bluuebunny/crossref_metadata_2025 huggingface dataset:
Montelukast improves regional air-trapping due to small airways obstruction in asthma
Authors: Zeidler M. R. , Kleerup E. C. , Goldin J. G. , Kim H. J. , Truong D. A. , Simmons M. D. , Sayre J. W. , Liu W. , Elashoff R. , Tashkin D. P.
Published: February 2006

Quantitative image analysis of high-resolution computed tomography (HRCT) performed at residual volume, before and after methacholine, is a sensitive method of detecting small airways involvement in asthma and response to therapy targeted to the small airways. Since an oral anti-leukotriene reaches the small airwaysviathe circulation, the present authors hypothesised that treatment with montelukast would lead to improved small airway patency.

A double-blind crossover study compared the effect of montelukastversusplacebo for 4 weeks in 16 mild-to-moderate steroid-naïve asthmatics. Small airways function was evaluated by HRCT at residual volume before and after methacholine to assess regional air-trapping and airways hyperresponsiveness, as well as by physiological studies of small airways.

Montelukast treatment resulted in significantly less regional air-trapping on HRCT on the pre-methacholine images when compared with placebo, as well as improvement in total quality of life scores and symptom sub-scores. However, montelukast treatment had no effect on increases in regional air-trapping on HRCT in response to methacholine. No differences were noted in global measures of small airways physiology between placebo and montelukast.

In conclusion, distal airways disease improves in asthmatic subjects treated with montelukast. This improvement can be detected with high-resolution computed tomography, but not with conventional physiological studies.
Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction
Authors: Yinon D. , Lowenstein L. , Suraya S. , Beloosesky R. , Zmora O. , Malhotra A. , Pillar G.
Published: February 2006

Pre-eclamptic toxaemia (PET) may be associated with both endothelial dysfunction (ED) and sleep-disordered breathing (SDB). It was hypothesised that females with PET would demonstrate both SDB and ED, and that a correlation between these two would suggest a potential causative association.

A total of 17 females with PET and 25 matched females with uncomplicated pregnancy were studied. They underwent a nocturnal ambulatory sleep study (using Watch_PAT100) and noninvasive evaluation of endothelial function utilising the reactive hyperaemia test (using Endo_PAT 2000). A higher ratio of post- to pre-occlusion pulse-wave amplitude (endothelial function index (EFI)) indicated better endothelial function.

Females with PET had a significantly higher respiratory disturbance index (RDI) and lower EFI than controls (18.4±8.4versus8.3±1.3·h−1, and 1.5±0.1versus1.8±0.1, respectively). Blood pressure significantly correlated with RDI and with EFI. EFI tended to correlate with RDI.

In conclusion, these results suggest that both sleep-disordered breathing and endothelial dysfunction are more likely to occur in females with pre-eclamptic toxaemia than in females with uncomplicated pregnancies. The current authors speculate that respiratory disturbances contribute to the functional abnormality of the blood vessels seen in females with pre-eclamptic toxaemia, although causality cannot be determined based on this study.
Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design
Authors: Gamble E. , Qiu Y. , Wang D. , Zhu J. , Vignola† A. M. , Kroegel C. , Morell F. , Hansel T. T. , Pavord I. D. , Rabe K. F. , Barnes N. C. , Jeffery P. K.
Published: February 2006

There is variability in the distribution of inflammatory cells in bronchial tissue in chronic obstructive pulmonary disease (COPD). Better strategies for biopsy sampling of the airway mucosa may improve the capacity to show a difference between study populations where variability in distribution exists.

The current authors have examined sources of biological variability in the quantification of inflammatory cells in endobronchial biopsies using immunostained samples taken from 51 subjects with COPD, with a mean forced expiratory volume in one second of 1.71 L, 55% predicted.

The distribution of variance contributed by different sources was similar for different inflammatory cell types. For CD8+ cells, a key inflammatory cell in COPD, the largest contribution to intra-subject variability (39%) was time (i.e.10 weeks between biopsies of placebo-treated subjects), followed by airway generation (23%), biopsy (2.5%), zone (within section; 1.4%) and section (0.4%).

Power calculations demonstrated that examining one section from one biopsy, from each of two airway generations, would require a sample size of 32 subjects per group to show a difference of one doubling or halving in CD8+ cells, compared with 47 subjects per group if only one airway generation was sampled.

Therefore, biopsies from more than one airway generation should be examined in order to maximise statistical power to detect a difference between study groups.
Diaphragm electromyograms recorded from multiple surface electrodes following magnetic stimulation
Authors: Glerant J. C. , Mustfa N. , Man W. D. , Luo Y. M. , Rafferty G. , Polkey M. I. , Moxham J.
Published: February 2006

The diaphragm compound-muscle action potential (CMAPdi), elicited by unilateral magnetic stimulation (UMS) of the phrenic nerve can be recorded using surface electrodes. However, there is no consensus on the best positioning of surface electrodes and there are no data on the reproducibility of the signal.

Using 36 surface electrode pairs, in five healthy subjects, the CMAPdi elicited by UMS and electrical stimulation (ES) were compared and 12 pairs were identified as providing acceptable signals. The latency and amplitude were measured for each CMAPdi, following UMS at 60–100% of maximal stimulator output, in 12 healthy subjects, on two occasions.

