bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells
Authors: Zeuner Ann , Pedini Francesca , Signore Michele , Ruscio Giusy , Messina Carlo , Tafuri Agostino , Girelli Gabriella , Peschle Cesare , De Maria Ruggero
Published: December 2005

Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by excessive erythrocyte production. Most patients with PV harbor an activating JAK2 mutation, but the molecular links between this mutation and erythrocyte overproduction are unknown. The interaction between death receptors and their ligands contributes to the physiological regulation of erythropoiesis through the inhibition of erythroblast proliferation and differentiation. With the use of an in vitro culture system to generate differentiating erythroid cells, we found that erythroblasts derived from patients with PV harboring the JAK2 V617F mutation were able to proliferate and generate higher numbers of mature erythroid cells in the presence of inhibitory signals delivered by CD95 (Fas/Apo-1) and TRAIL receptor stimulation. JAK2-mutated PV erythroblasts showed lower levels of CD95-induced caspase activation and incomplete caspase-mediated cleavage of the erythroid transcription factor GATA-1, which was entirely degraded in normal erythroblasts on CD95 stimulation. JAK2 mutation was associated in PV erythroblasts with cytokine-independent activation of the JAK2 effectors Akt/PKB and ERK/MAP and with a deregulated expression of c-FLIPshort, a potent cellular inhibitor of death receptor–induced apoptosis. These results show the presence in PV erythroblasts of proliferative and antiapoptotic signals that may link the JAK2 V617F mutation with the inhibition of death receptor signaling, possibly contributing to a deregulation of erythropoiesis.
Role of endothelial heparanase in delayed-type hypersensitivity
Authors: Edovitsky Evgeny , Lerner Immanuel , Zcharia Eyal , Peretz Tamar , Vlodavsky Israel , Elkin Michael
Published: December 2005

Heparanase is an endoglycosidase that cleaves heparan sulfate (HS), the main polysaccharide of the basement membrane (BM). HS is responsible for BM integrity and barrier function. Hence, enzymatic degradation of HS in the vascular subendothelial BM is a prerequisite for extravasation of immune cells and plasma components during inflammation. Here, we demonstrate a highly coordinated local heparanase induction upon elicitation of delayed-type hypersensitivity (DTH) reaction in the mouse ear. By monitoring in vivo activation of luciferase gene driven by the heparanase promoter, we demonstrate activation of heparanase transcription at an early stage of DTH. We report that heparanase is produced locally by the endothelium at the site of DTH-associated inflammation. Key DTH mediators, tumor necrosis factor-α and interferon-γ, were found to induce heparanase in cultured endothelial cells. Endothelium emerges as an essential cellular source of heparanase enzymatic activity that, in turn, allows for remodeling of the vascular BM, increased vessel permeability, and extravasation of leukocytes and plasma proteins. In vivo administration of antiheparanase siRNA or an inhibitor of heparanase enzymatic activity effectively halted DTH inflammatory response. Collectively, our results highlight the decisive role of endothelial heparanase in DTH inflammation and its potential as a promising target for anti-inflammatory drug development.
Human thymus contains multipotent progenitors with T/B lymphoid, myeloid, and erythroid lineage potential
Authors: Weerkamp Floor , Baert Miranda R. M. , Brugman Martijn H. , Dik Willem A. , de Haas Edwin F. E. , Visser Trudi P. , de Groot Christianne J. M. , Wagemaker Gerard , van Dongen Jacques J. M. , Staal Frank J. T.
Published: December 2005

It is a longstanding question which bone marrow–derived cell seeds the thymus and to what level this cell is committed to the T-cell lineage. We sought to elucidate this issue by examining gene expression, lineage potential, and self-renewal capacity of the 2 most immature subsets in the human thymus, namely CD34+CD1a– and CD34+CD1a+ thymocytes. DNA microarrays revealed the presence of several myeloid and erythroid transcripts in CD34+CD1a– thymocytes but not in CD34+CD1a+ thymocytes. Lineage potential of both subpopulations was assessed using in vitro colony assays, bone marrow stroma cultures, and in vivo transplantation into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The CD34+CD1a– subset contained progenitors with lymphoid (both T and B), myeloid, and erythroid lineage potential. Remarkably, development of CD34+CD1a– thymocytes toward the T-cell lineage, as shown by T-cell receptor δ gene rearrangements, could be reversed into a myeloid-cell fate. In contrast, the CD34+CD1a+ cells yielded only T-cell progenitors, demonstrating their irreversible commitment to the T-cell lineage. Both CD34+CD1a– and CD34+CD1a+ thymocytes failed to repopulate NOD/SCID mice. We conclude that the human thymus is seeded by multipotent progenitors with a much broader lineage potential than previously assumed. These cells resemble hematopoietic stem cells but, by analogy with murine thymocytes, apparently lack sufficient self-renewal capacity.
Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts
Authors: Gumá Mónica , Budt Matthias , Sáez Andrea , Brckalo Tamara , Hengel Hartmut , Angulo Ana , López-Botet Miguel
Published: December 2005

