bluuebunny/crossref_metadata_2025 huggingface dataset:
Vertebrate phylogeny of hydrogen sulfide vasoactivity
Authors: Dombkowski Ryan A. , Russell Michael J. , Schulman Alexis A. , Doellman Meredith M. , Olson Kenneth R.
Published: September 2004

Hydrogen sulfide (H2S) is a recently identified endogenous vasodilator in mammals. In steelhead/rainbow trout ( Oncorhynchus mykiss, Osteichthyes), H2S produces both dose-dependent dilation and a unique dose-dependent constriction. In this study, we examined H2S vasoactivity in all vertebrate classes to determine whether H2S is universally vasoactive and to identify phylogenetic and/or environmental trends. H2S was generated from NaHS and examined in unstimulated and precontracted systemic and, when applicable, pulmonary arteries (PA) from Pacific hagfish ( Eptatretus stouti, Agnatha), sea lamprey ( Petromyzon marinus, Agnatha), sandbar shark ( Carcharhinus milberti, Chondrichthyes), marine toad ( Bufo marinus, Amphibia), American alligator ( Alligator mississippiensis, Reptilia), Pekin duck ( Anas platyrhynchos domesticus, Aves), and white rat ( Rattus rattus, Mammalia). In otherwise unstimulated vessels, NaHS produced 1) a dose-dependent relaxation in Pacific hagfish dorsal aorta; 2) a dose-dependent contraction in sea lamprey dorsal aorta, marine toad aorta, alligator aorta and PA, duck aorta, and rat thoracic aorta; 3) a threshold relaxation in shark ventral aorta, dorsal aorta, and afferent branchial artery; and 4) a multiphasic contraction-relaxation-contraction in the marine toad PA, duck PA, and rat PA. Precontraction of these vessels with another agonist did not affect the general pattern of NaHS vasoactivity with the exception of the rat aorta, where relaxation was now dominant. These results show that H2S is a phylogenetically ancient and versatile vasoregulatory molecule that appears to have been opportunistically engaged to suit both organ-specific and species-specific homeostatic requirements.
Reduced plasma volume and mesenteric vascular reactivity in obese Zucker rats
Authors: Schreihofer Ann M. , Hair Clark D. , Stepp David W.
Published: September 2004

Obese Zucker rats (OZR) are mildly hypertensive with an apparently elevated sympathetic vasomotor tone compared with lean Zucker rats (LZR). Studies have also suggested enhanced adrenergic pressor reactivity in OZR but assumed comparable baroreflexes, or blood volume-to-body weight ratio, to LZR. In 15-wk-old OZR and LZR, we measured plasma volume and vascular reactivity to norepinephrine (NE) and phenylephrine (PE) with doses evaluated by body weight and plasma volume. Plasma volume measured by dye dilution (Evans blue; 200 μl of 0.5%) showed that OZR had comparable blood volumes to LZR but lower blood volume-to-body weight ratio (3.4 ± 0.2 ml/100 g) than LZR (5.7 ± 0.2 ml/100 g, P < 0.05). Ganglionic blockade (mecamylamine, 4 mg/kg) in isoflurane-anesthetized rats produced larger decreases in arterial pressure in OZR compared with LZR (52 ± 2 vs. 46 ± 2 mmHg). Pressor responses to NE (0.01–10 μg/kg) were exaggerated with doses analyzed by body weight but not analyzed by drug quantity. Pressor responses to PE (1–24 μg/kg) showed no difference with doses analyzed by body weight, but, analyzed by drug quantity, OZR showed a slight decrease in pressor reactivity. PE-induced increases in vascular resistance were exaggerated in the hindlimb circulation of OZR, normal in the renal circulation, and attenuated in the mesenteric circulation. The timing of the peak pressor response to PE corresponded with the increase in mesenteric vascular resistance, followed by rises in hindlimb and renal resistance. These data suggest that systemic adrenergic pressor reactivity is not enhanced in OZR, despite exaggerated vascular reactivity in the hindlimb of the OZR.
Statin Inhibition of Fc Receptor–Mediated Phagocytosis by Macrophages Is Modulated by Cell Activation and Cholesterol
Authors: Loike J.D. , Shabtai D.Y. , Neuhut R. , Malitzky S. , Lu E. , Husemann J. , Goldberg I.J. , Silverstein S.C.
Published: September 2004

Objectives—

An inflammatory response to altered lipoproteins that accumulate in the arterial wall is a major component of the pathogenesis of atherosclerosis. Statins reduce plasma levels of low-density lipoprotein (LDL) and are effective treatments for atherosclerosis. It is hypothesized that they also modulate inflammation. The aim of this study was to examine whether lovastatin inhibits macrophage inflammatory processes and clarify its mechanism of action.

Methods and Results—

We examined the effects of statins on phagocytosis of antibody-coated red blood cells by cultured human monocytes and mouse peritoneal macrophages. Lovastatin, simvastatin, and zaragozic acid, a squalene synthase inhibitor, blocked Fc receptor–mediated phagocytosis by cultured human monocytes and mouse peritoneal macrophages. The inhibitory effect of lovastatin on Fc receptor–mediated phagocytosis was prevented completely by addition of mevalonate, farnesyl pyrophosphate, LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic acid was reversed by addition of LDL, but not by the addition of geranylgeranyl pyrophosphate, to the medium. In addition, the effect of lovastatin on phagocytosis is a function of cell activation because treatment of cells with tumor necrosis factor-α or lipopolysaccharide prevented inhibition of phagocytosis by lovastatin.

