bluuebunny/crossref_metadata_2025 huggingface dataset:
Stable Compounds of Cigarette Smoke Induce Endothelial Superoxide Anion Production via NADPH Oxidase Activation
Authors: Jaimes Edgar A. , DeMaster Eugene G. , Tian Run-Xia , Raij Leopoldo
Published: April 2004

Objective—

Endothelial dysfunction is an early manifestation of cigarette smoke (CS) toxicity. We have previously demonstrated that CS impairs nitric oxide (NO)-mediated endothelial function via increased generation of superoxide anion (O

2
). In these studies, we investigated whether stable compounds present in CS activate specific pathways responsible for the increased endothelial O
OV0254;
2
production.

Methods and Results—

Short exposure of bovine pulmonary artery endothelial cells (BPAECs), human pulmonary artery endothelial cells, and rat pulmonary arteries to CS extracts (CSEs) resulted in a large increase in O
OV0254;
2
production (20-fold, 3-fold, and 2-fold increase, respectively;
P
<0.05 versus control), which was inhibited by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodinium, apocynin, and gp91 docking sequence-tat peptide but not by oxypurinol, the NO synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester, or the mitochondrial respiration inhibitor rotenone. Exposure of BPAECs to acrolein, a stable thiol-reactive agent found in CS, increased O
OV0254;
2
production 5-fold, which was prevented by prior inhibition of NADPH oxidase.

Conclusions—

These studies demonstrate that thiol-reactive stable compounds in CS can activate NADPH oxidase and increase endothelial O
OV0254;
2
production, thereby reducing NO bioactivity and resulting in endothelial dysfunction. Clinically, these studies may contribute to the development of agents able to mitigate CS-mediated vascular toxicity.
Lack of Complement Factor C3, but Not Factor B, Increases Hyperlipidemia and Atherosclerosis in Apolipoprotein E−/− Low-Density Lipoprotein Receptor−/− Mice
Authors: Persson Linda , Borén Jan , Robertson Anna-Karin L. , Wallenius Ville , Hansson Göran K. , Pekna Marcela
Published: April 2004

Objective—To investigate the effect of complement deficiency on atherogenesis and lipidemia, we used mice deficient in the third complement component (C3−/−) or factor B (FB−/−).

Methods and Results—Complement-deficient mice were crossed with mice deficient in both apolipoprotein E and the low-density lipoprotein receptor (Apoe−/−LDLR−/−). The percent lesion area in the aorta at 16 weeks, determined byen faceanalysis, was 84% higher inC3−/− mice than in controls (11.8%±0.4% versus 6.4%±0.8%, mean±SEM,P<0.00005). TheC3−/− mice also had 58% higher serum triglyceride levels (P<0.05) and a more proatherogenic lipoprotein profile, with significantly more low-density lipoprotein cholesterol and very-low-density lipoprotein triglycerides than control mice. TheC3−/− mice weighed 13% less (P<0.01) and had a lower body fat content (3.5%±1.0% versus 13.1%±3.0%,P<0.01). There were no differences betweenFB−/− mice and controls.

Conclusions—Complement activation by the classical or lectin pathway exerts atheroprotective effects, possibly through the regulation of lipid metabolism.
KCNE2 Protein Is Expressed in Ventricles of Different Species, and Changes in Its Expression Contribute to Electrical Remodeling in Diseased Hearts
Authors: Jiang Min , Zhang Mei , Tang Daniel G. , Clemo Henry F. , Liu Jie , Holwitt Dana , Kasirajan Vigneshwar , Pond Amber L. , Wettwer Erich , Tseng Gea-Ny
Published: April 2004

Background—

Mutations in KCNE2 have been linked to long-QT syndrome (LQT6), yet KCNE2 protein expression in the ventricle and its functional role in native channels are not clear.

Methods and Results—

We detected KCNE2 protein in human, dog, and rat ventricles in Western blot experiments. Immunocytochemistry confirmed KCNE2 protein expression in ventricular myocytes. To explore the functional role of KCNE2, we studied how its expression was altered in 2 models of cardiac pathology and whether these alterations could help explain observed changes in the function of native channels, for which KCNE2 is a putative auxiliary (β) subunit. In canine ventricle injured by coronary microembolizations, the rapid delayed rectifier current (
I
Kr
) density was increased. Although the protein level of ERG (
I
Kr
pore-forming, α, subunit) was not altered, the KCNE2 protein level was markedly reduced. These data are consistent with the effect of heterologously expressed KCNE2 on ERG and suggest that in canine ventricle, KCNE2 may associate with ERG and suppress its current amplitude. In aging rat ventricle, the pacemaker current (
I
f
) density was increased. There was a significant increase in the KCNE2 protein level, whereas changes in the α-subunit (HCN2) were not significant. These data are consistent with the effect of heterologously expressed KCNE2 on HCN2 and suggest that in aging rat ventricle, KCNE2 may associate with HCN2 and enhance its current amplitude.

