bluuebunny/crossref_metadata_2025 huggingface dataset:
P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells
Authors: Guimond Martin , Balassy Antonia , Barrette Mélanie , Brochu Sylvie , Perreault Claude , Roy Denis Claude
Published: October 2002

T lymphocytes have been found to harbor P-glycoprotein (Pgp) and to demonstrate modulation of its ion channel transporter function according to the state of activation of T lymphocytes. We hypothesized that cytotoxic chemicals that are extruded by Pgp could be used to specifically eliminate immunoreactive T-cell populations. In this study, we evaluated the capacity of 4,5-dibromorhodamine methyl ester (TH9402), a photosensitizer structurally similar to rhodamine, a dye transported by Pgp, and which becomes highly cytotoxic on activation with visible light to selectively deplete alloreactive T lymphocytes. Stimulation of T cells with mitogens or allogeneic major histocompatibility complex–mismatched cells resulted in the preferential retention of the TH9402 rhodamine-derivative in activated T cells, both CD4+ and CD8+. Photodynamic cell therapy of TH9402-exposed T cells led to the selective elimination of immunoreactive T-cell populations. In addition, this treatment preserved resting T cells and their capacity to respond to third-party cells. Inhibition of Pgp enhanced cellular trapping of the dye in nonactivated T cells and resulted in their depletion after exposure to light. Targeting of Pgp-deficient cells may therefore represent an appealing strategy for the prevention and treatment of graft-versus-host disease and other alloimmune or autoimmune disorders.
Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by Vβ CDR3 spectratyping and flow cytometry
Authors: Risitano Antonio M. , Kook Hoon , Zeng Weihua , Chen Guibin , Young Neal S. , Maciejewski Jaroslaw P.
Published: October 2002

We have hypothesized that in aplastic anemia (AA) the presence of antigen-specific T cells is reflected by their contribution to the expansion of a particular variable beta chain (Vβ) subfamily and also by clonal CDR3 skewing. To determine the role of disease-specific “signature” T-cell clones in AA, we studied preferential Vβ usage by flow cytometry and analyzed Vβ-CDR3 regions for the presence of oligoclonality. We first established the contribution of each Vβ family to the total CD4+ and CD8+ lymphocyte pool; in AA and paroxysmal nocturnal hemoglobinuria, a seemingly random overrepresentation of different Vβ families was observed. On average, we found expansion in 3 (of 22 examined) Vβ families per patient. When the contribution of individual Vβ families to the effector pool was examined, more striking Vβ skewing was found. Vβ-CDR3 size distribution was analyzed for the expanded Vβ families in isolated CD4+ and CD8+ populations; underrepresented Vβ families displayed more pronounced CDR3 skewing. Expanded CD4+Vβ subfamilies showed mostly a polyclonal CDR3 size distribution with only 38% of skewing in expanded Vβ families. In contrast, within overrepresented CD8+Vβ types, marked CDR3 skewing (82%) was seen, consistent with nonrandom expansion of specific CD8+ T-cell clones. No preferential expansion of particular Vβ families was observed, in relation to HLA-type. In patients examined after immunosuppressive therapy, an abnormal Vβ-distribution pattern was retained, but the degree of expansion of individual Vβ was lower. As Vβ skewing may correlate with relative Vβ size, oligoclonality in combination with numerical Vβ expansion can be applied to recognition of disease-specific T-cell receptors.
Myelodysplastic syndrome is not merely “preleukemia”
Authors: Albitar Maher , Manshouri Taghi , Shen Yu , Liu Diane , Beran Miloslav , Kantarjian Hagop M. , Rogers Anna , Jilani Iman , Lin Chung Wu , Pierce Sherry , Freireich Emil J. , Estey Elihu H.
Published: October 2002

Myelodysplastic syndrome (MDS) is a disease characterized by ineffective hematopoiesis. There are significant biologic and clinical differences between MDS and acute myeloid leukemia (AML). We studied a cohort of 802 patients, 279 (35%) with newly diagnosed MDS and 523 (65%) with newly diagnosed AML, and compared clinical and biologic characteristics of the 2 groups. Complete clinical and cytogenetic data were available on all patients, and a subgroup of patients was studied for apoptosis, angiogenesis, proliferation, and growth factors. Our results demonstrate that MDS is a discrete entity that is different from AML and is characterized primarily by increased apoptosis in early and mature hematopoietic cells. Using cell sorting and loss of heterozygosity, we demonstrate that the leukemic cells from MDS patients are capable of differentiation into mature myeloid cells and monocytes. We also demonstrate that there is a significant overlap between AML and MDS when MDS is defined on the basis of an arbitrary percentage of blasts of 20% or 30%. These data suggest that despite similarities between AML and MDS in their responses to treatment and outcomes, MDS is biologically and clinically different from AML and should not be considered an early phase of AML. The data indicate that MDS must be better defined on the basis of its biology rather than the percentage of blasts; further, the data suggest that there is a need to develop therapeutic approaches that specifically address the biologic abnormalities of MDS.
Persistent numbers of tetramer+ CD8+ T cells, but loss of interferon-γ+ HIV-specific T cells during progression to AIDS
Authors: Kostense Stefan , Vandenberghe Kristin , Joling Jeanine , Van Baarle Debbie , Nanlohy Nening , Manting Erik , Miedema Frank
Published: October 2002

