bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Changes Preceding Spontaneous Remission of Cancer
Authors: Schilder Johannes N. , de Vries Marco J. , Goodkin Karl , Antoni Mike
Published: September 2004

To develop hypotheses about psychological influences that may favorably affect tumor behavior, 11 patients were recruited who evinced spontaneous regression of histologically diagnosed and reviewed adenocarcinoma ( n = 3), lymphoma ( n =2), melanoma, chorion carcinoma, ovarian carcinoma, mesothelioma, liver carcinoma or sarcoma, and malignant giant cell tumor (a child). The authors studied retrospectively what had happened to these patients prior to the first signs of their clinical improvement. These patients seemed to have gained access to poignant activities and experiences, shortly prior to their tumor regression. Change involved an increased dystonic reaction to limited aspects of the personality and an increased syntonic reaction to a wider set of characteristics than normally accessed. These changes either followed other persons’ abusive behavior that “went beyond the pale” and elicited a different coping response than previously had been manifested by the patient, or were otherwise facilitated by particular events, independent of the patient’s behavior.
The Short-Term Treatment of a Long-Term Interpersonal Avoidance
Authors: Hyman Scott M. , Schneider Barry A.
Published: September 2004

This case study presents the 21-session cognitive-behavioral treatment of a young adult female diagnosed with Generalized Social Phobia (GSP) and Avoidant Personality Disorder (APD). Therapy utilized Beck’s modified cognitive therapy of personality disorders in addition to behavioral skills training. Therapist observation, client self-report, and objective measurements were used to assess behavioral change. Postintervention administrations of the Beck Depression Inventory–II (BDI-II), Beck Anxiety Inventory (BAI), and Minnesota Multiphasic Inventory–2 (MMPI-2) evinced a clinically significant reduction of symptoms. The results indicate that a short-term cognitive-behavioral approach may prove efficacious when treating APD.
A Mindfulness-Based Treatment of Obsessive-Compulsive Disorder
Authors: Singh Nirbhay N. , Wahler Robert G. , Winton Alan S. W. , Adkins Angela D. ,   The Mindfulness Research Group
Published: September 2004

Of those who suffer from obsessive-compulsive disorder (OCD), a substantial number do not respond well to the standard treatment of two trials of serotonin reuptake inhibitors and cognitive-behavioral therapy. In addition to being refractory to current treatments, these individuals often have comorbid disorders that contribute to a compromised quality of life. The authors present the case of such an individual who was assisted to improve her quality of life by accepting her OCD as a strength and enhancing her mindfulness so that she was able to incorporate her OCD in her daily life. Results showed that she successfully overcame her debilitating OCD and was taken off all medication within 6 months of intervention. Three years of postintervention follow-up showed that she was well adjusted, had a full and healthy lifestyle and that although some obsessive thoughts remained, they did not control her behavior.
Cognitive Therapy for Obsessive-Compulsive Disorder
Authors: Van Oppen Patricia
Published: September 2004

This case report is about a 31-year-old married female with a variety of obsessions, primarily focusing on harming obsessions. Because of anxiety, numerous washing rituals have taken place as well as the avoidance of situations. This client was diagnosed with Obsessive-Compulsive Disorder (OCD) and was seen for 25 sessions of individual cognitive therapy. The aim of this study therefore was to illustrate the assessment, case conceptualization, and course of treatment in a severe obsessive-compulsive client, using cognitive therapy. Several specific cognitive interventions, which address the estimations of catastrophes and the perceptions of personal responsibility, are presented and illustrated. At posttreatment and at follow-up, a clinically significant change for improvement was demonstrated for the obsessive-compulsive symptoms.
Fas-ligand (CD178) and TRAIL synergistically induce apoptosis of CD40-activated chronic lymphocytic leukemia B cells
Authors: Dicker Frank , Kater Arnon P. , Fukuda Tetsuya , Kipps Thomas J.
Published: September 2004

Chronic lymphocytic leukemia (CLL) B cells become sensitive to Fas (CD95)–mediated apoptosis 3 to 5 days after CD40 ligation. However, CD4+ cytotoxic T lymphocytes (CTLs) can kill CLL B cells via a Fas-ligand (CD178)–dependent process within 24 hours after CD40 cross-linking, when ligation of CD95 alone is insufficient to induce apoptosis. In addition to CD95, CD40-activated CLL cells also express DR5, a receptor for tumor-necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) that is expressed by CD4+ CTL. In addition, CD40 ligation in vitro and in vivo induces CLL cells to express the proapoptotic protein, BH3 interacting domain death agonist (Bid), which can facilitate crosstalk between mitochondrial-dependent, apoptosis-inducing pathways and death receptors, such as death receptor 5 (DR5). To evaluate whether ligation of CD95 and/or DR5 can induce apoptosis of CD40-activated CLL cells, we generated artificial cytotoxic effector cells that express both human TRAIL and CD178 (Chinese hamster ovary [CHO]–CD178/TRAIL) or only TRAIL (CHO-TRAIL) or CD178 (CHO-CD178). CHO-CD178/TRAIL cells were significantly more effective in killing CD40-activated CLL cells than either CHO-TRAIL or CHO-CD178 and, unlike the latter, could kill CLL cells 24 hours after CD40 ligation. We conclude that CD40 ligation induces CLL cells to express the proapoptotic molecule Bid and the death receptors CD95 and DR5, the latter of which can act synergistically to induce caspase-dependent apoptosis of CD40-activated CLL B cells.
Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1
Authors: Harder Kenneth W. , Quilici Cathy , Naik Edwina , Inglese Melissa , Kountouri Nicole , Turner Amanda , Zlatic Kristina , Tarlinton David M. , Hibbs Margaret L.
Published: September 2004

