bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnitude of HDL Cholesterol Variation After High-Dose Atorvastatin Is Genetically Determined at the LDL Receptor Locus in Patients With Homozygous Familial Hypercholesterolemia
Authors: Sposito Andrei C. , Gonbert Sophie , Bruckert Eric , Atassi Marielle , Beucler Isabel , Amsellem Sabine , Khallouf Oumayma , Benlian Pascale , Turpin Gerard
Published: September 2003

Objective—The combination of LDL apheresis with high doses of a potent hepatic hydroxymethylglutaryl coenzyme A reductase inhibitor, such as atorvastatin, has been the best therapy available for the prevention of cardiovascular disease in patients with homozygous familial hypercholesterolemia (HFH). However, some concerns have been made about the effect of atorvastatin on HDL cholesterol levels in these patients.

Methods and Results—HDL cholesterol levels were determined bimonthly over the course of 2 years of treatment with high-dose atorvastatin in genotypically defined HFH patients either receptor-defective (n=6) or receptor-negative (n=6) under long-term treatment with LDL apheresis. We additionally stratified the atorvastatin effect on HDL cholesterol according to the genotype as an indicator of residual in vivo LDL receptor activity. Our findings indicate that (1) an early and transitory reduction of plasma HDL cholesterol levels occurs during the first 4 weeks of atorvastatin treatment; (2) the degree of the transient HDL reduction is higher in receptor-negative than in receptor-defective patients (−21±11 versus −10±4%;P=0.01); and (3) after long-term treatment, HDL cholesterol concentration remains higher in receptor-defective than receptor-negative patients (P=0.026).

Conclusions—The present study reveals that HDL cholesterol reduction after high-dose atorvastatin is an early and transient event in HFH patients which magnitude depends on the presence of a residual LDL-R activity.
Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists
Authors: Mason R.P. , Marche P. , Hintze T.H.
Published: September 2003

Calcium channel blockers (CCBs) were developed as vasodilators, and their use in cardiovascular disease treatment remains largely based on that mechanism of action. More recently, with the evolution of second- and third-generation CCBs, pleiotropic effects have been observed, and at least some of CCBs’ benefit is attributable to these mechanisms. Understanding these effects has contributed greatly to elucidating disease mechanisms and the rationale for CCB use. Furthermore, this knowledge might clarify why drugs are useful in some disease states, such as atherosclerosis, but not in others, such as heart failure. Although numerous drugs used in the treatment of vascular disease, including statins and angiotensin-converting–enzyme inhibitors, have well-described pleiotropic effects universally accepted to contribute to their benefit, little attention has been paid to CCBs’ potentially similar effects. Accumulating evidence that at least 1 CCB, amlodipine, has pharmacologic actions distinct from L-type calcium channel blockade prompted us to investigate the pleiotropic actions of amlodipine and CCBs in general. There are several areas of research; foci here are (1) the physicochemical properties of amlodipine and its interaction with cholesterol and oxidants; (2) the mechanism by which amlodipine regulates NO production and implications; and (3) amlodipine’s role in controlling smooth muscle cell proliferation and matrix formation.
Atherosclerotic Plaque Rupture
Authors: Lutgens Esther , van Suylen Robert-Jan , Faber Birgit C. , Gijbels Marion J. , Eurlings Petra M. , Bijnens Ann-Pascale , Cleutjens Kitty B. , Heeneman Sylvia , Daemen Mat J.A.P.
Published: September 2003

It is generally established that the unstable plaque is the major cause of acute clinical sequelae of atherosclerosis. Unfortunately, terms indicating lesions prone to plaque instability, such as “vulnerable plaque,” and the different phenotypes of unstable plaques, such as plaque rupture, plaque fissuring, intraplaque hemorrhage, and erosion, are often used interchangeably. Moreover, the different phenotypes of the unstable plaque are mostly referred to as plaque rupture. In the first part of this review, we will focus on the definition of true plaque rupture and the definitions of other phenotypes of plaque instability, especially on intraplaque hemorrhage, and discuss the phenotypes of available animal models of plaque instability. The second part of this review will address the pathogenesis of plaque rupture from a local and a systemic perspective. Plaque rupture is thought to occur because of changes in the plaque itself or systemic changes in the patient. Interestingly, contributing factors seem to overlap to a great extent and might even be interrelated. Finally, we will propose an integrative view on the pathogenesis of plaque rupture.
Magnetic Resonance–Guided Cardiac Catheterization in a Swine Model of Atrial Septal Defect
Authors: Schalla Simon , Saeed Maythem , Higgins Charles B. , Martin Alastair , Weber Oliver , Moore Phillip
Published: September 2003

Background—

Radiation exposure during cardiac catheterization, limited image planes, and poor soft tissue definition are disadvantages of x-ray fluoroscopy that could be overcome with the use of MRI. This study evaluates the feasibility of real-time MRI (MR fluoroscopy) to guide left and right heart catheterization.

