuminate pol η as a potential pharmacologic target for developing new anticancer agents but also provide new directions for improving future chemotherapy regimen design considering the use of nucleoside analogues and cisplatin derivatives. (Mol Cancer Res 2006;4(4):257–65)
Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer
Authors: Murphy Susan K. , Huang Zhiqing , Wen Yaqing , Spillman Monique A. , Whitaker Regina S. , Simel Lauren R. , Nichols Teresa D. , Marks Jeffrey R. , Berchuck Andrew
Published: April 2006

Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner. (Mol Cancer Res 2006;4(4):283–92)
Human Subjects, Third Parties, and Informed Consent: A Brief Historical Perspective of Developments in the United States
Authors: Pelias Mary Kay
Published: April 2006

The protection of human subjects in biomedical research has become a source of increasing concern over the past century. During the early days of human experimentation, the human subject was rarely if ever consulted about his or her participation in research because scientists and physicians acted in the traditional paternalistic role with respect to their subjects and patients. However, as options for both researchers and their subjects increased, more attention was focused on the rights and obligations of participants on both sides of the research relationship. Investigators became more aware of the costs and benefits associated with their research programs, and subjects became more curious about the nature of research and what could be reasonably expected from their participation. This paper reviews the evolution of the doctrine of informed consent in biomedical research and the development of rules and guidelines for the conduct of research in the United States, for the benefit of both researchers and their human subjects.
How Do Women Decide? Accepting or Declining BRCA1/2 Testing in a Nationwide Clinical Sample in the United States
Authors: Sankar Pamela , Wolpe Paul Root , Jones Nora L. , Cho Mildred
Published: April 2006

Objective: To examine the role of the practitioner, informed consent, and genetic counseling in genetic testing decisions and to assess their relative influence on women’s decision to have clinical BRCA1/2 testing. Methods: Qualitative study using in-depth open-ended interviews with 68 women who had considered clinical BRCA1/2 testing. Results: Slightly less than half of the women who had considered BRCA1/2 testing were found to have had a clear and preexisting desire to test or not to test, irrespective of practitioner attitude or advice. Conclusion: The decision to accept or decline genetic testing is the result of a complex process that goes beyond interactions between health care providers and patients, indicating a caution against exclusive reliance on informed consent or counseling encounters.
Association between Electrocardiographic Left Ventricular Hypertrophy with Strain Pattern and Left Ventricular Structure and Function
Authors: Ogah O.S. , Adebiyi A.A. , Oladapo O.O. , Aje A. , Ojji D.B. , Adebayo A.K. , Salako B.L. , Falase A.O.
Published: April 2006

Background and Purpose: Electrocardiographic left ventricular hypertrophy (LVH) with strain pattern has been documented as a marker for LVH. Its presence on the ECG of hypertensive patients is associated with poor prognosis. The study was carried out to assess the association of the electrocardiographic strain with left ventricular mass (LVM) and function in hypertensive Nigerians. Material and Methods: ECG as well as echocardiograms were performed in 64 hypertensive patients with ECG-LVH and strain pattern, 65 patients with ECG-LVH by Sokolow-Lyon (SL) voltage criteria and 62 normal controls. Results: The study showed that electrocardiographic left ventricular (LV) strain pattern is associated with dilated left atrium, larger LV internal dimensions and greater absolute and indexed LVM in hypertensive Nigerians compared with ECG-LVH by SL voltage criteria alone or normal controls. Conclusion: The findings of this study support the fact that the ECG strain pattern is associated with increased LVM and an increased risk of developing abnormal LV geometry.
Effects of Differential Genotyping Error Rate on the Type I Error Probability of Case-Control Studies
Authors: Moskvina Valentina , Craddock Nick , Holmans Peter , Owen Michael J. , O’Donovan Michael C.
Published: April 2006