The Lyn tyrosine kinase plays essential inhibitory signaling roles within hematopoietic cells by recruiting inhibitory phosphatases such as SH2-domain containing phosphatase-1 (SHP-1), SHP-2, and SH2-domain containing 5′-inositol phosphatase (SHIP-1) to the plasma membrane in response to specific stimuli. Lyn-deficient mice display a collection of hematopoietic defects, including autoimmune disease as a result of autoantibody production, and perturbations in myelopoiesis that ultimately lead to splenomegaly and myeloid neoplasia. In this study, we demonstrate that loss of Lyn results in a stem/progenitor cell-intrinsic defect leading to an age-dependent increase in myeloid, erythroid, and primitive hematopoietic progenitor numbers that is independent of autoimmune disease. Despite possessing increased numbers of erythroid progenitors, and a more robust expansion of these cells following phenylhydrazine challenge, Lyn-deficient mice are more severely affected by the chemotherapeutic drug 5-fluorouracil, revealing a greater proportion of cycling progenitors. We also show that mice lacking SHIP-1 have defects in the erythroid and myeloid compartments similar to those in mice lacking Lyn or SHP-1, suggesting an intimate relationship between Lyn, SHP-1, and SHIP-1 in regulating hematopoiesis. (Blood. 2004;104:3901-3910)
Distribution of dehydration rates generated by maximal Gardos-channel activation in normal and sickle red blood cells
Authors: Lew Virgilio L. , Tiffert Teresa , Etzion Zipora , Perdomo Deisy , Daw Nuala , Macdonald Lynn , Bookchin Robert M.
Published: September 2004

The Ca2+-activated K+ channels of human red blood cells (RBCs) (Gardos channels, hIK1, hSK4) can mediate rapid cell dehydration, of particular relevance to the pathophysiology of sickle cell disease. Previous investigations gave widely discrepant estimates of the number of Gardos channels per RBC, from as few as 1 to 3 to as many as 300, with large cell-to-cell differences, suggesting that RBCs could differ extensively in their susceptibility to dehydration by elevated Ca2+. Here we investigated the distribution of dehydration rates induced by maximal and uniform Ca2+ loads in normal (AA) and sickle (SS) RBCs by measuring the time-dependent changes in osmotic fragility and RBC volume distributions. We found a remarkable conservation of osmotic lysis and volume distribution profiles during Ca2+-induced dehydration, indicating overall uniformity of dehydration rates among AA and SS RBCs. In light of these results, alternative interpretations were suggested for the previously proposed low estimates and heterogeneity of channel numbers per cell. The results support the view that stochastic Ca2+ permeabilization rather than Gardos-channel variation is the main determinant selecting which SS cells dehydrate through Gardos channels in each sickling episode. (Blood. 2005;105:361-367)
p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation
Authors: Chang Hong , Qi Connie , Yi Qi-Long , Reece Donna , Stewart A. Keith
Published: September 2004

We investigated the relevance of p53 deletions to the clinical outcome of patients with multiple myeloma (MM) treated with high-dose chemotherapy and autologous stem cell transplantation. Hemizygous p53 gene deletions were detected by fluorescence in situ hybridization in 10 of 105 (9.5%) patients studied. p53 deletions were associated with higher serum calcium (P = .0062) and creatinine (P = .013) levels, but there were no association with patient age, gender, β2-microglobulin, C-reactive protein, hemoglobin, albumin or bone lytic lesions, or immunoglobulin isotype. There were no associations of p53 deletions with 13q deletions or translocations t(11;14) or t(4;14). Patients with p53 deletions had significantly shorter progression-free (median, 7.9 versus 25.7 months, P = .0324) and overall survival (median, 14.7 versus 48.1 months, P = .0008) than patients without a p53 deletion. A multivariate analysis confirmed p53 deletion was an independent prognostic factor predicting shortened progression-free (P = .0009) or overall survival (P = .0002) in patients with MM after high-dose chemotherapy and autologous stem cell transplantation. (Blood. 2005;105:358-360)
Phospholipase D1 regulates high-affinity IgE receptor-induced mast cell degranulation
Authors: Hitomi Tomohiro , Zhang Juan , Nicoletti Liliana M. , Grodzki Ana Cristina G. , Jamur Maria C. , Oliver Constance , Siraganian Reuben P.
Published: September 2004

To investigate the role of phospholipase D (PLD) in FcϵRI signaling, the wild-type or the catalytically inactive forms of PLD1 or PLD2 were stably overexpressed in RBL-2H3 mast cells. FcϵRI stimulation resulted in the activation of both PLD1 and PLD2. However, PLD1 was the source of most of the receptor-induced PLD activity. There was enhanced FcϵRI-induced degranulation only in cells that overexpressed the catalytically inactive PLD1. This dominant-negative PLD1 enhanced FcϵRI-induced tyrosine phosphorylations of early signaling molecules such as the receptor subunits, Syk and phospholipase C-γ which resulted in faster release of Ca2+ from intracellular sources. Therefore, PLD1 negatively regulates signals upstream of the Ca2+ response. However, FcϵRI-induced PLD activation required Syk and was downstream of the Ca2+response, suggesting that basal PLD1 activity rather than that activated by cell stimulation controlled these early signaling events. Dominant-negative PLD1 reduced the basal phosphatidic acid formation in unstimulated cells, which was accompanied by an increase in FcϵRI within the lipid rafts. These results indicate that constitutive basal PLD1 activity by regulating phosphatidic acid formation controls the early signals initiated by FcϵRI aggregation that lead to mast cell degranulation. (Blood. 2004;104:4122-4128)
Disruption of Plasmodium berghei merozoite surface protein 7 gene modulates parasite growth in vivo
Authors: Tewari Rita , Ogun Solabomi A. , Gunaratne Ruwani S. , Crisanti Andrea , Holder Anthony A.
Published: September 2004