Although CD8+ T cells initially suppress human immunodeficiency virus (HIV) replication, cytotoxic T-cell precursor frequencies eventually decline and fail to prevent disease progression. In a longitudinal study including 16 individuals infected with HIV-1, we studied both the number and function of HIV-specific CD8+ T cells by comparing HLA-peptide tetramer staining and peptide-induced interferon-γ (IFN-γ) production. Numbers of IFN-γ–producing T cells declined during progression to acquired immunodeficiency syndrome (AIDS), whereas the number of tetramer+ T cells in many individuals persisted at high frequencies. Loss of IFN-γ–producing T cells correlated with declining CD4+ T-cell counts, consistent with the need of CD4+ T-cell help in maintaining adequate CD8+T-cell function. These data indicate that the loss of HIV-specific CD8+ T-cell activity is not due to physical depletion, but is mainly due to progressively impaired function of HIV-specific CD8+ T cells.
Immunization against murine multiple myeloma with fusions of dendritic and plasmacytoma cells is potentiated by interleukin 12
Authors: Gong Jianlin , Koido Shigeo , Chen Dongshu , Tanaka Yasuhiro , Huang Lei , Avigan David , Anderson Kenneth , Ohno Tsuneya , Kufe Donald
Published: October 2002

Fusions of cancer cells and dendritic cells (DCs) are effective in the treatment of animal tumor models and patients with metastatic renal carcinoma. In this study, we have fused DCs with mouse 4TOO plasmacytoma cells. The results demonstrate that vaccination of mice with the fusion cells (FC/4TOO) is associated with induction of antitumor humoral and cytotoxic T lymphocyte (CTL) responses. Immunization with FC/4TOO cells protected mice against tumor challenge. In addition, treatment of established multiple myeloma with FC/4TOO cells was associated with prolongation of survival but not with eradication of disease. As interleukin (IL)-12 potentiates the induction of immune responses, recombinant mouse IL-12 was administered with the FC/4TOO vaccine. Treatment of mice with FC/4TOO and IL-12 was associated with increased CTL activity and T-cell proliferation responses. Treatment with FC/4TOO and IL-12 also resulted in eradication of established disease. These findings demonstrate that immunization with FC/4TOO fusion cells and IL-12 potentiates antitumor immunity and the treatment of murine multiple myeloma.
Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor
Authors: Basser Russell L. , O'Flaherty Elizabeth , Green Michael , Edmonds Maria , Nichol Janet , Menchaca Dora M. , Cohen Brian , Begley C. Glenn
Published: October 2002

Clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis, have revealed few side effects associated with its use. We here report a case of pancytopenia associated with the development of neutralizing antibodies to TPO that occurred in a patient who had undergone multicycle chemotherapy with multiple cycles of subcutaneous administration of pegylated recombinant human megakaryocyte growth and development factor. Samples of the patient's bone marrow showed trilineage hypoplasia with absence of myeloid, erythroid, and megakaryocyte progenitor cells but with elevated endogenous levels of erythropoietin, granulocyte colony-stimulating factor, and stem-cell factor. To our knowledge, this is the first report of an aplastic anemia–like syndrome associated with neutralizing antibodies to TPO.
IRTAs: a new family of immunoglobulinlike receptors differentially expressed in B cells
Authors: Miller Ira , Hatzivassiliou Georgia , Cattoretti Giorgio , Mendelsohn Cathy , Dalla-Favera Riccardo
Published: October 2002

The IRTA1 and IRTA2 genes encode immunoglobulinlike cell surface receptors expressed in B cells and involved in chromosome 1q21 translocations in B-cell malignancy. We have now characterized and comparatively analyzed the structure and expression pattern of the entire family of IRTA genes, which includes 5 members contiguously located on chromosome 1q21. The IRTA messenger RNAs are expressed predominantly in the B-cell lineage within discrete B-cell compartments: IRTA1 is specific to the marginal zone, IRTA2 and IRTA3 are found in the germinal center light zone and in intraepithelial and interfollicular regions, and IRTA4 and IRTA5 are expressed predominantly in the mantle zone. All IRTA genes code for transmembrane receptors that are closely related to Fc receptors in their most amino-terminal extracellular domains and that possess cytoplasmic domains containing ITIM (immunotyrosine inhibition motifs)– and, possibly, ITAM (immunotyrosine activation motifs)–like motifs. These structural features suggest that the IRTA receptors may play a role in regulating activation of normal B cells and possibly in the development of neoplasia.
Increased dendritic cell number and function following continuous in vivo infusion of granulocyte macrophage–colony-stimulating factor and interleukin-4
Authors: Basak Saroj K. , Harui Airi , Stolina Marina , Sharma Sherven , Mitani Kohnosuke , Dubinett Steven M. , Roth Michael D.
Published: October 2002