CD94/NKG2C+ natural killer (NK) cells are increased in healthy individuals infected with human cytomegalovirus (HCMV), suggesting that HCMV infection may shape the NK cell receptor repertoire. To address this question, we analyzed the distribution of NK cell subsets in peripheral blood lymphocytes (PBLs) cocultured with HCMV-infected fibroblasts. A substantial increase of NK cells was detected by day 10 in samples from a group of HCMV+ donors, and CD94/NKG2C+ cells outnumbered the CD94/NKG2A+ subset. Fibroblast infection was required to induce the preferential expansion of CD94/NKG2C+ NK cells that was comparable with allogeneic or autologous fibroblasts, and different virus strains. A CD94-specific monoclonal antibody (mAb) abrogated the effect, supporting an involvement of the lectinlike receptor. Purified CD56+ populations stimulated with HCMV-infected cells did not proliferate, but the expansion of the CD94/NKG2C+ subset was detected in the presence of interleukin-15 (IL-15). Experiments with HCMV deletion mutants indicated that the response of CD94/NKG2C+ NK cells was independent of the UL16, UL18, and UL40 HCMV genes, but was impaired when cells were infected with a mutant lacking the US2-11 gene region. Taken together the data support that the interaction of CD94/NKG2C with HCMV-infected fibroblasts, concomitant to the inhibition of human leukocyte antigen (HLA) class I expression, promotes an outgrowth of CD94/NKG2C+ NK cells.
Comparable results of umbilical cord blood and HLA-matched sibling donor hematopoietic stem cell transplantation after reduced-intensity preparative regimen for advanced Hodgkin lymphoma
Authors: Majhail Navneet S. , Weisdorf Daniel J. , Wagner John E. , Defor Todd E. , Brunstein Claudio G. , Burns Linda J.
Published: December 2005

We compared the safety and efficacy of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning using either unrelated umbilical cord blood (UCB) donors or matched-sibling donors (MSDs) for 21 adults at high risk with advanced Hodgkin lymphoma (UCB, n = 9; MSD, n = 12). Both groups were comparable except for younger age in the UCB cohort (median, 28 vs 42 years; P = .02). Neutrophil recovery occurred earlier in the MSD group (median, 7 vs 10 days; P = .02). All patients had sustained donor engraftment by day 60. Cumulative incidence of acute severe graft-versus-host-disease (33% vs 33%; P = .99), chronic graft-versus-host-disease (11% vs 33%; P = .24), and 100-day treatment-related mortality (11% vs 17%; P = .80) were comparable. With median follow-up periods of 17 and 24 months, the 2-year progression-free survival rates were 25% (95% confidence interval [95% CI], 0%-55%) for UCB and 20% (95% CI, 0%-44%) for MSD allo-SCT (P = .67). Our results suggest comparable outcomes for reduced-intensity allo-SCT using UCB or MSD in adults at high risk with advanced Hodgkin lymphoma.
Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy
Authors: Ravin Suk See Ting–De , Kennedy Douglas R. , Naumann Nora , Kennedy Jeffrey S. , Choi Uimook , Hartnett Brian J. , Linton Gilda F. , Whiting-Theobald Narda L. , Moore Peter F. , Vernau William , Malech Harry L. , Felsburg Peter J.
Published: December 2005

X-linked severe combined immunodeficiency (XSCID) is characterized by profound immunodeficiency and early mortality, the only potential cure being hematopoietic stem cell (HSC) transplantation or gene therapy. Current clinical gene therapy protocols targeting HSCs are based upon ex vivo gene transfer, potentially limited by the adequacy of HSC harvest, transduction efficiencies of repopulating HSCs, and the potential loss of their engraftment potential during ex vivo culture. We demonstrate an important proof of principle by showing achievement of durable immune reconstitution in XSCID dogs following intravenous injection of concentrated RD114-pseudotyped retrovirus vector encoding the corrective gene, the interleukin-2 receptor γ chain (γc). In 3 of 4 dogs treated, normalization of numbers and function of T cells were observed. Two long-term–surviving animals (16 and 18 months) showed significant marking of B lymphocytes and myeloid cells, normalization of IgG levels, and protective humoral immune response to immunization. There were no adverse effects from in vivo gene therapy, and in one dog that reached sexual maturity, sparing of gonadal tissue from gene transfer was demonstrated. This is the first demonstration that in vivo gene therapy targeting HSCs can restore both cellular and humoral immunity in a large-animal model of a fatal immunodeficiency.
Ex vivo perfusion of human spleens maintains clearing and processing functions
Authors: Buffet Pierre A. , Milon Geneviève , Brousse Valentine , Correas Jean-Michel , Dousset Bertrand , Couvelard Anne , Kianmanesh Reza , Farges Olivier , Sauvanet Alain , Paye François , Ungeheuer Marie-Noëlle , Ottone Catherine , Khun Huot , Fiette Laurence , Guigon Ghislaine , Huerre Michel , Mercereau-Puijalon Odile , David Peter H.
Published: December 2005

The spleen plays a central role in the pathophysiology of several potentially severe diseases such as inherited red cell membrane disorders, hemolytic anemias, and malaria. Research on these diseases is hampered by ethical constraints that limit human spleen tissue explorations. We identified a surgical situation—left splenopancreatectomy for benign pancreas tumors—allowing spleen retrieval at no risk for patients. Ex vivo perfusion of retrieved intact spleens for 4 to 6 hours maintained a preserved parenchymal structure, vascular flow, and metabolic activity. Function preservation was assessed by testing the ability of isolated-perfused spleens to retain Plasmodium falciparum-infected erythrocytes preexposed to the antimalarial drug artesunate (Art-iRBCs). More than 95% of Art-iRBCs were cleared from the perfusate in 2 hours. At each transit through isolated-perfused spleens, parasite remnants were removed from 0.2% to 0.23% of Art-iRBCs, a proportion consistent with the 0.02% to 1% pitting rate previously established in artesunate-treated patients. Histologic analysis showed that more than 90% of Art-iRBCs were retained and processed in the red pulp, providing the first direct evidence of a zone-dependent parasite clearance by the human spleen. Human-specific physiologic or pathophysiologic mechanisms involving clearing or processing functions of the spleen can now be experimentally explored in a human tissue context.
Increased number of B-cells in bronchial biopsies in COPD
Authors: Gosman M. M. E. , Willemse B. W. M. , Jansen D. F. , Lapperre T. S. , van Schadewijk A. , Hiemstra P. S. , Postma D. S. , Timens W. , Kerstjens H. A. M. ,   the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) Study Group
Published: December 2005

Recently, it has been shown that the accumulated volume of B-cells in small airways is increased in chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4. Little is known about the number of B-cells in central airways in COPD.