Latencies obtained using UMS and ES ranged between 6.1–7.33 and 6.25–7.17 ms, respectively. Optimum CMAPdi were not recorded from the same electrode pair in all subjects, or for both hemidiaphragms in each subject. However, the optimal recording site for a particular individual remained unchanged on subsequent testing. When recorded from the optimal site, latencies and amplitudes of CMAPdi elicited on the two occasions were not significantly different.

The current study suggests that the use of multiple chest wall electrodes can identify an optimal electrode pair, from which it is possible to obtain reproducible compound-muscle action potential signals.
Laryngeal ultrasound: a useful method in predicting post-extubation stridor. A pilot study
Authors: Ding L-W. , Wang H-C. , Wu H-D. , Chang C-J. , Yang P-C.
Published: February 2006

The cuff-leak test was widely used for the prediction of post-extubation stridor, but controversial results limit its clinical application. The current study used real-time ultrasonography to evaluate the air-leak and hypothesised that the air-column width, measured by ultrasonography, may be correlated to the development of post-extubation stridor.

From June 1, 2001 to March 1, 2002, a total of 51 planned extubations in 51 consecutively intubated patients were included. All of the patients received ultrasonographical examinations of their vocal cords and larynx in addition to an air-column width measurement within 24 h prior to extubation.

The overall post-extubation stridor rate was 7.8%. The air-leak volume presented as median (interquartile range) were 300 (350) mL and 25 (20) mL, respectively, for the nonstridor and stridor groups. The air-column width during cuff deflation was 6.4 (2) mm and 4.5 (0.8) mm, respectively. They were found to be statistically significant.

In conclusion, the authors demonstrated that laryngeal ultrasonography could be a reliable, noninvasive method, in the evaluation of vocal cords, laryngeal morphology and the ease of airflow, which passed through vocal cords or subglottic area due to laryngeal oedema. The air-column width during cuff deflation was a potential predictor of post-extubation stridor.
Antioxidant intake, GSTM1 polymorphism and pulmonary function in healthy young adults
Authors: Tujague J. , Bastaki M. , Holland N. , Balmes J. R. , Tager I. B.
Published: February 2006

Dietary antioxidants may protect lung tissue against reactive oxygen species-induced injury, adverse respiratory effects and reduced pulmonary function. Genetic variability in antioxidant enzymes also determines response to oxidative stress in the lung. The current authors evaluated whether lung function levels are associated with dietary intake of antioxidants and the glutathioneS-transferase M1 (GSTM1) polymorphism.

The current study cohort consisted of healthy, nonsmoking freshmen students who were lifetime residents in the Los Angeles or the San Francisco Bay areas (CA, USA). Participants completed comprehensive residential history, health history and food frequency questionnaires. Blood for genotyping was collected and forced expiratory volume measurements were obtained.

Dietary vitamin C, magnesium and daily fruit servings were associated positively with forced expiratory volume in one second in males and with maximum mid-expiratory flow, forced expiratory flow after 75% of expelled volume, and the ratio of maximum mid-expiratory flow to forced vital capacity in females. In multivariable regression, vitamin C (or fruit for male students) and magnesium showed a consistent, positive association with lung function.

Among healthy female adolescents, dietary intake of vitamin C is associated with increased levels of lung function. The current study does not support a role for the glutathioneS-transferase M1-null genotype as an independent risk factor for decrements in lung function.
Obstructive and restrictive spirometric patterns: fixed cut-offs for FEV1/FEV6and FEV6
Authors: Vandevoorde J. , Verbanck S. , Schuermans D. , Kartounian J. , Vincken W.
Published: February 2006

The purpose of this study was to determine fixed cut-off points for forced expiratory volume in one second (FEV1)/FEV6and FEV6as an alternative for FEV1/forced vital capacity (FVC) and FVC in the detection of obstructive and restrictive spirometric patterns, respectively.

For the study, a total of 11,676 spirometric examinations, which took place on Caucasian subjects aged between 20–80 yrs, were analysed. Receiver–operator characteristic curves were used to determine the FEV1/FEV6ratio and FEV6value that corresponded to the optimal combination of sensitivity and specificity, compared with the commonly used fixed cut-off term for FEV1/FVC and FVC.

The data from the current study indicate that FEV1/ FEV6<73% and FEV6<82% predicted can be used as a valid alternative for the FEV1/FVC <70% and FVC <80% pred cut-off points for the detection of obstruction and restriction, respectively. The statistical analysis demonstrated very good, overall, agreement between the two categorisation schemes. For the spirometric diagnosis of airway obstruction (prevalence of 45.9%), FEV1/FEV6sensitivity and specificity were 94.4 and 93.3%, respectively; the positive and negative predictive values were 92.2 and 95.2%, respectively. For the spirometric detection of a restrictive pattern (prevalence of 14.9%), FEV6sensitivity and specificity were 95.9 and 98.6%, respectively; the positive and negative predictive values were 92.2 and 99.3%, respectively.

