bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose-Dependent Regulation of NAD(P)H Oxidase Expression by Angiotensin II in Human Endothelial Cells
Authors: Rueckschloss Uwe , Quinn Mark T. , Holtz Juergen , Morawietz Henning
Published: November 2002

Objective—

Angiotensin II (Ang II)–mediated induction of vascular superoxide anion formation could contribute to the development of endothelial dysfunction, hypertension, and atherosclerosis. An NAD(P)H oxidase has been identified as a major endothelial source of superoxide anions. However, the molecular mechanism underlying the regulation of NAD(P)H oxidase activity in response to Ang II is not well understood.

Methods and Results—

We investigated the dose-dependent regulation of superoxide anion formation and of NAD(P)H oxidase subunit expression in response to Ang II in human endothelial cells. Ang II regulates superoxide anion formation and the limiting subunit of endothelial NAD(P)H oxidase, gp91-phox, in a dose-dependent manner via Ang II type 1 (AT
1
) receptor–mediated induction and Ang II type 2 receptor–mediated partial inhibition at higher Ang II concentrations. Furthermore, AT
1
receptor blocker therapy before coronary bypass surgery downregulates the gp91-phox expression in internal mammary artery biopsies of patients with coronary artery disease.

Conclusions—

Our data support a dose-dependent induction of proatherosclerotic oxidative stress in human endothelial cells in response to Ang II. The expression of NAD(P)H oxidase subunit gp91-phox is critical for endothelial superoxide anion formation. AT
1
receptor blockade has an antiatherosclerotic and antioxidative potential by the reduction of oxidative stress in the vessel wall.
Increased Monocyte Adhesion to Aortic Endothelium in Rats With Hyperhomocysteinemia
Authors: Wang Guoping , Woo Connie W.H. , Sung Fion L. , Siow Yaw L. , O Karmin
Published: November 2002

Objective—

The stimulatory effect of homocysteine (Hcy) on monocyte chemoattractant protein (MCP)-1 expression in vitro has been suggested to play an important role in Hcy-mediated atherosclerosis. We investigated whether such a stimulatory effect occurs in vivo, leading to monocyte adhesion to the endothelium.

Methods and Results—

Sprague-Dawley rats were divided into 4 groups. Hyperhomocysteinemia was induced in 1 group of rats after 4 weeks of a high-methionine diet (serum Hcy levels were 4- to 5-fold higher than levels in control rats). The number of ED-1–positive cells present on the surface of aortic endothelium was significantly elevated in hyperhomocysteinemic rats. There was a significant increase in the expression of MCP-1, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in the endothelium. Antibodies recognizing MCP-1, VCAM-1, or E-selectin could abolish the enhanced monocyte binding to the aortic endothelium of hyperhomocysteinemic rats. Endothelium-dependent aortic relaxation was impaired in hyperhomocysteinemic rats.

Conclusions—

These results suggest that in the absence of other known risk factors, hyperhomocysteinemia stimulates the expression of MCP-1, VCAM-1, and E-selectin in vivo, leading to increased monocyte adhesion to the aortic endothelium. Such an effect may contribute significantly to the development of atherosclerosis by facilitating monocyte/macrophage infiltration into the arterial wall.
ATP-Binding Cassette Transporter 1 Participates in LDL Oxidation by Artery Wall Cells
Authors: Reddy Srinivasa T. , Hama Susan , Ng Carey , Grijalva Victor , Navab Mohamad , Fogelman Alan M.
Published: November 2002

Objective—We have previously reported that products of the lipoxygenase pathway, hydroperoxyoctadecadienoic acid and hydroperoxyeicosatetraenoic acid, as well as cholesterol linoleate hydroperoxides, collectively termed seeding molecules, are removed by apolipoprotein A-I (apoA-I) from the artery wall cells and render low density lipoprotein (LDL) resistant to oxidation by human artery wall cells. The mechanisms by which oxidized lipids are transported and/or transferred to lipoproteins and the pathways by which apoA-I facilitates their removal remain unclear. ATP-binding cassette transporter 1 (ABCA1) is known to facilitate the release of cellular phospholipids and cholesterol from the plasma membrane to apoA-I and high density lipoprotein. Therefore, we evaluated whether ABCA1 participates in LDL oxidation.

Methods and Results—In this report, we show that (1) chemical inhibitors of ABCA1 function, glyburide and DIDS, block artery wall cell–mediated oxidative modification of LDL, (2) inhibition of ABCA1 with the use of antisense (but not sense) oligonucleotides prevents LDL-induced lipid hydroperoxide formation and LDL-induced monocyte chemotactic activity by the artery wall cells, and (3) oxysterols that induce ABCA1 expression, such as 22(R)hydroxycholesterol, enhance cell-mediated LDL oxidation. Furthermore, we also show that 22(R)hydroxycholesterol induces the production of reactive oxygen species in the artery wall cells, which can be removed by incubating the artery wall cells with apoA-I.

Conclusions—Our data suggest that ABCA1 plays an important role in artery wall cell–mediated modification/oxidation of LDL by modulating the release of reactive oxygen species from artery wall cells that are necessary for LDL oxidation.
Retarded Intracellular Lipid Transport Associated With Reduced Expression of Cdc42, a Member of Rho-GTPases, in Human Aged Skin Fibroblasts
Authors: Tsukamoto Kosuke , Hirano Ken-ichi , Yamashita Shizuya , Sakai Naohiko , Ikegami Chiaki , Zhang Zhongyan , Matsuura Fumihiko , Hiraoka Hisatoyo , Matsuyama Akifumi , Ishigami Masato , Matsuzawa Yuji
Published: November 2002

Objective—

Many cell types in atherosclerotic lesions are thought to have various biological abnormalities, such as impaired lipid homeostasis and slow cell proliferation, which may be related to senescence at cellular and individual levels. One of the common characteristics of senescent cells in vitro is the alteration of actin cytoskeletons, which have been reported to be involved in the intracellular transport of lipids. Recently, we raised the hypothesis that Cdc42, which is a member of the Rho-GTPase family and is known to play an important role in actin dynamics, might be important in cellular lipid transport.

