bluuebunny/crossref_metadata_2025 huggingface dataset:
Securing the circuit of intrathecally administered cancer drugs: example of a collective approach
Authors: Marliot Guillaume , Le Rhun Emilie , Sakji Ilyes , Bonneterre Jacques , Cazin Jean-Louis
Published: June 2010

The treatment of leptomeningeal metastasis is based on protocols linking systemic chemotherapies and intrathecal injections of antineoplastic agents. Since the late 1960s, cases of accidental intrathecal injections of vinca-alkaloids, which have almost always proved fatal, have been documented. The most concerned countries, supported by the WHO, have published numerous recommendations aimed at reducing this type of risk. The aim of our work was to improve safety procedures for the intrathecal administration of antineoplastic drugs in an oncology hospital: the Centre Oscar Lambret, Lille, France. To this end, we compiled and analyzed a total of eight international recommendations. Our method was to meet the requirements of the AFSSAPS (French agency for the safety of health products), then to adopt recommended procedures in other countries, where appropriate.

We considered the whole drugs circuit from prescription to administration. Improvements basically focused on the computerization of prescription, the dilution in mini-bags of vinca-alkaloids, and the additional labeling of intrathecally administered preparations as well as those with some vinca-alkaloids. This multidisciplinary approach to improve our practices complements the precautions taken by healthcare teams.
Assessing Goodness of Fit: Simple Rules of Thumb Simply Do Not Work
Authors: Nye Christopher D. , Drasgow Fritz
Published: June 2010

Confirmatory factor analytic (CFA) models are frequently used in many areas of organizational research. Due to their popularity, CFA models and issues about their fit have received a vast amount of attention during the past several decades. The purpose of this study was to examine several measures of fit and the appropriateness of previously developed ‘‘rules of thumb’’ for their interpretation. First, an empirical example is used to illustrate the effects of nonnormality on maximum likelihood (ML) estimation and to demonstrate the importance of diagonally weighted least squares (DWLS) estimation for organizational research. Then, the results of a simulation study are presented to show that appropriate cutoff values for DWLS estimation vary considerably across conditions. Finally, regression equations are described to aid researchers in selecting cutoff values for assessing the fit of DWLS solutions, given a desired level of Type I error. The results summarized here have important implications for the interpretation and use of CFA models.
Remyelination of optic nerve lesions: spatial and temporal factors
Authors: Klistorner Alexandr , Arvind Hemamalini , Garrick Raymond , Yiannikas Con , Paine Mark , Graham Stuart L
Published: June 2010

Optic neuritis provides an in vivo model to study demyelination. The effects of myelin loss and recovery can be measured by the latency of the multifocal visual evoked potentials. We investigated whether the extent of initial inflammatory demyelination in optic neuritis correlates with the remyelinating capacity of the optic nerve. Forty subjects with acute unilateral optic neuritis and good visual recovery underwent multifocal visual evoked potentials testing at 1, 3, 6 and 12 months. Average latency changes were analyzed. Extensive latency delay at baseline significantly improved over time with rate of recovery slowed down after 6 months. Magnitude of latency recovery was independent of initial latency delay. Latency recovery ranged from 7 to 17 ms across the whole patient cohort (average = 11.3 (3.1) ms) despite the fact that in a number of cases the baseline latency delay was more than 35—40 ms. Optic nerve lesions tend to remyelinate at a particular rate irrespective of the size of the initial demyelinated zone with smaller lesions accomplishing recovery more completely. The extent of the initial inflammatory demyelination is probably the single most important factor determining completeness of remyelination. The time period favorable to remyelination is likely to be within the first 6 months after the attack.
Improving African health research capacity
Authors: Lazarus Jeffrey V. , Wallace Samantha A. , Liljestrand Jerker
Published: June 2010

The issue of strengthening local research capacity in Africa is again high on the health and development agenda. The latest initiative comes from the Wellcome Trust. But when it comes to capacity development, one of the chief obstacles that health sectors in the region must confront is the migration of health professionals to countries that offer more lucrative opportunities, like those in western Europe. To combat this ‘‘brain drain’’, already back in 1984, the Swedish International Development Cooperation Agency (Sida) created a training programme in which healthcare professionals from Africa conducted the bulk of their research in their own countries. However, the model was only partly successful. Several years ago, we assessed the preconditions for the renewal of Sida support for research and research training activities in the region. Based on our work to develop a critical mass of beneficial research capacity in the countries of sub-Saharan Africa, this article suggests several recommendations to both donors and governments that have broad application for general health research issues in the region.
Spironolactone ameliorates podocytic adhesive capacity via restoring integrin α3 expression in streptozotocin-induced diabetic rats
Authors: Shan Lin  , Dong Li  , Junya Jia  , Zhenfeng Zheng  , Zhonghui Jia  , Wenya Shang
Published: June 2010