Objectives: It is well known that genotyping error adversely affects the power of genetic case-control association studies but there is little research on its effects on type I error, and none that has addressed possible differences in genotype error rates between cases and controls. Methods: We used simulations to examine the influence of genotyping error on the type I error probability given by case-control studies. The effect of genotyping error on the magnitude of type I error was explored for a single marker of varying minor allele frequency (MAF), and for haplotypic tests based on two markers with varying MAF and linkage disequilibrium (LD) measure r2. Results: We show that even with low genotyping error rates (<0.01), systematic differences in the error rate between samples can result in type I error rates substantially above 0.05. The effect was maximal for markers with small MAF, markers in strong LD, and where a common allele is more frequently misclassified as a rare allele than vice versa. The problem was also exacerbated by the use of large samples. Conclusions: Our results show that small differential genotyping error rates between cases and controls pose significant problems for association analyses. Differential genotyping error rates are particularly likely to arise where genotype data are combined from multiple sites, or where case genotypes are examined against archived reference population cohort genotypes that are being generated in several countries. Although these strategies may be necessary to obtain adequately powered samples, our data show the importance of stringent quality control. Furthermore, associations based on rare haplotypes should be treated with caution.
Tryptase as Severity Marker in Drug Provocation Tests
Authors: Komericki P. , Arbab E. , Grims R. , Kränke B. , Aberer W.
Published: April 2006

Background: In the absence of objective symptoms, it is difficult to assess an adverse reaction during drug provocation testing. We evaluated the value of serum tryptase levels to distinguish between positive, negative and, even more important, so-called ‘hysterical’ reactions (conversion symptoms). The latter are occasionally observed in drug provocation tests when the patient experiences ambiguous subjective symptoms. Methods: In a prospective single-center study, 303 patients underwent 785 drug provocation tests. Blood was taken for tryptase measurement on each test day before and after drug challenge, and the changes in serum tryptase levels in patients with no reactions were compared with those who experienced immediate reactions to a drug. Results: Thirty-four of 785 drug provocations were clinically judged as being positive. Despite objective symptoms, median serum tryptase values in the afternoon were even lower than baseline levels. However, this decrease was not statistically significant. In the 751 patients suffering no objective reactions, the median values of posttesting tryptase values were statistically significantly decreased as compared with pretesting values. Conclusions: The measurement of serum tryptase levels does not appear to be helpful to differentiate mild allergic or nonallergic reactions from ‘hysterical’ ones. The milder decrease in the group with objective drug reactions might indicate slight mast cell activation in some patients. More severe clinical drug reactions led to stronger mast cell degranulation. Mild reactions did not increase the tryptase levels consistently.
Cross-Sensitization between Poppy Seed and Buckwheat in a Food-Allergic Patient with Poppy Seed Anaphylaxis
Authors: Oppel Tilmann , Thomas Peter , Wollenberg Andreas
Published: April 2006

The opium poppy, Papaver somniferum L., is the source of both poppy seeds and opium. The commercially available seeds are widely used as ingredients for various kinds of food. IgE-mediated sensitization to poppy seeds is rare, but, if present, clinical symptoms are usually severe. Cross-sensitizations between poppy seeds and other food allergens have been described with sesame, hazelnut, rye grain and kiwi fruit. We report the case of a 17-year-old female with an apparently food-allergic reaction after ingestion of a poppy seed cake. Allergological workup revealed a poppy seed anaphylaxis and led to the identification of a novel cross-sensitization with buckwheat.
Type I Regulatory T Cells in Autoimmunity and Inflammatory Diseases
Authors: Veldman Christian , Nagel Angela , Hertl Michael
Published: April 2006

Regulatory T cells exert a critical role in controlling autoimmunity and maintaining peripheral tolerance. The best described regulatory T cells are the naturally occurring CD4+CD25+ regulatory T cells, which have been shown to be continuously produced within the thymus. Other T-cell subsets bearing suppressive capacity have been reported, including T-helper-3 cells (Th3) and type 1 regulatory T (Tr1) cells. Tr1 cells have been shown to be induced upon antigen exposure under certain tolerogenic conditions and are characterized by the production of the immunosuppressive cytokines IL-10 and TGF-β, while Th3 cells preferentially produce TGF-β upon induction by intestinal tolerance. Recent progress has been made in the characterization of Tr1 cells in terms of isolation and induction, respectively. The present review provides an overview of the presence of Tr1 cells in inflammation, infection and neoplastic disorders. Moreover, the relationship between different regulatory T cell subsets and their transcriptional control is discussed. The recent development of methods allowing the ex vivo expansion of regulatory T cells may be the first step towards a cellular therapy with regulatory T cells to control T-cell-mediated pathology in inflammatory disorders.
Current State and Perspectives of Dendritic Cell Vaccination in Cancer Immunotherapy
Authors: Farkas A. , Conrad C. , Tonel G. , Borbenyi Z. , Kemeny L. , Dobozy A. , Nestle F.O.
Published: April 2006

Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination.
Establishing a Minimal Erythema Concentration of Methyl Nicotinate for Optimum Evaluation of Anti-Inflammatories
Authors: Jumbelic L.C. , Liebel F.T. , Southall M.D.
Published: April 2006

Topical administration of chemicals such as methyl nicotinate that induce erythema have been employed to measure the effectiveness of formulations containing anti-inflammatory agents. Prior studies have utilized a single concentration of methyl nicotinate, between 36.5 and 100 mM, for all test subjects in evaluations of topical formulations. However, individuals have different thresholds of response to methyl nicotinate; thus, a single concentration may not be appropriate for all individuals and could result in the apparent lack of anti-inflammatory activity of the formulation being evaluated. In the current study, we evaluated the use of a minimal erythema concentration (MEC) of methyl nicotinate, defined as the lowest concentration that produces a complete and even erythema at the test site, compared with a 36.5-mM concentration of methyl nicotinate. Hydroalcoholic gels containing the nonsteroidal anti-inflammatory drug ibuprofen were compared with placebo. Diffuse reflectance spectroscopy was employed to measure differences in cutaneous inflammatory response between the control (placebo)-treated group and the ibuprofen-treated group. When chemical erythema was induced using an MEC of methyl nicotinate, greater reductions in erythema were seen in ibuprofen-treated sites compared with sites treated with a 36.5-mM concentration of methyl nicotinate. In conclusion, for an accurate assessment method of erythema induced by methyl nicotinate, consideration should be given to determining the extent of response of an erythema-producing agent on an individual basis. An MEC of methyl nicotinate should be determined and employed for each individual to obtain more consistent and reliable efficacy results of anti-inflammatory activity.
Treatment of Head and Neck Dermatitis with Ciclopiroxolamine Cream – Results of a Double-Blind, Placebo-Controlled Study
Authors: Mayser Peter , Kupfer Jörg , Nemetz Diana , Schäfer Ute , Nilles Martin , Hort Wiebke , Gieler Uwe
Published: April 2006

In atopic dermatitis, microbial allergens may be pathogenetically significant. Apart from Staphyloccocus aureus, these are primarily lipophilic Malassezia yeasts. They are particularly involved in the pathogenesis of head and neck dermatitis (HND), a special form of atopic dermatitis, which is often difficult to treat. Fifty patients (21 men, 29 women) with moderate to severe HND of at least 6 months’ duration were included in a prospective double-blind study. All of them showed at least 10% involvement of the head-neck region. The severity of disease was evaluated by Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI) for the head-neck region and a pruritus score. IgE antibodies to Malassezia sympodialis and/or Malassezia furfur (at least CAP class 1) were a prerequisite for study enrollment. Either 1% ciclopiroxolamine cream (Batrafen; Aventis Pharma, Bad Soden, Germany) or the corresponding base cream were thinly applied to the affected areas twice daily for 28 days. Sixteen patients in the ciclopiroxolamine group and 13 patients in the placebo group completed the study. To assess the change in severity of atopic eczema, IGA differences between the individual measuring points were determined for all patients. There were significant differences in the IGA score change between the ciclopiroxolamine group and the placebo group, from t3 to t4, and over the total period. Similar, but not significant, changes were observed with the EASI score, in terms of affected skin area and itching. The present study is the first to examine the effect of antifungal single-drug therapy with a cream containing ciclopiroxolamine on the course of HND. The study medication was found to be significantly effective. To optimize this effect, suitable patients selected in terms of fungal load, specific IgE, prick test and particularly atopy patch test for Malassezia antigens could receive combined treatment with antimycotic-containing shampoos and/ or short-term systemic antimycotic therapy in severe cases.
Relationship between Symptoms and Quality of Life in a Sarcoidosis Population
Authors: Michielsen Helen J. , Peros-Golubicic Tatjana , Drent Marjolein , De Vries Jolanda
Published: April 2006

