bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipoprotein Response to Diets High in Soy or Animal Protein With and Without Isoflavones in Moderately Hypercholesterolemic Subjects
Authors: Lichtenstein Alice H. , Jalbert Susan M. , Adlercreutz Herman , Goldin Barry R. , Rasmussen Helen , Schaefer Ernst J. , Ausman Lynne M.
Published: November 2002

Objective—

The objective of this study was to assess the independent effect of soy relative to common sources of animal protein and soy-derived isoflavones on blood lipids.

Methods and Results—

Forty-two subjects with LDL cholesterol levels ≥3.36 mmol/L were fed each of four diets in randomized order for 6 weeks per phase. Diets contained a minimum of 25 g animal protein or isolated soy protein/4.2 MJ, with each containing trace amounts or 50 mg of isoflavones/4.2 MJ. Soy protein had a modest effect on total, LDL and HDL cholesterol, and triglyceride concentrations (−2%,
P
=0.017; −2%,
P
=0.042; +3%;
P
=0.034, −11%,
P
<0.001, respectively). Soy protein had no significant effect on plasma lipids in individuals with LDL cholesterol <4.14 mmol/L and significantly reduced total and LDL cholesterol and triglyceride concentrations in individuals with LDL cholesterol ≥4.14 mmol/L (−4%,
P
=0.001; −5%,
P
=0.003; −15%,
P
<0.001, respectively). No significant effect of isoflavones on plasma lipid levels was observed either constituent to the soy protein or supplemental to the animal protein.

Conclusions—

Although potentially helpful when used to displace products containing animal fat from the diet, the regular intake of relatively high levels of soy protein (>50 g/day) had only a modest effect on blood cholesterol levels and only in subjects with elevated LDL cholesterol levels (≥4.14 mmol/L). Soy-derived isoflavones had no significant effect.
Inhibition of the Apical Sodium-Dependent Bile Acid Transporter Reduces LDL Cholesterol and ApoB by Enhanced Plasma Clearance of LDL ApoB
Authors: Huff Murray W. , Telford Dawn E. , Edwards Jane Y. , Burnett John R. , Barrett P. Hugh R. , Rapp Stephen R. , Napawan Nida , Keller Bradley T.
Published: November 2002

Objective—

Cloning of the ileal apical sodium-dependent bile acid transporter (ASBT) has identified a new pharmacological target for the modulation of plasma lipoproteins. The objective of this study was to determine whether a novel, specific, minimally absorbed ASBT inhibitor (SC-435) decreases LDL cholesterol through the alteration of plasma apoB kinetics.

Methods and Results—

Miniature pigs were treated for 21 days with 10 mg/kg/day of SC-435 or placebo. SC-435 decreased plasma cholesterol by 9% and LDL cholesterol by 20% with no effect on other lipids. Autologous
131
I-VLDL,
125
I-LDL, and [
3
H]-leucine were injected simultaneously to determine apoB kinetics. LDL apoB concentrations decreased significantly by 10% resulting entirely from an increase in LDL–apoB fractional catabolic rate. SC-435 had no effect on either total LDL apoB production or VLDL apoB converted to LDL. SC-435 increased VLDL apoB production by 22%; however, the concentration was unchanged as a result of increased VLDL apoB direct removal. SC-435 increased hepatic mRNA and enzymatic activity for both cholesterol 7α-hydroxylase and HMG-CoA reductase. Hepatic LDL receptor mRNA increased significantly, whereas apoB expression was unaffected.

Conclusions—

A low dose of the ASBT inhibitor, SC-435, significantly reduces plasma LDL cholesterol through enhanced LDL receptor-mediated LDL apoB clearance, secondary to increased expression of cholesterol 7α-hydroxylase.
Differential Role of Heparan Sulfate Proteoglycans on Aggregated LDL Uptake in Human Vascular Smooth Muscle Cells and Mouse Embryonic Fibroblasts
Authors: Llorente-Cortés Vicenta , Otero-Viñas Marta , Badimon Lina
Published: November 2002

Objective—

Low density lipoprotein (LDL) receptor–related protein (LRP) binds and internalizes aggregated LDL (agLDL) in human vascular smooth muscle cells (VSMCs). To analyze the contribution of proteoglycans (PGs) to agLDL uptake in human VSMCs, in wild-type mouse embryonic fibroblasts (MEF line), and in LRP-deficient mouse embryonic fibroblasts (PEA13 line).

Methods and Results—

PGs in the medium and cellular and extracellular matrix have been isolated by metabolic radiolabeling with [
35
S]Na
2
SO
4
and characterized by selective digestion with heparinase I and III (4 U/mL each) and chondroitinase ABC (2 U/mL). To examine the contribution of PGs and LRPs to agLDL internalization, nonexpressing and LRP-expressing cells, treated or not with polysaccharidase, were incubated with agLDL (25, 50, and 100 μg/mL) for 18 hours. In human VSMCs, agLDL was unable to induce cholesteryl ester (CE) accumulation in antisense LRP-oligodeoxynucleotide–treated cells, and heparan sulfate (HS)-PG depletion leads to a reduction of the CE accumulation. In mouse fibroblasts, PEA13 compared with MEF showed lower, but still considerable, CE accumulation, and HS-PG depletion almost completely inhibited CE accumulation.

Conclusions—

In MEF, HS-PGs can function alone as receptors that bind and internalize agLDL in the absence of LRP, but in human VSMCs, although HS-PGs facilitate agLDL binding to the cells, LRP is essential for agLDL internalization.
Increased Serum Homocysteine and Sudden Death Resulting from Coronary Atherosclerosis With Fibrous Plaques
Authors: Burke Allen P. , Fonseca V. , Kolodgie Frank , Zieske Arthur , Fink Louis , Virmani Renu
Published: November 2002

Introduction—

Modest elevations of total homocysteine have been associated with increased risk for coronary atherosclerosis but correlation between elevated homocysteine and plaque morphology has not been described in humans.

