bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceived discrimination among men and women with normal weight and obesity. A population-based study from Sweden
Authors: Hansson Lena M. , Näslund Erik , Rasmussen Finn
Published: June 2010

Aims: We examined whether men and women with obesity reported different types of discrimination to a greater extent than those with normal weight, and explored whether these associations were modified by socioeconomic position. Method: National representative sample of men and women, with normal weight (n = 2,000), moderate obesity (n = 2,461) and severe obesity (n = 557). Participants were identified in a yearly population-based survey (1996—2006) and data on perceived discrimination and potential confounding factors were measured in 2008. Logistic regression models tested whether obesity was associated with perceived lifetime, workplace, healthcare and interpersonal discrimination. Results: The overall response rate was 56%. For men, moderate obesity was associated with workplace discrimination, while severely obese women were more likely to report this sort of discrimination than normal weight women. Severely obese individuals were twice as likely to report healthcare discrimination than normal weight individuals. Women, regardless of weight status group, were in turn twice as likely to report healthcare discrimination as men. Women with severe obesity were significantly more likely to report interpersonal discrimination compared with normal weight women. Socioeconomic position modified the association between weight status and healthcare discrimination. Highly educated individuals with moderate and severe obesity were more likely to report healthcare discrimination than their normal weight counterparts, whereas low educated individuals with normal weight, moderate and severe obesity were equally likely to report discrimination. Conclusions: In this large, population-based study, discrimination was more likely to be reported by obese individuals compared with those of normal weight. The associations, however, varied according to gender and socioeconomic position.
Should I Stay or Should I Go?
Authors: Carey Malcolm
Published: June 2010

This article critically explores some implications of service user participation within qualitative social work research. There are three main sections which concentrate upon practical impediments, ethical implications and political dilemmas attached to a participative hegemony. Among other arguments it is proposed that participation has become part of complex, yet deeply problematic, political and ethical processes; in which early drives for user emancipation have been compromised and supplanted by a fused market and liberal-humanistic or democratic discourse dominated by rhetoric, and government, institutional and professional interests. For more independent social work researchers, or potential researchers including practitioners, the methodology is also often inaccessible and largely unattainable. The article encourages critical scepticism regarding participation, and suggests that it is unlikely it can counter inequitable relations between researchers and participants; indeed it may substantiate or aggravate them further. Some possible forms of counter-hegemonic participative resistance are briefly noted.
Breaching Private Life with Authority
Authors: May-Chahal Corinne , Har Man Kwong
Published: June 2010

In the context of debates about social work's knowledge base and its essential role this article focuses on how core social work activity might be identified and offers some preliminary suggestions as to what may constitute it. Drawing on a naturally occurring conversation between a social worker and two service users two claims are made. First, that despite concerns with uncertainty in late modernity, some features of interaction remain inherently certain. These include (1) Materiality, the setting and its participants are taken as real; (2) Identity, participants engage on the basis that they are who they say they are; (3) Taken for granted aspects of social organization; for example, that all participants can hold a conversation until shown otherwise; and, (4) Historicity, referring to a preexisting set of accounts, justifications, reasons and communicative orderings. Second, these ‘background expectancies’ provide the resource for topic seeking and non-routine practices that may be necessary to social work such as ‘authorized breaching’ of the domestic sphere and private life.
Fiber-optic-based displacement transducer to measure bridge deflections
Authors: Rodrigues Carlos , Félix Carlos , Figueiras Joaquim
Published: June 2010

Structural health monitoring is an emerging area of strategic engineering with a great potential for extending the service life of civil infrastructures and reducing their maintenance costs. In spite of the deflection measurement being one of the main parameters for assessing the real state of a bridge, the measurement techniques and the existing deflection transducers often do not respond to the necessities of structural monitoring. Therefore, a novel displacement transducer to measure bridge deflections based on noncontact measurement technique supported by the liquid leveling method was developed. The measurement of bridge deflections is performed using a hydrostatic level position along the structure as an absolute reference and without any external physical reference to the ground. Fiber-optic sensors based on fiber Bragg grating technology are the sensing units of this original bridge deflection transducer. The transducer performance obtained in a set of experimental tests has shown an accurate linear response and a very good behavior under the environmental conditions simulated in a climatic chamber. A field application at the Lezíria Bridge across the Tagus River, Portugal, evinces the ability of the present transducer to be applied in both temporary and permanent structural health monitoring systems with automatic and remote data acquisition.
Experimental verification of the damage localization procedure based on modal filtering
Authors: Mendrok Krzysztof , Uhl Tadeusz
Published: June 2010

Modal filtering has numerous applications in the analysis of object dynamics. One possible use of this technique, recently presented in the literature, is damage detection. The method has several advantages but one major disadvantage — it does not provide any information about damage location. This article presents a solution that eliminates this drawback. The proposed method is tested first on a numerical example. Next, it is verified on the laboratory measurement data, and finally, it is applied to a real structure — a footbridge over a street in Krakow.
Effect of HIV Infection on Body Composition and Fat Distribution in Rwandan Women
Authors: Mutimura Eugene , Anastos Kathryn , Zheng Lin  , Cohen Mardge , Binagwaho Agnes , Kotler Donald P.
Published: June 2010