This study demonstrates that forced expiratory volume in one second/forced expiratory volume in six seconds <73% and forced expiratory volume in six seconds <82% predicted, can be used as valid alternatives to forced expiratory volume in one second/forced vital capacity <70% and forced vital capacity <80% predicted, as fixed cut-off terms for the detection of an obstructive or restrictive spirometric pattern in adults.
Inflammatory responses to the occupational inhalation of metal fume
Authors: Palmer K. T. , McNeill-Love R. , Poole J. R. , Coggon D. , Frew A. J. , Linaker C. H. , Shute J. K.
Published: February 2006

Occupational exposure to metal fume promotes a reversible increase in the risk of pneumonia, but by mechanisms which are unclear. To investigate, the current authors measured various markers of host defence function in welders and nonwelders.

Induced sputum and venous blood samples were collected from 27 welders with regular long-term exposure to ferrous metal fume and 31 unexposed matched controls. In sputum, the present authors measured cell counts, the soluble and cellular iron concentration, and levels of interleukin-8, tumour necrosis factor-α, myeloperoxidase, matrix metalloproteinase-9, immunoglobulin (Ig)A, α2-macroglobulin and unsaturated iron-binding capacity. Blood samples were assayed for evidence of neutrophil activation and pneumococcal IgG antibodies.

Welders had significantly higher iron levels and a substantially lower unsaturated iron-binding capacity in their sputum, but, despite a high iron challenge, there was a noteworthy absence of an inflammatory response. Only blood counts of eosinophils and basophils were significantly related to the extent of welding. Weak nonsignificant trends were observed for several other measures, consistent with low-grade priming of neutrophils.

In conclusion, these data suggest that chronic exposure to metal fume blunts responsiveness to inhaled particulate matter. However, the mechanism behind the lack of detectable local inflammatory response requires further investigation.
Limitation of cigarette consumption byCYP2A6*4,*7and*9polymorphisms
Authors: Minematsu N. , Nakamura H. , Furuuchi M. , Nakajima T. , Takahashi S. , Tateno H. , Ishizaka A.
Published: February 2006

The whole gene deletionCYP2A6*4, the defect of the main nicotine oxidase, contributes to limiting lifelong and daily cigarette consumption. However, the effects on smoking habits ofCYP2A6*7and*9, two major functional polymorphisms common in Asian populations, have not been reported.

The present study examined the relationship between polymorphisms*4,*7and*9with the smoking habits of 200 Japanese smokers who visited the Keio University Hospital (Tokyo, Japan).

The allele frequencies of*1(wild type),*4,*7and*9were 52, 17, 11 and 20%, respectively. When the three polymorphisms were considered simultaneously, the percentages of homozygous wild type, heterozygote, and homozygous mutants and compound heterozygotes were 26.0, 52.5 and 21.5%, respectively. Homozygous mutants and compound heterozygotes (n = 43) smoked fewer cigarettes daily than heterozygotes (n = 105) and homozygous wild-type individuals (n = 52). Smokers with*7/*7,*9/*9or*7/*9had lower daily cigarette consumption than smokers with*1/*1.

In conclusion, polymorphisms*4,*7and*9ofCYP2A6were detected in approximately three out of four Japanese smokers, and their daily cigarette consumption was genetically modulated by these functional polymorphisms.
Inhaled heparin in cystic fibrosis
Authors: Serisier D. J. , Shute J. K. , Hockey P. M. , Higgins B. , Conway J. , Carroll M. P.
Published: February 2006

Cystic fibrosis (CF) is characterised by inspissated airway secretions and chronic endobronchial infection associated with exuberant neutrophilic inflammation. Unfractionated heparin may be mucolytic and has demonstrated a number of anti-inflammatory properties; however, further safety data are needed in these subjects who are at risk of airway bleeding. The current study aimed to assess the medium-term safety and tolerability of moderately high-dose inhaled heparin in CF adults and to explore possiblein vivomucolytic and anti-inflammatory outcomes.

A randomised, double-blind, placebo-controlled crossover study of twice daily inhalation of 50,000 IU of heparin for 2 weeks was undertaken in CF adults, with a 1-week washout period. Eighteen subjects were randomised and 14 (mean±sdage 23±7.8 yrs and percentage-predicted forced expiratory volume in one second 52.1±15.56%) completed the study protocol.

Heparin neither affected blood coagulation parameters nor resulted in any increase in adverse events. Heparin inhalation had no significant effect upon forced expiratory volume in one second, symptoms of sputum clearance or sputum inflammatory markers.

The current pilot study demonstrated no evidence of improved sputum clearance with 50,000 IU of inhaled heparin given twice daily to adult cystic fibrosis subjects. However, inhaled heparin was safe and the future evaluation of larger doses over a longer period may be warranted.
The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children
Authors: Priftis K. N. , Papadimitriou A. , Gatsopoulou E. , Yiallouros P. K. , Fretzayas A. , Nicolaidou P.
Published: February 2006

The present authors evaluated adrenal reserve in asthmatic children on long-term inhaled corticosteroids and whether possible adrenal suppression could be predicted by growth retardation.