The present authors hypothesised that the number of B-cells in bronchial biopsies of large airways is higher in patients with COPD than in controls without airflow limitation and higher in more severe COPD. Therefore, bronchial biopsies were collected from 114 COPD patients (postbronchodilator forced expiratory volume in one second (FEV1) 63±9 % predicted value, FEV1/inspiratory vital capacity (IVC) 48±9%) and 28 controls (postbronchodilator FEV1108±12 % predicted value, FEV1/IVC 78±4%).

Paraffin sections were stained for B-cells (CD20+) and their number was determined in the subepithelial area (excluding muscle, glands and vessels). B-cell numbers were higher in patients with COPDversuscontrols (8.5versus3.9 cells·mm−2, respectively) and higher in patients with GOLD severity stage 3 (n = 11) than stage 2 (n = 103; 22.3versus7.8 cells·mm−2).

No relationship was found between the number of B-cells and clinical characteristics within the chronic obstructive pulmonary disease group. The authors suggest that these increased B-cell numbers may have an important contribution to the pathogenesis of chronic obstructive pulmonary disease.
Effect of clarithromycin on rhinovirus-16 infection in A549 cells
Authors: Jang Y. J. , Kwon H-J. , Lee B-J.
Published: December 2005

Clarithromycin (CM) has been found to inhibit the production of the intercellular adhesion molecule (ICAM)-1 and the secretion of interleukin (IL)-6 and IL-8, which may have beneficial effects on the pathophysiological changes related to rhinovirus (RV) infection. The effect of CM on RV infection in A549 cells was therefore investigated.

Cells were pre-treated with 1, 10 or 100 μM CM, either starting 3 days before infection and continuing thereafter, or by addition at the time of infection. RV titre, as measured by culture on Medical Research Council 5 cells, was reduced by CM, with the degree of reduction being greater when CM was added 3 days before infection than when it was added at the time of infection.

CM treatment inhibited the RV-induced increase in ICAM-1 mRNA and protein, as well as the RV-induced secretion of IL-1β, IL-6, and IL-8. These effects were greater in cells treated with 10 μM than in those treated with 100 μM CM, and the maximum effect was observed 3 days after viral infection. In contrast, secretion of IL-8 was not inhibited significantly when CM was added at the time of viral infection.

The findings of this study suggest that, in A549 cells, clarithromycin inhibits the induction of intercellular adhesion molecule-1 expression, cytokine elaboration, and viral infection.
Hypoxic ventilatory response in successful extreme altitude climbers
Authors: Bernardi L. , Schneider A. , Pomidori L. , Paolucci E. , Cogo A.
Published: December 2005

A very high ventilatory response to hypoxia is believed necessary to reach extreme altitude without oxygen. Alternatively, the excessive ventilation could be counterproductive by exhausting the ventilatory reserve early on.

To test these alternatives, 11 elite climbers (2004 Everest-K2 Italian Expedition) were evaluated as follows: 1) at sea level, and 2) at 5,200 m, after 15 days of acclimatisation at altitude. Resting oxygen saturation, minute ventilation, breathing rate, hypoxic ventilatory response, maximal voluntary ventilation, ventilatory reserve (at oxygen saturation = 70%) and two indices of ventilatory efficiency were measured.

Everest and K2 summits were reached 29 and 61 days, respectively, after the last measurement. Five climbers summited without oxygen, the other six did not, or succeeded with oxygen (two climbers). At sea level, all data were similar. At 5,200 m, the five summiters without oxygen showed lower resting minute ventilation, breathing rate and ventilatory response to hypoxia, and higher ventilatory reserve and ventilatory efficiency, compared to the other climbers.

Thus, the more successful climbers had smaller responses to hypoxia during acclimatisation to 5,200 m, but, as a result, had greater available reserve for the summit. A less sensitive hypoxic response and a greater ventilatory efficiency might increase ventilatory reserve and allow sustainable ventilation in the extreme hypoxia at the summit.
Parental education and children's respiratory and allergic symptoms in the Pollution and the Young (PATY) study
Authors: Gehring U. , Pattenden S. , Slachtova H. , Antova T. , Braun-Fahrländer C. , Fabianova E. , Fletcher T. , Galassi C. , Hoek G. , Kuzmin S. V. , Luttmann-Gibson H. , Moshammer H. , Rudnai P. , Zlotkowska R. , Heinrich J.
Published: December 2005

Inequalities in health between socio-economic groups are a major public health concern. The current authors studied associations between parental socio-economic status (SES) and children's respiratory and allergic symptoms in 13 diverse countries, including the Russian Federation, North America (Canada and the USA), and countries across Eastern and Western Europe.

Data of 57,000 children aged 6–12 yrs, originating from eight cross-sectional studies, were analysed. SES was defined by parental education. Respiratory and allergic symptoms were defined by parental questionnaire reports.

