bluuebunny/crossref_metadata_2025 huggingface dataset:
Poststroke Hyperglycemia
Authors: Gray Christopher S. , Hildreth Anthony J. , Alberti George K.M.M. , O’Connell Janice E.
Published: December 2003

Background and Purpose—

Poststroke hyperglycemia (PSH) is a frequent finding for which there is currently no evidence to justify routine treatment. The United Kingdom Glucose Insulin in Stroke Trial (GIST-UK) is the only trial of glucose modulation in acute stroke from which evidence can be derived for the immediate management of PSH. Using safety-monitoring data from the trial we aimed to describe the immediate recovery of PSH in treated and control patients, thus providing evidence for the use of glucose/potassium/insulin (GKI) infusions as a means of maintaining euglycemia.

Methods—

GIST-UK is a multicenter randomized controlled trial of GKI or saline infusions in acute stroke patients presenting with mild to moderate hyperglycemia (admission plasma glucose, 6.0 to 17 mmol). We analyzed the capillary BM and plasma glucose values in the 2 treatment groups to describe the recovery of PSH and the effectiveness of the GIST treatment regimen in maintaining euglycemia.

Results—

The majority of patients have only moderate PSH (mean plasma glucose, 8.37±SD 2.13). Without specific intervention, mean plasma glucose levels decline spontaneously. Treatment with the GIST GKI regimen rapidly achieved euglycemia at significantly lower levels than with saline hydration alone. Euglycemia was achieved with a median of 2 changes to the GKI regimen and a low risk of hypoglycemia.

Conclusions—

GKI infusions as described in the GIST trial are a safe and effective means of correcting PSH and maintaining euglycemia in the acute phase of stroke. The clinical benefits of routine management of hyperglycemia remain to be determined.
Dysexecutive Syndrome After Mild Cerebral Ischemia?
Authors: Winter Benjamin , Bert Bettina , Fink Heidrun , Dirnagl Ulrich , Endres Matthias
Published: December 2003

Background and Purpose—

We determined long-term functional outcome in a well-characterized mouse model of mild focal cerebral ischemia.

Methods—

We subjected 129/SV mice to sham operation or 30 minutes of left middle cerebral artery occlusion (MCAo) followed by reperfusion (89% survival rate). Six weeks later, animals were tested for neurological deficits, motor coordination on an accelerating Rota-rod apparatus, and spatial navigation in a water maze task. Brain lesion size was determined on NeuN-immunostained coronal brain sections by computer-assisted volumetry.

Results—

Mice had mild but distinct neurological deficits and no deficits in Rota-rod coordination or swimming speed 6 weeks after MCAo. Moreover, mice had normal spatial learning abilities in the place task. However, stroke mice had deficits in the probe trial and visible platform task, which correlated with striatal lesion size determined on NeuN-immunostained sections.

Conclusions—

After mild ischemia, mice recover with mild neurological deficits and normal motor coordination. Stroke mice have no obvious deficits in spatial learning in the Morris water maze but display distinct deficits related to strategy switching and relearning.
MICHEL TRĀD, IN MEMORIAM
Authors: Kallas Elie
Published: December 2003

Michel Trād (1912-1998), pionnier de la littérature vernaculaire libanaise du 20ème siècle, a conclu sa vie simple et pleine d'émerveillement, déçu par la modernité et par l'homme. Certains de ses poèmes - chantés par Fayrūz et Wad' al-Sāfī - ont fait le tour du monde néo-arabophone, mais à ce jour, aucun de ses recueils n'a été traduit. Cet article le commémore et tente de nous faire savourer son art, plaide pour son réalisme linguistique et sa spontanéité lyrique, illustre la potentialité métaphorique de ses mots-clefs, sans négliger la prosodie des vers. L'annexe comprend quelques traductions de poèmes extraits de son recueil Guélnār.
VOM SINN DER ZEIT AUS DER GESCHICHTE DES ARABISCHEN CHRONOGRAMMS
Authors: Bauer Thomas
Published: December 2003

Le sens du temps. Pages d'histoire du chronogramme arabe». Après des antécédents encore mal connus au VIIe/XIIIe siècle et au VIIIe/XIVe siècle, les chronogrammes «réguliers» sont bien attestés en arabe au IXe/XVe siècle; mais leur véritable carrière commença au Xe/XVIe siècle. Par la suite, les poètes, compositeurs de ce genre, s'imposèrent sont ici étudiés non seulement la structure et les occasions de ces poèmes, mais aussi leur évolution et la fascination que ce type d'écriture exerça.
BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells
Authors: Chu Su , Holtz Melissa , Gupta Mamta , Bhatia Ravi
Published: December 2003

