bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelin-1–Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator–Activated Receptor-α Partly Via Blockade of c-Jun NH
2
-Terminal Kinase Pathway
Authors: Irukayama-Tomobe Yoko , Miyauchi Takashi , Sakai Satoshi , Kasuya Yoshitoshi , Ogata Takehiro , Takanashi Masakatsu , Iemitsu Motoyuki , Sudo Tatsuhiko , Goto Katsutoshi , Yamaguchi Iwao
Published: February 2004

Background—

Peroxisome proliferator-activated receptor-α (PPAR-α) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, nuclear factor-κB, and AP-1. However, the roles of PPAR-α activators in endothelin (ET)-1–induced cardiac hypertrophy are not yet known.

Methods and Results—

First, in cultured neonatal rat cardiomyocytes, a PPAR-α activator, fenofibrate (10 μmol/L), and PPAR-α overexpression markedly inhibited the ET-1–induced increase in protein synthesis. Second, fenofibrate markedly inhibited ET-1–induced increase in c-Jun gene expression and phosphorylation of c-Jun and JNK. These results suggest that this PPAR-α activator interferes with the formation and activation of AP-1 protein induced by ET-1 in cardiomyocytes. Third, fenofibrate significantly inhibited the increase of ET-1 mRNA level by ET-1, which was also confirmed by luciferase assay. Electrophoretic mobility shift assay revealed that fenofibrate significantly decreased the ET-1–stimulated or phorbol 12-myristate 13-acetate–stimulated AP-1 DNA binding activity, and the nuclear extract probe complex was supershifted by anti-c-Jun antibody. Fourth, 24 hours after aortic banding (AB) operation, fenofibrate treatment significantly inhibited left ventricular hypertrophy and hypertrophy-related gene expression pattern (ET-1, brain natriuretic peptide, and β-myosin heavy chain mRNA) in AB rats.

Conclusions—

These results suggest that PPAR-α activation interferes with the signaling pathway of ET-1–induced cardiac hypertrophy through negative regulation of AP-1 binding activity, partly via inhibition of the JNK pathway in cultured cardiomyocytes. We also revealed that fenofibrate treatment inhibited left ventricle hypertrophy and phenotypic changes in cardiac gene expression in AB rats in vivo.
Incidence, Mechanism, Predictors, and Long-Term Prognosis of Late Stent Malapposition After Bare-Metal Stent Implantation
Authors: Hong Myeong-Ki , Mintz Gary S. , Lee Cheol Whan , Kim Young-Hak , Lee Seung-Whan , Song Jong-Min , Han Ki-Hoon , Kang Duk-Hyun , Song Jae-Kwan , Kim Jae-Joong , Park Seong-Wook , Park Seung-Jung
Published: February 2004

Background—

Predictors and long-term prognosis of late stent malapposition (LSM) after bare-metal stent (BMS) implantation are unknown.

Methods and Results—

We evaluated the incidence, mechanisms, predictors, and long-term prognosis of LSM after BMS implantation in 881 patients (992 native lesions) in whom intravascular ultrasound was performed at index and 6-month follow-up. LSM was defined as a separation of stent struts from the intimal surface of the arterial wall that was not presented at stent implantation. LSM occurred in 54 patients with 54 lesions (5.4% overall); the incidence was 10.3% (9 of 87) after directional coronary atherectomy (DCA) before stenting and 11.5% (11 of 96) after primary stenting in acute myocardial infarction (
P
=0.031 and
P
=0.007, respectively, versus elective stenting with conventional balloon pre-dilation, 4.3% [30 of 692]). There was an increase of external elastic membrane area (18.9±3.9 to 24.5±5.1 mm
2
,
P
<0.001) that was greater than the increase in plaque area (9.6±3.0 to 11.4±2.9 mm
2
,
P
<0.001). Independent predictors of LSM were primary stenting in acute myocardial infarction (
P
=0.023, OR=2.55, 95% CI=1.14 to 5.69) and DCA before stenting (
P
=0.025, OR=3.02, 95% CI=1.15 to 7.96). There were no significant differences in major adverse cardiac events between LSM and non-LSM groups during mean 3-year follow-up (1.9% versus 1.8%, respectively,
P
=NS).

Conclusions—

LSM occurs in ≈5% after BMS implantation. The predictors of LSM are primary stenting in acute myocardial infarction and DCA before stenting. Compared with complete stent apposition at follow-up, LSM after BMS implantation is not associated with any major adverse cardiac events during a mean 3-year follow-up after detection of LSM.
Magnetic Resonance Imaging Identifies the Fibrous Cap in Atherosclerotic Abdominal Aortic Aneurysm
Authors: Kramer Christopher M. , Cerilli Lisa A. , Hagspiel Klaus , DiMaria Joseph M. , Epstein Frederick H. , Kern John A.
Published: February 2004

Background—

MRI can distinguish components of atherosclerotic plaque. We hypothesized that contrast enhancement with gadolinium-DTPA (Gd-DTPA) could aid in the differentiation of plaque components in abdominal aortic aneurysm (AAA).