Conclusions—

The inhibition of Fc receptor–mediated phagocytosis of lovastatin is related to its effect on cholesterol biosynthesis rather than its effect on the formation of isoprenoids.
Arterial Permeability and Efflux of Apolipoprotein B–Containing Lipoproteins Assessed by In Situ Perfusion and Three-Dimensional Quantitative Confocal Microscopy
Authors: Proctor Spencer D. , Vine Donna F. , Mamo John C.L.
Published: September 2004

Objectives—

There is accumulating evidence that an increased risk of cardiovascular disease (CVD) is not simply caused by the degree of arterial exposure to plasma lipoproteins but, in addition, is determined by the affinity of the vasculature for different lipoprotein phenotypes. In this study we compare the delivery and efflux of 2 atherogenic lipoproteins to further understand the factors that regulate cholesterol accumulation in early atherogenesis.

Methods and Results—

Lipoproteins containing apolipoprotein (apo) B100 (a low-density lipoprotein [LDL]) and apoB48 (chylomicron remnants) were isolated and differentially conjugated with fluorophores and simultaneously perfused at equivalent concentrations in situ through rabbit carotid vessels. Perfusion systems were established to quantify and differentiate between lipoprotein arterial delivery and efflux. The total average rate of delivery for LDL particles (23 nm) compared with chylomicron remnants (50 nm) was 4427 particles/min
−1
per μm
3
and 452 particles/min
−1
per μm
3
, respectively. In contrast, the average rate of efflux was 3195 particles/min
−1
per μm
3
and 163 particles/min
−1
per μm
3
for LDL and chylomicron remnants, respectively.

Conclusions—

Results indicate that although LDL particles have a higher rate of delivery, they efflux more readily from arterial tissue compared with the larger chylomicron remnants. Collectively, our findings highlight that lipoproteins permeate through arterial tissue differently and may be dependent on the phenotype and potential interactions with extracellular matrix components.
Altered PDGF-BB–Induced p38 MAP Kinase Activation in Diabetic Vascular Smooth Muscle Cells
Authors: Yamaguchi Hiroshi , Igarashi Masahiko , Hirata Akihiko , Sugae Naoko , Tsuchiya Hiromi , Jimbu Yumi , Tominaga Makoto , Kato Takeo
Published: September 2004

Objective—

We investigated the regulation of p38 mitogen-activated protein kinase (MAPK) by platelet-derived growth factor (PDGF)-BB and its biological effects in cultured normal and diabetic rat vascular smooth muscle cells (VSMCs).

Methods and Results—

VSMC growth from diabetic rats was faster than that from normal rats. The expression of the PDGF β-receptor in diabetic VSMCs was significantly elevated compared with that in normal cells, and PDGF-BB–induced p38 phosphorylation in diabetic cells was more enhanced via MAPK kinase (MKK) 3/6. The level of PKC activity in diabetic cells increased more than that in normal cells with or without PDGF-BB. Although protein kinase C (PKC)-βII and PKC-δ were activated by diabetes, PDGF-BB could further enhance the level of PKC-δ alone. PDGF-BB–induced cell migration was more elevated in diabetic VSMCs, and the increase was significantly inhibited by SB-203580, rottlerin, and antisense oligodeoxynucleotides for PKC-δ. PDGF-BB–induced p38 phosphorylation also regulated cell growth, cyclooxygenase-2 levels, and arachidonic acid release, but not apoptosis. These levels were more elevated in diabetic cells, which were inhibited by SB-203580.

Conclusions—

Our study established that PDGF-BB phosphorylated p38 via PKC-δ and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs.
Enzymatic Modification of Low-Density Lipoprotein in the Arterial Wall
Authors: Torzewski Michael , Suriyaphol Prapat , Paprotka Kerstin , Spath Lena , Ochsenhirt Viola , Schmitt Andrea , Han Shan-Rui , Husmann Matthias , Gerl Verena B. , Bhakdi Sucharit , Lackner Karl J.
Published: September 2004

Objective—

Functionally interactive proteases of the plasminogen/plasmin and the matrix metalloproteinase (MMP) system degrade and reorganize the extracellular matrix of the vessel wall in atherosclerosis. Here we investigated whether such proteases are able to confer atherogenic properties onto low density lipoprotein by nonoxidative modification.

Methods and Results—

Similar to the recently described enzymatically-modified low-density lipoprotein (E-LDL), native LDL exposed to plasmin or matrix MMP-2 or MMP-9 and cholesterylester-hydrolase (CEH) showed extensive deesterification, with ratios of free cholesterol to total cholesterol rising to 0.8 compared with 0.2 in native LDL. When the ratio exceeded 0.6, both plasmin/CEH-LDL and MMP/CEH-LDL fused into larger particles. In parallel, they gained C-reactive protein–dependent complement-activating capacity. E-LDL produced with any protease/CEH combination was efficiently taken up by human macrophages, whereby marked induction of MMP-2 expression by E-LDL was observed. These in vitro findings had their in vivo correlates: urokinase-type plasminogen activator, MMP-2, and MMP-9 were detectable in both early and advanced human atherosclerotic lesions in colocalization with E-LDL.

