bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammation, Homocysteine, and Vitamin B6 Status After Ischemic Stroke
Authors: Kelly P.J. , Kistler J.P. , Shih V.E. , Mandell R. , Atassi N. , Barron M. , Lee H. , Silveira S. , Furie K.L.
Published: December 2003

Background and Purpose—

Epidemiological studies have described an association between low vitamin B6 (measured as pyridoxal 5′-phosphate [PLP]) and ischemic stroke, independent of homocysteine (tHcy). We investigated B6 status, tHcy, and inflammation (measured by C-reactive protein [CRP]) in patients with stroke and controls.

Methods—

Consecutive cases with new ischemic stroke were compared with matched controls. Fasting tHcy, PLP, and CRP were measured.

Results—

The adjusted odds ratio of low PLP in the highest compared with the lowest CRP quartile was 16.6 (2, 139.9,
P
=0.01). Age, CRP, supplemental vitamin use, and albumin were independent predictors of PLP (
P
<0.05 for all). No relationship was observed between CRP and tHcy.

Conclusion—

The relationship between inflammation and low B6 status may partially explain the findings of previous epidemiological studies.
Risk Factors for First-Ever Stroke in Older People in the North East of England
Authors: Rodgers Helen , Greenaway Jane , Davies Tina , Wood Ruth , Steen Nicholas , Thomson Richard
Published: December 2003

Background and Purpose—

Although older people potentially have most to gain from prevention, they have been excluded from or underrepresented in many stroke incidence studies. We sought to determine the risk factors for stroke in older people.

Methods—

A 5-year follow-up study of a population-based cohort of 4440 subjects aged >65 years in northern England. Subjects were recruited from 27 general practices between 1995 and 1997.

Results—

A total of 329 out of 4351 subjects with follow-up data suffered a first-ever stroke. On multivariate analysis, risk factors for stroke in older people included atrial fibrillation (hazard ratio [HR], 2.03 [95%CI, 1.31 to 3.16]); previous transient ischemic attack (1.87 [95% CI, 1.27 to 2.76]); smoking (1.72 [95% CI ,1.28 to 2.32]); and cardiovascular disease (1.55 [95% CI, 1.19 to 2.03]). The HR per 10-mm Hg increase in systolic blood pressure was 1.15 (95% CI, 1.06 to 1.24). Age was associated with a HR of 1.74 (95% CI, 1.42 to 2.12) per 10-year increase.

Conclusions—

“Classic risk factors” increase the risk of stroke in older people. Stroke is not an inevitable consequence of aging, so by identifying and modifying risk factors in older people there are opportunities to reduce the incidence and mortality of this devastating condition.
Mechanical properties of friction stir welded joints of 1050 – H24 aluminium alloy
Authors: Liu H. J. , Fujii H. , Maeda M. , Nogi K.
Published: December 2003

The friction stir welding (FSW) of 1050 - H24 aluminium alloy was performed to investigate the mechanical properties of the joints and determine the optimum FSW parameters. The mechanical properties of the joints were evaluated via tensile tests. The experimental results showed that a distinct softened region located at the weld and heat affected zones occurred in the joints. The degree of softening and tensile properties of the joints are significantly affected by the welding process parameters, such as welding speed and rotation speed. The optimum FSW parameters can be determined from the relations between the tensile properties and the welding parameters, and the maximum tensile strength of the joints is equivalent to 80% of that of the base material. When the welding parameters deviate from the optimum values, a crack like defect or significant softening is produced in the joints, thus the tensile properties of the joints deteriorate and the fracture locations of the joints change. All these results can be explained by the hardness distributions and welding defects in the joints.
Prediction of cooling rate and microstructure in laser spot welds
Authors: De A. , Walsh C. A. , Maiti S. K. , Bhadeshia H. K. D. H.
Published: December 2003

Theoretical and experimental investigations have been carried out to examine the influence of laser power and on time on the weld thermal cycle and weld metal microstructure and hardness during laser spot welding of low alloy steel. A transient heat transfer model that takes into account the temperature dependence of material properties and latent heat of phase transformation is employed to simulate thermal cycles and cooling rates experienced by the material under various combinations of power and on times. Two models for predicting the microstructure and hardness of the weld pool metal from the cooling rates are used to evaluate the results.
Monitoring of expulsion in small scale resistance spot welding
Authors: Farson D. F. , Chen J. Z. , Ely K. , Frech T.
Published: December 2003

Although there have been many investigations into monitoring and control of resistance spot welding (RSW) of sheet metal having a thickness greater than 0.5 mm, that of thinner components has rarely been investigated. Monitoring of expulsion in a small scale RSW process was carried out via measurement of voltage, electrode displacement, and force change during the welding current pulse. It was found that electrode displacement increased steadily during the current pulse for an expulsion free weld. For welds with visible expulsion, the electrode voltage had a small but readily observed spike; the electrode displacement showed a dip or a decrease in total amplitude; the force change during a welding cycle was of greater magnitude. Since the system uses a constant current power supply, the voltage increase corresponds to an increase in dynamic resistance associated with the expulsion event. It was also observed that the magnitude of the electrode displacement dip was directly related to the volume of expelled material. The force change is a relatively sensitive indicator for use in expulsion detection. Of the three signals, detection of the voltage spike is the most readily implemented method for monitoring expulsion in small scale RSW. It was also shown that, owing to the small magnitudes of the forces and displacements, careful design of the welding system is necessary to ensure that unwanted vibrations do not interfere with the process signals.
MEK1,2 response element mediates angiotensin II—stimulated plasminogen activator inhibitor-1 promoter activation
Authors: Chen Hong-Chi , Feener Edward P.
Published: December 2003