Podocyte responses to various injuries include detachment from the glomerular basement membrane (GBM) with impaired adhesion ability. Growing evidence suggests inappropriately enhanced aldosterone levels in glomeruli may contribute to podocytic injury and subsequently glomerulosclerosis in diabetic nephropathy (DN). In the present study, we aimed to investigate podocytic integrin α3 expression and urinary podocyte excretion in streptozotocin (STZ)-induced diabetic rats, and to evaluate their responses to spironolactone (SPL). STZ-induced male diabetic Wistar rats were treated with vehicle (the STZ group, n=7), or spironolactone (the STZ+SPL group, n=6) for 12 weeks, six additional rats of similar body weight serving as control. Urine specimens were obtained for measurement of urine albumin concentration and urinary podocyte quantitation upon completion of the 12 weeks. Urinary podocyte excretion was quantified by immunofluorescence and expression of integrin α3 was detected by immunohistochemistry and Western blotting. At 12 weeks, rats given STZ alone revealed an increase in blood glucose and were unaffected by spironolactone, whereas the STZ+SPL group showed considerable improvement in urine albumin and podocyte excretion, as well as up-regulation of integrin α3. Our results suggest that spironolactone ameliorates impaired podocytic adhesion capacity and prevents STZ-induced DN progression.
Low Temperature Plasma/Metal Salts Treatments for Improving Some Properties of Polyamide 6 Fibers
Authors: Raslan W.M. , El-Khatib E.M. , El-Halwagy A.A. , Ghalab S.
Published: June 2010

The effect of plasma treatments with oxygen and argon gases on some properties of polyamide 6 fibers is thoroughly investigated. The treated fabric with oxygen plasma is further treated with some metal salts solutions such as copper sulfate, nickel sulfate, and silver nitrate to study their effect on the antibacterial properties of polyamide fibers. The changes induced in roughness, wettability, and dyeability of polyamide 6 fabric are given. The surface morphology of treated fabric is characterized by using scanning electron microscopy. Density and crystallinity of the treated fabric are also evaluated. The antibacterial activity of treated polyamide 6 fabrics with oxygen plasma/metal salts solutions is improved. The dyeability and fastness properties are also enhanced.
In Situ Formation of Silver Nanoparticles within Chitosan-attached Cotton Fabric for Antibacterial Property
Authors: Thomas Varsha , Bajpai M. , Bajpai S.K.
Published: June 2010

This work involves chemical modification of cotton fabrics by natural, biocompatible, and biodegradable polysaccharide — chitosan — followed by incorporating silver nanoparticles in the fabrics. The excellent chelating property of chitosan binds the silver metal ions that are later on reduced to nanoparticles giving rise to chitosan-attached nanosilver-loaded fabrics. The silver nanoparticles-loaded chitosan-attached fabric has been characterized by surface plasmon resonance, transmission electron microscopy, energy dispersive X-ray analysis, and X-ray diffraction analysis. These chitosan-attached nanosilver-loaded fabrics exhibit excellent antibacterial action against model bacteria E. coli.
A Dedicated Screening Program for Geriatric HIV-Infected Patients Integrating HIV and Geriatric Care
Authors: Ruiz Marco , Cefalu Charles , Ogbuokiri Justina
Published: June 2010

Background: Clinicians caring for HIV-infected patients >60 years old encounter multiple clinical challenges. The use of a functional geriatrics screening for detection of significant comorbidities is important in this population. Methods: The geriatrics screening evaluated functional capabilities, depression, cognitive dysfunction, nutrition, mobility, medicines used, and interactions. Results: As of July 2009, 57 patients were screened (average age 62.6, 39 males and 18 females). A total of 17 patients (9 males and 8 females) were referred to the geriatrics/HIV program because of identified problems in multiple domains: 10 with cognitive dysfunction, 8 with problems in basic or instrumental activities of daily living, 6 with nutritional issues, 5 with depression, 5 with mobility problems, 4 with visual issues, and 2 with hearing difficulties. The average age was 62.9. Median CD4 count and viral load were 285 (15-714) cells/mm3 and 30 505 copies/mL (0-407 697), respectively. Conclusions: The functional yearly screening of patients >60 years with HIV needs to be part of regular care of patients infected with HIV as multiple functional problems can be diagnosed and addressed.
Low-Level Viremia Associated With the Use of TaqMan Assay
Authors: Szabo Susan , Moffett Lee E. , Cantwell- McNelis Kelly , James Christopher W. , Joseph Abraham
Published: June 2010

Poor correlation has been reported between the Roche Cobas AmpliPrep/Cobas (TaqMan) HIV-1 TaqMan assay and the Roche Cobas Amplicor HIV-1 Monitor version 1.5 Amplicor assay. We report 8 patients who experienced unexplained detectable viremia, despite exemplary medication adherence, following a change in viral quantification assay from Amplicor to TaqMan in January 2008. All patients were found to have undetectable HIV RNA by branched DNA (bDNA) assay.
Cardiac Risks Associated With Marathon Running
Authors: Day Sharlene M. , Thompson Paul D.
Published: June 2010

Context:

A recent cluster of sudden cardiac deaths in marathon runners has attracted considerable media attention and evoked concern over the safety of long-distance running and competition. This review discusses the acute and potential long-term risks associated with marathon running and puts these into perspective with the many health benefits afforded by habitual vigorous exercise.

