bluuebunny/crossref_metadata_2025 huggingface dataset:
Immature CD34+CD19− progenitor/stem cells in TEL/AML1-positive acute lymphoblastic leukemia are genetically and functionally normal
Authors: Hotfilder Marc , Röttgers Silja , Rosemann Annegret , Jürgens Heribert , Harbott Jochen , Vormoor Josef
Published: October 2002

One important question in stem cell biology of childhood acute lymphoblastic leukemia (ALL) is whether immature CD34+CD19− cells are part of the leukemic cell clone. CD34+CD19− cells from the bone marrow of 9 children with TEL/AML1-positive ALL were purified by flow sorting and subjected to reverse transcriptase–polymerase chain reaction (RT-PCR), fluorescence in situ hybridization, and methylcellulose cultures. In 3 of 8 patients analyzed by RT-PCR, noTEL/AML1-positive cells could be detected in the CD34+CD19− cell fraction. Altogether, the percentage of TEL/AML1-positive cells was low: 1.6% (n = 8; SD 2.2%) by nested real-time RT-PCR and 2.5% (n = 5; SD 2.6%) by fluorescence in situ hybridization. This correlated with the percentage of contaminating CD19+ leukemic cells in the CD34+CD19− cell fraction in 6 control sorts (mean 4.6%, SD 3.6%), indicating that the low levels of leukemic cells detected in the CD34+CD19− cell fraction could be attributed to sorter errors. Methylcellulose cultures in 3 patients provided further evidence that CD34+CD19− cells represent a candidate normal cell population. The clonogenicity of the CD34+CD19− cell fraction was similar to normal progenitors, including growth of primitive granulocyte, erythroid, macrophage, megakaryocyte colony-forming units. Each of 92 colonies from cultures with CD34+CD19− cells tested negative for TEL/AML1. In conclusion, our data support the hypothesis that the leukemia inTEL/AML1-positive childhood ALL originates in a CD19+ lymphoid progenitor. This has many therapeutic implications, eg, for purging of autologous stem cell products, flow cytometric monitoring of minimal residual disease, and targeting immunotherapy against the leukemic cell clone.
The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality
Authors: Taylor Patricia A. , Lees Christopher J. , Blazar Bruce R.
Published: October 2002

Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and the prevention of autoimmunity. Recently, CD4+CD25+ cells have been shown to be required for the ex vivo induction of tolerance to alloantigen via costimulatory blockade and to inhibit allogeneic skin graft rejection. Data presented here demonstrate that CD4+CD25+ cells play an important role in graft-versus-host disease (GVHD) generation. Depletion of CD4+CD25+ cells from the donor T-cell inoculum or in vivo CD25-depletion of the recipient before transplantation resulted in increased GVHD mediated by CD4+or whole T cells in several strain combinations irrespective of the total body irradiation conditioning regime. The infusion of freshly purified donor CD4+CD25+ cells modestly inhibited GVHD when administered in equal numbers with whole CD4+ cells. Because CD4+CD25+ cells only account for 5% to 10% of the total CD4+ population, the administration of high numbers of fresh donor CD4+CD25+ cells may not be clinically practical. However, we found that large numbers of CD4+CD25+ cells can be obtained by ex vivo activation and expansion. Cultured CD4+CD25+ cells, administered in equal numbers with CD4+ T cells or CD25-depleted whole T cells, resulted in significant inhibition of rapidly lethal GVHD. To our knowledge, this study is the first to demonstrate that activated, cultured CD4+CD25+ cells can offer substantial protection in a relevant in vivo animal model of disease. These data have important ramifications for clinical bone marrow and solid organ transplantation. CD4+CD25+ cells warrant consideration as an exciting new modality of cellular therapy for the inhibition of undesirable autologous and allogeneic responses.
Changes in T-cell receptor VB repertoire in aplastic anemia: effects of different immunosuppressive regimens
Authors: Kook Hoon , Risitano Antonio M. , Zeng Weihua , Wlodarski Marcin , Lottemann Craig , Nakamura Ryotaro , Barrett John , Young Neal S. , Maciejewski Jaroslaw P.
Published: October 2002

We studied the degree and the pattern of skewing of the variable region of β-chain (VB) T-cell receptor (TCR) repertoire in aplastic anemia (AA) at initial presentation and after immunosuppression using a high-resolution analysis of the TCR VB complementarity-determining region 3 (CDR3). Age-matched healthy individuals and multitransfused patients with non–immune-mediated hematologic diseases were used as controls. In newly diagnosed AA, the average frequency of CDR3 size distribution deviation indicative of oligoclonal T-cell proliferation was increased (44% ± 33% vs 9% ± 9%; P = .0001); AA patients with human leukocyte antigen (HLA)–DR2 and those with expanded paroxysmal nocturnal hemoglobinuria clones showed more skewed VB repertoires. Nonrandom oligoclonal patterns were found for VB6, VB14-16, VB21, VB23, and VB24 subfamilies in more than 50%, and for VB15, VB21, and VB24 in more than 70% of AA patients with HLA-DR2. Patients received immunosuppression with antithymocyte globulin (ATG)/cyclosporine (CsA) or cyclophosphamide (CTX) with CsA in combination, and their VB repertoire was reanalyzed after treatment. Whereas no significant change in the degree of VB skewing in patients who had received ATG was seen, patients treated with CTX showed a much higher extent of oligoclonality within all VB families, consistent with a profound and long-lasting contraction of the T-cell repertoire. VB analysis did not correlate with the lymphocyte count prior to lymphocytotoxic therapy; however, after therapy the degree of VB skewing was highly reflective of the decrease in lymphocyte numbers, suggesting iatrogenic gaps in the VB repertoire rather than the emergence of clonal dominance. Our data indicate that multiple specific clones mediate the immune process in AA.
Rescue of the lethal scl−/− phenotype by the human SCL locus
Authors: Sinclair Angus M. , Bench Anthony J. , Bloor Adrian J. C. , Li Juan , Göttgens Berthold , Stanley Maureen L. , Miller Jane , Piltz Sandie , Hunter Susie , Nacheva Elisabeth P. , Sanchez Marı́a-José , Green Anthony R.
Published: October 2002

