bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Cerebral Injury in CRH-R1 Deficient Mice after Focal Ischemia: A Potential Link to Microglia and Atrocytes that Express CRH-R1
Authors: Stevens Susan L , Shaw Tatyana E , Dykhuizen Emily , Lessov Nikola S , Hill Jennifer K , Wurst Wolfgang , Stenzel-Poore Mary P
Published: November 2003

Corticotropin releasing hormone (CRH) and its family of related peptides are involved in regulating physiologic responses to multiple stressors, including stroke. Although CRH has been implicated in the exacerbation of injury after stroke, the mechanism remains unclear. After ischemia, both excitotoxic damage and inflammation contribute to the pathology of stroke. CRH is known to potentiate excitotoxic damage in the brain and has been shown to modulate inflammatory responses in the periphery. Here the present authors examine the relative contribution of the two known CRH receptors, CRH-R1 and CRH-R2, to ischemic injury using CRH receptor knockout mice. These results implicate CRH-R1 as the primary mediator of ischemic injury in this mouse model of stroke. In addition, the authors examine a potential role for CRH in inflammatory injury after stroke by identifying functional CRH receptors on astrocytes and microglia, which are cells that are known to be involved in brain inflammation. By single cell PCR, the authors show that microglia and astrocytes express mRNA for both CRH-R1 and CRH-R2. However, CRH-R1 is the primary mediator of cAMP accumulation in response to CRH peptides in these cells. The authors suggest that astrocytes and microglia are cellular targets of CRH, which could serve as a link between CRH and inflammatory responses in ischemic injury via CRH-R1.
A Theoretical Model of Oxygen Delivery and Metabolism for Physiologic Interpretation of Quantitative Cerebral Blood Flow and Metabolic Rate of Oxygen
Authors: Hayashi Takuya , Watabe Hiroshi , Kudomi Nobuyuki , Kim Kyeong Min , Enmi Jun-Ichiro , Hayashida Kohei , Iida Hidehiro
Published: November 2003

The coupling of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) during physiologic and pathophysiologic conditions remains the subject of debate. In the present study, we have developed a theoretical model for oxygen delivery and metabolism, which describes the diffusion of oxygen at the capillary-tissue interface and the nonlinear nature of hemoglobin (Hb) affinity to oxygen, allowing a variation in simple-capillary oxygen diffusibility, termed “effective oxygen diffusibility (EOD).” The model was used to simulate the relationship between CBF and CMRO2, as well as oxygen extraction fraction (OEF), when various pathophysiologic conditions were assumed involving functional activation, ischemia, hypoxia, anemia, or hypo- and hyper-capnic CBF variations. The simulations revealed that, to maintain CMRO2 constant, a variation in CBF and Hb required active change in EOD. In contrast, unless the EOD change took place, the brain allowed small but significant nonlinear change in CMRO2 directly dependent upon oxygen delivery. Application of the present model to quantitative neuroimaging of CBF and CMRO2 enables us to evaluate the biologic response at capillary level other than Hb- and flow-dependent properties of oxygen transport and may give us another insight regarding the physiologic control of oxygen delivery in the human brain.
An overview of family systems approaches to library management
Authors: Stover Mark
Published: November 2003

Family systems theory has often been applied to the organizational environment. This article presents an overview of family systems approaches to management, with particular focus on libraries and information technology. Some of the family systems concepts that can be applied to the library environment include differentiation, mystification, emotional triangles, and pseudomutuality. Some of the positive aspects of a family system that are relevant to the organizational context include stages of development, family rituals, and family stories. Through examples and vignettes, the author demonstrates the application of family systems theory to the field of library management.
Knowledge management – the new librarianship? From custodians of history to gatekeepers to the future
Authors: Rowley Jennifer
Published: November 2003

Explores the knowledge management paradigm, and offers a model for understanding the future role of knowledge and information professionals. The article starts by exploring the concept of knowledge management and the strategies for its implementation in business organizations. This theme is developed into a consideration of knowledge management in the public sector. Three main roles are proposed for knowledge professionals: managing knowledge repositories; facilitating of knowledge flow and communication; and leveraging value generation capacity.
Lending procedures and the viability‐social objectives conflict in credit unions
Authors: Ralston Deborah , Wright April
Published: November 2003

Sound lending procedures in retail financial institutions involve identifying high‐risk applicants, modifying loan conditions such as security requirements, and monitoring repayments post‐loan approval. For managers of credit unions, this procedure is complicated by the need to achieve balance between the institution’s social objective of improving loan accessibility so members can attain lifestyle goals and the possibility of reducing the institution’s viability through loan default. The results of our survey of Australian credit unions, in which 70 per cent of respondents reported experiencing some bankruptcy‐related default on personal loans, indicate managers do not impose more stringent lending conditions on high‐risk borrowers. However, social and viability objectives could be better balanced through careful loan monitoring and timely arrears practices.
Internet supporting the procurement process: lessons from four case studies
Authors: Bartezzaghi Emilio , Ronchi Stefano
Published: November 2003

Industrial relationships among companies within the supply chain and procurement processes are changing to cope with new threats and opportunities arising from Internet technologies. The adoption of Web‐based tools in the procurement process allows firms to either reduce transaction costs or improve internal procurement process efficiency, or even increase collaboration with suppliers. The aim of this research is to analyze and understand main factors driving the adoption of Internet‐based tools in customer‐supplier relationships. The evidence presented is based on four in‐depth case studies (two European and two American) carried out within a joint‐research project of the Massachusetts Institute of Technology and Politecnico di Milano.
Application of chromosomal substitution techniques in gene‐function discovery
Authors: Cowley Allen W. , Roman Richard J. , Jacob Howard J.
Published: November 2003