Conclusions—

Plasmin and MMP-2/MMP-9 may not only be involved in remodeling of the extracellular matrix in progressing plaques, but they may also be involved in lipoprotein modification during genesis and progression of atherosclerotic lesions.
Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury
Authors: Imahashi Kenichi , Schneider Michael D. , Steenbergen Charles , Murphy Elizabeth
Published: September 2004

The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH
i
and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (
P
<0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F
1
F
0
-ATPase. In the presence of oligomycin (Oligo), an F
1
F
0
-ATPase inhibitor, the decrease in pH
i
was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pH
i
during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2–mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F
1
F
0
-ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.
Flow-Dependent Regulation of Endothelial Toll-Like Receptor 2 Expression Through Inhibition of SP1 Activity
Authors: Dunzendorfer Stefan , Lee Hyun-Ku , Tobias Peter S.
Published: September 2004

Innate immune system activation is associated with atherosclerotic lesion development. The specific sites of lesion development are believed to be defined by the shear stress of blood flow. Consequently, we investigated the responsiveness of human coronary artery endothelial cells (HCAECs) to Toll-like receptor (TLR) 2 and 4 agonists in an in vitro model of chronic laminar flow. HCAECs under chronic laminar flow were found to be normally responsive to lipopolysaccharide (and tumor necrosis factor) in terms of E-selectin expression but were found to be hyporesponsive to stimulation with the specific TLR2 ligands macrophage activating lipopeptide-2, PAM
2
-Cys, and Lip19; this was observed to be attributable to downregulation of TLR2 transcription and protein expression. We found that laminar flow induced SP1 serine phosphorylation by protein kinase CK2 and thereby blocked SP1 binding to the TLR2 promoter, which is required for TLR2 expression. This regulatory mechanism also blocked lipopolysaccharide- and tumor necrosis factor–induced TLR2 upregulation in HCAECs and could be important for suppression of other flow-sensitive endothelial proteins. These results extend the role of flow in controlling endothelial responsiveness. Given the current evidence that TLRs are proatherogenic, flow suppression of TLR2 expression may be atheroprotective.
17β-Estradiol Reduces Cardiomyocyte Apoptosis In Vivo and In Vitro via Activation of Phospho-Inositide-3 Kinase/Akt Signaling
Authors: Patten Richard D. , Pourati Isaac , Aronovitz Mark J. , Baur Jason , Celestin Flore , Chen Xin , Michael Ashour , Haq Syed , Nuedling Simone , Grohe Christian , Force Thomas , Mendelsohn Michael E. , Karas Richard H.
Published: September 2004

Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17β-estradiol (E2) reduces infarct size and cardiomyocyte apoptosis in animal models of myocardial infarction (MI). Here, we characterize the molecular mechanisms of E2 effects on cardiomyocyte survival in vivo and in vitro. Ovariectomized female mice were treated with placebo or physiological E2 replacement, followed by coronary artery ligation (placebo-MI or E2-MI) or sham operation (sham) and hearts were harvested 6, 24, and 72 hours later. After MI, E2 replacement significantly increased activation of the prosurvival kinase, Akt, and decreased cardiomyocyte apoptosis assessed by terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) staining and caspase 3 activation. In vitro, E2 at 1 or 10 nmol/L caused a rapid 2.7-fold increase in Akt phosphorylation and a decrease in apoptosis as measured by TUNEL staining, caspase 3 activation, and DNA laddering in cultured neonatal rat cardiomyocytes. The E2-mediated reduction in apoptosis was reversed by an estrogen receptor (ER) antagonist, ICI 182,780, and by phospho-inositide-3 kinase inhibitors, LY294002 and Wortmannin. Overexpression of a dominant negative-Akt construct also blocked E2-mediated reduction in cardiomyocyte apoptosis. These data show that E2 reduces cardiomyocyte apoptosis in vivo and in vitro by ER- and phospho-inositide-3 kinase–Akt–dependent pathways and support the relevance of these pathways in the observed estrogen-mediated reduction in myocardial injury.
Apolipoprotein B/Apolipoprotein A-I in Relation to the Metabolic Syndrome and Change in Carotid Artery Intima-Media Thickness During 3 Years in Middle-Aged Men
Authors: Wallenfeldt Karin , Bokemark Lena , Wikstrand John , Hulthe Johannes , Fagerberg Björn
Published: September 2004

Background and Purpose—

The apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio is a measure of the relationship between different lipoprotein particles and a powerful predictor of coronary death. The aim was to examine whether apoB/apoA-I was associated with the metabolic syndrome (MetS) at baseline and also with the future change in carotid artery intima-media thickness (IMT).

Methods—

In 313 58-year-old men, carotid artery IMT was measured bilaterally by high-resolution B-mode ultrasound at baseline and after 3 years of follow-up. Serum apolipoprotein concentrations and the components of MetS were measured at study entry.

Results—

ApoB/apoA-I showed statistically significant associations with body mass index, waist-to-hip ratio, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) particle size, insulin, and diastolic blood pressure. Two thirds of the patients with MetS had high apoB/apoA-I ratios (>0.90) compared with one third of those without the syndrome (
P
<0.001). The IMT change was associated with apoB, total cholesterol, LDL cholesterol, triglycerides, and inversely with HDL cholesterol and LDL particle size at entry, and there was a strong colinearity between these variables. The subjects with apoB/apoA-I above the first tertile (0.74) had a 20-μm-higher (95% CI, 7 to 33) annual increase in IMT compared with those below this level after adjustment for blood pressure and smoking.