Methods—

We determined serum homocysteine at postmortem from 87 men with coronary thrombus (62 of whom were diagnosed as acute), from 35 men with severe coronary disease without thrombus, and from 46 controls. In coronary deaths, atherosclerotic plaques at the sites of maximal luminal narrowing of the four epicardial coronary arteries were classified as fibrous plaques, fibrous cap atheromas, thin-cap atheromas, and healed ruptures, and macrophage infiltration was assessed semiquantitatively.

Results—

Median serum homocysteine postmortem as a result of acute thrombus was 10.4 μmol/L (
P
=0.4 versus controls), 12.1 μmol/L in men with organized thrombi (
P
=0.1 versus controls), 15.6 μmol/L in men without thrombus (
P
=0.007 versus controls), and 9.8 μmol/L in controls. The median homocysteine was 12.1 μmol/L in 65 men with healed infarcts (
P
=0.03 versus controls). The number of fibrous plaques was associated with log-normalized homocysteine (
P
=0.004), independent of age, albumin, smoking, hypertension, and serum cholesterol. Homocysteine levels in the upper tertile (>15 μmol/L) were associated with sudden death without acute or organized thrombus (odds ratio 3.8,
P
=0.03) independent of age and other risk factors; the coexistence of diabetes increased the association (odds ratio 25.1,
P
=0.009, versus lowest tertile ≤8.5 μmol/L).

Conclusions—

Increased serum homocysteine is associated with sudden death in the absence of acute coronary thrombosis, especially with concomitant diabetes, and with the presence of lipid-poor, fibrous plaques.
Nonfasting Apolipoprotein B and Triglyceride Levels as a Useful Predictor of Coronary Heart Disease Risk in Middle-Aged UK Men
Authors: Talmud Philippa J. , Hawe Emma , Miller George J. , Humphries Steve E.
Published: November 2002

Objective—

The Apolipoprotein-related Mortality Risk (AMORIS) study concluded that the apolipoprotein (apo)B/apoA-I ratio was the best predictor of coronary heart disease (CHD) risk. We have compared the pairwise combinations of total cholesterol, triglycerides (TGs), apoB, high density lipoprotein (HDL) cholesterol, low density lipoprotein cholesterol, and apoA-I on CHD risk prediction in middle–aged men.

Methods and Results—

Healthy middle-aged men (n=2508), free of CHD at baseline, were examined prospectively. Over 6 years of follow-up, there were 163 CHD events (including acute myocardial infarction, coronary artery surgery, and ECG evidence of silent myocardial infarction). The relative risk (RR) of CHD associated with cholesterol, TGs, apoB, apoA-I, apoB/apoA-I, low density lipoprotein cholesterol, and HDL cholesterol were examined by survival analysis. The apoB/apoA-I ratio was associated with the strongest effect on the RR (3.58, 95% CI 2.08 to 6.19). In multivariate analysis, apoA-I had no significant effect on risk. Examining RR by quartiles, apoB and HDL in combination (RR 8.38, 95% CI 3.21 to 21.92) were better predictors of CHD risk than apoB and TGs (RR 4.05, 95% CI 1.57 to 6.23). However, apoB and TGs in combination added risk information over and above lifestyle factors, whereas apoB and HDL cholesterol did not.

Conclusions—

The combined evaluation of apoB with TGs provides useful diagnostic criteria for CHD risk.
Simvastatin Promotes Atherosclerotic Plaque Stability in ApoE-Deficient Mice Independently of Lipid Lowering
Authors: Bea Florian , Blessing Erwin , Bennett Brian , Levitz Michael , Wallace Elizabeth P. , Rosenfeld Michael E.
Published: November 2002

Objective—

This study sought to determine whether simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has stabilizing effects on vulnerable atherosclerotic plaques that are independent of their lipid-lowering capabilities.

Methods and Results—

Simvastatin (50 mg/kg per day) was administered to 30-week-old apolipoprotein E–deficient mice exhibiting advanced unstable atherosclerotic lesions within the innominate/brachiocephalic artery. Simvastatin was administered in the chow to separate groups of mice for 6, 12, 18, or 24 weeks. Simvastatin significantly increased serum cholesterol after 12, 18, and 24 weeks of treatment. The average cross-sectional area of atherosclerotic lesion increased in the innominate artery after 12 and 24 weeks of treatment, concomitant with the increase in serum cholesterol. However, histological analysis of sections of the innominate artery stained with Movat and von Kossa stains demonstrated a 49% reduction in the frequency of intraplaque hemorrhage and a 56% reduction in the frequency of calcification, both markers of advanced and unstable atherosclerotic plaques.

Conclusions—

These data suggest that despite an increase in serum cholesterol and lesion size, simvastatin has stabilizing effects on advanced atherosclerotic lesions.
Growth Factors Enhance Interleukin-1β-Induced Persistent Activation of Nuclear Factor-κB in Rat Vascular Smooth Muscle Cells
Authors: Jiang Bingbing , Xu Shanqin , Brecher Peter , Cohen Richard A.
Published: November 2002

Objective—

Activation of extracellular signal-regulated kinases (ERKs) is required for interleukin-1β to persistently activate nuclear factor (NF)-κB and concomitantly express inducible NO synthase (iNOS) in rat vascular smooth muscle cells (VSMCs). The present study examined whether platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) could influence the VSMC response to interleukin-1β via an ERK-related signaling pathway.