Dendritic cells (DCs) are rare antigen-presenting cells that play a central role in stimulating immune responses. The combination of recombinant granulocyte macrophage–colony-stimulating factor (rGM-CSF) and recombinant interleukin-4 (rIL-4) provides an important stimulus for generating DCs from murine bone marrow precursors in vitro. Using miniature osmotic pumps, we now demonstrate that continuous infusion of these cytokines for 7 days had a similar effect in vivo, increasing the number and function of splenic DCs. Administration of rGM-CSF/rIL-4 (10 μg/d each) increased the concentration of CD11+ DCs by 2.7-fold and the absolute number of splenic DCs by an average of 5.7-fold. DC number also increased in peripheral blood and lymph nodes. The resultant DCs exhibited a different phenotype and function than those in control mice or mice treated with rGM-CSF alone. rGM-CSF/IL-4 increased both the myeloid (CD11c+/CD11b+) and the lymphoid (CD11c+/CD8α+) subpopulations, whereas rGM-CSF increased only myeloid DCs. DCs were highly concentrated in the T-cell areas of white pulp after rGM-CSF/IL-4 administration, whereas they were diffusely distributed throughout white pulp, marginal zones, and red pulp in mice treated with rGM-CSF alone. rGM-CSF/rIL-4 also significantly increased the expression of major histocompatibility complex (MHC) class I and MHC class II on CD11c+ cells and increased their capacity to take up antigens by macropinocytosis and receptor-mediated endocytosis. Splenic DCs generated in response to rGM-CSF/rIL-4 were functionally immature in terms of allostimulatory activity, but this activity increased after short-term in vitro culture. Systemic treatment with rGM-CSF/rIL-4 enhanced the response to an adenoviral-based vaccine and led to antigen-specific retardation in the growth of established tumor. We conclude that systemic therapy with the combination of rGM-CSF/rIL-4 provides a new approach for generating DCs in vivo.
Spontaneous generation and survival of blood dendritic cells in mononuclear cell culture without exogenous cytokines
Authors: Ho Christopher S. K. , Munster David , Pyke Christopher M. , Hart Derek N. J. , López J. Alejandro
Published: October 2002

Studies on purified blood dendritic cells (DCs) are hampered by poor viability in tissue culture. We, therefore, attempted to study some of the interactions/relationships between DCs and other blood cells by culturing unseparated peripheral blood mononuclear cell (PBMC) preparations in vitro. Flow cytometric techniques were used to undertake a phenotypic and functional analysis of DCs within the cultured PBMC population. We discovered that both the CD11c+ and CD11c− CD123hi DC subsets maintained their viability throughout the 3-day culture period, without the addition of exogenous cytokines. This viability was accompanied by progressive up-regulation of the surface costimulatory (CD40, CD80, CD86) and activation (CMRF-44, CMRF-56, CD83) molecules. The survival and apparent production of DCs in PBMC culture (without exogenous cytokines) and that of sorted DCs (with cytokines) were evaluated and compared by using TruCOUNT analysis. Absolute DC counts increased (for CD123hi and CD11c+ subsets) after overnight culture of PBMCs. Single-cell lineage depletion experiments demonstrated the rapid and spontaneous emergence of “new” in vitro generated DCs from CD14+/CD16+ PBMC radioresistant precursors, additional to the preexisting ex vivo DC population. Unlike monocyte-derived DCs, blood DCs increased dextran uptake with culture and activation. Finally, DCs obtained after culture of PBMCs for 3 days were as effective as freshly isolated DCs in stimulating an allogeneic mixed leukocyte reaction.
IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules
Authors: Underhill Gregory H. , Minges-Wols Heather A. , Fornek Jamie L. , Witte Pamela L. , Kansas Geoffrey S.
Published: October 2002

Long-lived antibody-secreting plasma cells are formed in the secondary lymphoid organs and subsequently home to the bone marrow, although the mechanisms that control this migration remain primarily unknown. In this study, we show that IgG plasma cells constitute a significant fraction of cervical lymph node cells from older mice deficient in both E- and P-selectin (E/P−/−), and that these cells can be prospectively isolated by phenotype. These IgG plasma cells were polyclonal, cytoplasmic Ig+, spontaneously secreted antibody, were in the G0/G1 phase of the cell cycle, and failed to express multiple B-cell surface markers. The plasma cells exhibited up-regulated cell surface expression of multiple adhesion molecules, including α4 and leukocyte function-associated antigen 1 (LFA-1) integrins, CD44, and P-selectin glycoprotein ligand 1 (PSGL-1). IgG plasma cells bound to vascular cell adhesion molecule 1 (VCAM-1) significantly better than IgM+B cells, indicating that the α4 integrins were constitutively active. A subset of IgG plasma cells also bound hyaluronic acid, the ligand for CD44. In addition, the IgG plasma cells interacted strongly with E-selectin, but poorly with P-selectin, despite elevated levels of PSGL-1 protein. The preferential interaction of plasma cells with E-selectin, but not P-selectin, correlated with elevated α1,3-fucosyltransferase-VII messenger RNA levels, but selective down-regulation of core 2 β1-6-N-glucosaminyltransferase levels, compared to B cells. These results demonstrate a unique adhesion profile for murine IgG plasma cells. Furthermore, the E/P−/− mice represent a novel system to isolate and purify significant numbers of primary IgG plasma cells.
Human Immune Associated Nucleotide 1: a member of a new guanosine triphosphatase family expressed in resting T and B cells
Authors: Cambot Marie , Aresta Sandra , Kahn-Perlès Brigitte , de Gunzburg Jean , Roméo Paul-Henri
Published: October 2002