Multiple logistic regressions showed that low parental education was associated with a decreased risk of inhalant allergy and itchy rash in school children. Furthermore, low parental education was associated with an increased prevalence of wheeze and nocturnal dry cough. No clear association was found between parental education and prevalence of doctor-diagnosed asthma and bronchitis. Part of the difference between socio-economic groups with regard to their children's symptoms was explained by established risk factors, such as parental allergy, smoking during pregnancy, pet ownership, crowding, mould/moisture in the home, use of gas for cooking, and air pollution (particulate matter with a diameter of <10 µm). However, differences remained after adjusting for these variables.

Children's health was associated with parental education. The association could not fully be explained by established risk factors.
Methacholine and adenosine 5′-monophosphate challenges in children with post-infectious bronchiolitis obliterans
Authors: Yoo Y. , Yu J. , Kim D. K. , Choi S. H. , Kim C. K. , Koh Y. Y.
Published: December 2005

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, but is also frequently demonstrated by children and adults with chronic obstructive lung diseases. AHR is usually measured by bronchial challenges using direct or indirect stimuli. The aim of this study was to compare these two types of bronchial challenge in children with post-infectious bronchiolitis obliterans (BO).

Methacholine and adenosine 5′-monophosphate (AMP) challenges were used as tools for the evaluation of AHR to direct and indirect stimuli, respectively, in children with post-infectious BO (n = 28). These results were compared with those of asthmatic (n = 30) and control children (n = 25).

Altogether, twenty-two patients (78.6%) with post-infectious BO were hyperreactive to methacholine with a provocative concentration causing a 20% fall in forced expiratory volume in one second(PC20) of <16 mg·mL−1, but only six (21.4%) were hyperreactive to AMP with a PC20of <200 mg·mL−1. All patients with asthma responded positively to methacholine, and most (28, 93.3%) also responded positively to AMP. The majority of controls were insensitive to both challenges.

Airway hyperresponsiveness to methacholine is a frequent, but by no means universal, finding in children with post-infectious bronchiolitis obliterans, but is usually not accompanied by airway hyperresponsiveness to adenosine 5′-monophosphate. This finding suggests that airway hyperresponsiveness in patients with post-infectious bronchiolitis obliterans has characteristics that differ from those of asthmatic subjects.
Investigation of young children with severe recurrent wheeze: any clinical benefit?
Authors: Saglani S. , Nicholson A. G. , Scallan M. , Balfour-Lynn I. , Rosenthal M. , Payne D. N. , Bush A.
Published: December 2005

The management of young children with severe recurrent wheeze is difficult because symptoms are often refractory to conventional asthma therapy and other diagnoses must be excluded. The present authors aimed to evaluate the outcome of detailed, invasive investigations in such patients.

Children aged between 3 months and 5 yrs with severe recurrent wheezing, who had been referred to a tertiary centre, underwent a protocol of investigations including a chest computed tomography scan, blood tests, nasal ciliary brushings, fibreoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial biopsy and passage of an oesophageal pH probe.

A total of 47 children (25 males) with a median age of 26 (range 5–58) months underwent investigation. Of these, 39% were atopic, two-thirds had evidence of gastro-oesophageal reflux and 37 out of 47 had an abnormal bronchoscopy. Findings included structural abnormalities (13 out of 37), excessive mucus (20 out of 37) and macroscopic inflammation (10 out of 37). BAL revealed bacterial growth in 12 out of 44 (27%) patients. Good quality endobronchial biopsies were obtained from 36 out of 46 (78%) patients; of these, 44% had tissue eosinophila and 28% had a thickened reticular basement membrane.

Additional investigations (including bronchoscopy) in young children with severe wheeze may help to identify positive diagnoses and provide information to support a clinical diagnosis of asthma. This hypothesis-generating work should form the basis of future interventional studies.
Management of asthma in patients supervised by primary care physicians or by specialists
Authors: Laforest L. , Van Ganse E. , Devouassoux G. , Chretin S. , Osman L. , Bauguil G. , Pacheco Y. , Chamba G.
Published: December 2005

French asthma patients may be supervised by general practitioners (GPs) and/or specialists. Therefore, this study examined asthma management in patients exclusively supervised by specialists (SPE), GPs, (GP) and both (GP+SPE group), and compared the findings.

Asthma patients were consecutively recruited in 348 pharmacies. Each patient completed a questionnaire providing data on personal characteristics, asthma management, perception of disease and asthma supervision. Asthma control was measured using the Asthma Control Test. Questionnaires were linked to computerised records of medications which had been dispensed before inclusion in the study.

From the 1,256 patients (mean age = 36.1 yrs, 54.3% females), 11.4, 36.6, and 52.0% were placed in the SPE, GP, and GP+SPE groups, respectively. During the previous 4 weeks, most patients in the SPE group were properly controlled (52.2versus26.4 and 21.5% in GP and GP+SPE groups, respectively). The SPE group made more use of fixed combinations of long-acting beta agonist and inhaled corticosteroid, while receiving less short-acting beta agonists, antitussives and antibiotics.

Striking differences in symptoms and asthma management were observed according to the type of asthma supervision. The current results strongly support the need to improve the management of asthma in primary care, and the coordination of care between general practitioners and specialists.
Training with inspiratory pressure support in patients with severe COPD
Authors: van 't Hul A. , Gosselink R. , Hollander P. , Postmus P. , Kwakkel G.
Published: December 2005

This study evaluates the effects of training with noninvasive ventilatory support in patients with chronic obstructive pulmonary disease in a randomised, controlled, observer-blinded trial.