The MEK1,2 (MAPK/ERK kinase 1 and 2) pathway mediates the up-regulation of plasminogen activator inhibitor-1 (PAI-1) expression in vascular smooth muscle cells by a variety of hormones, including angiotensin II. Transfection of constitutively active MEKK-1, an upstream activator of the mitogen-activated protein (MAP) kinase pathways, was used to isolate an enhancer element located between -89 and -50 bp in PAI-1 promoter that was activated by MEKK-1 and selectively blocked by the MEK1,2 inhibitor PD98059. Mutational analysis revealed that the MEKK-1 response element (MRE) contained 2 cis-acting Sp1- and AP-1—like sequences, located between -75 to -70 and -63 to -52 bp, respectively. Overexpression of Sp1 enhanced MEKK-1—induced MRE promoter activity and a dominant-negative c-Fos blocked this Sp1 response. The combination of Sp1 and c-Jun or c-Fos was required to activate this MRE. Angiotensin II (Ang II) stimulation increased c-Fos, c-Jun, and Sp1 binding to the MRE by 100-, 4.9-, and 1.9-fold, respectively, and these responses were inhibited by PD98059 and AT1 receptor antagonist candesartan. Intravenous Ang II infusion in rats increased aortic c-Fos binding to the MRE. This MRE sequence mediated a 4-fold increase of MEK1,2-dependent PAI-1/luciferase mRNA expression by angiotensin II stimulation. This report identifies the MEK1,2 response element that mediates angiotensin II—stimulated PAI-1 promoter activation and shows that activation of this element requires Sp1 and AP-1 co-activation.
BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone
Authors: Moreaux Jérôme , Legouffe Eric , Jourdan Eric , Quittet Philippe , Rème Thierry , Lugagne Cécile , Moine Philippe , Rossi Jean-François , Klein Bernard , Tarte Karin
Published: December 2003

Identification of growth factors in neoplasias may be a target for future therapies by blocking either growth factor receptor interaction or the induced pathway. Using gene expression profiling, we identified overexpression of 2 receptors for a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) in malignant plasma cells compared with normal plasma cells. APRIL and BAFF are involved in a variety of tumor and autoimmune diseases, including B-cell malignancies. We confirmed the expression of BAFF and APRIL receptors (B-cell maturation antigen [BCMA], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and BAFF-R) in a majority of 13 myeloma cell lines and in the purified primary myeloma cells of 11 patients. APRIL and BAFF were potent survival factors for exogenous cytokine-dependent myeloma cell lines and were autocrine growth factors for the RPMI8226 and L363 autonomously growing cell lines. These factors activated nuclear factor (NF)–κB, phosphatidylinositol-3 (PI-3) kinase/AKT, and mitogen-activated protein kinase (MAPK) kinase pathways and induced a strong up-regulation of the Mcl-1 and Bcl-2 antiapoptotic proteins in myeloma cells. BAFF or APRIL was also involved in the survival of primary myeloma cells cultured with their bone-marrow environment, and protected them from dexamethasone (DEX)–induced apoptosis. Finally, the serum levels of BAFF and APRIL were increased about 5-fold in patients with multiple myeloma (MM) as compared with healthy donors. Altogether, these data suggest that APRIL/BAFF inhibitors may be of clinical value in MM. (Blood. 2004;103:3148-3157)
Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack?
Authors: Demanet Christian , Mulder Arend , Deneys Veronique , Worsham Maria J. , Maes Piet , Claas Frans H. , Ferrone Soldano
Published: December 2003

Human leukocyte antigen (HLA) class I antigen defects may have a negative impact on the growing application of T-cell–based immunotherapeutic strategies for treatment of leukemia. Therefore in the present study, taking advantage of a large panel of HLA class I allele–specific human monoclonal antibodies, we have compared HLA class I antigen expression on leukemic cells with that on autologous and allogeneic normal cells. Down-regulation of HLA-A and/or -B allospecificities was present in the majority of the patients studied. However, down-regulation did not affect all HLA class I alleles uniformly, but was almost exclusively restricted to HLA-A allospecificities and to HLA-B allospecificities which belong to the HLA-Bw6 group. The latter allospecificities, at variance from those that belong to the HLA-Bw4 group, do not modulate the interactions of leukemic cells with natural killer (NK) cells. Therefore, our results suggest that the selective down-regulation of HLA-A and HLA-Bw6 allospecificities associated with HLA-Bw4 preservation provides leukemic cells with an escape mechanism not only from cytotoxic T lymphocytes (CTLs), but also from NK cells. As a result T-cell–based immunotherapeutic strategies for leukemia should utilize HLA-Bw4 alloantigens as restricting elements since a selective HLA-Bw4 allele loss would provide leukemic cells with an escape mechanism from CTLs, but would increase their susceptibility to NK cell–mediated lysis. (Blood. 2004;103:3122-3130)
Long-term outcome after bone marrow transplantation for severe aplastic anemia
Authors: Ades Lionel , Mary Jean-Yves , Robin Marie , Ferry Christèle , Porcher Raphael , Esperou Hélène , Ribaud Patricia , Devergie Agnès , Traineau Richard , Gluckman Eliane , Socié Gérard
Published: December 2003