Chronic myelogenous leukemia (CML) results from malignant transformation of a primitive hematopoietic cell by the BCR/ABL oncogene. The breakpoint cluster region/ABL (BCR/ABL) tyrosine kinase inhibitor imatinib mesylate (imatinib) is highly effective in inducing remissions in CML. However, the effects of imatinib on intracellular signaling in primary progenitor cells are not well described. We show that imatinib exposure resulted in a significant dose-responsive reduction in BCR/ABL kinase activity in CML CD34+ cells. However, imatinib treatment resulted in an increase in activity of p42/44 mitogen-activated protein kinase (MAPK), an important downstream effector of BCR/ABL. Increased MAPK activity was growth factor dependent. Pharmacologic inhibition of MAPK using MAPK/extracellular signal–regulated kinase kinase–1/2 (MEK-1/2) inhibitors significantly reduced CML progenitor proliferation. Combined treatment with a MEK-1/2 inhibitor and imatinib significantly increased suppression of CML progenitors compared with either inhibitor alone. In contrast, imatinib treatment resulted in a small reduction in AKT activity. Combined treatment with a phosphatidylinositol-3 (PI-3) kinase inhibitor and imatinib significantly increased suppression of CML progenitor growth compared with either inhibitor alone. We conclude that inhibition of BCR/ABL kinase activity in CML progenitors by imatinib results in a growth factor-dependent compensatory increase in MAPK activity and in only partial inhibition of PI-3 kinase activity. These mechanisms may contribute to incomplete elimination of CML progenitors by imatinib. (Blood. 2004;103:3167-3174)
The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status
Authors: Dreger Peter , Stilgenbauer Stephan , Benner Axel , Ritgen Matthias , Kröber Alexander , Kneba Michael , Schmitz Norbert , Döhner Hartmut
Published: December 2003

To assess the therapeutic value of sequential high-dose therapy (SHDT) including autologous stem cell transplantation in chronic lymphocytic leukemia (CLL) we performed a risk-matched comparison between 66 patients who had undergone a uniform SHDT regimen and a database of 291 patients treated conventionally. Matching variables were age, Binet stage, IgVH (variable region of the immunoglobulin heavy chain) gene mutational status, and lymphocyte count. Forty-four pairs fully matched for all 4 variables were identified. Patient groups were well balanced for additional risk factors including adverse genomic abnormalities and CD38 expression. With an overall median follow-up time of 70 and 86 months, respectively, survival was significantly longer for the SHDT patients than for the conventionally treated patients when calculated from diagnosis (hazard ratio [HR] 0.39; P = .03 [log rank]) or from study entry (HR 0.32; P = .006). The benefit for the SHDT group remained significant when the analyses were restricted to those 58 patients who had an unmutated VH status. Cox regression analysis confirmed SHDT as independent favorable prognostic factor for survival from diagnosis (HR 0.38, P = .04) as well as from study entry (HR 0.38, P = .03). These data suggest a survival benefit for patients with poor-risk CLL receiving SHDT during the course of their disease. (Blood. 2004;103:2850-2858)
Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood
Authors: Hirsch Betsy , Shimamura Akiko , Moreau Lisa , Baldinger Shari , Hag-alshiekh Maha , Bostrom Bruce , Sencer Susan , D'Andrea Alan D.
Published: December 2003

The clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelic BRCA2/FANCD1 mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA families.
In vivo neutralization of a C2 domain–specific human anti–Factor VIII inhibitor by an anti-idiotypic antibody
Authors: Gilles Jean Guy G. , Grailly Sabrina C. , De Maeyer Marc , Jacquemin Marc G. , VanderElst Luc P. , Saint-Remy Jean-Marie R.
Published: December 2003

Factor VIII (FVIII) administration elicits specific inhibitory antibodies (Abs) in about 25% of patients with hemophilia A. The majority of such Abs reacts with FVIII C2 domain. mAbBO2C11 is a high-affinity human monoclonal antibody (mAb) directed toward the C2 domain, which is representative of a major class of human FVIII inhibitors. Anti-idiotypic Abs were raised to mAbBO2C11 to establish their neutralizing potential toward inhibitors. One mouse anti-idiotypic mAb, mAb14C12, specifically prevented mAbBO2C11 binding to FVIII C2 domain and fully neutralized mAbBO2C11 functional inhibitory properties. Modeling of the 3-D conformation of mAb14C12 VH and alignment with the 3-D structure of the C2 domain showed putative 31 surface-exposed amino acid residues either identical or homologous to the C2 domain. These included one C2 phospholipid-binding site, Leu2251-Leu2252, but not Met2199-Phe2200. Forty putative contact residues with mAbBO2C11 were identified. mAb14C12 dose-dependently neutralized mAbBO2C11 inhibitory activity in mice with hemophilia A reconstituted with human recombinant FVIII (rFVIII), allowing full expression of FVIII activity. It also neutralized in an immunoprecipitation assay approximately 50% of polyclonal anti-C2 Abs obtained from 3 of 6 unrelated patients. mAb14C12 is the first example of an anti-idiotypic Ab that fully restores FVIII activity in vivo in the presence of an anti-C2 inhibitor. The present results establish the in vitro and in vivo proof of concept for idiotype-mediated neutralization of a major class of FVIII inhibitors.
Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines
Authors: Nefedova Yulia , Cheng Pingyan , Alsina Melissa , Dalton William S. , Gabrilovich Dmitry I.
Published: December 2003