Merozoite invasion of red blood cells is crucial to the development of the parasite that causes malaria. Merozoite surface proteins (MSPs) mediate the first interaction between parasite and erythrocyte. In Plasmodium falciparum, they include a complex of products from at least 3 genes (msp1, msp6, and msp7), one of which, msp7, is part of a gene family containing 3 and 6 adjacent members in Plasmodium yoelii and Plasmodium falciparum, respectively. We have identified and disrupted msp7 in the Plasmodium berghei gene family. The protein is expressed in schizonts and colocalizes with MSP1. The synthesis and processing of MSP1 was unaffected in the parasite with the disrupted gene (MSP7ko). Disruption of msp7 was not lethal but affected blood-stage parasite growth. MSP7ko parasites initially grew more slowly than wild-type parasites. However, when reticulocytes were prevalent, the rate of increase in parasitemia was similar, suggesting that MSP7ko parasites prefer to invade and grow within reticulocytes. (Blood. 2005;105:394-396)
Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis
Authors: Nick Jerry A. , Coldren Christopher D. , Geraci Mark W. , Poch Katie R. , Fouty Brian W. , O'Brien James , Gruber Michael , Zarini Simona , Murphy Robert C. , Kuhn Katherine , Richter Don , Kast Kelly R. , Abraham Edward
Published: September 2004

Recombinant human activated protein C (rhAPC) is a natural anticoagulant with potentially important anti-inflammatory properties. In humans with severe sepsis, rhAPC treatment reduces mortality, but mechanisms responsible have not been well characterized. Accumulation of activated neutrophils in the lungs and other organs during severe infection contributes to sepsis-induced organ dysfunction, including acute inflammatory lung injury. Because neutrophils express an APC receptor, we hypothesized that immunomodulatory effects of rhAPC occur, in part, via modulation of neutrophil responses. To examine this issue, we performed a double-blinded, placebo-controlled study of rhAPC in a human model of endotoxin-induced pulmonary inflammation. Administration of rhAPC significantly reduced leukocyte accumulation to the airspaces, independent of pulmonary cytokine or chemokine release. Neutrophils recovered from bronchoalveolar lavage fluid of volunteers receiving rhAPC demonstrated decreased chemotaxis ex vivo. Decreased neutrophil chemotaxis following exposure to rhAPC was confirmed in vitro. No differences were detected in gene expression, kinase activation, cytokine release, cell survival, or apoptosis of neutrophils recovered in the presence or absence of rhAPC. These studies demonstrate that rhAPC reduces both endotoxin-induced accumulation of leukocytes in the airspaces and neutrophil chemotaxis. These rhAPC-induced effects on neutrophil function may represent a mechanism by which rhAPC improves survival in patients with sepsis. (Blood. 2004;104:3878-3885)
Interventional bronchoscopy for tuberculous tracheobronchial stenosis
Authors: Low S-Y. , Hsu A. , Eng P.
Published: September 2004

This study investigated the use of interventional bronchoscopic techniques in the management of patients with symptomatic tracheobronchial stenosis from tuberculosis.

The current authors evaluated their experience with interventional bronchoscopic techniques in 21 consecutive patients at the Singapore General Hospital, Singapore, from November 1994 to March 2001. All patients underwent rigid bronchocopy using the Dumon rigid ventilating bronchosope under general anaesthesia. A combination of techniques was used (mechanical or balloon dilatation, Nd-YAG laser and stenting using the Dumon stent).

The mean±sdincrease in luminal diameter of the tracheal lesions was from 4.5±2.5 mm pre-procedure to 11.9±1.7 mm post-procedure, whereas that for the mainstem bronchi stenosis was from 2.6±1.0 mm to 8.3±2.4 mm. All patients had immediate relief of symptoms post-intervention. Two patients who presented with acute respiratory failure could be weaned off mechanical ventilation immediately post-procedure. At the end of the study period, 52% (11 out of 21) remained asymptomatic.

Bronchoscopic intervention provided immediate symptomatic relief in all of the studied patients. However, repeated sessions may be required to maintain this improvement. It is concluded that interventional bronchoscopic techniques are useful in the management of patients with tracheobronchial stenosis from tuberculosis.
Penetration of newer quinolones in the empyema fluid
Authors: Liapakis I.E. , Kottakis I. , Tzatzarakis M.N. , Tsatsakis A.M. , Pitiakoudis M.S. , Ypsilantis P. , Light R.W. , Simopoulos C.E. , Bouros D.E.
Published: September 2004

The degree of penetration of newer quinolones into the pleural fluid has not been studied. The objective of the present study was to determine the degree to which moxifloxacin and levofloxacin penetrate into empyemic pleural fluid using a new rabbit model of empyema.

