bluuebunny/crossref_metadata_2025 huggingface dataset:
Fas Signaling Induces Akt Activation and Upregulation of Endothelial Nitric Oxide Synthase Expression
Authors: Takemura Yukihiro , Fukuo Keisuke , Yasuda Osamu , Inoue Takahito , Inomata Norio , Yokoi Toyohiko , Kawamoto Hidenobu , Suhara Toshimitsu , Ogihara Toshio
Published: February 2004

A growing body of evidence has shown that Fas, a death receptor, mediates apoptosis-unrelated biological effects. Here, we report that Fas engagement with Fas ligand induced activation of Akt and upregulation of endothelial nitric oxide synthase expression without induction of apoptosis. In the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin, Fas ligand, however, induced apoptosis instead of upregulation of endothelial nitric oxide synthase expression. In vivo, systolic blood pressure was slightly higher in mutant mice with decreased cell surface Fas expression (
lpr
mice) compared with wild-type mice. In addition, chronic inhibition of nitric oxide synthesis by
N
G
-nitro-l-arginine induced a progressive increase in the levels of blood pressure in wild-type mice, whereas no further increase in the levels of blood pressure was observed in
lpr
mice. Furthermore, acetylcholine caused a lesser endothelium-dependent relaxation of the strips from
lpr
mice compared with wild-type mice, although the vasoconstrictor potency of phenylephrine was not different between the two groups. These findings indicate that Fas signaling may have a role in the regulation of endothelial function and blood pressure through modulating endothelial nitric oxide synthase expression in the Akt signal-dependent manner.
Modulation of Learning and Memory in Dahl Rats by Dietary Salt Restriction
Authors: Ruiz-Opazo Nelson , Lopez Lyle V. , Tonkiss John
Published: February 2004

The Dahl rat represents a robust animal model of salt-sensitive hypertension, with Dahl S rats being salt sensitive and Dahl R rats (the Dahl S counterparts) being salt resistant for the development of hypertension. Here we evaluate the effect of reduced dietary salt intake on learning and memory in the Dahl rat model. Salt restriction produced a significant impairment in social transmission of food preference and social recognition memory in Dahl S rats without affecting spatial learning. In contrast, social transmission of food preference and social recognition memory remained unaffected in Dahl R rats, whereas navigation performance was significantly improved. This effect on learning and memory was not generalized because sodium restriction did not influence object recognition memory in either Dahl S or Dahl R rats. The significant decrement in select cognitive functions in Dahl S rats produced by salt restriction are in sharp contrast to the well known positive effect of dietary salt restriction in alleviating high blood pressure and associated target organ complications, suggesting that caution must be exercised when weighing the benefits of salt restriction in improving cardiovascular health in salt-sensitive hypertension against the potential undesirable effects of reduced cognitive function.
Urinary Potassium Excretion and Sodium Sensitivity in Blacks
Authors: Aviv Abraham , Hollenberg Norman K. , Weder Alan
Published: February 2004

Based on racial differences in urinary potassium excretion and responses to diuretics, we present a model suggesting that a major cause of sodium sensitivity in blacks is an augmented activity of the Na-K-2Cl cotransport in the thick ascending limb of Henle’s loop. This would result in an increased ability to conserve not only sodium but also water, and an upward and rightward shift in the operating point of tubuloglomerular feedback, which may cause an increase in the glomerular capillary hydraulic pressure and predilection to glomerular injury with and without hypertension. In this sense, the biological implication of sodium sensitivity in blacks and in humans in general has ramifications above and beyond salt-evoked increase in blood pressure.
Angiotensin II and Cell Cycle Regulation
Authors: Wolf Gunter , Wenzel Ulrich O.
Published: February 2004