Methods and Results—

Twenty-three patients (19 males, age 70±8 years) with AAA underwent MRI on a 1.5-T clinical scanner 3±3 days before surgical grafting. T1- and T2-weighted (W) black blood spin echo imaging was performed in 1 axial slice, and the T1-W imaging was repeated after a Gd-DTPA–enhanced 3D magnetic resonance angiogram. A section of the aorta at the site of imaging was resected at surgery for histopathologic examination of tissue components and inflammatory cells. Signal-to-noise and contrast-to-noise ratios (CNR) were measured in visualized plaque components from multispectral MRI, and percent enhancement after contrast on T1-W imaging was calculated. The κ value for agreement between pathology and MRI for the number of tissue components was 0.785. T2-W imaging identified thrombus as regions of high signal and lipid core as low signal, with a CNR of 6.43±3.41. Nine patients had a fibrous cap pathologically, which was visualized as a discrete area of uniform increased signal on T2-W imaging with a CNR of 4.52±1.93 compared with lipid core. Within the cap, the percent enhancement after Gd-DTPA on T1-W imaging was 91±63%.

Conclusions—

Higher signal on T2-W MRI identifies the fibrous cap and thrombus within AAA. Contrast enhancement improves delineation of the fibrous cap. The addition of contrast to MRI plaque imaging may enhance identification of vulnerable plaque.
Usefulness of B-Type Natriuretic Peptide Assay in the Assessment of Symptomatic State in Hypertrophic Cardiomyopathy
Authors: Maron Barry J. , Tholakanahalli Venkatakrishna N. , Zenovich Andrey G. , Casey Susan A. , Duprez Daniel , Aeppli Dorothee M. , Cohn Jay N.
Published: February 2004

Background—

Hypertrophic cardiomyopathy (HCM) has a diverse clinical spectrum that often includes progressive heart failure symptoms and disability. Assessment of symptom severity may be highly subjective, encumbered by the heterogeneous clinical presentation. Plasma B-type natriuretic peptide (BNP) has been used widely as an objective marker for heart failure severity and outcome, predominantly in coronary heart disease with ventricular dilatation and systolic dysfunction.

Methods and Results—

We prospectively assessed plasma BNP as a quantitative clinical marker of heart failure severity in 107 consecutive HCM patients. BNP showed a statistically significant relationship to magnitude of functional limitation, assessed by New York Heart Association (NYHA) functional class: I, 136±159 pg/mL; II, 338±439 pg/mL; and III/IV, 481±334 pg/mL (
P
<0.001). Multivariable analysis showed that BNP was independently related to NYHA class as well as age and left ventricular wall thickness (each with a value of
P
=0.0001). BNP ≥200 pg/mL was the most reliable predictor of heart failure symptoms, with positive and negative predictive values of 63% and 79%, respectively. BNP power in distinguishing patients with or without heart failure symptoms was less than that for differentiating between no (or only mild) and severe symptoms (area under receiver operating characteristic curve=0.75 and 0.83, respectively).

Conclusions—

Plasma BNP is independently related to the presence and magnitude of heart failure symptoms in patients with HCM. As a clinical marker for heart failure, BNP is limited by considerable overlap in values between categories of heart failure severity as well as confounding variables of left ventricular wall thickness and age.
Impact of Microvascular Dysfunction on Left Ventricular Remodeling and Long-Term Clinical Outcome After Primary Coronary Angioplasty for Acute Myocardial Infarction
Authors: Bolognese Leonardo , Carrabba Nazario , Parodi Guido , Santoro Giovanni M. , Buonamici Piergiovanni , Cerisano Giampaolo , Antoniucci David
Published: February 2004

Background—

We hypothesized that preserved microvascular integrity in the area at risk would favorably influence left ventricular (LV) remodeling and long-term outcome after acute myocardial infarction.

Methods and Results—

Before and after successful primary angioplasty (percutaneous transluminal coronary angioplasty [PTCA]), 124 patients with acute myocardial infarction underwent intracoronary myocardial contrast echo (MCE). An MCE score index (MCESI) was derived by averaging the single-segment score (0=not visible, 1=patchy, 2=homogeneous contrast effect) within the area at risk. An MCESI ≥1 was considered adequate reperfusion. Mean follow-up was 46±32 months. After PTCA, 100 patients showed adequate reperfusion (no microvascular dysfunction, NoMD), whereas 24 did not (MD). MD patients had a higher mean creatine kinase (4153±2422 versus 2743±1774 U/L;
P
=0.002) and baseline wall-motion score index (2.61±0.31 versus 2.25±0.42;
P
<0.001) and a lower baseline ejection fraction (33±8% versus 40±7%;
P
<0.001). From day 1 on, LV volumes progressively increased in the MD patients (n=19) and were larger than those of NoMD patients (n=85) at 6 months (end-diastolic volume 170±55 versus 115±29 mL;
P
<0.001). MCESI was the most important independent predictor of LV dilation (OR 0.61, 95% CI 0.52 to 0.71,
P
<0.000001). By Cox analysis, MD represented the only predictor of cardiac death (OR 0.26, 95% CI 0.09 to 0.72,
P
=0.010) and combined events (cardiac death, reinfarction, and heart failure; OR 0.44, 95% CI 0.23 to 0.85,
P
=0.014). MD patients showed worse survival in terms of cardiac death (
P
<0.0001) and combined events (
P
<0.0001).