Twenty-nine patients with chronic obstructive pulmonary disease and with a ventilatory limited exercise capacity (forced expiratory volume in one second <60% predicted, breathing reserve at maximal exercise <20% of maximally voluntary ventilation, resting arterial oxygen tension ≥8 kPa (60 mmHg), end-exercise arterial oxygen saturation measured by pulse oximetry ≥85%) completed an 8-week supervised outpatient cycle exercise programme. Fourteen patients were randomised to training with inspiratory pressure support of 10 cmH2O and 15 patients to training with control (sham) inspiratory pressure support of 5 cmH2O. Outcome measures were the incremental shuttle walking test and a constant-load cycle endurance test at 75% of peak work rate including the measurement of physiological responses, and health status measured using the St. George's Respiratory Questionnaire.

Statistically significant between-group differences were found in favour of the inspiratory pressure support of 10 cmH2O group for improvement in shuttle walking distance (16±17versus3±13%), cycle endurance (164±124versus88±128%), and the reduction in minute ventilation during exercise (-11±10versus-2±9%).

It was concluded that exercise training with inspiratory pressure support of 10 cmH2O resulted in statistically significantly larger improvements in exercise performance than training with inspiratory pressure support of 5 cmH2O in patients with chronic obstructive pulmonary disease suffering from a ventilatory limited exercise capacity. Inspiratory pressure support of 10 cmH2O may be considered as adjunct during high-intensity exercise training.
High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis
Authors: Raghu G. , Freudenberger T. D. , Yang S. , Curtis J. R. , Spada C. , Hayes J. , Sillery J. K. , Pope C. E. , Pellegrini C. A.
Published: December 2005

The aim of this prospective study was to determine the prevalence and characteristics of acid gastro-oesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis (IPF).

Sixty-five consecutive patients with well-defined IPF were subjected to 24-h pH monitoring and oesophageal manometry. A total of 133 consecutive patients with intractable asthma and symptoms of GER were used as comparisons.

The prevalence of abnormal acid GER in IPF patients was 87%, with 76% and 63% demonstrating abnormal distal and proximal oesophageal acid exposures, respectively. Abnormal acid GER was significantly more common in IPF patients than asthma patients. Only 47% of IPF patients experienced classic GER symptoms. Despite treatment with standard doses of proton pump inhibitors (PPIs), 12 out of 19 patients receiving PPIs during the 24-h pH monitoring had abnormal oesophageal acid exposures by pH probe. There was no correlation between IPF severity and acid GER severity.

In conclusion, abnormal acid gastro-oesophageal reflux is highly prevalent, but often clinically occult in patients with idiopathic pulmonary fibrosis. Standard doses of proton pump inhibitors may not suppress the acid gastro-oesophageal reflux in this population. Therefore, further studies are needed to determine if acid abnormal gastro-oesophageal reflux represents an important risk factor for idiopathic pulmonary fibrosis development or progression, and if optimal suppression of acid gastro-oesophageal reflux slows the progression of idiopathic pulmonary fibrosis and/or decreases episodic exacerbations of idiopathic pulmonary fibrosis.
Delayed and persistent suppression of bronchoconstriction by trypsin in the airway lumen
Authors: Sharma A. , Goh H. L. , Asokananthan N. , Bakker A. , Stewart G. A. , Mitchell H. W.
Published: December 2005

Mucosal trypsin, a protease-activated receptor (PAR) stimulant, may have an endogenous bronchoprotective role on airway smooth muscle. To test this possibility the effects of lumenal trypsin on airway tone in segments of pig bronchus were tested.

Bronchial segments from pigs were mounted in an organ chamber containing Kreb's solution. Contractions were assessed from isovolumetric lumen pressure induced by acetylcholine (ACh) or carbachol added to the adventitia.

Trypsin, added to the airway lumen (300 µg·mL−1), had no immediate effect on smooth muscle tone but suppressed ACh-induced contractions after 60 min, for at least 3 h. Synthetic activating peptides (AP) for PAR1, PAR2or PAR3were without effect, but PAR4AP caused rapid, weak suppression of contractions. Lumenal thrombin was without effect and did not prevent the effects of trypsin. Effects of trypsin were reduced byNω-nitro-l-arginine methyl ester but not indomethacin. Trypsin, thrombin and PAR4AP released prostaglandin E2. Adventitially, trypsin, thrombin and PAR4AP (but not PAR2AP) relaxed carbachol-toned airways after <3 min.

The findings of this study show that trypsin causes delayed and persistent bronchoprotection by interacting with airway cells accessible from the lumen. The signalling mechanism may involve nitric oxide synthase but not prostanoids or protease-activated receptors.
Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension
Authors: Provencher S. , Chemla D. , Hervé P. , Sitbon O. , Humbert M. , Simonneau G.
Published: December 2005

Patients with pulmonary arterial hypertension (PAH) exhibit a limited increase in stroke volume on exercise, and the heart rate (HR) increases may reflect the main mechanism that allows cardiac output to increase. The current prospective study documented the contribution of HR to the 6-min walking distance (6MWD) in idiopathic (IPAH) and nonidiopathic PAH.

Eighty-three patients (46 IPAH and 37 nonidiopathic PAH) underwent haemodynamic evaluation and a 6MWD test. Chronotropic response (peak walking HR minus resting HR) and peripheral oxygen saturation were monitored. Fifty-seven patients were also assessed after 5±2 months of treatment (bosentan n = 38, epoprostenol n = 14, bosentan-epoprostenol n = 3, iloprost n = 2).