Conclusions—

KCNE2 protein is expressed in ventricles, and it can play diverse roles in ventricular electrical activity under (patho)physiological conditions.
Embolic Protection With Filtering or Occlusion Balloons During Saphenous Vein Graft Stenting Retrieves Identical Volumes and Sizes of Particulate Debris
Authors: Rogers Campbell , Huynh Rany , Seifert Philip A. , Chevalier Bernard , Schofer Joachim , Edelman Elazer R. , Toegel Gregory , Kuchela Arun , Woupio Amy , Kuntz Richard E. , Macon Natalie D.
Published: April 2004

Background—

Distal embolization of plaque particulate liberated during stenting may cause periprocedural complications. The number, size, and volume of debris released during stenting, however, have not been quantified, rendering embolic protection approaches empiric. We used a novel method of microparticle size assessment to measure volume and characterize individual sizes of particles captured by the PercuSurge GuardWire balloon or a vascular filter during saphenous vein graft stenting.

Methods and Results—

Braided nitinol filters (average distal pore size 100 μm) were used in 47 saphenous vein grafts in 44 patients. The PercuSurge GuardWire was used in 17 saphenous vein grafts in 16 patients. Particulate debris was subjected to microparticle size analysis (RapidVue, Beckman Coulter). All samples contained particulate debris. For both filter and GuardWire populations, most particles were <100 μm in longest dimension (87% and 90% of particles, respectively), and the distribution of particle sizes was identical. Total embolic load per lesion for both filters and GuardWire aspirates was also similar: median embolic load per filter was 16 mm
3
(range 2 to 84 mm
3
). Median embolic load per GuardWire was also 16 mm
3
(range 7 to 42 mm
3
). Histopathologic analysis demonstrated that most samples contained plaque elements and platelet-rich thrombus.

Conclusions—

During saphenous vein graft interventions, particulate retrieved with a vascular filtering device or an occlusion balloon was similar in amount and character. This supports the notion that unless soluble mediators play an important role in adverse acute clinical events after stenting, the clinical efficacy of filtering devices may be equal to that of occlusion devices.
Life-Years Gained From Defibrillator Implantation
Authors: Salukhe Tushar V. , Dimopoulos Konstantinos , Sutton Richard , Coats Andrew J. , Piepoli Massimo , Francis Darrel P.
Published: April 2004

Background—

Although treatment benefit in randomized controlled trials of defibrillators is often summarized by the numbers of lives saved (absolute risk difference), this may not be a good representation of what matters most to patients, namely, the amount of life they should expect to gain from implantation. The estimate of gain in life-years may depend on duration of follow-up. In this study, we examine this dependency.

Methods and Results—

We estimated, from published data of 8 landmark defibrillator trials, the cumulative benefit in life-years gained at time points from 3 months to 3 years. Because the trial populations, clinical status, and prognosis varied widely between studies, we expressed for each study the benefit at each time point as the proportion of benefit at 3 years. The average dependency of the benefit on duration of follow-up was then calculated. We found that the number of life-years gained from 1 device implantation increases with length of follow-up considered. Importantly, this increase is markedly nonlinear. Within the 3-year span addressable, the benefit rises with the square of time (gain ∞ t
1.94
,
R
2
=0.998,
P
<0.001).

Conclusions—

Measurable benefit from a defibrillator to patients’ life spans (life-years gained) is dramatically dependent on the time window over which the benefit is assessed. Because the effort of implantation is front loaded, yet benefit grows with time, the choice of an early time point artificially reduces apparent benefit and artificially increases the apparent number needed to treat to prevent an event. These are useful considerations for the formulation of treatment policy (and even for planning of the follow-up phase of clinical trials).
Flow Volume and Shunt Quantification in Pediatric Congenital Heart Disease by Real-Time Magnetic Resonance Velocity Mapping
Authors: Körperich Hermann , Gieseke Jürgen , Barth Peter , Hoogeveen Romhild , Esdorn Hermann , Peterschröder Andreas , Meyer Hans , Beerbaum Philipp
Published: April 2004

Background—

Flow quantification in real time by phase-contrast MRI (PC-MRI) may provide unique hemodynamic information in congenital heart disease, but available techniques have important limitations. We sought to validate a novel real-time magnetic resonance flow sequence in children.

Methods and Results—

In 14 pediatric patients (mean age 5.2±2.0 years) with cardiac left-to-right shunt, pulmonary (Q
p
) and aortic (Q
s
) flow rates were determined by nontriggered free-breathing real-time PC-MRI with single-shot echo-planar imaging combined with sensitivity encoding, which yielded 25 phase images per second at 2.7×2.7-mm in-plane resolution (field of view 30×34 cm
2
). Over a 9.5-second period that included 2 to 5 respiratory cycles, 16.6±2.6 subsequent stroke volumes (range 13 to 22) were acquired in each vessel. Results were compared with conventional retrospectively ECG-gated PC-MRI. Mean Q
p
/Q
s
by conventional PC-MRI was 1.91±0.64, and it was 1.94±0.68 (mean±SD) by real-time PC-MRI. For blood flow rate through pulmonary artery and aorta, we found differences of 2% to 3% (Bland-Altman analysis), with lower limits of agreement of −11% to −13% (mean−2 SD) and upper limits of 18% to 19% (mean+2 SD), which demonstrated good agreement between both methods. Mean difference for Q
p
/Q
s
was 1%, with limits of agreement ranging between −18% and 22% (mean±2 SD). High repeatability but some flow overestimation was observed in vitro (pulsatile flow phantom) with real-time PC-MRI, whereas conventional PC-MRI was accurate. Beat-to-beat stroke-volume variation was 6.1±2.3% in vivo and 3.7±0.3% in vitro.