Objective: To assess the association of HIV infection with body weight and composition in Rwandan women. Design: Body weight and composition, the latter determined by bioelectrical impedance analysis (BIA) and by anthropometry, were compared in 620 HIV-positive and 211 HIV-negative participants. Associations of HIV with body composition were assessed, and t tests compared the groups. Results: HIV-positive women were younger (-7.0 years, P < .001) and shorter (-2.1 cm, P < .001). Mean body weight, body mass index (BMI), total body fat, and waist-to-hip ratio (WHR) were similar. Mean fat-free mass was 2.5% greater in HIV-negative participants, and 19% of HIV-positive group had BMI <18.5 kg/m2 versus 26% of the HIV-negative group (P < .05). CD4 counts and body composition were not associated. Conclusions: Malnutrition was common in this cohort of Rwandan women. However, HIV infection was not associated with nutritional status. Factors other than malnutrition may influence quality-of-life outcomes in HIV-infected Rwandan women. Initiatives to improve nutritional status should be population-wide and not restricted to the HIV-infected population.
Distribution of CCR5-Δ32, CCR2-64I, and SDF1-3’A in Guangxi Zhuang Population
Authors: Qijian Su  , Zhidan Mai  , Ning Zang  , Shuzhi Wu  , Xin Xiao  , Hao Liang
Published: June 2010

Background: To investigate the distribution of CCR5-Δ32, CCR2-64I, and SDF1-3’A alleles in Guangxi province Zhuang population. Method: A total of 180 healthy individuals and 150 HIV-positive patients were recruited. All individuals were genotyped for CCR5 polymorphism using polymerase chain reaction (PCR), and CCR2 and SDF1 polymorphism using PCR restriction fragment length polymorphisms (PCR-RFLPs). Results: No CCR5-Δ32 mutation was found. CCR2-64I frequency was 24.7% in the healthy group and 20.3% in the HIV-positive group, and SDF1-3’A was 30.6% and 29.3% in the 2 groups, respectively. There were no significances in the frequencies of CCR2-64I (χ2 = 1.795, P = .180) and SDF1-3’A (χ2 = 0.116, P = .733) between the 2 groups. Conclusions: The protective CCR5-Δ32 mutation is absent in the Zhuang population, but CCR2-64I and SDF1-3’A are relatively common and seem not to confer protection against HIV-1 infection. The results suggest that the Zhuang people may have a similar genetic susceptibility to HIV-1 infection with most other Chinese ethnic groups.
Validation of Rapid HIV Antibody Tests in 5 African Countries
Authors: Piwowar-Manning Estelle M. , Tustin Nancy B. , Sikateyo Physiwell , Kamwendo Debbie , Chipungu Chifundo , Maharaj Rashika , Mushanyu Jabulani , Richardson Barbra A. , Hillier Sharon , Brooks Jackson J.
Published: June 2010

The sensitivity and specificity of 3 rapid HIV antibody tests were assessed at 5 clinical trial sites in Africa and 1 site in the United States using a minimum of 100 HIV antibody positive samples and 100 HIV antibody negative samples at each site. The overall sensitivity and specificity for the OraSure OraQuick, Abbott Determine, and Trinity Unigold tests were 99.3%, 99.8%, and 98.5%, respectively, and 99.3%, 99.4%, and 99.5%, respectively. There were no instances at any site in which false-negative or false-positive results were obtained for the same sample on more than 1 rapid test kit. The results of this study provide assurance that for these diverse sites in Africa, the accuracy of these kits is quite good. Given the excellent accuracy, relatively fast turnaround time, and minimal infrastructure required, these rapid tests for HIV antibody provide a very attractive and accurate testing format.
HIV-1 Seroprevalence and Awareness of Mother-to-Child Transmission Issues Among Women Seeking Antenatal Care in Tamil Nadu, India
Authors: Firth Jacqueline , Jeyaseelan L. , Christina Sheeba , Vonbara Venisa , Jeyaseelan Visalaksi , Elan Sujitha , Abraham Sulochana , Joseph Inbakumar , David Shoba , Cu-Uvin Susan , Lurie Mark , Wanke Christine , Lionel Jessie
Published: June 2010

Background: Despite increasing availability of HIV-1 testing, education, and methods to prevent transmission, Indian women and their children remain at risk of acquiring HIV. We assessed the seroprevalence and awareness about HIV among pregnant women presenting to a private tertiary care hospital in South India. Methods: Seroprevalence was determined via enzyme-linked immunosorbent assay (ELISA) testing, and questionnaires were analyzed using chi-square statistics and odds ratios to look for factors associated with HIV positivity. Results: A total of 7956 women who presented for antenatal care were interviewed. Fifty-one women of the 7235 women who underwent HIV testing (0.7%) were found to be HIV positive. Awareness of mother-to-child transmission (MTCT) of HIV (64%), HIV transmission through breast milk (42%), and prevention of MTCT (13%) was low. Conclusions: There is a need to educate South Indian women about HIV to give them information and the means to protect themselves and their unborn children from acquiring HIV.
Viscosupplementation with hylan G-F 20 in patients with osteoarthrosis of the knee
Authors: Bert Jack M. , Waddell David D.
Published: June 2010