Angiotensin II has emerged as an important growth factor for vascular, cardiac, and renal cells. Depending on the specific cell type and presence of other growth factors, angiotensin II induces proliferation (replication of DNA with subsequent successful division of cells), hypertrophy (increase in cell size, cell protein, and mRNA content without DNA replication), apoptosis (programmed cell death), or differentiation. Such angiotensin II-mediated modulation of growth process may underlie various pathophysiological processes such as atherosclerosis, vascular and cardiac remodeling, and progression of chronic renal disease. Clearly, angiotensin II-induced proliferation requires complete cell progression through the various steps of the cell cycle. In contrast, cells undergoing angiotensin II-mediated hypertrophy are arrested in the G
1
-phase. Upregulation of cell cycle-dependent kinase inhibitors (eg, p27
Kip1
) plays an important role in this process. Although accumulating evidence suggests that apoptosis is cell cycle-dependent, only few data are currently available concerning the interaction of angiotensin II with the cell cycle machinery in apoptosis. We review the various angiotensin II-mediated growth processes and their relationship to events governing cell cycle regulation.
Blood Pressure Response to Caffeine Shows Incomplete Tolerance After Short-Term Regular Consumption
Authors: Lovallo William R. , Wilson Michael F. , Vincent Andrea S. , Sung Bong Hee , McKey Barbara S. , Whitsett Thomas L.
Published: February 2004

Caffeine acutely raises blood pressure (BP). The clinical significance of this effect depends on whether BP responses persist in persons who consume caffeine on a daily basis. Accordingly, the ability of caffeine to raise BP after 5 days of regular daily intake was tested in a randomized controlled trial. Individual differences in tolerance formation were then examined. Men (n=49) and women (n=48) completed a double-blind, crossover trial conducted over 4 weeks. During each week, subjects abstained for 5 days from dietary caffeine and instead used capsules totaling 0 mg, 300 mg, and 600 mg of caffeine per day in 3 divided doses. On day 6, in the laboratory, they used capsules with either 0 mg or 250 mg of caffeine at 9:00
am
and 1:00
pm
. Systolic/diastolic BP increases as a result of 250 mg of caffeine remained significant (
P
<0.006/0.001) at all levels of previous daily consumption. Individual difference comparisons found that although half the subjects had complete loss of systolic and diastolic BP responses to the challenge doses, the other half showed no loss in BP response, even after using 600 mg of caffeine per day for the previous 5 days (
F
>7.90,
P
<0.001). The sexes did not differ in degree of tolerance formation. Daily caffeine consumption failed to eliminate the BP response to repeated challenge doses of caffeine in half of the healthy adults who were tested. Caffeine may therefore cause persistent BP effects in persons who are regular consumers, even when daily intake is at moderately high levels.
Phosphatidylinositol 3-Kinase/Akt Regulates Angiotensin II–Induced Inhibition of Apoptosis in Microvascular Endothelial Cells by Governing Survivin Expression and Suppression of Caspase-3 Activity
Authors: Ohashi Hirokazu , Takagi Hitoshi , Oh Hideyasu , Suzuma Kiyoshi , Suzuma Izumi , Miyamoto Noriko , Uemura Akiyoshi , Watanabe Daisuke , Murakami Tomoaki , Sugaya Takeshi , Fukamizu Akiyoshi , Honda Yoshihito
Published: February 2004

Angiotensin II (Ang II) plays essential roles in vascular homeostasis, neointimal formation, and postinfarct remodeling. Although Ang II has been shown to regulate apoptosis in cardiomyocytes and vascular smooth muscle cells, its role in vascular endothelial cells (ECs) remains elusive. To address this issue, we first performed TUNEL and caspase-3 activity assays with porcine microvascular ECs challenged by serum deprivation. Ang II significantly reduced the ratio of apoptotic cells and caspase-3 activity. The Ang II type 1 receptor (AT
1
) was responsible for these effects. Among the signaling molecules downstream of AT
1
, we revealed that PI3-kinase/Akt pathway plays a predominant role in the antiapoptotic effect of Ang II. Interestingly, the expression of survivin, a central molecule of cell survival, increased after Ang II stimulation. Overexpression of a dominant-negative form of Akt abolished both Ang II–induced antiapoptosis and survivin protein expression. In a murine model of hyperoxygen-induced retinal vascular regression, AT
1a
knockout mice showed a significant increase in retinal avascular areas. Our data indicate that Ang II plays a critical antiapoptotic role in vascular ECs by a mechanism involving PI3-kinase/Akt activation, subsequent upregulation of survivin, and suppression of caspase-3 activity.
Antioxidants Inhibit Nuclear Export of Telomerase Reverse Transcriptase and Delay Replicative Senescence of Endothelial Cells
Authors: Haendeler Judith , Hoffmann Jörg , Diehl J. Florian , Vasa Mariuca , Spyridopoulos Ioakim , Zeiher Andreas M. , Dimmeler Stefanie
Published: February 2004

