bluuebunny/crossref_metadata_2025 huggingface dataset:
Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8+CD57+CD28− compartment
Authors: Sze Daniel M.-Y. , Giesajtis Gillian , Brown Ross D. , Raitakari Maria , Gibson John , Ho Joy , Baxter Alan G. , Fazekas de St Groth Barbara , Basten Antony , Joshua Douglas E.
Published: July 2002

The occurrence of clonal T cells in multiple myeloma (MM), as defined by the presence of rearrangements in the T-cell receptor (TCR)–β chains detected on Southern blotting, is associated with an improved prognosis. Recently, with the use of specific anti–TCR-variable-β (anti–TCRVβ) antibodies, the presence in MM patients of expanded populations of T cells expressing particular Vβ regions was reported. The majority of these T-cell expansions have the phenotype of cytotoxic T cells (CD8+CD57+ and perforin positive). Since Vβ expansions can result from either a true clonal population or a polyclonal response, the clonality of CD8+TCRVβ+ T cells was tested by TCRVβ complementarity-determining region 3 length analysis and DNA sequencing of the variable region of the TCR. In this report, the CD57+ and CD57− subpopulations within expanded TCRVβ+CD8+ cell populations are compared, and it is demonstrated that the CD57+ subpopulations are generally monoclonal or biclonal, whereas the corresponding CD57− cells are frequently polyclonal. The oligoclonality of CD57+ expanded CD8+ T cells but not their CD57− counterparts was also observed in age-matched controls, in which the T-cell expansions were mainly CD8−. The CD8+CD57+ clonal T cells had a low rate of turnover and expressed relatively lower levels of the apoptotic marker CD95 than their CD57− counterparts. Taken together, these findings demonstrate that MM is associated with CD57+CD8+ T-cell clones, raising the possibility that the expansion and accumulation of activated clonal CD8+ T cells in MM may be the result of persistent stimulation by tumor-associated antigens, combined with a reduced cellular death rate secondary to reduced expression of the apoptosis-related molecule CD95.
Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/NFAT
Authors: Bochkov Valery N. , Mechtcheriakova Diana , Lucerna Marcus , Huber Joakim , Malli Roland , Graier Wolfgang F. , Hofer Erhard , Binder Bernd R. , Leitinger Norbert
Published: July 2002

Activation of endothelial cells by lipid oxidation products is a key event in the initiation and progression of the atherosclerotic lesion. Minimally modified low-density lipoprotein (MM-LDL) induces the expression of certain inflammatory molecules such as tissue factor (TF) in endothelial cells. This study examined intracellular signaling pathways leading to TF up-regulation by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a biologically active component of MM-LDL. OxPAPC induced TF activity and protein expression in human umbilical vein endothelial cells (HUVECs). However, OxPAPC neither induced phosphorylation or degradation of IκBα nor DNA binding of nuclear factor-κB (NF-κB). Furthermore, OxPAPC-induced TF expression was not inhibited by overexpression of IκBα. These results strongly indicate that OxPAPC-induced TF expression is independent of the classical NF-κB pathway. However, OxPAPC stimulated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and expression of early growth response factor 1 (EGR-1). Inhibitors of mitogen-activated kinase/ERK (MEK) or protein kinase C (PKC) blocked elevation of both EGR-1 and TF. Furthermore, overexpression of NAB2, a corepressor of EGR-1, inhibited effects of OxPAPC. In addition, OxPAPC induced rapid and reversible elevation of free cytosolic Ca++ levels and nuclear factor of activated T cells (NFAT)/DNA binding. Induction of TF expression by OxPAPC was partially inhibited by cyclosporin A, known to block calcineurin, a Ca++-dependent phosphatase upstream of NFAT. Treatment of OxPAPC with phospholipase A2 destroyed its biologic activity and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine was identified as one biologically active component of OxPAPC that induces TF expression. Together, the results demonstrate that OxPAPC induces TF expression in HUVECs through activation of PKC/ERK/EGR-1 and Ca++/calcineurin/NFAT pathways rather than by NF-κB–mediated transcription. Thus, oxidized phospholipids may contribute to inflammation by activating pathways alternative to the classical NF-κB pathway.
Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays
Authors: Husson Hervé , Carideo Elizabeth G. , Neuberg Donna , Schultze Joachim , Munoz Olivier , Marks Peter W. , Donovan John W. , Chillemi Antoinette C. , O'Connell Peter , Freedman Arnold S.
Published: July 2002

Follicular lymphomas (FLs) are neoplastic counterparts of normal germinal center (GC) B cells. FLs are characterized by t(14;18) with deregulation of the Bcl-2 (BCL2) gene. The presence of t(14;18) and overexpression of Bcl-2 is necessary, but not sufficient, to cause this disease. An array containing 588 complementary DNAs (cDNAs) was used to compare the gene expression between GC B cells and FL cells. To specifically monitor genes expressed in normal GC B and FL cells and not the entire tissue compartment, normal and malignant B cells were purified from tissues. Using the array, 37 genes were up-regulated and 28 were down-regulated in FL cells as compared to normal GC B cells. The expression level of each differentially expressed gene was verified by quantitative polymerase chain reaction. Following these studies 24 genes were up-regulated and 8 genes down-regulated with a P value less than .1. Included among the genes that were up-regulated in FLs were cell cycle regulator proteins CDK10, p120, p21CIP1, and p16INK4A; transcription factors/regulators Pax-5 and Id-2, which are involved in normal B-cell development; and genes involved in cell-cell interactions, tumor necrosis factor, interleukin-2Rγ (IL-2Rγ), and IL-4Rα. Among the genes that were down-regulated in FLs wereMRP8 and MRP14, which are involved in adhesion. Interestingly, several of these genes are localized within chromosomal regions already described to be altered in FLs. These findings provide a basis for future studies into the pathogenesis and pathophysiology of FL and may lead to the identification of potential therapeutic targets as well as antigens for immunotherapeutic strategies.
BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression
Authors: Maes Brigitte , Demunter Anouk , Peeters Benjamin , De Wolf-Peeters Christiane
Published: July 2002