Low-dose synacthen test (0.5 µg·1.73 m−2) was performed in 72 asthmatic children with a median age of 9.4 (range 4.2–15.7) yrs on long-term treatment (median 18 (range 6–84) months) with low-to-moderate doses (median 363 (range 127–1012) µg·m−2) of inhaled budesonide, as well as in 30 controls. Adrenal suppression was considered as a peak serum cortisol <495 nmol·L−1. The current authors calculated height standard deviation score (HSDS) at the time of testing and height velocity SDS (HVSDS) in the preceding year.

Mean HSDS was 0.06±1.3 and HVSDS was −0.9±2.3. Adrenal suppression was disclosed in 15 asthmatic children (20.8%). There were no differences in HSDS and HVSDS between children with and without adrenal suppression. There was no correlation between peak cortisol response and dose or duration of treatment. However, a positive relationship between HVSDS and duration of treatment was noted.

These data suggest that long-term treatment of asthmatic children with low and moderate doses of inhaled budesonide may result in mild adrenal suppression that cannot be predicted by growth deceleration. The negative influence of inhaled corticosteroids on growth becomes less the longer the duration of treatment.
Assessment of right ventricular function by strain rate imaging in chronic obstructive pulmonary disease
Authors: Vitarelli A. , Conde Y. , Cimino E. , Stellato S. , D'Orazio S. , D'Angeli I. , Nguyen B. L. , Padella V. , Caranci F. , Petroianni A. , D'Antoni L. , Terzano C.
Published: February 2006

The purpose of the current study was to compare right ventricular (RV) myocardial wall velocities (tissue Doppler imaging) and strain rate imaging (SRI) parameters with conventional echocardiographic indices evaluating RV function in chronic obstructive pulmonary disease (COPD) patients.

In total, 39 patients with COPD and 22 healthy subjects were included in the current study. Seventeen patients had pulmonary artery pressure <35 mmHg (group I) and 22 patients had pulmonary artery pressure >35 mmHg (group II). Tissue Doppler imaging, strain and strain rate (SR) values were obtained from RV free wall (FW) and interventricular septum. Respiratory function tests were performed (forced expiratory volume in one second/vital capacity (FEV1/VC) and carbon monoxide diffusion lung capacity per unit of alveolar volume (DL,CO/VA)).

Strain/SR values were reduced in all segments of group II patients compared with group I patients and controls with lowest values at basal FW site. A significant relationship was shown between peak systolic SR at basal FW site and radionuclide RV ejection fraction. A significant relationship was shown between peak systolic SR at basal FW site andDL,CO/VAand FEV1/VC.

In conclusion, in chronic obstructive pulmonary disease patients, strain rate imaging parameters can determine right ventricular dysfunction that is complementary to conventional echocardiographic indices and is correlated with pulmonary hypertension and respiratory function tests.
FEV6as a surrogate for FVC in detecting airways obstruction and restriction in the workplace
Authors: Akpinar-Elci M. , Fedan K. B. , Enright P. L.
Published: February 2006

Compared with measurements of forced vital capacity (FVC), using the forced expiratory volume in six seconds (FEV6) reduces test time and frustration. It was hypothesised that using FEV6in the workplace setting would result in an acceptably low misclassification rate for detecting airways obstruction and spirometry-defined restriction when compared with using the traditional FVC.

Experienced technicians from the National Institute for Occupational Safety and Health performed spirometry using dry rolling-seal spirometers as per American Thoracic Society guidelines in four workplace investigations. Airways obstruction was defined as an FEV1/FVC % below the lower limit of normal (LLN) using National Health and Nutrition Examination Survey III reference equations. Restriction was defined as an FVC below the LLN with a normal FEV1/FVC %. These “gold standard” definitions were compared with definitions based on FEV6(obstruction: FEV1/FEV6below the LLN; restriction: FEV6below the LLN with a normal FEV1/FEV6).

The median (range) age of the 1,139 workers was 37 yrs (18–71 yrs) and 51.4% were male. A significantly high overall agreement was obtained between the two definitions.

In conclusion, the current results confirm that forced expiratory volume in six seconds can be used as a surrogate for forced vital capacity in detecting airways obstruction and restriction in workers, although with some misclassification when compared to obtaining American Thoracic Society-acceptable manoeuvres of longer duration.
Stability of housekeeping genes in alveolar macrophages from COPD patients
Authors: Ishii T. , Wallace A. M. , Zhang X. , Gosselink J. , Abboud R. T. , English J. C. , Paré P. D. , Sandford A. J.
Published: February 2006

The stability of housekeeping genes is critical when performing gene expression studies. To date, there have been no studies that look at the stability of commonly used housekeeping genes in alveolar macrophages. Expression levels may be affected by culture, stimulation or disease severity.

The present study investigated the expression level of 10 housekeeping genes and analysed the stability of their expression in alveolar macrophages from chronic obstructive pulmonary disease patients (n = 22) who were classified according to disease severity.