An empyema was createdviathe intrapleural injection of turpentine (1 mL), followed 24 h later by instillation of 2 mL (1×1010)Escherichia colibacteria (ATCC 35218) into the pleural space of New Zealand white rabbits. After an empyema was verified by thoracentesis and pleural fluid analysis, moxifloxacin and levofloxacin (25 mg·kg−1for both,i.v.) were administered. Antibiotic levels were determined in samples of pleural fluid and in blood collected serially over 12 h. Antibiotic levels were measured using HPLC.

Each of the antibiotics penetrated well into the empyemic pleural fluid. Antibiotic penetration was the greatest for moxifloxacin (area under the curve (AUC) for pleural fluid/blood (AUCPF/AUCblood) ratio=1.37) followed by levofloxacin (ratio=1.13). The time to equilibration between the pleural fluid and blood antibiotic levels was more rapid for moxifloxacin (3.9 h) than for levofloxacin (4.4 h). With moxifloxacin, the peak pleural fluid concentration (Cmax,PF) was 2.77 µg·mL−1and occurred at a time to maximum pleural fluid concentration (Tmax,PF) of 6 h after infusion and decreased thereafter. The peak blood concentration (Cmax,blood) was 4.81 µg·mL−1at 1 h after administration. With levofloxacin, the peak pleural fluid level (Cmax,PF=1.39 µg·mL−1) occurred at 6 h (Tmax,PF=6 h) after infusion. The Cmax,bloodwas 1.88 µg·mL−1at 1 h after administration.

In conclusion, differences were found in the degree of penetration of the two quinolones into infected pleural fluid in rabbits. The clinical significance of these differences is unknown. More studies are needed to evaluate the pharmacokinetic parameters in the pleural space in humans.
Primary pulmonary lymphangiectasia in infancy and childhood
Authors: Barker P.M. , Esther C.R. , Fordham L.A. , Maygarden S.J. , Funkhouser W.K.
Published: September 2004

Primary pulmonary lymphangiectasia (PPL) is a rare disorder of unknown aetiology characterised by dilatation of the pulmonary lymphatics. PPL is widely reported to have a poor prognosis in the neonatal period and little is known about the clinical features of patients who survive the newborn period.

The current authors report the outcome in nine patients diagnosed in infancy with PPL over a 15-yr period at a single university-based hospital clinic and followed for a median of 6 yrs.

Although all of the patients initially experienced respiratory distress, respiratory symptoms improved in most patients after infancy and were notably better by the age of 6 yrs. Many patients had poor weight gain in the first years of life, which eventually improved. Radiological scans showed progressive resolution of neonatal infiltrates, but were characterised by hyperinflation and increased interstitial markings in older children. Most patients had evidence of bronchitis and grew pathogenic organisms from quantitative bronchoalveolar lavage culture. Pulmonary function tests showed predominantly obstructive disease that did not deteriorate over time.

In conclusion, these results suggest that primary pulmonary lymphangiectasia does not have as dismal a prognosis as previously described and symptoms and clinical findings improve after the first year of life.
BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease
Authors: Roberts K.E. , McElroy J.J. , Wong W.P.K. , Yen E. , Widlitz A. , Barst R.J. , Knowles J.A. , Morse J.H.
Published: September 2004

The aim of the present study was to determine if patients with both pulmonary arterial hypertension (PAH), due to pulmonary vascular obstructive disease, and congenital heart defects (CHD), have mutations in the gene encoding bone morphogenetic protein receptor (BMPR)-2.

The BMPR2 gene was screened in two cohorts: 40 adults and 66 children with PAH/CHD. CHDs were patent ductus arteriosus, atrial and ventricular septal defects, partial anomalous pulmonary venous return, transposition of the great arteries, atrioventicular canal, and rare lesions with systemic-to-pulmonary shunts.

Six novel missense BMPR2 mutations were found in three out of four adults with complete type C atrioventricular canals and in three children. One child had an atrial septal defect and patent ductus arteriosus; one had an atrial septal defect, patent ductus arteriosus and partial anomalous pulmonary venous return; and one had an aortopulmonary window and a ventricular septal defect.

Bone morphogenetic protein receptor 2 mutations were found in 6% of a mixed cohort of adults and children with pulmonary arterial hypertension/congenital heart defects. The current findings compliment recent reports in mouse models implicating members of the bone morphogenetic protein/transforming growth factor-β pathway inducing cardiac anomalies analogous to human atrioventricular canals, septal defects and conotruncal congenital heart defects. The small number of patients studied and the ascertainment bias inherent in selecting for pulmonary arterial hypertension require further investigation.
Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2
Authors: Humbert M. , Barst R.J. , Robbins I.M. , Channick R.N. , Galiè N. , Boonstra A. , Rubin L.J. , Horn E.M. , Manes A. , Simonneau G.
Published: September 2004

The efficacy and safety of combining bosentan, an orally active dual endothelin receptor antagonist and epoprostenol, a continuously infused prostaglandin, in the treatment of pulmonary arterial hypertension (PAH) was investigated.

In this double-blind, placebo-controlled prospective study, 33 patients with PAH started epoprostenol treatment (2 ng·kg−1min−1starting dose, up to 14±2 ng·kg−1min−1at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mgb.i.dfor 4 weeks then 125 mgb.i.d) or placebo.

Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening, and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event).