Conclusions—

Beat-to-beat quantification of pulmonary and aortic flows and hence left-to-right shunt within a few seconds is reliable by nontriggered real-time PC-MRI with echo-planar imaging and sensitivity encoding. Good spatial/temporal resolution and a large field of view may render the sequence valuable for multiple applications in congenital heart disease.
Statins Augment Collateral Growth in Response to Ischemia but They Do Not Promote Cancer and Atherosclerosis
Authors: Sata Masataka , Nishimatsu Hiroaki , Osuga Jun-ichi , Tanaka Kimie , Ishizaka Nobukazu , Ishibashi Shun , Hirata Yasunobu , Nagai Ryozo
Published: April 2004

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.
Role of Cardiac Myosin Binding Protein C in Sustaining Left Ventricular Systolic Stiffening
Authors: Palmer Bradley M. , Georgakopoulos Dimitrios , Janssen Paul M. , Wang Yuan , Alpert Norman R. , Belardi Diego F. , Harris Samantha P. , Moss Richard L. , Burgon Patrick G. , Seidman Christine E. , Seidman J.G. , Maughan David W. , Kass David A.
Published: April 2004

Despite advances in the molecular biology of cardiac myosin binding protein-C (cMyBP-C), little is understood about its precise role in muscle contraction, particularly in the intact heart. We tested the hypothesis that cMyBP-C is central to the time course and magnitude of left ventricular systolic elastance (chamber stiffening), and assessed mechanisms for this influence in intact hearts, trabeculae, and skinned fibers from wild-type (+/+) and homozygous truncated cMyBP-C (t/t) male mice. cMyBP-C protein was not detected by gel electrophoresis or Western blot in t/t myocardium. cMyBP-C t/t ventricles displayed reduced peak elastance, but more strikingly a marked abbreviation of the systolic elastance time course, which peaked earlier (27.6±2.1 ms) than in +/+ controls (47.8±1.6 ms). Control hearts reached only 42±4% of maximum elastance at the onset of ejection, with substantial further stiffening during ejection. This contrasted to t/t mutants, which reached 77±3% of peak elastance before ejection of peak. These unusual findings were not observed in alternative models involving severe cardiomyopathy, but were recapitulated in a cMyBP-C null mouse. The abbreviated elastance time course and lower peak were consistent with earlier time-to-peak trabecular tension, increased unloaded shortening velocity in t/t skinned muscle strips, and dramatically reduced myofilament stiffness at diastolic calcium concentrations. These results provide novel insights into the role of cMyBP-C in myocardial systolic mechanics. Abnormal sarcomere shortening velocity and abbreviated muscle stiffening may underlie development of cardiac dysfunction associated with deficient incorporation of cMyBP-C.
Arteriogenesis Proceeds via ICAM-1/Mac-1- Mediated Mechanisms
Authors: Hoefer Imo E. , van Royen Niels , Rectenwald John E. , Deindl Elisabeth , Hua Jing , Jost Marco , Grundmann Sebastian , Voskuil Michiel , Ozaki C. Keith , Piek Jan J. , Buschmann Ivo R.
Published: April 2004

Monocyte adhesion to shear stress-activated endothelium stands as an important initial step during arteriogenesis (collateral artery growth). Using multiple approaches, we tested the hypothesis that monocyte adhesion via intercellular adhesion molecule-1 (ICAM-1) and selectin interactions is essential for adaptive arteriogenesis. Forty-eight New Zealand White rabbits received either solvent, monocyte chemoattractant protein-1 (MCP-1) alone, MCP-1 plus ICAM-mab, or MCP-1 plus an IgG2a isotype control via osmotic minipumps. After 7 days, collateral conductance was evaluated: solvent 4.01 (mL/min per 100 mm Hg), MCP-1 plus ICAM-mab 8.04 (versus solvent
P
=NS), and MCP-1 alone 33.11 (versus solvent
P
<0.05). Furthermore, the right femoral arteries of ICAM-1
−/−
, Mac-1
−/−
and mice having defective selectin interactions (FT4/7
−/−
) as well as their corresponding controls were ligated. One week later, perfusion ratios were determined by the use of fluorescent microspheres. FT4/7
−/−
mice did not show any significant difference in perfusion restoration whereas ICAM-1
−/−
and Mac-1
−/−
mice had a significant reduction in arteriogenesis as compared with matching controls (FT4/7-WT 37±9%, FT4/7
−/−
32±3%,
P
=0.31; C57BL/6J 59±9%, ICAM-1
−/−
36±8%,
P
<0.05; Mac-1
−/−
42±3%,
P
<0.05). ICAM-1/Mac-1-mediated monocyte adhesion to the endothelium of collateral arteries is an essential step for arteriogenesis, whereas this process can proceed via selectin interaction independent mechanisms. Furthermore, in vivo treatment with monoclonal antibodies against ICAM-1 totally abolishes the stimulatory effect of MCP-1 on collateral artery growth, suggesting that the mechanism of the MCP-1-induced arteriogenesis proceeds via the localization of monocytes rather than the action of the MCP-1 molecule itself.
Parvalbumin Corrects Slowed Relaxation in Adult Cardiac Myocytes Expressing Hypertrophic Cardiomyopathy-Linked α-Tropomyosin Mutations
Authors: Coutu Pierre , Bennett Christina N. , Favre Elizabeth G. , Day Sharlene M. , Metzger Joseph M.
Published: April 2004