Conclusions—

The apoB/apoA-I ratio was strongly associated with MetS and its components at baseline. ApoB/apoA-I at baseline was related to the change in carotid artery IMT during 3 years of follow-up. There was a strong colinearity between apoB/apoA and the atherogenic lipids.
Findings From the Reanalysis of the NINDS Tissue Plasminogen Activator for Acute Ischemic Stroke Treatment Trial
Authors: Ingall Timothy John , O’Fallon William Michael , Asplund Kjell , Goldfrank Lewis Robert , Hertzberg Vicki S. , Louis Thomas Arthur , Christianson Teresa J. Hengy
Published: September 2004

Background and Purpose—

Following publication of concerns about the results of the National Institute of Neurological Disorders and Stroke (NINDS) intravenous tissue plasminogen activator (t-PA) in acute stroke treatment trial, NINDS commissioned an independent committee “to address whether there is concern that eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials and, whether the subgroup imbalance (in baseline stroke severity) invalidates the entire trial.”

Methods—

The original NINDS trial data were reanalyzed to assess the t-PA treatment effect, the effect of the baseline imbalance in stroke severity between the treatment groups on the t-PA treatment effect, and whether subgroups of patients did not benefit from receiving t-PA.

Results—

A clinically important and statistically significant benefit of t-PA therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-PA treated patients. The adjusted t-PA to placebo odds ratio (OR) of a favorable outcome was 2.1 (95% CI, 1.5 to 2.9). Although these exploratory analyses found no statistical evidence that the t-PA treatment effect differed among patient subgroups, the study was not powered to detect subgroup treatment differences.

Conclusions—

These findings support the use of t-PA to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-PA trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-PA in acute ischemic stroke patients.
The Relative Impact of Inadequate Primary and Secondary Prevention on Cardiovascular Mortality in the United States
Authors: Qureshi Adnan I. , Suri M. Fareed K. , Kirmani Jawad F. , Divani Afshin A.
Published: September 2004

Background and Purpose—

We developed a model to estimate the costs incurred by ineffective primary and secondary prevention in terms of excess cardiovascular disease (CVD) mortality in a nationally representative sample of the US population.

Methods—

Cox proportional hazards analyses were used to examine the effect of inadequate risk factor control on the incidence of fatal stroke and myocardial infarction (MI) during a follow-up period of 13.4±3.6 years after adjusting for differences in age, gender, and ethnicity in a national cohort of 9252 adults who participated in the Second National Health and Nutrition Examination Survey (NHANES) Mortality Follow-up Study. Inadequate risk factor modification was defined by presence of either blood pressure >140/90 mm Hg, serum cholesterol >200 mg/dL, or active cigarette smoking. Using the data from 4115 adults screened in the NHANES 1999 to 2000, population attributable risk (PAR) percent and associated cost incurred (expressed as proportion of total 1-year cost incurred for CVD mortality in year 2001) was estimated.

Results—

CVD mortality risk increased in a stepwise manner for persons with no previous MI or stroke and ≥2 inadequately controlled risk factors (2×); and previous history of MI and stroke and adequately controlled risk factors (2.6×), 1 inadequately controlled risk factor (4.3×), and ≥2 inadequately controlled risk factors (5.7×). The PAR was 14% (estimated cost incurred $13.2 billion) among persons with ≥2 inadequately controlled risk factors without previous MI or stroke (estimated 17% of total US population). Among persons with previous MI or stroke, the PAR was 7% (cost incurred $6.2 billion) and 8% (cost incurred $7.4 billion) for 1 inadequately controlled risk factor and ≥2 inadequately controlled risk factors, respectively. An excess of cost of $13.6 billion was spent on 4% of the total population (persons with inadequate secondary prevention).

Conclusions—

The model demonstrates the differential risk of mortality from inadequately controlled cardiovascular risk factors in primary and secondary prevention settings. The large financial cost incurred by inadequate primary and secondary prevention justifies intensive efforts directed toward detection and treatment of cardiovascular risk factors.
Systematic Review of Computed Tomographic Angiography for Assessment of Carotid Artery Disease
Authors: Koelemay Mark J.W. , Nederkoorn Paul J. , Reitsma Johannes B. , Majoie Charles B.
Published: September 2004

Background and Purpose—

To review the literature on the diagnostic accuracy of computed tomographic angiography (CTA) compared with arteriography/intra-arterial digital subtraction angiography as reference standard for assessment of symptomatic carotid artery disease.

Methods—

The PubMed, MEDLINE, PREMEDLINE, EMBASE, and CINAHL databases were searched to retrieve studies published between 1990 and July 2003, comparing CTA and intra-arterial digital subtraction angiography in patients with symptomatic carotid artery disease that presented raw data for detection of a <70% or 70% to 99% stenosis or an occlusion. Two observers independently assessed methodological quality and constructed 2×2 tables for sensitivity and specificity of CTA for detection of a 70% to 99% stenosis versus <70% stenosis or an occlusion, and for <99% stenosis versus occlusion. A bivariate random effects model was used to calculate the pooled sensitivity and specificity of CTA for detection of these lesions.