Two recurrent translocations have been associated with mucosa-associated lymphoid tissue (MALT)–type lymphoma, t(11;18)(q21;q21) and t(1;14)(p22;q32). The first, t(11;18)(q21;q21), results in the fusion protein API2-MLT (API2-MALT1). Through t(1;14)(p22;q32), the BCL10 gene is entirely transferred to the IgH gene, resulting in its overexpression. Wild-type BCL10 is implicated in apoptosis, and it has been suggested that mutated forms gain oncogenic activity. The occurrence of genomicBCL10 mutations in 35 gastric MALT-type lymphomas with or without t(11;18)(q21;q21) (10 and 25 cases, respectively) was investigated. DNA extracted from either whole tissue sections or microdissected clusters of tumor cells was used. Five polymerase chain reactions amplifying the coding exons were performed and were followed by direct sequencing of the products. Twenty differences with the published BCL10 sequence, all single nucleotide substitutions, were detected in 16 cases. Of these, 12 represented known polymorphisms, either at codon 8, 213, or 5. Of the remaining 8 substitutions, 2 were silent and 6 resulted in amino acid substitutions. Mutation analysis results were correlated with the BCL10 expression pattern. Aberrant nuclear BCL10 expression was detected in 14 cases. No association could be demonstrated between the latter and the presence of BCL10 mutations. In contrast, all 10 cases carrying t(11;18)(q21;q21) showed nuclear expression, whereas this staining pattern was absent in 21 of 25 cases without t(11;18)(q21;q21). These results demonstrate that BCL10mutations are rare in gastric MALT-type lymphoma and are not related to the aberrant nuclear expression of BCL10. In contrast, they indicate that the presence of the API2-MLT fusion protein is associated with aberrant nuclear BCL10 expression.
Cat sensitivity: 7-yr audit in children attending a paediatric allergy clinic in North Italy
Authors: Pescollderungg L , Pietrobelli A , Boner AL
Published: July 2002

Sensitivity to cats and exposure to cat allergen is a common cause of asthma exacerbation in children. To date, there is no data on the prevalence of cat sensitivity in children living in North Italy. Therefore, a 7-yr survey was performed in patients attending an allergy clinic for the first time. Skin prick tests (SPT) for perennial allergens and for pollens relevant to the region were performed in 4,957 children attending the outpatient clinic 1992-1998. A questionnaire on present or past cat ownership was presented to all cat-skin prick test positive children. An evaluation of cat ownership on the general population was made by telephone interview on a random sample of 1,268 families living in the same area. With a 3-mm wheal as a positive cut-off 439 (8.85%) children had a positive SPT to cats. Of these 103 (23.4%) had a cat at home and 336 (76.6%) never had a cat in the house. With a greater positive cut-off(a wheal diameter > or =4 mm) 140 (2.8%) showed a positive SPT to cats of these 35 (25%) had a cat at home and 105 (75%) had only an indirect exposure to the pet. Of the telephone interviewed families; 16% stated they had a cat at home. Cat sensitivity is less prevalent in Italy, in this hospital based population, compared with other European countries and this is in agreement with a lower rate of cat ownership. Cat sensitivity was three times more frequent in children who never had a cat at home, than in children living with cats, when the selected positive cut-off was either a wheal diameter of 3 mm or > or =4 mm. Thus in a population with a low prevalence of cat ownership public exposure seems to be more important than domestic exposure for the development of sensitivity.
Health effects of daily indoor nitrogen dioxide exposure in people with asthma
Authors: Smith BJ , Nitschke M , Pilotto LS , Ruffin RE , Pisaniello DL , Willson KJ
Published: July 2002

Household gas appliances produce nitrogen dioxide (NO2), which may be associated with an increase in symptoms in asthmatics. The relationship between indoor NO2 exposure, and respiratory symptoms in people with asthma was evaluated. Self-reported asthmatics (n=125) wore lapel badges that measured NO2 daily over 6 weeks at home. Outdoor pollutants, spores and meteorological parameters were measured daily, in addition to smoking status and demographic factors. Seven asthma symptoms were recorded in diaries, for analysis by same day and also with 1 day lag exposures, using a generalized estimating equation. Significant interactions were demonstrated between NO2 at age < or =14 yrs, with respect to the symptoms of chest tightness on the same day (odds ratio (OR): 1.29, 95% confidence interval (CI): 1.16-1.43) and with a 1 day lag (OR: 1.29, 95% CI: 1.14-1.46), breathlessness on exertion with a 1 day lag (OR: 1.13, 95% CI: 1.00-1.28), daytime asthma attacks on the same day (OR: 1.13, 95% CI: 1.02-1.26) night asthma attacks on the same day (OR: 1.16, 95% CI:1.03-1.30) and with a 1 day lag (OR: 1.15, 95% CI; 1.03-1.29) after adjustment for potential confounders. A significant interaction between NO2 and age 35-49 yrs was demonstrated for coughs with a 1 day lag (OR: 1.15, 95% CI: 1.01-1.31). Daily personal exposures to NO2 are associated with asthmatic symptoms in children.
Regulation of lipopolysaccharide-mediated interleukin-1beta release by N-acetylcysteine in THP-1 cells
Authors: Parmentier M , Hirani N , Rahman I , Donaldson K , MacNee W , Antonicelli F
Published: July 2002