From January 1978 to December 2001, 133 patients with severe aplastic anemia (SAA) underwent non-T cell-depleted allogeneic bone marrow transplantation from an HLA-identical sibling donor, at the Hospital Saint Louis using either the combination of cyclophosphamide (Cy) and thoracoabdominal irradiation (TAI; n = 100) or Cy and antithymocyte globulin (ATG; n = 33), as a conditioning regimen. With 13.6 years of follow-up, the 10-year survival estimate was 64%. Four factors were associated with lower survival: older age, use of Cy-TAI, any form of treatment prior to transplantation (either androgens or immunosuppressive therapy, [IST]), and grade II to IV acute graft-versus-host disease (GvHD). TAI was the sole factor associated with the occurrence of acute GvHD. The risk of cancers (15-year cumulative incidence, 10.9%) was associated with older age and with the use of cyclosporine as IST before transplantation. Cumulative incidences and risk factors of nonmalignant late effect including avascular osteonecrosis and late bacterial, viral, and fungal infection were also analyzed. Improved results using Cy-ATG as conditioning can lead to more than 90% chance of cure in patients with SAA. Even if, in our experience, the role of Cy-ATG versus that of Cy-TAI remained inextricably related to the year of transplantation, the major detrimental role of the GvHD disease in the long-term outcome and its relation to TAI supports avoidance of irradiation in the conditioning regimen. Furthermore, avoidance of any IST before transplantation in patients with a sibling donor is a prerequisite for attaining such excellent results.
VEGF-A165 augments erythropoietic development from human embryonic stem cells
Authors: Cerdan Chantal , Rouleau Anne , Bhatia Mickie
Published: December 2003

Combinations of hematopoietic cytokines and the ventral mesoderm inducer BMP-4 have recently been shown to augment hematopoietic cell fate of human embryonic stem cells (hESCs) during embryoid body (EB) development. However, factors capable of regulating lineage commitment of hESC-derived hematopoiesis have yet to be reported. Here we show that vascular endothelial growth factor (VEGF-A165) selectively promotes erythropoietic development from hESCs. Effects of VEGF-A165 were dependent on the presence of hematopoietic cytokines and BMP-4, and could be augmented by addition of erythropoietin (EPO). Treatment of human EBs with VEGF-A165 increased the frequency of cells coexpressing CD34 and the VEGF-A165 receptor KDR, as well as cells expressing erythroid markers. Although fetal/adult globins were unaffected, VEGF-A165 induced the expression of embryonic zeta (ζ) and epsilon (ϵ) globins, and was accompanied by expression of the hematopoietic transcription factor SCL/Tal-1. In addition to promoting erythropoietic differentiation from hESCs, the presence of VEGF-A165 enhanced the in vitro self-renewal potential of primitive hematopoietic cells capable of erythroid progenitor capacity. Our study demonstrates a role for VEGF-A165 during erythropoiesis of differentiating hESCs, thereby providing the first evidence for a factor capable of regulating hematopoietic lineage development of hESCs.
Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and γ-glutamyl carboxylase) gene variants with warfarin sensitivity
Authors: Shikata Eriko , Ieiri Ichiro , Ishiguro Shingo , Aono Hironao , Inoue Kazuko , Koide Tomoko , Ohgi Shigetsugu , Otsubo Kenji
Published: December 2003

We analyzed mutations of 7 vitamin K—dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr → Met of the factor II gene, -402G → A, (37-bp repeat)n, and -746T → C of the factor VII gene, and (CAA repeat)n of the γ-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, -402G, (37-bp repeat)6 and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G → A, (CAA repeat)n, CYP2C9*3, and 165Thr → Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K—dependent protein genes is useful for predicting anticoagulant responses.
Differential gene expression of human stem progenitor cells derived from early stages of in utero human hematopoiesis
Authors: Shojaei Farbod , Gallacher Lisa , Bhatia Mickie
Published: December 2003