Results—

Some 864 patients (66% male) with a mean age of 66 years were studied in the 28 studies included in the meta-analysis. In all studies, a single-slice CT-scan was used. Only 8 studies satisfied all methodological quality criteria. The pooled sensitivity and specificity for detection of a 70% to 99% stenosis were 85% (95% CI, 79% to 89%) and 93% (95% CI, 89% to 96%), respectively. For detection of an occlusion, the sensitivity and specificity were 97% (95% CI, 93% to 99%) and 99% (95% CI, 98% to 100%), respectively. Incomplete reporting of demographic characteristics and technical differences in the individual studies obstructed a meaningful subgroup analysis.

Conclusions—

CTA is an accurate modality for detection of severe carotid artery disease, especially for detection of occlusions. The fair methodological quality of the included studies must be taken into account when interpreting these results.
Fibrinogen Concentration and Risk of Ischemic Stroke and Acute Coronary Events in 5113 Patients With Transient Ischemic Attack and Minor Ischemic Stroke
Authors: Rothwell Peter M. , Howard Sally C. , Power Dermot A. , Gutnikov Sergei A. , Algra Ale , van Gijn Jan , Clark Tanne G. , Murphy Michael F.G. , Warlow Charles P.
Published: September 2004

Background and Purpose—

Fibrinogen is an independent risk factor for coronary events in population-based studies and in patients with coronary heart disease, but there is uncertainty about prediction of stroke, particularly in secondary prevention.

Methods—

We studied unpublished data from 3 prospective studies of patients with recent transient ischemic attack (TIA) or minor ischemic stroke: the United Kingdom TIA Aspirin (UK-TIA) trial (n=1860); the Dutch TIA trial (n=2960); and the Oxford TIA Study (n=293). By separate and pooled analysis, we used Cox models to determine the relationship between fibrinogen and risk of ischemic stroke and other vascular events during 23 272 patient-years of follow-up and adjusted for other risk factors.

Results—

There was no significant heterogeneity in fibrinogen risk associations between studies. Fibrinogen predicted subsequent ischemic stroke, with a pooled hazard ratio (HR) for values above the median of 1.34 (95% CI, 1.13 to 1.60;
P
=0.001). The association tended to be stronger in patients with nonlacunar (HR=1.42; 95% CI, 1.13 to 1.78;
P
=0.002) than lacunar syndromes (HR=1.09; 95% CI, 0.80 to 1.49;
P
=0.58), but was not significantly so (
P
=0.18). There was no association with hemorrhagic stroke (adjusted HR=1.09; 95% CI, 0.55 to 2.17;
P
=0.81). Fibrinogen predicted acute coronary events (adjusted HR=1.42; 95% CI, 1.18 to 1.70;
P
<0.001) and all ischemic vascular events (adjusted HR=1.31; 95% CI, 1.15 to 1.49;
P
<0.001), but not nonvascular death (adjusted HR=1.24; 95% CI, 0.90 to 1.70;
P
=0.19).

Conclusions—

In patients with a previous TIA or ischemic stroke, risks of recurrent ischemic stroke and acute coronary events increase linearly with fibrinogen levels, but the relationships are weaker than in some previous population-based studies.
Medical and Nonmedical Determinants of Decision Making about Potentially Life-Prolonging Interventions
Authors: van der Heide Agnes , Vrakking Astrid , van Delden Hans , Looman Caspar , van der Maas Paul
Published: September 2004

Patient characteristics may influence medical decision making in various ways. The contribution of several patient characteristics to medical decision making was studied. Thirty oncologists, 29 nursing home physicians, and 22 cardiologistswere interviewed (overall response = 60%). Respondents were asked whether they would apply a specified intervention for a number of hypothetical seriously ill patients, who varied with respect to factors thatwere not relevant to the outcome of treatment. The condition that made patients clearly eligible for treatment was kept constant. In amultivariate regression model, patients with a better physical condition, a more obvious social role, and a lower age weremore likely to be treated thanwere other patients. Medical decision making is not exclusively based on empirical evidence but also related to morally complex issues such as patient age and social status.
Correcting Biases in Standard Gamble and Time Tradeoff Utilities
Authors: van Osch Sylvie M. C. , Wakker Peter P. , van den Hout Wilbert B. , Stiggelbout Anne M.
Published: September 2004

The standard gamble (SG) method and the time tradeoff (TTO) method are commonly used tomeasure utilities. However, they are distorted by biases due to loss aversion, scale compatibility, utility curvature for life duration, and probability weighting. This article applies corrections for these biases and provides new data on these biases and their corrections. The SG and TTO utilities of 6 rheumatoid arthritis health states were assessed for 45 healthy respondents. Various corrections of utilities were considered. The uncorrected TTO scores and the corrected (for utility curvature) TTO scores provided similar results. This article provides arguments suggesting that the TTO scores are biased upward rather than having balanced biases. The only downward bias in TTO scores was small and probably cannot offset the upward biases. TheTTOscores are higher than the theoretically most preferred correction of the SG, the mixed correction. These findings suggest that uncorrected SG scores, which are higher than TTO scores, are too high.
Pramipexole v. Levodopa as Initial Treatment for Parkinson’s Disease: A Randomized Clinical-Economic Trial
Authors: Noyes Katia , Dick Andrew W. , Holloway Robert G. ,   Parkinson Study Group
Published: September 2004