Aging is associated with a rise in intracellular reactive oxygen species (ROS) and a loss of telomerase reverse transcriptase activity. Incubation with H
2
O
2
induced the nuclear export of telomerase reverse transcriptase (TERT) into the cytosol in a Src-family kinase–dependent manner. Therefore, we investigated the hypothesis that age-related increase in reactive oxygen species (ROS) may induce the nuclear export of TERT and contribute to endothelial cell senescence. Continuous cultivation of endothelial cells resulted in an increased endogenous formation of ROS starting after 29 population doublings (PDL). This increase was accompanied by mitochondrial DNA damage and preceded the onset of replicative senescence at PDL 37. Along with the enhanced formation of ROS, we detected an export of nuclear TERT protein from the nucleus into the cytoplasm and an activation of the Src-kinase. Moreover, the induction of premature senescence by low concentrations of H
2
O
2
was completely blocked with the Src-family kinase inhibitor PP2, suggesting a crucial role for Src-family kinases in the induction of endothelial cell aging. Incubation with the antioxidant
N
-acetylcysteine, from PDL 26, reduced the intracellular ROS formation and prevented mitochondrial DNA damage. Likewise, nuclear export of TERT protein, loss in the overall TERT activity, and the onset of replicative senescence were delayed by incubation with
N
-acetylcysteine. Low doses of the statin, atorvastatin (0.1 μmol/L), had also effects similar to those of
N
-acetylcysteine. We conclude that both antioxidants and statins can delay the onset of replicative senescence by counteracting the increased ROS production linked to aging of endothelial cells.
Neointimal Smooth Muscle Cells Display a Proinflammatory Phenotype Resulting in Increased Leukocyte Recruitment Mediated by P-Selectin and Chemokines
Authors: Zeiffer Ute , Schober Andreas , Lietz Michael , Liehn Elisa A. , Erl Wolfgang , Emans Neil , Yan Zhong-qun , Weber Christian
Published: February 2004

Leukocyte recruitment is crucial for the response to vascular injury in spontaneous and accelerated atherosclerosis. Whereas the mechanisms of leukocyte adhesion to endothelium or matrix-bound platelets have been characterized, less is known about the proadhesive role of smooth muscle cells (SMCs) exposed after endothelial denudation. In laminar flow assays, neointimal rat SMCs (niSMCs) supported a 2.5-fold higher arrest of monocytes and “memory” T lymphocytes than medial SMCs, which was dependent on both P-selectin and VLA-4, as demonstrated by blocking antibodies. The increase in monocyte arrest on niSMCs was triggered by the CXC chemokine GRO-α and fractalkine, whereas “memory” T cell arrest was mediated by stromal cell–derived factor (SDF)-1α. This functional phenotype was paralleled by a constitutively increased mRNA and surface expression of P-selectin and of relevant chemokines in niSMCs, as assessed by real-time PCR and flow cytometry. The increased expression of P-selectin in niSMCs versus medial SMCs was associated with enhanced NF-κB activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-κB by adenoviral IκBα in niSMCs resulted in a marked reduction of increased leukocyte arrest in flow. Furthermore, P-selectin expression by niSMCs in vivo was confirmed in a hypercholesterolemic mouse model of vascular injury by double immunofluorescence and by RT-PCR after laser microdissection. In conclusion, we have identified a NF-κB–mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.
Functional Basis of Sinus Bradycardia in Congenital Heart Block
Authors: Hu Keli , Qu Yongxia , Yue Yuankun , Boutjdir Mohamed
Published: February 2004