Before treatment, the 6MWD was related to numerous demographic, haemodynamic and walking test characteristics. Stepwise regression analysis indicated that the only factors significantly associated with the 6MWD were stroke volume and chronotropic response in both IPAH and nonidiopathic PAH patients. Following treatment, changes in 6MWD were significantly related to changes in chronotropic response in both IPAH and nonidiopathic PAH.

In conclusion, baseline stroke volume and chronotropic response were independently associated with the 6-min walking distance in pulmonary arterial hypertension. The lack of chronotropic response may reflect the loss in normal physiological reserve in more unwell patients.
Baroreflex control of heart rate during sleep in severe obstructive sleep apnoea: effects of acute CPAP
Authors: Bonsignore M. R. , Parati G. , Insalaco G. , Castiglioni P. , Marrone O. , Romano S. , Salvaggio A. , Mancia G. , Bonsignore G. , Di Rienzo M.
Published: December 2005

Baroreflex control of heart rate during sleep (baroreflex sensitivity; BRS) has been shown to be depressed in obstructive sleep apnoea (OSA), and improved after treatment with continuous positive airway pressure (CPAP). Whether CPAP also acutely affects BRS during sleep in uncomplicated severe OSA is still debatable.

Blood pressure was monitored during nocturnal polysomnography in 18 patients at baseline and during first-time CPAP application. Spontaneous BRS was analysed by the sequence method, and estimated as the mean sequence slope.

CPAP did not acutely affect mean blood pressure or heart rate but decreased cardiovascular variability during sleep. Mean BRS increased slightly during CPAP application (from 6.5±2.4 to 7.5±2.9 ms·mmHg−1), mostly in response to decreasing blood pressure. The change in BRS did not correlate with changes in arterial oxygen saturation or apnoea/hypopnoea index.

The small change in baroreflex control of heart rate during sleep at first application of continuous positive airway pressure in severe obstructive sleep apnoea was unrelated to the acute resolution of nocturnal hypoxaemia, and might reflect autonomic adjustments to positive intrathoracic pressure, and/or improved sleep architecture. The small increase in baroreflex control of heart rate during sleep may be of clinical relevance as it was accompanied by reduced cardiovascular variability, which is acknowledged as an independent cardiovascular risk factor.
Inhaled corticosteroids: effects on the airway vasculature in bronchial asthma
Authors: Horvath G. , Wanner A.
Published: December 2005

Inhaled corticosteroids suppress airway inflammation and components of airway remodelling in bronchial asthma. In the tracheobronchial (airway) vasculature, these include the inhibition of inflammatory hyperperfusion, microvascular hyperpermeability, mucosal oedema formation, and the formation of new blood vessels (angiogenesis).

Corticosteroids are now known to exert their effects on the airway vasculature through genomic and nongenomic mechanisms. Genomic actions involve the regulation of target genes, and suppress most of the vascular elements of inflammation and angiogenesis in the airway. In contrast, nongenomic actions are mediated by rapid cellular mechanisms, and induce transient vasoconstriction in the airway, thereby reversing inflammatory hyperperfusion.

The vascular actions of corticosteroids contribute to controlling clinical symptoms of asthma primarily by influencing airway calibre in the lung periphery and airway hyperreactivity.

In this review article, recent advances into the understanding of cellular mechanisms and the clinical implications of the interaction of inhaled corticosteroids and the airway vasculature in asthma are reviewed.
Appropriateness and delay to initiate therapy in ventilator-associated pneumonia
Authors: Luna C. M. , Aruj P. , Niederman M. S. , Garzón J. , Violi D. , Prignoni A. , Ríos F. , Baquero S. , Gando S.
Published: December 2005

Inappropriate therapy (IT) and delayed initiation of appropriate therapy (DIAT) result in inadequate therapy in patients with ventilator-associated pneumonia (VAP). The aim of the current study was to assess the impact of DIAT in VAP. A total of 76 mechanically ventilated patients with bacteriologically confirmed VAP were prospectively evaluated in the intensive care unit of six hospitals in Buenos Aires, Argentina.

Appropriate therapy was defined as coverage of all the identified pathogens by the antimicrobial therapy administered at the time of VAP clinical diagnosis. The clinical pulmonary infection score was measured during the 3 days before, at the onset and during the days which followed the onset of VAP. A total of 24 patients received adequate therapy; mortality was 29.2%. The remaining 52 patients received either IT (n = 16) or DIAT (n = 36); the mortality was 63.5% combined, and 75.0 and 58.3% for IT and DIAT, respectively (statistically significant compared with adequate therapy).

Inappropriate therapy and delayed initiation of appropriate therapy increased the mortality of ventilator-associated pneumonia. Patients with inappropriate therapy and/or delayed initiation of appropriate therapy had a more gradual increase in clinical pulmonary infection score than those receiving adequate therapy, and this increase was found to occur prior to the time of the clinical diagnosis.

In conclusion, these findings might provide the rationale for a trial of earlier initiation of therapy, based on clinical grounds in an effort to improve the outcome of patients with ventilator-associated pneumonia.
Occult alveolar haemorrhage in pulmonary veno-occlusive disease
Authors: Rabiller A. , Jaïs X. , Hamid A. , Resten A. , Parent F. , Haque R. , Capron F. , Sitbon O. , Simonneau G. , Humbert M.
Published: December 2005

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary arterial hypertension that affects predominantly post-capillary pulmonary vessels. A major concern with PVOD is the poor response to available therapies and the risk of pulmonary oedema with continuous intravenous epoprostenol.