A consomic rat strain is one in which an entire chromosome is introgressed into the isogenic background of another inbred strain using marker assisted selection. The development and initial physiologic screening of two inbred consomic rat panels on two genetic backgrounds (44 strains) is well underway. The primary uses of consomic strains are: (1) to assign traits and quantitative trait loci (QTL) to chromosomes by surveying the panel of strains with substituted chromosomes; (2) to rapidly develop congenic strains over a narrow region using several approaches described in this review and perform F2 linkage studies to positionally locate QTL in a fixed genetic background. In addition, consomic strains overcome many of the problems encountered with segregating crosses where, even if linkage is found, each individual in the cross is genetically unique and the combination of genes cannot be reproduced or studied in detail. Consomic strains provide greater statistical power to detect linkage than traditional F2 crosses because of their fixed genetic backgrounds, and can produce sufficient numbers of genetically identical rats to validate the relationship between a trait and a particular chromosome. These strains allow studies to be performed in a replicative or longitudinal manner to elucidate in greater detail the sequential changes responsible for the observed phenotypes of these animals, and they enable one to assess the impact of a causal gene region in a genome by allowing comparisons of the effect of replacement of a specific chromosome upon a disease susceptible or resistant genomic background. Consomics can be used to quickly develop multiple chromosome substitution models to investigate gene–gene interactions of complex traits or diseases. Finally, they often provide the best available inbred control strain for particular physiological comparisons with the inbred parental strains. Consomic rat strains are proving to be a unique scientific resource that greatly extends our understanding of genes and complex normal and pathological function.
Physiological genomics: tools and concepts
Authors: Cowley Allen W.
Published: November 2003

Physiological genomics is an emerging field that brings together the disciplines of genomics and cell, organ and whole animal systems integrative physiology in an effort to attach function to the DNA sequences of complex living systems. The term ‘genomics’ was coined in the early 1990s to describe the innovative high‐throughput sequencing technologies and computational approaches that enabled the study of an organism's DNA in the full haploid set of chromosomes, rather than the study of a single gene or a family of functionally or structurally related genes. Thus the term ‘physiological genomics’ was applied to research that was directed toward an understanding of the relationship of genes to complex physiological functions.
Ion channels: their structure, function and control – an overview
Authors: Kurachi Yoshihisa , North Alan
Published: November 2003

In the past two decades, investigations on ion channels have made remarkable progress. Since the development of patch clamp recording techniques in 1980s, investigators have been able to detect the real‐time behaviour of single channels on many kinds of cell membrane. Rapid advances in molecular biology techniques led to the cloning and identification of a variety of ion channel genes, many of which have been the targets of knock‐outs or disruptions. Recent significant progress in structural biology has enabled us to grasp the molecular architecture of some ion channels, and their structure–function relationship. In this special issue, knowledge from these various approaches are summarized and presented by seven specialists in the respective fields. This discussion took place on 24 March, 2003, during the joint annual scientific sessions of the 80th Japanese Physiological and the 76th Pharmacological Society meetings in Fukuoka, Japan. The symposium was held just after the outbreak of hostilities in Iraq, and some of the speakers originally invited could not participate. Fortunately, two excellent substitute speakers took part (Drs Zamponi and Findlay on Ca2+ channels).
Synthesis and study of platinum silylene complexes of the type (R3P)2Pt=SiMes2 (Mes = 2,4,6-trimethylphenyl)
Authors: Feldman Jay D , Mitchell Gregory P , Nolte Jörn-Oliver , Tilley T Don
Published: November 2003

The synthesis and characterization of neutral platinum silylene complexes (R3P)2Pt=SiMes2 (R = i-Pr (1) or cyclohexyl (2), Mes = 2,4,6-trimethylphenyl) is reported. The dimesitylsilylene ligand in 2 is displaced by a number of ligands including phosphines, alkenes, alkynes, and O2. Complex 2 reacts with ROH substrates (R = H, Me, Et) to give (Cy3P)2Pt and Mes2Si(OR)(H) and with H2 to give trans-(Cy3P)2Pt(H)SiHMes2 (3). Reaction of H2SiMes2 with (Cy3P)2Pt gave cis-(Cy3P)2Pt(H)SiHMes2 (4). EXSY NMR experiments of 4 reveal that exchange of silicon and platinum hydrides occurs via reductive elimination  oxidative addition and not via a silylene intermediate.Key words: silylene, EXSY, platinum, hydride.
Ferrocenyl-penta-(β-naphthyl)benzene  Synthesis, structure, and dynamic behaviour
Authors: Harrington Laura E , Britten James F , McGlinchey Michael J
Published: November 2003

3-Ferrocenyl-2,4,5-tri-(β-naphthyl)cyclopentadienone undergoes a DielsAlder reaction with di-(β-naphthyl) acetylene to yield, after elimination of carbon monoxide, ferrocenyl-penta-(β-naphthyl)benzene (4). 1H and 13C variable-temperature NMR studies on 4 reveal the existence of multiple diastereoisomers at low temperature. These data are interpreted in terms of slowed rotation of the naphthyl groups, and are supported by the X-ray crystal structure of 4, which exhibits disorder at three of the naphthyl sites.Key words: sterically crowded molecules, hindered rotations, crystallography, NMR.
Crystal structures, magnetic properties, and absorption spectra of nickel(II) thiocyanato complexes: a comparison of different coordination geometries
Authors: Larue Bruno , Tran Lan-Tâm , Luneau Dominique , Reber Christian
Published: November 2003