Methods and Results—

Anesthetized pigs (n=7) with defects of the atrial septum were catheterized using venous and arterial access. A prototype active tracking catheter was used to obtain blood pressures and samples from cardiac chambers and great vessels using antegrade, transseptal, and retrograde approaches. MR fluoroscopy was used for catheter steering. Velocity-encoded cine MRI was used to measure pulmonary and aortic blood flow to calculate vascular resistances. Image planes used during catheter manipulation used rapid sequencing to planes directed by the operator to include the tip of the catheter and the chamber to be entered. All areas of interest were effectively entered, and samples were obtained. In the presence of an acute atrial septal defect, a Q
p
/Q
s
ratio of 1.3±0.2 was measured, and no significant differences in pressure between inferior vena cava, right atrium, and left atrium were found. Pulmonary and aortic flow were 4.9±0.6 and 3.7±0.4 L/min, and pulmonary and systemic vascular resistance were 312±134 and 2006±336 dyne · s · cm
−5
.

Conclusions—

Left and right heart catheterization using MR guidance is feasible. The combination of hemodynamic catheterization data with anatomic and functional MRI may significantly improve the evaluation of patients with congenital heart disease while avoiding radiation exposure.
Inflammation in the Prediabetic State Is Related to Increased Insulin Resistance Rather Than Decreased Insulin Secretion
Authors: Festa Andreas , Hanley Anthony J.G. , Tracy Russell P. , D’Agostino Ralph , Haffner Steven M.
Published: September 2003

Background—

Elevated levels of proinflammatory proteins are predictive of both cardiovascular (CV) disease and type 2 diabetes. Previously, atherogenic changes in traditional CV risk factors in the prediabetic state were mainly seen in insulin-resistant subjects rather than in those with a predominant defect in insulin secretion.

Methods and Results—

We studied in prediabetic individuals from the Insulin Resistance Atherosclerosis Study (IRAS) the relation of C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-1, and fibrinogen to defects in insulin sensitivity (S
I
) and first-phase insulin secretion, respectively, as assessed using a frequently sampled intravenous glucose tolerance test. One hundred forty-eight of 906 (16.3%) nondiabetic individuals developed diabetes after a mean follow-up of 5.2 years. Prediabetic individuals who were insulin resistant had higher levels of PAI-1 (mean [95% CI], 25.83 ng/mL [22.42 to 29.77] versus 16.31 ng/mL [12.56 to 21.18];
P
=0.003) and CRP (mean [95% CI], 2.88 mg/L [2.33 to 3.56] versus 1.68 mg/L [1.13 to 2.49];
P
=0.018) than insulin-sensitive individuals, but individuals with decreased acute insulin response tended to have lower rather than higher levels of inflammatory proteins compared with those with high insulin secretion. Prediabetic subjects who were predominantly insulin resistant had higher levels of inflammatory proteins compared with both prediabetic subjects with decreased insulin secretion as well as nonconverters. By contrast, prediabetic subjects with a predominant defect in first-phase insulin secretion had levels of inflammatory proteins indistinguishable from those in nonconverters.

Conclusions—

We have shown an increased proinflammatory state in prediabetic individuals who are predominantly insulin resistant but not in those with a primary defect in β-cell function. These results provide additional evidence that prediabetic subjects may be at an increased risk of heart disease, and this risk seems to be restricted to subjects with high insulin resistance.
Rosiglitazone Reduces the Accelerated Neointima Formation After Arterial Injury in a Mouse Injury Model of Type 2 Diabetes
Authors: Phillips J. William , Barringhaus Kurt G. , Sanders John M. , Yang Zandong , Chen Meng , Hesselbacher Sean , Czarnik Ann C. , Ley Klaus , Nadler Jerry , Sarembock Ian J.
Published: September 2003

Background—

Hyperglycemia (HG) and hyperinsulinemia (HI) may be factors enhancing the atherosclerotic complications of diabetes. We hypothesized that specific feeding of C57BL/6 apolipoprotein (apo) E
−/−
mice would alter their metabolic profiles and result in different degrees of neointima (NI) formation. We additionally hypothesized that an insulin-sensitizing agent (rosiglitazone) would prevent the development of type 2 diabetes and reduce neointima formation after carotid wire injury measured at 28 days.

Methods and Results—

Fasting glucose and insulin levels were elevated in the Western diet (WD) group, with a trend toward higher insulin levels and euglycemia in the fructose diet (FD)–fed mice. NI formation was exaggerated in the WD group compared with the FD or chow control groups. In the WD mice given rosiglitazone, glucose and insulin levels remained normal and NI formation was significantly reduced, as was NI macrophage content.

Conclusions—

These findings demonstrate that apoE
−/−
mice fed a WD develop type 2 diabetes with an exaggerated NI response to injury. FD mice maintain euglycemia but develop insulin resistance, with an intermediate degree of NI growth compared with chow diet controls. Rosiglitazone prevents the development of hyperglycemia and hyperinsulinemia and normalizes the insulin release profile in the apoE
−/−
, WD-fed mouse and significantly reduces NI formation by 65% after carotid wire injury while reducing macrophage infiltration. These data support the hypothesis that type 2 diabetes in the setting of elevated cholesterol accelerates the response to vascular injury and suggest that agents that improve insulin sensitivity may have therapeutic value in reducing restenosis in type 2 diabetes.
Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction
Authors: Hayashidani Shunji , Tsutsui Hiroyuki , Shiomi Tetsuya , Ikeuchi Masaki , Matsusaka Hidenori , Suematsu Nobuhiro , Wen Jing , Egashira Kensuke , Takeshita Akira
Published: September 2003

Background—

Increased expression of monocyte chemoattractant protein-1 (MCP-1) has recently been described in clinical and experimental failing heart. However, its pathophysiological significance in heart failure remains obscure. We thus determined whether MCP-1 is increased in post-myocardial infarction (MI) hearts and its blockade can attenuate the development of left ventricular (LV) remodeling and failure.