Evidence Acquisition:

Data sources included peer-reviewed publications from 1979 to January 2010 as identified via PubMed and popular media.

Results:

Marathon running is associated with a transient and low risk of sudden cardiac death. This risk appears to be even lower in women and is independent of marathon experience or the presence of previously reported symptoms. Most deaths are due to underlying coronary artery disease. The value of preparticipation screening is limited by its insensitivity and impracticality of widespread implementation. Appropriate preparation and deployment of trained medical personnel and availability of automatic external defibrillators are expected to have a major impact on survival from cardiac arrests during marathons. Cardiac biochemical and functional abnormalities are commonly observed transiently following completion of a marathon, although their clinical significance is unknown.

Conclusions:

Sudden cardiac deaths associated with marathon running are exceedingly rare events. Prevention should focus on recognition and investigation of prodromal symptoms, if present, and access to rapid defibrillation and trained medical personnel. The robust association of endurance running with improved quality of life and longevity underscores the importance of putting risks into perspective with other well-established health benefits of regular vigorous exercise.
Exercise-Induced Bronchospasm
Authors: Molis Marc A. , Molis Whitney E.
Published: June 2010

Context:

Exercise-induced bronchospasm (EIB) is a phenomenon of airway narrowing that occurs during or after exercise or physical exertion. This condition has been reported in a range of sporting activities but is most common in participants of cold-weather sports (eg, Nordic skiing) and indoor sports (eg, ice-skating and swimming). Traditionally, the terms exercise induced-asthma ( EIA) and EIB have been used interchangeably; however, more recent evidence suggests that these entities are separate and should be described as such, given that their treatments differ.

Evidence Acquisition:

Literature from 2000 to 2010 was obtained through searches of PubMed, Medline, and Google, with the keywords exercise-induced asthma, exercise-induced bronchospasm, asthma and athlete, and asthma and sport and with an emphasis on the current literature (last 3 to 4 years).

Results:

Although the current literature suggests a differentiation between EIA and EIB, this differentiation is not always clear, and the terms are still often used interchangeably. This lack of distinction makes it difficult to draw conclusions on optimal diagnosis and treatment of EIB.

Conclusion:

EIB is prevalent in elite-level athletes, with certain groups being at increased risk. Diagnostic testing should be used when possible, given that recent studies suggest poor correlation between symptoms and testing. The mainstay of treatment remains the use of short-acting β-adrenergic agonists.
The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity
Authors: Campbell Clinton J. V. , Lee Jung Bok , Levadoux-Martin Marilyne , Wynder Tracy , Xenocostas Anargyros , Leber Brian , Bhatia Mickie
Published: June 2010

The molecular basis for the unique proliferative and self-renewal properties that hierarchically distinguish human stem cells from progenitors and terminally differentiated cells remains largely unknown. We report a role for the Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) as an indispensable regulator of self-renewal in human stem cells and show that a functional dependence on Mcl-1 defines the human stem cell hierarchy. In vivo pharmacologic targeting of the Bcl-2 family members in human hematopoietic stem cells (HSCs) and human leukemic stem cells reduced stem cell regenerative and self-renewal function. Subsequent protein expression studies showed that, among the Bcl-2 family members, only Mcl-1 was up-regulated exclusively in the human HSC fraction on in vivo regeneration of hematopoiesis. Short hairpin RNA–knockdown of Mcl-1 in human cord blood cells did not affect survival in the HSC or hematopoietic progenitor cell fractions in vitro but specifically reduced the in vivo self-renewal function of human HSCs. Moreover, knockdown of Mcl-1 in ontogenetically primitive human pluripotent stem cells resulted in almost complete ablation of stem cell self-renewal function. Our findings show that Mcl-1 is an essential regulator of stem cell self-renewal in humans and therefore represents an axis for therapeutic interventions.
Serum response factor is an essential transcription factor in megakaryocytic maturation
Authors: Halene Stephanie , Gao Yuan , Hahn Katherine , Massaro Stephanie , Italiano Joseph E. , Schulz Vincent , Lin Sharon , Kupfer Gary M. , Krause Diane S.
Published: June 2010

Serum response factor (Srf) is a MADS–box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. To test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F knockout (KO) mice are born with normal Mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased number and percentage of CD41+ megakaryocytes (WT: 0.41% ± 0.06%; KO: 1.92% ± 0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation, and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are down-regulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production partly because of regulation of cytoskeletal genes.
Dissolution of arterial platelet thrombi in vivo with a bifunctional platelet GPIIIa49-66 ligand which specifically targets the platelet thrombus
Authors: Zhang Wei , Li Yong-Sheng , Nardi Michael A. , Dang Suying , Yang Jing , Ji Yong , Li Zongdong , Karpatkin Simon , Wisniewski Thomas
Published: June 2010