Increased levels of inflammatory cytokines such as interleukin (IL)-1 and IL-8 occur in the bronchoalveolar lavage fluid in various lung diseases. Cytokine gene expression is controlled by transcription factors such as nuclear factor-kappaB (NF-kappaB) which can be activated by a number of stimuli including the oxidants prevent. It was hypothesized that lipopolysaccharide (LPS)-induced IL-1beta secretion may be modulated by the intracellular thiol redox status of the cells. The effect of the antioxidant compound, N-acetyl-L-cysteine (NAC), on IL-1beta release and regulation of NF-kappaB in a human myelo-monocytic cell line (THP-1) differentiated into macrophages was studied. LPS (10 microg x mL(-1)) increased IL-1beta release at 24 h compared to control levels (p<0.001). NAC (5 mM) also enhanced LPS-induced IL-1beta release from THP-1 cells (p<0.001). In addition, treatment of cells with cycloheximide, an inhibitor of protein synthesis, inhibited the NAC-mediated IL-1beta release. Under the same conditions, NF-kappaB binding was activated by LPS and NAC increased this LPS-mediated effect. Western blot analysis revealed that NAC treatment leads to an increase in p50 and p65 protein synthesis. These data indicate that N-acetyl-L-cysteine modulates interleukin-1kappa release by increasing levels of the homo- and heterodimeric forms of nuclear factor-kappaB.
Evaluation of impulse oscillation system: comparison with forced oscillation technique and body plethysmography
Authors: Hellinckx J. , Cauberghs M. , De Boeck K. , Demedts M.
Published: July 2002

The impulse oscillation system (IOS) has been developed recently to measure respiratory system resistance (Rrs) and reactance (Xrs) at different frequencies up to ≥25 Hz. IOS has, however, not been validated against established techniques.

This study compared IOS with the classical pseudorandom noise forced oscillation technique (FOT) and body plethysmographic airway resistance (Raw) in 49 subjects with a variety of lung disorders and a wide range ofRaw(0.10–1.28 kPa·L−1·s).

Rrs,IOSwas slightly greater thanRrs,FOT, especially at lower frequencies, with a mean±sd difference at 5–6 Hz of 0.14±0.09 kPa·L−1·s. Comparisons with the wave-tube technique applied on two analogues indicated an overestimation by IOS.Xrs,IOSandXrs,FOTwere very similar, with a slightly higher resonant frequency with IOS than with FOT (mean difference±sd 1.35±3.40 Hz).Rawwas only moderately correlated withRrs-FOTandRrs-IOS; although the mean differences were small (0.04±0.14 kPa·L−1·s forRrs6,FOTand −0.10±0.14 kPa·L−1·s forRrs5,IOS), IOS and FOT markedly underestimated high resistance values.

In conclusion, the impulse oscillation system yields respiratory system resistance and reactance values similar, but not identical to those provided by the forced oscillation technique.
Sarcoidosis severity and socioeconomic status
Authors: Rabin D.L. , Richardson M.S.A. , Stein S.R. , Yeager H.
Published: July 2002

Several chronic diseases are more severe in persons who are Black, of low socioeconomic status (SES), and underinsured. The authors ask if this is true for sarcoidosis. Associations among sarcoidosis disease severity, SES, insurance coverage, and functional limitations were analysed.

Back and White sarcoidosis patients (n=110) of a municipal and university hospital sarcoidosis registry were interviewed by telephone. Data on disease severity were abstracted from patient charts.

Most patients reported good or excellent health by demographic characteristics. Low SES and no or public insurance were associated with worse health status and more severe dyspnoea. More advanced radiographic stage was associated with lower income, and forced vital capacity impairment with less education. Physical and social activity limitations due to physical and emotional disability were related to no or public insurance and lower income, but not education.

Sarcoidosis severity is associated with socioeconomic status and insurance indicators; no or public insurance and low income are associated with functional limitations. Sarcoidosis-associated limitations are substantial, emphasizing the social significance of sarcoidosis. Lack of private insurance may inhibit the use of medical care, contributing to disease severity and impairment.
Exercise tolerance in children with cystic fibrosis undergoing lung transplantation assessment
Authors: Aurora P. , Prasad S.A. , Balfour-Lynn I.M. , Slade G. , Whitehead B. , Dinwiddie R.
Published: July 2002

The aim of this study was to compare the 6-min walk test against the recently developed 3-min step test, as measures of exercise tolerance in children with moderate to severe cystic fibrosis (CF) lung disease referred for lung transplantation assessment.

Twenty-eight children with CF (16 girls, 12 boys), with a mean age of 13.7 yrs (range 7.2–17.8 yrs) and mean forced expiratory volume in one second of 34% predicted (range 17%–67%) were recruited. All subjects performed both the 6-min walk and 3-min step-tests. Outcome measures were maximum rise in heart rate (HR), and maximum fall in arterial oxygen saturation (Sa,O2).

There was no significant difference in resting HR orSa,O2prior to starting the two tests. Both step and walk tests produced significant rises in median HR (from 114–149 min−1, p<0.0005, and 119–138 min−1, p<0.0005, respectively) and significant falls inSa,O2(both from 94–92%, p<0.0005). The step test produced a significantly greater percentage rise in HR (30%versus18%, p<0.0005) and a significantly greater percentage fall inSa,O2(4%versus2%, p=0.002). Bland-Altman analysis gave wide 95% limits of agreement (10.7–29.3% for rise in HR, −2.1–4.6% for fall inSa,O2). The step test was well tolerated.