The bone marrow (BM) microenvironment plays a critical role in malignant cell growth, patient survival, and response to chemotherapy in hematologic malignancies. However, mechanisms associated with this environmental influence remain unclear. In this study, we investigated the role of Notch family proteins in myeloma and other malignant lymphoid cell line growth and response to chemotherapeutic drugs. All 8 tested cell lines expressed Notch-3 and Notch-4; 7 cell lines expressed Notch-1; and 6 expressed Notch-2 proteins. Interaction with BM stroma (BMS) activated Notch signaling in tumor cells. However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis. This protection was associated with up-regulation of p21WAF/Cip and growth inhibition of cells. Overexpression of Notch-1 in Notch-1- U266 myeloma cells up-regulated p21 and resulted in protection from drug-induced apoptosis. Thus, this is a first report demonstrating that Notch-1 signaling may be a primary mechanism mediating the BMS influence on hematologic malignant cell growth and survival. (Blood. 2004; 103:3503-3510)
Intracellular serpin SERPINB6 (PI6) is abundantly expressed by human mast cells and forms complexes with β-tryptase monomers
Authors: Strik Merel C. M. , Wolbink Angela , Wouters Dorine , Bladergroen Bellinda A. , Verlaan Angelique R. , van Houdt Inge S. , Hijlkema Sanne , Hack C. Erik , Kummer J. Alain
Published: December 2003

SERPINB6 (PI6) is a member of the intracellular serine protease inhibitors (serpins). Previous studies showed that SERPINB6 is localized mainly in the cytoplasm of endothelial cells, some epithelial cells, monocytes, and neutrophils. In these cells SERPINB6 is thought to prevent cellular damage by scavenging leaking lysosomal proteases. We show here, using novel, well-defined monoclonal antibodies, that SERPINB6 is abundantly expressed by mast cells in all organs and by the human mast cell line HMC-1. Gel filtration experiments revealed that the latter cells contain a high-molecular-weight form of SERPINB6, which consists of sodium dodecyl sulfate (SDS)-stable complexes of this inhibitor with monomeric β-tryptase. Expression of SERPINB6 by mast cells was compared with those of tryptase and CD117 (c-kit) in biopsies from patients with different forms of mast cell disease. In all cases the lesional mast cells expressed SERPINB6, and, in diffuse cutaneous mastocytosis and mastocytoma, SERPINB6 was expressed by a substantially higher number of mast cells when compared with tryptase. In conclusion, SERPINB6 is abundantly expressed by normal mast cells and by mast cells in mastocytoma lesions. We suggest that in mast cells, SERPINB6 serves to regulate the activity of endogenous β-tryptase in the cytoplasm. (Blood. 2004;103:2710-2717)
Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants
Authors: Rauser Georg , Einsele Hermann , Sinzger Christian , Wernet Dorothee , Kuntz Gabriele , Assenmacher Mario , Campbell John D. M. , Topp Max S.
Published: December 2003

Adoptive transfer of cytomegalovirus (CMV)-specific T cells can restore long-lasting, virus-specific immunity and clear CMV viremia in recipients of allogeneic stem cell transplants if CD4+ and CD8+ CMV-specific T cells are detected in the recipient after transfer. Current protocols for generating virus-specific T cells use live virus, require leukapheresis of the donor, and are time consuming. To circumvent these limitations, a clinical-scale protocol was developed to generate CMV-specific T cells by using autologous cellular and serum components derived from a single 500-mL blood draw. CMV-specific T cells were stimulated simultaneously with CMV-specific major histocompatibility complex class I (MHC I)- restricted peptides and CMV antigen. Activated T cells were isolated with the interferon-γ (IFN-γ) secretion assay and expanded for 10 days. In 8 randomly selected, CMV-seropositive donors, 1.34 × 108 combined CD4+ and CD8+ CMV-specific T cells, on average, were generated, as determined by antigen-triggered IFN-γ production. CMV-infected fibroblasts were efficiently lysed by the generated T cells, and CMV-specific CD4+ and CD8+ T cells expanded if they were stimulated with natural processed antigen. On the other hand, CD4+ and CD8+ T cell-mediated alloreactivity of generated CMV-specific T-cell lines was reduced compared with that of the starting population. In conclusion, the culture system developed allowed the rapid generation of allodepleted, highly enriched, combined CD4+ and CD8+ CMV-specific T cells under conditions mimicking good manufacturing practice. (Blood. 2004; 103:3565-3572)
Clinical and functional assessment of patients with idiopathic pulmonary fibrosis: results of a 3 year follow-up
Authors: Agusti C , Xaubet A , Agusti AG , Roca J , Ramirez J , Rodriguez-Roisin R
Published: December 2003

The purpose of this study was to analyse the information provided by different techniques used in the assessment of patients with idiopathic pulmonary fibrosis (IPF) and their role in the prediction of lung function decline with the decline. Twenty seven subjects with IPF (55 +/- 14 (mean +/- SD) yrs) were studied at the initial staging. Nineteen of them (70%) were included in a follow-up over 3 yrs (32 +/- 6 months), whilst the remaining 8 patients were lost to follow-up. During the period of the study, 6 of the 19 patients died. A significant correlation between diffusing capacity of the lungs for carbon monoxide (DLCO) (and carbon monoxide transfer coefficient (KCO) = DLCO/alveolar volume (VA)) and the increase in alveolar-arterial oxygen tension difference (A-aPO2) during exercise (delta A-aPO2) was observed at diagnosis (r = -0.58). Despite the treatment with prednisone (1 mg.kg-1 daily during 4 weeks, tapered to an individualized maintenance daily dose of 15-30 mg), the 13 patients controlled throughout the whole period of the study showed a marked impairment in lung volumes; forced vital capacity (FVC) -0.46 +/- 0.09 l, from 69 +/- 16 to 52 +/- 11% of predicted, and total lung capacity (TLC) -0.39 +/- 0.11 l, from 75 +/- 16 to 62 +/- 14%, and in DLCO -0.6 +/- 0.2 mmol.min-1.kPa-1, from 56 +/- 15 to 47 +/- 18%, predicted. By contrast, both mean arterial oxygen tension (PaO2) and A-aPO2 at rest remained unchanged throughout the 3 yrs follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanisms of increased epithelial lung clearance of DTPA in diffuse fibrosing alveolitis
Authors: Labrune S , Chinet T , Collignon MA , Barritault L , Huchon GJ
Published: December 2003