This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension. Several cases of early and late major complications were reported. Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension.
Inhaled IFN-γ for persistent nontuberculous mycobacterial pulmonary disease due to functional IFN-γ deficiency
Authors: Hallstrand T.S. , Ochs H.D. , Zhu Q. , Liles W.C.
Published: September 2004

Pulmonary infection with nontuberculous mycobacteria (NTM) in previously healthy human immunodeficiency virus-seronegative individuals is difficult to treat. Recently, functional interferon (IFN)-γ deficiency has been identified in individuals susceptible to this disease. Treatment with inhaled IFN-γ for NTM pulmonary disease associated with functional IFN-γ deficiency has not been previously described.

In this study, the IFN-γ pathway was characterised in an individual who had progressive NTM pulmonary infection, despite appropriate multidrug antibiotic therapy, and 10 healthy controls. Levels of IFN-γ and tumour necrosis factor-α in whole blood were assessed before and after incubation with lipopolysaccharide, heat-killedEscherichia coli, heat-killedStaphylococcus aureusand phorbol myristate acetate/ionomycin. The coding regions of interleukin (IL)-12, IL-18 and the IL-12 receptor were sequenced using nested primers. IFN-γ1b (100 µg·dose−1) was administered to the affected individual by ultrasonic nebuliser 3 days·week−1for 3 months.

In vitrowhole blood production of IFN-γ with and without physiological stimuli was consistent with functional IFN-γ deficiency in the affected individual. There was no evidence of mutation in the coding regions of IL-12p35, IL-12p40, IL-12Rβ1 and IL-18 in the affected individual. Treatment with inhaled IFN-γ resulted in rapid and sustained clearance of the organism from the airways and stabilisation of lung function.

In conclusion, inhaled interferon-γ can be effective for the treatment of nontuberculous mycobacteria pulmonary disease associated with functional interferon-γ deficiency.
Safety of research bronchoscopy, biopsy and bronchoalveolar lavage in asthma: Table 1—
Authors: Elston W.J. , Whittaker A.J. , Khan L.N. , Flood-Page P. , Ramsay C. , Jeffery P.K. , Barnes N.C.
Published: September 2004

Bronchoscopy with endobronchial biopsy (EBB) and/or bronchoalveolar lavage (BAL) has become an important research tool in asthma. A recent report has suggested audit and reporting of the safety of these procedures.

A total of 159 asthmatic patients (84 males, 75 females), aged 18–52 (median 27) yrs, forced expiratory volume in one second 53–120 (median 88) % predicted, underwent 273bronchoscopies in six clinical research studies. On 228 occasions, EBB and BAL were performed and, on 45 occasions, EBB was performed alone. On 48 occasions, bronchoscopy was performed 24 h post-allergen challenge.

Adverse events occurred on 34 out of 273 occasions, none of which were following allergen challenge. Post-EBB and BAL, four patients developed pleuritic chest pain, shortness of breath and fever. A further two patients experienced pleuritic chest pain alone post-EBB/BAL. Bronchospasm or worsening of asthma symptoms occurred on 14 occasions, 13 post-EBB/BAL and on one occasion post-EBB alone. Fever/flu-like symptoms were reported on nine occasions following EBB and BAL. One subject had haemoptysis post-EBB/BAL, but required no intervention.

In conclusion, bronchoscopy, endobronchial biopsy and bronchoalveolar lavage can be performed safely in asthmatic patients. Most of the complications were seen where bronchoalveolar lavage and endobronchial biopsy were both performed, suggesting that bronchoalveolar lavage accounts for most of the adverse events.
European framework to decrease the burden of TB/HIV
Authors: de Colombani P. , Banatvala N. , Zaleskis R. , Maher D.
Published: September 2004

Tuberculosis (TB) in Europe is declining in countries in western and central Europe, but the burden is still high and increasing in eastern Europe. HIV/AIDS is increasing dramatically in eastern Europe. HIV-related tuberculosis (TB/HIV) morbidity and mortality are expected to accelerate significantly in the future.

This framework aims to guide European countries in developing their national plan for reducing TB/HIV morbidity and mortality. It results from an extensive consultation process undertaken by the World Health Organization Regional Office for Europe and by those responsible for HIV/AIDS and TB programmes and their partners. It builds on strategies developed globally and in Europe for TB control and for HIV/AIDS prevention and care.

This framework sets out the rationale for effective collaboration between HIV/AIDS and tuberculosis national programmes. It identifies five strategic components (political commitment, collaborative prevention, intensified case-finding, coordinated treatment and strengthened surveillance) and eight key operations (central coordination, policy development, surveillance, training, supply management, service delivery, health promotion and research).
Post-genome respiratory epidemiology: a multidisciplinary challenge
Authors: Kauffmann F. ,   the Post Genome Respiratory Epidemiology group
Published: September 2004

The introduction of genetic approaches in respiratory epidemiology is novel for most epidemiologists, and the post-genome phase poses new challenges. After describing specific questions pertinent to the field of asthma and chronic obstructive pulmonary disease, two main methodological aspects regarding technological and scientific advances are presented in this review. The first one concerns biological aspects in the genome and post-genome phases,i.e.how to study the genome, the transcriptome and the proteome. The second area concerns genetic epidemiology, considering design (case control and family based) and statistical analytical issues. Key aspects are large sample size, good phenotyping and the consideration of environment-by-gene interaction according to windows of opportunity.

Needs that have been identified include the following. 1) Networking for setting standards in the field and access to sufficiently large samples. 2) Multidisciplinarity; the collaboration of epidemiologists, clinicians, geneticists and specialists in bioinformatics, in addition to specialists in disciplines less familiar to epidemiologists, to be prepared for new phenotypic characterisations based on transcriptome and proteome. 3) Training in genetic analytical techniques for some respiratory epidemiologists, as well as in respiratory epidemiology for some genetic epidemiologists.