The 3-min step test produced a greater fall inSa,O2and a greater rise in HR than the 6-min walk test in children with moderate to severe CF lung disease. It may be of value when assessing a child's suitability for lung transplantation.
Increased frequency dependence of specific airway resistance in patients with laryngeal hemiplegia
Authors: Fasano V. , Raiteri L. , Bucchioni E. , Guerra S. , Cantarella G. , Massari M.G. , Cesana B.M. , Allegra L.
Published: July 2002

The aim of this study was to investigate whether patients with laryngeal hemiplegia (LH) show a frequency-dependent increase in specific airway resistance (sRaw), measured by body plethysmography.

In addition to the flow-volume loop, usually considered in the functional evaluation of upper airway obstructions, variations in sRawat respiratory frequencies of 30±5 (=0.5 Hz), 60±5 (=1 Hz) and 90±5 breaths·min−1(=1.5 Hz) in 21 never-smoking patients (LH group, mean age±sd 55±12.09 yrs; 17 females) whose unilateral vocal-cord paralysis was documented by laryngoscopy and who had no signs or symptoms of other respiratory diseases studied. They were compared to 21 healthy control subjects (C group: 50.1±15.44 yrs; 10 females).

The sRawvalues at 30±5 breaths·min−1were similar in the two groups (5.54±1.88versus5.68±1.06 cmH2O·s−1; p=ns), but at increasing frequencies (30±5, 60±5 and 90±5 breaths·min−1), they progressively and significantly increased in the LH patients (from 5.54±1.88 to 6.63±1.96 and 8.05±2.6 cmH2O·s−1; p<0.0005), and not significantly in controls (5.68±1.06, 5.85±0.95 and 5.9±1.12 cmH2O·s; p=ns). Linear discriminant analysis using ΔsRaw(sRawat 1.5 Hz-sRawat 0.5 Hz) and forced inspiratory flow at 50% of the vital capacity made it possible to correctly classify all of the controls and 19 of the 21 patients.

In conclusion, the multiple, rapid and noninvasive plethysmographical testing of frequency-dependent increase in specific airway resistance with the flow-volume loop, allows the sufficiently satisfactory discrimination of laryngeal hemiplegia patients from controls.
Influence of setting on unattended respiratory monitoring in the sleep apnoea/hypopnoea syndrome
Authors: Lloberes P. , Sampol G. , Levy G. , Aristizabal D. , Sagales T. , De la Calzada M. , Roca A. , Cañas I. , Morell F.
Published: July 2002

The high demand for full polysomnography and the better quality of sleep at home are the main reasons for performing home sleep studies. Home respiratory monitoring has been evaluated in several studies, but the influence of setting on the results of unattended respiratory monitoring has not been assessed to date.

Unattended monitoring of respiratory variables at home and in the sleep laboratory was conducted in 35 consecutive patients with suspected sleep apnoea/hypopnoea syndrome. Respiratory variables during sleep, rate of successful studies and patient preference were compared.

The data acquisition failure rate was 2.8% in the sleep laboratory and 5.7% at home. The mean difference between apnoea/hypopnoea indices (AHI) obtained from home and laboratory studies was −0.21±8 (95% confidence interval 3.27–2.84). Using the method comparison approach of Bland and Altman, the limits of agreement of the mean difference between AHI home and AHI laboratory were −16.7 and 17.1. No difference was observed between the studies in time spent in different body positions. When patients were asked where they would prefer to repeat the sleep study, 53% replied at home, 28% in hospital and 19% showed no preference.

It was concluded that the setting of unattended respiratory monitoring (home or sleep laboratory) influences neither the number of valid studies nor the results of the respiratory parameters measured; most patients, however, preferred home studies.
Response of nitric oxide pathway to l-arginine infusion at the altitude of 4,350 m
Authors: Schneider J-C. , Blazy I. , Déchaux M. , Rabier D. , Mason N.P. , Richalet J-P.
Published: July 2002

It was hypothesized that hypoxia may inhibit nitric oxide (NO) production by reducing the availability of endothelial NO synthase (NOS III) substrate.

To evaluate the effect of l-arginine on the NO release in high altitude, 11 subjects were infused with l-arginine (0.5 g·kg−1) during 30 min in normoxia and after 36 h at 4,350 m (hypoxia). The l-citrulline and cyclic guanosine monophosphate (cGMP) concentrations were measured to investigate NO synthesis and guanylyl cyclase activity respectively. l-citrulline concentration, arterial oxygen saturation (Sa,O2), systemic blood pressure, heart rate and acute mountain sickness (AMS) score were measured at rest and 15, 30 and 45 min after starting infusion.

The results showed that baseline l-citrulline was lower in hypoxia (p<0.05). l-arginine infusion increased l-citrulline concentration in both conditions. However, in hypoxia l-citrulline concentration remained lower than in normoxia (p<0.05). The concentration of cGMP was lower in hypoxia (p<0.05). In hypoxia,Sa,O2increased from 15 min after the start of the infusion to 45 min (p<0.05). Blood pressure and heart rate were not affected by l-arginine infusion.

Subjects who experienced symptoms of AMS showed a slight decrease in AMS score with l-arginine.