The stem cell leukemia (SCL) gene encodes a basic helix-loop-helix transcription factor with a critical role in the development of both blood and endothelium. Loss-of-function studies have shown that SCL is essential for the formation of hematopoietic stem cells, for subsequent erythroid development and for yolk sac angiogenesis. SCL exhibits a highly conserved pattern of expression from mammals to teleost fish. Several murine SCLenhancers have been identified, each of which directs reporter gene expression in vivo to a subdomain of the normal SCL expression pattern. However, regulatory elements necessary for SCL expression in erythroid cells remain to be identified and the size of the chromosomal domain needed to support appropriate SCL transcription is unknown. Here we demonstrate that a 130-kilobase (kb) yeast artificial chromosome (YAC) containing the human SCL locus completely rescued the embryonic lethal phenotype ofscl−/− mice. Rescued YAC+scl−/− mice were born in appropriate Mendelian ratios, were healthy and fertile, and exhibited no detectable abnormality of yolk sac, fetal liver, or adult hematopoiesis. The human SCL protein can therefore substitute for its murine homologue. In addition, our results demonstrate that the human SCL YAC contains the chromosomal domain necessary to direct expression to the erythroid lineage and to all other tissues in which SCL performs a nonredundant essential function.
A novel mechanism of factor VIII protection by von Willebrand factor from activated protein C–catalyzed inactivation
Authors: Nogami Keiji , Shima Midori , Nishiya Katsumi , Hosokawa Kazuya , Saenko Evgueni L. , Sakurai Yoshihiko , Shibata Masaru , Suzuki Hiroshi , Tanaka Ichiro , Yoshioka Akira
Published: October 2002

The protective effect of von Willebrand factor (VWF) toward activated protein C (APC)–catalyzed inactivation of factor VIII (FVIII) has been attributed mainly to inhibition of FVIII binding to phospholipid. In the present study, we demonstrated that VWF-mediated FVIII protection from APC also results from direct inhibition of FVIII binding to APC. Inhibition of FVIII binding to anhydro-APC by VWF would be consistent with partial or complete overlap of the FVIII binding sites for APC and VWF. We examined, therefore, the inhibitory effects of 6 synthetic peptides spanning residues 1996 to 2028 around the previously localized APC binding region (FVIII residues 2009-2018). Peptide 2009 to 2018 inhibited FVIII binding to anhydro-APC by 83% (50% inhibition, 55 μM). Similarly, peptide 2013 to 2022 inhibited FVIII binding to VWF by 84% (50% inhibition, 25 μM). It was also found that peptides 2009 to 2018 and 2013 to 2022 optimally bound to anhydro-APC and VWF, respectively. A rabbit antipeptide IgG, raised against peptide 2009 to 2022, blocked the binding of both anhydro-APC and VWF to FVIII. This immunoglobulin G inhibited proteolytic cleavage of FVIII by APC. Our results indicate that the essential regions for the binding of APC and VWF to FVIII overlap and that the protective effect of VWF on APC-catalyzed FVIII inactivation includes competitive inhibition of APC binding to FVIII by VWF.
Purification and characterization of the yeast-expressed erythropoietin mutant Epo (R103A), a specific inhibitor of human primary hematopoietic cell erythropoiesis
Authors: Burns Suzanne , Arcasoy Murat O. , Li Li , Kurian Elizabeth , Selander Katri , Emanuel Peter D. , Harris Kevin W.
Published: October 2002

A drug that specifically inhibits erythropoiesis would be clinically useful. The erythropoietin (Epo) mutant Epo (R103A) could potentially be used for this purpose. Epo (R103A) has a single amino acid substitution of alanine for arginine at position 103. Because of this mutation, Epo (R103A) is only able to bind to one of the 2 subunits of the erythropoietin receptor (EpoR) homodimer and is thus a competitive inhibitor of Epo activity. To produce large quantities of Epo (R103A) to test in animal models of thalassemia and sickle cell disease, we expressed and purified recombinant Epo (R103A) from the yeast Pichia pastoris. Using this method milligram quantities of highly purified Epo (R103A) are obtained. The yeast-expressed Epo (R103A) is properly processed and glycosylated and specifically inhibits Epo-dependent cell growth and125I-Epo binding. Epo (R103A) does not, however, directly induce apoptosis in 32D cells expressing EpoR. Epo (R103A) inhibits erythropoiesis of human CD34+ hematopoietic cells and completely blocks erythroid burst-forming unit formation in normal human bone marrow colony assays. Yeast-expressed Epo (R103A) is a specific inhibitor of primary erythropoiesis suitable for testing in animal models.
Successful treatment of murine β-thalassemia intermedia by transfer of the human β-globin gene
Authors: May Chad , Rivella Stefano , Chadburn Amy , Sadelain Michel
Published: October 2002