Guanine nucleotide-binding protein, beta polypeptide 2-like 1 (GNB2L1), hypoxanthine phosphoribosyl transferase 1 (HPRT1) and ribosomal protein L32 (RPL32) were the most stably expressed in alveolar macrophages, irrespective of disease severity. There was no difference in the expression levels of 10 housekeeping genes between mild and moderate/severe patients. GNB2L1, HPRT1 and RPL32 were also stably expressed in alveolar macrophages cultured with no stimulation, or with interleukin-1β, lipopolysaccharide or tumour necrosis factor-α stimulation.

In conclusion, as fluctuations in the expression of some housekeeping genes were observed, including glyceraldehyde-3-phosphate dehydrogenase, it is recommended that guanine nucleotide binding protein, beta polypeptide 2-like 1 be used as a reference gene for alveolar macrophages in similar study designs, or that the stability of housekeeping genes be validated in alveolar macrophages prior to expression studies.
Identification of hBD-3 in respiratory tract and serum: the increase in pneumonia
Authors: Ishimoto H. , Mukae H. , Date Y. , Shimbara T. , Mondal M. S. , Ashitani J. , Hiratsuka T. , Kubo S. , Kohno S. , Nakazato M.
Published: February 2006

Human β-defensin (hBD)-3, a 45 amino acid antimicrobial peptide, was originally isolated from human skin. hBD-3 mRNA has also been detected in the airways by RT-PCR. While hBD-3 may be involved in antimicrobial defences within the respiratory tract, the presence of hBD-3 peptide in the respiratory system has not yet been confirmed.

The antimicrobial activity of the synthesised hBD-3 peptide was measured by a radial diffusion assay and a colony count assay. The present authors confirmed the presence of hBD-3 peptide in homogenates of human lung and serum using reverse-phase HPLC coupled with a highly sensitive RIA. The localisation of the hBD-3 peptide was investigated by immunohistochemistry. In addition, the serum concentrations of hBD-3 were measured by RIA.

hBD-3 exhibited a strong antimicrobial activity, which was unaffected by increasing salt concentrations. Immunohistochemically, the current authors observed the expression of hBD-3 in bronchial and bronchiolar epithelial cells. The mean±sdserum concentration of hBD-3 in patients with bacterial pneumonia was 239.4±17.8 pg·mL−1in the acute phase and, decreased to 159.3±20.1 pg·mL−1after the completion of therapy.

In conclusion, these findings will help elucidate the role of human β-defensin-3 in host immune responses and identify the pathophysiological significance of this molecule in respiratory infections.
Corticosteroid effects on cell signalling
Authors: Barnes P. J.
Published: February 2006

Corticosteroids are the most effective anti-inflammatory therapy for asthma. Inflammation in asthma is characterised by the increased expression of multiple inflammatory genes regulated by pro-inflammatory transcription factors, such as nuclear factor-κB and activator protein-1, which bind to and activate coactivator molecules that acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways, mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase 2 to the activated transcription complex.

Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes in order to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase-1, which inhibits mitogen-activated protein kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side-effects.

In some patients with steroid-resistant asthma, there are abnormalities in glucocorticoid receptor signalling pathways. In chronic obstructive pulmonary disease patients and asthmatic patients who smoke, histone deacetylase 2 is markedly impaired as a result of oxidative/nitrative stress, and so inflammation is resistant to the anti-inflammatory effects of corticosteroids.

The therapeutic implications of these new findings are discussed.
Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans
Authors: Behndig A. F. , Mudway I. S. , Brown J. L. , Stenfors N. , Helleday R. , Duggan S. T. , Wilson S. J. , Boman C. , Cassee F. R. , Frew A. J. , Kelly F. J. , Sandström T. , Blomberg A.
Published: February 2006

Pulmonary cells exposed to diesel exhaust (DE) particlesin vitrorespond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurredin vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly.

A total of 15 volunteers were exposed to DE (100 µg·m−3airborne particulate matter with a diameter of <10 µm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status.

Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure.

In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.
Endobronchial ultrasound and positron emission tomography positive mediastinal lymph nodes
Authors: Plat G. , Pierard P. , Haller A. , Hutsebaut J. , Faber J. , Dusart M. , Eisendrath P. , Sculier J-P. , Ninane V.
Published: February 2006

Positron emission tomography with 18F-fluoro-2-deoxy-d-glucose (FDG-PET) is more accurate than computed tomography for staging of mediastinal (hilar) lymph nodes. In the case of positive findings, tissue sampling of lymph nodes is required. The diagnostic/staging yield of transbronchial needle aspiration (TBNA) following endobronchial ultrasound (EBUS) localisation was assessed in this particular clinical setting. The number of avoided surgical procedures was evaluated.

All consecutive patients referred for staging and/or diagnosis of mediastinal FDG-PET positive lesions were included. Data were prospectively collected. TBNA sampling of lymph nodes was performed after EBUS localisation. If no diagnosis was reached, further surgical sampling or adequate follow-up was performed.

From January 2003 to June 2004, 33 patients were included. The average number of TBNA samples per patient was 4.2±1.5. Cytological or histological diagnoses were obtained in 27 (82%) of the patients, of which 78% were obtained after previous EBUS localisation. In 25 (76%) of the 33 patients, surgical staging procedures were suppressed.