Methods and Results—

In the present study, we found that the protein expression levels and GTP-binding activities of Cdc42 were decreased in aged human skin fibroblasts. Moreover, we found the intracellular kinetics of Golgi-associated lipids to be retarded in these cells, which was demonstrated by the fluorescence recovery after photobleaching (FRAP) technique and the use of
N
-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminohexanoyl-
d
-erythro-sphingosine as a tracer. To correlate the decreased expression of Cdc42 with the retarded FRAP, we complemented the amount of wild-type c-
myc
–tagged Cdc42Hs (myc-Cdc42Hs-WT) by adenovirus-mediated gene transfer. We further tested the effect of the dominant-active form (myc-Cdc42Hs-DA, V12Cdc42Hs) or dominant-negative form (myc-Cdc42Hs-DN, N17Cdc42Hs) of Cdc42Hs on FRAP. Introduction of myc-Cdc42Hs-WT or myc-Cdc42Hs-DA recovered the retarded FRAP in the aged fibroblasts. Conversely, control fibroblasts infected with myc-Cdc42Hs-DN exhibited significantly retarded FRAP.

Conclusions—

These data clearly indicate that the expression of Cdc42, a small G protein, is decreased in the aged cells in close association with the retarded intracellular lipid transport. The present study demonstrates a possible function of Cdc42 in the mediation of intracellular lipid transport.
Endothelial Determinants of Dendritic Cell Adhesion and Migration
Authors: Weis Michael , Schlichting Christoph L. , Engleman Edgar G. , Cooke John P.
Published: November 2002

Objective—Atherosclerosis is a chronic disease triggered by endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to influence inflammatory immunity. A fundamental aspect of DC function is their capacity to adhere and migrate through vascular endothelial cells (ECs). We investigated the role of endothelial activation and dysregulation of the NO pathway on DC adhesion and migration.

Methods and Results—We discovered that DC adhesion and migration are modulated by changes in endothelial function. DC adhesion and transmigration were markedly increased after exposing ECs to hypoxia, oxidized low density lipoprotein, or tumor necrosis factor-α. Specifically, inhibition of endothelial NO synthase increased DC binding and transmigration.l-Arginine or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition partially decreased DC-EC interaction.

Conclusions—The results of this study suggest that the adhesion and migration of DCs are increased by stimuli known to accelerate atherogenesis. Vice versa, augmentation of endothelial NO synthase activity prevents DC adhesion. These findings may provide insight into the inflammatory processes occurring in atherosclerosis. Because DCs control immunity, regulating DC-EC interaction may be relevant to inflammation and atherogenesis.
Associations Between Cardiorespiratory Fitness and C-Reactive Protein in Men
Authors: Church T.S. , Barlow C.E. , Earnest C.P. , Kampert J.B. , Priest E.L. , Blair S.N.
Published: November 2002

Objective—

This study examined the association between cardiorespiratory fitness and C-reactive protein (CRP), with adjustment for weight and within weight categories.

Methods and Results—

We calculated median and adjusted geometric mean CRP levels, percentages of individuals with an elevated CRP (≥2.00 mg/L), and odds ratios of elevated CRP across 5 levels of cardiorespiratory fitness for 722 men. CRP values were adjusted for age, body mass index, vitamin use, statin medication use, aspirin use, the presence of inflammatory disease, cardiovascular disease, and diabetes, and smoking habit. We found an inverse association of CRP across fitness levels (
P
for trend<0.001), with the highest adjusted CRP value in the lowest fitness quintile (1.64 [1.27 to 2.11] mg/L) and the lowest adjusted CRP value in the highest fitness quintile (0.70 [0.60 to 0.80] mg/L). Similar results were found for the prevalence of elevated CRP across fitness quintiles. We used logistic regression to model the adjusted odds for elevated CRP and found that compared with the referent first quintile, the second (odds ratio [OR] 0.43, 95% CI 0.22 to 0.85), third (OR 0.33, 95% CI 0.17 to 0.65), fourth (OR 0.23, 95% CI 0.12 to 0.47), and fifth (OR 0.17, 95% CI 0.08 to 0.37) quintiles of fitness had significantly lower odds of elevated CRP. Similar results were found when examining the CRP-fitness relation within categories of body fatness (normal weight, overweight, and obese) and waist girth (<102 or ≥102 cm).

Conclusions—

Cardiorespiratory fitness levels were inversely associated with CRP values and the prevalence of elevated CRP values in this sample of men from the Aerobics Center Longitudinal Study.
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase-Independent Inhibition of CD40 Expression by Atorvastatin in Human Endothelial Cells
Authors: Wagner Andreas H. , Gebauer Matthias , Güldenzoph Björn , Hecker Markus
Published: November 2002

Objective—

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert potent anti-inflammatory effects that are independent of their cholesterol-lowering action. We have investigated the effects of these drugs on cytokine-stimulated CD40 expression in human cultured endothelial cells and monocytes.