The β-thalassemias are caused by more than 200 mutations that reduce or abolish β-globin production. The severity of the resulting anemia can lead to lifelong transfusion dependency. A genetic treatment based on globin gene transfer would require that transgene expression be erythroid specific, elevated, and sustained over time. We report here that long-term synthesis of chimeric hemoglobin (muα2:huβ2A) could be achieved in mice with β-thalassemia intermedia following engraftment with bone marrow cells transduced with a lentiviral vector encoding the humanβ-globin gene. In the absence of any posttransduction selection, the treated chimeras exhibit durably increased hemoglobin levels without diminution over 40 weeks. Ineffective erythropoiesis and extramedullary hematopoiesis (EMH) regress, as reflected by normalization of spleen size, architecture, hematopoietic colony formation, and disappearance of liver EMH. These findings establish that a sustained increase of 3 to 4 g/dL hemoglobin is sufficient to correct ineffective erythropoiesis. Hepatic iron accumulation is markedly decreased in 1-year-old chimeras, indicating persistent protection from secondary organ damage. These results demonstrate for the first time that viral-mediated globin gene transfer in hematopoietic stem cells effectively treats a severe hemoglobin disorder.
Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children
Authors: Woolfrey Ann E. , Anasetti Claudio , Storer Barry , Doney Kristine , Milner Laurie A. , Sievers Eric L. , Carpenter Paul , Martin Paul , Petersdorf Effie , Appelbaum Frederick R. , Hansen John A. , Sanders Jean E.
Published: October 2002

Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P < .0001). Three-year cumulative relapse rates were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates of death not due to relapse were 20%, 22%, 60%, and 41%, respectively, for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute GVHD occurred in 43% of patients given HLA-matched transplants and in 59% given partly matched transplants (P = .10); clinical extensive chronic GVHD occurred in 32% and 38%, respectively (P = .23). LFS rates were lower in patients with advanced disease (P < .0001), age 10 years or older (P = .002), or short duration of CR1 (P = .007). Thus, in addition to phase of disease, age and duration of CR1 were predictors of outcome after unrelated-donor transplantation for treatment of ALL in children. Outcome was particularly favorable in younger patients with early phases of the disease.
Epstein-Barr virus–specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy
Authors: Rossig Claudia , Bollard Catherine M. , Nuchtern Jed G. , Rooney Cliona M. , Brenner Malcolm K.
Published: October 2002

Primary T cells expressing chimeric receptors specific for tumor or viral antigens have considerable therapeutic potential. Unfortunately, their clinical value is limited by their rapid loss of function and failure to expand in vivo, presumably due to the lack of costimulator molecules on tumor cells and the inherent limitations of signaling exclusively through the chimeric receptor. Epstein-Barr virus (EBV) infection of B lymphocytes is near universal in humans and stimulates high levels of EBV-specific helper and cytotoxic T cells, which persist indefinitely. Our clinical studies have shown that EBV-specific T cells generated in vitro will expand, persist, and function for more than 6 years in vivo. We now report that EBV-specific (but not primary) T cells transduced with tumor-specific chimeric receptor genes can be expanded and maintained long-term in the presence of EBV-infected B cells. They recognize EBV-infected targets through their conventional T-cell receptor and tumor targets through their chimeric receptors. They efficiently lyse both. EBV-specific T cells expressing chimeric antitumor receptors may represent a new source of effector cells that would persist and function long-term after their transfer to cancer patients.
Breathing techniques--adjunctive treatment modalities for asthma? A systematic review
Authors: Ernst E
Published: October 2002

Breathing techniques are used by a large proportion of asthma sufferers. This systematic review was aimed at determining whether or not these interventions are effective. Four independent literature searches identified six randomized controlled trials. The results of these studies are not uniform. Collectively the data imply that physiotherapeutic breathing techniques may have some potential in benefiting patients with asthma. The safety issue has so far not been addressed satisfactorily. It is concluded that too few studies have been carried out to warrant firm judgements. Further rigorous trials should be carried out in order to redress this situation.
Excess incidence of asthma among Finnish cleaners employed in different industries
Authors: Karjalainen A. , Martikainen R. , Karjalainen J. , Klaukka T. , Kurppa K.
Published: October 2002

The incidence and risk of asthma among female cleaners employed in different industries was explored. An increased risk of asthma has been associated with the cleaning profession, in some but not all studies.

All Finnish females employed as cleaners and all those employed in administrative work were followed for asthma incidence through a record linkage in 1986–1998. An individual was defined as an “incident case of asthma” if they received rights for special reimbursement of asthma medication from the national health insurance or were recognized as having occupational asthma. Age-adjusted relative risks (RR) were estimated for cleaners in comparison with those employed in administrative work.