Background: As sarcoidosis is a multisytemic disorder, patients may suffer from various symptoms. The relationship between frequently reported symptoms and quality of life (QOL) has not yet been studied. Objectives: The aim of the present cross-sectional study was to examine the predictive value of the most frequently reported subjective symptoms on QOL after controlling for demographic variables and clinical parameters. Methods: A cross-sectional study was conducted at an outpatient pulmonary clinic in Zagreb, Croatia. One hundred and fifty outpatients with sarcoidosis were seen between January 2002 and May 2004. Symptoms were assessed with a symptom inventory questionnaire, and QOL was measured using the World Health Organization Quality of Life Assessment Instrument. Clinical parameters were derived from the patients’ medical files. Regression analyses were performed to examine the predictive value of symptoms on QOL. Results: The four most frequently mentioned symptoms were fatigue, breathlessness, reduced exercise capacity and arthralgia. In various combinations, being female, using corticosteroids and fatigue predicted the QOL domains physical and psychological health as well as level of independence. Con- clusions: Fatigue appeared to be the most important symptom in predicting various QOL domains after controlling for demographics, disease stage and clinical parameters. Therefore, considering improvement in the patients’ QOL, it is recommended to focus not only on objective health parameters, but also on fatigue in the management of sarcoidosis.
Rotation Frequency of Human Bronchial and Nasal Epithelial Spheroids as an Indicator of Mucociliary Function
Authors: Gamarra Fernando , Bergner Albrecht , Stauss Elisabeth , Stocker Ingrid , Grundler Stefan , Huber Rudolf Maria
Published: April 2006

Background: We evaluated a new in vitro model for mucociliary transport function. Spheroids of human respiratory epithelium show beating cilia at their surface. When cultured in their own mucus, spheroids can rotate along their axis due to coordinated ciliary beating. Objective and Methods: To assess whether this setup yields meaningful results we measured rotation frequency (RF) of human bronchial or nasal epithelial spheroids under different temperatures and concentrations of isoproterenol. Isoproterenol was administered either as caged compound releasing active isoproterenol after illumination with UV light, or through a permeable membrane in a two-chamber system. Results: Under stable conditions, RF remained constant over 200 min. Between 27 and 35°C, there was a temperature-dependent increase: RF27°C = 0.27 ± 0.08 s–1, and RF37°C = 0.43 ± 0.10 s–1 (means ± SEM). Isoproterenol (10–5, 10–4 and 10–3 mmol/l) induced concentration-dependent increases in RF (9, 20 and 25%, respectively; medians) if applied in the two-chamber system. The experiments with caged isoproterenol did not yield conclusive results, probably because the byproducts from photolysis negatively affected ciliary function. The transport velocity at the surface of bronchial and nasal spheroids was estimated to be 2.96 and 3.62 mm/min (medians), respectively, which is in the same range as mucus transport velocity measured in vivo in humans. Conclusions: This setup can be used to study mucociliary transport function under controlled conditions in vitro, in particular as RF is likely to reflect not only ciliary beat frequency, but also the coordination of ciliary beating and the properties of the mucus.
N-Terminal Proteolysis of the Endothelin B Receptor Abolishes Its Ability to Induce EGF Receptor Transactivation and Contractile Protein Expression in Vascular Smooth Muscle Cells
Authors: Grantcharova Evelina , Reusch H. Peter , Grossmann Solveig , Eichhorst Jenny , Krell Hans-Willi , Beyermann Michael , Rosenthal Walter , Oksche Alexander
Published: April 2006

Objective—

The extracellular N terminus of the endothelin B (ET
B
) receptor is cleaved by a metalloprotease in an agonist-dependent manner, but the physiological role of this N-terminal proteolysis is not known. In this study, we aimed to determine the functional role of the ET
B
receptor and of its N-terminal cleavage in vascular smooth muscle cells (VSMCs).