Conclusions—

In reperfused acute myocardial infarction, MD within the risk area is an important predictor of both LV remodeling and unfavorable long-term outcome.
Isolation and Culture of Arterial Smooth Muscle Cells From Human Placenta
Authors: Leik Courtney E. , Willey Amy , Graham Martin F. , Walsh Scott W.
Published: February 2004

A simple and economical technique was developed to isolate and culture human arterial smooth muscle cells from chorionic plate vessels. Placentas from healthy women were collected at the time of term delivery. Chorionic plate arteries were identified, excised, and cut into small pieces. An explant technique was used to grow cultures of placental arterial smooth muscle (PASM) cells. Small pieces of vessel with lumens down were placed in 100-mm culture plates and grown in Dulbecco modified eagle medium and 10% fetal bovine serum. Cells appeared from explants within 1 week and grew to confluence in approximately 4 weeks. At confluence, PASM cell cultures had a uniform cell morphology that was characterized by elongated cells in parallel rows, typical of smooth muscle cells. Smooth muscle cell phenotype was evaluated by morphology and by immunoblotting and immunofluorescence of smooth muscle myofilament proteins. All PASM cell cultures expressed α-smooth muscle actin, β-tropomyosin, and h-caldesmon. Expression was similar to that of human aortic smooth muscle cells, but not to endothelial cells or fibroblasts. PASM cells stained uniformly for α-smooth muscle actin and lacked staining for a fibroblast-specific antigen. PASM cells were evaluated for their response to inflammatory mediators, tumor necrosis factor-α, and interleukin-1β by measurement of interleukin-8 production. Cells cultured for 18 hours showed a progressive increase in interleukin-8 production with time. Treatment with inflammatory mediators increased interleukin-8 production by 3-fold as compared with media control. This technique provides a simple method to obtain normal human arterial smooth muscle cells for in vitro studies of physiology and pathophysiology.
WNK4
Intron 10 Polymorphism Is Not Associated With Hypertension
Authors: Speirs Helen J.L. , Morris Brian J.
Published: February 2004

A polymorphism in intron 10 of the serine-threonine kinase with no lysine (K) 4 gene
WNK4
(G→A, base 1156666 on chromosome 17) has recently been associated with essential hypertension in a white American population. We have attempted to replicate this finding in a well characterized cohort of 184 unrelated hypertensive Australians of British extraction in which biological power was enhanced by them each having 2 hypertensive parents. Controls were 219 normotensive ethnically matched subjects whose parents were both normotensive. Genotyping was performed using the homogeneous MassEXTEND Assay. This showed a frequency of 0.10 for the minor allele in each group (
P
=0.88). Moreover, blood pressure, body mass index, sex, and plasma lipid levels were similar across genotypes. In conclusion, our study provides no support for an association of the intron 10 variant of
WNK4
with essential hypertension in the Anglo-Australian population studied.
C-Reactive Protein Modifies the Relationship Between Blood Pressure and Microalbuminuria
Authors: Stuveling Erik M. , Bakker Stephan J.L. , Hillege Hans L. , Burgerhof Johannes G.M. , de Jong Paul E. , Gans Reinold O.B. , de Zeeuw Dick
Published: February 2004

C-reactive protein (CRP) and microalbuminuria reflect intimately related components of the atherosclerotic disease process. Epidemiological studies found only modest associations between CRP and microalbuminuria. Blood pressure, one of the components of the metabolic syndrome in the general population, is the main determinant of microalbuminuria in diabetes and hypertension. We questioned whether CRP modifies the relationship of blood pressure and other cardiovascular risk factors with microalbuminuria in a cross-sectional study in 8592 inhabitants from Groningen, The Netherlands. The crude data showed an increase in the prevalence of microalbuminuria with increasing CRP quartiles (4.8, 9.6, 14.5, and 18.6%,
P
<0.0001). On stratification for cardiovascular risk factors, the data revealed a significant and positive interaction between mean arterial pressure (MAP) and quartiles of CRP with respect to the risk of microalbuminuria (Wald statistic 9.2,
P
=0.03). In subjects with a MAP <90 mm Hg, a nonsignificant trend in the association between CRP quartiles and microalbuminuria was found (prevalence: 3.9%, 5.8%, 6.6%, 8.7%;
P
=0.11). This trend was much steeper and significant in subjects with an MAP >90 mm Hg (prevalence: 6.7%, 13.6%, 20.4%, 25.1%;
P
<0.0001). Controlling for other risk factors in multivariate analyses, the positive interaction persisted (
P
=0.0004). No significant interactions between other risk factors and CRP with respect to the risk of microalbuminuria were encountered. Thus, CRP modifies the relation between blood pressure and microalbuminuria.
Restoration of Resting Sarcomere Length After Uniaxial Static Strain Is Regulated by Protein Kinase Cε and Focal Adhesion Kinase
Authors: Mansour Haytham , de Tombe Pieter P. , Samarel Allen M. , Russell Brenda
Published: February 2004

Physiological or pathological stresses and strains produce longer or wider muscle cells, but resting sarcomere length remains constant. Our goal was to investigate the cellular mechanisms for controlling this optimal, resting sarcomere length. To do so, we cultured neonatal rat cardiomyocytes on microfabricated peg-and-groove, laminin-coated silicone surfaces and applied a uniaxial static strain of 10%. Sarcomere length was accurately measured by fast Fourier transform analysis of images before, within 5 minutes of, and 4 to 6 hours after imposition of the strain. Sarcomere length of aligned cardiomyocytes (1.94±0.07 μm) was lengthened acutely (2.06±0.06 μm), and recovered (1.95±0.07 μm) by 4 hours. Puromycin, an mRNA translational inhibitor, prevented recovery of resting sarcomere length by 4 hours, thus indicating a requirement for new protein synthesis in the recovery process. Furthermore, activation of protein kinase Cε (PKCε) was necessary for length recovery, as nonselective PKC inhibitors [staurosporine (5 μmol/L) and chelerythrine chloride (10 μmol/L)], and a replication-defective adenovirus (Adv) encoding a dominant-negative mutant of PKCε prevented the restoration of sarcomere length. To assess the importance of focal adhesion complexes, cardiomyocytes were infected with an Adv encoding a dominant-negative inhibitor of focal adhesion kinase (FAK) (Adv-GFP-FRNK). Adv-GFP-FRNK also prevented resting sarcomere length recovery, whereas a control Adv encoding only GFP did not. In conclusion, using our novel culture system, we provide evidence indicating that the length remodeling process requires new protein synthesis, PKCε and FAK.
Contribution of
I
Kr
to Rate-Dependent Action Potential Dynamics in Canine Endocardium
Authors: Hua Fei , Gilmour Robert F.
Published: February 2004