Methods and Results—

Treatment of VSMCs with PDGF or EGF alone potently induced ERK phosphorylation and DNA synthesis but did not induce NF-κB activation or iNOS expression. However, either PDGF or EGF markedly enhanced interleukin-1β-induced persistent NF-κB activation and iNOS expression but did not affect the early and transient NF-κB activation. Growth factor-induced DNA synthesis was attenuated in the presence of interleukin-1β. Inhibition of ERK phosphorylation with selective inhibitors (PD98059 or U0126) attenuated interleukin-1β-induced persistent NF-κB activation and iNOS expression in either the absence or presence of the growth factors.

Conclusions—

These results indicate that interleukin-1β-induced expression of NF-κB-dependent genes, such as iNOS, is potentiated in the presence of growth factors through a mechanism requiring ERK-dependent enhanced NF-κB activation, and the results also suggest that NF-κB activation is not required for PDGF or EGF to trigger DNA synthesis in VSMCs.
B-Lymphocyte Deficiency Increases Atherosclerosis in LDL Receptor–Null Mice
Authors: Major Amy S. , Fazio Sergio , Linton MacRae F.
Published: November 2002

Objective—

Atherosclerosis is an inflammatory disease characterized by innate and adaptive immune responses. We investigated the role of B cells and antibodies in the development of atherosclerosis in low density lipoprotein (LDL) receptor–deficient (LDLR
−/−
) mice.

Methods and Results—

Using wild-type and B cell–deficient mice as bone marrow donors, we were able to generate LDLR
−/−
mice that possessed <1.0% of their normal B cell population. B cell–deficient LDLR
−/−
mice on a Western diet showed marked decreases in total serum antibody and anti–oxidized LDL antibody. B cell deficiency was associated with a 30% to 40% increase in the lesion area in the proximal and distal aortas. Real-time reverse transcription–polymerase chain reaction and enzyme-linked immunospot analyses showed a decrease in proatherogenic (interferon-γ) and antiatherogenic (interleukin-10 and transforming growth factor-β) cytokine mRNA and a decrease in interleukin-4– and interferon-γ–producing cells. Additionally, we observed a decrease in splenocyte proliferation to oxidized LDL in the B cell–deficient LDLR
−/−
mice, suggesting that B lymphocytes may play a role in the presentation of lipid antigen.

Conclusions—

Collectively, these data demonstrate that B cells and/or antibodies are protective against atherosclerosis and that this protection may be conferred by B cell–mediated immune regulation.
The Atheroprotective Effect of Dietary Soy Isoflavones in Apolipoprotein E−/− Mice Requires the Presence of Estrogen Receptor-α
Authors: Adams Michael R. , Golden Deborah L. , Register Thomas C. , Anthony Mary S. , Hodgin Jeffrey B. , Maeda Nobuyo , Williams J. Koudy
Published: November 2002

Objective—Although the mechanisms by which dietary soy inhibits atherosclerosis are unclear, one line of evidence implicates an important role for its phytoestrogenic isoflavones. We sought to determine whether soy isoflavones exert atheroprotective effects through estrogen receptor–dependent processes and, if so, which estrogen receptor subtype (ie, α or β) is involved.

Methods and Results—We compared the effects of diets rich in soy protein that were either isoflavone depleted (0.04 mg/g protein isolate) or isoflavone-replete, or Soy(+IF) (1.72 mg/g protein isolate) in apolipoprotein E–deficient (ee) mice that had been crossed with estrogen receptor-α– and -β–deficient mice to produce double-knockout ααeeand ββeemice and (estrogen receptor) wild-type controls (AAeeand BBee). Both male and ovariectomized female mice were studied (n=10 to 17 per treatment group; total n=201). After 16 weeks, atherosclerosis was assessed by quantifying the aortic content of esterified cholesterol. Atherosclerosis was reduced 20% to 27% (P<0.05) by Soy(+IF) in ββee, BBee, and AAeemice but was unaffected in ααeemice. The inhibitory effect of Soy(+IF) was unrelated to sex, total plasma cholesterol, VLDL, LDL, and HDL cholesterol.

Conclusions—The results indicate a necessary role for estrogen receptor-α–dependent processes in mediating the atheroprotective effects of dietary soy isoflavones.
PRESERVING BODIES, SAVING SOULS: RELIGIOUS INCONGRUITY IN A NORTHERN MALAGASY MINING TOWN
Authors: Walsh Andrew
Published: November 2002

This article discusses the manifestation of incongruent religious ideals in a northern Malagasy sapphire mining community. It focuses particularly on how members of an Evangelical Christian congregation and long-time resident animists of the place interpret one another's practices, and on how these interpretations reflect a fundamental disparity in how they understand the material world that they share. It argues that the conflict that has emerged between them can only be understood in light of this significant disparity.
Assessing the effect of deep inhalation on airway calibre: a novel approach to lung function in bronchial asthma and COPD
Authors: Pellegrino R , Sterk PJ , Sont JK , Brusasco V
Published: November 2002