In conclusion, transbronchial needle aspiration after endobronchial ultrasound localisation should be considered as a primary method of evaluation of lymph nodes positive by positron emission tomography with 18F-fluoro-2-deoxy-d-glucose, and may replace the majority of surgical mediastinal staging/diagnostic procedures.
The potential impact of anaemia of chronic disease in COPD
Authors: Similowski T. , Agustí A. , MacNee W. , Schönhofer B.
Published: February 2006

Anaemia of chronic disease (ACD), with chronically low levels of circulating haemoglobin, is an immune driven abnormality that occurs in many inflammatory diseases, and also in chronic heart failure. Although chronic obstructive pulmonary disease (COPD) is “traditionally” associated with polycythaemia, the systemic inflammation that is now recognised as a feature of COPD makes it a possible cause of ACD. If present in COPD, anaemia could worsen dyspnoea and limit exercise tolerance.

Preliminary evidence suggests that anaemia in COPD patients may be more prevalent than expected, concerning 10–15% of patients suffering from severe forms of the disease. A database study conducted in 2,524 COPD patients being prescribed long-term oxygen therapy has shown that a low haematocrit is a strong predictor of survival in this population, before body mass index, and is associated with more hospitalisations and a longer cumulative duration of hospitalisation. COPD patients with low haemoglobin levels have a poorer prognosis than COPD patients with normal haemoglobin levels in the event of acute gastrointestinal bleeding or after elective aneurysm repair. Raising haemoglobinaemia through transfusion decreases minute ventilation and work of breathing in COPD patients.

These preliminary evidences point to the need to study the prevalence of anaemia, and its physiological and clinical impact in chronic obstructive pulmonary disease. When this body of knowledge is available, the question of the putative benefits of raising haemoglobinaemia in chronic obstructive pulmonary disease will have to be addressed.
Sleep-disordered breathing and upper airway size in pregnancy and post-partum
Authors: Izci B. , Vennelle M. , Liston W. A. , Dundas K. C. , Calder A. A. , Douglas N. J.
Published: February 2006

Sleep-disordered breathing and snoring are common in pregnancy. The aim of this study was to determine whether pregnancy was associated with upper airway narrowing.

One-hundred females in the third trimester of pregnancy were recruited and 50 agreed to be restudied 3 months after delivery. One-hundred nonpregnant females were also recruited. Upper airway dimensions were measured using acoustic reflection.

Snoring was less common in nonpregnant (17%) than pregnant females (41%; odds ratio (OR) 3.34; 95% confidence interval (CI) 1.65–6.74) and returned to nonpregnant levels after delivery (18%; OR 0.15; 95% CI 0.06–0.40). Pregnant females had significantly smaller upper airways than nonpregnant females at the oropharyngeal junction when seated (mean difference 0.12; 95% CI 0.008–0.25), and smaller mean pharyngeal areas in the seated (mean difference 0.14; 95% CI 0.001–0.28), supine (mean difference 0.11; 95% CI 0.01–0.22) and lateral postures (mean difference 0.13; 95% CI 0.02–0.24) compared with the nonpregnant females. Pregnant females had smaller mean pharyngeal areas compared with post-partum in the seated (mean difference 0.18; 95% CI 0.02–0.32), supine (mean difference 0.20; 95% CI 0.06–0.35) and lateral postures (mean difference 0.26; 95% CI 0.12–0.39).

In conclusion, this study confirmed increased snoring and showed narrower upper airways during the third trimester of pregnancy.
Cortistatin-17 and Somatostatin-14 Display the Same Effects on Growth Hormone, Prolactin, and Insulin Secretion in Patients with Acromegaly or Prolactinoma
Authors: Grottoli S. , Gasco V. , Broglio F. , Baldelli R. , Ragazzoni F. , Gallenca F. , Mainolfi A. , Prodam F. , Muccioli G. , Ghigo E.
Published: February 2006

Context: Cortistatin binds all somatostatin receptor subtypes but also has particular central actions; moreover, a specific cortistatin receptor has also been discovered.

Objective: We compared the endocrine effects of cortistatin-17 with those of somatostatin-14 in patients with acromegaly (ACRO) or prolactinoma (PRLOMA). Normal subjects (NS) were studied as control group.

Design: All subjects underwent the following tests: 1) saline, 2) somatostatin-14 (2.0 μg/kg·h iv, 0–120 min) and 3) cortistatin-17 (2.0 μg/kg·h iv, 0–120 min) infusion.

Results: Cortistatin-17 and somatostatin-14 inhibited GH secretion to the same extent in ACRO (P < 0.05) and NS (P < 0.01). Cortistatin-17 and somatostatin-14 inhibited PRL secretion in PRLOMA (P < 0.05), to some extent in ACRO (P value not significant), but not in NS. Insulin secretion was inhibited by both cortistatin-17 and somatostatin-14 to the same extent in all groups (P < 0.05).

Conclusions: Cortistatin-17 and somatostatin-14 display the same effects on GH, PRL, and insulin secretion in patients with ACRO or PRLOMA.
The Influence of Depression, Body Mass Index, and Smoking on Serum Inhibin B Levels in Late Reproductive-Aged Women
Authors: Lambert-Messerlian G. M. , Harlow B. L.
Published: February 2006

Context: Women experiencing depression have difficult psychosocial functioning, and recent data suggest an earlier onset of menopause. Understanding the biological mechanism for the impairment of reproductive function associated with depression is important.