Implications for research, considering ethical aspects, public health aspects and organisational aspects in the field of genetic and environmental respiratory epidemiology also need to be addressed.
Spirometric reference equations for European females and males aged 65–85 yrs
Authors: García-Río F. , Pino J.M. , Dorgham A. , Alonso A. , Villamor J.
Published: September 2004

The aim of this study was to describe spirometric reference equations for healthy never-smoking European adults aged 65–85 yrs and to compare the predicted values of this sample with those from other studies including middle-aged and/or older adults.

Reference equations and normal ranges for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory volume in six seconds (FEV6), FEV1/FVC ratio and FEV1/FEV6ratio were derived from a healthy subgroup of 458 subjects aged 65–85 yrs. Spirometry examinations followed the 1994 American Thoracic Society recommendations and the quality of the data was continuously monitored and maintained. Reference values and lower limits of normal were derived using a piecewise polynomial model with age and height as predictors.

The reference values of FEV1and FVC from the present study were higher than those given by prediction equations from the European Community for Coal and Steel. By contrast, use of prediction equations from Caucasian-American elderly subjects (Cardiovascular Health Study) consistently overpredicted FVC and FEV1in females by 8.5 and 2.1%, respectively. In males, equations from the Cardiovascular Health Study overpredicted FVC by 2.8%, whilst underpredicting FEV1by 2.5%.

In conclusion, these results underscore the importance of using prediction equations appropriate to the origin, age and height characteristics of the subjects being studied.
Regulation of interleukin-1β and interleukin-1β inhibitor release by human airway epithelial cells
Authors: Yang Y. , Bin W. , Aksoy M.O. , Kelsen S.G.
Published: September 2004

In asthma, human airway epithelial cells (HAECs) regulate the intensity of mucosal inflammation, in part, by releasing the pro-inflammatory cytokine interleukin (IL)-1β. However, the IL-1β inhibitors, IL-1 receptor antagonist (IL-1RA) and soluble IL-1 receptor type II (sIL-1RII), regulate IL-1β bioactivity. In order to better understand the control of IL-1β activity in the airway mucosa, the role(s) of tumour necrosis factor (TNF)-α, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the release of IL-1β and its inhibitors by cultured HAECs were examined.

HAECs were treated with TNF-α (2–200 ng·mL−1), dibutyryl cAMP (0.01–1 mM), 8-bromo-cGMP (0.01–1 mM) or vehicle for 24 h, and cytokine levels in the HAEC-conditioned medium were measured by enzyme-linked immunosorbent assay.

HAECs produced IL-1β, IL-1RA and sIL-1RII constitutively, but the inhibitor concentrations greatly exceeded that of IL-1β (by ∼100- and ∼550-fold, respectively). TNF-α dose-dependently increased the levels of all IL-1β cytokine family members. However, over the range of TNF-α concentrations studied, IL-1β concentration increased more than those of its inhibitors. cAMP increased constitutive and TNF-α-stimulated IL-1β release but reduced that of sIL-1RII. In contrast, cGMP had no effect on IL-1β but reduced IL-1RA and sIL-1RII release.

Under basal conditions, the disproportionate release of inhibitors relative to interleukin-1β by human airway epithelial cells probably prevents interleukin-1β-mediated biological effects. Tumour necrosis factor-α, cyclic adenosine monophosphate and cyclic guanosine monophosphate may potentiate mucosal inflammation by increasing interleukin-1β levels relative to those of its inhibitors in the airway mucosa.
Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II): rationale and methods
Authors: Weiland S.K. , Björkstén B. , Brunekreef B. , Cookson W.O.C. , von Mutius E. , Strachan D.P. ,   the International Study of Asthma and Allergies in Childhood Phase II Study Group
Published: September 2004

International comparative studies, investigating whether disease incidence or prevalence rates differ between populations and, if so, which factors explain the observed differences, have made important contributions to the understanding of disease aetiology in many areas. In Phase I of the International Study of Asthma and Allergies in Childhood (ISAAC), the prevalence rates of symptoms of asthma, allergic rhinitis and atopic eczema in 13–14-yr-olds, assessed by standardised questionnaires, were found to differ >20-fold between the 155 study centres around the world. Phase II of ISAAC aims to identify determinants of these differences by studying informative populations.

A detailed study protocol was developed for use in community-based random samples of children aged 9–11 yrs. The study modules include standardised questionnaires with detailed questions on the occurrence and severity of symptoms of asthma, allergic rhinitis and atopic eczema, their clinical management, and a broad range of previous and current exposure conditions. In addition, standardised protocols were applied for examination of flexural dermatitis, skin-prick testing, bronchial challenge with hypertonic saline, blood sampling for immunoglobulin E analyses and genotyping, and dust sampling for assessment of indoor exposures to allergens and endotoxin.

To date, ISAAC II field work had been completed or started in 30 study centres in 22 countries.

The majority of centres are in countries that participated in International Study of Asthma and Allergies in Childhood Phase I and reflect almost the full range of the observed variability in Phase I prevalence rates.
Exercise-induced flow limitation, dynamic hyperinflation and exercise capacity in patients with bronchial asthma
Authors: Kosmas E.N. , Milic-Emili J. , Polychronaki A. , Dimitroulis I. , Retsou S. , Gaga M. , Koutsoukou A. , Roussos Ch. , Koulouris N.G.
Published: September 2004

It is known that, in stable asthmatics at rest, tidal expiratory flow limitation (EFL) and dynamic hyperinflation (DH) are seldom present. This study investigated whether stable asthmatics develop tidal EFL and DH during exercise with concurrent limitation of maximal exercise work rate (WRmax).