There were 2,414 and 5,235 cases of asthma among the cleaners and administrative workers, respectively. The RR was 1.50 (95% confidence interval (CI) 1.43–1.57) in cleaners. The risk was increased in cleaners working in nearly all major sectors of economic activity, but cleaners employed by companies concerned with the manufacture of basic metals (RR 2.47; 95% CI 1.68–3.64) and food products (RR 2.19; 95% CI 1.69–2.85) had the highest risk. Only 25 of the “cases of asthma” among cleaners had been recognized as being occupational asthma.

It could be concluded that cleaners have an increased risk of persistent adult-onset asthma. Factors inherent to the environment where cleaning is performed or differences in the cleaning agents used may explain the observed differences between industries.
Physical exercise, sports, and lung function in smokingversusnonsmoking adolescents
Authors: Holmen T.L. , Barrett-Connor E. , Clausen J. , Holmen J. , Bjermer L.
Published: October 2002

Associations between adolescent smoking habits and exercise, particularly participation in sports and lung function were studied.

All students aged 13–19 yrs in Nord-Trøndelag County, Norway, 1995–1997, were invited to join a cross-sectional study. Information on smoking habits and exercise was obtained by self-administered questionnaire. Spirometry was performed in accordance with American Thoracic Society standards.

Of the 6,811 students (aged 13–18 yrs, without asthma), 2,993 (44%) reported never-smoking, and 1,342 (20%) reported current smoking (10% daily). Frequency of physical exercise was inversely associated with smoking, but participants in individual sports with lesser endurance, especially body-building and fighting sports, were more likely to be daily smokers than nonparticipants. Both daily (53%) and occasional smokers (43%) were more likely to have quit sports than never-smokers (26%). Never-smokers showed a positive dose-response between physical exercise and lung function (forced vital capacity and forced expiratory volume in one second, adjusted for age and height). No similar significant association was observed in daily smokers.

These data suggest that smoking habits in different sports should be considered when promoting physical activity as smoking prevention, and sports organizations should include smoking prevention programmes. Adolescents with better lung function may self-select into sports; this possibility needs to be studied in a longitudinal design.
Dissociation between airway responsiveness to methacholine and responsiveness to antigen
Authors: Kamachi A. , Nasuhara Y. , Nishimura M. , Takahashi T. , Homma Y. , Ohtsuka Y. , Munakata M.
Published: October 2002

Repeated aerosolized antigen challenges to brown Norway (BN) rats generate nonspecific airway hyperresponsiveness (AHR). On the other hand, some studies have demonstrated that repeated antigen challenge could attenuate antigen-specific AHR in BN rats. The authors questioned whether such dissociation in airway responses actually occurs when assessed in a single study in the same animals.

The authors simultaneously measured AHR to methacholine and antigen-specific AHR in rats that were repeatedly exposed to aerosolized ovalbumin (OA) for 1 or 3 months after sensitization. Four days after the last challenge, airway responses to methacholine and OA, morphometry of the airways, the cell profile in bronchoalveolar lavage fluid, and cytokine messenger ribonucleic acid (mRNA) expression in the lungs were evaluated.

The two types of AHR were modulated in opposite directions by repeated antigen challenges. The AHR to methacholine was significantly increased in the rats receiving antigen challenges compared with the control rats receiving saline challenges after sensitization; whereas, the antigen-specific AHR was significantly decreased. The number of alveolar macrophages in lavaged fluid and the expression of transforming growth factor-β1mRNA in lung tissue was significantly different between the antigen-challenged rats and the control rats.

In conclusion, dissociation between nonspecific airway hyperresponsiveness and antigen-specific airway hyperresponsiveness in brown Norway rats after repeated antigen challenges was demonstrated. Sustained airway inflammation with macrophages and/or upregulation of transforming growth factor-β1messenger ribonucleic acid in the lung tissue may be responsible for this dissociation.
Ehlers-Danlos syndrome type IV with few extrathoracic findings: a newly recognized point mutation in the COL3A1 gene
Authors: Watanabe A. , Kawabata Y. , Okada O. , Tanabe N. , Kimura H. , Hatamochi A. , Shinkai H. , Sakai N. , Shimada T. , Hiroshima K. , Kuriyama T.
Published: October 2002

Ehlers-Danlos syndrome type IV (EDS IV) is caused by mutation within the COL3A1 gene, resulting in the disorder of type III procollagen. The diagnosis is confirmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fibroblasts or by identifying the mutation in the COL3A1 gene.

The authors report a case of EDS IV caused by a novel point mutation in the COL3A1 gene in a 16-yr-old female. Recurrent haemoptysis and cavitary formation of the lung were evidence of pulmonary involvement. However, extrathoracic manifestations of EDS IV were mostly absent.