Viscosupplementation (VIS) is one of several treatment modalities for osteoarthritis of the knee. It is useful in the treatment of osteoarthritis when other methods of conservative care have failed and it may be a safer method of treatment than oral chemical therapy which can have significant side effects with even short-term usage. The biochemical effects of hyaluronic acid are incompletely understood, however there are several accepted modes of action which result in a positive clinical effect on the function of the knee joint. There is some evidence that hyaluronic acid preparations with a higher molecular weight may be more beneficial to the patient. It is commonly used after arthroscopic meniscectomy and or debridement of the knee in a patient with chondral disease. The clinical effects have been well documented in multiple studies in patients with mild to moderate osteoarthritis in study groups before or after arthroscopic surgery of the knee. Adverse events do occur and are easily treated with only rare case reports of systemic effects. Furthermore, there is some evidence that VIS can prolong the need for total knee arthroplasty in the older patient as well.
Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR
Authors: Klechevsky Eynav , Flamar Anne-Laure , Cao Yanying , Blanck Jean-Philippe , Liu Maochang , O'Bar Amy , Agouna-Deciat Olivier , Klucar Peter , Thompson-Snipes LuAnn , Zurawski Sandra , Reiter Yoram , Palucka A. Karolina , Zurawski Gerard , Banchereau Jacques
Published: June 2010

We evaluated human CD8+ T-cell responses generated by targeting antigens to dendritic cells (DCs) through various lectin receptors. We found the immunoreceptor tyrosine-based inhibitory motif-containing DC immunoreceptor (DCIR) to mediate potent cross-presentation. A single exposure to a low dose of anti-DCIR–antigen conjugate initiated antigen-specific CD8+ T-cell immunity by all human DC subsets including ex vivo–generated DCs, skin-isolated Langerhans cells, and blood myeloid DCs and plasmacytoid DCs. The delivery of influenza matrix protein (FluMP) through DCIR resulted in expansion of FluMP-specific memory CD8+ T cells. Enhanced specific CD8+ T-cell responses were observed when an antigen was delivered to the DCs via DCIR, compared with those induced by a free antigen, or antigen conjugated to a control monoclonal antibody or delivered via DC-SIGN, another lectin receptor. DCIR targeting also induced primary CD8+ T-cell responses against self (MART-1) and viral (HIV gag) antigens. Addition of Toll-like receptor (TLR) 7/8 agonist enhanced DCIR-mediated cross-presentation as well as cross-priming, particularly when combined with a CD40 signal. TLR7/8 activation was associated with increased expansion of the primed CD8+ T cells, high production of interferon-γ and tumor necrosis factor-α, and reduced levels of type 2–associated cytokines. Thus, antigen targeting via the human DCIR receptor allows activation of specific CD8+ T-cell immunity.
A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils
Authors: Massena Sara , Christoffersson Gustaf , Hjertström Elina , Zcharia Eyal , Vlodavsky Israel , Ausmees Nora , Rolny Charlotte , Li Jin-Ping , Phillipson Mia
Published: June 2010

During infection, chemokines sequestered on endothelium induce recruitment of circulating leukocytes into the tissue where they chemotax along chemokine gradients toward the afflicted site. The aim of this in vivo study was to determine whether a chemokine gradient was formed intravascularly and influenced intraluminal neutrophil crawling and transmigration. A chemokine gradient was induced by placing a macrophage inflammatory protein-2 (MIP-2)–containing (CXCL2) gel on the cremaster muscle of anesthetized wild-type mice or heparanase-overexpressing transgenic mice (hpa-tg) with truncated heparan sulfate (HS) side chains. Neutrophil-endothelial interactions were visualized by intravital microscopy and chemokine gradients detected by confocal microscopy. Localized extravascular chemokine release (MIP-2 gel) induced directed neutrophil crawling along a chemotactic gradient immobilized on the endothelium and accelerated their recruitment into the target tissue compared with homogeneous extravascular chemokine concentration (MIP-2 superfusion). Endothelial chemokine sequestration occurred exclusively in venules and was HS-dependent, and neutrophils in hpa-tg mice exhibited random crawling. Despite similar numbers of adherent neutrophils in hpa-tg and wild-type mice, the altered crawling in hpa-tg mice was translated into decreased number of emigrated neutrophils and ultimately decreased the ability to clear bacterial infections. In conclusion, an intravascular chemokine gradient sequestered by endothelial HS effectively directs crawling leukocytes toward transmigration loci close to the infection site.
Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug
Authors: Hu Jinsong , Handisides Damian R. , Van Valckenborgh Els , De Raeve Hendrik , Menu Eline , Vande Broek Isabelle , Liu Qian , Sun Jessica D. , Van Camp Ben , Hart Charles P. , Vanderkerken Karin
Published: June 2010