A total of 20 asthmatics in a stable condition and aged 32±13 yrs (mean±sd) with a forced expiratory volume in one second (FEV1) of 101±21% of the predicted value were studied. Only three patients exhibited an FEV1below the normal limits. On a first visit, patients performed a symptom-limited incremental (20 W·min−1) bicycle exercise test. On the second visit, the occurrence of EFL (using the negative expiratory pressure technique) and DH (viareduction in inspiratory capacity) were assessed at rest and when cycling at 33, 66 and 90% of their predetermined WRmax. FEV1was measured to detect exercise-induced asthma, 5 and 15 min after stopping exercise at 90% WRmax.

Only one patient showed EFL at rest, whereas 13 showed EFL and DH during exercise. In these 13 asthmatics, exercise capacity was significantly reduced (WRmax75±9% pred) compared to the seven non-EFL patients (WRmax95±13% pred). Moreover, a significant correlation of WRmax(% pred) to the change in inspiratory capacity (percentage of resting value) from rest to 90% WRmaxwas found. Tidal EFL during exercise was not associated with exercise-induced asthma, which was detected in only three patients.

In conclusion, tidal expiratory flow limitation and dynamic hyperinflation during exercise are common in stable asthmatics with normal spirometric results and without exercise-induced asthma, and may contribute to reduction in exercise capacity.
Endobronchial brachytherapy in the treatment of malignant lung tumours
Authors: Escobar-Sacristán J.A. , Granda-Orive J.I. , Gutiérrez Jiménez T. , Delgado J.M. , Rodero Baños A. , Saez Valls R.
Published: September 2004

A prospective study was made to assess the short-term clinical and endoscopic response to high-dose-rate endobronchial brachytherapy (HDREB) in patients with malignant endobronchial tumours.

From July 1995 to May 2000, 288 HDREB sessions were carried out on 81 patients. The mean patient age was 61.57 yrs (range 34–82); males were predominant (87.65%). Tumours were primary in 76 patients (93.82%) and metastatic in five patients (6.18%). The inclusion criteria were malignant endobronchial tumour and either palliative treatment for incurable disease or intent-to-cure treatment for residual malignancy on the bronchial resection surface after surgery or an inoperable tumour. The exclusion criteria were as follows: impediments to catheter placement, expected survival <2 months, Karnofsky index <60, or absence of informed consent. The clinical response of a symptom was categorised as complete (disappearance of the symptom), partial (less than complete) or absent. The endoscopic response was considered to be complete if lesions disappeared and biopsy findings remained negative 1 month after the last radiation session; partial if lesions improved to some extent, but the biopsy findings were positive; and absent if there was no change in relation to baseline. The technique consisted of delivering high-dose irradiation from an Ir192source to a target volume using one or two endobronchial catheters inserted under optical or video bronchoscopic guidance. Four sessions were scheduled at weekly intervals and 500 cGy was applied per session over a length of 1–9 cm, measured 0.5–1 cm from the centre of the source.

In total, 85% of the symptoms analysed (haemoptysis, cough, dyspnoea, expectoration, and stridor) disappeared with HDREB, which was categorised as a complete response. The endoscopic response was complete in 56.79% of patients, partial or less than complete in 40.74% and absent in 2.46%. One major complication occurred (bronchial fistula 1.2%), but no lethal haemoptysis. Minor complications (pneumonitis, bronchospasm and bronchial stenosis) each occurred in one patient (1.2%).

High-dose-rate endobronchial brachytherapy is a good palliative treatment for endoluminal lung neoplasms, effectively alleviating symptoms and endoscopic evidence in many cases with an acceptable rate of complications. High-dose-rate endobronchial brachytherapy can be carried out as an intent-to-cure procedure in highly selected cases.
Smoking cessation improves both direct and indirect airway hyperresponsiveness in COPD
Authors: Willemse B.W.M. , ten Hacken N.H.T. , Rutgers B. , Lesman-Leegte I.G.A.T. , Timens W. , Postma D.S.
Published: September 2004

Smoking induces chronic obstructive pulmonary disease (COPD) and is associated with airway inflammation and airway hyperresponsiveness (AHR). It has not been studied in COPD whether direct (methacholine) and indirect (adenosine-5'-monophosphate (AMP)) stimuli are associated with airway inflammation and neither whether smoking cessation improves these features.

The current authors cross-sectionally investigated the relationship of AHR to methacholine and AMP with lung function and inflammatory cells in the sputum of 33 smokers with COPD. In addition, changes in these parameters were prospectively assessed in 14 smokers who successfully quit smoking for 1 yr.

The presence of AHR to both methacholine and AMP was associated with lower lung function, but not with sputum inflammation. AHR to methacholine and AMP improved significantly after a 1-yr smoking cessation, yet this was unrelated to changes in sputum cell counts. The numbers of neutrophils and epithelial cells significantly increased with smoking cessation.