To the best of the authors' knowledge, all previously reported Ehlers-Danlos syndrome IV patients with respiratory disease had the characteristic findings or histories of Ehlers-Danlos syndrome IV. In the present case, connective tissue friability was suspected due to tissue laceration observed in the biopsied lung specimen, and the diagnosis was made beginning from this pivotal finding.
The combination of single-dose montelukast and loratadine on exercise-induced bronchospasm in children
Authors: Peroni D.G. , Piacentini G.L. , Pietrobelli A. , Loiacono A. , De Gasperi W. , Sabbion A. , Micciolo R. , Boner A.L.
Published: October 2002

The aim of the study was to evaluate the protective effect of single-dose, combination treatment comprising montelukast (5 mg) and loratadine (10 mg), on exercise-induced bronchoconstriction in asthmatic children. The combination was compared to placebo, loratadine and montelukast alone.

Nineteen children were enrolled in a double-blind randomised, single-dose, crossover study. For each treatment patients undertook two treadmill exercise tests, 2 and 12 h respectively after single-dose administration.

No significant differences were seen in the maximum fall in forced expiratory volume in one second (FEV1) 2 h after treatment and placebo. Whereas significant differences in maximum fall in FEV1were observed between treatment groups 12 h after administration. Loratadine alone did not show any significant protection or any additional effect in comparison with montelukast alone. Single doses of montelukast and montelukast plus loratadine were significantly more effective than loratadine at 12 h.

The present study, performed using single-dose treatments, demonstrated that maximal protective effect by montelukast was obtained 12 h after dosing and that montelukast plus loratadine did not result in significant additive bronchoprotective effects on exercise-induced bronchoconstriction.
Bronchial challenge with flour: early response is dependent on the dose of activated allergen inhaled
Authors: Choudat D. , Fabriès J.F. , Martin J.C. , Villette C.
Published: October 2002

Specific bronchial challenges provide information about the relationship between inhaled dose of allergen and change in lung function, but the intermediate pathways remain largely obscure. The aim of this study was to investigate the relationships between the early asthmatic response and 1) the inhaled dose of wheat flour, 2) the concentration of wheat flour, 3) the duration of the exposure, and 4) the deactivation of inhaled allergens and mediators.

Thirty-one patients with occupational asthma to wheat flour were studied. Particle aerosols were generated by a computer-controlled aerosoliser and the results were expressed as the provocative dose causing a 20% fall in forced expiratory volume in one second (FEV1) (PD20). The cumulative dose (from the beginning of the challenge), the last inhaled dose, and an estimated dose (taking into account exponential deactivation), were calculated.

Twenty patients had high reactivity to flour (reaching a PD20value). Eleven patients had intermediate reactivity (no measurable PD20but significantly greater fall in FEV1compared with lactose challenge). A better correlation between change in FEV1and dose was obtained for the estimated dose than for the cumulative or last inhaled dose.

The bronchial response to wheat flour can be measured by the individual specific hyperreactivity and is expressed by provocative dose of flour. However, deactivation of the allergen and mediators has to be taken into account. This problem can be addressed by using a mathematical model.
Domestic exposure to formaldehyde significantly increases the risk of asthma in young children
Authors: Rumchev K.B. , Spickett J.T. , Bulsara M.K. , Phillips M.R. , Stick S.M.
Published: October 2002

Concern has arisen in recent years about indoor air pollution as a risk factor for asthma.

Formaldehyde exposure was examined in relation to asthma among young children (between 6 months and 3 yrs old) in a population-based control study carried out in Perth, Western Australia, between 1997–1999. An association between exposure to formaldehyde and asthma in young children has been suggested. Cases (n=88), whose parents were recruited at Princess Margaret Hospital Accident and Emergency Dept (Perth, Western Australia), were children discharged with asthma as the primary diagnosis. Controls (n=104), who were children in the same age group without asthma diagnosed by a doctor, were identified from birth records through the Health Dept of Western Australia (Perth, Western Australia). Health outcomes for the children were studied using a respiratory questionnaire and skin-prick tests. Formaldehyde, average temperature and relative humidity were measured on two occasions, winter (July–September 1998) and summer (December 1998–March 1999) in the child's bedroom and in the living room.

The study found seasonal differences in formaldehyde levels in the children's bedrooms and living rooms with significantly greater formaldehyde exposure during the summer period for case and control subjects. The generalised estimating equation model showed that children exposed to formaldehyde levels of ≥60 µg·m−3are at increased risk of having asthma.

The results suggest that domestic exposure to formaldehyde increases the risk of childhood asthma.
Resistance to Fas-mediated apoptosis in human lung fibroblast
Authors: Tanaka T. , Yoshimi M. , Maeyama T. , Hagimoto N. , Kuwano K. , Hara N.
Published: October 2002

The current authors have demonstrated previously that epithelial cell apoptosis, induced by the Fas-Fas ligand pathway, might be involved in fibrosing lung diseases. Whereas lung epithelial cells are sensitive to the Fas-mediated apoptosis, lung fibroblasts may be resistant to Fas-mediated apoptosis and replace damaged epithelial cells.

The WI-38 lung fibroblast cell line and primary lung fibroblasts were used to examine the resistant to Fas-mediated apoptosis and the association of anti-apoptotic proteins with this resistance.