Hypertrophic cardiomyopathy mutations A63V and E180G in α-tropomyosin (α-Tm) have been shown to cause slow cardiac muscle relaxation. In this study, we used two complementary genetic strategies, gene transfer in isolated rat myocytes and transgenesis in mice, to ascertain whether parvalbumin (Parv), a myoplasmic calcium buffer, could correct the diastolic dysfunction caused by these mutations. Sarcomere shortening measurements in rat cardiac myocytes expressing the α-Tm A63V mutant revealed a slower time to 50% relengthening (T50R: 44.2±1.4 ms in A63V, 36.8±1.0 ms in controls; n=96 to 108;
P
<0.001) when compared with controls. Dual gene transfer of α-Tm A63V and Parv caused a marked decrease in T50R (29.8±1.0 ms). However, this increase in relaxation rate was accompanied with a decrease in shortening amplitude (114.6±4.4 nm in A63+Parv, 137.8±5.3 nm in controls). Using an asynchronous gene transfer strategy, Parv expression was reduced (from ≈0.12 to ≈0.016 mmol/L), slow relaxation redressed, and shortening amplitude maintained (T50R=33.9±1.6 ms, sarcomere shortening amplitude=132.2±7.0 nm in A63V+PVdelayed; n=56). Transgenic mice expressing the E180G α-Tm mutation and mice expressing Parv in the heart were crossed. In isolated adult myocytes, the α-Tm mutation alone (E180G
+
/PV
−
) had slower sarcomere relengthening kinetics than the controls (T90R: 199±7 ms in E180G
+
/PV
−
, 130±4 ms in E180G
−
/PV
−
; n=71 to 72), but when coexpressed with Parv, cellular relaxation was faster (T90R: 36±4 ms in E180G
+
/PV
+
). Collectively, these findings show that slow relaxation caused by α-Tm mutants can be corrected by modifying calcium handling with Parv.
Isolation of a Regulatory Region of Activin Receptor-Like Kinase 1 Gene Sufficient for Arterial Endothelium-Specific Expression
Authors: Seki Tsugio , Hong Kwon-Ho , Yun Jihye , Kim Seong-Jin , Oh S. Paul
Published: April 2004

Activin receptor-like kinase 1 (
Acvrl1
;
Alk1
) is a type I receptor for transforming growth factor-β (TGF-β). ALK1 plays a pivotal role in vascular development and is involved in the development of hereditary hemorrhagic telangiectasia 2 (HHT2), a dominantly inherited vascular disorder, and pulmonary hypertension. We have previously shown that
Alk1
is expressed predominantly in arterial endothelial cells (ECs). Despite recent discoveries of a number of artery-specific genes, the regulatory elements of these genes have not been characterized. To investigate the
cis
-acting elements essential for the artery-specific
Alk1
expression, we have generated a series of transgenic constructs with various lengths and regions of
Alk1
genomic fragments connected to a
LacZ
reporter gene, and analyzed the reporter gene expression in transgenic mice. We found that a 9.2-kb genomic fragment, which includes 2.7-kb promoter region and the entire intron 2, is sufficient to drive arterial endothelium-specific expression. The defined regulatory region, as well as the transgenic mouse lines, would be invaluable resources in studying the mechanisms underlying angiogenesis, arteriogenesis, and vascular disorders, such as HHT and pulmonary hypertension. The full text of this article is available online at
http://circres.ahajournals.org
.
Pooling of Animal Experimental Data Reveals Influence of Study Design and Publication Bias
Authors: Macleod Malcolm R. , O’Collins Tori , Howells David W. , Donnan Geoffrey A.
Published: April 2004

Background and Purpose—

The extensive neuroprotective literature describing the efficacy of candidate drugs in focal ischemia has yet to lead to the development of effective stroke treatments. Ideally, the choice of drugs taken forward to clinical trial should be based on an unbiased assessment of all available data. Such an assessment might include not only the efficacy of a drug but also the in vivo characteristics and limits—in terms of time window, dose, species, and model of ischemia used—to that efficacy. To our knowledge, such assessments have not been made. Nicotinamide is a candidate neuroprotective drug with efficacy in experimental stroke, but the limits to and characteristics of that efficacy have not been fully described.

Methods—

Systematic review and modified meta-analysis of studies of experimental stroke describing the efficacy of nicotinamide. The search strategy ensured ascertainment of studies published in full and those published in abstract only. DerSimonian and Laird random effects meta-analysis was used to account for heterogeneity between studies.

Results—

Nicotinamide improved outcome by 0.287 (95% confidence interval 0.227 to 0.347); it was more effective in temporary ischemia models, after intravenous administration, in animals without comorbidities, and in studies published in full rather than in abstract. Studies scoring highly on a quality measure gave more precise estimates of the global effect.

Conclusions—

Meta-analysis provides an effective technique for the aggregation of data from experimental stroke studies. We propose new standards for reporting such studies and a systematic approach to aggregating data from the neuroprotective literature.
Transient Ischemic Attack and Stroke Can Be Differentiated by Analyzing Early Diffusion-Weighted Imaging Signal Intensity Changes
Authors: Winbeck Kerstin , Bruckmaier Kathrin , Etgen Thorleif , von Einsiedel Helga Gräfin , Röttinger M. , Sander Dirk
Published: April 2004

Background—

Diffusion-weighted imaging (DWI) has been established to diagnose acute cerebral ischemia. Signal intensity changes occur not only in patients with definite stroke but also in up to 67% of transient ischemic attack (TIA) patients. We investigated the predictive value of DWI signal intensity changes to distinguish between TIA and stroke.