Both direct and indirect airway hyperresponsiveness are associated with lower lung function, but not with sputum inflammation in chronic obstructive pulmonary disease. Interestingly, 1-yr smoking cessation improved both direct and indirect airway hyperresponsiveness, yet without a significant association with changes in lung function or sputum inflammation. Thus, other factors are likely to induce these improvements,e.g.a reduction in stimulation of irritant receptors, airway wall changes or mucus hypersecretion.
Chest wall kinematics and respiratory muscle action in ankylosing spondylitis patients
Authors: Romagnoli I. , Gigliotti F. , Galarducci A. , Lanini B. , Bianchi R. , Cammelli D. , Scano G.
Published: September 2004

No direct measurements of the pressures produced by the ribcage muscles, the diaphragm and the abdominal muscles during hyperventilation have been reported in patients with ankylosing spondylitis. Based on recent evidence indicating that abdominal muscles are important contributors to stimulation of ventilation, it was hypothesised that, in ankylosing spondylitis patients with limited ribcage expansion, a respiratory centre strategy to help the diaphragm function may involve coordinated action of this muscle with abdominal muscles.

In order to validate this hypothesis, the chest wall response to a hypercapnic/hyperoxic rebreathing test was assessed in six ankylosing spondylitis patients and seven controls by combined analysis of: 1) chest wall kinematics, using optoelectronic plethysmography, this system is accurate in partitioning chest wall expansion into the contributions of the ribcage and the abdomen; and 2) respiratory muscle pressures, oesophageal, gastric and transdiaphragmatic (Pdi); the pressure/volume relaxation characteristics of both the ribcage and the abdomen allowed assessment of the peak pressure of both inspiratory and expiratory ribcage muscles, and of the abdominal muscles.

During rebreathing, chest wall expansion increased to a similar extent in patients to that in controls; however, the abdominal component increased more and the ribcage component less in patients. Peak inspiratory ribcage, but not abdominal, muscle pressure was significantly lower in patients than in controls. End-inspiratoryPdiincreased similarly in both groups, whereas inspiratory swings inPdiincreased significantly only in patients. No pressure or volume signals correlated with disease severity.

The diaphragm and abdominal muscles help to expand the chest wall in ankylosing spondylitis patients, regardless of the severity of their disease. This finding supports the starting hypothesis that a coordinated response of respiratory muscle activity optimises the efficiency of the thoracoabdominal compartment in conditions of limited ribcage expansion.
Adenocarcinoma of the lung mimicking inflammatory lung disease with honeycombing
Authors: Lantuejoul S. , Colby T.V. , Ferretti G.R. , Brichon P.Y. , Brambilla C. , Brambilla E.
Published: September 2004

Pulmonary adenocarcinoma of the lung and its variants are well-defined entities, since the recent WHO classification of lung tumours. However, scant descriptions have been allocated to associated stromal changes, such as prominent inflammation and fibrosis, which can overshadow a tumoral proliferation and masquerade as a benign reactive process and this has not been recognised as a histopathological variant.

The case of a 72-yr-old farmer who presented a multifocal well-differentiated adenocarcinoma that mimicked honeycomb lung with bronchiolectasis radiologically, on computed tomography scan and histologically at open lung biopsy, is reported. Histological pitfalls in the biopsy were represented by mild atypical cuboidal or columnar epithelial cells lining bronchiolar structures resembling florid bronchiolar metaplasia in a background of extensive fibrosis and inflammation, features that mimicked inflammatory honeycombing. However, histological analysis of the surgical resection of the main lesion, performed because of a clinical alteration of the patient, confirmed the diagnosis of multifocal adenocarcinoma of mixed subtype. A monomorphic proliferation of clear cells, lack of associated ciliated or squamous cells and presence of significant cytologic atypia gave a diagnosis of malignancy.

This case illustrates how inflammatory and fibrotic changes may conceal a correct diagnosis of carcinoma and emphasises the importance of adequate sampling in such cases.
Mutations in the IGF-II pathway that confer resistance to lytic reovirus infection
Authors: Sheng Jinsong , Organ Edward L , Hao Chuanming , Wells K Sam , Ruley H Earl , Rubin Donald H
Published: September 2004

Background

Viruses are obligate intracellular parasites and rely upon the host cell for different steps in their life cycles. The characterization of cellular genes required for virus infection and/or cell killing will be essential for understanding viral life cycles, and may provide cellular targets for new antiviral therapies.

Results

A gene entrapment approach was used to identify candidate cellular genes that affect reovirus infection or virus induced cell lysis. Four of the 111 genes disrupted in clones selected for resistance to infection by reovirus type 1 involved the insulin growth factor-2 (IGF-II) pathway, including: the mannose-6-phosphate/IGF2 receptor (Igf2r), a protease associated with insulin growth factor binding protein 5 (Prss11), and the CTCF transcriptional regulator (Ctcf). The disruption of Ctcf, which encodes a repressor of Igf2, was associated with enhanced Igf2 gene expression. Plasmids expressing either the IGF-II pro-hormone or IGF-II without the carboxy terminal extension (E)-peptide sequence independently conferred high levels of cellular resistance to reovirus infection. Forced IGF-II expression results in a block in virus disassembly. In addition, Ctcf disruption and forced Igf2 expression both enabled cells to proliferate in soft agar, a phenotype associated with malignant growth in vivo.

Conclusion

These results indicate that IGF-II, and by inference other components of the IGF-II signalling pathway, can confer resistance to lytic reovirus infection. This report represents the first use of gene entrapment to identify host factors affecting virus infection. Concomitant transformation observed in some virus resistant cells illustrates a potential mechanism of carcinogenesis associated with chronic virus infection.