Previous modeling studies have suggested that the rapid component of the delayed rectifier (
I
Kr
) may contribute importantly to action potential dynamics during tachycardia. To test this idea experimentally,
I
Kr
was measured as the E-4031–sensitive current in isolated canine endocardial myocytes at 37°C using the perforated patch-clamp technique. Command potentials were trains of action potential waveforms recorded at cycle lengths (CLs) of 1000, 500, 320, 170, and 120 ms. Action potential duration (APD) alternans occurred at CLs of 170 and 120 ms. During an action potential,
I
Kr
increased gradually to a maximum at −55 to −60 mV. Peak
I
Kr
increased initially as CL was shortened from 1000 to 500 ms (from 0.55±0.03 to 0.57±0.03 pA/pF), but decreased progressively as CL was shortened further (to 0.45±0.03 pA/pF at CL=120 ms). Baseline
I
Kr
was negligible at CLs of 1000 to 320 ms, but increased to 0.12±0.01 pA/pF at a CL of 120 ms. During APD alternans, peak
I
Kr
was larger for the short than for the long action potential (0.48±0.03 versus 0.46±0.03 pA/pF). A computer model of
I
Kr
based on these data indicated that increasing
I
Kr
suppressed alternans and decreasing
I
Kr
increased alternans. In support of the latter result, inhibition of
I
Kr
by E-4031 increased the maximal amplitude of alternans. These results indicate that
I
Kr
contributes importantly to rate-related alterations of repolarization, including APD alternans. Modifying
I
Kr
may be a promising approach to suppressing alternans and thereby preventing ventricular tachyarrhythmias.
Collateral Artery Growth (Arteriogenesis) After Experimental Arterial Occlusion Is Impaired in Mice Lacking CC-Chemokine Receptor-2
Authors: Heil Matthias , Ziegelhoeffer Tibor , Wagner Shawn , Fernández Borja , Helisch Armin , Martin Sandra , Tribulova Silvia , Kuziel William A. , Bachmann Georg , Schaper Wolfgang
Published: February 2004

Arteriogenesis has been associated with the presence of monocytes/macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein-1 (MCP-1, or CCL2 in the new nomenclature) to the CCR2-chemokine receptor on macrophages. To determine whether the CCL2-CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth. In an in vitro CCL2-driven chemotaxis assay, mononuclear cells isolated from wild-type BALB/c mice exhibited CCL2 concentration–dependent migration, whereas this migration was abolished in cells from CCR2
−/−
mice on a BALB/c genetic background. In vivo, blood flow recovery as measured by laser Doppler (LDI) and MRI (MRI) was impaired in CCR2
−/−
mice on either the BALB/c or C57BL/6 genetic backgrounds. Three weeks after femoral artery ligation, LDI perfusion ratio of operated versus nonoperated distal hindlimb in BALB/c wild-type mice increased to 0.45±0.06 and in CCR2
−/−
animals only to 0.21±0.03 (
P
<0.01). In C57BL/6 mice, ratio increased to 0.96±0.09 and 0.85±0.08 (
P
<0.05), respectively. MRI at 3 weeks (0.76±0.06 versus 0.62±0.01;
P
<0.05) and hemoglobin oxygen saturation measurements confirmed these findings. Active foot movement score significantly decreased and gastrocnemius muscle atrophy was significantly greater in CCR2
−/−
mice. Morphometric analysis showed a lesser increase in collateral vessel diameters in CCR2
−/−
mice. Importantly, the number of invaded monocytes/macrophages in the perivascular space of collateral arteries of CCR2
−/−
animals was dramatically reduced in comparison to wild-type mice. In conclusion, our results demonstrate that the CCR2 signaling pathway is essential for efficient collateral artery growth.
Rhythmic Ryanodine Receptor Ca
2+
Releases During Diastolic Depolarization of Sinoatrial Pacemaker Cells Do Not Require Membrane Depolarization
Authors: Vinogradova Tatiana M. , Zhou Ying-Ying , Maltsev Victor , Lyashkov Alexey , Stern Michael , Lakatta Edward G.
Published: February 2004