Methods and Results—

VSMCs expressing either the full-length ET
B
receptor or an N-terminally truncated ET
B
receptor (corresponding to the N-terminally cleaved receptor) were analyzed for ligand-induced mitogen-activated protein kinase activation and expression of contractile proteins. In VSMCs expressing the full-length ET
B
receptor, IRL1620 (an ET
B
-selective agonist) induced a biphasic extracellular signal-regulated kinase 1/2 (ERK1/2) activation and increased expression of contractile proteins (smooth muscle myosin-1 [SM-1]/SM-2, SM22α, and α-actin). Interestingly, the second phase of ERK1/2 activation required metalloprotease activity, epidermal growth factor (EGF) receptor transactivation, and predominantly activation of G
i
proteins. In contrast, in VSMCs expressing N-terminally truncated ET
B
receptors, IRL1620 did not elicit EGF transactivation and failed to increase contractile protein expression.

Conclusions—

This study is the first to show that stimulation of full-length ET
B
receptors promotes expression of contractile proteins and may thus participate in the differentiation of VSMCs.
AMP-Activated Protein Kinase Is Involved in Endothelial NO Synthase Activation in Response to Shear Stress
Authors: Zhang Yingjia , Lee Tzong-Shyuan , Kolb Erik M. , Sun Kai , Lu Xiao , Sladek Frances M. , Kassab Ghassan S. , Garland Theodore , Shyy John Y.-J.
Published: April 2006

Objective—

The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK–eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner).

Methods and Results—

By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice.

Conclusions—

Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone.
Abnormal Interactions of Calsequestrin With the Ryanodine Receptor Calcium Release Channel Complex Linked to Exercise-Induced Sudden Cardiac Death
Authors: Terentyev Dmitry , Nori Alessandra , Santoro Massimo , Viatchenko-Karpinski Serge , Kubalova Zuzana , Gyorke Inna , Terentyeva Radmila , Vedamoorthyrao Srikanth , Blom Nico A. , Valle Giorgia , Napolitano Carlo , Williams Simon C. , Volpe Pompeo , Priori Silvia G. , Gyorke Sandor
Published: April 2006

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (
RyR2
) and cardiac calsequestrin (
CASQ2
) genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact as parts of a multimolecular Ca
2+
-signaling complex; however, direct evidence for such interactions and their potential significance to myocardial function remain to be determined. We identified a novel CASQ2 mutation in a young female with a structurally normal heart and unexplained syncopal episodes. This mutation results in the nonconservative substitution of glutamine for arginine at amino acid 33 of CASQ2 (R33Q). Adenoviral-mediated expression of CASQ2
R33Q
in adult rat myocytes led to an increase in excitation–contraction coupling gain and to more frequent occurrences of spontaneous propagating (Ca
2+
waves) and local Ca
2+
signals (sparks) with respect to control cells expressing wild-type CASQ2 (CASQ2
WT
). As revealed by a Ca
2+
indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized myocytes, the increased occurrence of spontaneous Ca
2+
sparks and waves was associated with a dramatic decrease in intra-SR [Ca
2+
]. Recombinant CASQ2
WT
and CASQ2
R33Q
exhibited similar Ca
2+
-binding capacities in vitro; however, the mutant protein lacked the ability of its WT counterpart to inhibit RyR2 activity at low luminal [Ca
2+
] in planar lipid bilayers. We conclude that the R33Q mutation disrupts interactions of CASQ2 with the RyR2 channel complex and impairs regulation of RyR2 by luminal Ca
2+
. These results show that intracellular Ca
2+
cycling in normal heart relies on an intricate interplay of CASQ2 with the proteins of the RyR2 channel complex and that disruption of these interactions can lead to cardiac arrhythmia.
Thrombin and NAD(P)H Oxidase–Mediated Regulation of CD44 and BMP4-Id Pathway in VSMC, Restenosis, and Atherosclerosis
Authors: Vendrov Aleksandr E. , Madamanchi Nageswara R. , Hakim Zeenat S. , Rojas Mauricio , Runge Marschall S.
Published: April 2006