Bronchoconstriction in bronchial asthma and chronic obstructive pulmonary disease (COPD) may be due to decreased airway calibre and/or to the inability of the airways to distend after a deep inhalation (DI). The purpose of this review is to discuss the physiological and clinical relevance of this latter mechanism. During induced constriction, DI shows remarkable bronchodilatation in normal subjects, but a blunted or null effect in asthmatics. In contrast, during spontaneous bronchospasm DI tends to decrease airway calibre. From a functional point of view, airway inflammation, remodelling, and peripheral bronchoconstriction could prevent airway smooth muscle from stretching. Therapeutic intervention improving lung function may change the response to DI. For example, bronchodilators allow expiratory airflow before DI to increase more than after DI, because of decreased bronchial hysteresis. This suggest that bronchodilation might be systematically underestimated from parameters derived from maximal expiratory manoeuvres. Inhaled corticosteroids tend to increase the dilator effect of DI, likely due to decreased bronchial and peribronchial oedema. In conclusion, measuring the effects of deep inhalation on lung function is an easy and simple test able to evaluate the structural changes occurring in the airways and to monitor the effectiveness of therapy.
Benefits at 3 yrs of an asthma education programme coupled with regular reinforcement
Authors: Ignacio-García J-M. , Pinto-Tenorio M. , Chocrón-Giraldez M.J. , Cabello-Rueda F. , López-Cozar Gil A.I. , Ignacio-García J-M. , de Ramón-Garrido E.
Published: November 2002

The benefits at 3 yrs of an asthma self-management education programme coupled with educational reinforcement were assessed at follow-up visits in 63 adults with chronic asthma.

Changes in asthma-related morbidity parameters, lung function and use of different classes of drugs before intervention and after 1, 2 and 3 yrs of the asthma education programme were compared using Friedman one-way analysis of variance.

Improvements in the number of days off work or school, general practitioner consultations, admissions to emergency services, hospital admissions and nocturnal awakenings, as well as increases in forced expiratory volume in one second (FEV1), were significant. Comparison of data obtained at 1 yr and 2–3 yrs showed significant differences in the number of asthma-associated sleep disruptions, days off work or school and unscheduled visits to the general practitioner, as well as FEV1, but significant differences between the data obtained at 2 and 3 yrs were not observed. The percentage of patients using oral steroids had decreased significantly at 3 yrs.

In adults with chronic asthma, an asthma self-management education programme coupled with educational reinforcement was effective at decreasing asthma morbidity, improving lung function and decreasing consumption of oral steroids.
The anti-IgE antibody omalizumab improves asthma-related quality of life in patients with allergic asthma
Authors: Buhl R. , Hanf G. , Solèr M. , Bensch G. , Wolfe J. , Everhard F. , Champain K. , Fox H. , Thirlwell J.
Published: November 2002

The aim of the present study was to determine the effect of treatment with omalizumab, an anti-immunoglobulin E antibody, on asthma-related quality of life (AQoL) in patients with moderate-to-severe allergic asthma.

A total of 546 patients with allergic asthma were randomised to double-blind subcutaneous treatment with either placebo or omalizumab for 52 weeks. A constant beclomethasone dipropionate dose was maintained during the first 16 weeks (steroid-stable phase). This was followed by a 12-week steroid-reduction phase. The core study was followed by a 24-week double-blind extension phase. AQoL was evaluated at baseline and at the end of the steroid-stable (week 16), steroid-reduction (week 28) and extension phases (week 52) using the Juniper Asthma Quality of Life Questionnaire (AQLQ).

Baseline AQLQ scores were comparable for the two treatment groups. Relative to placebo, omalizumab-treated patients demonstrated statistically significant improvements from baseline across all four AQLQ domains, as well as overall AQoL score, at weeks 16 (except environmental exposure), 28 and 52. Patients on omalizumab were also more likely to achieve clinically significant improvements in AQoL during the course of the study. Overall, almost 70% of patients and investigators rated treatment with omalizumab as “excellent/good”, compared with ∼40% of placebo recipients.

Clinical studies show that omalizumab enhances disease control whilst reducing corticosteroid consumption in patients with allergic asthma. The results of the present study show that these changes are paralleled by improvements in asthma-related quality of life that are meaningful to such patients.
Single-cell analysis: a novel approach to tumour necrosis factor-α synthesis and secretion in sarcoidosis
Authors: Pantelidis P. , McGrath D.S. , Southcott A.M. , du Bois R.M.
Published: November 2002

Tumour necrosis factor (TNF)-α is thought to be a key early cytokine in the pathogenesis of sarcoidosis, despite conflicting data. Largely the product of mononuclear phagocyte activation, it is unclear whether TNF-α production at disease sites is a feature of all mononuclear phagocytes that accumulate there or whether it is secreted by a subset of these cells. Using the reverse haemolytic plaque assay, the aims of this study were to determine if the upregulation of TNF-α could be confirmed and to investigate whether this was monocyte or macrophage specific. The reverse haemolytic plaque assay allows the measurement of cytokine production at a single cell level.

A greater number of alveolar macrophages produced TNF-α compared to autologous monocytes in sarcoidosis but not in controls and, based on cell size, it was confirmed that this was the product of more mature macrophages and that the secretion of TNF-α by monocytes and macrophages was heterogeneous: not all monocytes and macrophages secrete TNF-α. No differences in the average levels of TNF-α secretion by peripheral blood monocytes or alveolar macrophages were observed.

This study has demonstrated that a subset of mononuclear phagocytes, mature macrophages, are responsible for tumour necrosis factor secretion and this could have implications for targeted management in sarcoidosis in the future.
Nerve growth factor levels and localisation in human asthmatic bronchi
Authors: Olgart Höglund C. , de Blay F. , Oster J-P. , Duvernelle C. , Kassel O. , Pauli G. , Frossard N.
Published: November 2002

Nerve growth factor (NGF) has recently been suggested to be an important mediator of inflammation. In support of this, serum levels of NGF have been shown to be enhanced in asthmatics. However, it has not yet been shown whether the levels of NGF are also altered locally in asthmatic airways, when compared with healthy subjects, and the localisation of potential sources of NGF in the human bronchus have not yet been described. The aim of the present study was to assess NGF levels in bronchoalveolar lavage fluid (BALF) from asthmatics and to compare them to those of control subjects. Furthermore, the authors wanted to localise potential sources of NGF in bronchial tissue, and to number NGF-immunopositive infiltrating cells in the bronchial submucosa.