Thiocyanatonickel(II) compounds with composition {(AsPh4)2[Ni(NCS)4]} 1, {(Cat)[Ni(NCS)4]} 2, {(AsPh4)4 [Ni2(NCS)8]} 3, {(Cat)2[Ni2(NCS)8]·2CH3NO2} 4, and {(Et4N)4[Ni(NCS)6]} 5 (Cat2+ = (p-xylylenebis(triphenyphosphonium))2+) were prepared. The crystal structures of compounds 1, 3, and 4 were determined. Compound 1 crystallizes in the monoclinic C2/c space group with a = 22.761(2) Å, b = 15.055(1) Å, c = 15.054(1) Å, β = 108.915(1)°, V = 4879.9(6) Å3, and Z = 4. Compound 3 crystallizes in the triclinic P1 space group with a = 11.2183(6) Å, b = 14.2551(8) Å, c = 16.629(1) Å, α = 79.326(1)°, β = 73.605(1)°, γ = 75.496(1)°, V = 2451.0(2) Å3, Z = 2. Compound 4 crystallizes in the monoclinic P21/n space group with a = 13.1148(9) Å, b = 27.128(2) Å, c = 14.882(1) Å, β = 114.056(2)°, V = 4834.8(6) Å3, Z = 4. The magnetic properties of compounds 1-4 were studied over the 2300 K temperature range. Compounds 1 and 2 with monometallic [Ni(NCS)4]2 complex units have similar magnetic properties, in agreement with nickel(II) ions in pseudo-tetrahedral environments. Compounds 3 and 4 with bimetallic [Ni2(NCS)8]4 complex units exhibit magnetic properties, which are indicative of Ni(II)Ni(II) ferromagnetic interactions with zero-field splitting effects caused by the pseudo-square-pyramidal or pseudo-trigonal-bipyramidal coordination environments of the nickel(II) ion in compounds 3 and 4, respectively. The structures and magnetic results for all compounds are correlated with NIRUVvis absorption spectra.Key words: nickel(II) thiocyanato complexes, crystal structures, paramagnetism, molecular magnetism, exchange coupling, absorption spectroscopy.
The reversible hydration of the malaria pigment β-hematin
Authors: Bohle D Scott , Kosar Andrew D , Stephens Peter W
Published: November 2003

β-Hematin, the crystalline heme detoxification product of red blood cell digestion by the malaria parasite, can reversibly absorb up to 14% of its mass in water. Heating hydrated β-hematin to temperatures greater than 150 °C results in loss of the hydrated water, which is readily reabsorbed on standing in air at room temperature. The amount of water absorbed is source dependent with highly crystalline samples produced by the anhydrous-base-mediated dehydrohalogenation being twice as absorptive as more amorphous samples produced by the aqueous acid precipitation method. Infrared spectroscopy and thermal gravimetric analysis have been used to measure the amount of water lost and gained during these experiments. X-ray powder diffraction has been used to characterize the effect of hydration state on the lattice parameters. Taken together these experiments resolve literature discrepancies concerning the elemental composition of synthetic and extracted natural β-hematin.Key words: malaria pigment, hemozoin, β-hematin, hydration, thermal gravimetric analysis, powder diffraction.
Regression of Collateral Function After Recanalization of Chronic Total Coronary Occlusions
Authors: Werner Gerald S. , Emig Ulf , Mutschke Oliver , Schwarz Gero , Bahrmann Philipp , Figulla Hans R.
Published: November 2003

Background—

Collaterals can maintain myocardial function or preserve viability in chronic total coronary occlusions (CTOs). It is unknown whether and to what extent collaterals regress after successful recanalization of a CTO.

Methods and Results—

In 103 patients with successful recanalization of a CTO collateral function was assessed by intracoronary Doppler and pressure recordings before and after recanalization, and again after 5.0±1.3 months. Doppler (CFI) and pressure-derived collateral function indexes (CPI) and collateral (R
Coll
) and peripheral resistance indexes (R
P
) were calculated. In 10 patients with reocclusion, all without myocardial infarction during follow-up, collateral function had reached a similar level as before the first recanalization. In the other 93 patients with or without restenosis, collateral function was attenuated during follow-up. CPI had decreased by 23% immediately after recanalization (
P
<0.001) and decreased further by another 23% at follow-up (
P
<0.001). The R
Coll
increased immediately after recanalization by 82% (
P
<0.001) and by a further 273% at follow-up (
P
<0.001). In contrast, R
P
increased only by 22% after recanalization (
P
<0.001) and by an additional 12% at follow-up (
P
<0.05). The initial size of the collaterals but not the incidence of a restenosis influenced the collateral regression. Only 18% of patients at follow-up had collaterals with a CPI >0.30, presumably sufficient to prevent ischemia during acute occlusion.

Conclusions—

Collateral function regresses during long-term follow-up, especially in collaterals with a small diameter. In the majority of patients, collaterals are not readily recruitable in the case of acute occlusion. However, collaterals have the potential to recover in the case of chronic reocclusion.
Blockade of Nucleoside Transport Is Required for Delivery of Intraarterial Adenosine Into the Interstitium
Authors: Gamboa Alfredo , Ertl Andrew C. , Costa Fernando , Farley Ginnie , Manier M. Lisa , Hachey David L. , Diedrich André , Biaggioni Italo
Published: November 2003

Background—

Adenosine, a known mediator of preconditioning, has been infused into the coronary circulation to induce therapeutic preconditioning, eg, in preparation for angioplasty. However, results have been disappointing. We tested the hypothesis that endothelial nucleoside transporter acts as a barrier impeding the delivery of intravascular adenosine into the underlying myocardium and that this can be overcome with dipyridamole, a nucleoside transporter blocker.