Patients with HIV-1 immune-related thrombocytopenia have a unique antibody (Ab) against integrin GPIIIa49-66 capable of inducing oxidative platelet fragmentation via Ab activation of platelet nicotinamide adenine dinucleotide phosphate oxidase and 12-lipoxygenase releasing reactive oxygen species. Using a phage display single-chain antibody (scFv) library, we developed a novel human monoclonal scFv Ab against GPIIIa49-66 (named A11) capable of inducing fragmentation of activated platelets. In this study, we investigated the in vivo use of A11. We show that A11 does not induce significant thrombocytopenia or inhibit platelet function. A11 can prevent the cessation of carotid artery flow produced by induced artery injury and dissolve the induced thrombus 2 hours after cessation of blood flow. In addition, A11 can prevent, as well as ameliorate, murine middle cerebral artery stroke, without thrombocytopenia or brain hemorrhage. To further optimize the antithrombotic activity of A11, we produced a bifunctional A11-plasminogen first kringle agent (SLK), which homes to newly deposited fibrin strands within and surrounding the platelet thrombus, reducing effects on nonactivated circulating platelets. Indeed, SLK is able to completely reopen occluded carotid vessels 4 hours after cessation of blood flow, whereas A11 had no effect at 4 hours. Thus, a new antithrombotic agent was developed for platelet thrombus clearance.
MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-κB–dependent lymphoma
Authors: Milhollen Michael A. , Traore Tary , Adams-Duffy Jennifer , Thomas Michael P. , Berger Allison J. , Dang Lenny , Dick Lawrence R. , Garnsey James J. , Koenig Erik , Langston Steven P. , Manfredi Mark , Narayanan Usha , Rolfe Mark , Staudt Louis M. , Soucy Teresa A. , Yu Jie , Zhang Julie , Bolen Joseph B. , Smith Peter G.
Published: June 2010

MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIκBα, decrease in nuclear p65 content, reduction of nuclear factor-κB (NF-κB) transcriptional activity, and G1 arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-κB pathway inhibition. Treatment of germinal-center B cell–like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-κB pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-κB pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-κB–dependent lymphomas.
Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly
Authors: Janda Ales , Sedlacek Petr , Hönig Manfred , Friedrich Wilhelm , Champagne Martin , Matsumoto Tadashi , Fischer Alain , Neven Benedicte , Contet Audrey , Bensoussan Danielle , Bordigoni Pierre , Loeb David , Savage William , Jabado Nada , Bonilla Francisco A. , Slatter Mary A. , Davies E. Graham , Gennery Andrew R.
Published: June 2010

Seventeen patients transplanted with hematopoietic cells to correct severe T lymphocyte immunodeficiency resulting from complete DiGeorge anomaly were identified worldwide, and retrospective data were obtained using a questionnaire-based survey. Patients were treated at a median age of 5 months (range, 2-53 months) between 1995 and 2006. Bone marrow was used in 11 procedures in 9 cases: 6 from matched unrelated donors, 4 from human leukocyte antigen (HLA)-identical siblings, and one haploidentical parent with T-cell depletion. Unmobilized peripheral blood was used in 8 cases: 5 from HLA-identical siblings, one from a matched unrelated donor, one from an HLA-identical parent, and one unrelated matched cord blood. Conditioning was used in 5 patients and graft-versus-host disease prophylaxis in 11 patients. Significant graft-versus-host disease occurred in 9 patients, becoming chronic in 3. Median length of follow-up was 13 months, with transplantation from HLA-matched sibling showing the best results. Median survival among deceased patients (10 patients) was 7 months after transplantation (range, 2-18 months). The overall survival rate was 41%, with a median follow-up of 5.8 years (range, 4-11.5 years). Among survivors, median CD3 and CD4 counts were 806 (range, 644-1224) and 348 (range, 225-782) cells/mm3, respectively, CD4+/CD45RA+ cells remained very low, whereas mitogen responses were normalized.
Factors influencing age at diagnosis of primary ciliary dyskinesia in European children
Authors: Kuehni C.E. , Frischer T. , Strippoli M-P.F. , Maurer E. , Bush A. , Nielsen K.G. , Escribano A. , Lucas J.S.A. , Yiallouros P. , Omran H. , Eber E. , O'Callaghan C. , Snijders D. , Barbato A.
Published: June 2010

Primary ciliary dyskinesia (PCD) is a hereditary disorder of mucociliary clearance causing chronic upper and lower airways disease. We determined the number of patients with diagnosed PCD across Europe, described age at diagnosis and determined risk factors for late diagnosis.

Centres treating children with PCD in Europe answered questionnaires and provided anonymous patient lists.

In total, 223 centres from 26 countries reported 1,009 patients aged <20 yrs. Reported cases per million children (for 5–14 yr olds) were highest in Cyprus (111), Switzerland (47) and Denmark (46). Overall, 57% were males and 48% hadsitus inversus. Median age at diagnosis was 5.3 yrs, lower in children withsitus inversus(3.5versus5.8 yrs; p<0.001) and in children treated in large centres (4.1versus4.8 yrs; p = 0.002). Adjusted age at diagnosis was 5.0 yrs in Western Europe, 4.8 yrs in the British Isles, 5.5 yrs in Northern Europe, 6.8 yrs in Eastern Europe and 6.5 yrs in Southern Europe (p<0.001). This strongly correlated with general government expenditures on health (p<0.001).