Methods and Results—

Anterior MI was produced in mice by ligating the left coronary artery. After 4 weeks, MI mice exerted LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV. MCP-1 mRNA levels were increased by 40-fold in noninfarcted LV 1 day after ligation, which persisted until 28 days. To block the MCP-1 signals, an N-terminal deletion mutant of the human MCP-1 gene was transfected into the limb skeletal muscle 3 days before and 14 days after ligation. This method improved the survival rate of mice with MI at 4 weeks (61% versus 87%,
P
<0.05) as well as attenuated LV cavity dilatation and contractile dysfunction, interstitial fibrosis, recruitment of macrophages, and myocardial gene expression of tumor necrosis factor-α and transforming growth factor-β compared with the nontreated MI mice despite the comparable infarct size calculated as percent LV circumference.

Conclusions—

The activation of MCP-1 expression contributes to the LV remodeling and failure after MI. An anti-MCP-1 gene therapy can be a useful novel strategy for preventing post-MI heart failure.
Sustained Improvement After Combined Anterior Mitral Leaflet Extension and Myectomy in Hypertrophic Obstructive Cardiomyopathy
Authors: van der Lee Chris , Kofflard Marcel J.M. , van Herwerden Lex A. , Vletter Willem B. , ten Cate Folkert J.
Published: September 2003

Background—

Mitral leaflet extension (MLE) combined with septal myectomy is a new surgical approach to treat hypertrophic obstructive cardiomyopathy (HOCM) and an enlarged mitral leaflet area. The study presents the long-term clinical results and outcome of this technique.

Methods and Results—

MLE entails grafting a glutaraldehyde-preserved autologous pericardial patch onto the center portion of the anterior mitral valve leaflet. Twenty-nine patients with HOCM were studied. Mean follow-up (±SD) was 3.4±2.1 years (range 3 months to 7.7 years). The preoperative calculated mitral leaflet area was 16.7±3.4 cm
2
. New York Heart Association functional class improved significantly from 2.8±0.4 to 1.3±0.4 (
P
<0.05), width of the interventricular septum decreased from 23±4 to 17±2 mm (
P
<0.05), left ventricular outflow tract gradient decreased from 100±20 to 17±14 mm Hg (
P
<0.01), severity of mitral regurgitation graded on a scale from 0 to 4+ decreased from 2.5±0.9 to 0.5±0.6 (
P
<0.01), and severity of the systolic anterior motion of the mitral valve graded on a scale from 0 to 3+ decreased from 2.9±0.3 to 0.5±0.7 (
P
<0.01) postoperatively. There were no deaths associated with surgery.

Conclusions—

Long-term follow-up shows sustained improvement in functional status, reduction of outflow tract obstruction, and attenuation of mitral regurgitation and systolic anterior motion of the mitral valve. In this respect, the new technique widens the surgical applications in HOCM.
Delayed Maturation of Catecholamine Phenotype in Nucleus Tractus Solitarius of Rats With Glial Angiotensinogen Depletion
Authors: Ogier Michael , Bezin Laurent , Cottet-Emard Jean-Marie , Bader Michael , Vincent Madeleine , Pequignot Jean-Marc , McGregor John , Bricca Giampiero
Published: September 2003

Cerebral catecholamines and angiotensins are both involved in the regulation of cardiovascular function. Recent in vitro studies have suggested that angiotensin II modulates noradrenergic neurotransmission by controlling both the expression and neuritic trafficking of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. To assess the potential existence of such mechanisms in vivo, we compared TH phenotype ontogeny in the nucleus tractus solitarius (NTS), which is the first central relay of the baroreflex, between control Sprague-Dawley rats and TGR(ASrAOGEN) rats (TG) with glial specific angiotensinogen (AOGEN) depletion. TG displayed a delayed increase in both TH-mRNA and TH protein levels, which sharply rises in the NTS of control rats within the fourth week. The delayed maturation of TH phenotype also affected the presence of TH protein in the neuropil, not only within the NTS region but also within the ventrolateral medulla. This was evidenced by a large decrease in the density of TH-containing neuronal processes in TG at 4 weeks only, without noticeable modification of the labeling of the neuritic marker MAP2, suggesting that neuritic trafficking of TH protein was transiently altered. These results indicate that glial AOGEN is crucial to coordinate within the fourth week the mechanisms driving the maturation of NTS catecholaminergic neurons and suggest that impairment of the central angiotensinergic system early in development can lead to cardiovascular dysfunction related to altered maturation of catecholaminergic neurons located in both the dorsal and the ventrolateral medulla.
Adrenomedullin Is Decreased in Preeclampsia Because of Failed Response to Epidermal Growth Factor and Impaired Syncytialization
Authors: Li Hongshi , Dakour Jamal , Kaufman Susan , Guilbert Larry J. , Winkler-Lowen Bonnie , Morrish Donald W.
Published: September 2003