The aim of this study was to elucidate possible mechanisms of increased epithelial lung clearance in diffuse fibrosing alveolitis (DFA). We investigated the relationships between epithelial lung clearance as assessed by the clearance of aerosolized 99mTc-diethylene-triamine-penta-acetic acid (RC-DTPA), luminal alveolitis as assessed by bronchoalveolar lavage, and pulmonary function, in 30 nonsmokers with DFA. In 14 of these patients, RC-DTPA and lung function were determined before and during therapy with prednisolone (0.5 mg.kg-1 daily). RC-DTPA was higher in patients with DFA (4.45 +/- 2.50%.min-1) than in normal subjects (1.18 +/- 0.31%.min-1). RC-DTPA did not correlate with the number of alveolar neutrophils, but correlated positively with the number of alveolar lymphocytes, and negatively with vital capacity (VC). RC-DTPA decreased from 6.1 +/- 2.8 to 3.8 +/- 1.9%.min-1 with prednisolone. RC-DTPA before prednisolone correlated positively with the prednisolone-associated improvement in VC. We conclude that in patient with DFA, RC-DTPA is increased, and decreases but does not return to normal with corticosteroid therapy. Our data suggest that in DFA the increase in RC-DTPA could be related to the recoil-induced stretch of the respiratory epithelium and to alveolar lymphocytic inflammation.
Production of IL-1 and its receptor antagonist is regulated differently by IFN-gamma and IL-4 in human monocytes and alveolar macrophages
Authors: Sone S , Orino E , Mizuno K , Yano S , Nishioka Y , Haku T , Nii A , Ogura T
Published: December 2003

Interleukin-4 (IL-4) has previously been found to downregulate interleukin-1 (IL-1) production, but to upregulate the production of IL-1 receptor antagonist (IL-1ra) in human monocytes stimulated with lipopolysaccharide (LPS). In the present study we wanted to determine whether the production of IL-1ra in human monocytes and alveolar macrophages (AMs) is regulated differently at the protein and messenger ribonucleic acid (mRNA) levels by IL-4 and interferon-gamma (IFN-gamma). AMs and monocytes obtained from healthy donors by bronchoalveolar lavage and centrifugal elutriation were stimulated with LPS in the presence or absence of IL-4 or IFN-gamma, and the expression of mRNA for IL-1 and IL-1ra was measured by Northern blot analysis. The production of IL-1 and IL-1ra was quantitated by enzyme immunoassays (EIAs). Spontaneous IL-1ra production was seen in AMs after incubation for 4 h in medium alone, but not in blood monocytes, at both the protein and mRNA levels. The spontaneous expression of the IL-1ra gene in AMs was augmented by incubation with IL-4. Interleukin-1 beta (IL-1 beta) production by LPS-stimulated AMs and monocytes was upregulated by IFN-gamma, but downregulated by IL-4. Interestingly, when stimulated with LPS, IFN-gamma inhibited IL-1ra production by monocytes, but up-regulated its production in human AMs at the protein and mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Extent of centrilobular and panacinar emphysema in smokers' lungs: pathological and mechanical implications
Authors: Saetta M , Kim WD , Izquierdo JL , Ghezzo H , Cosio MG
Published: December 2003

In order to quantify the extent of centrilobular (CLE) and panacinar (PLE) emphysema and the degree of the possible overlap between the two forms in smokers, the lungs of 25 smokers undergoing lung resection for peripheral lung tumours were studied. The extent of CLE and PLE was assessed by point counting, and the lungs were classified as having pure CLE (C, n = 5), predominant CLE with areas of PLE (CP, n = 7), predominant PLE with features of CLE (PC, n = 7), and pure PLE (P, n = 6) according to the percentage of lung involved by either form. Preoperative pulmonary function tests and the score of inflammation and the diameters of the small airways were also measured. Mean linear intercept (Lm), a measure of mean interalveolar wall distances and forced expiratory volume in one second (FEV1) were similar in the four groups. Small airway pathology was a predominant feature in lungs with CLE, and was significantly decreased in a stepwise fashion as the amount of PLE increased. This was especially so for the amount of muscle in the airway wall and the diameters of the airways. By contrast, lung compliance was higher in panacinar than in centrilobular emphysema.(ABSTRACT TRUNCATED AT 250 WORDS)
Pretransplant clinicopathological correlation in end-stage primary pulmonary hypertension
Authors: Madden BP , Gosney J , Coghlan JG , Kamalvand K , Caslin AW , Smith P , Yacoub M , Heath D
Published: December 2003