Methods—

Clinical data, conventional magnetic resonance imaging (MRI), and DWI were collected in 60 consecutive patients with TIA and 37 consecutive patients with stroke. DWI was performed within 24 hours after symptom onset. Using an image analyzing system, we calculated the ratio of the lesion and corresponding contralateral normal tissue average signal intensity (rAI).

Results—

Eighteen of 60 TIA patients (30%) revealed focal abnormalities on DWI. The mean duration of symptoms was 5.3 hours in TIA patients with DWI lesions and 5.2 hours in patients without lesions. The time to DWI was comparable in TIA and stroke patients. Even within 6 hours after symptom onset, the signal intensity was significantly higher (
P
=0.03) in stroke patients (n=13, rAI=1.26) as compared with TIA patients with DWI lesions (n=9, rAI=1.16).

Conclusions—

Our data indicate that already within 6 hours after symptom onset, TIA and stroke might be differentiated by analyzing the signal intensity of the lesions.
Combination Therapy in Ischemic Stroke: Synergistic Neuroprotective Effects of Memantine and Clenbuterol
Authors: Culmsee Carsten , Junker Vera , Kremers Wolfram , Thal Serge , Plesnila Nikolaus , Krieglstein Josef
Published: April 2004

Background and Purpose—

Although excitotoxic overactivation of glutamate receptors has been identified as a major mechanism of ischemic brain damage, glutamate receptor antagonists failed in stroke trials, in most cases because of limited therapeutic windows or severe adverse effects. Therefore, we chose memantine and clenbuterol, both approved safe and efficient in their respective therapeutical categories, and examined combinations of these neuroprotectants for possible therapeutic interactions in ischemic stroke.

Methods—

Combinations of the
N
-methyl-
d
-aspartate (NMDA) receptor antagonist memantine (20 mg/kg) with the β
2
-adrenoceptor agonist clenbuterol (0.3 to 3 mg/kg) were tested in a mouse model of permanent focal cerebral ischemia. In addition, combinations of memantine (1 to 10 nmol/L) and clenbuterol (1 to 10 nmol/L) were examined in cultured hippocampal neurons exposed to glutamate (500 μmol/L) or staurosporine (200 nmol/L).

Results—

The infarct size was further reduced by combination therapy as compared with effects of the respective neuroprotectants alone. Of note, in combination with memantine, the therapeutic window of clenbuterol was significantly prolonged up to 2 hours after ischemia. Experiments in postnatal cultures of rat hippocampal neurons exposed to glutamate or staurosporine confirmed that neuroprotection by combinations of memantine and clenbuterol exceeded the effects of the individual compounds.

Conclusions—

Combinations of memantine with clenbuterol extend the respective therapeutic window and provide synergistic cerebroprotective effects after stroke.
Hemorrhage in the Atherosclerotic Carotid Plaque: A High-Resolution MRI Study
Authors: Chu Baocheng , Kampschulte Annette , Ferguson Marina S. , Kerwin William S. , Yarnykh Vasily L. , O’Brien Kevin D. , Polissar Nayak L. , Hatsukami Thomas S. , Yuan Chun
Published: April 2004

Background and Purpose—

High-resolution, multicontrast magnetic resonance imaging (MRI) has developed into an effective tool for the identification of carotid atherosclerotic plaque components, such as necrotic core, fibrous matrix, and hemorrhage/thrombus. Factors that may lead to plaque instability are lipid content, thin fibrous cap, and intraplaque hemorrhage. Determining the age of intraplaque hemorrhage can give insight to the history and current condition of the biologically active plaque. The aim of this study was to develop criteria for the identification of the stages of intraplaque hemorrhage using high-resolution MRI.

Methods—

Twenty-seven patients, scheduled for carotid endarterectomy (CEA), were imaged on a 1.5-T GE SIGNA scanner (sequences: 3-dimensional time of flight, double-inversion recovery, T1-weighted (T1W), PDW and T2W). Two readers, blinded to histology, reviewed MR images and grouped hemorrhage into fresh, recent, and old categories using a modified cerebral hemorrhage criteria. The CEA specimens were serially sectioned and graded as to presence and stage of hemorrhage.

Results—

Hemorrhage was histologically identified and staged in 145/189 (77%) of carotid artery plaque locations. MRI detected intraplaque hemorrhage with high sensitivity (90%) but moderate specificity (74%). Moderate agreement in classifying stages occurred between MRI and histology (Cohen κ=0.7, 95% CI: 0.5 to 0.8 for reviewer 1 and 0.4, 95% CI: 0.2 to 0.6 for reviewer 2), with moderate agreement between the 2 MRI readers (κ=0.4, 95% CI: 0.3 to 0.6).

Conclusion—

Multicontrast MRI can detect and classify carotid intraplaque hemorrhage with high sensitivity and moderate specificity.
Interaction Between Hypertension, apoE, and Cerebral White Matter Lesions
Authors: de Leeuw Frank-Erik , Richard Florence , de Groot Jan Cees , van Duijn Cornelia M. , Hofman Albert , van Gijn Jan , Breteler Monique M.B.
Published: April 2004

Background and Purpose—

Cerebral white matter lesions (WMLs) are frequently found on magnetic resonance imaging scans in both cognitively intact and demented elderly persons. Vascular risk factors, especially hypertension, are related to their presence. However, not every person with vascular risk factors has WMLs, which suggests interaction with other determinants, eg, genetic factors. The ε4 allele of the apolipoprotein E gene (apoE) may be a candidate because this allele is associated with both the vascular risk factors and the consequences (cognitive impairment, dementia) of WMLs.