This European survey suggests that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures. Prospective studies should assess the impact this delay might have on patient prognosis and on health economic costs across Europe.
Rhinovirus induces MUC5AC in a human infection model andin vitroviaNF-κB and EGFR pathways
Authors: Hewson C.A. , Haas J.J. , Bartlett N.W. , Message S.D. , Laza-Stanca V. , Kebadze T. , Caramori G. , Zhu J. , Edbrooke M.R. , Stanciu L.A. , Kon O.M. , Papi A. , Jeffery P.K. , Edwards M.R. , Johnston S.L.
Published: June 2010

Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection upregulates MUC5ACin vivois unknown and the molecular mechanisms involved are incompletely understood.

We investigated RV induction of MUC5ACin vivoandin vitroto identify targets for development of new therapies for asthma exacerbations.

RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16, and in asthmatic, but not normal, subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5ACin vivo. RV induction of MUC5AC in bronchial epithelial cellsin vitrooccurredvianuclear factor-κB-dependent induction of matrix metalloproteinase-mediated transforming growth factor-α release, thereby activating an epidermal growth factor receptor-dependent cascade culminating,viamitogen-activated protein kinase activation, in specificity protein-1 transactivation of the MUC5AC promoter.

RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbationsin vivo. Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hypersecretion in RV-induced illness.
Choice of nasal nitric oxide technique as first-line test for primary ciliary dyskinesia
Authors: Marthin J.K. , Nielsen K.G.
Published: June 2010

Nasal nitric oxide (nNO) has a well-known potential as an indirect discriminative marker between patients with primary ciliary dyskinesia (PCD) and healthy subjects, but real-life experience and usefulness in young children is sparsely reported. Three nNO sampling methods were examined and compared as first-line tests for PCD.

Healthy subjects, confirmed PCDs, consecutive referrals with PCD-like symptoms and patients with cystic fibrosis (CF) had nNO sampled during breath hold (BH-nNO), oral exhalation against resistance (OE-R-nNO) and tidal breathing (TB-nNO) aiming to expand age range into infancy.

282 subjects, 117 consecutive referrals, 59 PCDs, 49 CF patients and 57 healthy subjects, were included. All methods separated significantly between PCD and non-PCD, including CF with reliability, in ranking order BH-nNO>OE-R-nNO>TB-nNO. Acceptability in children ranked in reverse order. A problematic high fraction (39%) of false positive TB-nNO was found in young children. An unexpected large fraction (6.8%) of PCDs had nNO values above cut-off.

nNO is a helpful first-line tool in real-life PCD work-up in all age groups if the sampling method is chosen according to age. nNO can be misleading in a few patients with true PCD. Further studies are strongly needed in young children.
Smoke exposure as a determinant of autoantibody titre in α1-antitrypsin deficiency and COPD
Authors: Wood A.M. , de Pablo P. , Buckley C.D. , Ahmad A. , Stockley R.A.
Published: June 2010

Liberation of elastin peptides from damaged lung may be a mechanism of autoimmune lung disease. Citrullination, and anti-citrullinated protein antibody formation occurs in smokers, but the role of smoking in autoantibody generation relevant to pulmonary disease is unclear.

Anti-elastin, anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) antibodies were measured in 257 subjects with α1-antitrypsin deficiency (AATD), 113 subjects with usual chronic obstructive pulmonary disease (COPD) and 22 healthy nonsmokers. Levels were compared between groups, against phenotypic features and against smoke exposure.

Anti-elastin antibodies were higher in controls relative to AATD (p = 0.008) and usual COPD (p<0.00001), and in AATD relative to usual COPD (p<0.00001). Anti-elastin levels showed a threshold at 10 pack-yrs, being higher in those who had smoked less (p = 0.004). No relationships between antibody levels and clinical phenotype were seen after adjustment for smoke exposure. Anti-CCP antibodies were higher in usual COPD than AATD (p = 0.002) but the relationship to smoke exposure was less clear.

Smoke exposure is the main determinant of anti-elastin antibody levels, which fall after 10 pack-yrs. Local antibody complexes may be a better measure of elastin directed autoimmunity than circulating levels.
Streptococcus pneumoniaeinfection suppresses allergic airways disease by inducing regulatory T-cells
Authors: Preston J.A. , Thorburn A.N. , Starkey M.R. , Beckett E.L. , Horvat J.C. , Wade M.A. , O'Sullivan B.J. , Thomas R. , Beagley K.W. , Gibson P.G. , Foster P.S. , Hansbro P.M.
Published: June 2010

An inverse association exists between some bacterial infections and the prevalence of asthma. We investigated whetherStreptococcus pneumoniaeinfection protects against asthma using mouse models of ovalbumin (OVA)-induced allergic airway disease (AAD).