TAL-1 is a basic helix-loop-helix oncoprotein that is expressed in up to 30% of T-cell acute lymphoblastic leukemias but not in the T lineage. We have cloned a complementary DNA, called Human Immune Associated Nucleotide 1 (hIAN1), whose messenger RNA (mRNA) level expression is inversely correlated to the TAL-1 mRNA level in human leukemic T-cell lines. The hIAN1 encodes a 38-kd protein that belongs to a novel family of proteins conserved from plants to humans and characterized by motifs related to, but highly divergent from, the consensus motifs found in guanosine triphosphate (GTP)–binding proteins. Despite these divergent amino acids at positions involved in GTP/guanosine diphosphate (GDP) binding and guanosine triphosphatase (GTPase) activities, we found that hIAN1 specifically binds GDP (Kd = 0.47 μM) and GTP (Kd = 6 μM) and exhibits intrinsic GTPase activity. Among mature hematopoietic cells, hIAN1 is specifically expressed in resting T and B lymphocytes, and its expression level tremendously decreased at the protein but not the mRNA level during B- or T-lymphocyte activation, suggesting a specific role for this new type of GTPase during the immune response.
Population depletion activates autonomous CD154-dependent survival in biopsylike Burkitt lymphoma cells
Authors: Challa Anita , Eliopoulos Aristides G. , Holder Michelle J. , Burguete Alondra Schweizer , Pound John D. , Chamba Anita , Grafton Gillian , Armitage Richard J. , Gregory Christopher D. , Martinez-Valdez Hector , Young Lawrence , Gordon John
Published: October 2002

Population size is governed through cells reacting to a variety of intrinsic and extrinsic cues. Tumors, while liberated from many of the homeostatic constraints placed on physiologic counterparts, can nonetheless remain subject to both social and environmental control. Burkitt lymphoma cells faithful to the biopsy phenotype were used to model the reliance of the colony, if any, on an inbuilt population sensor. Below a normally suicidal threshold number of cells, low picomolar quantities of exogenous CD40 ligand (CD40L/CD154) were found to sustain the clone without the discernible shift in phenotype that accompanies high CD40L encounter. Although CD154 was undetectable in populous cultures, message was induced as numbers became limiting. Correspondingly, attempts to neutralize endogenous CD40L activity failed to perturb cells at optimal densities but resulted in their marked decline as the critical threshold was approached. These data reveal an auto-inducible survival mechanism seemingly regulated through the monitoring of population size, a process somewhat akin to that of “quorum sensing” among gram-negative bacteria in which diffusible molecules provide a means of communication to coordinate gene expression with population density. This process could be activated as cells discern depletions in their community or when deprived of signals otherwise furnished within an appropriate environmental niche.
A small outbreak of Legionnaires' disease in a cargo ship under repair
Authors: Caylà J.A. , Maldonado R. , González J. , Pellicer T. , Ferrer D. , Pelaz C. , Gracia J. , Baladrón B. , Plaséncia A.
Published: October 2002

It was reported that two mechanics working on a cargo ship under repair in the port of Barcelona had died after having fever.

An investigation was made into the possibility of any additional cases and the presence ofLegionella pneumophilain the ship they were repairing and in their hotel. The contaminated water system was treated with sodium hypochlorite.

Both patients died after having been repeatedly diagnosed as having influenza. The two cases occurred among those who had been working with the pump of the ship's water system, while no cases were observed among the other workers (p=0.02). Various serogroups ofL. pneumophilawere isolated from the ship's water pump and distribution system. However, organism of serogroup 1, subgroup Pontiac (Knoxville) were identified with identical deoxyribonucleic acid (DNA) patterns in the lung tissue of one patient and in the cooling water circuit valve of the ship's water pump. The first postintervention control water samples showed no further growth of legionella, but serogrups 4 and 8 were identified 8 months later.

This legionellosis outbreak, although small, was highly lethal, probably due to the high levels of bacteria to which the patients were exposed and also because of the failure of correct diagnosis. International recommendations on prevention and control of legionellosis, which include ships under repair, are required.
Increased nitrotyrosine in exhaled breath condensate in cystic fibrosis
Authors: Balint B. , Kharitonov S.A. , Hanazawa T. , Donnelly L.E. , Shah P.L. , Hodson M.E. , Barnes P.J.
Published: October 2002

Exhaled nitric oxide (ENO), a marker of inflammation in airway diseases is decreased in cystic fibrosis (CF) patients, perhaps because nitric oxide (NO) is metabolized to oxidative end-products. A stable product, 3-nitrotyrosine, may indicate local formation of reactive nitrogen species.

Whether NO metabolites in exhaled breath condensate may be increased in CF patients was investigated. The fractional concentration of ENO (Feno), nitrotyrosine and oxides of nitrogen in exhaled breath condensate from 36 stable CF patients were compared to 14 normal subjects using an enzyme immunoassay and fluorescence assay.

Nitrotyrosine levels in breath condensate were increased significantly in stable CF patients, compared with normal subjects (25.3±1.5versus6.3±0.8 ng·mL−1, p<0.0001). There was an inverse correlation between the levels of nitrotyrosine and the severity of lung disease.Fenolevels were significantly lower in CF patients than in normal subjects (4.4±0.3versus5.6±0.4 (parts per billion), p<0.05). No correlation was found between nitrotyrosine andFenolevels in CF. There was no significant difference in the levels of nitrite and nitrate between CF patients and normals.