Objective: The objective of the study was to determine whether a lifetime history of depression is associated with reduced ovarian reserve as reflected in serum levels of the granulosa cell product, inhibin B.

Design: Residual serum samples from a subset of patients in the Harvard Study of Cycles and Moods were collected.

Setting: Patients were recruited from seven Boston-area communities.

Patients: Women with or without a history of major depression, based on structured clinical interviews for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, were enrolled. A subset of patients who had provided an early follicular phase blood specimen at study enrollment and two or more other samples over the first 18-month period of follow-up were included.

Intervention: There were no interventions.

Main Outcome Measure: Serum inhibin B levels were measured.

Results: Serum FSH levels were higher in women with a history of depression, whereas inhibin B levels did not differ between groups. Body mass index and age were significantly and inversely related to serum inhibin B levels. Smoking history was noted, for the first time, to have a significant negative association with inhibin B levels.

Conclusions: Smoking has a direct negative effect on ovarian reserve, as suggested by decreased serum inhibin B levels. In contrast, effects of depression on the reproductive axis may occur at the level of the pituitary and/or hypothalamus rather than at the gonadal level, as suggested by increased serum FSH levels.
Abp1 regulates pseudopodium number in chemotaxing Dictyostelium cells
Authors: Wang Yanqin , O'Halloran Theresa J.
Published: February 2006

When starved, Dictyostelium cells respond to extracellular signals, polarize, and move with strong persistence into aggregation centers. Actin and actin-associated proteins play key roles in regulating both the morphology and directed movements of cells during chemotactic aggregation. Recently, we identified an ortholog of Abp1 in Dictyostelium (Dabp1). The first actin binding protein identified in yeast, Abp1 functions in actin-based endocytosis in yeast and in receptor-mediated endocytosis in mammalian cells. To explore the functions for Abp1 in Dictyostelium, we examined the phenotypes of cells that overexpressed the Dabp1 protein and cells that eliminated Dabp1 expression. In these mutants, most actin-based processes were intact. However, cell motility was altered during early development. During chemotactic streaming, more than 90% of wild-type cells had a single leading pseudopodium and a single uropodium, whereas more than 27% of Dabp1 null cells projected multiple pseuodpodia. Similarly, ∼90% of cells that overexpressed Dabp1 projected multiple pseudopodia during chemotactic streaming, and displayed reduced rates of cell movement. Expression of the SH3 domain of Dabp1 showed this domain to be an important determinant in regulating pseudopodium number. These results suggest that Abp1 controls pseudopodium number and motility in early stages of chemotactic aggregation in Dictyostelium.
Ca2+ oscillations induced by testosterone enhance neurite outgrowth
Authors: Estrada Manuel , Uhlen Per , Ehrlich Barbara E.
Published: February 2006

Testosterone has short- and long-term roles in regulating neuronal function. Here, we show rapid intracellular androgen receptor-independent effects of testosterone on intracellular Ca2+ in neuroblastoma cells. We identified testosterone-induced Ca2+ signals that began primarily at the neurite tip, followed by propagation towards the nucleus, which was then repeated to create an oscillatory pattern. The initial transient depended upon production of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], but subsequent transients required both extracellular Ca2+ influx and Ca2+ release from intracellular stores. Inhibition of pertussis toxin-sensitive G-protein receptors or the use of siRNA for the Ins(1,4,5)P3 receptor type 1 blocked the Ca2+ response, whereas inhibition or knock-down of the intracellular androgen receptor was without effect. Cytosolic and nuclear Ca2+ were buffered with parvalbumin engineered to be targeted to the cytosol or nucleus. Cytoplasmic parvalbumin blocked Ca2+ signaling in both compartments; nuclear parvalbumin blocked only nuclear signals. Expression of a mutant parvalbumin did not modify the testosterone-induced Ca2+ signal. Neurite outgrowth in neuroblastoma cells was enhanced by the addition of testosterone. This effect was inhibited when cytosolic Ca2+ was buffered and was attenuated when parvalbumin was targeted to the nucleus. Our results are consistent with a fast effect of testosterone, involving Ins(1,4,5)P3-mediated Ca2+ oscillations and support the notion that there is synergism in the pathways used for neuronal cell differentiation involving rapid non-genomic effects and the classical genomic actions of androgens.
Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance
Authors: Nguyen Tam , Bjorkman Jonas , Paton Barbara C. , Crane Denis I.
Published: February 2006