The administration of agonistic anti-Fas antibody (CH-11) or cycloheximide alone did not induce apoptosis, whereas the co-administration of CH-11 with cycloheximide induced apoptosis in WI-38 cells, in which caspase‐8 and ‐3, but not ‐9, were activated, and X chromosome-linked inhibitor of apoptosis (ILP) and FLICE-like inhibitor protein (FLIPL), but not bcl‐xLand bcl‐2, were remarkably down regulated. Primary lung fibroblasts were also resistant to Fas-mediated apoptosis, and ILP and FLIP appeared to be involved in this resistance. Furthermore, the results of immunohistochemistry demonstrated that fibroblasts expressed ILP and FLIPLproteins in lung tissues from patients with idiopathic pulmonary fibrosis.

These results suggest that anti-apoptotic proteins such as X chromosome-linked inhibitor of apoptosis and FLICE-like inhibitor protein may play an important role in preventing Fas-mediated apoptosis in lung fibroblasts, and participate in the development of pulmonary fibrosis.
Hospital-acquired pneumonia: microbiological data and potential adequacy of antimicrobial regimens
Authors: Leroy O. , Giradie P. , Yazdanpanah Y. , Georges H. , Alfandari S. , Sanders V. , Devos P. , Beaucaire G.
Published: October 2002

Adequate antimicrobial therapy is a main approach employed to decrease the mortality associated with hospital-acquired pneumonia (HAP). All methods that optimise empirical treatment without increasing antibiotic selective pressure are relevant. Categorisation of patients according to HAP time of onset, severity and risk factors (American Thoracic Society (ATS) classification) or duration of mechanical ventilation and prior antibiotics (Trouillet's classification) are two such methods. The aim of this study was to catagorise patients with HAP according to these classifications and to determine the frequency of resistant pathogens and the most adequate antimicrobial regimens in each group.

A total 124 patients with bacteriologically proven HAP were studied. The ATS classification categorised patients by increasing frequency of resistant pathogens from 0–30.3%. The ATS empirical antibiotic recommendations appeared valid but proposed combinations including vancomycin for 72.5% of patients. Trouillet's classification categorised patients into four groups with a frequency of resistant pathogens from 4.9–35.6%. Vanomycin was proposed for 48.5% of patients.

The American Thoracic Society classification appears to be more specific than Trouillet's for predicting the absence of resistant causative pathogens in hospital-acquired pneumonia but could lead to a greater use of vanomycin. Stratification combining the two classifications is an interesting alternative.
Effect of surfactant on pharyngeal mechanics in sleeping humans: implications for sleep apnoea
Authors: Morrell M.J. , Arabi Y. , Zahn B.R. , Meyer K.C. , Skatrud J.B. , Safwan Badr M.
Published: October 2002

Instillation of surfactant into the pharyngeal lumen reduces the pressure required to reopen an occluded airway, and decreases the apnoea/hypopnoea index (AHI). The authors hypothesised that surfactant also reduces the sleep-related increase in pharyngeal resistance. To test this hypothesis two single blind, crossover, placebo-controlled studies were performed.

In protocol A seven male, asymptomatic snoring subjects were studied during sleep. Inspiratory pharyngeal resistance was calculated from plots of airflowversussupraglottic pressure (seven breaths) before and after surfactant or saline instillation. In protocol B, in a different group of seven male subjects with sleep apnoea (AHI 15.2 (12) events·h−1) the effect of surfactant or saline on sleep disordered breathing was measured, for 1 h immediately before and after surfactant or saline instillation.

Surfactant decreased pharyngeal resistance calculated at peak pressure (group mean (sd): preversuspost 83.7 (76.4)versus49.4 (71.1) cmH2O·L−1·s−1) and significantly reduced the respiratory disturbance index (RDI preversuspost 79.7 (58.7)versus59.6 (56.9) events·h−1). Saline did not decrease resistance (preversuspost 58.6 (31.1)versus72.5 (73.4) cmH2O·L−1·s−1) or RDI (preversuspost 75.3 (42.4)versus79.9 (46.1) events·h−1).

Surfactant reduced the collapsibility of the pharynx and led to a modest reduction in respiratory disturbance index. The authors speculate that surfactant may delay occlusion by reducing the liquid “bridging” within the folded pharyngeal lining.
Obliterative bronchiolitis: varying presentations and clinicopathological correlation
Authors: Markopoulou K.D. , Cool C.D. , Elliot T.L. , Lynch D.A. , Newell J.D. , Hale V.A. , Brown K.K. , Schwarz M.I. , Tuder R.M.
Published: October 2002

In obliterative bronchiolitis, inflammation and fibrosis lead to narrowing or occlusion of bronchiolar lumina.

To determine how bronchiolar structural alterations relate to lung physiology, 19 patients with a pathological diagnosis of obliterative bronchiolitis were studied. The bronchiolar inflammatory and fibrotic features were correlated to the clinical presentation, and lung function tests.