Methods and Results—

We infused saline or adenosine (0.125 and 0.5 mg/min) into the brachial artery while monitoring forearm blood flow (FBF) and interstitial adenosine levels with microdialysis probes implanted in the flexor digitorum superficialis of the forearm in 7 healthy volunteers during intravenous administration of saline or dipyridamole (loading dose, 0.142 mg/kg per min for 5 minutes followed by 0.004 mg/kg per min). Adenosine produced near maximal forearm vasodilation, increasing FBF from 4.0±0.7 to 10.4±1.9 and 13.1±1.6 mL/100 mL per min for the low and high doses, respectively, but did not increase muscle dialysate adenosine concentration (from 88±21 to 65±23 and 85±26 nmol/L). Intravenous dipyridamole enhanced resting muscle dialysate adenosine (from 77±25 to 147±50 nmol/L), adenosine-induced increase in FBF (from 4.1±0.8 to 12.6±3 and 15.1±3 mL/100 mL per min for the low and high dose, respectively), and the delivery of adenosine into the interstitium (to 290±80 and 299±143 nmol/L for the low and high dose, respectively,
P
=0.04).

Conclusions—

Intravascular adenosine is likely ineffective in inducing myocardial preconditioning because of poor interstitial delivery. This can be overcome by blocking the nucleoside transporter with dipyridamole.
Microalbuminuria and All-Cause Mortality in Treated Hypertensive Individuals
Authors: Romundstad Solfrid , Holmen Jostein , Hallan Hans , Kvenild Kurt , Ellekjær Hanne
Published: November 2003

Background—

In hypertensive individuals, few prospective studies are available in which the association between microalbuminuria (MA) and all-cause mortality in the 2 sexes have been studied within the same population.

Methods and Results—

We conducted a 4.3-year follow-up of 2307 men and 3062 women (≥20 years old) with self-reported treated hypertension, all identified in the Nord-Trøndelag Health Study (HUNT), Norway, 1995 to 1997 (n=65 258). The main outcome measures were relative risk (RR) of all-cause mortality according to increasing albuminuria, defined at different levels of albumin-to-creatinine ratio (ACR). There was a consistent positive association between increasing ACR and all-cause mortality in men. The adjusted RR for ACR in the fourth quartile (≥1.70 mg/mmol) was 1.6 (95% CI, 1.0 to 2.6), compared with ACR in the first quartile (<0.55 mg/mmol). The corresponding RR in women was 1.5 (95% CI, 0.8 to 3.1). We found a positive association between mortality and increasing number of urine samples with ACR above different cutoff levels, especially in men. In 3 urine samples, the lowest ACR level associated with mortality in men was 0.86 mg/mmol, RR 1.6 (95% CI, 1.1 to 2.4). The sex differences persisted after exclusion of those who died during the first year of follow-up, those with hypertension not treated optimally, and those with known cardiovascular disease.

Conclusions—

The association between ACR and all-cause mortality was stronger in treated hypertensive men than in women. The persistent sex differences indicate that hypertensive women tolerate MA better than men and that MA in women should be interpreted differently than in men.
Preprocedural Level of Soluble CD40L Is Predictive of Enhanced Inflammatory Response and Restenosis After Coronary Angioplasty
Authors: Cipollone Francesco , Ferri Claudio , Desideri Giovambattista , Paloscia Leonardo , Materazzo Guido , Mascellanti Marco , Fazia Maria , Iezzi Annalisa , Cuccurullo Chiara , Pini Barbara , Bucci Marco , Santucci Anna , Cuccurullo Franco , Mezzetti Andrea
Published: November 2003

Background—

Inflammation plays a pathogenic role in the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). CD40–CD40L interaction is involved in the pathogenesis of atherosclerosis; however, its role in the pathophysiology of restenosis is still unclear. We tested the hypothesis that soluble CD40L (sCD40L) may be involved in the process of restenosis and that it exerts its effect by triggering a complex group of inflammatory reactions on endothelial and mononuclear cells.

Methods and Results—

We studied 70 patients who underwent PTCA and who had repeated angiograms at 6-month follow-up. Plasma sCD40L was measured before and 1, 5, 15, and 180 days after PTCA, whereas plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin, and monocyte chemoattractant protein (MCP)-1 were measured before and 24 hours after PTCA. Furthermore, the release of adhesion molecules and MCP-1 and the ability to repair an injury in endothelial cells, as well as the generation of O
2
−
in monocytes, were analyzed in vitro after stimulation with serum from patients or healthy control subjects. Restenosis occurred in 18 patients (26%). Restenotic patients had preprocedural sCD40L significantly higher than patients with favorable outcomes (2.13±0.3 versus 0.87±0.12 ng/mL,
P
<0.0001). Elevated sCD40L at baseline was significantly correlated with adhesion molecules and MCP-1 generation after PTCA and with lumen loss at 6-month follow-up. Furthermore, high sCD40L was directly associated in vitro with adhesion molecules and MCP-1 generation and impaired migration in endothelial cells and with enhanced O
2
−
generation in monocytes.