The aim of the study was to see if there was any correlation between the histopathology, ultrastructure, pulmonary endocrinology and clinical manifestations of end-stage primary pulmonary hypertension. Twenty patients undergoing heart-lung transplantation for the disease were studied. The nature and duration of symptoms and signs, results of haematological, electrocardiographic, radiographic, echocardiographic and haemodynamic studies, and the response of patients to vasodilators were compared with data from histopathological and ultrastructural study of lungs removed at transplantation. Length of clinical history and clinical evidence of severe disease were not necessarily associated with advanced histopathology, nor did the presence of small, contracted muscular pulmonary arteries imply responsiveness to vasodilators. Numbers of gastrin-releasing peptide-containing pulmonary endocrine cells were greater in lungs in which there was activity of myofibroblasts in pulmonary arterial vessels, and correlated negatively with mean pulmonary artery pressure and pulmonary artery systolic pressure. Whereas the prognosis of primary pulmonary hypertension cannot as yet be defined by other than its clinical manifestations, intimal proliferation as well as vasoconstriction may be important in its pathogenesis. The release of gastrin-releasing peptide from pulmonary endocrine cells may possibly be involved in this process.
Sendai virus infection changes the subcellular localization of tryptase Clara in rat bronchiolar epithelial cells
Authors: Sakai K , Kohri T , Tashiro M , Kishino Y , Kido H
Published: December 2003

Tryptase Clara activates the infectivity of Sendai and influenza viruses proteolytically. In this study, we investigated changes in the subcellular localization of tryptase Clara in rat bronchioles with progression of Sendai virus infection. Tryptase Clara and Sendai virus F2 antigen were localized by light and electron immunohistochemical studies. In the uninfected rat lung, tryptase Clara was specifically localized in the secretory granules of respiratory bronchiolar epithelial nonciliated cells, but not in bronchiolar ciliated, or alveolar cells. In the initial stage of Sendai virus infection with slight pathological changes, however, anti-tryptase Clara was highly reactive in luminal peripheral membranes of both nonciliated and ciliated epithelial cells of the bronchioles together with some Sendai virus envelope glycoprotein, F2 antigen. In the progressed stage, tryptase Clara was hard to detect, with heavy accumulation of F2 antigen in the epithelial cells. These immunohistochemical results support our previous findings that in the bronchial lavage fluid tryptase Clara is significantly increased both in amount and activity after viral infection. These results suggest that Sendai virus stimulates the secretion of tryptase Clara from nonciliated bronchiolar epithelial cells to the airway lumen. Accumulation of tryptase Clara on the luminal surface of the bronchiolar epithelial cells and/or in the airway lumen may produce favourable conditions for proteolytic viral activation and multiplication.
Effect of a mucoactive compound (CO 1408) on airway hyperreactivity and inflammation induced by passive cigarette smoke exposure in guinea-pigs
Authors: Hernandez A , Daffonchio L , Brandolini L , Zuccari G
Published: December 2003

Environmental exposure to tobacco smoke contributes to the onset of several lung diseases, e.g. chronic bronchitis and asthma, including an increase in airway reactivity. We have investigated the effect of a new mucoactive compound, CO 1408, on airway hyperreactivity and lung inflammation induced in guinea-pigs by passive cigarette smoke exposure. Animals were exposed to cigarette smoke in a Plexi-glass box, three times a day for four days. Airway reactivity to histamine was assessed ex-vivo in lung parenchymal strips. As a measure of lung inflammation, the number of leucocytes was evaluated in bronchoalveolar lavage (BAL) fluids and histological sections. Passive smoke exposure potentiated histamine-induced contraction in lung parenchymal strips, a phenomenon associated with an increase in proinflammatory cells in the BAL fluids and enhanced eosinophil infiltration into parenchymal tissues. Pretreatment with oral CO 1408 at 400 mg.kg-1 but not 100 mg.kg-1, completely prevented the cigarette smoke-induced airway hyperreactivity. 400 mg.kg-1 CO 1408 also inhibited the increase in cell numbers in the BAL fluids, but not eosinophil recruitment in parenchymal tissues. The present data indicate the ability of CO 1408 to modulate smoke-induced airway hyperreactivity and, to some extent, lung inflammation, an effect which might be of value in the therapy of obstructive pulmonary diseases.
Effects of inhaled nitric oxide on methacholine-induced bronchoconstriction: a concentration response study in rabbits
Authors: Hogman M , Wei SZ , Frostell C , Arnberg H , Hedenstierna G
Published: December 2003

Inhaled nitric oxide (NO), at a concentration of 80 ppm, counters the increase in respiratory resistance (Rrs) induced by methacholine, but fails to prevent a reduction in lung compliance (Crs) in a rabbit model. This study reports the effects of 3, 30 and 300 ppm of inhaled NO. New Zealand White rabbits were intubated and mechanically ventilated with 30% oxygen during neurolept anaesthesia. Methacholine (3 mg.ml-1) was nebulized, with or without NO inhalation. Inhalation of 3 and 30 ppm NO had no effect on the induced bronchoconstriction, whereas 300 ppm fully blocked the increase in Rrs. The decrease in Crs due to methacholine was not countered by 3, 30 or 300 ppm NO. On the contrary, inhalation of 300 ppm NO in itself decreased Crs from 5.0 +/- 0.1 to 4.3 +/- 0.1 ml.cmH2O-1. Also, mean arterial pressure (60 +/- 7 to 54 +/- 5 mmHg), alveolar-arterial oxygen tension gradient (0.8 +/- 0.8 to 2.3 +/- 1.8 kPa) and methaemoglobin (0.5 +/- 0.2 to 1.5 +/- 0.5%) changed significantly on inhalation of NO 300 ppm prior to methacholine challenge. We conclude that 3 and 30 ppm NO inhalation does not alter methacholine-induced bronchoconstriction. Inhalation of 300 ppm NO blocks an increase in resistance but fails to counter the reduction in compliance due to methacholine. This suggests that the bronchodilating effects of NO in rabbits in vitro are confined to the large airways.
Factors affecting the long-term variability of bronchial responsiveness in an adult general practice population
Authors: Trigg CJ , Tooley M , D'Souza MF , Herdman MJ , Thomas JM , Davies RJ
Published: December 2003