Hypoxia is associated with increased metastatic potential and poor prognosis in solid tumors. In this study, we demonstrated in the murine 5T33MM model that multiple myeloma (MM) cells localize in an extensively hypoxic niche compared with the naive bone marrow. Next, we investigated whether hypoxia could be used as a treatment target for MM by evaluating the effects of a new hypoxia-activated prodrug TH-302 in vitro and in vivo. In severely hypoxic conditions, TH-302 induces G0/G1 cell-cycle arrest by down-regulating cyclinD1/2/3, CDK4/6, p21cip-1, p27kip-1, and pRb expression, and triggers apoptosis in MM cells by up-regulating the cleaved proapoptotic caspase-3, -8, and -9 and poly ADP-ribose polymerase while having no significant effects under normoxic conditions. In vivo treatment of 5T33MM mice induces apoptosis of the MM cells within the bone marrow microenvironment and decreases paraprotein secretion. Our data support that hypoxia-activated treatment with TH-302 provides a potential new treatment option for MM.
Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced- intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-Hodgkin lymphoma: results of a phase 2 study
Authors: Bethge Wolfgang A. , Lange Thoralf , Meisner Christoph , von Harsdorf Stephanie , Bornhaeuser Martin , Federmann Birgit , Stadler Michael , Uharek Lutz , Stelljes Matthias , Knop Stefan , Wulf Gerald , Trenschel Rudolf , Vucinic Vladan , Dittmann Helmut , Faul Christoph , Vogel Wichard , Kanz Lothar , Bunjes Donald
Published: June 2010

Forty patients were enrolled in this phase 2 study combining radioimmunotherapy (RIT) using yttrium-90-ibritumomab-tiuxetan (15 MBq [0.4 mCi]/kg) with reduced-intensity conditioning (RIC) using fludarabine (90 mg/m2) and 2 Gy total body irradiation followed by allogeneic hematopoietic cell transplantation (HCT) from related (n = 13) or unrelated (n = 27) donors for the treatment of advanced non-Hodgkin lymphoma. Diagnoses were follicular lymphoma (n = 17), chronic lymphocytic leukemia (n = 13), mantle cell lymphoma (n = 8), marginal zone lymphoma (n = 1), and lymphoplasmacytic lymphoma (n = 1). Median age was 55 years (range, 34-68 years). All patients were high risk with refractory disease or relapse after preceding autologous HCT. No additional toxicities attributable to RIT were observed. Engraftment was rapid and sustained. Incidences of acute graft-versus-host disease 2-4 and chronic graft-versus-host disease were 43% and 53%, respectively. Kaplan-Meier–estimated nonrelapse mortality was 45% at 2 years. Twenty-two of 40 patients (55%) are alive, resulting in a Kaplan-Meier–estimated 2-year survival of 51% for all, 67% for follicular lymphoma, 49% for chronic lymphocytic leukemia, and 37% for mantle cell lymphoma patients. The combined use of RIT with RIC is feasible with acceptable toxicity, even in elderly and heavily pretreated patients. This study is registered at www.clinicaltrials.gov as #NCT00302757.
Usefulness of serum procalcitonin levels in pulmonary tuberculosis
Authors: Ugajin M. , Miwa S. , Shirai M. , Ohba H. , Eifuku T. , Nakamura H. , Suda T. , Hayakawa H. , Chida K.
Published: June 2010

There are very few data on serum procalcitonin (PCT) levels in pulmonary tuberculosis (PTB) patients who are negative for HIV.

We assessed serum PCT in consecutive patients diagnosed with pulmonary tuberculosis or community-acquired pneumonia (CAP) on admission to discriminate between PTB and CAP, and examined the value of prognostic factors in PTB.

102 PTB patients, 62 CAP patients, and 34 healthy volunteers were enrolled. Serum PCT in PTB patients was significantly lower than in CAP patients (mean±sd0.21±0.49versus4.10±8.68 ng·mL−1; p<0.0001). By receiver-operating characteristic curve analysis, serum PCT was an appropriate discrimination marker for PTB and CAP (area under the curve 0.866). PTB patients with ≥0.5 ng·mL−1(normal cut-off) had significantly shorter survival than those with <0.5 ng·mL−1(p<0.0001).