Conclusions—

We conclude that increased sCD40L is associated with late restenosis after PTCA. This may provide an important biochemical link between restenosis and aspirin-insensitive platelet activation. These results provide a rationale for studies with new antiplatelet treatments in patients who underwent PTCA.
Phosphoproteome Analysis of Cardiomyocytes Subjected to β-Adrenergic Stimulation
Authors: Chu Guoxiang , Egnaczyk Gregory F. , Zhao Wen , Jo Su-Hyun , Fan Guo-Chang , Maggio John E. , Xiao Rui-Ping , Kranias Evangelia G.
Published: November 2003

Posttranslational modification of target substrates underlies biological processes through activation/inactivation of signaling cascades. To concurrently identify the phosphoprotein substrates associated with cardiac β-adrenergic signaling, the mouse myocyte phosphoproteome was analyzed using 2-D gel electrophoresis in combination with
32
P autoradiography. Phosphoprotein spots, detected by silver staining, were identified using MALDI-TOF mass spectrometry in conjunction with computer-assisted protein spot matching. Stimulation with isoproterenol (1 μmol/L for 5 minutes) was associated with maximal increases in myocyte contractile parameters, and significant stimulation of the phosphorylation of troponin I (190±23%) and succinyl CoA synthetase (160±16%), whereas the phosphorylation of pyruvate dehydrogenase (48±10%), NADH-ubiquinone oxidoreductase (46±6%), heat shock protein 27 (18±3%), αB-crystallin (20±3%), and an unidentified 26-kDa protein (29±7%) was significantly decreased, compared with unstimulated cells (100%). After sustained (30 minutes) stimulation with isoproterenol, only the alterations in the phosphorylation levels of troponin I and NADH-ubiquinone oxidoreductase were maintained and de novo phosphorylation of a phosphoprotein (≈20 kDa and pI 5.5) was observed. The tryptic peptide fragments of this phosphoprotein were sequenced using postsource decay mass spectrometry, and the protein was subsequently cloned and designated as p20, based on its high sequence homology with rat and human skeletal p20. The mouse cardiac p20 contains the conserved domain sequences for heat shock proteins, and the
RRAS
consensus sequence for cAMP-PKA substrates. LC-MS/MS phosphorylation mapping confirmed phosphorylation of Ser
16
in p20 on β-agonist stimulation. Adenoviral gene transfer of p20 was associated with significant increases in contractility and Ca transient peak in adult rat cardiomyocytes, suggesting an important role of p20 in cardiac function. These findings suggest that cardiomyocytes undergo significant posttranslational modification via phosphorylation in a multitude of proteins to dynamically fine-tune cardiac responses to β-adrenergic signaling.
Durability of Carotid Endarterectomy
Authors: Ecker Robert D. , Pichelmann Mark A. , Meissner Irene , Meyer Fredric B.
Published: November 2003

Background and Purpose—We sought to determine the incidence of recurrent stenosis after carotid endarterectomy.

Methods—One thousand consecutive carotid endarterectomy patients were followed prospectively. The surgery was performed in a standard fashion. Cerebral protection was provided with intraoperative electroencephalographic monitoring and selective shunting. All arteriotomies were repaired with a patch graft. Each patient was seen 3 months after surgery and then yearly, with a duplex ultrasound obtained at each visit. Evidence for new ischemic events or recurrent stenosis of ≥70% was recorded.

Results—The 30-day combined minor and major stroke and death rate was 1.9%. At 7.1-year follow-up, 0.1% of patients had recurrent stenosis ≥70%, the majority of which were asymptomatic.

Conclusions—Carotid endarterectomy is a low-risk procedure for the treatment of carotid occlusive disease, with excellent long-term durability. Although less invasive, carotid angioplasty must demonstrate equal robustness in long-term follow-up before it is considered a routine alternative to surgery.
Stroke Mortality Associated With Living Near Main Roads in England and Wales
Authors: Maheswaran Ravi , Elliott Paul
Published: November 2003

Background and Purpose—

Air pollution is associated with stroke, and road traffic is a major source of outdoor air pollution. Using proximity to roads as a proxy for exposure to road traffic pollution, we examined the hypothesis that living near main roads increases the risk of stroke mortality.

Methods—

We used a small-area ecological study design based on 113 465 census enumeration districts in England and Wales. Stroke mortality (
International Classification of Disease
, 9th revision, codes 430 through 438) in England and Wales from 1990 to 1992 for people ≥45 years of age was examined through the use of 1991 population denominators. Exposure was calculated as distance from each enumeration district population centroid to the nearest main road. We adjusted for age, sex, socioeconomic deprivation (using Carstairs index), regional variation, urbanization, and metropolitan area using Poisson regression.

Results—

The analysis was based on 189 966 stroke deaths and a population of 19 083 979. After adjustment for potential confounders, stroke mortality was 7% (95% confidence interval [CI], 4 to 9) higher in men living within 200 m of a main road compared with men living ≥1000 m away. The corresponding increase in risk for women was 4% (95% CI, 2 to 6) and the risk for men and women combined was 5% (95% CI, 4 to 7). These raised risks diminished with increasing distance from main roads.

Conclusions—

Living near main roads is associated with excess risk of mortality from stroke, and if causality were assumed, ≈990 stroke deaths per year would have been attributable to road traffic pollution.
Involvement of Thrombolysis in Recombinant Tissue Plasminogen Activator-Induced Cerebral Hemorrhages and Effect on Infarct Volume and Postischemic Endothelial Function
Authors: Gautier Sophie , Petrault Olivier , Gele Patrick , Laprais Maud , Bastide Michelle , Bauters Anne , Deplanque Dominique , Jude Brigitte , Caron Jacques , Bordet Régis
Published: November 2003

Background and Purpose—

In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function.