BALF and bronchial biopsies were obtained from seven control subjects and seven asthmatic patients by fibreoptic bronchoscopy. NGF protein levels were quantified by enzyme-linked immunosorbent assay in BALF. NGF localisation was examined by immunohistochemistry on bronchial biopsy sections.

The asthmatics exhibited significantly enhanced NGF levels in BALF. Intense NGF-immunoreactivity was observed in bronchial epithelium, smooth muscle cells and infiltrating inflammatory cells in the submucosa, and to a lesser extent in the connective tissue. The asthmatics exhibited a higher number of NGF-immunoreactive infiltrating cells in the bronchial submucosa than control subjects.

This study provides evidence that nerve growth factor is locally produced in the airways, and shows that this production is enhanced in asthmatics. These findings suggest that nerve growth factor is produced by both structural cells and infiltrating inflammatory cells in human bronchusin vivo, and the authors suggest that the increase in nerve growth factor protein in bronchoalveolar lavage fluid observed in asthmatic patients may originate both from structural cells, producing increased nerve growth factor levels in inflammatory conditons, and from the increase in nerve growth factor-immunopositive cells determined in the bronchial submucosa.
Asbestos bodies in the sputum of asbestos workers: correlation with occupational exposure
Authors: Paris C. , Galateau-Salle F. , Creveuil C. , Morello R. , Raffaelli C. , Gillon J.C. , Billon-Galland M.A. , Pairon J.C. , Chevreau L. , Letourneux M.
Published: November 2002

A cross-sectional medical survey including collection of three consecutive sputum samples was carried out among 270 retired workers of a textile and friction materials factory, in order to investigate the relationship between asbestos body identification and asbestos exposure.

The individual cumulative asbestos exposure, determined by means of a plant-specific job-exposure matrix based on asbestos air measurements in the workshops, proved to be heavy with a mean cumulative exposure of 217 fibres·mL−1×yr. Macrophages and asbestos bodies were identified in sputum samples by light microscopy.

The lung origin of the sputum, suggested by the presence of macrophages and/or asbestos bodies, was confirmed in 82.6% of subjects, and 53% of these samples were positive for asbestos bodies. The prevalence of asbestos bodies was not related to sex, smoking status or latency. Conversely, multivariate analysis showed a positive relationship with cumulative exposure, duration and intensity of exposure to asbestos, as well as age and time since retirement.

These findings suggest that sputum analysis for asbestos bodies may remain a relevant and noninvasive marker of heavy occupational exposure to asbestos, even years after retirement. Owing to the new perspectives in lung cancer screening, it might contribute to the identification of high-risk subjects.
Murine gammaherpes virus as a cofactor in the development of pulmonary fibrosis in bleomycin resistant mice
Authors: Lok S.S. , Haider Y. , Howell D. , Stewart J.P. , Hasleton P.S. , Egan J.J.
Published: November 2002

Studies of human tissue have suggested an association between productive Epstein Barr virus and idiopathic pulmonary fibrosis (IPF). However, a pathogenic role for the virus has not been established. This study was undertaken to develop an animal model, which would explore the association between viral infection and pulmonary fibrosis.

BALB/c mice (n=30), resistant to bleomycin, were primed with murine gammaherpesvirus 68 and then given intraperitoneal bleomycin. The mice were sacrificed at 28 days after bleomycin and their lungs assessed histologically and biochemically. Lung pathology was scored 0–3 for fibrotic and inflammatory change.

BALB/c mice given virus and bleomycin showed more lung fibrosis (median score 2.2) compared to those given bleomycin alone (median 0), virus alone (median 0.2) or phosphate-buffered saline (PBS) control (median 0). Similarly mice given both virus and bleomycin showed more lung inflammation (median score 1.9) compared to those given bleomycin (median 0.5), virus (median 0.8), or PBS control (median 0.2). There was a significant difference in collagen content between the bleomycin and virus group (mean 1.86 mg) compared to the belomycin alone group (mean 1.52 mg).

These results suggest that virus alone does not result in pulmonary fibrosis but that replicating virus in the presence of an exogenous injury may promote the development of pulmonary fibrosis.
Dose reduction of inhaled corticosteroids under concomitant medication with montelukast in patients with asthma
Authors: Kanniess F. , Richter K. , Janicki S. , Schleiss M.B. , Jörres R.A. , Magnussen H.
Published: November 2002

The present study aimed at comparing the effects of a dose reduction of inhaled corticosteroids on lung function, indirect measures of airway inflammation and clinical scores during treatment with a leucotriene receptor antagonist.

In 50 patients (mean forced expiratory volume in one second (FEV1) 94% predicted), steroid doses (800 µg beclomethasone dipropionate) were first reduced to 50% and then to 25%, for 6 weeks each. One group received a placebo and the other group received montelukast (10 mg).

The first reduction did not cause significant effects. During the second, FEV1and peak expiratory flow decreased in both groups (p<0.001). Daytime symptoms were not altered with placebo but were reduced by montelukast (p<0.05). Night-time symptoms were slightly elevated with placebo (p<0.05) but not montelukast, as well as the use of supplemental salbutamol. Changes in provocative concentration of methacholine causing a 20% fall in FEV1(PC20), sputum eosinophils and exhaled nitric oxide were mostly nonsignificant for both placebo and montelukast.