In contrast to peroxisomes in normal cells, remnant peroxisomes in cultured skin fibroblasts from a subset of the clinically severe peroxisomal disorders that includes the biogenesis disorder Zellweger syndrome and the single-enzyme defect D-bifunctional protein (D-BP) deficiency, are enlarged and significantly less abundant. We tested whether these features could be related to the known role of microtubules in peroxisome trafficking in mammalian cells. We found that remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules. Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse with a Zellweger-syndrome-like phenotype, and a less-pronounced effect was observed for fibroblasts from an infantile Refsum patient who was homozygous for a milder PEX1 mutation. By contrast, such changes were not seen for patients with peroxisomal disorders characterized by normal peroxisome abundance and size. Stable overexpression of PEX11β to induce peroxisome proliferation largely re-established the alignment of peroxisomal structures along peripheral microtubules in both PEX1-null and D-BP-deficient cells. In D-BP-deficient cells, peroxisome division was apparently driven to completion, as induced peroxisomal structures were similar to the spherical parental structures. By contrast, in PEX1-null cells the majority of induced peroxisomal structures were elongated and tubular. These structures were apparently blocked at the division step, despite having recruited DLP1, a protein necessary for peroxisome fission. These findings indicate that the increased size, reduced abundance, and disturbed cytoplasmic distribution of peroxisomal structures in PEX1-null and D-BP-deficient cells reflect defects at different stages in peroxisome proliferation and division, processes that require association of these structures with, and dispersal along, microtubules.
Distinct domains of the spinal muscular atrophy protein SMN are required for targeting to Cajal bodies in mammalian cells
Authors: Renvoisé Benoît , Khoobarry Kevinee , Gendron Marie-Claude , Cibert Christian , Viollet Louis , Lefebvre Suzie
Published: February 2006

Mutations of the survival motor neuron gene SMN1 cause the inherited disease spinal muscular atrophy (SMA). The ubiquitous SMN protein facilitates the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs). The protein is detected in the cytoplasm, nucleoplasm and enriched with snRNPs in nuclear Cajal bodies. It is structurally divided into at least an amino-terminal region rich in basic amino acid residues, a central Tudor domain, a self-association tyrosine-glycine-box and an exon7-encoded C-terminus. To examine the domains required for the intranuclear localization of SMN, we have used fluorescently tagged protein mutants transiently overexpressed in mammalian cells. The basic amino acid residues direct nucleolar localization of SMN mutants. The Tudor domain promotes localization of proteins in the nucleus and it cooperates with the basic amino acid residues and the tyrosine-glycine-box for protein localization in Cajal bodies. Moreover, the most frequent disease-linked mutant SMNΔex7 reduces accumulation of snRNPs in Cajal bodies, suggesting that the C-terminus of SMN participates in targeting to Cajal bodies. A reduced number of Cajal bodies in patient fibroblasts associates with the absence of snRNPs in Cajal bodies, revealing that intranuclear snRNA organization is modified in disease. These results indicate that direct and indirect mechanisms regulate localization of SMN in Cajal bodies.
Androgens modulate the inflammatory response during acute wound healing
Authors: Gilliver Stephen C. , Ashworth Jason J. , Mills Stuart J. , Hardman Matthew J. , Ashcroft Gillian S.
Published: February 2006

Impaired wound healing states in the elderly lead to substantial morbidity and mortality, and a cost to the health services of over $9 billion per annum. In addition to intrinsic ageing processes that per se cause delayed healing, studies have suggested marked differences in wound repair between the sexes. We have previously reported that, castration of male mice results in a striking acceleration of local cutaneous wound healing and dampens the associated inflammatory response. In this study, we report that systemic 5α-reductase inhibition, which blocks the conversion of testosterone to its more active metabolite 5α-dihydrotestosterone, mimics the effects of castration in a rat model of cutaneous wound healing. The mechanisms underlying the observed effects involve a direct, cell-specific upregulation of pro-inflammatory cytokine expression by macrophages, but not fibroblasts, in response to androgens. Androgens require the transforming growth factor β signalling intermediate Smad3 to be present in order to influence repair and local pro-inflammatory cytokine levels. That reducing 5α-dihydrotestosterone levels through 5α-reductase antagonism markedly accelerates healing suggests a specific target for future therapeutic intervention in impaired wound healing states in elderly males.
A signalling cascade involving PKC, Src and Cdc42 regulates podosome assembly in cultured endothelial cells in response to phorbol ester
Authors: Tatin Florence , Varon Christine , Génot Elisabeth , Moreau Violaine
Published: February 2006

The involvement of Src, Cdc42, RhoA and PKC in the regulation of podosome assembly has been identified in various cell models. In endothelial cells, the ectopic expression of constitutively active mutants of Src or Cdc42, but not RhoA, induced the formation of podosomes. Short-term exposure to phorbol-12-myristate-13-acetate (PMA) induced the appearance of podosomes and rosettes after initial disruption of stress fibres. Molecular analysis of PMA-induced podosomes and rosettes revealed that their composition was identical to that of podosomes described in other models. Pharmacological inhibition and siRNA knock-down experiments revealed that both PKCα and PKCδ isotypes were necessary for podosome assembly. However, only constitutively active PKCα could mimic PMA in podosome formation. Src, Cdc42 and RhoA were required downstream of PKCs in this process. Src could be positioned between PKC and Cdc42 in a linear cascade leading to podosome assembly. Using in vitro matrix degradation assays, we demonstrated that PMA-induced podosomes are endowed with proteolytic activities involving MT1-MMP-mediated activation of MMP2. Endothelial podosomes may be involved in subendothelial matrix degradation during endothelium remodelling in pathophysiological processes.