There have been few longitudinal studies of bronchial responsiveness. We wanted to assess the long-term variability and associations of bronchial responsiveness in the general population. Spirometry, bronchial provocation tests, skin-prick tests for allergy, and respiratory symptom questionnaires were repeated every 4 months, for 2 years (August 1987-August 1989), in 122 volunteers recruited from a cross-sectional survey of population. Provocation dose producing a 20% fall in forced expiratory volume in one second (PD20FEV1) and dose-response slope (SL), which gives values for methacholine responsiveness, were measured in all subjects. SL correlated well with PD20FEV1 but repeatability was impaired in those subjects with unmeasurably high PD20FEV1. The 95% range for repeatability of PD20FEV1 was +/- 3.11 doubling doses and +/- 4.52 doubling slopes for SL. Bronchial responsiveness increased in those with self-reported colds and reduced FEV1 in winter 1987-1988, and in males in winter 1988-1989. Bronchial responsiveness increased during the summer (June-August) of both years, significantly in year 1. We conclude that bronchial responsiveness showed minor seasonal variability and that colds were the strongest predictors of increased bronchial responsiveness over the 2 yr period.
The opioid agonist codeine and antagonist naltrexone do not affect voluntary suppression of capsaicin induced cough in healthy subjects
Authors: Hutchings HA , Eccles R
Published: December 2003

Opioids exert an analgesic action by mimicking the effects of endogenous neurotransmitter substances in the central nervous system. Opioids are widely used as antitussives, and it is reasonable to assume that endogenous opioids are involved in the control of cough. In order to investigate this hypothesis, a parallel design study was carried out to examine the effects of 50 mg codeine (opioid agonist), 50 mg naltrexone (opioid antagonist) and placebo on capsaicin-induced cough in 80 healthy volunteers (mean age 25 yrs). Volunteers received two capsaicin challenge units (each consisting of five inhalations of different concentrations of capsaicin, 0.00-3.33 x 10(-4) M). On one challenge unit subjects were instructed to suppress cough, and on the other challenge unit subjects coughed freely. Coughs were recorded on a tape cassette player and later played back into a pen recorder to produce integrated sound traces. The number of coughs in the suppression challenge unit was significantly reduced in all three treatment groups compared to that recorded in the non-suppression challenge unit. Comparisons between the three treatment groups showed that there was no statistical difference between the three groups both before and 90 min after treatment for the total coughs in the suppression challenge unit and for the total coughs in the non-suppression challenge unit. These results demonstrate that capsaicin-induced cough can be voluntarily suppressed, but that both suppressed and non-suppressed cough were unaffected by treatment with codeine, naltrexone or placebo. These results do not provide any support for the hypothesis that capsaicin-induced cough is influenced by endogenous opioid substances.
An out-patient nutritional supplementation programme in COPD patients
Authors: Sridhar MK , Galloway A , Lean ME , Banham SW
Published: December 2003

Studies that have assessed the role of nutritional supplementation in patients with emphysematous chronic obstructive pulmonary disease (COPD) have shown conflicting results. Improved respiratory muscle strength and exercise capacity have been demonstrated following intensive and costly nutritional support programmes under controlled conditions. We have evaluated a simple programme of out-patient nutritional support in a clinical setting. Twelve malnourished COPD patients (9 male and 3 female; mean age 66 yrs; < 90% ideal body weight) were studied. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), estimation of maximal oxygen uptake (VO2max) during exercise, respiratory muscle strength (PImax and PEmax), and measurement of body weight, height, triceps skinfold thickness, and mid-arm muscle circumference were performed before and after a 4 month period of out-patient nutritional support. Patients were advised by a dietician on increasing their daily caloric intake by a minimum of 50% above estimated daily energy expenditure. Three patients withdrew from the study. The mean increase in body weight in the nine remaining patients after 4 months of supplementation was 0.3 kg. There was no significant improvement in the anthropometric measures, lung function, respiratory muscle strength or VO2max for the group as a whole. Three patients who gained more than 1 kg weight were from a higher socioeconomic background compared with those who failed to do so. We conclude that achieving weight gain and improving lung function by means of simple out-patient nutritional programmes in a clinical setting is difficult.
Factor analysis of exercise capacity, dyspnoea ratings and lung function in patients with severe COPD
Authors: Wegner RE , Jorres RA , Kirsten DK , Magnussen H
Published: December 2003