These data demonstrate that a 75% reduction in the dose of steroid given to patients with asthma led to a deterioration in lung function not prevented by montelukast, whereas changes in clinical state seemed to favour montelukast treatment. It therefore appears that potential effects of montelukast, in the presence of low-dose steroids, could not be attributed to single indices of lung function or airway inflammation.
Factors associated with unknown aetiology in patients with community-acquired pneumonia
Authors: Ewig S. , Torres A. , Ángeles Marcos M. , Angrill J. , Rañó A. , de Roux A. , Mensa J. , Martínez J.A. , de la Bellacasa J.P. , Bauer T.
Published: November 2002

Despite comprehensive diagnostic work-up, the aetiology of community-acquired pneumonia (CAP) remains undetermined in 30–60% of cases. The authors studied factors associated with undiagnosed pneumonia.

Patients hospitalised with CAP and being evaluated by two blood cultures, at least one valid lower respiratory tract sample, and serology on admission were prospectively recorded. Patients who had received antimicrobial pretreatment were excluded. Patients with definite or probable aetiology were compared to those with undetermined aetiology by uni- and multivariable analysis.

A total 204 patients were eligible for the study. The aetiology remained undetermined in 82 (40%) patients, whereas a definite aetiology could be established in 89 (44%) and a probable one in 33 (16%). In multivariable analysis, factors associated with undetermined aetiology included age >70 yrs, renal and cardiac comorbidity, and nonalveolar infiltrates on the chest radiograph. There was no association of undiagnosed pneumonia with mortality.

Age and host factors were associated with unknown aetiology of community-acquired pneumonia. Some of these cases may also represent fluid volume overload mimicking pneumonia.
Serum levels of CC16, SP-A and SP-B reflect tobacco-smoke exposure in asymptomatic subjects
Authors: Robin M. , Dong P. , Hermans C. , Bernard A. , Bersten A.D. , Doyle I.R.
Published: November 2002

Since the 16-kDa bronchiolar Clara cell protein (CC16) and the alveolar surfactant-associated proteins (SP)-A and -B leak into the circulation when parenchymal health is disturbed, the aim of this study was to determine whether their serum levels could serve as early peripheral markers of tobacco smoke-induced epithelial injury.

Sixty-nine (51 yrs (32–54) median (25–75th percentile)) nonsmokers and 54 (42 yrs (31–53)) asymptomatic smokers were enrolled in the study.

Serum levels of SP-A did not differ between subjects (270 (208–389)versus259 (168–392) µg·L−1), however, CC16 levels decreased (10.6 (8.7–14.6)versus7.6 (6.0–11.2) µg·L−1) and SP-B levels increased (2,529 (2,091–2,943)versus3,053 (2,613–4,188) µg·L−1) in the smokers. When tobacco smoke exposure, serum creatinine (renal index), age and sex were used as independent variables, CC16 was negatively influenced by cumulative smoking and positively influenced by age. SP-A and -B were negatively influenced by creatinine and positively influenced by cumulative smoking. Serum SP-B was inversely correlated with forced expiratory volume in one second/vital capacity, suggesting an association between obstructive disease and parenchymal lung health.

The authors suggest that serum surfactant-associated proteins-A and -B reflect increased alveolocapillary leakage whereas Clara cell secretory protein 16 reflects tobacco smoke-induced Clara cell toxicity. Their evaluation may allow the effects of tobacco smoke on different levels of the respiratory tract, cellular toxicity and epithelial leakage to be distinguished.
Measurement of overinflation by multiple linear regression analysis in patients with acute lung injury
Authors: Bersten AD
Published: November 2002

Strategies to optimize alveolar recruitment and prevent lung overinflation are central to ventilatory management of patients with acute lung injury (ALI). The recent description of overinflation using multilinear regression analysis of airway pressure (Paw) and flow (V') data allows a functional assessment of lung mechanics. However, this technique has not been studied in ALI patients. During 15 positive end-expiratory pressure (PEEP) trials in 10 ALI patients, respiratory elastance was partitioned into volume-independent (E1) and volume-dependent (E2VT) components, where Paw=(E1+E2VT)V+RrsV'+Po; where V is volume, VT is tidal volume, Rrs is respiratory resistance and Po is static recoil pressure at end-expiration (equivalent to total PEEP). Then, %E2 was calculated as (100E2VT)/(E1+E2VT); a measure of lung overinflation when %E2>30%. Alveolar recruitment, assessed as a PEEP-induced increase in V>50 mL at a constant Paw occurred in 14 of 15 trials (299+/-34 mL, mean+/-SEM), but was independent of the degree of lung inflation. Lung overinflation was common (six of 15 clinically set PEEP levels) and occurred despite a dynamic elastic distending pressure (Pel,dyn) <30 cmH2O during 18 of 36 PEEP titrations. During a PEEP titration the resultant %E2 was directly related to delta(peak airway pressure-Po) (rs=0.86, p<0.001) and delta(Pel,dyn-Po) (rs=0.89, p<0.001). The 95% predictive intervals for a 2 cmH2O change in either driving pressure were %E2 values of 30.4-68.1% and 32.8-69.2%, respectively. Single or continuous measurement of %E2 (a measure of lung inflation) is a readily available method for titrating ventilatory parameters. Further, during a positive end-expiratory pressure titration a change in ventilatory driving pressure > or =2 cmH2O is indicative of overinflation.
Efficacy of Curosurf in a rat model of acute respiratory distress syndrome
Authors: van Helden HP , Kuijpers WC , Langerwerf PE , Langen RC , Haagsman HP , Bruijnzeel PL
Published: November 2002