The present authors hypothesised that alveolar haemorrhage may be a characteristic feature of pulmonary veno-occlusive disease, as compared with other forms of pulmonary arterial hypertension that predominantly involve pre-capillary pulmonary arteries.

This paper reports a series of 19 patients with either PVOD (n = 8) or idiopathic pulmonary arterial hypertension (IPAH; n = 11) who underwent bronchoalveolar lavage. Cytological analyses were performed and differential counts were made on Perls-stained preparations. The Golde score was used to assess alveolar haemorrhage. As compared with IPAH, PVOD was characterised by a higher percentage of haemosiderin-laden macrophages (40±37versus3±6%), resulting in elevated Golde scores (81±88versus4±10).

It was concluded that occult alveolar haemorrhage is a common feature of pulmonary veno-occlusive disease. Detecting occult alveolar haemorrhage may be of interest in the diagnostic approach of pulmonary veno-occlusive disease.
Area-level socio-economic status and health status among adults with asthma and rhinitis
Authors: Blanc P. D. , Yen I. H. , Chen H. , Katz P. P. , Earnest G. , Balmes J. R. , Trupin L. , Friedling N. , Yelin E. H. , Eisner M. D.
Published: December 2005

Socio-economic status (SES) may affect health status in airway disease at the individual and area level.

In a cohort of adults with asthma, rhinitis or both conditions, questionnaire-derived individual-level SES and principal components analysis (PCA) of census data for area-level SES factors were used. Regression analysis was utilised to study the associations among individual- and area-level SES for the following four health status measures: severity of asthma scores and the Short Form-12 Physical Component Scale (SF-12 PCS) (n = 404); asthma-specific quality of life (QoL) scores (n = 340); and forced expiratory volume in one second (FEV1) per cent predicted (n = 218).

PCA yielded a two-factor solution for area-level SES. Factor 1 (lower area-level SES) was significantly associated with poorer SF-12 PCS and worse asthma QoL. These associations remained significant after adding individual-level SES. Factor 1 was also significantly associated with severity of asthma scores, but not after addition of the individual-level SES. Factor 2 (suburban area-level SES) was associated with lower FEV1per cent predicted in combined area-level and individual SES models.

In conclusion, area-level socio-economic status is linked to some, but not all, of the studied health status measures after taking into account individual-level socio-economic status.
Estimated numbers and prevalence of PI*S and PI*Z alleles of α1-antitrypsin deficiency in European countries
Authors: Blanco I. , de Serres F. J. , Fernandez-Bustillo E. , Lara B. , Miravitlles M.
Published: December 2005

The current study focuses on developing estimates of the numbers of individuals carrying the two most common deficiency alleles, PI*S and PI*Z, for α1-antitrypsin deficiency (AT-D) in Europe.

Criteria for selection of epidemiological studies were: 1) AT phenotyping performed by isoelectrofocusing or antigen–antibody crossed electrophoresis; 2) rejection of “screening studies”; 3) statistical precision factor score of ≥5 for Southwest, Western and Northern Europe, ≥4 for Central Europe, ≥3 for Eastern Europe; and 4) samples representative of the general population.

A total of 75,390 individuals were selected from 21 European countries (one each from Austria, Belgium, Latvia, Hungary, Serbia-Montenegro, Sweden and Switzerland; two each from Denmark, Estonia and Lithuania; three each from Portugal and the UK; four each from Finland, the Netherlands, Norway and Spain; five each from Russia and Germany; six from Poland; eight from Italy; and nine from France). The total AT-D populations of a particular phenotype in the countries selected were: 124,594 ZZ; 560,515 SZ; 16,323,226 MZ; 630,401 SS; and 36,716,819 MS. The largest number of ZZ (5,000–15,000) were in Italy, Spain, Germany, France, the UK, Latvia, Sweden and Denmark, followed by Belgium, Portugal, Serbia-Montenegro, Russia, The Netherlands, Norway and Austria (1,000–2,000), with <1,000 in each of the remaining countries.

A remarkable lack in number of reliable epidemiological studies and marked differences among these European countries and regions within a given country was also found.
Validation of a predictive rule for the management of community-acquired pneumonia
Authors: Capelastegui A. , España P. P. , Quintana J. M. , Areitio I. , Gorordo I. , Egurrola M. , Bilbao A.
Published: December 2005

The CURB-65 score (Confusion, Urea >7 mmol·L−1, Respiratory rate ≥30·min−1, low Blood pressure, and age ≥65 yrs) has been proposed as a tool for augmenting clinical judgement for stratifying patients with community-acquired pneumonia (CAP) into different management groups.

The six-point CURB-65 score was retrospectively applied in a prospective, consecutive cohort of adult patients with a diagnosis of CAP seen in the emergency department of a 400-bed teaching hospital from March 1, 2000 to February 29, 2004. A total of 1,100 inpatients and 676 outpatients were included.

The 30-day mortality rate in the entire cohort increased directly with increasing CURB-65 score: 0, 1.1, 7.6, 21, 41.9 and 60% for CURB-65 scores of 0, 1, 2, 3, 4, and 5, respectively. The score was also significantly associated with the need for mechanical ventilation and rate of hospital admission in the entire cohort, and with duration of hospital stay among inpatients.