In this study we aimed to determine the relationship between exercise capacity, clinical ratings of dyspnoea and lung function parameters in patients with severe chronic obstructive pulmonary disease (COPD) by means of the statistical method of factor analysis. Sixty two patients (mean age +/- SD, 66 +/- 9 yrs) in stable clinical condition, with a forced expiratory volume in one second (FEV1) < 65% of predicted were investigated. Before the study, therapy was optimized, including inhaled bronchodilators, theophylline and steroids. Exercise capacity was determined from the best 6 min walking distance achieved in five self-paced treadmill walks performed on consecutive days. Lung function testing comprised spirometry and body plethysmography. Four different tools were chosen to rate dyspnoea and quality of life: the Baseline Dyspnoea Index (BDI), the Oxygen Cost Diagram (OCD), a modified Medical Research Council (MRC) Scale, and the Chronic Respiratory Disease Questionnaire (CRQ). Principal component factor analysis revealed that the data could be reduced to three hypothetical underlying variables (factors), which accounted for 79% of the total variance. BDI, MRC, OCD, CRQ and walking distance were attributed to the first factor, forced expiratory volume in one second and airway resistance to the second factor, and lung volumes to the third factor. Thus, our data suggest that the pathophysiological condition of severe COPD is characterized by three statistically independent entities: 1) exercise capacity, dyspnoea and quality of life ratings; 2) airway obstruction; and 3) pulmonary hyperinflation.(ABSTRACT TRUNCATED AT 250 WORDS)
ICAM-1 and integrin expression on isolated human alveolar type II pneumocytes
Authors: Guzman J , Izumi T , Nagai S , Costabel U
Published: December 2003

Adhesion molecules are involved in the recruitment of leucocytes to sites of inflammation. In this study, we determined the expression of several adhesion molecules on isolated human alveolar type II pneumonocytes. Type II pneumocytes were isolated from 10 normal lung specimens, by enzymatic digestion with dispase, followed by metrizamide gradient centrifugation and panning on immunoglobulin G (IgG)-coated plastic dishes. With the freshly isolated type II cells, immunostaining was performed using a sensitive immunoperoxidase slide technique. In all cases, 60-90% of type II cells were positive for intercellular adhesion molecule-1 (ICAM-1) (CD54). A minor portion of type II cells expressed the alpha 4 (CD49d) subunit of the beta 1-integrins, and the alpha-v (CD51) subunit of the vitronectin receptor. CD11a, CD11b, CD11c, CD18, CD49b, and CD49f failed to demonstrate any immunostaining with type II cells. In conclusion, the observation of the expression of ICAM-1 and, to a lesser degree, of some integrin subunits, may indicate that alveolar type II cells participate in local immune and inflammatory responses.
Use of budesonide Turbuhaler in young children suspected of asthma
Authors: Bisgaard H , Pedersen S , Nikander K
Published: December 2003

The question addressed in this study was the ability of young children to use a dry-powder inhaler, Turbuhaler. One hundred and sixty five children suspected of asthma, equally distributed in one year age-groups from 6 months to 8 yrs, inhaled from a Pulmicort Turbuhaler, 200 micrograms budesonide-dose-1, through a filter. The amount of drug trapped by the filter was used as a measure of drug released to the patient. None of the children had prior experience in the use of a Turbuhaler, but they were instructed carefully, together with their parents, in the clinic. The median dose released revealed an age-dependent increase, with a considerable scatter. Accordingly, the dose delivered could not be predicted in these young children. The limitation to effective use in young children appeared to be lack of sufficient co-operation, rather than physical limitations, as even some very young children appeared to obtain a sufficient activation of the device. It is likely that repeated training at home may improve these findings. In conclusion, our results indicate that dry-powder inhalers are not reliable in all circumstances for treatment of young children, and that careful and repeated tuition is required if such devices are to be used.
Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part II)
Authors: Kroegel C , Warner JA , Virchow JC  , Matthys H
Published: December 2003

The second part of this review on eosinophils focuses on biological cell functions and surveys the various deleterious mechanisms involved in the eosinophil-dominated inflammatory reaction. It discusses the possible pathogenic role of eosinophils in several eosinophil-related diseases, such as parasitic infections, interstitial lung disorders and bronchial diseases, such as parasitic infections, interstitial lung disorders and bronchial diseases, graft rejection, vasculitic granulomatous disorders, pleural effusion, and bronchogenic tumours. The final section of the article highlights the possible recent pharmacological and future therapeutic approaches in modifying eosinophil recruitment and function.
Prognosis of occupational asthma
Authors: Paggiaro PL , Vagaggini B , Bacci E , Bancalari L , Carrara M , Di Franco A , Giannini D , Dente FL , Giuntini C
Published: December 2003

Several studies on the prognosis of occupational asthma have shown that a significant proportion of patients continue to experience asthmatic symptoms and nonspecific bronchial hyperresponsiveness after cessation of work. The determinants of this unfavourable prognosis of asthma are: long duration of exposure before the onset of asthma; long duration of symptoms before diagnosis; baseline airway obstruction; dual response after specific challenge test; and the persistence of markers of airway inflammation in bronchoalveolar lavage fluid and bronchial biopsy. The relevance of immunological markers in the outcome of occupational asthma has not yet been assessed. Further occupational exposure in sensitized subjects leads to persistence and sometimes to progressive deterioration of asthma, irrespective of the reduction of exposure to the specific sensitizer, and only the use of particular protective devices effectively prevents the progression of the disease. A long-term follow-up study of toluene diisocyanate (TDI)-induced asthma showed that the improvement in bronchial hyperresponsiveness to methacholine occurred in a small percentage of subjects and only a long time after work cessation. Bronchial sensitivity to TDI may disappear, but non-specific bronchial hyperresponsiveness often persists unchanged, suggesting a permanent deregulation of airway tone. Steroid treatment significantly reduces nonspecific bronchial hyperresponsiveness only when started immediately after diagnosis.
Prevention of occupational asthma
Authors: Venables KM
Published: December 2003