Curosurf, a natural lung surfactant, is considered a potential candidate for improving the treatment of acute respiratory distress syndrome (ARDS). To investigate this in a rat model of early-stage ARDS, Curosurf (62.5, 125 or 250 mg x kg(-1)) was administered by intratracheal bolus at 10 or 24 h following an intratracheal lipopolysaccharide (LPS; 1.6 mg x kg(-1)) challenge. Survival, respiratory frequency (fR), lung wet weight (LWW), total protein and cell differentiation in bronchoalveolar lavage fluid (BALF) were assessed. Curosurf treatment at 10 h after LPS challenge resulted in 100% survival at both 62.5 and 125 mg x kg(-1); at a dose of 250 mg x kg(-1) administered at 10 h after LPS, 1 out of 6 animals died. At a dose of 125 mg x kg(-1) Curosurf administered at 24 h after LPS, 1 out of 6 animals died. In contrast, only 35% of animals survived when not treated with Curosurf. Curosurf treatment resulted in an improved fR and in a significantly decreased LWW, total protein and number of polymorphonuclear cells in BALF. In conclusion, Curosurf treatment improved respiratory frequency and decreased mortality, pulmonary oedema and inflammation. As the decreased mortality was observed in spontaneously breathing nonoxygenated animals, the results cannot be extrapolated to human artificially ventilated acute respiratory distress syndrome patients with the expectation of a decreased mortality. The results suggest, however, that Curosurf may be an important therapeutic measure in early-stage acute respiratory distress syndrome.
Elevation of specific immunoglobulin A antibodies to both allergen and bacterial antigen in induced sputum from asthmatics
Authors: Nahm DH , Kim HY , Park HS
Published: November 2002

The antigenic specificity and pathogenetic significance of immunoglobulins in airway secretion from asthmatic patients have not been established. Elevated levels of B-cells and immunoglobulin (Ig)A antibodies have been reported in sputum of asthmatics and these levels correlated with the eosinophil counts and levels of degranulated cytotoxic proteins from eosinophils. This study aimed to investigate the antigen specificity and possible pathogenetic significance of antibodies in airway secretion from asthmatic patients. Specific IgA and IgG antibodies to both allergen (Dermatophagoides farinae) and bacterial antigen (capsular polysaccharide antigen from Streptococcus pneumoniae) were measured in sputum from 16 atopic asthmatic patients sensitized to D. farinae and 12 nonatopic, nonasthmatic controls by enzyme-linked immunosorbent assay. Sputum was induced by inhalation of hypertonic saline. Eosinophil cationic protein (ECP) levels in sputum from asthmatic patients were measured by the Pharmacia CAP system. Levels of IgA to both D. farinae and S. pneumoniae and IgG to D. farinae in the sputum from asthmatic patients were significantly higher than those from controls (p<0.005). No significant difference was found in the levels of IgG to S. pneumoniae between the two groups. In asthmatic patients, there were significant correlations between IgA to D. farinae and S. pneumoniae (r=0.76, p=0.003). Sputum ECP levels correlated significantly with IgA to D. farinae (r=0.55, p=0.03) and S. pneumoniae (r=0.56, p=0.03) and IgG to D. farinae (r=0.52, p=0.04), but not with IgG to S. pneumoniae in asthmatic patients. In conclusion, specific immunoglobulin A antibodies to both allergen and bacterial antigen were elevated in induced sputum from atopic asthmatics and their possible involvement in eosinophil degranulation was suggested.
Sputum eosinophilia is more closely associated with airway responsiveness to bradykinin than methacholine in asthma
Authors: Polosa R , Renaud L , Cacciola R , Prosperini G , Crimi N , Djukanovic R
Published: November 2002

Hyperresponsiveness of the airways to various spasmogenic stimuli is a characteristic feature of bronchial asthma. However, the association between the different stimuli to which asthmatic airways are hyperresponsive and airways inflammation is not completely understood. We have investigated the relationship between airway inflammation and airway hyperresponsiveness in asthma, as assessed by bronchoprovocation tests to methacholine and bradykinin, two well defined bronchoconstrictor agonists. Sputum induction by hypertonic saline and methacholine and bradykinin challenges were performed in 14 nonsmoking subjects with mild-to-moderate asthma. Airway responsiveness to either agonist did not correlate with sputum neutrophils, lymphocytes, and macrophages. Whilst the absolute number of eosinophilia failed to be significantly related to methacholine responsiveness (r=-0.47; p=0.09), it correlated markedly and significantly with provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (r=0.72; p<0.01). When expressed as % of total cell counts, sputum eosinophils correlated with both types of responsiveness (r=-056; p=0.04 and r=-0.76, p<0.001, respectively). Although the concentration of eosinophil cationic protein (ECP) in the sputum correlated with the absolute numbers of eosinophils (r=0.62; p<0.02), no correlation was found between ECP levels and the airway responsiveness to any of the agonists tested. In subjects with mild-to-moderate asthma, airway responsiveness to bradykinin is more strongly associated with the magnitude of eosinophilic inflammation in the airways than methacholine. This finding underlines the selectivity of diverse agonists in assessing airway hyperresponsiveness and cellular inflammation in asthma.
Characteristics of asthma in the elderly
Authors: Weiner P , Magadle R , Waizman J , Weiner M , Rabner M , Zamir D
Published: November 2002

Asthma occurs more frequently in the elderly than is usually appreciated and may, therefore, be underdiagnosed and undertreated. This study evaluated the relationship between asthma symptoms and the degree of airflow obstruction in elderly and young asthmatics. Fifteen young asthmatics (<65 yrs) (group A), 15 aged >65 yrs with onset of symptoms before 65 yrs (group B), and 15 aged >65 yrs with onset of symptoms after 65 yrs (group C), were studied. Patients used daily diary cards, during 2 weeks, to record inhaled beta2-agonist consumption and severity of asthma symptoms. Long-standing asthma was associated with a significantly lower forced expiratory volume in one second as compared with recent onset asthma. The asthma-symptom score was highest in group A, lower in group B and significantly lower in group C. When symptoms were related to the degree of obstruction (asthma index), it was higher in the young asthmatics than in both groups of elderly patients. In conclusion, elderly patients with long-standing asthma had more severe airway obstruction than patients with recently acquired disease. Older patients particularly those with long-standing disease complained less about asthma symptoms. Within the various groups of patients, subjective symptoms of asthma were negatively related to asthma duration.
Four years' experience of intravenous colomycin in an adult cystic fibrosis unit
Authors: Ledson MJ , Gallagher MJ , Cowperthwaite C , Convery RP , Walshaw MJ
Published: November 2002