Methods and Results—

Reverse transcription-polymerase chain reaction and Western blot analysis revealed that treatment of either cell type with atorvastatin, cerivastatin, or pravastatin (1 to 10 μmol/L) inhibited interferon-γ plus tumor necrosis factor-α-stimulated CD40 expression by ≈50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 μmol/L). In contrast, mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells. Transcription factor analysis revealed an inhibition by atorvastatin of nuclear factor-κB plus signal transducer and activator of transcription-1-dependent de novo synthesis of interferon regulatory factor-1, governing cytokine-stimulated CD40 expression in these cells. One consequence of this statin-dependent downregulation of CD40 expression was a decrease in CD40 ligand-induced endothelial interleukin-12 expression.

Conclusions—

By interfering with cytokine-stimulated CD40 expression in vascular cells, statins thus seem capable of attenuating CD40 ligand-induced proinflammatory responses, including atherosclerosis. In addition, they point to the coexistence of HMG-CoA reductase-dependent and -independent effects of statins in the same cell type.
Inflammation and Restenosis in the Stent Era
Authors: Welt Frederick G.P. , Rogers Campbell
Published: November 2002

The pathophysiology of restenosis involves early elements of direct injury to smooth muscle cells, deendothelialization, and thrombus deposition. Over time, this leads to smooth muscle cell proliferation/migration and extracellular matrix deposition. There is an increasing body of evidence to suggest that inflammation plays a pivotal role linking early vascular injury to the eventual consequence of neointimal growth and lumen compromise. The widespread use of coronary stents has fundamentally altered the vascular response to injury by causing a more intense and prolonged inflammatory state. Many of the cellular and molecular elements responsible for leukocyte recruitment have been elucidated, providing potential therapeutic targets for restenosis. This review seeks to provide an integrated view of the pathophysiology of restenosis that explains the central role of inflammation.
Superoxide Generation in Directional Coronary Atherectomy Specimens of Patients With Angina Pectoris
Authors: Azumi Hiroshi , Inoue Nobutaka , Ohashi Yoshitaka , Terashima Mitsuyasu , Mori Takao , Fujita Hideki , Awano Kojiro , Kobayashi Katsuya , Maeda Kazumi , Hata Katsuya , Shinke Toshiro , Kobayashi Seiichi , Hirata Ken-ichi , Kawashima Seinosuke , Itabe Hiroyuki , Hayashi Yoshitake , Imajoh-Ohmi Shinobu , Itoh Hiroshi , Yokoyama Mitsuhiro
Published: November 2002

Objective—

NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22
phox
, an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22
phox
, the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined.

Methods and Results—

DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22
phox
and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22
phox
and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22
phox
or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris.

Conclusions—

ROS generated by p22
phox
-based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease.
Pharmacological Potentiation of Natriuretic Peptide Limits Polymorphonuclear Neutrophil-Vascular Cell Interactions
Authors: Mtairag El Mostafa , Houard Xavier , Rais Samira , Pasquier Catherine , Oudghiri Mounia , Jacob Marie-Paule , Meilhac Olivier , Michel Jean-Baptiste
Published: November 2002

Objective—Activated polymorphonuclear neutrophils (PMNs) are the main source of circulating neutral endopeptidase (NEP). We tested the hypothesis that NEP inhibition could potentiate the effect of atrial natriuretic peptide (ANP) on PMN-vascular cell interactions in vitro.

Methods and Results—ANP alone and its potentiation by retrothiorphan, the NEP inhibitor, significantly inhibited superoxide, lysozyme, and matrix metalloproteinase (MMP)-9 release byN-formyl-Met-Leu-Phe-stimulated PMNs. Activated PMNs degraded exogenous ANP, which was prevented by NEP inhibition. Hypoxia significantly increased the adhesion of PMNs to endothelial cells and their subsequent MMP-9 release by 60% and 150%, respectively (P<0.01). ANP and its potentiation by retrothiorphan limited PMN adhesion to hypoxic endothelial cells and thus decreased their MMP-9 release (P<0.01). Smooth muscle cells (SMCs) incubated with conditioned medium ofN-formyl-Met-Leu-Phe-stimulated PMNs exhibited morphological and biochemical changes characteristic of apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positivity, nuclear condensation/fragmentation, poly ADP-ribose polymerase cleavage, and DNA laddering). SMC detachment and subsequent apoptosis could be related to leukocyte elastase-induced pericellular proteolysis, inasmuch as both events are inhibited by elastase inhibitors. ANP and its potentiation by retrothiorphan were able to limit elastase release, fibronectin degradation, and SMC apoptosis.

Conclusions—ANP potentiation by NEP inhibition could limit PMN activation and its consequences on vascular cells.
Metabolism of ApoA-I as Lipid-Free Protein or as Component of Discoidal and Spherical Reconstituted HDLs
Authors: Kee Patrick , Rye Kerry-Anne , Taylor John L. , Barrett P. Hugh R. , Barter Philip J.
Published: November 2002

Objective—

Apolipoprotein (apo)A-I exists in 3 forms in plasma: as lipid-free apoA-I, as a component of pre–β-migrating discoidal high density lipoproteins (HDLs), and as a component of α-migrating spherical HDLs. This study investigates (1) the in vivo metabolism of apoA-I in each of these forms and (2) the effects of hepatic lipase (HL) on apoA-I metabolism.