Mice were intratracheally infected or treated with killedS. pneumoniaebefore, during or after OVA sensitisation and subsequent challenge. The effects ofS. pneumoniaeon AAD were assessed.

Infection or treatment with killedS. pneumoniaesuppressed hallmark features of AAD, including antigen-specific T-helper cell (Th) type 2 cytokine and antibody responses, peripheral and pulmonary eosinophil accumulation, goblet cell hyperplasia, and airway hyperresponsiveness. The effect of infection on the development of specific features of AAD depended on the timing of infection relative to allergic sensitisation and challenge. Infection induced significant increases in regulatory T-cell (Treg) numbers in lymph nodes, which correlated with the degree of suppression of AAD. Tregs reduced T-cell proliferation and Th2 cytokine release. The suppressive effects of infection were reversed by anti-CD25 treatment.

Respiratory infection or treatment withS. pneumoniaeattenuates allergic immune responses and suppresses AAD. These effects may be mediated byS. pneumoniae-induced Tregs. This identifies the potential for the development of therapeutic agents for asthma fromS. pneumoniae.
Combined airway and oesophageal stenting in malignant airway–oesophageal fistulas: a prospective study
Authors: Herth F.J.F. , Peter S. , Baty F. , Eberhardt R. , Leuppi J.D. , Chhajed P.N.
Published: June 2010

Malignant airway–oesophageal fistulas (AEF) are a serious complication of advance oesophageal or lung cancer.

The aim of this study was to assess the quality of life before and after stent insertion, and to examine the role of treatment and location of AEF as factors influencing survival in AEF patients managed with airway and/or oesophageal stent insertion.

112 patients with AEF were included prospectively. 83 (74%) patients had advanced lung cancer and 29 (26%) patients had oesophageal cancers.

Airway stents were inserted in 65 (58%) patients, oesophageal stents in 37 (33%) patients, and both airway and oesophageal stents in 10 (9%) patients. Seven (6%) patients developed respiratory failure and required transient ventilator support in the intensive care unit (four patients with airway stenting, two patients with double stents and one patient in the oesophageal stenting group). None of the patients developed stent migration or needed stent repositioning. Overall, mean survival was 236.6 days (airway stent 219.1 days, oesophageal stent 262.8 days and combined airway–oesophageal stent 252.9 days). Backward, stepwise regression revealed the site of stent placement (airway and/or oesophagus; p<0.028), exact location of the fistula in airway (p = 0.011) and additional treatment with chemotherapy and/or radiation (p<0.001) as independent risk factors predicting increased survival. The mean quality of life score (QoL) was 81 prior to stent insertion and 72 post-stent insertion (p<0.001).

Airway and/or oesophageal stent insertion provides an effective approach to improve the QoL in patients with malignant AEF.
Lean mass predicts asthma better than fat mass among females
Authors: Sood A. , Qualls C. , Li R. , Schuyler M. , Beckett W.S. , Smith L.J. , Thyagarajan B. , Lewis C.E. , Jacobs D.R.
Published: June 2010

The obesity phenotype associated with asthma is not known. Our objective was to define the relative contribution of various distributions of fat and lean mass to asthma prevalence.

Data were obtained from 2,525 participants (including 1,422 females) who underwent dual-energy X-ray absorptiometry (DEXA) at the year 20 examination in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Total, truncal, arm and leg distributions of fat and lean mass were adjusted to the person's height. Self-reported asthma was the outcome.

Asthma among females was associated with greater total fat mass, arm fat mass, total lean mass, truncal lean mass and arm lean mass. Among males, none of these mass measures were significantly associated with asthma. Among females, the association with asthma was stronger for total lean mass than for total fat mass. Further, among various regional distributions of lean and fat mass in females, truncal lean mass was the strongest predictor.

Total lean mass is more strongly associated with asthma than total fat mass among females. These findings are contrary to the popular perception that excess physiological fat drives the obesity–asthma association. Rather, we hypothesise that ectopic fat within the “lean” tissues drives this association among females.
The 6-min walk distance in healthy subjects: reference standards from seven countries
Authors: Casanova C. , Celli B.R. , Barria P. , Casas A. , Cote C. , de Torres J.P. , Jardim J. , Lopez M.V. , Marin J.M. , Montes de Oca M. , Pinto-Plata V. , Aguirre-Jaime A.
Published: June 2010

The 6-min walk distance (6MWD) predicted values have been derived from small cohorts mostly from single countries. The aim of the present study was to investigate differences between countries and identify new reference values to improve 6MWD interpretation.

We studied 444 subjects (238 males) from seven countries (10 centres) ranging 40–80 yrs of age. We measured 6MWD, height, weight, spirometry, heart rate (HR), maximum HR (HRmax) during the 6-min walk test/the predicted maximum HR (HRmax% pred), Borg dyspnoea score and oxygen saturation.