Hematopoietic stem progenitor cells (HSPCs) are highly enriched in a rare subset of Lin-CD34+CD38- cells. Independent of stage of human development, HSPC function segregates to the subset of Lin-CD34+CD38- cells. However, fetal-derived HSPCs demonstrate distinct self-renewal and differentiation capacities compared with their adult counterparts. Here, to characterize the molecular nature of fetal HSPCs, suppressive subtractive hybridization was used to compare gene expression of HSPCs isolated from fetal blood (FB-HSPCs) versus adult mobilized peripheral blood (MPB-HSPCs). We identified 97 differentially expressed genes that could be annotated into distinct groups that include transcription factors, cell cycle regulators, and genes involved in signal transduction. Candidate regulators, such as Lim only domain-2 (LMO2), nuclear factor–kappa B (NF-κB), tripartite motif 28 (Trim28), and N-myc protooncogene (MYCN), and a novel homeobox gene product were among transcripts that were found to be differentially expressed and could be associated with specific proliferation and differentiation properties unique to FB-HSPCs. Interestingly, the majority of genes associated with signal transduction belong to Ras pathway, highlighting the significance of Ras signaling in FB-HSPCs. Genes differentially expressed in FB-HSPCs versus adult MPB-HSPCs were verified using quantitative real-time polymerase chain reaction (Q-PCR). This approach also resulted in the identification of a transcript that is highly expressed in FB-HSPCs but not detectable in more differentiated Lin-CD34+CD38+ FB progenitors. Our investigation represents the first study to compare phenotypically similar, but functionally distinct, HSPC populations and to provide a gene profile of unique human HSPCs with higher proliferative capacity derived from early in utero human blood development.
Contributions of β2-microglobulin–dependent molecules and lymphocytes to iron regulation: insights from HfeRag1-/- and β2mRag1-/- double knock-out mice
Authors: Miranda Carlos J. , Makui Hortence , Andrews Nancy C. , Santos Manuela M.
Published: December 2003

Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a β2-microglobulin (β2m)-associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of β2mRag1-/- double-deficient mice, lacking all β2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with β2m single knock-out mice. To evaluate whether the observed phenotype in β2mRag1-/- mice was due solely to the absence of Hfe or to other β2m-dependent molecules, we generated HfeRag1-/- double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with β2mRag1-/- mice. These results suggest that other β2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity. (Blood. 2004;103: 2847-2849)
Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice
Authors: Nicolas Gaël , Andrews Nancy C. , Kahn Axel , Vaulont Sophie
Published: December 2003

Hereditary hemochromatosis (HH) type I is a disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, its penetrance seems very low. The goal of our study was to determine whether hepcidin, a recently identified iron-regulatory peptide, could be a genetic modifier contributing to the HH phenotype. In mice, deficiency of either HFE (Hfe-/-) or hepcidin (Usf2-/-) is associated with the same pattern of iron overload observed in patients with HH. We intercrossed Hfe-/- and Usf2+/- mice and asked whether hepcidin deficiency increased the iron burden in Hfe-/- mice. Our results showed that, indeed, liver iron accumulation was greater in the Hfe-/-Usf2+/- mice than in mice lacking Hfe alone. This result, in agreement with recent findings in humans, provides a genetic explanation for some variability of the HH phenotype. (Blood. 2004;103: 2841-2843)
IgG antiplatelet immunity is dependent on an early innate natural killer cell–derived interferon-γ response that is regulated by CD8+ T cells
Authors: Sayeh Ebrahim , Sterling Katherine , Speck Edwin , Freedman John , Semple John W.
Published: December 2003

The mechanisms responsible for immunoglobulin G (IgG) immunity against allogeneic platelets are poorly understood. We studied the role that murine recipient CD8+ T and natural killer (NK) cells play in immunity against allogeneic platelets. BALB/c mice were depleted of the cells by cell-specific antibodies, transfused weekly with platelets from C57BL/6 mice, and serum IgG antidonor antibodies were measured by flow cytometry. While allogeneic platelet transfusions into wild-type recipients stimulated IgG antidonor antibodies in all mice by the fifth transfusion, CD8-depleted mice had significantly (P < .001) enhanced antibody production. Isotype analysis revealed that CD8+ T cells suppressed T-helper 2 (Th2)-associated IgG1 but enhanced Th1-associated IgG2a. Compared with wild-type mice, platelet transfusions into CD8-depleted mice stimulated enhanced intracellular interferon (IFN)-γ production by CD4- lymphocytes within 24 hours after the first transfusion. The early IFN-γ response correlated with nitric oxide-dependent splenic cytotoxicity (P < .001). In asialo ganglioside monosialic acid 1 (GM1)-depleted mice transfused with allogeneic platelets, the IFN-γ production, splenic cytotoxicity, and IgG antidonor antibody response were significantly suppressed. These results demonstrate that IgG antiplatelet immunity is dependent on an early NK cell-derived IFN-γ response that is negatively regulated by CD8+ T cells and suggest that targeting innate NK cell responses may significantly reduce platelet alloimmunization. (Blood. 2004;103:2705-2709)
Pentoxifylline does not protect against hyperoxic lung injury in rats
Authors: Naureckas ET , Factor P , Benjaminov O , Hoffer E , Sriram V , Sznajder JI
Published: December 2003

Hyperoxia has been used extensively as a model of acute lung injury. The drug pentoxifylline has been shown to have a protective effect in other models of lung injury. We sought to determine whether pentoxifylline protects against hyperoxic lung injury in rats by decreasing the accumulation of neutrophils within the lung. A total of 84 rats were studied. Twenty four rats were randomized into four groups. Two groups of rats were pretreated for 48 h with either pentoxifylline (20 mg.kg-1) or saline, and then exposed to > 95% O2 for 60 h while treatments continued. Two groups of control rats received the same treatment regimens as the O2-exposed animals, but breathed room air. Neutrophil accumulation in the lung was quantified both by histology and myeloperoxidase activity. Lung neutrophil accumulation increased in the oxygen-exposed group receiving pentoxifylline as compared to oxygen- or air-exposed rats receiving saline injections. Total glutathione was higher in lung homogenates from the hyperoxic, pentoxifylline-treated group than in homogenates from the other three groups. To study survival, 60 rats were exposed to > 95% O2 for 120 h, 30 rats were pretreated with pentoxifylline, and 30 received saline. Survival after 120 h of exposure to hyperoxia was not altered by pentoxifylline treatment (pentoxifylline treated: 6 out of 30 survived; saline treated: 2 out of 30 survived). We conclude that pentoxifylline does not reduce mortality or lung injury in rats exposed to hyperoxia and is associated with an increase in lung neutrophil accumulation.
Foetal airway motor tone in prenatal lung development of the pig
Authors: Sparrow MP , Warwick SP , Mitchell HW
Published: December 2003