Methods and Results—

Wild-type and HL transgenic rabbits were studied. When lipid-free
125
I-apoA-I and
125
I-apoA-I in pre–β-migrating discoidal reconstituted HDLs (rHDLs) were injected into wild-type rabbits, the label rapidly appeared in α-migrating particles and decayed with the same fractional catabolic rate (FCR) as when they were injected as a component of spherical rHDLs. Spherical rHDLs did not change in size when they were injected into wild-type rabbits but were reduced in size in HL transgenic rabbits. The FCR of apoA-I in HL transgenic rabbits was double that in wild-type rabbits.

Conclusions—

In vivo, (1) lipid-free apoA-I rapidly incorporates into preexisting α-migrating particles, (2) pre–β-migrating discoidal HDLs are rapidly converted into α-migrating HDLs, (3) the FCR of apoA-I is independent of the form in which it is introduced into plasma, and (4) HL reduces the size of α-migrating HDLs and increases the rate of catabolism of apoA-I.
Val64Ile Polymorphism in the C-C Chemokine Receptor 2 Is Associated With Reduced Coronary Artery Calcification
Authors: Valdes Ana M. , Wolfe Megan L. , O’Brien Eamonn J. , Spurr Nigel K. , Gefter Warren , Rut Andrew , Groot Pieter H.E. , Rader Daniel J.
Published: November 2002

Objective—

Studies in mice have shown that genetic disruption of monocyte chemotactic protein-1 or its receptor, the C-C chemokine receptor 2 (CCR2), inhibits atherosclerosis, but few data exist in humans to suggest that the monocyte chemotactic protein-1—CCR2 interaction is important in atherogenesis. A common polymorphism in the human CCR2 gene resulting in a substitution of isoleucine for valine (Val64Ile) has been associated with other disease phenotypes in humans.

Methods and Results—

A cohort of first-degree relatives of persons with premature coronary artery disease was recruited and quantitatively phenotyped for the extent of CAC, a marker of coronary atherosclerosis, by using electron beam CT. The extent of CAC was significantly lower in subjects with the CCR2-Ile64 variant (Val/Ile and Ile/Ile genotypes) than in subjects carrying 2 Val64 alleles, even after adjustment for traditional risk factors.

Conclusions—

This study provides genetic evidence linking CCR2 with coronary atherosclerosis in humans.
Vascular Endothelial Growth Factor–Induced Genes in Human Umbilical Vein Endothelial Cells
Authors: Yang Suya , Toy Karen , Ingle Gladys , Zlot Constance , Williams P. Mickey , Fuh Germaine , Li Bing , de Vos Abraham , Gerritsen Mary E.
Published: November 2002

Objective—

This study evaluated the relative roles of the vascular endothelial growth factor (VEGF) receptors KDR and Flt-1 in the mediation of altered gene expression elicited by VEGF.

Methods and Results—

We used mutants of VEGF selective for the KDR and Flt-1 receptors to differentiate gene expression patterns mediated by wild-type VEGF (VEGFwt) in human umbilical vein endothelial cells. RNA was extracted from cells treated for 24 hours with 1 nmol/L of each ligand, and gene expression was monitored by using oligonucleotide arrays (Affymetrix U95A). We report that activation of KDR was sufficient to upregulate all the genes induced by VEGFwt. In contrast, there were no genes selectively upregulated by the Flt-selective mutant. However, high concentrations of the Flt-selective mutant could augment the expression of some genes induced by submaximal concentrations of VEGFwt but not the KDR-selective mutant.

Conclusions—

The binding of VEGF to its receptor, KDR, is necessary and sufficient to induce the gene expression profile induced by this growth factor. Furthermore, in human umbilical vein endothelial cells, the Flt-1 receptor appears to act as a decoy receptor, tempering the response to lower concentrations of VEGF.
Improvement of Collateral Perfusion and Regional Function by Implantation of Peripheral Blood Mononuclear Cells Into Ischemic Hibernating Myocardium
Authors: Kamihata Hiroshi , Matsubara Hiroaki , Nishiue Takashi , Fujiyama Soichiro , Amano Katsuya , Iba Osamu , Imada Takanobu , Iwasaka Toshiji
Published: November 2002

Objective—

This study was performed to evaluate the angiogenic effect of implantation of peripheral blood mononuclear cells (PB-MNCs) compared with bone marrow mononuclear cells (BM-MNCs) into ischemic hibernating myocardium.

Methods and Results—

A NOGA electromechanical system was used to map the hibernating region and to inject cells. PB-MNCs and BM-MNCs contained similar levels of vascular endothelial growth factor and basic fibroblast growth factor, whereas contents of angiogenic cytokines (interleukin-1β and tumor necrosis factor-α) were larger in PB-MNCs. Numbers of endothelial progenitors were ≈500-fold higher in BM-MNCs. In BM-MNC–implanted myocardia of pigs, an increase in systolic function (ejection fraction from 33% to 52%) and regional blood flow (2.1-fold) and a reduction of the ischemic area (from 29% to 8%) were observed. PB-MNC implantation reduced the ischemic area (from 31% to 17%), the extent of which was less than that seen with BM-MNCs. In saline-implanted myocardium, the ischemic area expanded (from 28% to 38%), and systolic function deteriorated. Angiography revealed an increase in collateral vessel formation by PB-MNC or BM-MNC implantation. Capillary numbers were increased 2.6- and 1.7-fold by BM-MNC and PB-MNC implantation, respectively. BM-MNCs but not PB-MNCs were incorporated into neocapillaries.