Eleven patients demonstrated airflow limitation, one had a restrictive pattern and one had a mixed pattern, two had isolated gas trapping, but four had normal spirometry. Mild-to-moderate bronchiolar inflammation was invariably present. It involved 60% of bronchioles subepithelially and 54% in the adventitia. Subepithelial fibrosis was observed in 15 patients and adventitial in 12. Adventitial bronchiolar inflammation correlated with forced expiratory volume in one second and forced vital capacity and inversely correlated with residual volume. Subepithelial fibrosis inversely correlated with subepithelial and adventitial inflammation. High-resolution computed tomography in 10 patients revealed inspiratory (five out of 10) and expiratory air trapping (five out of five), ground glass opacities (seven out of 10), bronchial wall thickening (five out of 10), bronchiectasis (two out of 10) and centrilobular nodules (two out of 10).

The present study suggests that inflammation and fibrosis occurs in bronchioles at different time points in the disease process, or that there is no transition between these types of pathology in the same patient. No correlation was observed between the degree of bronchiolar fibrosis and the degree of airflow limitation.
The Liverpool Lung Project: a molecular epidemiological study of early lung cancer detection
Authors: Field J.K. , Youngson J.H.
Published: October 2002

Lung cancer is the major cause of death from neoplastic disease in the world, and even with politically-motivated smoking cessation campaigns throughout Europe, the disease remains the major cause of death. The development of molecular epidemiological population-based research into early lung cancer detection, such as the Liverpool Lung Project (LLP), may provide a way forward. This is the first major molecular epidemiological study of detection of early lung cancer.

The use of molecular epidemiological risk assessments prior to clinical diagnosis and markers of preclinical carcinogenesis in patients with a high risk of developing lung cancer will reduce the incidence of clinically-detectable lung cancer, given the appropriate intervention strategies.

The aims are as follows: 1) to prepare a molecular genetic and epidemiological risk assessment model based on environmental exposures and genetic predisposition; 2) to develop an archive of specimens relating to at-risk individuals and those with lung cancer; 3) to redefine lung cancer based on molecular pathology using the fields of expression profiling, genetic instability and molecular cytogenetics; 4) to identify and assess novel markers of precarcinogenesis in high-risk populations; and 5) to facilitate the development of new treatment strategies (e.g.chemoprevention programmes and targeted drug therapies).

The LLP has two components: 1) a case-controlled study of newly-diagnosed cases of lung cancer that will provide a baseline, risk assessment; and 2) a prospective cohort study to be carried out over a 10-yr period that will identify markers of preclinical carcinogenesis. In-depth interviews are carried out using structured and semi-structured questionnaires. Sputum, blood and tumour specimens are collected and will be assessed for specific molecular markers (e.g.genetic instability, mutation and expression profiling, and methylation status).

Conclusions from The Liverpool Lung Project will be based around molecular-epidemiological and genotyping risk assessment models, as well as redefining the disease, and ultimately contributing to the development of new early lung cancer detection and treatment strategies.
Side-effects of antituberculosis drug treatment in patients with chronic renal failure
Authors: Quantrill S.J. , Woodhead M.A. , Bell C.E. , Hardy C.C. , Hutchison A.J. , Gokal R.
Published: October 2002

Patients with chronic renal failure (CRF) have a high incidence of tuberculosis (TB). Those from the Indian subcontinent are at particular risk. The frequency of side-effects associated with antituberculous treatment in a group of patients with CRF was studied.

All cases of TB in patients with CRF occurring over a 13‐yr period at the Manchester Royal Infirmary, from 1986–1999, were identified by diagnostic coding, microbiology records and a TB database. The case notes were then reviewed.

Twenty-four cases were identified, eight predialysis and 16 requiring regular dialysis. TB occurring in the dialysis group was extrapulmonary in every case. Nineteen of 24 (79%) patients were of Indian subcontinent origin and 14 of 16 (87%) dialysis patients were non-Caucasian. Adverse effects of treatment occurred in two of eight (25%) in the predialysis group and nine of 16 (56%) of the dialysis group. These were most commonly neuropsychiatric (6), hepatic (4) and gastrointestinal (4). Neuropsychiatric symptoms occurred exclusively in dialysis patients.

In conclusion, a high incidence of side-effects from antituberculous medication, especially neuropsychiatric, hepatic and gastrointestinal, was identified in patients with chronic renal failure. Careful monitoring for side-effects is essential in this group, and consideration should be given to administering antituberculous chemoprophylaxis to all high-risk groups.
Noninvasive ventilation for chest wall and neuromuscular disorders
Authors: Shneerson J.M. , Simonds A.K.
Published: October 2002

Neuromuscular and chest wall disorders are individually uncommon but together form an important group of conditions that can lead to chronic ventilatory failure. This is best recognised in scoliosis, kyphosis, following a thoracoplasty, in muscular dystrophies, such as Duchenne muscular dystrophy (DMD), and myotonic dystrophy, after poliomyelitis and with motor neurone disease (amyotrophic lateral sclerosis).

If bulbar function is impaired, tracheostomy ventilation may be required, but in other situations, noninvasive ventilation is preferable. Positive pressure techniques using nasal and face masks are usually the first choice, but negative pressure ventilation is an alternative.

There are no randomised-controlled trials regarding the indications for initiating noninvasive ventilation, but this is usually provided if there are symptoms due to nocturnal hypoventilation or right heart failure in the presence of a raised carbon dioxide tension in arterial blood (Pa,CO2) either at night or, more usually, in the daytime as well. There is no evidence that “prophylactic” ventilatory support is of benefit if this is provided before ventilatory failure has appeared. Careful selection of patients is required, especially in the presence of progressive neuromuscular disorders such as DMD and motor neurone disease.