To explore the mechanisms of adrenomedullin (ADM) regulation in normal and preeclamptic (PE) states, we determined placental production of ADM and ADM regulation by cytokines. Isolated, purified cytotrophoblast cultures from normal (n=8) and PE (n=10) placentas were cultured for 3 days in the absence or presence of 10 ng/mL epidermal growth factor (EGF), 1 ng/mL transforming growth factor (TGF)-β1, 10 ng/mL tumor necrosis factor (TNF)-α, or 100 U/mL interferon (IFN)-γ. Cells were also cultured for 3 days in 10% fetal bovine serum for determination of syncytial formation by desmoplakin staining. Pieces of normal and PE placentas were snap-frozen for ADM mRNA measurement. Results showed that basal ADM production into culture medium by radioimmunoassay was significantly lower in PE placental cells. EGF significantly stimulated ADM production in normal trophoblasts but did not in PE placentas. None of the factors TNF-α, TGF-β1, or IFN-γ altered ADM secretion in either normal or PE placentas. ADM expression by Northern blot analysis demonstrated a 34.3±8.3% reduction in mRNA expression in PE placentas. Syncytialization, as assessed by desmoplakin-outlined syncytial units, was decreased in PE placentas (day 3: normal, 16.7±1.3%; PE, 5.5±2.0%;
P
<0.01, ANOVA). However, there was a normal increment in syncytialization in response to EGF in normal and PE trophoblast preparations (EGF day 3: normal, 43.8±5.6%; PE, 46.1±12.3%). We conclude that spontaneous placental syncytialization is impaired in PE and that ADM production is markedly reduced in PE, possibly owing to an impaired EGF response. These abnormalities indicate poor placental production of ADM as the likely cause of a failed compensatory increase in maternal serum ADM levels in PE.
Endothelin-1 Stimulates Arterial VCAM-1 Expression Via NADPH Oxidase-Derived Superoxide in Mineralocorticoid Hypertension
Authors: Li Lixin , Chu Yi , Fink Gregory D. , Engelhardt John F. , Heistad Donald D. , Chen Alex F.
Published: September 2003

Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O
2
−
). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or β-galactosidase (β-gal) reporter gene (5×10
10
plaque formation units [pfu]/mL), and the effect of transgene expression on O
2
−
and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ET
A
receptor antagonist ABT-627 (3×10
−8
mol/L), NADPH oxidase inhibitor apocynin (10
−4
mol/L), or dominant negative Rac1 gene transfer. The levels of O
2
−
and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not β-gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O
2
−
from an ET
A
receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
Paradoxical Elevation in Adiponectin Concentrations in Women With Preeclampsia
Authors: Ramsay Jane E. , Jamieson Nigel , Greer Ian A. , Sattar Naveed
Published: September 2003

Adiponectin is a recently identified, insulin-sensitizing and anti-inflammatory protein released by adipocytes, which is paradoxically reduced in obesity. It suppresses endothelial activation. Physiological insulin resistance occurs in normal pregnancy and is exaggerated in women with preeclampsia (PE), together with enhanced inflammatory and endothelial activation. Women with increased body mass index (BMI) and insulin resistance are predisposed to PE. We hypothesized that adiponectin concentrations are reduced in normal pregnancy compared with postpartum values and further reduced in women with PE. Fifteen women with PE and 30 control subjects with similar first trimester BMI had adiponectin concentrations measured in the third trimester; postpartum measurements were repeated in 16 control subjects. Adiponectin concentration in healthy pregnant women correlated inversely with early pregnancy BMI (
r
=−0.47,
P
=0.01) and fasting insulin concentrations (
r
=−0.58,
P
=0.001). However, adiponectin concentrations did not differ significantly in pregnancy and postpartum samples (mean change, −0.15 μg/mL; 95% CI, −2.28 to 1.98,
P
=0.88). Plasma adiponectin concentrations were markedly elevated (
P
=0.01) in women with PE (mean, 21.6; SD, 8.18 μg/mL) compared with control subjects (mean, 14.7; SD, 7.06 μg/mL). Moreover, in PE, adiponectin concentrations did not correlate with first trimester BMI or insulin or with serum urate or creatinine concentrations or urinary protein levels. We conclude that plasma adiponectin concentrations are not elevated in normal human pregnancy and paradoxically elevated (by 47%) in women with PE. This may be secondary to exaggerated nonspecific adipocyte lipolysis or as a physiological response to enhance fat utilization and attenuate endothelial damage. Future studies should determine whether adiponectin concentrations help improve prediction of PE.
TRPV2 Is a Component of Osmotically Sensitive Cation Channels in Murine Aortic Myocytes
Authors: Muraki Katsuhiko , Iwata Yuko , Katanosaka Yuki , Ito Tomohiro , Ohya Susumu , Shigekawa Munekazu , Imaizumi Yuji
Published: September 2003