The terminal airways from embryonic lung in situ or as explants exhibit rhythmic spontaneous contractions. Our objective was to see whether narrowing responses of the airways occurred throughout the bronchial tree in the first trimester foetus and, if so, to characterize them. The bronchial tree was freed of vasculature and parenchyma from the lungs of 20-35 g pig foetuses (44-48 days gestation). The airway lumen was visualized directly with transmitted light, and narrowing was recorded in real time by video-imaging microscopy. From the main stem bronchi to the terminal regions of late generation branches (20-35 microns i.d.) strong bronchoconstrictor responses to micromolar concentrations of acetylcholine (ACh), histamine, substance P and K+ depolarizing solution were seen, whilst inhibition of narrowing with beta-adrenoceptor agonists was evidence of beta-receptors on the smooth muscle. Moreover, strong narrowing responses to electrical field stimulation, which were blocked by atropine, indicated that functional cholinergic nerves were present. A remarkable display of spontaneous narrowing in the airways of many of the bronchial tree preparations caused the movement of lung liquid to and fro. We speculate that the bronchomotor tone and associated spontaneous activity, which move the lung fluid along the airways, serve to maintain an even positive pressure in localized areas of the bronchial tree which is essential to provide the stimulus for continued growth of the lung.
Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma
Authors: Spiteri MA , Knight RA , Jeremy JY , Barnes PJ , Chung KF
Published: December 2003

Little information is available on the specific role of alveolar macrophages (AMs) in modulating local cellular reactions to inhaled allergens in atopic asthma. We investigated the influence of alveolar macrophages obtained by bronchoalveolar lavage (BAL) on the proliferative responses of lavage and peripheral lymphocytes from 12 patients with atopic asthma, 6 nonasthmatic symptomatic atopic subjects, and 6 nonatopic normal volunteers, in the context of in vitro exposure to relevant and nonrelevant allergens. Fresh nonadherent bronchoalveolar lavage cells from atopic asthmatic patients, depleted of alveolar macrophages, proliferated spontaneously more than nonadherent bronchoalveolar lavage cells from normal subjects. Addition of autologous asthmatic alveolar macrophages reduced this endogenous "activation". Asthmatic and normal alveolar macrophages also inhibited phytohaemagglutinin-stimulated proliferation of both autologous and allogeneic nonadherent peripheral blood mononuclear cells (PBMC). In contrast, autologous asthmatic alveolar macrophages induced strong proliferation of peripheral blood mononuclear cells when stimulated with allergen to which the patient was skin test and radio allergosorbent test (RAST) reactive; however, no response was seen with allergens to which the patient was insensitive. No such allergen-specific proliferation was seen with alveolar macrophages from nonasthmatic atopic subjects. These data support the presence of functionally-active alveolar macrophages within the airways of atopic asthmatic patients, that under normal stable conditions suppress the induction of peripheral blood mononuclear cell responses, and which only on contact with specific allergen appear to switch to inducer alveolar macrophages, with consequent peripheral blood mononuclear cell hyperactivation.
The expression of intercellular adhesion molecule-1 and the beta 1-integrins in asthma
Authors: Manolitsas ND , Trigg CJ , McAulay AE , Wang JH , Jordan SE , D'Ardenne AJ , Davies RJ
Published: December 2003

Expression of intercellular adhesion molecule-1 (ICAM-1) appears to be important to the development of bronchial hyperresponsiveness and eosinophilia in Ascaris sensitized monkeys. Beta 1-integrins are expressed on epithelial cells, and may contribute to adherence of epithelial cells to the basement membrane. The aim of this study was to determine whether adhesion receptor expression was altered in human asthmatic bronchial epithelium. Using monoclonal antibody staining, we have examined the expression of ICAM-1 and the alpha 1-alpha 6-subunits of the beta 1-integrin family in bronchial mucosal biopsies from 33 asthmatic and 13 nonasthmatic subjects. The epithelium was positive for ICAM-1 in 26 out of 33 asthmatics, although negative in all 13 nonasthmatics. ICAM-1 expression was not associated with bronchial responsiveness or with medication requirements. Beta 1-integrin staining showed that alpha 2-, alpha 3- and alpha 6-subunits stained the epithelium in all cases. Alpha 4 staining was weakly positive in the epithelium in five asthmatics. Alpha 5 staining was weak in asthmatics and normals. Alpha 4 and alpha 6-subunits also stained inflammatory cells. Epithelial upregulation of ICAM-1 is present in asthma. Beta 1-integrins with alpha 2-, alpha 3- and alpha 6-subunits appear to be constitutively expressed in bronchial epithelium.
Regional deposition of saline aerosols of different tonicities in normal and asthmatic subjects
Authors: Phipps PR , Gonda I , Anderson SD , Bailey D , Bautovich G
Published: December 2003