Localized, subsarcolemmal Ca
2+
release (LCR) via ryanodine receptors (RyRs) during diastolic depolarization of sinoatrial nodal cells augments the terminal depolarization rate. We determined whether LCRs in rabbit sinoatrial nodal cells require the concurrent membrane depolarization, or are intrinsically rhythmic, and whether rhythmicity is linked to the spontaneous cycle length. Confocal linescan images revealed persistent LCRs both in saponin-permeabilized cells and in spontaneously beating cells acutely voltage-clamped at the maximum diastolic potential. During the initial stage of voltage clamp, the LCR spatiotemporal characteristics did not differ from those in spontaneously beating cells, or in permeabilized cells bathed in 150 nmol/L Ca
2+
. The period of persistent rhythmic LCRs during voltage clamp was slightly less than the spontaneous cycle length before voltage clamp. In spontaneously beating cells, in both transient and steady states, LCR period was highly correlated with the spontaneous cycle length; and regardless of the cycle length, LCRs occurred predominantly at a constant time, ie, 80% to 90% of the cycle length. Numerical model simulations incorporating LCRs reproduce the experimental results. We conclude that diastolic LCRs reflect rhythmic intracellular Ca
2+
cycling that does not require the concomitant membrane depolarization, and that LCR periodicity is closely linked to the spontaneous cycle length. Thus, the biological clock of sinoatrial nodal pacemaker cells, like that of many other rhythmic functions occurring throughout nature, involves an intracellular Ca
2+
rhythm.
Carotid Arterial Remodeling
Authors: Henry Ronald M.A. , Kostense Piet J. , Dekker Jacqueline M. , Nijpels Giel , Heine Robert J. , Kamp Otto , Bouter Lex M. , Stehouwer Coen D.A.
Published: February 2004

Background and Purpose—

Deteriorating glucose tolerance is associated with an increased cardiovascular disease (CVD) risk. The underlying mechanisms remain unclear. Arterial remodeling is the change in structural properties through time in response to atherogenic and/or hemodynamic alterations and aims to maintain circumferential wall stress constant (σ
C
). Arterial remodeling has not been studied in relation to glucose tolerance.

Methods—

The study population consisted of 278 people with normal glucose metabolism, 168 with impaired glucose metabolism, and 301 with type 2 diabetes (DM-2); their mean age was 67.8 years. We assessed carotid intima-media thickness (IMT), interadventitial diameter (IAD), lumen diameter (LD), and σ
C
.

Results—

After adjustment for age, sex, height, body mass index, and prior CVD, DM-2 was associated with increased IAD, IMT, and σ
C
but not LD (regression coefficients: 0.24 mm; 95% confidence interval [CI], 0.07 to 0.41; 0.050 mm; 95% CI, 0.024 to 0.077; 5.00 kPa; 95% CI, 0.92 to 9.08; and 0.13 mm; 95% CI, −0.03 to 0.29, respectively). After additional adjustment for pulse pressure, the association between DM-2 and IAD disappeared, whereas the association with IMT remained. After adjustment, impaired glucose metabolism was not significantly associated with LD (0.12 mm; 95% CI, −0.06 to 0.33), σ
C
(0.25 kPa; 95% CI, −4.49 to 4.98), IAD (0.08 mm; 95% CI, −0.11 to 0.27), or IMT (0.029 mm; 95% CI, −0.002 to 0.060). However, the IMT regression coefficient was half that of DM-2.

Conclusions—

DM-2 is associated with preserved LD at increased IMT, which, however, does not normalize the increased σ
C
. In contrast, impaired glucose metabolism is not associated with changes in LD or IAD, whereas IMT is moderately increased but σ
C
remains constant. Carotid remodeling in DM-2 thus appears maladaptive, which may explain the increased CVD risk, especially stroke, in DM-2.
Evolution of Diaschisis in a Focal Stroke Model
Authors: Carmichael S. Thomas , Tatsukawa Keith , Katsman Diana , Tsuyuguchi Naohiro , Kornblum Harley I.
Published: February 2004

Background and Purpose—

Stroke produces diaschisis in adjacent and connected regions. The sequential changes in diaschisis over time and the relationship of regions of diaschisis to functional cortical areas and regions of poststroke neuroplasticity have not been determined.

Methods—

Small cortical strokes were produced in the barrel cortex of rats. Relative glucose metabolism was determined in vivo over time with [
18
F]fluorodeoxyglucose small-animal positron emission tomography. Cerebral blood flow was measured with [
14
C]iodoantipyrine. Regions of hypometabolism and hypoperfusion were compared with histological damage in the same animals.

Results—

Small cortical strokes produce an initial network of hypometabolism in a broad region of cortex adjacent to the stroke and in the striatum and thalamus on day 1. Cerebral blood flow is diminished only immediately around the cortical infarct on day 1. A substantial area of cortex adjacent to the stroke remains hypometabolic on day 8. This persistent cortical hypometabolism occupies the somatosensory cortex, forelimb motor cortex, and second somatosensory area.

Conclusions—

Focal stroke produces ipsilateral diaschisis in connected cortical regions that is clearly distant from subtotal damage and may play a role in poststroke neuroplasticity.
Gene Therapy and Endovascular Treatment of Intracranial Aneurysms
Authors: Ribourtout Edith , Raymond Jean
Published: February 2004

Background—

Endovascular treatment of intracranial aneurysms is safe and effective but too often is followed by recurrences. Gene therapy may improve healing after embolization, and endovascular approaches may offer future in situ delivery systems designed to prevent aneurysm rupture.

Summary of Review—

Advances in coil technology have focused on coating strategies designed to modify the biological reaction to the embolic agent. Gene therapy in cardiovascular applications is limited by low efficiency and transient gene expression. Current advances include the potential use of circulating progenitor cells for ex vivo genetic manipulations followed by in vivo delivery. Direct gene transfer may also be enhanced in situ by coils carrying antibody-tethered adenovirus or through the use of cell-specific or radiation-inducible promoters. Candidate genes that may be of value in promoting healing after endovascular treatment include growth factors and metalloproteinase inhibitors. A better understanding of the biology of aneurysm is necessary to conceive strategies designed to control the development of these lesions before their rupture.