The elevation in nitrotyrosine may reflect increased formation of reactive nitrogen species such as peroxynitrite or direct nitration by granulocyte peroxidases, indicating increased oxidative stress in airways of cystic fibrosis patients.
Influenza: vaccination and treatment
Authors: Stephenson I. , Nicholson K.G.
Published: October 2002

Few conditions exert such an enormous toll of absenteeism, suffering, medical consultations, hospitalization, death and economic loss as influenza. Patients at high risk of complications and mortality include the elderly and those with pre-existing cardiopulmonary disease.

The outbreak in 1997 in Hong Kong, of avian H5N1 influenza in man, which resulted in six deaths among 18 hospitalized cases, and the recent isolation of H9N2 viruses from two children in Hong Kong, are reminders that preparation must be made for the next pandemic. Since the 1970s, efforts to control influenza have mostly focussed on the split product and surface antigen vaccines. These vaccines are of proven efficacy in healthy adults and are effective in elderly people with and without medical conditions putting them at high risk of complications and death following influenza infection.

However, vaccine coverage is patchy and often low, and outbreaks of influenza are not uncommon in well-immunized residents of nursing homes. New vaccines and methods of vaccine delivery are being developed in attempts to overcome the limitations of existing vaccines.

The antiviral drugs amantadine and rimantadine were developed in the 1960s, but have not been used widely due to their spectrum of activity, rapid emergence of resistance, and adverse effects associated with amantadine. The site of enzyme activity of the influenza neuraminidase is highly conserved between types, subtypes and strains of influenza and has emerged as the target of an exciting new class of antiviral agents that are effective both prophylactically and as therapy.
Pharmacological treatment of the biochemical defect in cystic fibrosis airways
Authors: Rodgers H.C. , Knox A.J.
Published: October 2002

The understanding of the biochemical defect in cystic fibrosis (CF) has advanced considerably since discovery of the CF gene in 1989 and characterization of its product. Studies showing that the abnormality in chloride flux could be corrected by transfection of wild-type cystic fibrosis transmembrane conductance regulator (CFTR) complimentary deoxyribonucleic acid (cDNA) have led to gene therapy trials on both sides of the Atlantic. However, gene therapy as a treatment for CF has yet to be realized.

Pharmacological manipulation of the biochemical defect may provide an alternative or complementary approach to treatment. This review will discuss pharmacological agents in development which could correct the abnormal ion movement.

The mechanisms of action of these pharmacological agents can be divided broadly into drugs which affect the most common CF mutation, ΔF508, which increase trafficking of the mutant CF protein to the apical membrane; drugs which increase chloride secretion; and drugs which reduce sodium reabsorption across the apical membrane.

Treatment options for cystic fibrosis have developed rapidly since discovery of the cystic fibrosis gene over a decade ago. The targeting of specific therapies for particular cystic fibrosis genotypes and the use of combination treatments of chloride channel openers with sodium channel blockers are likely to be key advances in the next decade.
Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening
Authors: Postma D.S. , Sevette C. , Martinat Y. , Schlösser N. , Aumann J. , Kafé H.
Published: October 2002

The study addressed the question whether the novel inhaled prodrug corticosteroid ciclesonide is equally effective when inhaled in the morning compared to the evening.

For this purpose a double-blind, randomized, parallel group study was initiated in which 209 asthmatic patients (forced expiratory volume in one second=50–90% predicted) inhaled either 200 µg ciclesonide in the morning or in the evening, for 8 weeks. Efficacy was assessed by means of spirometry as well as daily recordings of morning and evening peak expiratory flow (PEF), symptoms and use of rescue medication. The 24-h urinary cortisol excretion was measured to evaluate any effect on hypothalamic-pituitary-adrenol axis.

Ciclesonide significantly improved asthma control. Morning and evening administration was shown to be equally effective for the different spirometry variables, evening PEF, symptoms, use of rescue medication and number of asthma exacerbations. Regarding morning PEF, the improvements after evening dosing were more prominent and equivalence of morning and evening administration could not be demonstrated. No relevant influence on cortisol excretion was found.

Overall, the study indicates that ciclesonide can be given either in the morning or in the evening to meet the patients' preference and individual medical needs, although evening administration may lead to a more pronounced improvement in morning peak expiratory flow.
Noninvasive ventilation and obstructive lung diseases
Authors: Cuvelier A. , Muir J-F.
Published: October 2002

The key role of noninvasive positive pressure ventilation (NPPV) is well documented in chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF) since it may avoid endotrachal intubation in >50% of cases when used as the initial treatment. However, currently only minimal data is available to assess usefulness of NPPV in COPD patients on a long-term basis. Even if such studies are difficult to manage, there is clearly a need for prospective studies comparing long-term oxygen therapy (LTOT) and NPPV in the most severe COPD in a large amount of patients and on a real long-term basis of several years. Two randomized prospective studies are being completed in Europe and the first preliminary results show that NPPV is associated with a reduction of hospitalization for chronic respiratory failure decompensation.

The main beneficial effect of long-term mechanical ventilation in COPD patients with chronic respiratory failure implies a correction of nocturnal hypoventilation that could persist beyond the ventilation period because of a temporary improvement in carbon dioxide sensitivity that is often blunted in these patients.

A synthesis from the literature suggest to consider NPPV for severe COPD patients who present with chronic hypoxia and hypercapnia and develop an unstable respiratory condition. Instability may be appreciated on a clinical basis and confirmed by a progressive worsening of arterial blood gas tensions, leading to frequent cardiorespiratory decompensations with ominous ARF episodes. NPPV should also be considered after an ARF episode successfully treated by noninvasive ventilation but with the impossibility to wean the patient from the ventilator.