Methods—

We investigated apoE genotype, blood pressure levels, and their interaction in relation to subcortical and periventricular WMLs in 971 participants in the Rotterdam Scan Study.

Results—

ApoE ε4 carriers had a significantly higher subcortical WML volume than did apoE ε3ε3 carriers (adjusted mean difference, 0.5; 95% confidence interval, 0.2 to 0.8), irrespective of hypertension. This was not found for periventricular WMLs. Participants with both hypertension and at least 1 apoE ε4 allele had the highest degree of both types of WML; the interaction was statistically significant for subcortical WMLs (
P
=0.016).

Conclusions—

apoE ε4 carriers are at increased risk for WMLs if they suffer from hypertension as well. This may reflect a diminished capacity for neuronal repair in apoE ε4 carriers.
More Accurate Identification of Reversible Ischemic Injury in Human Stroke by Cerebrospinal Fluid Suppressed Diffusion-Weighted Imaging
Authors: Bykowski Julie L. , Latour Lawrence L. , Warach Steven
Published: April 2004

Background and Purpose—The apparent diffusion coefficient (ADC) derived from diffusion-weighted (DWI) MRI has been used to differentiate reversible from irreversible ischemic injury. However, the ADC can be falsely elevated by partial volume averaging of cerebrospinal fluid (CSF) with parenchyma, limiting the accuracy of this approach. This study tested the hypothesis that the accuracy of differentiating reversible from irreversible ischemic injury could be improved by CSF suppression at image acquisition.

Methods—Sixteen patients presenting within 6 hours from symptoms, and having partial reversal of the acute lesion on DWI were studied using conventional CSF-suppressed DWI. Lesions were segmented from coregistered acute DWI and follow-up fluid-attenuated inversion recovery (FLAIR) series. The segmented volumes were applied to conventional (ADCC) and CSF-suppressed ADC (ADCFLIPD) maps to classify each voxel as progressed to infarct or reversed. Individual voxel ADC values were pooled across all patients. Sensitivity to predict reversal, specificity, and accuracy were calculated for both methods.

Results—A total of 25 313 voxels were classified as progressed and 31 952 voxels reversed. Across all lesion voxels, ADCFLIPDvalues more accurately depicted tissue fate compared with ADCCvalues (P<0.0001). The largest difference in the two methods was in voxels with <75% parenchyma, where the accuracy of ADCCwas only 50% compared with 62% for ADCFLIPD.

Conclusion—CSF-suppressed ADC measurements gave a more accurate identification of reversible ischemic injury in this sample. We predict that multimodal MRI models of tissue viability in ischemic stroke will be more accurate if CSF-suppressed ADC measurements are used.
Neuroprotection by Hyperbaric Oxygenation After Experimental Focal Cerebral Ischemia Monitored by MRI
Authors: Schäbitz Wolf-Ruediger , Schade Holger , Heiland Sabine , Kollmar Rainer , Bardutzky Jürgen , Henninger Nils , Müller Harald , Carl Ulrich , Toyokuni Shinya , Sommer Clemens , Schwab Stefan
Published: April 2004

Background—

Hyperbaric oxygenation (HBO) after focal cerebral ischemia reduces infarct size and improves outcome when applied early after stroke. Here, we evaluated effects of HBO on permanent focal cerebral ischemia and applied magnetic resonance imaging (MRI) monitoring to study lesion evolution.

Methods—

Rats underwent permanent middle cerebral artery occlusion (MCAO). Two hours later, animals were treated with HBO (100% O
2
/2 atm; n=17) for 1 hour or treated with room air (n=17). Animals underwent serial MRI studies (DWI, PI, T2) beginning 90 minutes after MCAO. Neuroscore was assessed (5-point rating scale). Animals were euthanized and brains were 2,3,5-triphenyltetrazolium chloride (TTC)-stained for infarct volume calculation 120 hours after MCAO. Immunohistochemistry was performed with antibodies against c-FOS and 4-hydroxy-2-nonenal-modified proteins (HNE) to check for effects of oxidative stress caused by HBO treatment.

Results—

HBO reduced infarct volume by 38% (
P
<0.001). As shown by MRI, neuroprotection began 5 hours after ischemia and remained effective for 5 days. The relative regional cerebral blood flow was not different between groups at 3.5 and 5 hours after occlusion. There was less neurological deficit in HBO-treated animals compared with controls (
P
<0.05). Lipid peroxidation of cerebral vessels after HBO treatment as measured by HNE staining and pattern of c-FOS induction were not significantly different between groups at 3.5 and 8 hours after ischemia.