Serum PCT is not habitually elevated in HIV-negative PTB patients and is a useful biomarker for discriminating between PTB and CAP; however, when serum PCT is outside the normal range, it is a poor prognostic marker.
Harmonisation of TB control in the WHO European region: the history of the Wolfheze Workshops
Authors: Veen J. , Migliori G.B. , Raviglione M. , Rieder H.L. , Dara M. , Falzon D. , Kuyvenhoven J.V. , Schwoebel V. , Zaleskis R.
Published: June 2010

In 1990 a workshop was organised in the village of Wolfheze (the Netherlands), where experts discussed the critical interventions that would foster elimination of TB in Europe. This event has been followed by several more over the following two decades to become known as the “Wolfheze Workshops”. This article provides a brief overview of the history and the impact the Wolfheze Workshops have had on the commitment of European governments to standardise definitions, recording and reporting systems and, thus, permitted comparison of interventions and improving TB control across borders. The Wolfheze Workshops have been and still are an essential platform for this exchange of experiences, promoting common approaches.
Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP
Authors: Boeck L. , Eggimann P. , Smyrnios N. , Pargger H. , Thakkar N. , Siegemund M. , Marsch S. , Rakic J. , Tamm M. , Stolz D.
Published: June 2010

Ventilator-associated pneumonia (VAP) affects mortality, morbidity and cost of critical care. Reliable risk estimation might improve end-of-life decisions, resource allocation and outcome. Several scoring systems for survival prediction have been established and optimised over the last decades. Recently, new biomarkers have gained interest in the prognostic field. We assessed whether midregional pro-atrial natriuretic peptide (MR-proANP) and procalcitonin (PCT) improve the predictive value of the Simplified Acute Physiologic Score (SAPS) II and Sequential Related Organ Failure Assessment (SOFA) in VAP.

Specified end-points of a prospective multinational trial including 101 patients with VAP were analysed. Death <28 days after VAP onset was the primary end-point.

MR-proANP and PCT were elevated at the onset of VAP in nonsurvivors compared with survivors (p = 0.003 and p = 0.017, respectively) and their slope of decline differed significantly (p = 0.018 and p = 0.039, respectively). Patients with the highest MR-proANP quartile at VAP onset were at increased risk for death (log rank p = 0.013). In a logistic regression model, MR-proANP was identified as the best predictor of survival. Adding MR-proANP and PCT to SAPS II and SOFA improved their predictive properties (area under the curve 0.895 and 0.880).

We conclude that the combination of two biomarkers, MR-proANP and PCT, improve survival prediction of clinical severity scores in VAP.
The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement
Authors: Solovic I. , Sester M. , Gomez-Reino J.J. , Rieder H.L. , Ehlers S. , Milburn H.J. , Kampmann B. , Hellmich B. , Groves R. , Schreiber S. , Wallis R.S. , Sotgiu G. , Schölvinck E.H. , Goletti D. , Zellweger J.P. , Diel R. , Carmona L. , Bartalesi F. , Ravn P. , Bossink A. , Duarte R. , Erkens C. , Clark J. , Migliori G.B. , Lange C.
Published: June 2010

Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB).

Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette–Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection withMycobacterium tuberculosis.

Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistentM. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB.

This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.
Valproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study
Authors: Scherpereel A. , Berghmans T. , Lafitte J.J. , Colinet B. , Richez M. , Bonduelle Y. , Meert A.P. , Dhalluin X. , Leclercq N. , Paesmans M. , Willems L. , Sculier J.P.
Published: June 2010

No treatment is recommended for patients with malignant mesothelioma (MM) failing after first-line cisplatin-based chemotherapy.In vitrodata suggested that valproic acid, a histone deacetylase inhibitor (HDACi), had a proapoptotic effect and synergised with doxorubicin to induce apoptosis in MM cells. Our primary end-point was to determine response rate of combined valproic acid and doxorubicin in patients with unresectable MM failing after platinum-based chemotherapy.

Treatment consisted of doxorubicin (60 mg·m-2) plus valproic acid. An interim analysis for response rate was planned after the first 16 registered patients. All the cases were centrally reviewed.

From July 2006 to March 2009, 45 eligible patients with pleural MM were registered. The majority of the patients were male (73%), had a performance status (PS) ≥80 (76%) and an epithelioid subtype (80%). There were seven partial responses (response rate 16%; 95% CI 3–25%), all in patients with PS 80–100. The best disease control rate was 36% (95% CI 22–51%). Two toxic deaths were observed (febrile neutropenia and cerebral thrombotic event), both in patients with poor PS (60–70).

Valproic acid, an HDACi, plus doxorubicin appeared an effective chemotherapy regimen in good PS (80–100) patients with refractory or recurrent MM, for which no standard therapy was available.
Increased Rho-kinase expression and activity and pulmonary endothelial dysfunction in smokers with normal lung function
Authors: Duong-Quy S. , Dao P. , Hua-Huy T. , Guilluy C. , Pacaud P. , Dinh-Xuan A.T.
Published: June 2010

Endothelial dysfunction is one of the main consequences of the toxic effects of cigarette smoke on the vascular system. Increasing evidence suggests that the small G-protein RhoA and its downstream effectors, the Rho-kinases (ROCKs), are involved in systemic endothelial dysfunction induced by cigarette smoke. This study aimed to evaluate the role of the RhoA/ROCKs pathway in pulmonary artery endothelial function in current smokers with normal lung function.