There are no randomised-controlled trials concerning the outcome of noninvasive ventilation in these conditions, but studies have shown an improved quality of life, physical activity and haemodynamics, normalisation of blood gases and slight improvement in other physiological measures, such as the vital capacity and maximal mouth pressures. Survival in chest wall disorders is ∼90% at 1 yr and 80% at 5 yrs, and similar figures have been obtained in nonprogressive neuromuscular conditions. If, however, the underlying disorder is deteriorating, particularly if it involves the bulbar muscles, it may limit survival despite the provision of adequate noninvasive ventilatory support.
The role of supplemental oxygen during submaximal exercise in patients with cystic fibrosis
Authors: McKone E.F. , Barry S.C. , FitzGerald M.X. , Gallagher C.G.
Published: October 2002

Repeated bouts of submaximal exercise are an important part of most pulmonary rehabilitation programmes. Patients with moderate-to-severe cystic fibrosis (CF) often demonstrate oxygen desaturation during submaximal exercise, which may limit their ability to participate in these programmes. This study examines whether arterial desaturation contributes to submaximal exercise limitation by testing whether supplemental O2improves submaximal exercise capacity.

Eight patients with CF (mean forced expiratory volume in one second 41% predicted) each underwent two submaximal exercise tests on a bicycle ergometer at 80% of maximal workload. The two tests were identical except for the addition of supplemental O2(inspiratory O2fraction 39%) during one of the tests.

Exercise duration was significantly longer in the supplemental O2studyversuscontrol (673±63 sversus835±99 s). Arterial O2saturation was also higher in the supplemental O2study than the control exercise test (96±0.3%versus86±1.5%). There was no statistical difference at end exercise between O2consumption, minute ventilation and heart rate. There was a significant relationship between improvement in exercise capacity and the amount of desaturation during the control exercise test.

Results indicate that supplemental oxygen improves submaximal exercise capacity in patients with moderate-to-severe cystic fibrosis. Oxygen therapy may be an important intervention to improve participation and maximise the benefits of pulmonary exercise rehabilitation programmes.
The effect of postrehabilitation programmes among individuals with chronic obstructive pulmonary disease
Authors: Brooks D. , Krip B. , Mangovski-Alzamora S. , Goldstein R.S.
Published: October 2002

The purpose of this study was to examine the effects of two postrehabilitation programmes on functional exercise tolerance and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD).

Subjects with COPD (n=109) were randomised to receive either enhanced follow-up (EF) or conventional follow-up (CF). Subjects in the EF group attended a monthly support group and received a telephone call from a staff member at the midpoint (2 weeks) between their visits. Both groups had scheduled appointments with a physical therapist and physician at 3‐monthly intervals after discharge.

Longitudinal data were recorded in 85 subjects (37 EF and 48 CF). Over the course of the study, there was no difference in distance walked in 6 min between the two groups but a significant difference for time and a group-time interaction. There was no difference in total chronic respiratory disease questionnaire score between groups at baseline or at any time interval despite a significant difference with time.

There was a clear deterioration in functional exercise capacity and health-related quality of life after completion of respiratory rehabilitation but no difference between the groups.
Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension: Table 1—
Authors: Hoeper M.M. , Spiekerkoetter E. , Westerkamp V. , Gatzke R. , Fabel H.
Published: October 2002

Treatment with aerosolised iloprost, a prostacyclin analogue, has beneficial effects in patients with pulmonary arterial hypertension (PAH). It is unclear if patients, whose clinical condition deteriorates under treatment with aerosolised iloprost, benefit from switching to continuous intravenous iloprost.

The current authors report on 16 patients with severe PAH who received continuous intravenous iloprost after primary or secondary failure of treatment with aerosolised iloprost. Determinants of efficacy were survival, New York Heart Association (NYHA) class, and walking distance in the 6‐min walk test.

Of 93 patients with PAH treated with aerosolised iloprost, 16 required switching to intravenous iloprost for clinical deterioration. These patients had severe right heart failure with a cardiac index of 1.6±0.2 L·min−1·m−2and a mixed-venous oxygen saturation of 52±6%. Five of these patients showed no improvement and eventually died. Three patients had further deterioration in NYHA class and exercise capacity; two of them underwent lung transplantation; the third patient is still alive. Eight patients showed marked clinical improvement; one underwent lung transplantation and the others are currently alive and stable. In the latter group of patients, the walking distance in the 6‐min walk test increased from 205±94 to 329±59 m. It was not possible to identify clinical or haemodynamic factors that would predict whether switching from inhaled to intravenous iloprost would have a beneficial effect.

In patients with pulmonary arterial hypertension who deteriorated while being treated with aerosolised iloprost, switching to continuous intravenous iloprost caused substantial improvement in exercise capacity in eight of 16 patients but could not prevent progression of pulmonary hypertension in the remaining eight patients. Since it was impossible to predict the individual effects of this approach, intravenous prostaglandin treatment should be considered in pulmonary arterial hypertension patients who deteriorate while receiving iloprost aerosol.