Conclusion—

As monitored by MRI HBO treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage.
The Labor Market of the Early Roman Empire
Authors: Temin Peter
Published: April 2004

The available evidence on wages and labor contracts supports the existence of a functioning labor market in the early Roman empire, in which workers could change jobs in response to market-driven rewards. Slaves were included in the general labor market because Roman slavery, unlike that in the United States and in Brazil, permitted frequent manumission to citizen status. Slaves' ability to improve their status provided them with incentives to cooperate with their owners and act like free laborers. As a result, the supply and demand for labor were roughly equilibrated by wages and other payments to most workers, both slave and free.
Manure Matters on the Great Plains Frontier
Authors: Cunfer Geoff
Published: April 2004

American farmers followed a long-term sequence of clearing land, farming it for several decades, and then abandoning it in favor of new land elsewhere. For 300 years, farmers moved across the continent until they reached the Great Plains, and the end of the frontier, in the 1870s. Fertility and crop yields declined for fifty years by the 1930s, an agricultural crisis was looming. Only the adoption of synthetic fertilizer after World War II allowed farmers to continue annual cropping.
Searching for a Common Idiom among African Texts
Authors: Rotberg Robert I.
Published: April 2004

Texts and consciousness are important, and require analysis in a variety of different modern African historical settings. It is also wise, and critical, to unmask obscurantist rhetoric, and to reevaluate received, politically correct, accounts. Subjecting the nationalist period to that kind of heightened commentary is essential. But re-ordering the past so as to unmask the distortions of despotsand otherabusers of their own truths is also necessary. Fully discovering who killed Herbert Chitepo, and thus who gave rise to the despotic regime of Robert Mugabe, would be an earnest of that endeavor.
Effects of Left Inferior Prefrontal Stimulation on Episodic Memory Formation: A Two-Stage fMRI—rTMS Study
Authors: Köhler Stefan , Paus Tomáš; , Buckner Randy L. , Milner Brenda
Published: April 2004

Successful recovery of words from episodic memory relies strongly on semantic processes at the time of encoding. Evidence from several functional magnetic resonance imaging (fMRI) studies has shown that changes in neural activity in the left inferior prefrontal cortex (LIPFC) during semantic encoding predict subsequent memory performance. This evidence has been taken to suggest that LIPFC plays a critical role in memory formation. Functional neuroimaging findings, however, do not establish a causal brain-behavior relationship. To determine whether there is a causal link between LIPFC involvement at encoding and subsequent success in memory performance, we conducted a two-part study in which we first used fMRI to localize encoding-related activation in LIPFC and then employed repetitive transcranial magnetic stimulation (rTMS) to manipulate neural processes in LIPFC during semantic encoding. To demonstrate the neuroanatomical specificity of any observed effect and to control for nonspecific rTMS side effects, we also stimulated neural processes in two control sites. Using frameless stereotaxy, we positioned the stimulation coil to target (1) the LIPF region that was activated during fMRI (mean xyz = −48 35 5); (2) the homologous righthemisphere region; and (3) an additional left parietal control site. At each site, “stimulated” items (600 msec of 7-Hz rTMS with Cadwell Round Coil) were intermixed with items presented without concurrent stimulation. Subsequently, subjects performed a recognition memory task for the words encountered. We found support for the predicted causal brain-behavior relationship, which was specific to LIPFC. When comparing recognition scores for stimulated items, normalized for variations in performance on nonstimulated trials, we found that words encoded under LIPFC stimulation were subsequently recognized with higher accuracy than words encoded under stimulation in the two cortical control sites. By contrast, no performance difference emerged when the two control sites were compared with each other. Based on additional analyses of the rTMS effects observed directly at the time of encoding (i.e., on semantic-decision performance), we suggest that LIPFC stimulation may have produced its effect on recognition memory, at least in part, through the triggering of more extensive processing of the stimulated items and an ensuing gain in item distinctiveness. Physiological processes of facilitation probably also contributed to the observed memory benefit. Together, these findings suggest that LIPFC does play a causal role in episodic memory formation.
Is the Fusiform Face Area Specialized for Faces, Individuation, or Expert Individuation?
Authors: Rhodes Gillian , Byatt Graham , Michie Patricia T. , Puce Aina
Published: April 2004

Several brain imaging studies have identified a region of fusiform gyrus (FG) that responds more strongly to faces than common objects. The precise functional role of this fusiform face area (FFA) is, however, a matter of dispute. We sought to distinguish among three hypotheses concerning FFA function: face specificity, individuation, and expert individuation. According to the face-specificity hypothesis, the FFA is specialized for face processing. Alternatively, the FFA may be specialized for individuating visually similar items within a category (the individuation hypothesis) or for individuating within categories with which a person has expertise (the expert-individuation hypothesis). Our results from two experiments supported the face-specificity hypothesis. Greater FFA activation to faces than Lepidoptera, another homogeneous object class, occurred during both free viewing and individuation, with similar FFA activation to Lepidoptera and common objects (Experiment 1). Furthermore, during individuation of Lepidoptera, 83% of activated FG voxels were outside the face FG region and only 15% of face FG voxels were activated. This pattern of results suggests that distinct areas may individuate faces and Lepidoptera. In Experiment 2, we tested Lepidoptera experts using the same experimental design. Again, the results supported the face-specificity hypothesis. Activation to faces in the FFA was greater than to both Lepidoptera and objects with little overlap between FG areas activated by faces and Lepidoptera. Our results suggest that distinct populations of neurons in human FG may be tuned to the features needed to individuate the members of different object classes, as has been reported in monkey inferotemporal cortex, and that the FFA contains neurons tuned for individuating faces.
The Role of Spared Calcarine Cortex and Lateral Occipital Cortex in the Responses of Human Hemianopes to Visual Motion
Authors: Morland Antony B. , Lê Sandra , Carroll Erin , Hoffmann Michael B. , Pambakian Alidz
Published: April 2004