Purpose. To determine the 2-year incremental cost effectiveness of initial pramipexole treatment compared with initial levodopa treatment in patientswith early Parkinson’s disease (PD). Methods. 301 subjects with early PD were randomized to either pramipexole or levodopa and followed every 3 months over a 2-year period. Costs were assigned to patient collected health utilization data using a variety of methods. Health state preferences were estimated using the EuroQol. Results. Pramipexole strategy was an estimated $2,138 (SE = $1,182) more expensive than levodopa strategy. The incremental cost-effectiveness of pramipexole compared with levodopa was $106,900/QALY (EQ-5D), compared with pramipexole being dominated by levodopa using the EQVAS. Conclusions.Although considerable uncertainty exists in the 2-year cost-effectiveness of initial pramipexole compared with initial levodopa in the treatment of early PD, our estimates suggest that pramipexole may not be welfare enhancing during the first 2 years of treatment. If initial pramipexole results in long-term improvements in quality of life, its cost-effectiveness will become more favorable.
Unfinished Symphony: A Tribute to the Life and Career of Bernie O’Brien (1959–2004)
Authors: Briggs Andrew , Buxton Martin , Drummond Mike , Goeree Ron , Sculpher Mark J. , Willan Andrew R.
Published: September 2004

The death of Bernie O’Brien in February 2004 brought a premature end to one of the most productive and influential careers in the area of health technology assessment and economic evaluation. A long-term member of the Society for Medical Decision Making, Bernie will be remembered for his research contributions in areas including outcome valuation, decision modeling, statistical methods in economic evaluation, and applied cost-effectiveness studies. He was also an excellent communicator and teacher and, above all, a fun guy to work with. In this article, the authors provide a review of Bernie’s academic contributions.
Musical Expressions of Life: A Look at the 18th and 19th Century from a Human Becoming Perspective
Authors: Jonas-Simpson Christine
Published: September 2004

What follows is an exploration of 18th and 19th century music of theWestern world through a nursing science lens, specifically that of the human becoming theory. This article was written while I was enrolled in a music history course, which afforded me the opportunity to explore music as musical expressions of life. Rooted in the human becoming philosophical perspective, which focuses on unitary human experience and the quality of human life, I discuss musical expressions of life with examples from various composers throughout the 18th and 19th century. This article concludes with a reflection on musical expressions and their contribution to the enhancement of the quality of human life, a focus of nursing from a human becoming perspective.
Criterion-Related Validity in Multiple-Hurdle Designs: Estimation and Bias
Authors: Mendoza Jorge L. , Bard David E. , Mumford Michael D. , Ang Siew C.
Published: September 2004

Employee selection often involves a series of sequential tests (or hurdles). However, validation strategies under this complex design are not found in the literature. Missing is a discussion of the statistical properties important in establishing criterion-related validity in multiple-hurdle designs. The authors address this gap in the literature by suggesting a general statistical model for range restriction corrections. Because the multiple-hurdle design includes as special cases predictive and concurrent designs, the corrections apply also to these designs. The general correction model is based on algorithms from the missing data literature. Two missing data procedures are examined: the estimation-maximization procedure and the Bayesian multiple imputation (MI) procedure. These procedures are large-sample equivalent and often yield similar results. The MI procedure, however, has the added advantage of providing easily obtainable standard errors. A hypothetical example of a multiple-hurdle design is used to illustrate the procedures.
Developing a Procedure to Correct for Range Restriction That Involves Both Institutional Selection and Applicants’ Rejection of Job Offers
Authors: Yang Hyuckseung , Sackett Paul R. , Nho Yongjin
Published: September 2004

A common research problem in validation studies is the estimation of the population correlation between predictor X and performanceY from a non–randomly selected sample. Procedures for getting unbiased estimates of population correlations in a limited set of conditions in which no rejection of job offers is assumed have been developed. However, in applied selection settings, it is very likely that some of the candidates who have received job offers reject them through a selfselection process. If an estimation model based on the assumption that there is no rejection of job offers via self-selection is used, estimates of population parameters may be biased due to model misspecification. In the current study, a procedure is developed that is applicable to a variety of realistic validation settings, including a setting in which both institutional selection and applicant’s rejection of job offers are involved. Data requirements of the procedure are also discussed.
Measuring Gender Composition in Work Groups: A Comparison of Existing Methods
Authors: Williams Helen M. , Meân Lindsey J.
Published: September 2004

Reviewing research on diversity and relational demography in teams and work groups, the authors compare different ways of measuring gender composition and demonstrate that existing practice can be theoretically biased. The authors conclude that within group-level analyses, the proportion of women should be used; whereas within individual-level analyses, the appropriate approach depends on whether a gender-by-gender composition interaction effect is found. The generalizability of this approach to other types of diversity is also discussed.
Soluble factors elaborated by human brain endothelial cells induce the concomitant expansion of purified human BM CD34+CD38– cells and SCID-repopulating cells
Authors: Chute John P. , Muramoto Garrett G. , Fung Jennifer , Oxford Carol
Published: September 2004