This paper focuses on the prevention of asthma caused by exposure to sensitizing agents in the workplace. Control of exposure (primary prevention) is the most direct method of reducing the number of incident cases. Screening programmes are also necessary as a "safety net", and have value as secondary prevention, because early detection may improve long-term prognosis. It is recommended that regulatory or advisory bodies with responsibility for occupational asthma publish a guidance document on occupational asthma explaining their current concepts. Surveillance activities provide information on how common asthma is relative to other occupational lung diseases, and on the relative frequency of occurrence of asthma caused by different agents. Publication of a list of sensitizing agents would aid those with responsibility for control of exposure in the workplace. Epidemiological research on exposure-response relations is is necessary as a background to prevention. This paper recommends such studies. Immunotoxicological research also has a role in testing hypotheses that cannot be tested in human subjects. Some standardization of screening programmes in industry is desirable. A short symptoms questionnaire is economical and acceptable to workers, but there are other approaches. Finally, evaluative research on prevention measures gives information on their effectiveness and efficiency.
From granuloma to fibrosis in interstitial lung diseases: molecular and cellular interactions
Authors: Mornex JF , Leroux C , Greenland T , Ecochard D
Published: December 2003

Granuloma is a feature of many chronic interstitial lung diseases, and may serve as a focus for subsequent fibrosis. Granulomas are composed of structured masses of cells of the macrophage lineage, which adopt an epithelioid aspect, interspersed with lymphocytes. They are formed around local centres of irritation. During their resolution, fibroblasts congregate around the structures and may penetrate the interior. In many cases, granulomas can disappear without leaving lasting traces. However, especially when damage has occurred to the surrounding tissue, permanent scarring and fibrosis may occur. Both types of cell present in the granuloma are capable of secreting a number of factors influencing the accumulation and proliferation of fibroblasts, both positively and negatively. The possible roles played by the different factors and, especially, interactions between them are discussed in the light of fibrosis formation. Possible therapeutic interventions are summarized.
The cardiovascular effects of obstructive sleep apnoeas: analysis of pathogenic mechanisms
Authors: Bonsignore MR , Marrone O , Insalaco G , Bonsignore G
Published: December 2003

Obstructive sleep apnoeas (OSA) exert immediate marked cardiovascular effects, and may favour the development of systemic and pulmonary hypertension in the long-term. As for the pathogenesis of the acute cardiovascular changes, the first studies high-lighted the role of OSA-induced hypoxia and mechanical changes. However, more recent work pointed to the role played by the arousal reaction terminating OSA, and to the activity of the autonomic nervous system during apnoea and inter-apnoeic phase. As for the pathogenesis of chronic cardiovascular changes, recent findings suggest that the link between OSA and systemic hypertension may be through an abnormal function of the carotid body and underline the importance of chronic intermittent hypoxia versus continuous hypoxia in the development of stable systemic hypertension. On the other hand, OSA do not appear to enhance strongly the development of stable pulmonary hypertension. In this review, we analyze OSA-induced cardiovascular changes with particular emphasis on to the interplay of the possible pathogenic mechanisms involved. Acute OSA-induced cardiovascular alterations during the apnoeic phase appear to result mainly from the mechanical effects of OSA, while during the interapnoeic phase they seem mostly determined by chemical factors (hypoxia, hypercapnia) and by the arousal reaction. In addition, the role of reflex changes elicited by resumption of ventilation should be reconsidered, since lung inflation seems to exert a positive effect on the cardiovascular changes occurring at the end of OSA. This would be in contrast with the inhibitory effects described as "lung inflation reflex", and deserves further study.
Statistical approaches to the identification of late asthmatic reactions
Authors: Stenton SC , Avery AJ , Walters EH , Hendrick DJ
Published: December 2003

Late asthmatic reactions can be difficult to recognize because of their prolonged time course and the confounding effects of superimposed circadian rhythms of ventilatory function. Conventional methods of analysis are rather arbitrary. They depend for example on a 15 or 20% fall in forced expiratory volume in one second (FEV1) from baseline or from time-matched control measurements. We have, therefore, investigated whether statistical approaches applied to individual subjects can assist in the identification of late asthmatic reactions. In two separate series of aerosol inhalation tests, three symptomatic workers, three asthmatic controls and three nonasthmatic controls were challenged blindly with increasing doses of two chemical agents, and saline. One of the agents, sodium isononanoyl oxybenzene sulphonate (SINOS) was a suspected cause of occupational asthma. Prior to the challenges, FEV1 was measured hourly on three control days. Cumulative late changes on both control and active challenge days were quantified as the area between a line extrapolated from a 10.00 h baseline and the actual measurements from 12.00-22.00 h (the 2-12 h area decrement). The area decrement measurements on control and active challenge days were compared using Student's t-tests. The sensitivity of this method for detecting late asthmatic reactions among potentially positive tests (SINOS challenge tests in the workers) was examined, as was its specificity. The latter was determined from the false positive rate among the negative tests. A second statistical method based on the pooled standard deviation of serial (hourly) FEV1 measurements was investigated in the same way. In total, the data from 220 challenge and 30 control days were available for analysis.(ABSTRACT TRUNCATED AT 250 WORDS)