Methods—

Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA (10 mg/kg) associated with TLP (rtPA+TLP). In addition, MCA reactivity was assessed in rtPA- or rtPA+TLP-treated SHR versus control Wistar-Kyoto rats or SHR.

Results—

No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPA+TLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8±2.3 petechiae versus 3.0±1.0 petechiae in rtPA group;
P
<0.001). This increased severity was associated with a significant increase of both infarct volume (182±10 versus 144±15 mm
3
in rtPA group;
P
<0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9±0.5% versus 13±1% in rtPA group;
P
<0.05).

Conclusions—

Treatment with rtPA led to intracerebral hemorrhages, in contrast to saline-treated animals, and the presence of TLP increased the severity of these hemorrhages, in parallel with increased infarct volume and worsened endothelial function.
Carotid Intima-Media Thickness Measurements in Intervention Studies
Authors: Bots Michiel L. , Evans Gregory W. , Riley Ward A. , Grobbee Diederick E.
Published: November 2003

Background—

Carotid intima-media thickness (CIMT) measurements are currently widely used in randomized controlled trials (RCTs) to study the efficacy of interventions. In designing a RCT with CIMT as a primary outcome, several ultrasound options may be considered. We discuss the various options and provide a pooled estimate of CIMT progression. In addition, we quantify the effect of these choices on the sample size for a RCT.

Summary of Comment—

To estimate the average CIMT progression rate, we performed a pooled analysis using CIMT progression rates of control groups from published RCTs. The pros and cons of the following ultrasound options are discussed: which arterial segments may be studied; whether near and far wall CIMT measurements should be performed; whether a single image (1 angle of interrogation) or multiple images (more angles of interrogation) should be used; whether a manual or an automated edge detection reading system should be used; and whether images should be read in a random fashion or in batches. The pooled analysis showed an annual rate of change in mean common CIMT of 0.0147 mm (95% CI, 0.0122 to 0.0173) and in mean maximum CIMT of 0.0176 mm (95% CI, 0.0149 to 0.0203).

Conclusions—

Given the current evidence together with our experience with recently developed ultrasound protocols, we favor the use of mean maximum CIMT rather than mean common CIMT as the primary outcome measure in RCTs designed to evaluate the efficacy of pharmacological and nonpharmacological interventions in carotid artery atherosclerosis.
Ceramide inhibition of phospholipase D and its relationship to RhoA and ARF1 translocation in GTPγS-stimulated polymorphonuclear leukocytes
Authors: Mansfield Pamela J. , Carey Shannon S. , Hinkovska-Galcheva Vania , Shayman James A. , Boxer Laurence A.
Published: November 2003

Phospholipase D (PLD) regulates the polymorphonuclear leukocyte (PMN) functions of phagocytosis, degranulation, and oxidant production. Ceramide inhibition of PLD suppresses PMN function. In streptolysin O–permeabilized PMNs, PLD was directly activated by guanosine 5′-[gamma-thio]triphosphate (GTPγS) stimulation of adenosine diphosphate (ADP)–ribosylation factor (ARF) and Rho, stimulating release of lactoferrin from specific granules of permeabilized PMNs; PLD activation and degranulation were inhibited by C2-ceramide but not dihydro-C2-ceramide. To investigate the mechanism of ceramide's inhibitory effect on PLD, we used a cell-free system to examine PLD activity and translocation from cytosol to plasma membrane of ARF, protein kinase C (PKC)α and β, and RhoA, all of which can activate PLD. GTPγS-activated cytosol stimulated PLD activity and translocation of ARF, PKCα and β, and RhoA when recombined with cell membranes. Prior incubation of PMNs with 10 μM C2-ceramide inhibited PLD activity and RhoA translocation, but not ARF1, ARF6, PKCα, or PKCβ translocation. However, in intact PMNs stimulated with N-formyl-1-methionyl-1-leucyl-1-phenylalamine (FMLP) or permeabilized PMNs stimulated with GTPγS, C2-ceramide did not inhibit RhoA translocation. Exogenous RhoA did not restore ceramide-inhibited PLD activity but bound to membranes despite ceramide treatment. These observations suggest that, although ceramide may affect RhoA in some systems, ceramide inhibits PLD through another mechanism, perhaps related to the ability of ceramide to inhibit phosphatidylinositol-bisphosphate (PIP2) interaction with PLD.
Expression of HbC and HbS, but not HbA, results in activation of K-Cl cotransport activity in transgenic mouse red cells
Authors: Romero Jose R. , Suzuka Sandra M. , Nagel Ronald L. , Fabry Mary E.
Published: November 2003

Elevation of K-Cl cotransport in patients with homozygous hemoglobin (Hb) S or HbC increases red cell mean corpuscular hemoglobin concentration (MCHC) and contributes significantly to pathology. Elucidation of the origin of elevated K-Cl cotransport in red cells with mutant hemoglobins has been confounded by the concomitant presence of reticulocytes with high K-Cl cotransport. In red cells of control mice (C57BL), transgenic mice that express only human HbA, and transgenic mice that express both mouse globins and human HbS, volume stimulation is weak and insensitive to NO3- and dihydroindenyl-oxy-alkanoic acid (DIOA). DIOA and NO3- are inhibitors in all other mammalian red cells. In contrast, in knock-out mice expressing exclusively human hemoglobin HbC or HbS+γ, replacement of isotonic Cl- media by hypotonic Cl- resulted in strong volume stimulation and sensitivity to DIOA, okadaic acid, and NO3-. In summary, we find that HbC, under all conditions, and HbS+γ, in the absence of mouse globins, have significant quantitative and qualitative effects on K-Cl cotransport in mouse red cells and activate mouse K-Cl. We conclude that human globins are able to stimulate the activity and/or regulation of K-Cl cotransport in mouse red cells. These observations support the contention that HbS and HbC stimulate K-Cl cotransport in human red cells.
A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation
Authors: Hildebrandt Gerhard C. , Duffner Ulrich A. , Olkiewicz Krystyna M. , Corrion Leigh A. , Willmarth Nicole E. , Williams Debra L. , Clouthier Shawn G. , Hogaboam Cory M. , Reddy Pavan R. , Moore Bethany B. , Kuziel William A. , Liu Chen , Yanik Gregory , Cooke Kenneth R.
Published: November 2003