Nearly all strains of Pseudomonas aeruginosa are sensitive to colomycin sulphomethate, but studies in the 1970s using large doses demonstrated significant renal and neurotoxic side-effects and it is not now commonly used. In this study colomycin (2 megaunits i.v. t.d.s.) has been used extensively in adult cystic fibrosis (CF) patients and its use reviewed to determine its efficacy and safety profile. Fifty-two CF patients (28 male, 24 female; mean age 26 yrs, range 17-39 yrs) received 135 courses (mean two courses each, range 1-7, median length 14 days) of i.v. colomycin (2,414 patient days in total). It was used in combination with one other i.v. antibiotic in 114 courses (85%) and with two others in 18 (13%). In all cases there was significant improvement in spirometry (pretreatment forced expiratory volume in one second (FEV1) % predicted mean 44.4, range 10-101; post-treatment mean 51.3, range 14-108; p<0.0001). No patient had any neurotoxicity but one developed a skin rash and myositis. There was no change in renal function (urea mean pretreatment 4.1 mmol x L(-1) (sD 1.4), mean post-treatment 43 (2.2), p=NS; creatinine mean pretreatment 77.9 mmol x L(-1) (15.3), mean post-treatment 803 (21.6), p=NS). In the authors' experience intravenous colomycin sulphomethate in moderate doses is an effective and safe antipseudomonal antibiotic which is easy to administer. Other clinicians should consider its use in patients with cystic fibrosis.
Leukocyte counts and macrophage phenotypes in induced sputum and bronchoalveolar lavage fluid from normal subjects
Authors: Lensmar C , Elmberger G , Sandgren P , Skold CM , Eklund A
Published: November 2002

It is unclear whether leukocytes in induced sputum (IS) and bronchoalveolar lavage (BAL) represent the same cell populations. To compare leukocyte counts and macrophage phenotypes and investigate any measurable dithiothreitol (DTT)-mediated effect on macrophage immunocytochemical staining results, IS and BAL samples from nine healthy smokers and seven nonsmokers were examined. BAL and IS samples were processed and cell viability and cell counts were assessed. The macrophages were characterized by seven monoclonal antibodies (RFD1, RFD7, CD11b, CD54, CD68, CD71 and HLA-DR) using an indirect immunoalkaline phosphatase method. Intraindividual comparison of IS and BAL showed that IS samples from smokers and nonsmokers contained a lower total cell count (p<0.01 smokers, p<0.05 nonsmokers), a lower percentage of macrophages (both p<0.05) and a higher percentage of neutrophils (both p<0.05) than BAL samples. In addition, nonsmokers sputum samples contained a lower proportion of lymphocytes (p<0.05) than BAL. The macrophage expression of RFD7 and CD71 was higher in smokers sputum samples (both p<0.05) than in BAL, while nonsmokers sputum macrophages showed a higher expression of CD54 and CD71 (both p<0.05) than BAL macrophages. DTT-incubated BAL samples showed no difference in macrophage antigen expression from BAL samples not exposed to DTT. In conclusion, the relative proportions of leukocytes and the macrophage phenotypes differed between induced sputum and bronchoalveolar lavage suggesting that the methods provide samples from different lung compartments, inhabited by cells with different phenotypes.
Effects of alkaline protease or restrictocin deficient mutants of Aspergillus fumigatus on human polymorphonuclear leukocytes
Authors: Ikegami Y , Amitani R , Murayama T , Nawada R , Lee WJ , Kawanami R , Kuze F
Published: November 2002

Several substances including proteases and restrictocin have been suggested as candidates for virulence determinants in invasive pulmonary aspergillosis. However, the roles of such substances are not well understood. This study compared the in vitro suppressive effects of Aspergillus fumigatus culture filtrates (ACFs), on the functions of human polymorphonuclear leukocytes (PMNLs), the principal cells in the host defence against aspergillus hyphae, from a clinically isolated wild-type and isogenic mutant strains which lack production of elastolytic alkaline protease (Alp) and/or restrictocin. ACFs were obtained by culturing conidia of each strain in Medium- 199 at 37 degrees C for 5 days. ACFs of the wild-type significantly (p<0.01) suppressed chemotaxis, superoxide anion (O2-) release and PMNL-mediated hyphal damage, compared with the control (Medium-199). ACFs of the mutant strains that lack Alp or restrictocin significantly (p<0.01) suppressed chemotaxis and O2(-)-release, but did not suppress hyphal damage, compared with the control. The wild-type significantly (p<0.01) suppressed chemotaxis of PMNLs compared with the mutant strains lacking Alp or restrictocin, whereas there were no significant differences in suppression of O2(-)-release and hyphal damage by PMNLs. ACF of a mutant strain that lacks both Alp and restrictocin had much less activity, but significantly (p<0.01) suppressed chemotaxis of PMNLs compared with the control. In conclusion, alkaline protease and restrictocin may play roles in the suppressive effect of Aspergillus fumigatus culture filtrates on the functions of human polymorphonuclear leukocytes. Other antiphagocytic substances produced by Aspergillus fumigatus remain to be identified.