Nonisotonic aerosols are frequently used in the diagnosis and therapy of lung disease. The purpose of this work was to study the difference in the pattern of deposition of aerosols containing aqueous solutions of different tonicities. 99mTechnetium-diethyltriaminepentaacetic acid (99mTc-DTPA)-labelled saline aerosols, with mass median aerodynamic diameter 3.7-3.8 microns and geometric standard deviation 1.4, were inhaled under reproducible breathing conditions on two occasions. Hypotonic and hypertonic solutions were used in 11 normals subjects, isotonic and hypertonic solutions in 9 asthmatics. The regional deposition was quantified by a penetration index measured with the help of a tomographic technique. There was a small but significant increase (6.7%) in the penetration index of the hypotonic as compared to the hypertonic aerosols in the normal subjects. The region that was markedly affected was the trachea. The differences in the penetration of the isotonic and hypertonic aerosols in the asthmatics appeared to be strongly dependent on the state of the airways at the time of the study. These findings can be interpreted in terms of effects of growth or shrinkage of nonisotonic aerosols, as well as of airway narrowing, on regional deposition of aerosols. Tonicity of aerosols appears to affect their deposition both through physical and physiological mechanisms. This should be taken into account when interpreting the effects of inhaled aqueous solutions of various tonicities in patients in vivo.
Effect of inhaled bradykinin on indices of airway responsiveness in asthmatic subjects
Authors: Polosa R , Rajakulasingam K , Prosperini G , Bellofiore S , Britten S , Milazzo LV , Holgate ST
Published: December 2003

Asthma is characterized by airway hyperresponsiveness, a physiopathological abnormality which may result from the complex interplay between inflammatory cells and proinflammatory mediators. Although kinins are thought to play a role in the pathogenesis of bronchial asthma, it is not known whether bradykinin is able to induce airway hyperresponsiveness. We have, therefore, investigated the effect of inhaled bradykinin on the changes in airway calibre and in airway hyperresponsiveness to histamine, in a double-blind, randomized study of nine asthmatic subjects. Subjects were studied on two study periods, separated by at least 15 days. On the first day of each study period, subjects inhaled either a single dose of bradykinin or methacholine (placebo) with changes in airway calibre being followed as forced expiratory volume in one second (FEV1) and as the maximum expiratory flow rate measured at 70% of the vital capacity below total lung capacity (TLC) from a partial forced expiratory manoeuvre (Vp30) at 3, 5, 10, 15, 30, 45 and 60 min, and then every hour for 7 h. Airway responsiveness to histamine, expressed as the provocative concentrations producing a 20% fall in FEV1 and 40% fall in Vp30 (PC20FEV1 and PC40Vp30), was measured at 3 and 7 h after inhaling the agonists, then on days 1, 3, 7 and 14. Inhalation of bradykinin caused rapid bronchoconstriction that peaked at 3-5 min. When compared to placebo, no significant difference in histamine responsiveness was seen after bradykinin in terms of changes in PC20FEV1 values.(ABSTRACT TRUNCATED AT 250 WORDS)
Primarily nasal origin of exhaled nitric oxide and absence in Kartagener's syndrome
Authors: Lundberg JO , Weitzberg E , Nordvall SL , Kuylenstierna R , Lundberg JM , Alving K
Published: December 2003

The exact origin of nitric oxide (NO) in exhaled air is not known. We wanted to further investigate at what site exhaled NO is produced and to determine whether children with Kartagener's syndrome exhibited altered levels of exhaled NO. NO was measured by chemiluminescence technique in air sampled directly from the nose and in normally exhaled air of four children (2.5-13 years old) with Kartagener's syndrome, 20 healthy children, four healthy adults, and four conscious tracheostomized adults. NO was almost absent (98% reduced) in air sampled directly from the nose in four children with Kartagener's syndrome (4 +/- 1 parts per billion (ppb)), compared to age-matched controls (221 +/- 14 (ppb)). Tracheostomized adult subjects had considerably higher NO values in nasally (22 +/- 3 ppb) and orally (14 +/- 2 ppb) exhaled air, compared to levels in air exhaled through the tracheostomy (2 +/- 0 ppb). Treatment with intranasal corticosteroids for 14 days, or with antibiotics for 1 week, did not affect exhaled NO. These results clearly show that, basically, all NO in exhaled air of healthy subjects originates from the upper respiratory tract, with only a minor contribution from the lower airways. Furthermore, the absence of nasal NO in children with Kartagener's syndrome could be of use as a simple noninvasive diagnostic test.
Morphological and cellular basis for airflow limitation in smokers
Authors: Saetta M , Finkelstein R , Cosio MG
Published: December 2003