To characterize novel signaling pathways that underlie NAD(P)H oxidase–mediated signaling in atherosclerosis, we first examined differences in thrombin-induced gene expression between wild-type and p47phox
−/−
(NAD[P]H oxidase–deficient) VSMC. Of the 9000 genes analyzed by cDNA microarray method at the G
1
/S transition point, 76 genes were similarly and significantly modulated in both the cell types, whereas another 22 genes that encompass various functional groups were regulated in NAD(P)H oxidase–dependent manner. Among these 22 genes, thrombin-induced NAD(P)H oxidase–mediated regulation of Klf15, Igbp1, Ak4, Adamts5, Ech1, Serp1, Sec61a2, Aox1, Aoh1, Fxyd5, Rai14, and Serpinh1 was shown for the first time in VSMC. The role of NAD(P)H oxidase in the regulation of a subset of these genes (CD44, BMP4, Id1, and Id3) was confirmed using modulators of reactive oxygen species (ROS) generation, a ROS scavenger and in gain-of-function experiments. We then characterized regulation of these genes in restenosis and atherosclerosis. In both apoE
−/−
mice and in a mouse vascular injury model, these genes are regulated in NAD(P)H oxidase–dependent manner during vascular lesion formation. Based on these findings, we propose that NAD(P)H oxidase–dependent gene expression in general, and the CD44 and BMP4-Id signaling pathway in particular, is important in restenosis and atherosclerosis.
Feedback and Cognition in Arm Motor Skill Reacquisition After Stroke
Authors: Cirstea C.M. , Ptito A. , Levin M.F.
Published: April 2006

Background and Purpose—

A debated subject in stroke rehabilitation relates to the best type of training approach for motor recovery. First, we analyzed the effects of repetitive movement practice in 2 feedback conditions (knowledge of results [KR]; knowledge of performance, [KP]) on reacquisition of reaching. Second, we evaluated the impact of cognitive impairment on motor relearning ability.

Methods—

A randomized controlled clinical trial was conducted in Montreal-area rehabilitation centers between 1998 and 2003 with 37 patients with chronic hemiparesis. Patients were randomly assigned to 3 groups: (1) KR (n=14) practiced a reaching task involving 75 repetitions per day, 5 days per week for 2 weeks, with 20% KR about movement precision; (2) KP (n=14) trained on the same task and schedule as KR but with faded KP about joint motions; and (3) control (C; n=9) practiced a nonreaching task. Physical (motor impairment, function) and kinematic (movement time, precision, segmentation, variability) variables were assessed before and after (immediately, 1 month) practice. Cognitive functions (memory, attention, mental flexibility, planning) were also evaluated.

Results—

Kinematic gains in KR (precision) and KP (time, variability) exceeded those in C and depended on memory and mental flexibility deficits. In KP, more severely impaired patients made the most clinical gains (>2×C), which were related to memory and planning abilities.

Conclusions—

Use of KP during repetitive movement practice resulted in better motor outcomes. Stroke severity together with cognitive impairments are important factors for choosing motor rehabilitation interventions after stroke.
An Exploration of Spending Behaviors among Japanese Tourists
Authors: Rosenbaum Mark S. , Spears Daniel L.
Published: April 2006

This article provides a two-part, exploratory analysis of planned spending on shopping, dining, and other recreational activities among Japanese tourists in Hawaii. The empirical findings from the first study reveal that Japanese tourists primarily plan to engage in duty-free shopping during their stay in Hawaii. In contrast, American tourists plan to engage in cultural activities and fine dining opportunities during their Hawaiian vacation. A second study was used to explore the propensity of Japanese tourists in Hawaii to shop at both high-end boutiques and discounted retail outlets. The results of a two-step cluster analysis reveal that Japanese tourists may be classified into two exclusive groups, shopping enthusiasts and nonshoppers. The data support the conclusion that shopping enthusiasts plan to patronize three types of retail outlets in Hawaii: duty-free stores, factory outlets, and designer boutiques. Managerial implications and directives for future theoretical development are provided.
A Model of Multidestination Travel: Implications for Marketing Strategies
Authors: Tussyadiah Iis P. , Kono Tatsuhito , Morisugi Hisa
Published: April 2006

Because tourists derive utility from the enjoyment of destination characteristics, Lancaster's approach is putatively appropriate to address the particular structure of the tourism industry. Most research efforts regarding tourism destination, including those applying Lancaster's model, specifically address the choice of a single destination. This article is intended to explain multiple destination choice using Lancaster's characteristics model and a discussion of model implications of some marketing strategies for destinations as well as for tour operators. The model developed herein explains that packages of multiple destinations can create preferable combinations of characteristics for certain travelers. Furthermore, the model provides useful strategies for tour operators in combining destinations into a travel menu or package.
Reference Group Influences among Chinese Travelers
Authors: Hsu Cathy H. C. , Kang Soo K. , Lam Terry
Published: April 2006