Changes in membrane tension resulting from membrane stretch represent one of the key elements in blood flow regulation in vascular smooth muscle. However, the molecular mechanisms involved in the regulation of membrane stretch remain unclear. In this study, we provide evidence that a vanilloid receptor (TRPV) homologue, TRPV2 is expressed in vascular smooth muscle cells, and demonstrate that it can be activated by membrane stretch. Cell swelling caused by hypotonic solutions activated a nonselective cation channel current (NSCC) and elevated intracellular Ca
2+
([Ca
2+
]
i
) in freshly isolated cells from mouse aorta. Both of these signals were blocked by ruthenium red, an effective blocker of TRPVs. The absence of external Ca
2+
abolished this increase in [Ca
2+
]
i
caused by the hypotonic stimulation and reduced the activation of NSCC. Significant immunoreactivity to mouse TRPV2 protein was detected in single mouse aortic myocytes. Moreover, the expression of TRPV2 was found in mesenteric and basilar arterial myocytes. Treatment of mouse aorta with TRPV2 antisense oligonucleotides resulted in suppression of hypotonic stimulation-induced activation of NSCC and elevation of [Ca
2+
]
i
as well as marked inhibition of TRPV2 protein expression. In Chinese hamster ovary K1 (CHO) cells transfected with TRPV2 cDNA (TRPV2-CHO), application of membrane stretch through the recording pipette and hypotonic stimulation consistently activated single NSCC. Moreover, stretch of TRPV2-CHO cells cultured on an elastic silicon membrane significantly elevated [Ca
2+
]
i
. These results provide a strong basis for our purpose that endogenous TRPV2 in mouse vascular myocytes functions as a novel and important stretch sensor in vascular smooth muscles.
Role of Neutral Amino Acid Transport and Protein Breakdown for Substrate Supply of Nitric Oxide Synthase in Human Endothelial Cells
Authors: Simon Alexandra , Plies Lars , Habermeier Alice , Martiné Ursula , Reining Marco , Closs Ellen I.
Published: September 2003

Endothelial dysfunction is often associated with a relative substrate deficiency of the endothelial nitric oxide synthase (eNOS) in spite of apparently high intracellular arginine concentrations. For a better understanding of the underlying pathophysiological mechanisms, we aimed to characterize the intracellular arginine sources of eNOS. Our previous studies in human endothelial EA.hy926 cells suggested the existence of two arginine pools: pool I can be depleted by extracellular lysine, whereas pool II is not freely exchangeable with the extracellular space, but accessible to eNOS. In this study, we demonstrate that the eNOS accessible pool II is also present in human umbilical vein endothelial cells (HUVECs), but not in ECV bladder carcinoma cells transfected with an expression plasmid for eNOS. In the endothelial cells, one part of pool II (referred to as pool IIA) consisted of recycling of citrulline to arginine. This part could be depleted by neutral amino acids that match the substrate profile of system N transporter 1 (SN1), presumably by the removal of intracellular citrulline. SN1 was expressed in EA.hy926 cells and HUVECs as shown by real-time RT-PCR. The second part of pool II (referred to as pool IIB) could not be depleted by any of the cationic or neutral amino acids tested. Our data demonstrate that pool IIB is nourished by protein breakdown and thus represents a substrate pool likely to accumulate protein-derived endogenous inhibitors of eNOS. Preferential use of the arginine pool IIB under pathophysiological conditions might therefore explain the arginine paradox.
Why have Educational Evaluators Chosen Not to Do Randomized Experiments?
Authors: Cook Thomas D.
Published: September 2003

This article analyzes the reasons that have been adduced within the community of educational evaluators for not doing randomized experiments. The objections vary in cogency. Those that have most substance are not insurmountable, however, and strategies are mentioned for dealing with them. However, the objections are serious enough, and the remedies partial enough, that it seems hardly warranted to call experiments the “gold standard” of causal inference. Yet even if they are not perfect in research practice, this article shows how they are logically and empirically superior to all currently known alternatives. The article particularly addresses the objection that school personnel will not accept experiments. It shows that hundreds of them have been done there by researchers with backgrounds in psychology and public health who study the prevention of unhealthy behaviors. But experiments are much rarer among researchers trained in education who study changing academic performance. Reasons are adduced for this difference in academic culture within school-based research.
Using Random Allocation to Evaluate Social Interventions: Three Recent U.K. Examples
Authors: Oakley Ann , Strange Vicki , Toroyan Tami , Wiggins Meg , Roberts Ian , Stephenson Judith
Published: September 2003

Although widely accepted in medicine and health services research, randomized controlled trials (RCTs) are often viewed with hostility by social scientists, who cite a variety of reasons as to why this approach to evaluation cannot be used to research social interventions. This article discusses the three central themes in these debates, which are those of science, ethics, and feasibility. The article uses three recent U.K. trials of social interventions (day care for preschool children, social support for disadvantaged families, and peer-led sex education for young people) to consider issues relating to the use of random allocation for social intervention evaluation and to suggest some practical strategies for the successful implementation of “social” RCTs. The article argues that the criteria of science, ethics, and feasibility can and should apply to social intervention trials in just the same way as they do to clinical trials.
Misleading Evidence and Evidence-Led Policy: Making Social Science more Experimental
Authors: Sherman Lawrence W.
Published: September 2003