Conclusions—

Catheter-based implantation of PB-MNCs can effectively improve collateral perfusion and regional function in hibernating ischemic myocardium by its ability to mainly supply angiogenic factors and cytokines.
PERVERSION OF POWER: WITCHCRAFT AND THE SEXUALITY OF EVIL IN THE SOUTH AFRICAN LOWVELD
Authors: Niehaus Isak
Published: November 2002

During recent years, fears of witchcraft and the violent punishment of witches have become commonplace in the Bushbuckridge region of the South African lowveld. My fieldwork in a village of Bushbuckridge highlights the crucial importance of sexuality in witchcraft discourses. Narratives about the sexual practices of witches formed part of the same moral system as those about the unacceptable sexual conduct of ordinary villagers. But there were also important differences between these. Whilst the unacceptable sexual conduct of ordinary villagers transgressed general moral ideals, the sexual practices of witches transgressed local hierarchies of domination and were conceptualised as perversions of power. I suggest that the most appropriate perspective on witchcraft is one that seeks to integrate a concern with broader political economic processes with a rigorous analysis of the micro-politics of sexuality, kinship and morality.
WITCHCRAFT AND THE EXCHANGE OF SEX, BLOOD, AND MONEY AMONG AFRICANS IN CAPE TOWN, SOUTH AFRICA
Authors: Bähre Erik
Published: November 2002

In post-apartheid South Africa witchcraft is an ever-growing concern, as political liberation has not led to liberation from occult forces. The study of modernity and globalisation has revealed the significance of the study of witchcraft in contemporary Africa. Among Xhosa migrants in Cape Town the discourse on witchcraft also revealed very specific problems that people encountered within close relationships. The lived conflicts, anxieties and desires were revealed in the exchange of sex, blood (as a metaphor for life itself ), and money. This same pattern of exchange appeared in witchcraft, and particularly the role of witch familiars. Witch familiars embodied the anxieties and desires that people experienced on a daily basis concerning sex, blood, and flows of money in intimate relations. The structural problems that were part of the migrants' social configurations were thus revealed in a structural pattern of exchange within witchcraft.
Health utilities in evaluating intervention in the sleep apnoea/hypopnoea syndrome
Authors: Chakravorty I. , Cayton R.M. , Szczepura A.
Published: November 2002

Formulating a rational health policy necessitates the ability to compare between different healthcare interventions and disease scenarios. Continuous positive airway pressure (CPAP) therapy with a conservative lifestyle strategy in sleep apnoea/hypopnoea syndrome (SAHS) was evaluated using health utility and quality-adjusted life years (QALYs) as outcome measures.

A total 71 SAHS (apnoea/hypopnoea index =15 h
-1
) patients completed a randomised, parallel group study over 3 months using utilities derived by the standard gamble approach (U
sg
) and European quality of life questionnaire (Euroqol) (U
eq
).

The severely impaired health status at baseline improved by 23% (U
sg
0.32 to 0.55) adding 8 QALYs in the CPAP group, compared to a 4% improvement with 4.7 QALYs added in the lifestyle group (U
sg
0.31 to 0.35). The U
eq
showed a marginal change with CPAP (0.73 to 0.77) but did not demonstrate any improvement with lifestyle intervention.

The health status impairment in sleep apnoea/hypopnoea syndrome patients is markedly improved by continuous positive airway pressure compared to a modest improvement with conservative lifestyle strategies using the standard gamble utility, which may be incorporated in effectiveness and economic analyses. The European quality of life questionnaire did not reflect a similar degree of impact and is probably not useful in this population.
Pseudomonas aeruginosainduces MUC5AC productionviaepidermal growth factor receptor
Authors: Kohri K. , Ueki I.F. , Shim J-J. , Burgel P-R. , Oh Y-M. , Tam D.C. , Dao-Pick T. , Nadel J.A.
Published: November 2002

Hypersecretory disease associated withPseudomonas aeruginosa(PA) infections is characterised by increased goblet cells and increased mucin production. Recently, an epidermal growth factor receptor (EGFR) signalling cascade was shown to be a common pathway through which many stimuli induce mucin MUC5AC expression in airways by differentiation to a goblet cell phenotype. This study looked at whether PA products induce EGFR expression and activation and thus result in mucin MUC5AC production.

Human airway epithelial (NCI–H292) cells were stimulated with PA culture supernatant (Sup). MUC5AC protein production, MUC5AC and EGFR messenger ribonucleic acid (mRNA) expression, and phosphorylated EGFR and phosphorylated p44/42 mitogen-activated protein kinase (MAPK) were all examined using enzyme-linked immunosorbent assay, byin situhybridisation and by immunoblotting.

PA Sup induced MUC5AC mRNA and subsequent protein expression, EGFR and p44/42 MAPK phosphorylation and EGFR mRNA expression. Induction of MUC5AC mRNA and protein expression and EGFR and p44/42 MAPK phosphorylation were inhibited completely by pretreatment with a selective EGFR tyrosine kinase inhibitor. Pretreatment with a selective inhibitor of MAPK kinase prevented MUC5AC production and p44/42 MAPK phosphorylation but not EGFR phosphorylation.

The authors conclude that PA products induce mucin MUC5AC production in human airway epithelial cellsviathe expression and activation of epidermal growth factor receptor.
Oxidative burst in lipopolysaccharide-activated human alveolar macrophages is inhibited by interleukin-9
Authors: Pilette C. , Ouadrhiri Y. , Van Snick J. , Renauld J-C. , Staquet P. , Vaerman J-P. , Sibille Y.
Published: November 2002

Interleukin (IL)-9 is known to regulate many cell types involved in T-helper type 2 responses classically associated with asthma, including B- and T-lymphocytes, mast cells, eosinophils and epithelial cells. In contrast, target cells mediating the effects of IL-9 in the lower respiratory tract remain to be identified. Therefore, the authors evaluated the activity of IL-9 on human alveolar macrophages (AM) from healthy volunteers.