Thus, noninvasive positive pressure ventilation could be proposed as a preventive treatment in severe chronic obstructive pulmonary disease patients with unstable respiratory condition associated with fluctuating hypercapnia before, during and after an acute respiratory failure episode, avoiding the need for a tracheotomy. Adjunction of noninvasive ventilation to exercise rehabilitation is under evaluation.
Microbial investigation in ventilator-associated pneumonia
Authors: Ioanas M. , Ferrer R. , Angrill J. , Ferrer M. , Torres A.
Published: October 2002

Ventilator-associated pneumonia (VAP) is a serious infectious condition in intensive care unit (ICU) patients, currently related to a high mortality rate. Therefore, this complication of mechanical ventilation requires a prompt diagnosis and adequate antibiotic treatment. The detection of the causative organism is imperative for guiding an appropriate therapy as there is strong evidence of the adverse effect of inadequate empirical treatment on outcome. The major difficulty of the microbial investigation is to obtain the sample from the lower respiratory tract, mainly because of the potential contamination with upper airways flora, which may result in a misinterpretation of the cultures.

Microbial investigation in VAP is based on the culture of samples obtained from lower respiratory tract by noninvasive or invasive methods. The most common techniques of sampling are the endotracheal aspirate (ETA), which is considered a noninvasive method, the protected specimen brush (PSB) and the bronchoalveolar lavage (BAL), both being invasive methods of investigation. The latter were designed as an attempt to avoid the colonizing flora of the upper airways. The best of these diagnostic approaches is still controversial. In terms of outcome, there is strong evidence that the impact of both invasive and noninvasive methods seems to be similar. In terms of cost, however, the endotracheal aspirate is less expensive compared to BAL or PSB. On the other hand, invasive methods could be particularly beneficial in patients who are not responding to the initial empirical antibiotic treatment.

The rationale for the quantitative culture of the respiratory samples is to differentiate between infection and colonization of lower airways, because the bacterial colonization is a frequent event in mechanically ventilated patients. The thresholds currently employed for the diagnosis of the pneumonia are the following: ETA samples, ≥105–106colony forming units (cfu)·mL−1; PSB samples, ≥103cfu·mL−1; and BAL samples, ≥104 cfu·mL−1.

Intending to provide a practical approach to the issue, the present manuscript reviews the available noninvasive (blood culture, endotracheal aspirate) and invasive (protected specimen brush, bronchoalveolar lavage, blinded methods and lung biopsy) techniques used for the diagnosis of ventilator-associated pneumonia.
High or standard initial dose of budesonide to control mild-to-moderate asthma?
Authors: Chanez P. , Karlstrom R. , Godard P.
Published: October 2002

Guidelines on the use of inhaled steroids in asthma advocate that the daily dose should be chosen according to the severity of the disease. However, the question of the optimal starting dose remains to be properly addressed, as does the issue of the adjustment in dose required for a given patient.

Whether a high initial dose of budesonide (800 µgb.i.d) was more efficacious than a standard dose (200 µgb.i.d) in controlling mild-to-moderate asthma was investigated, and whether the dose could be decreased, based on peak expiratory flow (PEF), symptom-score, β2-agonist use in a double-blind, randomized, parallel-group 18-week study.

One-hundred and sixty-nine patients (mean age 38 yrs, mean forced expiratory volume in one second 74% predicted) were enrolled. No difference was detected between the two groups in improvement in morning PEF (+61 L·min−1in the high-dose group, +60 L·min−1in the standard-dose group by 16 weeks). Morning and evening PEF values stabilized before the end of the first 4 weeks.

No difference between groups was observed in symptom score, β2-agonist use, number of exacerbation per interval and the best forced expiratory volume in one second achieved. The proportion of subjects being able to decrease the doses of budesonide was similar in both treatment strategies. It is concluded that both high and standard initial doses are equally effective in controlling symptoms and improving lung function in mild-to-moderate asthma.
Increased nitric oxide production by neutrophils in bronchial asthma
Authors: Ramesh G. , Jindal S.K. , Ganguly N.K. , Dhawan V.
Published: October 2002

This study was designed to assess the production of nitric oxide (NO) by neutrophils in bronchial asthma.

Thirty asthmatic patients (ten each of mild, moderate and severe asthma) and ten healthy controls were included in the study. Neutrophils from peripheral venous blood were stimulated with latex, and production of nitrite (an NO metabolise) and l-citrulline (a co-product of NO) was studied. It was postulated that peripheral blood neutrophils, being in a primed or activated state in asthma, would reflect the changes occurring in bronchial tree neutrophils.

Nitrite and l-citrulline production by neutrophils was significantly higher in asthmatics (p<0.001) and increased with disease severity. A strong negative correlation was observed between peak expiratory flow and both nitrite (r=−0.87, p<0.001) and l-citrulline (r=−0.88, p<0.001) production.