Conclusions—

Many technical difficulties remain to be solved, but the combination of gene therapy and endovascular techniques offers multiple therapeutic possibilities in the future control of intracranial aneurysms.
Multifractal Fingerprints in the Visual Arts
Authors: Mureika J. R. , Cupchik G. C. , Dyer C. C.
Published: February 2004

The similarity in fractal dimensions of paint “blobs” in samples of gestural expressionist art implies that these pigment structures are statistically indistinguishable from one another. This conclusion suggests that such dimensions cannot be used as a “finger-print” for identifying the work of a single artist. To overcome this limitation, the authors have adopted the multifractal spectrum as an alternative tool for artwork analysis. For the pigment blobs, it is demonstrated that this spectrum can be used to isolate a construction paradigm or art style. Additionally, the fractal dimensions of edge structures created by luminance gradients on the canvas are analyzed, yielding a potential method for visual discrimination of fractally similar paintings
A Symphony of Sensations in the Spectator: Le Corbusier's Poème électronique and the Historicization of New Media Arts
Authors: Mondloch Katie
Published: February 2004

This essay seeks to historicize the technological production of artistic virtual space, which is often misconstrued as having originated with contemporary new media art production. The author critically investigates Le Corbusier's Poème électronique, a 1958 automated multimedia performance commissioned by the Philips Corporation for its pavilion at the World's Fair in Belgium, as a paradigmatic example of much earlier attempts to create a spatialized, virtual experience in the spectator. The author argues that the highly disciplined spectatorship conditions of the Poème électronique have many suggestive parallels with those of contemporary artistic production in new media, thus offering a theoretical and historical foundation for art-historical discourse regarding the proliferation of immersive multimedia artworks in contemporary practice
Late Merger of Degree Clauses
Authors: Bhatt Rajesh , Pancheva Roumyana
Published: February 2004

In this article, we propose that degree heads and degree clauses form a constituent not at the point where the degree head is merged, but after QR of the degree head and countercyclic merger of the degree clause. We derive a generalization originally outlined in Williams 1974 that the scope of the comparative degree quantifier is exactly as high as the site of attachment of the degree clause. This generalization is shown to follow from the derivational mechanism of countercyclic merger and a semantic property of the comparative degree head, namely, its nonconservativity
Who—or What—are the Rats (and Mice) in the Laboratory
Authors: Birke Lynda
Published: February 2004

This paper explores the many meanings attached to the designation,"the rodent in the laboratory" (rat or mouse). Generations of selective breeding have created these rodents. They now differ markedly from their wild progenitors, nonhuman animals associated with carrying all kinds of diseases.Through selective breeding, they have moved from the rats of the sewers to become standardized laboratory tools and (metaphorically) saviors of humans in the fight against disease. This paper sketches two intertwined strands of metaphors associated with laboratory rodents.The first focuses on the idea of medical/scientific progress; in this context, the paper looks at laboratory rodents often depicted (in advertising for laboratory products) as epitomizing medical triumph or serving as helpers or saviors. The second strand concerns the ambiguous status of the laboratory rodent who is both an animal (bites) and not an animal (data).The paper argues that, partly because of these ambiguous and multiple meanings, the rodent in the laboratory is doubly "othered"—first in the way that animals so often are made other to ourselves and then other in the relationship of the animal in the laboratory to other animals.
Illegal Hunting and Angling:The Neutralization of Wildlife Law Violations
Authors: Eliason Stephen
Published: February 2004

This study provides a descriptive account of rationalizations for poaching used by wildlife law violators. There has been little research on motivations for poaching. This study uses qualitative data obtained from surveys and in-depth interviews with wildlife law violators and conservation officers in Kentucky to examine rationalizations used by wildlife law violators to excuse and justify participation in this type of illegal activity. Comments from conservation officers and violators revealed widespread use of rationalizations, with denial of responsibility being most common. The study also used claims of entitlement, defense of necessity, and denial of necessity of the law. Findings contribute to our knowledge of why people illegally take wildlife resources.
Tracing the Profile of Animal Rights Supporters: A Preliminary Investigation
Authors: Jerolmack Colin
Published: February 2004

A question about the "moral rights" of nonhuman animals in the 1993 and 1994 General Social Survey (GSS) effected an understanding of some of the demographics of those supporting animal rights. This study checked results against related questions concerning attitudes toward animal testing and meat consumption. The stereotypical profile of an animal rights supporter is female, well educated, upper-middle class, middle-aged, and white. The data in this study do not support the stereotype. Instead, the young, non-black minorities, and the less educated were more likely to support animal rights; income was not a significant predictor. Other predictors examined included religious denomination, frequency of church attendance, and attitudes toward environmental protection. This study's findings suggest the need to rethink "post-materialist" and "post-citizenship" theories about who supports animal rights. This paper also points the way toward future studies to examine the causal linkages between the predictors and animal rights attitudes.
NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a
Authors: Gu Ting-Lei , Tothova Zuzana , Scheijen Blanca , Griffin James D. , Gilliland D. Gary , Sternberg David W.
Published: February 2004