The decreased l-citrulline suggests a hypoxia-induced impairment of nitric oxide synthase III or a decrease in l-arginine availability. The improvement of arterial oxygen saturation by pretreatment with l-arginine could be ascribed to an enhancement of the ventilation/perfusion ratio. Collectively, these results are consistent with a decrease in nitric oxide production in hypoxia that could be antagonized by supplying nitric oxide synthase cosubstrate.
A new asthma severity index: a predictor of near-fatal asthma?
Authors: Lee P. , Abisheganaden J. , Chee C.B.E. , Wang Y.T.
Published: July 2002

Bronchial hyperresponsiveness (BHR), measured as the provocative dose of inhaled histamine or methacholine required to produce a 20% fall in forced expiratory volume in one second (FEV1) (PD20), is widely used as one of the indices of asthma severity. Excessive bronchoconstriction, reflected by the maximal percentage fall in forced vital capacity (FVC) at PD20(ΔFVC %) during BHR testing, is considered to be the most important pathophysiological determinant in fatal asthma. The present study hypothesized that an index which combines both the ease of airway narrowing and excessive bronchoconstriction, ΔFVC %/log(PD20), may be better in assessing asthma severity, especially in those at risk of near-fatal attacks.

The dose-response curves of 46 asthmatics who underwent methacholine challenge testing were studied. Group 1 (n=14) patients had mild disease, Group 2 (n=21) had moderate disease and Group 3 (n=11) had severe disease, as classified according to the Global Initiative for Asthma. Nine patients had prior intubation for near-fatal asthma.

ΔFVC %/log (PD20) was better than ΔFVC % and PD20in categorizing patients into the three severity groups (p<0.0001), but more importantly, it was able to discriminate patients with previous intubation from those without (p=0.04). It also correlated better with FEV1(% predicted), frequency of symptoms and inhaled steroid requirement than either index alone.

It is concluded that the percentage fall in forced vital capacity/log of the provocative dose causing a 20% fall in forced expiratory volume in one second combines information on the ease and excessive degrees of airway narrowing in asthma. This new index may be better at assessing asthma severity and in discriminating those at risk of near-fatal attacks.
Chronic intermittent hypercapnic hypoxia increases pulmonary arterial pressure and haematocrit in rats
Authors: McGuire M. , Bradford A.
Published: July 2002

Sleep-disordered breathing is associated with pulmonary hypertension and raised haematocrit. The multiple episodes of apnoea in this condition cause chronic intermittent hypoxia and hypercapnia but the effects of such blood gas changes on pulmonary pressure or haematocrit are unknown. The present investigation tests the hypothesis that chronic intermittent hypercapnic hypoxia causes increased pulmonary arterial pressure and erythropoiesis.

Rats were treated with alternating periods of normoxia and hypercapnic hypoxia every 30 s for 8 h per day for 5 days per week for 5 weeks, as a model of the intermittent blood gas changes which occur in sleep-disordered breathing in humans. Haematocrit, red blood cell count and haemoglobin concentration were measured each week and systemic and pulmonary arterial blood pressure and heart weight were measured after 5 weeks.

In relation to control, chronic intermittent hypercapnic hypoxia caused a significant increase in systemic (104.3±4.7 mmHgversus121.0±10.4 mmHg) and pulmonary arterial pressure (20.7±6.8 mmHgversus31.3±7.2 mmHg), right ventricular weight (expressed as ratios) and haematocrit (45.2±1.0%versus51.5±1.5%).

It is concluded that the pulmonary hypertension and elevated haematocrit associated with sleep-disordered breathing is caused by chronic intermittent hypercapnic hypoxia.
Changes in xylosyltransferase activity and in proteoglycan deposition in bleomycin-induced lung injury in rat
Authors: Koslowski R. , Pfeil U. , Fehrenbach H. , Kasper M. , Skutelsky E. , Wenzel K-W.
Published: July 2002

Several lines of evidence support the hypothesis of the involvement of altered proteoglycan deposition in the development of lung diseases. UDP-d-xylose: core protein β-d-xylosyltransferase (UDP-xylosyltransferase; EC 2.4.2.26) is a key enzyme for the glycosylation of proteoglycan core proteins. This study examined the catalytic activity of UDP-xylosyltransferase in lung tissue and in isolated fibroblasts, as well as the deposition of the proteoglycans versican, biglycan and decorin in rat lung tissue during bleomycin-induced lung injury.

Rats were given, endotracheally, a single dose of bleomycin. Deposition of proteoglycans in lung tissue was assessed by immunohistochemistry and the catalytic activity of xylosyltransferase was determined with an acceptor peptide of the sequence Q-E-E-E-G-S-G-G-G-Q-G-G as a substrate.

The results show coincidence of increasing xylosyltransferase activities in lung tissue with accumulation of versican at alveolar entrance rings and in fibrotic regions in close proximity to α-smooth muscle actin-positive cells. In contrast, no changes in biglycan and decorin deposition in fibrotic lungs were observed, except for decorin in alveolar type II pneumocytes and alveolar macrophages. Bleomycin treatment of isolated rat lung fibroblasts resulted in a concentration-dependent increase of xylosyltransferase activity up to 2 mU bleomycin·mL−1.