Idiopathic pneumonia syndrome (IPS) is a major complication after allogeneic bone marrow transplantation (allo-BMT) and involves the infiltration of donor leukocytes and the secretion of inflammatory cytokines. We hypothesized that leukocyte recruitment during IPS is dependent in part upon interactions between chemokine receptor 2 (CCR2) and its primary ligand monocyte chemoattractant protein–1 (MCP-1). To test this hypothesis, IPS was induced in a lethally irradiated parent → F1 mouse BMT model. Compared with syngeneic controls, pulmonary expression of MCP-1 and CCR2 mRNA was significantly increased after allo-BMT. Transplantation of CCR2-deficient (CCR2-/-) donor cells resulted in a significant reduction in IPS severity compared with transplantation of wild-type (CCR2+/+) cells and in reduced bronchoalveolar lavage (BAL) fluid cellularity and BAL fluid levels of tumor necrosis factor–α (TNF-α) and soluble p55 TNF receptor (sTNFRI). In addition, neutralization of MCP-1 resulted in significantly decreased lung injury compared with control-treated allogeneic recipients. Experimental data correlated with preliminary clinical findings; patients with IPS have elevated levels of MCP-1 in the BAL fluid at the time of diagnosis. Collectively, these data demonstrate that CCR2/MCP-1 interactions significantly contribute to the development of experimental IPS and suggest that interventions blocking these receptor-ligand interactions may represent novel strategies to prevent or treat this lethal complication after allo-BMT.
Insulin-Like Growth Factor (IGF)-I/IGF-Binding Protein-3 Complex: Therapeutic Efficacy and Mechanism of Protection against Type 1 Diabetes
Authors: Chen Wei , Salojin Konstantin V. , Mi Qing-Sheng , Grattan Marsha , Meagher T. Craig , Zucker Peter , Delovitch Terry L.
Published: November 2003

IGF-I regulates islet β-cell growth, survival, and metabolism and protects against type 1 diabetes (T1D). However, the therapeutic efficacy of free IGF-I may be limited by its biological half-life in vivo. We investigated whether prolongation of its half-life as an IGF-I/IGF binding protein (IGFBP)-3 complex affords increased protection against T1D and whether this occurs by influencing T cell function and/or islet β-cell growth and survival. Administration of IGF-I either alone or as an IGF-I/IGFBP-3 complex reduced the severity of insulitis and delayed the onset of T1D in nonobese diabetic mice, but IGF-I/IGFBP-3 was significantly more effective. Protection from T1D elicited by IGF-I/IGFBP-3 was mediated by up-regulated CCL4 and down-regulated CCL3 gene expression in pancreatic draining lymph nodes, activation of the phosphatidylinositol 3-kinase and Akt/protein kinase B signaling pathway of β-cells, reduced β-cell apoptosis, and stimulation of β-cell replication. Reduced β-cell apoptosis resulted from elevated Bcl-2 and Bcl-XL activity and diminished caspase-9 activity, indicating a novel role for a mitochondrial-dependent pathway of β-cell death. Thus, IGF-I/IGFBP-3 affords more efficient protection from insulitis, β-cell destruction, and T1D than IGF-I, and this complex may represent an efficacious therapeutic treatment for the prevention of T1D.
echinoidmutants exhibit neurogenic phenotypes and show synergistic interactions with the Notch signaling pathway
Authors: Ahmed Amina , Chandra Shweta , Magarinos Marta , Vaessin Harald
Published: November 2003

During neurogenesis in Drosophila, groups of ectodermal cells are endowed with the capacity to become neuronal precursors. The Notch signaling pathway is required to limit the neuronal potential to a single cell within each group. Loss of genes of the Notch signaling pathway results in a neurogenic phenotype: hyperplasia of the nervous system accompanied by a parallel loss of epidermis. Echinoid (Ed), a cell membrane associated Immunoglobulin C2-type protein, has previously been shown to be a negative regulator of the EGFR pathway during eye and wing vein development. Using in situ hybridization and antibody staining of whole-mount embryos, we show that Ed has a dynamic expression pattern during embryogenesis. Embryonic lethal alleles of ed reveal a role of Ed in restricting neurogenic potential during embryonic neurogenesis, and result in a phenotype similar to that of loss-of-function mutations of Notch signaling pathway genes. In this process Ed interacts closely with the Notch signaling pathway. Loss of edsuppresses the loss of neuronal elements caused by ectopic activation of the Notch signaling pathway. Using a temperature-sensitive allele of edwe show, furthermore, that Ed is required to suppress sensory bristles and for proper wing vein specification during adult development. In these processes also, ed acts in close concert with genes of the Notch signaling pathway. Thus the extra wing vein phenotype of ed is enhanced upon reduction of Delta (Dl) or Enhancer of split [E(spl)] proteins. Overexpression of the membrane-tethered extracellular region of Ed results in a dominant-negative phenotype. This phenotype is suppressed by overexpression of E(spl)m7 and enhanced by overexpression of Dl. Our work establishes a role of Ed during embryonic nervous system development, as well as adult sensory bristle specification and shows that Ed interacts synergistically with the Notch signaling pathway.
Requirements for FGF3 and FGF10 during inner ear formation
Authors: Alvarez Yolanda , Alonso Maria Teresa , Vendrell Victor , Zelarayan Laura Cecilia , Chamero Pablo , Theil Thomas , Bösl Michael R. , Kato Shigeaki , Maconochie Mark , Riethmacher Dieter , Schimmang Thomas
Published: November 2003