AM preincubated with IL-9 before lipopolysaccharide (LPS) stimulation exhibited a decreased oxidative burst, as previously shown with IL-4. The inhibitory effect of IL-9 was abolished by anti-hIL-9Rα monoclonal antibody, and presence of IL-9 receptors on AM was demonstrated by immunofluorescence. Both IL-4 and IL-9 failed to modulate tumour necrosis factor-α, IL-8 and IL-10 release by LPS-stimulated AM. However, several observations suggested that IL-9 and IL-4 act through different mechanisms: 1) interferon-γ antagonised the IL-4- but not the IL-9-mediated inhibition of AM oxidative burst; 2) expression of CD14 was downregulated by IL-4 but not by IL-9 and 3) production of tumour growth factor-β by activated AM was potentiated by IL-9 and not by IL-4, and was required for the IL-9-mediated inhibition of AM oxidative burst.

These observations provide additional information concerning the activity of interleukin-9 in the lung, related to inflammatory or fibrosing lung processes.
Evidence of local exercise-induced systemic oxidative stress in chronic obstructive pulmonary disease patients
Authors: Couillard A. , Koechlin C. , Cristol J.P. , Varray A. , Prefaut C.
Published: November 2002

Chronic inactivity may not be the sole factor involved in the myopathy of chronic obstructive pulmonary disease (COPD) patients. One hypothesis is that exercise-induced oxidative stress that leads to muscle alterations may also be involved. This study investigated whether exercise localised to a peripheral muscle group would induce oxidative stress in COPD patients.

Eleven COPD patients (FEV11.15±0.4 L (mean±sd)) and 12 healthy age-matched subjects with a similar low quantity of physical activity performed endurance exercise localised to a peripheral muscle group, the quadriceps of the dominant leg. The authors measured plasma levels of thiobarbituric reactive substances (TBARs) as an index of oxidative stress, the release in superoxide anion (O2·−) by stimulated phagocytes as an oxidant, and blood vitamin E as one antioxidant.

Quadriceps endurance was significantly lower in the COPD patients compared with healthy subjects (136±16 sversus385±69 s (mean±sem), respectively). A significant increase in TBARs 6 h after quadriceps exercise was only found in the COPD patients. In addition, significantly higher O2·−release and lower blood vitamin E levels were found in COPD patients than in controls at rest. This blood vitamin E level was significantly correlated with the resting level of plasma TBARs in the COPD patients.

This study mainly showed that quadriceps exercise induced systemic oxidative stress in chronic obstructive pulmonary disease patients and that vitamin E levels were decreased in these patients at rest. The exact relevance of these findings to chronic obstructive pulmonary disease myopathy needs to be elucidated.
Combined treatment with acetazolamide and medroxyprogesterone in chronic obstructive pulmonary disease patients
Authors: Wagenaar M. , Je Vos P. , Heijdra Y.F. , Teppema L.J. , Folgering H.T.M.
Published: November 2002

Medroxyprogesterone acetate (MPA) and acetazolamide (ACET) are two ventilatory stimulants which are used in hypoxic and hypercapnic patients with chronic obstructive pulmonary disease (COPD).

In a double-blind randomised study, the effects of a 2-week treatment with MPA (30 mgb.i.d.) or ACET (250 mgb.i.d.), followed by a 2-week treatment with a combination of both drugs (MPA/ACET), on daytime and nocturnal ventilatory and blood gas parameters in 17 stable hypercapnic COPD patients were investigated.

ACET, MPA and MPA/ACET treatment decreased mean daytime carbon dioxide tension in arterial blood by 0.4, 0.7 and 1.2 kPa, respectively. Minute ventilation was improved only with combined therapy, from 9.3 to 11.2 L·min−1.

With MPA/ACET therapy, the hypercapnic and hypoxic ventilatory responses significantly increased, from 3.7 to 5.8 L·min−1·kPa−1and from −0.13 to −0.40 L·min−1·%−1, respectively. The mouth exclusion pressure response to hypoxia increased during combination therapy, from −0.01 to −0.03 kPa·%−1. Nocturnal end-tidal carbon dioxide tension decreased with MPA and MPA/ACET treatment, by 0.9 and 1.4 kPa, respectively. MPA/ACET significantly increased mean nocturnal arterial oxygen saturation values, from 85.5 to 90.2%.

The authors conclude that short-term combined treatment with medroxyprogesterone acetate and acetazolamide has a more favourable effect on day and night-time blood gas values and chemical drive than single drug treatment.
RSV bronchiolitis and risk of wheeze and allergic sensitisation in the first year of life
Authors: Schauer U. , Hoffjan S. , Bittscheidt J. , Köchling A. , Hemmis S. , Bongartz S. , Stephan V.
Published: November 2002

Severe respiratory syncytial virus (RSV) infection has been hypothesised to be a risk factor for the development of allergy and asthma, but epidemiological studies in older children have been inconclusive. The current study hypothesises that the effect of RSV bronchiolitis might be most prominent during the first year after bronchiolitis.

Forty-two infants had experienced RSV bronchiolitis severe enough to cause hospitalisation. For each child with RSV infection, two controls were acquired from a birth cohort and matched for date of birth and sex. All the children were followed prospectively and underwent a follow-up examination at a mean age of 1 yr, which included physical examination, and serum immunoglobulin (Ig) E tests for common food and inhaled allergens.