The CD34+CD38– phenotype identifies a population in the bone marrow that is enriched in the steady state for hematopoietic stem cells (HSCs). Following ex vivo culture of CD34+ cells, HSC content is difficult to measure since committed CD34+CD38+ progenitors down-regulate CD38 surface expression during culture. In this study, we sought to define the phenotype of human HSCs following ex vivo culture under conditions that support the expansion of human cells capable of repopulating non-obese diabetic/severe combined immunodeficiency (SCID)–repopulating cells (SRCs). Contact coculture of fluorescence-activated cell sorter (FACS)–sorted bone marrow (BM) CD34+CD38– cells with human brain endothelial cells (HUBECs) supported a 4.4-fold increase in CD34+CD38– cells with a concordant 3.6-fold increase in SRCs over 7 days. Noncontact HUBEC cultures and the addition of thrombopoietin, stem cell factor (SCF), and macrophage colony stimulating factor I receptor (Fms)–like tyrosine kinase 3 (Flt-3) ligand supported further increases in CD34+CD38– cells (6.4-fold and 13.1-fold), which correlated with significant increases in SRC activity. Moreover, cell-sorting studies performed on HUBEC-cultured populations demonstrated that SRCs were significantly enriched within the CD34+CD38– subset compared with the CD34–CD38– population after culture. These results indicate that human HSCs can be identified and characterized by phenotype following expansion culture. These studies also demonstrate that HUBEC-elaborated soluble factors mediate a unique and potent expansion of human HSCs.
A stochastic model for retinocollicular map development
Authors: Koulakov Alexei A , Tsigankov Dmitry N
Published: September 2004

Background

We examine results of gain-of-function experiments on retinocollicular maps in knock-in mice [Brown et al. (2000) Cell 102:77]. In wild-type mice the temporal-nasal axis of retina is mapped to the rostral-caudal axis of superior colliculus. The established map is single-valued, which implies that each point in retina maps to a unique termination zone in superior colliculus. In homozygous Isl2/EphA3 knock-in mice the map is double-valued, which means that each point on retina maps to two termination zones in superior colliculus. This is because about 50 percent of cells in retina express Isl2, and two types of projections, wild-type and Isl2/EphA3 positive, form two branches of the map. In heterozygous Isl2/EphA3 knock-ins the map is intermediate between the homozygous and wild-type: it is single-valued in temporal and double-valued in the nasal parts of retina. In this study we address possible reasons for such a bifurcation of the map.

Results

We study the map formation using stochastic model based on Markov chains. In our model the map undergoes a series of reconstructions with probabilities dependent upon a set of chemical cues. Our model suggests that the map in heterozygotes is single-valued in temporal region of retina for two reasons. First, the inhomogeneous gradient of endogenous receptor in retina makes the impact of exogenous receptor less significant in temporal retina. Second, the gradient of ephrin in the corresponding region of superior colliculus is smaller, which reduces the chemical signal-to-noise ratio. We predict that if gradient of ephrin is reduced by a genetic manipulation, the single-valued region of the map should extend to a larger portion of temporal retina, i.e. the point of transition between single-and doulble-valued maps should move to a more nasal position in Isl2-EphA3 heterozygotes.

Conclusions

We present a theoretical model for retinocollicular map development, which can account for intriguing behaviors observed in gain-of-function experiments by Brown et al., including bifurcation in heterozygous Isl2/EphA3 knock-ins. The model is based on known chemical labels, axonal repulsion/competition, and stochasticity. Possible mapping in Isl2/EphB knock-ins is also discussed.
Hepatitis B virus variants in an HIV-HBV co-infected patient at different periods of antiretroviral treatment with and without lamivudine
Authors: Santos Eneida A , Sucupira Michel VF , Arabe Juçara , Gomes Selma A
Published: September 2004

Background

Lamivudine inhibits replication of both human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and is commonly used as part of antiretroviral therapy. The main limitation in the use of lamivudine is resistant mutation selection. Most of these mutations affect the YMDD motif of the HBV DNA polymerase. The resistance occurs through M550V or M550I aminoacid replacements. The M550V variation may be accompanied by L526M mutation, notably in HIV-HBV co-infected patients. The aim of this study was to investigate mutations associated with lamivudine resistance in a hemodialysis patient chronically co-infected with HIV-1 and HBV, who was submitted to several antiretroviral treatments.

Methods

HBV isolates derived from three blood samples collected at different times of antiretroviral therapies with and without lamivudine, were titred and submitted to nucleotide sequencing.

Results

HBV isolate derived from a sample collected in 1999 during an antiretroviral treatment with lamivudine showed the lamivudine resistant double mutation (L526M, M550V). However, no mutation associated with lamivudine resistance was observed in the HBV genome derived from the sample collected during a period of treatment without lamivudine (2001). After reinstitution of lamivudine (2002), the predominant HBV population exhibited a rare triple mutation (V519L, L526M, M550V), which has previously been associated with an in vitro reduction of virus antigenicity (escape mutant). HBV DNA was detected at high levels (108–109 copies/ml) in the three blood samples.

Conclusions

Reintroduction of lamivudine as part of antiretroviral treatment in a patient who had developed lamivudine resistant HBV strains favored the predominance of an HBV isolate with reduced antigenicity. The absence of hepatitis acute exacerbation in this patient may be correlated to the absence of significant variations of the viral load, which was independent of the presence of mutations in the HBV DNA polymerase.
A rational treatment of Mendelian genetics
Authors: Porteous John W
Published: September 2004

Background

The key to a rational treatment of elementary Mendelian genetics, specifically to an understanding of the origin of dominant and recessive traits, lies in the facts that: (1) alleles of genes encode polypeptides; (2) most polypeptides are catalysts, i.e. enzymes or translocators; (3) the molecular components of all traits in all cells are the products of systems of enzymes, i.e. of fluxing metabolic pathways; (4) any flux to the molecular components of a trait responds non-linearly (non-additively) to graded mutations in the activity of any one of the enzymes at a catalytic locus in a metabolic system; (5) as the flux responds to graded changes in the activity of an enzyme, the concentrations of the molecular components of a trait also change.