Members of the fibroblast growth factor (FGF) gene family control formation of the body plan and organogenesis in vertebrates. FGF3 is expressed in the developing hindbrain and has been shown to be involved in inner ear development of different vertebrate species, including zebrafish, Xenopus, chick and mouse. In the mouse, insertion of a neomycin resistance gene into the Fgf3 gene via homologous recombination results in severe developmental defects during differentiation of the otic vesicle. We have addressed the precise roles of FGF3 and other FGF family members during formation of the murine inner ear using both loss- and gain-of-function experiments. We generated a new mutant allele lacking the entire FGF3-coding region but surprisingly found no evidence for severe defects either during inner ear development or in the mature sensory organ,suggesting the functional involvement of other FGF family members during its formation. Ectopic expression of FGF10 in the developing hindbrain of transgenic mice leads to the formation of ectopic vesicles, expressing some otic marker genes and thus indicating a role for FGF10 during otic vesicle formation. Expression analysis of FGF10 during mouse embryogenesis reveals a highly dynamic pattern of expression in the developing hindbrain, partially overlapping with FGF3 expression and coinciding with formation of the inner ear. However, FGF10 mutant mice have been reported to display only mild defects during inner ear differentiation. We thus created double mutant mice for FGF3 and FGF10, which form severely reduced otic vesicles, suggesting redundant roles of these FGFs, acting in combination as neural signals for otic vesicle formation.
Foxj1 is required for apical localization of ezrin in airway epithelial cells
Authors: Huang Tao , You Yingjian , Spoor Melanie S. , Richer Edward J. , Kudva Vrinda. V. , Paige Renee C. , Seiler Michael P. , Liebler Janice M. , Zabner Joseph , Plopper Charles G. , Brody Steven L.
Published: November 2003

Establishment and maintenance of epithelial cell polarity depend on cytoskeletal organization and protein trafficking to polarized cortical membranes. ERM (ezrin, radixin, moesin) family members link polarized proteins with cytoskeletal actin. Although ERMs are often considered to be functionally similar, we found that, in airway epithelial cells, apical localization of ERMs depend on cell differentiation and is independently regulated. Moesin was present in the apical membrane of all undifferentiated epithelial cells. However, in differentiated cells, ezrin and moesin were selectively localized to apical membranes of ciliated airway cells and were absent from secretory cells. To identify regulatory proteins required for selective ERM trafficking, we evaluated airway epithelial cells lacking Foxj1, an F-box factor that directs programs required for cilia formation at the apical membrane. Interestingly, Foxj1 expression was also required for localization of apical ezrin, but not moesin. Additionally, membrane-cytoskeletal and threonine-phosphorylated ezrin were decreased in Foxj1-null cells, consistent with absent apical ezrin. Although apical moesin expression was present in null cells, it could not compensate for ezrin because ERM-associated EBP50 and the β2 adrenergic receptor failed to localize apically in the absence of Foxj1. These findings indicate that Foxj1 regulates ERM proteins differentially to selectively direct the apical localization of ezrin for the organization of multi-protein complexes in apical membranes of airway epithelial cells.
The non-classical export routes: FGF1 and IL-1α point the way
Authors: Prudovsky Igor , Mandinova Anna , Soldi Raffaella , Bagala Cinzia , Graziani Irene , Landriscina Matteo , Tarantini Francesca , Duarte Maria , Bellum Stephen , Doherty Holly , Maciag Thomas
Published: November 2003

Non-classical protein release independent of the ER-Golgi pathway has been reported for an increasing number of proteins lacking an N-terminal signal sequence. The export of FGF1 and IL-1α, two pro-angiogenic polypeptides, provides two such examples. In both cases, export is based on the Cu2+-dependent formation of multiprotein complexes containing the S100A13 protein and might involve translocation of the protein across the membrane as a `molten globule'. FGF1 and IL-1α are involved in pathological processes such as restenosis and tumor formation. Inhibition of their export by Cu2+ chelators is thus an effective strategy for treatment of several diseases.
Wee1-dependent mechanisms required for coordination of cell growth and cell division
Authors: Kellogg Douglas R.
Published: November 2003

Wee1-related kinases function in a highly conserved mechanism that controls the timing of entry into mitosis. Loss of Wee1 function causes fission yeast and budding yeast cells to enter mitosis before sufficient growth has occurred, leading to formation of daughter cells that are smaller than normal. Early work in fission yeast suggested that Wee1 is part of a cell-size checkpoint that prevents entry into mitosis before cells have reached a critical size. Recent experiments in fission yeast and budding yeast have provided new support for this idea. In addition, studies in budding yeast have revealed the existence of highly intricate signaling networks that are required for regulation of Swe1, the budding yeast homolog of Wee1. Further understanding of these signaling networks may provide important clues to how cell growth and cell division are coordinated.