Risk factors for the development of recurrent wheezing and IgE antibodies were analysed for the whole group of 126 children. A positive test for IgE antibodies was noted in 14 of 42 (33%) RSV children and in 2 of 84 (2.3%) children in the control group. RSV bronchiolitis was the most important risk factor for allergic sensitisation. Likewise, 13 children (15.5%) of the RSV group and three (3.6%) children of the control group suffered from recurrent wheezing, and RSV bronchiolitis posed a considerable risk for recurrent wheezing.

Severe respiratory syncytial virus bronchiolitis during the first year of life is an important risk factor for the development of recurrent wheezing and sensitisation to common allergens during the subsequent year.
Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF
Authors: Henry M.T. , McMahon K. , Mackarel A.J. , Prikk K. , Sorsa T. , Maisi P. , Sepper R. , FitzGerald M.X. , O'Connor C.M.
Published: November 2002

The purpose of this study was to examine the role of interstitial collagenases, members of the family of matrix metalloproteinases, in the development of pulmonary fibrosis.

The activity, levels and molecular forms of collagenases (matrix metalloproteinases (MMP)-1, -8 and -13), gelatinase B (MMP-9) and its main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis patients with varying degrees of pulmonary parenchymal involvement.

Collagenase activity was elevated in IPF and group 3 sarcoidosis patients. A positive correlation between BALF collagenase activity and MMP-8 levels was also observed. Western immunoblotting revealed the presence of two isoforms of MMP-8 in patient samples; an 80 kD form representing latent enzyme from polymorphonuclear neutrophils and a 55 kD form representing the fibroblast-type proform. MMP-9 levels were also elevated in both IPF and group 3 sarcoidosis patients, while TIMP-1 levels remained normal, indicating a shift in the balance between the enzyme and inhibitor, favouring MMP-9.

Matrix metalloproteinase-8 is the major contributor to the bronchoalveolar lavage fluid collagenase activity in the airways of patients with idiopathic pulmonary fibrosis and sarcoidosis and may initiate collagen destruction and remodelling leading to the development of pulmonary fibrosis.
Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cellsin vivo
Authors: Fehrenbach H. , Fehrenbach A. , Pan T. , Kasper M. , Mason R.J.
Published: November 2002

Keratinocyte growth factor (KGF) is a potent mitogen of pulmonary bronchial and alveolar epithelial cells. However, it is unclear which type(s) of airway epithelial cells (AEC) proliferate(s) in response to KGF.

AEC proliferation was induced in rats by either endobronchial instillation of 5 mg recombinant human (rHu) KGF per kg body weight or by adenoviral transfer of the human KGF gene (Ad5-HuKGF). Alterations in terminal airway AEC were followed for up to 7 days after rHuKGF, and for up to 28 days after Ad5-HuKGF.

Cell proliferation, as assessed by immunohistochemistry (IHC) for incorporated 5-bromo-2′-deoxyuridine (BrdU) and quantified by stereology, peaked at days 1–2 and was resolved by day 7 after rHuKGF and by day 21 after Ad5-HuKGF. Double immunofluorescence labelling for BrdU or Ki-67 on the one hand, and for Clara cell specific protein 10 (CC10) and calcitonin-gene related peptide on the other hand, demonstrated that Clara cells, not pulmonary neuroendocrine cells, proliferated in response to human KGF. TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling) method in conjunction with IHC for MNF116 failed to detect significant numbers of apoptotic AEC. IHC in conjunction with stereology revealed transient phenotypic alterations with a decrease in CC10, an increase in surfactant protein D and an increase in CD44v6 in AEC.

The authors conclude that Clara cells responded to human keratinocyte growth factorin vivoby proliferation as well as by changes in protein expression, whereas no significant response was observed in pulmonary neuroendocrine cells. As Clara cells are intimately involved in airway epithelial repair, ion and fluid transport, and modulate lung inflammation, the potential of human keratinocyte growth factor to protect the lung may in part rely on the response of Clara cells.
Risk of over-diagnosis of COPD in asymptomatic elderly never-smokers
Authors: Hardie J.A. , Buist A.S. , Vollmer W.M. , Ellingsen I. , Bakke P.S. , Mørkve O.
Published: November 2002

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has defined stage 1 chronic obstructive pulmonary disease (COPD) as forced expiratory volume in one second/forced vital capacity (FEV1/FVC)% <70% and a FEV1% predicted of >80%. Stage 2 has been defined as FEV1/FVC <70% and a FEV1% pred of <80%. The authors examined the extent of COPD misdiagnosis using this definition in healthy, never-smoker, asymptomatic adults aged >70 yrs in Bergen, Norway. A respiratory questionnaire was mailed to a random sample of 2,871 persons aged>70 yrs. In a random, well-defined subgroup of 208 never-smoker respondents with no current respiratory disease and significant dyspnoea or heart disease/hypertension complicated with dyspnoea, 71 were able to perform an acceptable spirometry. Approximately 35% of these healthy, elderly never-smokers had an FEV1/FVC% of <70% and would be classified as having at least a stage 1 COPD. This percentage increased with age and in those aged >80 yrs ∼50% would be classified as having COPD and approximately one-third would have an FEV1of <80% pred (stage 2 COPD). The estimated 5th percentile of FEV1was consistently <80% pred.