Increasing demands by government for “evidence-led” policy raise the risk that research evidence will mislead government rather than leading to an unbiased conclusion. The need for unbiased research conclusions has never been greater, yet few consumers of research understand the statistical biases with which science must always struggle. This article introduces the volume's discussion of those issues with an explanation of the major threats of bias in social science research and a map of the differing scientific opinions on how to deal with those threats. The thesis of the volume is that many of these threats could be reduced by making social science more experimental. The fact that even experimental evidence contains threats of bias does not alter that claim but merely suggests another: that educated consumers of social science may be the best defense against misleading evidence of all kinds.
Populating an International Web-Based Randomized Trials Register in the Social, Behavioral, Criminological, and Education Sciences
Authors: Turner Herbert , Boruch Robert , Petrosino Anthony , Lavenberg Julia , de Moya Dorothy , Rothstein Hannah
Published: September 2003

Underlying the work of the Campbell Collaboration (C2) is the Sociological, Psychological, Educational, and Criminological Trials Register (C2-SPECTR). A Web-accessible database, C2-SPECTR is unique in the world. With more than 11,600 citations, it is an international register on randomized controlled trials (RCTs) or possible trials. This article describes the framework for populating C2-SPECTR, other registers that are prospective, and the practical issues of implementation. The authors discuss the growing importance of RCTs and the recent histories of organizations that have influenced this growth—the Cochrane Collaboration, the C2, and the What Works Clearinghouse. Next, the authors describe the origins of C2-SPECTR and plans to populate it and a prospective register. The authors conclude with plans for implementing the surveillance systems and the anticipated challenges in actualizing these plans.
Discourses of Female Violence and Societal Gender Stereotypes
Authors: Gilbert Paula Ruth
Published: September 2003

The way that society talks about women and their use of violence and force has grave implications for social policy and women's experiences in the criminal justice system. Society's cultural stereotypes about women and gender color the way professionals in law enforcement, the legal system, the courts, and social policy agencies treat women who commit violent acts of aggression. This article will attempt to shed some light on how gender stereotypes that continue to permeate our society create the very cultural discourses that people in positions of power and in the population at large use to talk about women and violence.
Women's Use of Force
Authors: Worcester Nancy
Published: September 2003

This article discusses the complexities, challenges, and urgency surrounding addressing women's use of force. The author emphasizes that women's and girls'use of force needs to be analyzed using a framework that keeps power and control central to the definition of domestic violence and identifies that violence by men and women takes place within a social, historical, and economic context in which men's and women's roles, opportunities, and social power differ. The article builds on an understanding of women's use of force in heterosexual relationships; however, a similar contextual analysis is also applied to women's use of force in teen dating relationships, lesbian relationships, and against children.
A Working Analysis of Women’s Use of Violence in the Context of Learning, Opportunity, and Choice
Authors: Perilla Julia L. , Frndak Kim , Lillard Debbie , East Cynthia
Published: September 2003

This article explores women’s uses of violence by bringing together feminist sociopolitical analysis and bell hooks’s concept of patriarchal violence in the home. The voices of women from diverse backgrounds, sexual orientations, and ethnicities illustrate each of the three components (learning, opportunity, and choice) of Zemsky’s and Gilbert, Poorman, and Simmons’s model of domestic violence. The ideas emerging from this initial exploration of the issue lend support to the importance of contextualizing individual acts of violence within frameworks that include, among other elements, ethnicity and sexual orientation. The authors emphasize the importance of inviting the voices of women who have been affected by intimate partner violence to guide the ongoing dialogue and exploration of this social issue.
Making Social Change
Authors: McMahon Martha , Pence Ellen
Published: September 2003

The arrest of large numbers of women under laws originally designed to protect them from male violence tells us very little about women’s use of violence against their intimate partners. However, it does tell us about the difficulties of organizing to protect women from violence and about some of the unanticipated challenges of engaging the legal and criminal justice systems as ways of protecting women from violence. The authors offer strategies that activists can use to advocate for women who have been victims of domestic violence and who have been arrested for using domestic violence.
The Words Change, But the Melody Lingers
Authors: Ferraro Kathleen J.
Published: September 2003

Acceptance of expert testimony on the battered woman syndrome in criminal and civil cases has established expectations about “real” battered women that reinforce conventional notions of femininity. Despite well-documented and publicized analyses of the status of the syndrome as no longer reflecting the range of knowledge relevant to battered women in legal settings, the expectations of helplessness promoted by the syndrome persist. In this article, specific cases are discussed in which the characteristics described in the syndrome are contrasted with the assertiveness, strength, and strategic decision making expressed by female defendants who had been battered. The negative consequences of the persistence of the battered woman syndrome in court are also described.
The pale cast of thought: an essay review of Thinks … by David Lodge
Authors: Barnett S. Anthony
Published: September 2003