Airflow limitation has two well-defined components, increased resistance, which is found predominantly in the small airways, and loss of elastic recoil. Small airways contribute to the increased resistance to flow by the narrowing of the airway lumen. Morphometric studies have shown that smokers have increased epithelial abnormalities, cellular inflammatory infiltrates in the airway wall, increased muscle and fibrosis, when compared with nonsmokers. Along with these anatomical changes, an increased percentage of airways < 400 microns in diameter is found. In addition to the measured changes, other nonmeasurable, dynamic events occur in the airways of smokers, which further decrease lumen diameter. There is ample evidence to show that the airways of smokers react to nonspecific stimuli by constricting, which results in increased resistance and decreased forced expiratory volume in one second (FEV1). The pathological changes found in smokers, that could be responsible for active muscle constriction and airway narrowing include: 1) airway epithelial damage, resulting in increased permeability and impairment of other epithelial function; 2) chronic airway inflammation; 3) structural changes in the airway wall; and 4) loss of alveolar attachments. However, not all smokers develop the abovementioned airway abnormalities. We describe how smokers could develop either centrilobular emphysema (CLE), or panlobular emphysema (PLE). We have found that smokers with CLE have more abnormal and narrower small airways, and flow limitation is correlated with the small airway abnormalities and not with loss of recoil. In contrast, smokers with PLE have much less severe airway abnormalities, diffuse emphysema that can be detected microscopically at a stage when FEV1 might be only mildly abnormal, and early changes in elastic recoil as evidenced by the changes in the pressure-volume curve of the lung. Furthermore, in PLE, airflow limitation is correlated with loss of recoil but not with abnormalities in the small airways. We believe that the mechanisms involved in the pathogenesis of the two types of emphysema in smokers are different; an airborne mechanism for CLE, possibly related to airway hyperresponsiveness, and a bloodborne mechanism for PLE, which may be related to dysfunction of alpha 1-antiproteases. We conclude that the separation of smokers based on their emphysema type is essential if we are to understand the pathogenesis of chronic obstructive pulmonary disease (COPD) in these subjects.
Chondrosarcoma of the lobar bronchus with prolonged postoperative survival
Authors: Azimullah PC , Teengs JP , Boerma EJ
Published: December 2003

Primary chondrosarcoma originating from the bronchus is very rare. We describe the case of a 71 year old man with a large chondrosarcoma originating from the left lower lobe bronchus. The tumour was resected and, in contrast to most patients with such tumours, this patient is well, without complaints or abnormalities on X-ray or computed tomographic (CT) scan, 3 yrs after surgery. Tumour characteristics, symptoms, diagnosis and treatment are discussed. Radical surgical resection is the treatment of choice.
Chronic eosinophilic pneumonia progressing to lung fibrosis
Authors: Yoshida K , Shijubo N , Koba H , Mori Y , Satoh M , Morikawa T , Abe S
Published: December 2003

A 65 year old Japanese man was hospitalized with fever. Opacities distributed mainly in the subpleural regions were found on chest computed tomographic scan (CT), and these promptly cleared with corticosteroid therapy. Four years later, he presented with severe eosinophilia. Both chest X-ray and high resolution CT scan showed ground-glass opacities and honeycombing, suggesting lung fibrosis. A lung biopsy demonstrated intra-alveolar eosinophil infiltration, interstitial thickening with eosinophil infiltration, and a widely-distributed desquamative interstitial pneumonia-like reaction. With corticosteroid therapy, the ground-glass opacities decreased with a corresponding clinical improvement, although lung honeycombing and blood eosinophilia remained. In this case, circulating intercellular adhesion molecule-1 and circulating and bronchoalveolar lavage fluid eosinophil granule proteins were felt to be more effective markers for evaluating disease activity than the blood eosinophil number.
Tuberculosis control in Europe and international migration
Authors: Rieder HL , Zellweger JP , Raviglione MC , Keizer ST , Migliori GB
Published: December 2003

This is a consensus-based position paper of a Task Force, comprising representatives of nongovernmental and governmental organizations in the European Region of the International Union Against Tuberculosis and Lung Disease and the World Health Organization, on tuberculosis control in the countries of Europe and international migration. Tuberculosis among the foreign population entering European countries represents an increasing and important proportion of all tuberculosis cases reported in these countries. Adequate surveillance systems allow the identification of population segments at an excess risk of tuberculosis compared to the general population. Among groups of foreigners with a risk considerably exceeding that of the general population, screening for tuberculosis and infection with M. tuberculosis yields a large number of persons in many countries who can benefit from curative and preventive interventions. The Task Force recommends that European countries: 1) have notification systems based on both mandatory laboratory and physician reports of tuberculosis cases, to allow identification of population segments at an excess incidence of tuberculosis compared to the general population; 2) consider screening of high incidence and prevalence groups among the entering foreign population for tuberculosis and infection with M. tuberculosis amenable to curative and preventive i intervention; 3) utilize existing governmental and nongovernmental organizations to provide culturally and socially sensitive services to ensure proper follow-up and implementation of interventions; 4) provide comprehensive curative and preventive services to treat tuberculosis; and 5) evaluate efficiency and efficacy of screening procedures on an ongoing basis.
The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice
Authors: Báfica André , Scanga Charles A , Equils Ozlem , Sher Alan
Published: December 2003