The Global Initiative for Chronic Obstructive Lung Disease criteria will probably lead to a significant degree of over-diagnosis of chronic obstructive pulmonary disease in those aged >70 yrs. The criteria used to define the various stages of chronic obstructive pulmonary disease need to be age-specific.
Extrinsic allergic alveolitis induced by the yeastDebaryomyces Hansenii
Authors: Yamamoto Y. , Osanai S. , Fujiuchi S. , Yamazaki K. , Nakano H. , Ohsaki Y. , Kikuchi K.
Published: November 2002

A 65-yr-old female developed cough, fever and dyspnoea following repeated exposure to a home ultrasonic humidifier. High-resolution computed tomography showed ground-glass opacity in both lung fields. Arterial blood gas analysis gave an oxygen tension of 8.38 kPa (63 Torr). Pulmonary function testing revealed restrictive ventilatory impairment with a reduction in the diffusing capacity. The diagnosis of extrinsic allergic alveolitis (EAA) was confirmed by radiographic findings, pathological evidence of alveolitis and reproductive development by a provocation test to the humidifier water. The yeastDebaryomyces Hanseniiwas the only microorganism cultured from the water of the humidifier. The double diffusion precipitating test and lymphocyte proliferative response was positive for an extract ofD. Hansenii, providing evidence to incriminate this fungus. This is the first described case of EAA caused byD. Hansenii.
The European Community Respiratory Health Survey II
Authors:   The European Community Respiratory Health Survey II Steering Committee
Published: November 2002

The European Community Respiratory Health Survey (ECRHS) II will determine the incidence of and risk factors for the development of allergic disease, atopy and rapid loss of lung function in middle-aged adults living in Europe.

From 1991–1993, >18,000 individuals took part in ECRHS I and provided information on symptoms and exposure to known or suspected risk factors for asthma. Blood samples for assessment of specific immunoglobulin E to environmental allergen were taken and lung function and bronchial responsiveness to methacholine were assessed. From 1999–2001, study participants were re-contacted to determine symptom status and exposure to a variety of factors, including tobacco smoke, animals, occupational agents and air pollutants (including particulate matter). In a subsample of responders, exposure to house dust-mite allergen was assessed by analysis of dust samples taken from participants' mattresses. In addition, blood samples suitable for deoxyribonucleic acid extraction were collected and stored.

Currently, European Community Respiratory Health Survey II is being conducted in 29 centres in 14 countries. At the time of writing this paper, 27 centres had begun the study and ∼12,000 participants had completed a short postal questionnaire, ∼9,000 had completed a more detailed health assessment and 3,500 participants had provided dust samples. Historical air-pollution data have been collated and the programme of monitoring particles with a 50% cut-off aerodynamic diameter of 2.5 µm has been completed in 21 centres in 10 countries.
Haemodynamic evaluation of pulmonary hypertension
Authors: Chemla D. , Castelain V. , Hervé P. , Lecarpentier Y. , Brimioulle S.
Published: November 2002

Pulmonary hypertension is characterised by the chronic elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) leading to right ventricular enlargement and hypertrophy. Pulmonary hypertension may result from respiratory and cardiac diseases, the most severe forms occurring in thromboembolic and primary pulmonary hypertension.

Pulmonary hypertension is most often defined as a mean PAP >25 mmHg at rest or >30 mmHg during exercise, the pressure being measured invasively with a pulmonary artery catheter. Doppler echocardiography allows serial, noninvasive follow-up of PAPs and right heart function. When the adaptive mechanisms of right ventricular dilatation and hypertrophy cannot compensate for the haemodynamic burden, right heart failure occurs and is associated with poor prognosis.

The haemodynamic profile is the major determinant of prognosis. In both primary and secondary pulmonary hypertension, special attention must be paid to the assessment of pulmonary vascular resistance index (PVRI), right heart function and pulmonary vasodilatory reserve.

Recent studies have stressed the prognostic values of exercise capacity (6-min walk test), right atrial pressure, stroke index and vasodilator challenge responses, as well as an interest in new imaging techniques and natriuretic peptide determinations. Overall, careful haemodynamic evaluation may optimise new diagnostic and therapeutic strategies in pulmonary hypertension.
Surfactant in children with malignancies, immunosuppression, fever and pulmonary infiltrates
Authors: Griese M. , Neumann M. , von Bredow T. , Schmidt R. , Ratjen F.
Published: November 2002

In children with malignancies and immunosuppression, significant morbidity and mortality result from respiratory complications. The aim of the present study was to investigate whether or not this is associated with altered surfactant components or functions.

Bronchoalveolar lavage fluid from 24 children with malignancies, immunosuppression, pulmonary infiltrates and fever unresponsive to empirical antibiotic treatment were compared to that from 24 healthy children. Levels of surfactant protein (SP) A and D and their binding capacity forPseudomonas aeruginosa, as well as levels of SP-B and SP-C, were assessed by enzyme-linked immunosorbent assay. The large and small surfactant aggregate forms were separated and the biophysical activity of large surfactant aggregates was determined using a pulsating bubble surfactometer.

Compared to healthy controls, SP-A levels were increased four-fold, the increase being most pronounced in those children with pathogens recovered from their bronchoalveolar lavage fluid. In children with malignancies, levels of SP-C were increased two-fold and of small surfactant aggregates five-fold. No differences were observed in levels of SP-B or SP-D, binding capacity of SP-A or SP-D or the surface activity of large surfactant aggregates.

The increased levels of surfactant protein A, particularly in children with recovered microorganisms, and unchanged binding capacity of surfactant protein A are consistent with upregulated local host defence mechanisms. Increased surfactant protein A and C may also be responsible for the conserved biophysical activity of surfactant in children with malignancies, immunosuppression, pulmonary infiltrates and fever.