The CURB-65 score (Confusion, Urea >7 mmol·L−1, Respiratory rate ≥30·min−1, low Blood pressure, and age ≥65 yrs), and a simpler CRB-65 score that omits the blood urea measurement, helps classify patients with community-acquired pneumonia into different groups according to the mortality risk and significantly correlates with community-acquired pneumonia management key points. The new score can also be used as a severity adjustment measure.
Cough and hypereosinophilia due toFIP1L1-PDGFRAfusion gene with tyrosine kinase activity
Authors: Chung K. F. , Hew M. , Score J. , Jones A. V. , Reiter A. , Cross N. C. P. , Bain B. J.
Published: December 2005

Eosinophil-associated conditions, such as asthma and eosinophilic bronchitis, have been associated with chronic persistent cough, usually responding to corticosteroid therapy.

This case study reports a case of persistent cough associated with gastro-oesophageal reflux (GOR) and hypereosinophilia. Treatment of GOR with proton pump inhibitors and fundoplication did not control the cough. However, high dose prednisolone, but not inhaled corticosteroids, did.

The presence of theFIP1L1-PDGFRAfusion gene in myeloid cells was confirmed by fluorescencein situhybridisation analysis usingCHIC2deletion as a surrogate marker. The cough and other disease features were subsequently suppressed by the tyrosine kinase inhibitor, imatinib.

This is the first case of persistent cough caused by hypereosinophilic syndrome characterised byFIP1L1-PDGFRAfusion gene and aberrant tyrosine kinase activity.
Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features
Authors: Kim D. S. , Park J. H. , Park B. K. , Lee J. S. , Nicholson A. G. , Colby T.
Published: December 2005

Although acute exacerbations of idiopathic pulmonary fibrosis are well recognised, there are no studies documenting their prevalence or identifying pre-existing risk factors.

This study analysed the clinical, radiological and pathological data of 11 patients who satisfied the criteria for acute exacerbation among 147 patients with biopsy-proven idiopathic pulmonary fibrosis. There were five additional patients who had similar demographics, radiology and surgical lung biopsy pathology, but had clinically less severe disease, and so were not included. The 2-yr frequency of acute exacerbation was 9.6% after the diagnosis. Most exacerbations were idiopathic, although two cases presented after surgical lung biopsy and one after bronchoalveolar lavage.

No significant risk factor was found by univariate proportional hazard analysis. Imaging revealed diffuse bilateral ground-glass opacification superimposed on subpleural reticular and honeycombing densities. The biopsies of four patients taken during acute exacerbation exhibited diffuse alveolar damage superimposed upon usual interstitial pneumonia.

The findings of this study demonstrate that acute exacerbation of idiopathic pulmonary fibrosis is rather common and this exacerbation is likely to have a spectrum of severity.
The contribution of transforming growth factor-β and epidermal growth factor signalling to airway remodelling in chronic asthma
Authors: Boxall C. , Holgate S. T. , Davies D. E.
Published: December 2005

Asthma is increasing in prevalence in the developing world, affecting ∼10% of the world’s population. It is characterised by chronic lung inflammation and airway remodelling associated with wheezing, shortness of breath, acute bronchial hyperresponsiveness to a variety of innocuous stimuli and a more rapid decline in lung function over time.

Airway remodelling, involving proliferation and differentiation of mesenchymal cells, particularly myofibroblasts and smooth muscle cells, is generally refractory to corticosteroids and makes a major contribution to disease chronicity. Transforming growth factor-β is a potent profibrogenic factor whose expression is increased in the asthmatic airways and is a prime candidate for the initiation and persistence of airway remodelling in asthma.

This review highlights the role of transforming growth factor-β in the asthmatic lung, incorporating biosynthesis, signalling pathways and functional outcome.In vivo, however, it is the balance between transforming growth factor-β and other growth factors, such as epidermal growth factor, which will determine the extent of fibrosis in the airways.

A fuller comprehension of the actions of transforming growth factor-β, and its interaction with other signalling pathways, such as the epidermal growth factor receptor signalling cascade, may enable development of therapies that control airway remodelling where there is an unmet clinical need.
Obstructive sleep apnoea and its therapy influence high-density lipoprotein cholesterol serum levels
Authors: Börgel J. , Sanner B. M. , Bittlinsky A. , Keskin F. , Bartels N. K. , Buechner N. , Huesing A. , Rump L. C. , Mügge A.
Published: December 2005

Recent studies suggest an association of obstructive sleep apnoea (OSA) with cardiovascular risk factors, such as dyslipidaemia.

The present study analyses the effects of OSA and its therapy on serum lipid concentrations in 470 OSA patients in a single centre study.

Multivariate regression showed a significant association between the apnoea–hypopnoea index and high-density lipoprotein cholesterol (HDL-C) serum levels (n = 366), independent of age, sex, body mass index, diabetes and lipid lowering medication. There were no independent associations with total cholesterol, triglyceride and low-density lipoprotein cholesterol serum levels. During follow-up (6 months) with effective bilevel or continuous positive airway pressure therapy in 127 patients (lipoproteins: n = 86) without change in their lipid lowering therapy, the mean HDL-C serum level increased significantly by 5.8% from 46.9±15.8 to 49.6±15.3 mg·dL−1(mean±SD).

An independent relationship was found between the change of apnoea–hypopnoea index and the change of high-density lipoprotein cholesterol or triglycerides, respectively. All patients with abnormal serum lipid/lipoprotein levels improved significantly under bilevel or continuous positive airway pressure therapy. This study demonstrates an influence of obstructive sleep apnoea and its therapy on high-density lipoprotein cholesterol levels.