Conclusions

It is then possible to account rationally, and without misrepresenting Mendel, for: the origin of dominant and recessive traits; the occurrence of Mendel's 3(dominant):1(recessive) trait ratio; deviations from this ratio; the absence of dominant and recessive traits in some circumstances, the occurrence of a blending of traits in others; the frequent occurrence of pleiotropy and epistasis.
Mild hypothermia after near drowning in twin toddlers
Authors: Hein Ortrud Vargas , Triltsch Andreas , von Buch Christoph , Kox Wolfgang J , Spies Claudia
Published: September 2004

Introduction

We report a case of twin toddlers who both suffered near drowning but with different post-trauma treatment and course, and different neurological outcomes.

Methods and results

Two twin toddlers (a boy and girl, aged 2 years and 3 months) suffered hypothermic near drowning with protracted cardiac arrest and aspiration. The girl was treated with mild hypothermia for 72 hours and developed acute respiratory dysfunction syndrome and sepsis. She recovered without neurological deficit. The boy's treatment was conducted under normothermia without further complications. He developed an apallic syndrome.

Conclusion

Although the twin toddlers experienced the same near drowning accident together, the outcomes with respect to neurological status and postinjury complications were completely different. One of the factors that possibly influenced the different postinjury course might have been prolonged mild hypothermia.
G-CSF-mobilized CD34+ cells cultured in interleukin-2 and stem cell factor generate a phenotypically novel monocyte
Authors: Sconocchia Giuseppe , Fujiwara Hiroshi , Rezvani Katayoun , Keyvanfar Keyvan , El Ouriaghli Frank , Grube Matthias , Melenhorst Jos , Hensel Nancy , Barrett A John
Published: September 2004

To study the early stages of development from stem cells of the CD56+ cell population [which includes natural killer (NK) cells], granulocyte-colony stimulating factor-mobilized peripheral blood CD34+ cells from healthy donors were sorted to >99% purity and cultured in the presence of stem cell factor and interleukin (IL)-2. After 3 weeks in culture, the majority of cells acquired CD33, with or without human leukocyte antigen-DR and CD14. In 20 stem cell donors tested, 8.7 ± 8.8% of cells were CD56+. Two major CD56+ subsets were identified: CD56bright, mainly CD33− cells (7±10%, n=11) with large, granular lymphocyte morphology, and CD56dim, mainly CD33+ (2.5±2, n=11) cells with macrophage morphology. The CD56bright population had cytoplasmic granzyme A but lacked killer inhibitory receptor, suggesting they were immature NK cells. The CD56dim, CD33+, population lacked NK markers. They may represent a minor subset of normal monocytes at a developmental stage comparable with the rare CD56+ CD33+ hybrid myeloid/NK cell leukemia. Consistent with a monocyte nature, CD56dimCD33+ proliferated and produced a variety of cytokines upon lipopolysaccharide stimulation, including IL-8, IL-6, monocyte chemoattractant protein-1, and macrophage-derived chemokine but not interferon-γ. In a short-term cytotoxicity assay, they failed to kill but powerfully inhibited the proliferation of the NK-resistant cell line P815. The generation of CD56+ cells was negatively regulated by hyaluronic acid and IL-4, indicating that extracellular matrix may play an important role in the commitment of CD34+ cells into CD56 myeloid and lymphoid lineages.
Insulin-Like Growth Factor-I Regulation of Hepatic Scavenger Receptor Class BI
Authors: Cao Wen M. , Murao Koji , Imachi Hitomi , Yu Xiao , Dobashi Hiroaki , Yoshida Kazuya , Muraoka Tomie , Kotsuna Noriko , Nagao Sachi , Wong Norman C. W. , Ishida Toshihiko
Published: September 2004

High-density lipoprotein mediates a normal physiological process called reverse cholesterol transport. This process enables the transfer of cholesterol from peripheral tissues to the liver for further metabolism and eventual secretion in the form of bile. The scavenger receptor of the B class (SR-BI), human homolog of SR-BI, and CD36 and LIMPII analogous-1 (CLA-1) are different names for the same receptor that facilitates hepatocellular uptake of cholesterol from high-density lipoprotein. The pivotal role of this receptor in enterohepatic circulation of cholesterol and bile salts underlies our interest to study the regulation of hepatic SR-BI gene in response to the actions of IGF-I. The results of our studies showed that endogenous expression of SR-BI/CLA-1 was suppressed by exposure to GH or IGF-I in cultured HepG2 cells. This observation extended to a whole animal model of rats continuously infused with IGF-I. IGF-I decreased transcriptional activity of the SR-BI promoter. However, the inhibitory effect of IGF-I on SR-BI/CLA-1 promoter activity was abrogated by wortmannin, a specific inhibitor of phosphoinositide 3-kinase (PI3-K). Exposure of HepG2 cells to IGF-I elicited a rapid phosphorylation of Akt. We also demonstrated that the constitutively active form of both p110, a subunit of PI3-K, and Akt inhibited activity of the human SR-BI/CLA-1 promoter. Furthermore, the dominant-negative mutant of Akt abolished the ability of IGF-I to suppress activity of the SR-BI/CLA-1 promoter. In conclusion, PI3-K/Akt pathways participate in IGF-I-suppression of SR-BI/CLA-1 expression, which suggests that the activation of Akt plays an important role in cholesterol metabolism in liver.