Lung tissues were obtained from nonsmokers and smokers who underwent lobectomy for lung carcinoma. Arterial relaxation in response to acetylcholine (ACh) was assessed in isolated pulmonary arterial rings. Protein expressions and activities of endothelial nitric oxide synthase (eNOS), ROCKs and the myosin phosphatase subunit 1 (MYPT-1) were sought.

Relaxation in response to ACh was significantly lower in smokers as compared with nonsmokers (n = 8 in each group), consistent with reduced eNOS activity in the former compared with the latter. eNOS protein expression remained, however, the same in both groups. Expression of ROCKs, guanosine triphosphate-RhoA and phosphorylated MYPT-1 were significantly increased in smokers compared with controls.

Pulmonary endothelial dysfunction is present in smokers whose lung function has not yet been impaired. Reduced activity of eNOS accounts at least in part for this endothelial dysfunction. Increased expression and activity of ROCKs accounts for another part through direct or indirect inhibition of the Rho-A/ROCKs pathway on nitric oxide synthesis and sustained pulmonary vasoconstriction through inhibition of myosin phosphatase.
Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension
Authors: Dahal B.K. , Kosanovic D. , Pamarthi P.K. , Sydykov A. , Lai Y-J. , Kast R. , Schirok H. , Stasch J-P. , Ghofrani H.A. , Weissmann N. , Grimminger F. , Seeger W. , Schermuly R.T.
Published: June 2010

An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH.

This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH.

Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCsin vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells.

Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.
Antibodies induced with recombinant VP1 from human rhinovirus exhibit cross-neutralisation
Authors: Edlmayr J. , Niespodziana K. , Popow-Kraupp T. , Krzyzanek V. , Focke-Tejkl M. , Blaas D. , Grote M. , Valenta R.
Published: June 2010

Human rhinoviruses (HRVs) are the major cause of the common cold and account for 30–50% of all acute respiratory illnesses. Although HRV infections are usually harmless and invade only the upper respiratory tract, several studies demonstrate that HRV is involved in the exacerbation of asthma.

VP1 is one of the surface-exposed proteins of the viral capsid that is important for the binding of rhinoviruses to the corresponding receptors on human cells. Here we investigated its potential usefulness for vaccination against the common cold.

We expressed VP1 proteins from two distantly related HRV strains, HRV89 and HRV14, inEscherichia coli. Mice and rabbits were immunised with the purified recombinant proteins.

The induced antibodies reacted with natural VP1 and with whole virus particles as shown by immunoblotting and immunogold electron microscopy. They exhibited strong cross-neutralising activity for different HRV strains. Therefore, recombinant VP1 may be considered a candidate HRV vaccine to prevent HRV-induced asthma exacerbations.
Lung exposure to nanoparticles modulates an asthmatic response in a mouse model
Authors: Hussain S. , Vanoirbeek J.A.J. , Luyts K. , De Vooght V. , Verbeken E. , Thomassen L.C.J. , Martens J.A. , Dinsdale D. , Boland S. , Marano F. , Nemery B. , Hoet P.H.M.
Published: June 2010

The aim of this study was to investigate the modulation of an asthmatic response by titanium dioxide (TiO2) or gold (Au) nanoparticles (NPs) in a murine model of diisocyanate-induced asthma.

On days 1 and 8, BALB/c mice received 0.3% toluene diisocyanate (TDI) or the vehicle acetone–olive oil (AOO) on the dorsum of both ears (20 μL). On day 14, the mice were oropharyngeally dosed with 40 μL of a NP suspension (0.4 mg·mL−1(∼0.8 mg·kg−1) TiO2or Au). 1 day later (day 15), the mice received an oropharyngeal challenge with 0.01% TDI (20 μL). On day 16, airway hyperreactivity (AHR), bronchoalveolar lavage (BAL) cell and cytokine analysis, lung histology, and total serum immunoglobulin E were assessed.

NP exposure in sensitised mice led to a two- (TiO2) or three-fold (Au) increase in AHR, and a three- (TiO2) or five-fold (Au) increase in BAL total cell counts, mainly comprising neutrophils and macrophages. The NPs taken up by BAL macrophages were identified by energy dispersive X-ray spectroscopy. Histological analysis revealed increased oedema, epithelial damage and inflammation.

In conclusion, these results show that a low, intrapulmonary doses of TiO2or Au NPs can aggravate pulmonary inflammation and AHR in a mouse model of diisocyanate-induced asthma.
Exercise is associated with improved asthma control in adults
Authors: Dogra S. , Kuk J.L. , Baker J. , Jamnik V.
Published: June 2010

Global asthma control levels are suboptimal. The influence of regular exercise on asthma control is unclear.

We assessed the effects of a 12-week supervised exercise intervention followed by 12 weeks of self-administered exercise on adults with partially controlled asthma (n = 21) and matched controls (n = 15). Assessments were conducted at baseline and week 12 for both the exercise and control group, and again at week 24 for the exercise group.