When, in the twenty-first century, psychologists or popularisers ask ‘what is consciousness?’, or refer to the ‘mind body problem’, what are they up to?Does their discourse, sometimes called cognitive science, fall within the modern idea of the natural sciences? Like many before them, some try to reduce human beings to machines: both mind and the brain become computers. Kinds of knowledge outside the sciences are ignored or derogated. Cognitive scientists consequently make it difficult or impossible for them to understand themselves, let alone other people, or to adopt a moral stance. This essay, in contrast, was not generated by a computer, nor is it addressed to one.
Margaret Cavendish as natural philosopher: gender andearly modern science
Authors: Tillery Denise
Published: September 2003

Margaret Cavendish, Duchess of Newcastle (1623-73), was a prolific writer with a strong interest in science. Her work, long ignored, has recently been garnering serious critical attention. This article considers her Observations on Experimental Philosophy as more than just a critique of the Royal Society's mechanistic science. Whilst she was certainly responding to other scientific texts she read, Cavendish also practised her own version of natural philosophy, one that relied on observation to support her objections to Robert Hooke and other Royal Society scientists. Hers was a scientific practice that relied on passive observation rather than invasive experiment. As an early modern woman interested innatural philosophy, she demonstrates concernfor herreaders’ abilities to comprehend difficult texts, and she models herself as a reader of scientific texts and a practitioner of science herself.
Representations of science in the nineteenth century periodical press
Authors: Cantor Geoffrey , Shuttleworth Sally , Topham Jonathan R.
Published: September 2003

Public interest in science is often thought to have been much greater in the nineteenth century than at the present time. However, little attention has been paid to the media used to disseminate science to different audiences in nineteenth century Britain. In particular, the vast bulk of general periodicals which fill our library shelves continues to be largely impenetrable. Yet readers encountered a great quantity and an extensive variety of scientific, technical, and medical information in the pages of such general periodicals as Punch, the Boy's Own Paper, and Dickens's Household Words. This article describes the work of the ‘Science in the nineteenth-century periodical’ (SciPer) project at the universities of Leeds and Sheffield, which seeks to identify and analyse the representation of science in the non-specialist periodical press. The project has prepared an electronic index of the science content of a range of periodicals, chosen to reflect the increasing range of reading audiences addressed in the nineteenth century. In addition to detailing the methodology employed, this article includes examples of the project's findings, showing how both science and scientists were presented in such journals as the Comic Annual and the Review of Reviews.
Experimentation or exploitation? The investigations of David Ferrier, Dr Benjulia, and Dr Seward
Authors: Pedlar Valerie
Published: September 2003

This article places the work of David Ferrier in the context of the vivisection movement and the agitation of its opponents. Between 1873 and 1874, Ferrier used the facilities of the laboratory attached to the Wakefield Lunatic Asylum to experiment first on animals and then, post-mortem, on patients who had died while in the asylum. These experiments and others on monkeys aroused considerable controversy at the time, and led to Ferrier's being prosecuted by antivivisectionists. His work made an important contribution to the understanding of the brain and of neurological disturbance, but raises important questions as to whether the cruelty of experimentation can be justified in the interests of ultimate good. Heart and Science (1883), where there is a specific reference to Ferrier in the preface, is Wilkie Collins's fictional protest against vivisection, and the second part of this article analyses the ways in which the concerns of the antivivisectionists are explored in the novel, particularly through the character of Dr Benjulia. Collins shows the dehumanising effect of the habitual practice of cruelty to animal subjects. He also dramatises the concern of antivivisectionists that animal experimentation was motivated primarily by thoughts of professional advance. The final part of the article focuses on Dracula (1897). Dr Seward, the superintendent of the lunatic asylum, has a Faustian desire for knowledge of the brain. Fascinated by his patient Renfield's zoophagy, he experiments in a tentative way, measuring himself against two prominent vivisectionists, Sir John Scott Burdon-Sanderson and David Ferrier. Instead of polemic, this novel, a gothic fantasy, offers an imaginative exploration of the themes of professional advancement, vivisection, and the limitations of science.
From Copenhagen to infinity and beyond: Science meets literature on stage
Authors: Shepherd-Barr Kirsten
Published: September 2003

Works like Copenhagen and After Darwin have shownthat ‘science plays’ can be an especially successful and powerful meeting point of literature and science. Here, we continue the exploration of science and theatre offered in last year's special issue of ISR on science and theatre, by looking at science plays from both a literary and a theatrical perspective. What is it that makes them work as theatre?In many science plays, form and content merge to convey the ideas in a highly theatrical way that reflects the scientific substance and themes. As analysis of specific textual examples shows, this interdependence of formal and thematic properties has become one of the hallmarks of the contemporary genre of science plays, along with their often provocative and innovative challenges to stage realism.
The lacunae of science: observing the unobserved in the practices of knowledge
Authors: Rauch Alan
Published: September 2003