Some patients, who are rendered perimetrically blind in one hemifield by cortical lesions, nevertheless exhibit residual visual capacities within their field defects. The neural mechanism that mediates the residual visual responses has remained the topic of considerable debate. One explanation posits the subcortical visual pathways that bypass the primary visual cortex and innervate the extrastriate visual areas as the substrate that underlies the residual vision. The other explanation is that small islands of the primary visual cortex remain intact and provide the signals for residual vision. We have performed behavioral and functional magnetic resonance imaging experiments to investigate the validity of the two explanations of residual vision. Our behavioral experiments indicated that of the seven hemianopes tested, two had the ability to discriminate the direction of a drifting grating. This residual visual response was shown with fMRI to be the result of spared islands of calcarine cortical activity in one of the hemianopes, whereas only lateral occipital activity was documented in the other patient. These results indicate that the underlying neural correlates of residual vision can vary between patients. Moreover, our study emphasizes the necessity of ruling out the presence of islands of preserved function and primary visual cortex before assigning residual visual capacities to the properties of visual pathways that bypass the primary visual cortex.
A Feedback Model of Visual Attention
Authors: Spratling M. W. , Johnson M. H.
Published: April 2004

Feedback connections are a prominent feature of cortical anatomy and are likely to have a significant functional role in neural information processing. We present a neural network model of cortical feedback that successfully simulates neurophysiological data associated with attention. In this domain, our model can be considered a more detailed, and biologically plausible, implementation of the biased competition model of attention. However, our model is more general as it can also explain a variety of other top-down processes in vision, such as figure/ground segmentation and contextual cueing. This model thus suggests that a common mechanism, involving cortical feedback pathways, is responsible for a range of phenomena and provides a unified account of currently disparate areas of research.
Grammaticality Judgment in Aphasia: Deficits Are Not Specific to Syntactic Structures, Aphasic Syndromes, or Lesion Sites
Authors: Wilson Stephen M. , Saygın Ayşe Pınar
Published: April 2004

We examined the abilities of aphasic patients to make grammaticality judgments on English sentences instantiating a variety of syntactic structures. Previous studies employing this metalinguistic task have suggested that aphasic patients typically perform better on grammaticality judgment tasks than they do on sentence comprehension tasks, a finding that has informed the current view that grammatical knowledge is relatively preserved in agrammatic aphasia. However, not all syntactic structures are judged equally accurately, and several researchers have attempted to provide explanatory principles to predict which structures will pose problems to agrammatic patients. One such proposal is Grodzinsky and Finkel's (1998) claim that agrammatic aphasics are selectively impaired in their ability to process structures involving traces of maximal projections. In this study, we tested this claim by presenting patients with sentences with or without such traces, but also varying the level of difficulty of both kinds of structures, assessed with reference to the performance of age-matched and young controls. We found no evidence that agrammatic aphasics, or any other subgroup, are selectively impaired on structures involving traces: Some judgments involving traces were made quite accurately, whereas other judgments not involving traces were made very poorly. Subgroup analyses revealed that patient groups and agematched controls had remarkably similar profiles of performance across sentence types, regardless of whether the patients were grouped based on Western Aphasia Battery classification, an independent screening test for agrammatic comprehension, or lesion site. This implies that the pattern of performance across sentence types does not result from any particular component of the grammar, or any particular brain region, being selectively compromised. Lesion analysis revealed that posterior temporal areas were more reliably implicated in poor grammaticality judgment performance than anterior areas, but poor performance was also observed with some anterior lesions, suggesting that areas important for syntactic processing are distributed throughout the left peri-sylvian region.
An “Oblique Effect” in Infants' Haptic Perception of Spatial Orientations
Authors: Gentaz Edouard , Streri Arlette
Published: April 2004

The present research addresses the question of the “oblique effect” (better discrimination of the vertical orientation than of an oblique orientation) in manual haptic perception of orientations (without visual control) by 5-month-old infants. A familiarization/reaction to novelty procedure was used. The results revealed the occurrence of a haptic oblique effect. These findings are similar to those obtained in infant visual perception. We suggest that 5-month-old infants predominately use vertical orientation as a reference norm to perceive haptically spatial orientations. We discuss the implications of these results for both orientation processing and anatomofunctional level contributing specifically to the haptic oblique effect.
A Neurocomputational Model of Analogical Reasoning and its Breakdown in Frontotemporal Lobar Degeneration
Authors: Morrison Robert G. , Krawczyk Daniel C. , Holyoak Keith J. , Hummel John E. , Chow Tiffany W. , Miller Bruce L. , Knowlton Barbara J.
Published: April 2004

Analogy is important for learning and discovery and is considered a core component of intelligence. We present a computational account of analogical reasoning that is compatible with data we have collected from patients with cortical degeneration of either their frontal or anterior temporal cortices due to frontotemporal lobar degeneration (FTLD). These two patient groups showed different deficits in picture and verbal analogies: frontal lobe FTLD patients tended to make errors due to impairments in working memory and inhibitory abilities, whereas temporal lobe FTLD patients tended to make errors due to semantic memory loss. Using the “Learning and Inference with Schemas and Analogies” model, we provide a specific account of how such deficits may arise within neural networks supporting analogical problem solving.