The data suggest a participation of myofibroblasts with increased xylosyltransferase activities in accumulation of versican in fibrotic foci of injured lung tissue at the early stages of development of lung fibrosis.
Patent foramen ovale causing position-dependent shunting in a patient, when laying down her corset
Authors: Grutters J.C. , ten Berg J.M. , van der Zeijden J. , Jaarsma W. , Ernst J.M.P.G. , Westermann C.J.J.
Published: July 2002

A 75-;yr-old female presented with platypnoea and orthodeoxia, shortly after laying down an old and pinching corset. The injection of activated Haemaccel in the right cubital vene during transoesophageal echocardiography, in the upright position, revealed a direct blood flow from the superior caval vein at a patent foremen ovale, consequently opening it and causing a large right-to-left shunt which was calculated at 28.5%. In the supine position there was only a minimal opening of the patent foremen ovale with a calculated right-to-left shunt of 9.5%. The patent foremen ovale was successfully closed percutaneously with a CardioSEALTM.
The repeatability of nonbronchoscopic bronchoalveolar lavage differential cell counts
Authors: Warke T.J. , Kamath S. , Fitch P.S. , Brown V. , Shields M.D. , Ennis M.
Published: July 2002

Airway inflammation in children can be assessed by nonbronchoscopic bronchoalveolar lavage (BAL). Little is known about the repeatability of cell counts in the BAL obtained.

Children (n=43) attending for elective surgery were studied. Cell counts were obtained following a nonbronchoscopic lavage. Two samples were obtained with either: 1) the catheter wedged in the same position (n=21) or 2) the catheter reinserted and wedged again (n=22). Slides (n=30) from nonbronchoscopic lavage samples were selected at random and two independent observers counted 500 cells on each slide on two occasions. The repeatability of the lavage sampling and cell counting was assessed for different cell types.

The inter- and intra-observer repeatability for the differential cell counting demonstrated that there was good repeatability for all cell types except lymphocytes (interobserver: Lin's concordance coefficient 0.42; repeatability coefficient 0.66). Quantification of eosinophil (%) was highly repeatable using either method (Lin's concordance coefficient 1) 0.99, 2) 0.95; repeatability coefficient 1) 0.58, 2) 1.36).

Nonbronchoscopic lavage is a repeatable technique for the quantification of eosinophils. Variation in the sampling method can be reduced by taking two separate samples and averaging the differential cell counts. Furthermore, increasing the number of cells counted should ensure accurate quantification of lymphocytes.
The European Community Respiratory Health Survey: what are the main results so far?
Authors: Janson C. , Anto J. , Burney P. , Chinn S. , de Marco R. , Heinrich J. , Jarvis D. , Kuenzli N. , Leynaert B. , Luczynska C. , Neukirch F. , Svanes C. , Sunyer J. , Wjst M.
Published: July 2002

The European Community Respiratory Heath Survey (ECRHS) was the first study to assess the geographical variation in asthma and allergy in adults using the same instruments and definitions. The database of the ECRHS includes information from ∼140,000 individuals from 22 countries. The aim of this review is to summarize the results of the ECRHS to date.

The ECRHS has shown that there are large geographical differences in the prevalence of asthma, atopy and bronchial responsiveness, with high prevalence rates in English speaking countries and low prevalence rates in the Mediterranean region and Eastern Europe. Analyses of risk factors have highlighted the importance of occupational exposure for asthma in adulthood. The association between sensitization to individual allergens and bronchial responsiveness was strongest for indoor allergens (mite and cat). Analysis of treatment practices has confirmed that the treatment of asthma varies widely between countries and that asthma is often undertreated.

In conclusion, the European Community Respiratory Health Survey has shown that the prevalence of asthma varies widely. The fact that the geographical pattern is consistent with the distribution of atopy and bronchial responsiveness supports the conclusion that the geographical variations in the prevalence of asthma are true and most likely due to environmental factors.
“Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases”, summary of the ERS Research Seminar in Budapest, Hungary, September, 1999
Authors: Horváth I. , MacNee W. , Kelly F.J. , Dekhuijzen P.N.R. , Phillips M. , Döring G. , Choi A.M.K. , Yamaya M. , Bach F.H. , Willis D. , Donnelly L.E. , Chung K.F. , Barnes P.J.
Published: July 2002

In recent years, there has been increasing interest in noninvasive monitoring of airway inflammation and oxidative stress. Several volatile and nonvolatile substances can be measured in exhaled breath and have been suggested as potential biomarkers of these events.

Exhaled gases, including carbon monoxide (CO), alkanes (ethane, pentane), and substances measured in breath condensate, such as hydrogen peroxide (H2O2) and isoprostanes were all suggested as potential markers of oxidative stress in the lung.

A European Respiratory Society (ERS) International Research Seminar entitled “Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases” was organized by the Airway Regulation and Provocation Group of the Clinical Allergy and Immunology Assembly in Budapest, Hungary in September, 1999 to integrate the latest knowledge on these issues and accelerate further improvement in this area. During this 2-day event several issues were raised about: the use and standardization of measurements in exhaled breath; problems of measuring expired H2O2and other mediators in breath condensate; role and regulation of haemoxygenase (HO)-1 in the lung; and conditions and factors influencing exhaled CO.

This report is a summary of the main presentations at the seminar, together with the current areas of research in this rapidly expanding field.
Quantitative computed tomography assessment of lung structure and function in pulmonary emphysema
Authors: Madani A. , Keyzer C. , Gevenois P.A.
Published: July 2002

Accurate diagnosis and quantification of pulmonary emphysema during life is important to understand the natural history of the disease, to assess the extent of the disease, and to evaluate and follow-up therapeutic interventions.

Since pulmonary emphysema is defined through pathological criteria, new methods of diagnosis and quantification should be validated by comparisons against histological references.

Recent studies have addressed the capability of computed tomography (CT) to quantify pulmonary emphysema accurately. The studies reviewed in this article have been based on CT scans obtained after deep inspiration or expiration, on subjective visual grading and on objective measurements of attenuation values. Especially dedicated software was used for this purpose, which provided numerical data, on both two- and three-dimensional approaches, and compared CT data with pulmonary function tests.