The mean±sd6MWD was 571±90 m (range 380–782 m). Males walked 30 m more than females (p<0.001). A multiple regression model for the 6MWD included age, sex, height, weight and HRmax% pred (adjusted r2= 0.38; p<0.001), but there was variability across centres (adjusted r2= 0.09–0.73) and its routine use is not recommended. Age had a great impact in 6MWD independent of the centres, declining significantly in the older population (p<0.001). Age-specific reference standards of 6MWD were constructed for male and female adults.

In healthy subjects, there were geographic variations in 6MWD and caution must be taken when using existing predictive equations. The present study provides new 6MWD standard curves that could be useful in the care of adult patients with chronic diseases.
Exercise reduces airway sodium ion reabsorption in cystic fibrosis but not in exercise asthma
Authors: Schmitt L. , Wiebel M. , Frese F. , Dehnert C. , Zugck C. , Bärtsch P. , Mairbäurl H.
Published: June 2010

When ventilating large volumes of air during exercise, airway fluid secretion is essential for airway function. Since these are impaired in cystic fibrosis and exercise-induced asthma, it was the aim of this study to determine how exercise affects airway Na+and Cl-transport and whether changes depend on exercise intensity.

Nasal potential was measured in Ringer’s solution, with amiloride to block Na+transport, and in low chloride-containing isoproterenol to assess Cl-channels. Nasal potential was measured at rest and during submaximal and maximal bicycle ergometer exercise in individuals with cystic fibrosis, exercise-induced asthma and controls.

At rest, nasal potential was significantly higher in cystic fibroses than in the others. Maximal exercise decreased nasal potentials in cystic fibrosis and controls but not in exercise asthma. Submaximal exercise decreased nasal potentials only in cystic fibrosis. Cl-transport was not affected.

Our results indicate that nasal potentials and Na+transport were decreased by maximal exercise in healthy and cystic fibrosis, whereas submaximal exercise decreased potentials in cystic fibrosis only. Exercise did not affect nasal potentials in asthmatics. Decreased reabsorption during exercise might favour airway fluid secretion during hyperpnoea. This protective effect appears blunted in patients with exercise-induced asthma.
Reconsidering the arm span–height relationship in patients referred for spirometry
Authors: Capderou A. , Berkani M. , Becquemin M-H. , Zelter M.
Published: June 2010

The interpretation of pulmonary function tests relies on reference values corrected for age, sex and height. Height may be difficult to measure in patients with deformities of the thoracic cage or those unable to stand up properly. Current practice is to substitute arm span to height, once corrected either by a fixed factor or by an age- and sex-dependent regression equation. However arm span may be difficult to measure in some patients.

This study evaluated the relationship between arm span, measured height, height as mentioned on an identity document (ID), sex and age in a population of 2,452 Caucasian subjects with no chest or spine deformities.

The present study demonstrates that age and sex have to be taken into account to best predict height from arm span or ID height values. The equations predicting height from ID height give the best diagnosis concordance compared to reference in males and females. Age correction does not improve concordance below 70 yrs.

The estimation of height from ID height can be substituted to that from arm span when clinically relevant, providing ID height has been measured before the occurrence of stature problems.
PoGO: Prediction of Gene Ontology terms for fungal proteins
Authors: Jung Jaehee , Yi Gangman , Sukno Serenella A , Thon Michael R
Published: June 2010

Background

Automated protein function prediction methods are the only practical approach for assigning functions to genes obtained from model organisms. Many of the previously reported function annotation methods are of limited utility for fungal protein annotation. They are often trained only to one species, are not available for high-volume data processing, or require the use of data derived by experiments such as microarray analysis. To meet the increasing need for high throughput, automated annotation of fungal genomes, we have developed a tool for annotating fungal protein sequences with terms from the Gene Ontology.

Results

We describe a classifier called PoGO (Prediction of Gene Ontology terms) that uses statistical pattern recognition methods to assign Gene Ontology (GO) terms to proteins from filamentous fungi. PoGO is organized as a meta-classifier in which each evidence source (sequence similarity, protein domains, protein structure and biochemical properties) is used to train independent base-level classifiers. The outputs of the base classifiers are used to train a meta-classifier, which provides the final assignment of GO terms. An independent classifier is trained for each GO term, making the system amenable to updating, without having to re-train the whole system. The resulting system is robust. It provides better accuracy and can assign GO terms to a higher percentage of unannotated protein sequences than other methods that we tested.

Conclusions

Our annotation system overcomes many of the shortcomings that we found in other methods. We also provide a web server where users can submit protein sequences to be annotated.
Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor
Authors: Frijters Raoul , Fleuren Wilco , Toonen Erik JM , Tuckermann Jan P , Reichardt Holger M , van der Maaden Hans , van Elsas Andrea , van Lierop Marie-Jose , Dokter Wim , de Vlieg Jacob , Alkema Wynand
Published: June 2010

Background

Glucocorticoids (GCs) control expression of a large number of genes via binding to the GC receptor (GR). Transcription may be regulated either by binding of the GR dimer to DNA regulatory elements or by protein-protein interactions of GR monomers with other transcription factors. Although the type of regulation for a number of individual target genes is known, the relative contribution of both mechanisms to the regulation of the entire transcriptional program remains elusive. To study the importance of GR dimerization in the regulation of gene expression, we performed gene expression profiling of livers of prednisolone-treated wild type (WT) and mice that have lost the ability to form GR dimers (GRdim).