Interpersonal influence is known to contribute to an individual's psychological formation (e.g., personal value, norm, attitude, perception). Reference group influence in the services sector, however, has received limited attention, with most works conducted in the setting of tangible products, not of services. In particular, reference group influences are exerted on a traveler when communication among group members provides the opportunity to share direct experiences of others about a particular destination or service and/or induces the selection of a destination or other travel services. Therefore, the purpose of the study was to segment travelers based on their perceptions of various reference groups'influences about visiting Hong Kong as a destination and to profile each segment according to travelers' benefits sought, attitudes, behaviors, and sociodemographic characteristics. A Two Step ® cluster analysis generated three distinctive segments with different benefits sought, perceived behavioral control, attitudes, and behavioral intentions. Marketing implications for each segment were provided.
Toward a Destination Visitor Attendance Estimation Model: Whistler, British Columbia, Canada
Authors: Kelly Joe , Williams Peter W. , Schieven Arlene , Dunn Ian
Published: April 2006

The nongated and multiple entry point character of many destinations makes it difficult to accurately estimate visitor attendance. This research describes a modeling procedure for credibly estimating tourist attendance in such destinations. It demonstrates the application of the approach in the mountain tourism destination of Whistler, British Columbia, Canada. This article suggests that while the model is capable of providing timely and relevant attendance estimates for destination managers, its credibility is dependent on access to a substantive base of both audited attendance data concerning anchored visitors and specific behavioral information collected on a systematic basis from footloose visitors in the destination. The findings are offered as a contribution to the growing literature on tourism destination and special event visitor attendance estimation and performance assessment.
Promoting Destinations via Film Tourism: An Empirical Identification of Supporting Marketing Initiatives
Authors: Hudson Simon , Ritchie J. R. Brent
Published: April 2006

Film tourism is a growing phenomenon worldwide, fueled by both the growth of the entertainment industry and the increase in international travel. This article proposes a model for exploiting film tourism marketing opportunities. It identifies the optimum marketing factors that encourage film tourists to visit destinations that appear (or are depicted) in the movies. Factor analysis reveals four types of marketing activities in which destinations can engage to promote film tourism: proactive efforts to encourage producers and studios to film at the location, efforts to generate media publicity around the film and its location, marketing activities that promote the film location after production, and peripheral marketing activities that leverage film tourism potential. Results of a stepwise multiple regression analysis indicate a high correlation between film tourism success and one of the four factors: the proactive efforts of destinations that encourage producers and studios to film at their location.
The Need for Ethical Reflection in Engineering Design
Authors: van de Poel Ibo , van Gorp A. C.
Published: April 2006

The authors explore whether the need for ethical reflection on the part of designing engineers is dependent on the type of design process. They use Vincenti's (1992) distinction between normal and radical design and different levels of design hierarchy. These two dimensions are coupled with the concept of ill-structured problems, which are problems in which possible solutions cannot be ordered on a scale from better to worse. Design problems are better structured at lower hierarchical levels and in cases of normal design. Better structured design problems require less ethical reflection on the part of designing engineers if such situations are characterized by the existence of generally accepted normative frameworks. Engineers could then deal with moral problems within the bounds of such frameworks and without the need for further reflection. On the basis of a number of empirical cases, the authors explore whether these ideas hold water. They discuss four cases ranging from a high-level radical design process to a low-level normal design process.
Ethics, Culture, and Structure in the Negotiation of Straw Bale Building Codes
Authors: Henderson Kathryn
Published: April 2006

This study explores building code negotiation between straw bale advocates’ ecology-oriented values and health and safety values that underlie building codes in general by focusing on how values and ethics are articulated and embodied in practice and discourse in the two states where straw bale building standards were first initiated. The local, contingent nature of interactions, grounded in particular practices, material culture, and written and visual texts in which values were embedded, coupled with organizational factors contributed to strategies for a prescriptive code in Arizona and for a performance code in New Mexico. Examination of situated practice in standards development for unconventional materials that may not fit well with practices based on conventional technologies sheds light on how norms associated with the ethics of safe building are enmeshed in existing practice where they can be taken for granted as ethical absolutes and illustrates the kinds of insights available through paying attention to ethics in practice.