There was a significant treatment effect on asthma control in the exercise group, as measured by the Asthma Control Questionnaire (ACQ), from baseline to week 12, compared with the control group. A clinically significant improvement (0.5 increase in ACQ score) was observed for asthma quality of life and ACQ in the exercise group from baseline to week 12. There was a significant improvement in aerobic fitness from baseline to week 24 in the exercise group.

In conclusion, a 12-week supervised exercise intervention led to improvements in asthma control and quality of life in partially controlled asthmatics motivated to exercise. These improvements were maintained, while aerobic fitness and perceived asthma control significantly improved over an additional 12 weeks of self-administered exercise. These findings indicate that a structured exercise intervention can improve asthma control.
Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study
Authors: Ghofrani H.A. , Hoeper M.M. , Halank M. , Meyer F.J. , Staehler G. , Behr J. , Ewert R. , Weimann G. , Grimminger F.
Published: June 2010

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III.

In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0–2.5 mgt.i.d.titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points.

Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm−5from baseline (709 dyn·s·cm−5; p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%.

These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.
Determinants of change in airway reactivity over 11 years in the SAPALDIA population study
Authors: Curjuric I. , Zemp E. , Dratva J. , Ackermann-Liebrich U. , Bridevaux P-O. , Bettschart R.W. , Brutsche M. , Frey M. , Gerbase M.W. , Knöpfli B. , Künzli N. , Pons M. , Schwartz J. , Schindler C. , Rochat T. ,   the SAPALDIA team
Published: June 2010

We investigated determinants of change in bronchial reactivity in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA), a population-based cohort with wide age range (29–72 yrs at follow-up).

The role of sex, age, atopic status, smoking and body mass index (BMI) on percentage change in bronchial reactivity slope from the baseline value was analysed in 3,005 participants with methacholine tests in 1991 and 2002, and complete covariate data. Slope was defined as percentage decline in forced expiratory volume in 1 s from its maximal value per micromole of methacholine.

Bronchial hyperreactivity prevalence fell from 14.3 to 12.5% during follow-up. Baseline age was nonlinearly associated with change in reactivity slope: participants aged <50 yrs experienced a decline and those above an increase during follow-up. Atopy was not associated with change, but accentuated the age pattern (p-value for interaction = 0.038). Smoking significantly increased slope by 21.2%, as did weight gain (2.7% increase per BMI unit). Compared with persistent smokers, those who ceased smoking before baseline or during follow-up experienced a significant decrease in slope (-27.7 and -23.9%, respectively). Differing, but not statistically different, age relationships and effect sizes for smoking and BMI between sexes were found.

Mean bronchial reactivity increases after 50 yrs of age, possibly due to airway remodelling or ventilation–perfusion disturbances related to cumulative lifetime exposures.
Involvement of p63 in the herpes simplex virus-1-induced demise of corneal cells
Authors: Orosz László , Gallyas Éva , Kemény Lajos , Mándi Yvette , Facskó Andrea , Megyeri Klára
Published: June 2010

Background

The transcription factor p63 plays a pivotal role in the development and maintenance of epithelial tissues, including the ocular surface. In an effort to gain insight into the pathogenesis of keratitis caused by HSV-1, we determined the expression patterns of the p63 and Bax proteins in the Staatens Seruminstitute Rabbit Cornea cell line (SIRC).

Methods

SIRC cells were infected with HSV-1 at various multiplicities and maintained for different periods of time. Virus replication was measured by indirect immunofluorescence assay and Western blot analysis. Cell viability was determined by MTT assay. The apoptotic response of the infected cells was quantified by ELISA detecting the enrichment of nucleosomes in the cytoplasm. Western blot analysis was used to determine the levels of p63 and Bax proteins.

Results

Indirect immunofluorescence assays and Western blot analyses demonstrated the presence of HSV-1 glycoprotein D (gD) in the infected SIRC cell line, and the pattern of gD expression was consistent with efficient viral replication. The results of MTT and ELISA assays showed that HSV-1 elicited a strong cytopathic effect, and apoptosis played an important role in the demise of the infected cells. Mock-infected SIRC cells displayed the constitutive expression of ΔNp63α. The expressions of the Bax-β and TAp63γ isoforms were considerably increased, whereas the level of ΔNp63α was decreased in the HSV-1-infected SIRC cells. Experiments involving the use of acyclovir showed that viral DNA replication was necessary for the accumulation of TAp63γ.

Conclusion

These data suggest that a direct, virus-mediated cytopathic effect may play an important role in the pathogenic mechanism of herpetic keratitis. By disturbing the delicate balance between the pro-survival ΔN and the pro-apoptotic TA isoforms, HSV-1 may cause profound alterations in the viability of the ocular cells and in the tissue homeostasis of the ocular surface.
Rule-based spatial modeling with diffusing, geometrically constrained molecules
Authors: Gruenert Gerd , Ibrahim Bashar , Lenser Thorsten , Lohel Maiko , Hinze Thomas , Dittrich Peter
Published: June 2010

Background

We suggest a new type of modeling approach for the coarse grained, particle-based spatial simulation of combinatorially complex chemical reaction systems. In our approach molecules possess a location in the reactor as well as an orientation and geometry, while the reactions are carried out according to a list of implicitly specified reaction rules. Because the reaction rules can contain patterns for molecules, a combinatorially complex or even infinitely sized reaction network can be defined.