It is concluded that nitric oxide production by neutrophils is increased in bronchial asthma and can possibly contribute to airway narrowing and disease severity.
Is the increase in childhood asthma coming to an end? Findings from three surveys of schoolchildren in Rome, Italy
Authors: Ronchetti R. , Villa M.P. , Barreto M. , Rota R. , Pagani J. , Martella S. , Falasca C. , Paggi B. , Guglielmi F. , Ciofetta G.
Published: October 2002

Time trends in the prevalence of asthma, family history of asthma and atopy in Roman schoolchildren were assessed. The study population consisted of all children (aged 6–14 yrs) attending two primary schools in Rome, situated in urban areas that differed markedly in socioeconomic conditions and environmental pollution. Three questionnaire-based surveys were conducted in 1974, 1992 and 1998 in 2,259, 1,229 and 1,139 children. The prevalence of asthma in males and females increased significantly during 1974–1992 and remained stable from 1992–1998. In age groups born in the subsequent 4-yr periods it increased almost linearly, for children born from 1962–1965 to 1982–1985 (4.4%–12.5%), and remained remarkably stable in children born after 1985. Because the prevalence of asthma had a steeper trend in males than in females (approximately 0.55%·yr−1versus0.25%·yr−1), the male:female asthma ratio increased (1:38 in 1974; 1:84 in 1992 and 1:62 in 1998). No single environmental factor, including area of residence, seemed to influence the prevalence of asthma. Family history of asthma and atopy also increased steadily (0.72%·yr−1and 0.30%·yr−1respectively) more than doubling during the 24-yr study period. The strong relationship between asthma and a family history of atopy not only persisted but also strengthened over time (23.3% of asthmatic children belonged to families with atopic illnesses in 1974 but 44.2% in 1998). The environmental factors that might explain the almost three-fold rise in childhood asthma between 1974 and 1992 remain unknown but the genetic background of the disease has presumably remained unchanged since the early 1970s. The fact that the prevalence of asthma increased no further during the past 6 yrs suggests that the progressive induction of asthma symptoms in genetically predisposed subjects is a self-limiting process that has probably come to an end in the authors' study area.
Off-line sampling of exhaled air for nitric oxide measurement in children: methodological aspects
Authors: Jöbsis Q. , Schellekens S.L. , Kroesbergen A. , Hop W.C.J. , de Jongste J.C.
Published: October 2002

Measurement of nitric oxide in exhaled air is a noninvasive method to assess airway inflammation in asthma. This study was undertaken to establish the reference range of exhaled NO in healthy school-aged children and to determine the influence of ambient NO, noseclip and breath-holding on exhaled NO, using an off-line balloon sampling method.

All children attending a primary school (age range 8–13 yrs) underwent NO measurements on two occasions with high and low ambient NO. Each time, the children performed four expiratory manoeuvres into NO-impermeable balloons, with and without 10 s of breath-holding and with and without wearing a noseclip. Exhalation flow and pressure were not controlled. NO was measured within 4 h after collection, by means of chemiluminescence. All children completed a questionnaire on respiratory and allergic disorders, and performed flow/volume spirometry.

With low ambient NO, the mean exhaled NO value of 72 healthy children with negative questionnaires and normal lung function was 5.1±0.2 parts per billion (ppb)versusa mean of 6.8±0.3 ppb in the remaining 49 children with positive questionnaires for asthma and allergy, and/or recent symptoms of cold (p=0.001). Exhaled and ambient NO were significantly related, especially with ambient NO >10 ppb (r=0.86, p=0.0001versusr=0.34, p=0.004 for ambient values <10 ppb). The use of a noseclip, with low ambient NO and without breath-holding, caused a small decrease in exhaled NO values (p=0.001). The effect of breath-holding on exhaled NO depended on ambient NO. With ambient NO >10 ppb, exhaled NO decreased, whereas with ambient NO <10 ppb, exhaled NO increased after 10 s breath-hold.

It is concluded that off-line sampling in balloons is a simple and, hence, attractive method for exhaled nitric oxide measurements in children which differentiates between groups with and without self-reported asthma, allergy and colds, when ambient nitric oxide is <10 parts per billion. Wearing a noseclip and breath-holding affected measured values and should, therefore be standardized or, preferably, avoided.
Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema
Authors: Majo J. , Ghezzo H. , Cosio M.G.
Published: October 2002

Previously, it had been shown that T-lymphocytes are the predominant inflammatory cells found in the alveolar wall of smokers and their numbers correlated with the extent of emphysema. However, the phenotype of these cells was not defined. The aim of this study was to describe the different T-cell phenotypes and investigate the possible presence of apoptosis in the lung parenchyma of smokers.

Samples from lungs were obtained at surgery from 15 patients who smoked and six who had never smoked. Samples were frozen and prepared for histological and immunocytochemical examination. Slides were stained for CD3+, CD4+, CD8+, γδ T-cells, CD56 natural killers ((NK) cells), and elastase (neutrophils). Anti-CD95 monoclonal antibodies andin situend-labelling techniques were used to detect Fas expression and apoptosis. Positive staining cells were expressed as cells·mm alveolar wall−1, percentage of total cells, and Fas/APO and apoptosis index. Emphysema was identified macroscopically, microscopically and reported as present or absent. All subjects had pulmonary function tests before surgery.

Neutrophils were the predominant cell in the lung parenchyma of nonsmokers and smokers without emphysema. In smokers with emphysema, the CD3+ and CD8+ were the predominant cells (p<0.05) in the alveolar wall. γδ cells were increased in all smokers and no increased numbers of NK cells was found. The T-cell numbers·mm alveolar wall−1showed a bilinear relationship with the amount smoked increasing at an inflection point of 30 packs yr−1(R2=0.345; p<0.01). Apoptosis in smokers showed a bilinear relationship with the amount smoked increasing sharply in smokers with emphysema (R2=0.3613; p<0.009).