More recently, fractal and textural analyses were applied to computed tomography scans to assess the presence, the extent, and the types of emphysema. Quantitative computed tomography has already been used in patient selection for surgical treatment of pulmonary emphysema and in pharmacotherapeutical trials. However, despite numerous and extensive studies, this technique has not yet been standardized and important questions about how best to use computed tomography for the quantification of pulmonary emphysema are still unsolved.
Long-term treatment of pulmonary hypertension with aerosolized iloprost
Authors: Machherndl S. , Kneussl M. , Baumgartner H. , Schneider B. , Petkov V. , Schenk P. , Lang I.M.
Published: July 2002

Pulmonary arterial hypertension (PAH), defined as elevated pulmonary arterial pressure and pulmonary vascular resistance, is an end-point of a variety of conditions. The only therapy that has been shown to improve both quality of life and survival is intravenous prostacyclin (prostaglandin I2(PGI2), epoprostenol).

The effect of long-term aerosolized iloprost (Ilomedin, Schering, Berlin, Germany and Vienna, Austria), a stable prostacyclin analogue and potent vasodilator, on haemodynamics and functional status was investigated in 12 patients with severe pulmonary hypertension. Haemodynamic measurements and vasodilator testing by right heart catheterization were performed prior to and after long-term iloprost inhalation therapy.

Haemodynamic improvement or increased exercise tolerance was not observed in any of the patients. After a mean±sd treatment period of 10±5 months, mean±sd pulmonary vascular resistance had increased from 11±3 Wood Units (mmHg·L−1·min) to 13±4 Wood Units, with unchanged arterial oxygen saturation (92±4%versus91±4%). Within the study period, three patients went into right heart failure and had to be placed on intravenous epoprostenol.

The authors conclude that inhaled iloprost in addition to conventional therapy in the presently recommended dose of 100 µg·day−1delivered in 8–10 2 h portions, is not an efficient vasodilator therapy in severe pulmonary hypertension. It remains to be shown whether dose increases and/or combination protocols will be effective, or whether inhalation of iloprost may be safe for selected cases of pulmonary hypertension.
Methacholine inhalation challenge: a shorter, cheaper and safe approach
Authors: Izbicki G. , Bar-Yishay E.
Published: July 2002

Increased nonspecific bronchial hyperresponsiveness to pharmacological agents such as histamine or methacholine (MCh) is a hallmark of asthma. The measurement of airway reactivity is quite sensitive but testing is tedious, and time and money consuming. The present aim was, therefore, to design the shortest possible, yet safe inhalation challenge protocol applicable for a lung function referral centre.

All records of studies performed in our institution during 1996 were analyzed retrospectively with a baseline ratio (bl) of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ≥0.7 (n=449). It was questioned what the initial dose should be, and whether some inhalation steps could have been skipped without losing pertinent information and/or causing an adverse response (a fall in FEV1>40%). When unavailable, provocative dose causing a 20% fall in FEV1(PD20) values were obtained by linear inter- or extrapolation of the existing data.

The present study showed that three-fold concentration steps could have been employed with minimal change in outcome. Only 15/449 patients (3.3%) would have experienced a severe response. Five subjects (of 169, 3.0%) with FEV1/FVCbl0.7–0.8 reacted to inhalation up to 0.073 µmol. Four subjects (of 280, 1.4%) with FEV1/FVCbl≥0.8 reacted to inhalation up to 0.219 µmol.

The authors suggest that: 1) an initial dose of 0.219 µmol (initial concentration=0.21 mg·mL−1) may be used when the baseline ratio of forced expiratory volume in one second to forced vital capacity ≥0.8 and 0.073 µmol (initial concentration=0.07 mg·mL−1) when the baseline ratio is <0.8; 2) a tripling dose protocol is easier to perform, cheaper and 30.2% faster, yet just as safe; and 3) other abbreviated protocols used in epidemiologic settings may not be applicable in a referral centre setting.
Bronchoconstriction induced by inhaled adenosine 5′-monophosphate in subjects with allergic rhinitis
Authors: Prieto L. , Gutiérrez V. , Liñana J. , Marín J.
Published: July 2002

Adenosine and its related nucleotide, adenosine 5′-monophosphate (AMP) induce bronchoconstriction in asthmatics, probably caused by histamine release from airway mast cells. The objective of this study was to determine the effect of inhaled AMP on lung function in subjects with allergic rhinitis.

A total of 52 adults (28 subjects with allergic rhinitis, 14 asthmatics and 10 healthy subjects) were challenged with increasing concentrations of AMP and methacholine. Airflow was assessed after each concentration and the response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall (PC20) in forced expired volume in one second (FEV1).

All 14 asthmatics, 10 subjects with allergic rhinitis and none of the healthy controls were hyperresponsive to AMP. Subjects with allergic rhinitis had higher prevalence of hyperresponsiveness to AMP than healthy controls (p=0.038). Although the prevalence of hyperresponsiveness for methacholine and for AMP in subjects with allergic rhinitis was similar (39% and 36%, respectively), four subjects had hyperresponsiveness to methacholine but not to AMP, whereas three subjects had hyperresponsiveness to AMP but not to methacholine.