For our implementation (based on LAMMPS), we have chosen an already existing formalism (BioNetGen) for the implicit specification of the reaction network. This compatibility allows to import existing models easily, i.e., only additional geometry data files have to be provided.

Results

Our simulations show that the obtained dynamics can be fundamentally different from those simulations that use classical reaction-diffusion approaches like Partial Differential Equations or Gillespie-type spatial stochastic simulation. We show, for example, that the combination of combinatorial complexity and geometric effects leads to the emergence of complex self-assemblies and transportation phenomena happening faster than diffusion (using a model of molecular walkers on microtubules). When the mentioned classical simulation approaches are applied, these aspects of modeled systems cannot be observed without very special treatment. Further more, we show that the geometric information can even change the organizational structure of the reaction system. That is, a set of chemical species that can in principle form a stationary state in a Differential Equation formalism, is potentially unstable when geometry is considered, and vice versa.

Conclusions

We conclude that our approach provides a new general framework filling a gap in between approaches with no or rigid spatial representation like Partial Differential Equations and specialized coarse-grained spatial simulation systems like those for DNA or virus capsid self-assembly.
Optimization of somatic cell injection in the perspective of nuclear transfer in goldfish
Authors: Bail Pierre-Yves Le , Depince Alexandra , Chenais Nathalie , Mahe Sophie , Maisse Gerard , Labbe Catherine
Published: June 2010

Background

Nuclear transfer has the potential to become one strategy for fish genetic resources management, by allowing fish reconstruction from cryopreserved somatic cells. Survival rates after nuclear transfer are still low however. The part played by unsuitable handling conditions is often questioned, but the different steps in the procedure are difficult to address separately. In this work led on goldfish (Carassius auratus), the step of somatic cells injection was explored. Non-enucleated metaphase II oocytes were used as a template to explore the toxicity of the injection medium, to estimate the best location where the cell should be injected, and to assess the delay necessary between cell injection and oocyte activation.

Results

Trout coelomic fluid was the most suitable medium to maintain freshly spawned oocytes at the metaphase II stage during oocyte manipulation. Oocytes were then injected with several media to test their toxicity on embryo development after fertilization. Trout coelomic fluid was the least toxic medium after injection, and the smallest injected volume (10 pL) allowed the same hatching rates as the non injected controls (84.8% ± 23). In somatic cell transfer experiments using non enucleated metaphase II oocytes as recipient, cell plasma membrane was ruptured within one minute after injection. Cell injection at the top of the animal pole in the oocyte allowed higher development rates than cell injection deeper within the oocyte (respectively 59% and 23% at mid-blastula stage). Embryo development rates were also higher when oocyte activation was delayed for 30 min after cell injection than when activation was induced without delay (respectively 72% and 48% at mid-blastula stage).

Conclusions

The best ability of goldfish oocytes to sustain embryo development was obtained when the carrier medium was trout coelomic fluid, when the cell was injected close to the animal pole, and when oocyte activation was induced 30 min after somatic cell injection. Although the experiments were not designed to produce characterized clones, application of these parameters to somatic cell nuclear transfer experiments in enucleated metaphase II oocytes is expected to improve the quality of the reconstructed embryos.
In-vivo high resolution imaging of optic nerve head drusen using spectral-domain Optical Coherence Tomography
Authors: Murthy Ravi K , Storm Laura , Grover Sandeep , Brar Vikram S , Chalam Kakarla V
Published: June 2010

Background

Optic nerve head drusen (ONHD) are white calcareous deposits, seen either superficially on the optic nerve head or buried within it. Diagnosis of ONHD is made by one or more ways: clinical exam, autofluorescence, ultrasound of the optic nerve, CT scan and/or visual field examination. The present study describes features of ONHD based on another diagnostic modality, the spectral-domain OCT (Spectralis).

Methods

This is a retrospective case series of 5 patients with bilateral ONHD with a best-corrected visual acuity of 20/20 and no other posterior segment pathology. All the patients underwent fundus photography, fundus autofluorescence, B-scan ultrasonography, Spectralis OCT and Humphrey 30-2 threshold visual fields.

Results

All 5 patients had surface ONHD which were autofluorescent and echodense on B-scan ultrasonography. Spectralis OCT findings in the corresponding areas include 'scattered spots with high reflectivity' casting a shadow underneath. The reflectivity can be distinctly differentiated from the blood vessels on the optic nerve. Two patients had an arcuate scotoma on the Humphrey visual fields. No correlation was found between the changes on Spectralis OCT with that of visual field.

Conclusions

Spectralis OCT is another useful ancillary investigation in the diagnosis of ONHD and we describe the features in the present study.