Between 30% and 50% of patients with advanced-stage anaplastic large-cell lymphoma (ALCL) harbor the balanced chromosomal rearrangement t(2;5)(p23;q35), which results in the generation of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). To further study survival signaling by NPMALK, we generated Ba/F3 cell lines with either inducible or constitutive expression of NPM-ALK and examined the regulation of the AKT target FOXO3a. We hypothesized that NPM-ALK signaling through phosphoinositol 3-kinase (PI 3-kinase) and AKT would regulate FOXO3a, a member of the forkhead family of transcription factors, thereby stimulating proliferation and blocking programmed cell death in NPM-ALK-transformed cells. In Ba/F3 cells with induced or constitutive expression of NPM-ALK, concomitant AKT activation and phosphorylation of its substrate, FOXO3a, was observed. In addition, transient expression of NPM-ALK in U-20S cells inhibited FOXO3a-mediated transactivation of reporter gene expression. Furthermore, NPM-ALK-induced FOXO3a phosphorylation in Ba/F3 cells resulted in nuclear exclusion of this transcriptional regulator, up-regulation of cyclin D2 expression, and down-regulation of p27kip1 and Bim-1 expression. NPMALK reversal of proliferation arrest and of p27kip1 induction was dependent on the phosphorylation of FOXO3a. Thus, FOXO3a is a barrier to hematopoietic transformation that is overcome by phosphorylation and cytoplasmic relocalization induced by the expression of NPM-ALK. (Blood. 2004;103:4622-4629)
pDP4, a novel glycoprotein secreted by mature granulocytes, is regulated by transcription factor PU.1
Authors: Rosenbauer Frank , Wagner Katharina , Zhang Pu , Knobeloch Klaus-Peter , Iwama Atsushi , Tenen Daniel G.
Published: February 2004

The transcription factor PU.1 (Spi-1) is a well-characterized regulator of myeloid and lymphoid development. However, its role in mature functional cells is poorly studied. Here we report the characterization of the novel murine gene pDP4 (PU.1 difference product 4), which is absent from fetal livers of PU.1-deficient mice. pDP4 is transcribed as a single 3.2-kb mRNA with a 1518-base pair open reading frame encoded by 5 exons on chromosome 14. pDP4 expression is strongest in small intestine and bone marrow, in which it is expressed predominately in mature neutrophils. Interestingly, however, pDP4 expression is markedly down-regulated in neutrophils of the peripheral blood and peritoneum. The pDP4 gene encodes a secreted 57-kDa glycoprotein with an olfactomedin-like C-terminus. PU.1 binds to a functional site within the pDP4 promoter, and pDP4 expression in myeloid cells is strictly dependent on PU.1 and the presence of this site. In conclusion, we have identified a novel PU.1-regulated extracellular glycoprotein of the olfactomedin-like family with a possible role in neutrophilic trafficking. (Blood. 2004;103:4294-4301)
CD34+CD38- hematopoietic precursors derived from human embryonic stem cells exhibit an embryonic gene expression pattern
Authors: Lu Shi-Jiang , Li Fei , Vida Loyda , Honig George R.
Published: February 2004

Gene expression patterns of CD34+CD38- cells derived from human embryonic stem cells (ESCs) were compared with those of cells isolated from adult human bone marrow (BM) using microarrays; 1692 and 1494 genes were expressed at levels at least 3-fold above background in cells from BM and ESCs, respectively. Of these, 494 showed similar levels of expression in cells from both sources, 791 genes were overexpressed in cells from BM (BM versus ESCs, at least 2-fold), and 803 genes were preferentially expressed in cells from ESCs (ESCs versus BM, at least 2-fold). The message of the flt-3 gene was markedly decreased in cells from ESCs, whereas there was substantial flt-3 expression in cells from BM. High levels of embryonic ϵ-globin expression were observed—but no adult β-globin message—in CD34+CD38- cells from ESCs, whereas high levels of β-globin expression—but no embryonic ϵ-globin message—could be detected in cells from BM. Furthermore, high levels of major histocompatibility complex (MHC) gene expression were demonstrated in cells from BM but very low levels of MHC message in corresponding cells from ESCs. These observations demonstrate that CD34+CD38- cells derived from ESCs correspond consistently to an early developmental stage at which the yolk sac and fetal liver are the primary sites of hematopoiesis.
Chronic lymphocytic leukemia: revelations from the B-cell receptor
Authors: Stevenson Freda K. , Caligaris-Cappio Federico
Published: February 2004

The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)
T cells in the lung of patients with hypersensitivity pneumonitis accumulate in a clonal manner
Authors: Facco Monica , Trentin Livio , Nicolardi Linda , Miorin Marta , Scquizzato Elisa , Carollo Davide , Baesso Ilenia , Bortoli Michela , Zambello Renato , Marcer Guido , Agostini Carlo , Semenzato Gianpietro
Published: February 2004