To conclude, inhaled adenosine 5′-monophosphate causes airway narrowing in a significantly higher proportion of subjects with allergic rhinitis than healthy volunteers. Furthermore, methacholine and adenosine 5′-monophosphate hyperresponsiveness are not detected in the same individuals with allergic rhinitis, thus suggesting that responsiveness to the two bronchoconstrictor stimuli is not reflecting the same abnormalities of the airways.
Smoking-related interstitial lung diseases: a concise review
Authors: Ryu J.H. , Colby T.V. , Hartman T.E. , Vassallo R.
Published: July 2002

Interstitial lung diseases (also known as diffuse infiltrative lung diseases) are a heterogeneous group of parenchymal lung disorders of known or unknown cause. These disorders are usually associated with dyspnoea, diffuse lung infiltrates, and impaired gas exchange. The majority of interstitial lung diseases are of unknown cause. Known causes of interstitial lung disease include inhalation of organic and inorganic dusts as well as gases or fumes, drugs, radiation, and infections.

This review summarizes the clinical, radiological, and histopathological features of four interstitial lung disorders that have been linked to smoking. These disorders include desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, pulmonary Langerhans' cell histiocytosis, and idiopathic pulmonary fibrosis. Available evidence suggests most cases of desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and pulmonary Langerhans' cell histiocytosis are caused by cigarette smoking in susceptible individuals. Smoking cessation should be a main component in the initial therapeutic approach to smokers with these interstitial lung diseases. In addition, smoking appears to be a risk factor for the development of idiopathic pulmonary fibrosis.
Passive respiratory mechanics: the occlusion techniques
Authors: Gappa M. , Colin A.A. , Goetz I. , Stocks J.
Published: July 2002

The aim of this position paper is to define quality control and acceptance criteria for measuring passive respiratory mechanics in infants using the occlusion techniques to ensure that valid results are obtained. These guidelines cover numerous aspects including: 1) terminology and definitions; 2) equipment; 3) data acquisition; 4) data handling and analysis; 5) reporting of results. Adherence to these guidelines should ensure that measurement of passive respiratory mechanics in infants in different lung function laboratories could be performed with an acceptable degree of safety, precision, and reproducibility. This will facilitate multi-centre collection of data and performance of clinical investigations.
Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis
Authors: Maeyama T. , Kuwano K. , Kawasaki M. , Kunitake R. , Hagimoto N. , Matsuba T. , Yoshimi M. , Inoshima I. , Yoshida K. , Hara N.
Published: July 2002

The caspase cascade is an executioner of apoptosis, mediated by Fas. Fas-associating protein with death domain (FADD) interacts with Fas and initiates apoptosis through activating caspase-8. It has previously been demonstrated that the Fas-Fas ligand pathway may be involved in the pathophysiology of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate Fas-signalling molecules in epithelial cells in IPF.

The immunohistochemistry for FADD and caspase-1 and -3 and terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick endlabelling (TUNEL) methods were performed in lung tissues from 10 patients with IPF obtained by thoracoscopic biopsy and in seven normal lung parenchyma specimens. The induction of caspases expression and activation by Fas-ligation on lung epithelial cell line A549 was also investigated.

The immunoreactivity grade for FADD and caspase-1 and -3, and positive signals for TUNEL were significantly increased in epithelial cells of IPF compared with controls. Fas-ligation induced upregulation of caspase-1 and -3 expression in the nucleus and cytoplasm in A549 cells. Procaspase-1, -3, and -8 were activated in apoptotic cells, but not in viable cells.

Although direct measurement of the caspase activity in lung epithelial cells of idiopathic pulmonary fibrosis could not be made, these results suggest that the Fas-signalling pathway is upregulated in lung epithelial cells of idiopathic pulmonary fibrosis.
Apoptotic response of eosinophils in chronic eosinophilic pneumonia
Authors: Saita N. , Yamanaka T. , Kohrogi H. , Ando M. , Hirashima M.
Published: July 2002

To clarify the pathogenesis of chronic eosinophilic pneumonia (CEP), the apoptosis of eosinophils from bronchoalveolar lavage (BAL-Eos) was compared with that of eosinophils from peripheral blood (PB-Eos) in six cases of CEP.

The survival rate of eosinophils and the percentage of apoptotic cells of both types of eosinophils were examined, and the effects of interleukin 5 (IL-5) were evaluated. The role of Fas expression in apoptosis of these eosinophils was also studied.

The survival rate of BAL-Eos on the third day of culture was significantly higher than that of PB-Eos (p<0.01). This was associated with a lower proportion of apoptotic cells in BAL-Eos than in PB-Eos; the percentages of apoptotic cells in PB-Eos and BAL-Eos after 24 h of incubation were 21.7±3.4% and 10.6±1.7% respectively. IL-5 suppressed apoptosis and increased the survival rate of both PB-Eos and BAL-Eos. It was found that the apoptotic character of BAL-Eos differed from that of PB-Eos in at least three ways. Firstly, the positive rate of Fas expression on PB-Eos was increased after 24 h of incubation, whereas that on BAL-Eos did not change. Secondly, the expression of Fas on PB-Eos was suppressed by IL-5 (18.5±4.2%–8.3±3.2%, p<0.05), whereas IL-5 failed to suppress Fas expression on BAL-Eos (3.3±1.6%–3.6±1.0%). Lastly, binding of antibody to Fas antigen induced apoptosis of PB-Eos, but not of BAL-Eos.

These data suggested that Fas seemed to be involved in the apoptosis of PB-Eos, whereas BAL-Eos were Fas-resistant in chronic eosinophilic pneumonia. In conclusion, apoptosis of eosinophils might be suppressed by proinflammatory cytokines such as IL-5 leading to their accumulation in the lung. Chronic stimulation of eosinophils in the alveolar space with IL-5 may play a crucial role chronic eosinophilic disorders.