Microbial-induced proinflammatory pathways are thought to play a key role in the activation of human immunodeficiency virus type 1 (HIV-1) gene expression. The induction of Toll-like receptor (TLR) tolerance leads to a complex reprogramming in the pattern of inflammatory gene expression and down-modulates tumor necrosis factor α (TNF-α), interleukin (IL)-1, and IL-6 production. Using transgenic (Tg) mice that incorporate the entire HIV-1 genome, including the long-terminal repeat, we have previously demonstrated that a number of different TLR ligands induce HIV-1 gene expression in cultured splenocytes as well as purified antigen-presenting cell populations. Here, we have used this model to determine the effect of TLR-mediated tolerance as an approach to inhibiting microbial-induced viral gene expression in vivo. Unexpectedly, Tg splenocytes and macrophages, rendered tolerant in vitro to TLR2, TLR4, and TLR9 ligands as assessed by proinflammatory cytokine secretion and nuclear factor-κB activation, showed enhanced HIV-1 p24 production. A similar enhancement was observed in splenocytes tolerized and then challenged with heterologous TLR ligands. Moreover, TLR2- and TLR4-homotolerized mice demonstrated significantly increased plasma p24 production in vivo despite lower levels of TNF-α. Together, these results demonstrate that HIV-1 expression is enhanced in TLR-reprogrammed host cells, possibly reflecting a mechanism used by the virus to escape the effects of microbial-induced tolerance during natural infection in vivo.
Altering immune tolerance therapeutically: the power of negative thinking
Authors: Prud’homme Gérald J
Published: December 2003

The etiology of most human autoimmune diseases remains largely unknown. However, investigators have identified several negative regulatory mechanisms acting at the level of innate and/or adaptive immunity. Mutations resulting in a deficiency of some key regulatory molecules are associated with systemic or organ-specific inflammatory disorders, which often have a prominent autoimmune component. Genetic studies have implicated the negative regulator cytotoxic T-lymphocyte antigen 4 (CTLA-4) and other regulatory molecules in human autoimmune diseases. In addition to CTLA-4, key inhibitory molecules include programmed death 1 and B and T lymphocyte attenuator. Transforming growth factor β1 and interleukin-10 also play major anti-inflammatory and regulatory roles. Tumor cells and infectious agents use negative regulatory pathways to escape immunity. The therapeutic blockage of negative signaling (particularly of CTLA-4) increases immunity against tumor antigens but also induces or aggravates autoimmune diseases. It appears that under normal conditions, the immune system is under strong “negative influences” that prevent autoimmunity and that release of this suppression results in disease. Regulation involves communication between the immune system and nonlymphoid tissues, and the latter can deliver inhibitory or stimulatory signals. Recent studies reveal that the generation of negative signals by selective engagement of inhibitory molecules is feasible and is likely to be of therapeutic benefit in autoimmune diseases and allograft rejection.
Anti-inflammatory and antiproliferative actions of PPAR-γ agonists on T lymphocytes derived from MS patients
Authors: Schmidt Stephan , Moric Edin , Schmidt Martina , Sastre Magdalena , Feinstein Douglas L , Heneka Michael T
Published: December 2003

Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-γ isoform is expressed in human T lymphocytes, and oral administration of PPAR-γ agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-γ agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR-γ agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-γ agonist GW347845 on human T leukemia cells (Jurkat cells) and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 multiple sclerosis patients and 12 healthy donors. PIO, ciglitazone, and GW347845 suppressed PHA-induced T cell proliferation by 40–50% and secretion of interferon-γ and tumor necrosis factor α, by 30–50%. Inhibition of proliferation was increased to ∼80% and that of proinflammatory cytokine secretion, to 80–90% when PBMCs were first preincubated with PPAR-γ agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-γ agonists. Inhibition of proliferation was also observed in the tetanus toxoid-specific T cell line KHS.TT2, albeit to a lesser extent. The antiproliferative effects of PIO and GW347845 were accompanied by a decrease of cell viability. Electron microscopy and Western blot analysis revealed DNA condensation and down-regulation of bcl-2, suggesting the induction of apoptosis in activated T lymphocytes. In summary, the data support the potential use of PPAR-γ agonists as immunomodulatory, therapeutic agents for autoimmune diseases.
Modulation of macrophage differentiation and activation by decoy receptor 3
Authors: Chang Yung-Chi , Hsu Tsui-Ling , Lin Hsi-Hsien , Chio Chung-Ching , Chiu Allen W , Chen Nien-Jung , Lin Chi-Hung , Hsieh Shie-Liang
Published: December 2003

Decoy receptor 3 (DcR3) is a soluble receptor of the tumor necrosis factor receptor superfamily and is readily detected in certain cancer patients. Recently, we demonstrated that DcR3.Fc-treated dendritic cells skew T cell responses to a T helper cell type 2 phenotype. In this study, we further asked its ability to modulate CD14+ monocyte differentiation into macrophages induced by macrophage-colony stimulating factor in vitro. We found that DcR3.Fc was able to modulate the expression of several macrophage markers, including CD14, CD16, CD64, and human leukocyte antigen-DR. In contrast, the expression of CD11c, CD36, CD68, and CD206 (mannose receptor) was not affected in the in vitro culture system. Moreover, phagocytic activity toward immune complexes and apoptotic bodies as well as the production of free radicals and proinflammatory cytokines in response to lipopolysaccharide were impaired in DcR3.Fc-treated monocyte-derived macrophages. This suggests that DcR3.Fc might have potent, suppressive effects to down-regulate the host-immune system.