Results

The GR target genes identified in WT mice were predominantly related to glucose metabolism, the cell cycle, apoptosis and inflammation. In GRdim mice, the level of prednisolone-induced gene expression was significantly reduced compared to WT, but not completely absent. Interestingly, for a set of genes, involved in cell cycle and apoptosis processes and strongly related to Foxo3a and p53, induction by prednisolone was completely abolished in GRdim mice. In contrast, glucose metabolism-related genes were still modestly upregulated in GRdim mice upon prednisolone treatment. Finally, we identified several novel GC-inducible genes from which Fam107a, a putative histone acetyltransferase complex interacting protein, was most strongly dependent on GR dimerization.

Conclusions

This study on prednisolone-induced effects in livers of WT and GRdim mice identified a number of interesting candidate genes and pathways regulated by GR dimers and sheds new light onto the complex transcriptional regulation of liver function by GCs.
Mass spectrometry-based quantitative proteomic analysis of Salmonella enterica serovar Enteritidis protein expression upon exposure to hydrogen peroxide
Authors: Kim Kihoon , Yang Edward , Vu Gia-Phong , Gong Hao , Su Jing , Liu Fenyong , Lu Sangwei
Published: June 2010

Background

Salmonellaenterica, a common food-borne bacterial pathogen, is believed to change its protein expression profile in the presence of different environmental stress such as that caused by the exposure to hydrogen peroxide (H2O2), which can be generated by phagocytes during infection and represents an important antibacterial mechanism of host cells. AmongSalmonellaproteins, the effectors ofSalmonellapathogenicity island 1 and 2 (SPI-1 and SPI-2) are of particular interest since they are expressed during host infectionin vivoand are important for invasion of epithelial cells and for replication in organs during systemic infection, respectively. However, the expression profiles of these proteins upon exposure to H2O2or to host cellsin vivoduring the established phase of systemic infection have not been extensively studied.

Results

Using stable isotope labeling coupled with mass spectrometry, we performed quantitative proteomic analysis ofSalmonellaentericaserovar Enteritidis and identified 76 proteins whose expression is modulated upon exposure to H2O2. SPI-1 effector SipC was expressed about 3-fold higher and SopB was expressed approximately 2-fold lower in the presence of H2O2, while no significant change in the expression of another SPI-1 protein SipA was observed. The relative abundance of SipA, SipC, and SopB was confirmed by Western analyses, validating the accuracy and reproducibility of our approach for quantitative analysis of protein expression. Furthermore, immuno-detection showed substantial expression of SipA and SipC but not SopB in the late phase of infection in macrophages and in the spleen of infected mice.

Conclusions

We have identifiedSalmonellaproteins whose expression is modulated in the presence of H2O2. Our results also provide the first direct evidence that SipC is highly expressed in the spleen at late stage of salmonellosisin vivo. These results suggest a possible role of SipC and other regulated proteins in supporting survival and replication ofSalmonellaunder oxidative stress and during its systemic infectionin vivo.
The epidemiology of hematogenous vertebral osteomyelitis: a cohort study in a tertiary care hospital
Authors: Bhavan Kavita P , Marschall Jonas , Olsen Margaret A , Fraser Victoria J , Wright Neill M , Warren David K
Published: June 2010

Background

Vertebral osteomyelitis is a common manifestation of osteomyelitis in adults and associated with considerable morbidity. Limited data exist regarding hematogenous vertebral osteomyelitis. Our objective was to describe the epidemiology and management of hematogenous vertebral osteomyelitis.

Methods

We performed a 2-year retrospective cohort study of adult patients with hematogenous vertebral osteomyelitis at a tertiary care hospital.

Results

Seventy patients with hematogenous vertebral osteomyelitis were identified. The mean age was 59.7 years (±15.0) and 38 (54%) were male. Common comorbidities included diabetes (43%) and renal insufficiency (24%). Predisposing factors in the 30 days prior to admission included bacteremia (19%), skin/soft tissue infection (17%), and having an indwelling catheter (30%). Back pain was the most common symptom (87%). Seven (10%) patients presented with paraplegia. Among the 46 (66%) patients with a microbiological diagnosis, the most common organisms were methicillin-susceptible S. aureus [15 (33%) cases], and methicillin-resistant S. aureus [10 (22%)]. Among the 44 (63%) patients who had a diagnostic biopsy, open biopsy was more likely to result in pathogen recovery [14 (93%) of 15 with open biopsy vs. 14 (48%) of 29 with needle biopsy; p = 0.003]. Sixteen (23%) patients required surgical intervention for therapeutic purposes during admission.

Conclusions

This is one of the largest series of hematogenous vertebral osteomyelitis. A microbiological diagnosis was made in only approximately two-thirds of cases. S. aureus was the most common causative organism, of which almost half the isolates were methicillin-resistant.