Hypersensitivity pneumonitis (HP) is characterized by an alveolitis sustained by CD8+ T lymphocytes showing a limited expression of the T cell receptor (TCR). We previously demonstrated that a bias in T cell selection occurs in the lower respiratory tract of patients with HP, with a compartmentalization in the lung of CD8+ T cells bearing (TCR)-β variable (TCRBV) #2, 3, 5, 6, 8, and 13 gene segments. We herein characterized the clonal T cell populations present in the lung and in the blood of patients with HP. Heteroduplex analyses, cloning, and sequencing T cells bearing TCR indicate oligoclonal expansions of T cells expressing homologous or identical complementary-determining region 3. Furthermore, T cell clones isolated from the two compartments expressed similar, sometimes identical, junctional regions. Removal from antigenic exposure led to the disappearance of T cell clones. Our findings indicate that expansions of T lymphocytes bearing clonal TCRBV region gene segments take place in the lung of patients with HP during exposure. The evidence that identical T cell clones are present in the lung and the blood of the same patient suggests that the immune reaction occurring at lung level gives rise to a systemic reaction.
Cross-regulation of CD86 by CD80 differentially regulates T helper responses fromMycobacterium tuberculosissecretory antigen-activated dendritic cell subsets
Authors: Balkhi Mumtaz Yaseen , Latchumanan Vinoth K , Singh Balwan , Sharma Pawan , Natarajan Krishnamurthy
Published: February 2004

We report that stimulation of Mycobacterium tuberculosis secretory antigen- and tumor necrosis factor α-matured BALB/c mouse bone marrow dendritic cells (BMDCs) with anti-CD80 monoclonal antibody up-regulated CD86 levels on the cell surface. Coculture of these BMDCs with naïve, allogeneic T cels now down-regulated T helper cell type 1 (Th1) responses and up-regulated suppressor responses. Similar results were obtained with splenic CD11c+/CD8a− DCs but not to the same extent with CD11c+/CD8a+ DCs. Following coculture with T cells, only BMDCs and CD11c+/CD8a− DCs and not CD11c+/CD8a+ DCs displayed increased levels of surface CD86, and further, coculturing these DCs with a fresh set of T cells attenuated Th1 responses and increased suppressor responses. Not only naïve but even antigen-specific recall responses of the Th1-committed cells were modulated by DCs expressing up-regulated surface CD86. Further analyses showed that stimulation with anti-CD80 increased interleukin (IL)-10 and transforming growth factor-β-1 levels with a concomitant reduction in IL-12p40 and interferon-γ levels from BMDCs and CD11c+/CD8a− DCs and to a lesser extent, from CD11c+/CD8a+ DCs. These results suggest that cross-talk between costimulatory molecules differentially regulates their relative surface densities leading to modulation of Th responses initiated from some DC subsets, and Th1-committed DCs such as CD11c+/CD8a+ DCs may not allow for such modulation. Cognate antigen-presenting cell (APC):T cell interactions then impart a level of polarization on APCs mediated via cross-regulation of costimulatory molecules, which govern the nature of subsequent Th responses.
Theory of mind ability in children with specific language impairment
Authors: Gillott Alinda , Furniss Frederick , Walter Ann
Published: February 2004

Whilst evidence of theory of mind impairments in children with autism is well established, possible impairments in children with language disorder have only recently been investigated. Children with specific language impairment aged between eight and 12 years were matched by age and gender to high functioning children with autism and normally developing peers. The theory of mind abilities of the groups were compared using the strange stories task. Both the children with specific language impairment and the children with autism gave fewer correct mental state answers than normally developing children, but whereas the children with autism gave more inappropriate mental state answers than the children who were developing normally, the children who were developing normally and the children with language disorders did not differ in this respect. These findings are discussed within the context of theory of mind issues in autism and the classification of language disorders.
Teacher and speech-language therapist collaboration: being equal and achieving a common goal?
Authors: Hartas Dimitra
Published: February 2004

Collaboration is a key aspect in developing effective educational provision for pupils with special educational needs. In this study, collaboration is conceptualized as a dynamic system for educational efforts which endorses collegial, interdependent and co-equal styles of interaction between teachers and speech and language therapists (SLTs). Twenty-five teachers and seventeen SLTs were asked to complete a questionnaire and participate in group discussions to provide information about their perception of collaboration with their colleagues at a school that caters for children with language and communication difficulties. Across qualitative and quantitative analyses, results consistently suggested that most teachers and SLTs see time commitment=constraints and rigid organizational structures as being the hindering factors in their collaborative workings with others. On the other hand, willingness to make professional changes and learn from each other, individual contribution and shared beliefs and values are seen as supportive factors. Teachers and SLTs see collaboration as a distinct, formal activity that can only occur within a prespecified time and space allocated to it, encouraging individuals to engage in prescribed activities while they remain within their own professional boundaries. Implications for policy and practice are discussed and issues for future research are raised.
Children's views of speech and language therapy in school: consulting children with communication difficulties
Authors: Owen Rosalind , Hayett Lucy , Roulstone Sue
Published: February 2004

Children have the right to express their views and to participate actively in decisions that concern them. Implementing this principle in clinical practice poses a methodological challenge to therapists working with children with communication difficulties. In a pilot study, therapists working in mainstream primary schools conducted semi-structured interviews with 12 clients, aged 6–11 years with communication difficulties. The interviews elicited valuable information about these children's experience of speech and language therapy and about their general communication at school and at home. Methods of interviewing were evaluated and recommendations made for ways of increasing children's participation in planning and reviewing therapy.
A phonological screening tool for Cantonese-speaking children
Authors: So Lydia K.H. , Leung Cheung-Shing Samuel
Published: February 2004

To assess whether children have phonological disorders, we need to make use of screening tools of the child's first language. This paper describes and evaluates one published phonological screening tool that has been developed for Cantonese-speaking children, the Cantonese Segmental Phonology Test (CSPT). Such a test is also valid for assessing children who speak Cantonese and other languages outside Hong Kong. In this review, we also report various findings on normal and disordered Cantonese phonological development based on this test.