It is concluded that the pathogenesis of emphysema might be mediated by T-lymphocytes, mainly CD8+ cytolytic T-cells, and that apoptosis might be one of the mechanisms of lung destruction leading to the development of emphysema. If this is the case, it could be speculated that T-cell inflammation is a response to antigenic stimuli originating in the lung and induced by cigarette smoking.
Pulmonary ventilation imaged by magnetic resonance: at the doorstep of clinical application
Authors: Kauczor H.U. , Chen X.J. , van Beek E.J.R. , Schreiber W.G.
Published: October 2002

Over the past few years, magnetic resonance imaging (MRI) has emerged as an important instrument for functional ventilation imaging. The aim of this review is to summarize established clinical methods and emerging techniques for research and clinical arenas.

Before the advent of MRI, chest radiography and computed tomography (CT) dominated morphological lung imaging, while functional ventilation imaging was accomplished with scintigraphy. Initially, MRI was not used for morphological lung imaging often, due to technical and physical limitations. However, recent developments have considerably improved anatomical MRI, as well as advanced new techniques in functional ventilation imaging, such as inhaled contrast aerosols, oxygen, hyperpolarized noble gases (Helium‐3, Xenon‐129), and fluorinated gases (sulphur­hexafluoride). Straightforward images demonstrating homogeneity of ventilation and determining ventilated lung volumes can be obtained. Furthermore, new image­derived functional parameters are measurable, such as airspace size, regional oxygen partial pressure, and analysis of ventilation distribution and ventilation/perfusion ratios.

There are several advantages to using MRI: lack of radiation, high spatial and temporal resolution and a broad range of functional information. The MRI technique applied in patients with chronic obstructive pulmonary disease, emphysema, cystic fibrosis, asthma, and bronchiolitis obliterans, may yield a higher sensitivity in the detection of ventilation defects than ventilation scintigraphy, CT or standard pulmonary function tests.

The next step will be to define the threshold between physiological variation and pathological defects. Using complementary strategies, radiologists will have the tools to characterize the impairment of lung function and to improve specificity.
Noninvasive pressure preset ventilation for the treatment of Cheyne-Stokes respiration during sleep
Authors: Willson G.N. , Wilcox I. , Piper A.J. , Flynn W.E. , Norman M. , Grunstein R.R. , Sullivan C.E.
Published: October 2002

Cheyne-Stokes respiration (CSR) during sleep is common in patients with congestive heart failure (CHF). This pattern of breathing fragments sleep, leading to daytime symptoms of sleepiness and fatigue. It was hypothesized that by controlling CSR with noninvasive pressure preset ventilation (NPPV), there would be a decrease in sleep fragmentation and an improvement in sleep quality.

Nine patients (eight males, one female; mean±sd 65±11 yrs) with symptomatic CSR diagnosed on overnight polysomnography (apnoea/hypopnoea index (AHI) 49±10·h−1, minimum arterial oxygen saturation (Sa,O2, 77±7%) and CHF (left ventricular ejection fraction 25±8%) were studied. After a period of acclimatization to NPPV (variable positive airway pressure (VPAP) II STTM, Sydney, NSW, Australia and bilevel positive airway pressure (BiPAP)TM, Murraysville, PA, USA), sleep studies were repeated on therapy.

NPPV almost completely abolished CSR in all patients with a reduction in AHI from 49±10 to 6±5·h−1(p<0.001). Residual respiratory events were primarily due to upper airway obstruction at sleep on-set. Arousal index was markedly decreased from 42±6 to 17±7·h−1(p<0.001). Sleep architecture showed a trend toward improvement with a reduction in stage 1 and 2 (79±7% during the diagnostic nightversus72±10% during NPPV, (p=0.057)), whilst sleep efficiency, slow-wave sleep (SWS), and rapid eye movement (REM) were not altered.

Controlling Cheyne-Stokes respiration with noninvasive pressure preset ventilation resulted in reduced arousal and improved sleep quality in the patients with congestive heart failure. Noninvasive pressure preset ventilation should be considered a potential therapy for Cheyne-Stokes respiration in congestive heart failure in those patients who do not respond or fail to tolerate nasal continuous positive airway pressure therapy.
ABO/Secretor genetic complex and susceptibility to asthma in childhood
Authors: Ronchetti F. , Villa M.P. , Ronchetti R. , Bonci E. , Latini L. , Pascone R. , Bottini N. , Gloria-Bottini F.
Published: October 2002

A positive association has recently been reported in adult subjects between O/nonSecretor phenotype and asthma. To confirm this association, this study investigated the joint ABO/Secretor phenotype in a cohort of 165 asthmatic children. Three-hundred and sixty-two consecutive newborn infants from the same population were also studied as controls.

The proportion of O/nonSecretor in asthmatic children was higher than in controls, thus confirming the association found in adults. The association was more marked in males than in females. In males, the pattern of association between the joint ABO/Secretor phenotype and asthma is dependent on the age at on-set of symptoms.

Since the oligosaccharide composition of cell membrane and mucosal secretions is controlled by the cooperative interaction of ABO and Secretor genes, and since such composition influences the adhesion of infectious agents, the age pattern could reflect a more general interaction between developmental maturation and oligosaccharide structure concerning their effects on susceptibility to viral and bacterial agents.