The purpose of this paper is to address the interstitial spaces that exist not only between disciplinary methods, but often even within distinct modes of inquiry guided by their own strict disciplinary rules. Case studies are used, drawn from cetacean behaviour as well as from the history of science, in an effort to explore the role of absences - ‘lacunae’ - in patterns of human inquiry. This is an approach that owes a great deal to the field of cultural studies, which has undertaken in recent decades to understand what is ‘missing’ from the canonical frameworks of literature and culture. Rather than being an expression of the need for more or better knowledge, or even for more diverse knowledge, what is at the heart of this venture is the desire to understand and appreciate the cultural ‘topography’ of knowledge. In the constantly shifting landscape of knowledge, where determinative lacunae are inescapable, knowledge will, as a consequence of cultural values, reconstitute itself in terms of meaning, of visibility, of significance, and of consequence.
IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation
Authors: Jordan William J. , Brookes Paul A. , Szydlo Richard M. , Goldman John M. , Lechler Robert I. , Ritter Mary A.
Published: September 2003

Despite the success of human leukocyte antigen (HLA) typing in allogeneic stem cell transplantation (SCT) it is rare to find an unrelated donor that is perfectly matched, making identification of “permissive” mismatches of paramount importance. Here, we describe novel associations between donor T-cell cytokine production during donor-antipatient mixed lymphocyte reactions (MLRs) and acute graft-versus-host disease (aGVHD). The data reveal positive correlations between both Th1-type and Th2-type cytokine production and GVHD and the assay established could potentially represent a useful tool for identification of permissible unrelated SCT donors. Associations between interleukin 13 (IL-13) levels and aGVHD were by far the strongest predictor of a GVHD (P = .0002). All patients suffering severe (grade III) aGVHD following SCT had donors who produced very high pretransplantation IL-13 responses, while those developing little or no aGVHD (grades 0-I) produced no IL-13 at all. IL-13 levels were independent of all other cytokines measured as well as cytotoxic T-lymphocyte precursor (CTLp) frequencies. The cytokines IL-5, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) also predicted development of aGVHD (P < .05 for all 3), appearing to be coproduced in the assay and correlating with estimated CTLp frequencies. The data challenge the notion that aGVHD is purely a Th1-type cytokine-driven response, high-lighting a novel and highly significant link between the Th2-type cytokine IL-13 and aGVHD.
Graft-versus-host-reactive donor CD4 cells can induce T cell-mediated rejection of the donor marrow in mixed allogeneic chimeras prepared with nonmyeloablative conditioning
Authors: Kim Yong-Mi , Mapara Markus Y. , Down Julian D. , Johnson Kevin W. , Boisgerault Florence , Akiyama Yoshinobu , Benichou Gilles , Pelot Michele , Zhao Guiling , Sykes Megan
Published: September 2003

Murine mixed hematopoietic chimerism can be achieved following nonmyeloablative conditioning with cyclophosphamide, T cell–depleting monoclonal antibodies, and thymic irradiation. Donor lymphocyte infusions (DLIs) 35 days after bone marrow transplantation (BMT) convert mixed to full donor chimerism and mediate graft-versus-lymphoma effects without graft-versus-host disease. We evaluated the role of T-cell subsets in DLIs in converting mixed to full donor chimerism in a fully major histocompatibility complex–mismatched strain combination. Whereas DLIs administered on day 35 converted 100% of mixed chimeras to full donor chimerism, conversion was less frequent when either CD4 or CD8 cells were depleted, indicating that both subsets contribute to the conversion. Surprisingly, administration of CD8-depleted DLIs led to complete loss of donor chimerism in a high proportion (54%) of recipients compared with CD4-plus CD8-depleted DLIs (15%) or CD4-depleted DLIs (0%) (P < .05). DLIs administered at early time points after BMT (eg, day 21) also precipitated rejection of donor marrow by recipient αβ T cells, in association with donor CD4 cell expansion and high production of interleukin 2 (IL-2), IL-4, and interferon-γ. Thus, DLIs can paradoxically induce marrow rejection by residual host αβ T cells. These results have implications for the timing of and use of subset depletion of DLIs in recipients of nonmyeloablative transplants.
Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors
Authors: Miklos David B. , Kim Haesook T. , Zorn Emmanuel , Hochberg Ephraim P. , Guo Luxuan , Mattes-Ritz Alex , Viatte Sebastien , Soiffer Robert J. , Antin Joseph H. , Ritz Jerome
Published: September 2003

Minor histocompatibility antigens (mHAs) recognized by donor T cells play a central role as immunologic targets of graft-versus-host disease (GVHD) and graft versus leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Men who have undergone sex-mismatched allogeneic HSCT are at high risk for GVHD because of immune responses directed against mHAs encoded by genes on the Y chromosome (termed H-Y antigens). We hypothesized that the immunogenicity of mHAs results in a coordinated response involving B cells as well as T cells. To test this, we measured antibody responses to a well-characterized H-Y antigen, dead box RNAhelicase Y (DBY), and its homolog, DBX, in 150 HSCT patients. Using Western blot and enzyme-linked immunosorbent assay (ELISA), we found that 50% of male patients who received stem cell grafts from female donors developed antibody responses to recombinant DBY protein. Antibodies to DBY were also detected in 17% of healthy women, but not in healthy men. Antibody responses were directed primarily against areas of amino acid disparity between DBY and DBX. These studies demonstrate that the immune response to mHA includes the generation of specific antibodies and suggests that the serologic response to these antigens may also be useful in the identification of new mHAs.