Congenital heart block (CHB) is a conduction abnormality characterized by complete atrioventricular (AV) block. CHB affects fetuses and/or newborn of mothers with autoantibodies reactive with ribonucleoproteins 48-kDa SSB/La, 52-kDa SSA/Ro, and 60-kDa SSA/Ro. We recently established animal models of CHB and reported, for the first time, significant sinus bradycardia preceding AV block. This unexpected observation implies that the spectrum of conduction abnormalities extends beyond the AV node to also affect the SA node. To test this hypothesis, we investigated the functional basis of this sinus bradycardia by characterizing the effects of antibodies from mothers with CHB children (positive IgG) on ionic currents that are known to significantly contribute to spontaneous pacing in SA node cells. We recorded L- (
I
Ca.L
) and T- (
I
Ca.T
) type Ca
2+
, delayed rectifier K
+
(
I
K
), hyperpolarization-activated (
I
f
) currents, and action potentials (APs) from young rabbit SA node cells. We demonstrated that positive IgG significantly inhibited both
I
Ca.T
and
I
Ca.L
and induced sinus bradycardia but did not affect
I
f
and
I
K
. Normal IgG from mothers with healthy children did not affect all the currents studied and APs. These results establish that IgG from mothers with CHB children causes substantial inhibition of
I
Ca.T
and
I
Ca.L
, two important pacemaker currents in rabbit SA node cells and point to both
I
Ca.T
and
I
Ca.L
as major players in the ionic mechanism by which maternal antibodies induce sinus bradycardia in CHB. These novel findings have important clinical significance and suggest that sinus bradycardia may be a potential marker in the detection and prevention of CHB. The full text of this article is available online at
http://circres.ahajournals.org
Prostacyclin Induces Apoptosis of Vascular Smooth Muscle Cells by a cAMP-Mediated Inhibition of Extracellular Signal-Regulated Kinase Activity and Can Counteract the Mitogenic Activity of Endothelin-1 or Basic Fibroblast Growth Factor
Authors: Li Rung-chi , Cindrova-Davies Tereza , Skepper Jeremy N. , Sellers Lynda A.
Published: February 2004

Prostanoids can suppress vascular smooth muscle cell (VSMC) proliferation, but the mechanism through which this is mediated has not been identified. In this study, we show rat aortic VSMCs to express the EP
1
, EP
2
, EP
3
, EP
4
, and IP receptors. The EP
4
receptor–specific agonist, 11-deoxy-PGE
1
, induced a time-dependent phosphorylation of protein kinase C and extracellular signal-regulated kinase (ERK) 1/2 in serum-depleted (0.1%) VSMCs, whereas the EP
2
receptor agonist, butaprost, was without effect. PGI
2
or iloprost at the IP receptor inhibited basal ERK phosphorylation with IC
50
values of ≈10 nmol/L. Iloprost also attenuated the sustained activation of ERK induced by endothelin-1 or basic fibroblast growth factor (bFGF). Endothelin-1 or bFGF significantly increased the number of VSMCs counted 24 hours later compared with basal, and both responses were blocked by the MEK inhibitor, U0126, or iloprost. Under basal conditions, U0126 or iloprost reduced the number of viable cells and increased caspase-3 activity, which could be reversed by coapplication with endothelin-1, bFGF, or the adenylate cyclase inhibitor, SQ22536. Endothelin-1, bFGF, or SQ22536 prevented the depression to below basal levels of ERK phosphorylation induced by iloprost. Forskolin activated caspase-3 and attenuated basal ERK phosphorylation, which were prevented by SQ22536, endothelin-1, or bFGF. These data suggest that iloprost induces apoptosis via a cAMP-mediated suppression of ERK activity. In turn, this apoptotic response can be blocked by a mitogenic stimulus that re-establishes ERK activity back to basal levels, but at the expense of any concomitant proliferative activity. However, ERK stimulation by a selective EP
4
receptor agonist, suggests that prostanoids may have diverse and complex roles in VSMC physiology.
Platelet-Derived Growth Factor-AB Promotes the Generation of Adult Bone Marrow–Derived Cardiac Myocytes
Authors: Xaymardan Munira , Tang Lilong , Zagreda Leze , Pallante Benedetta , Zheng Jingang , Chazen Joseph L. , Chin Andrew , Duignan Inga , Nahirney Patrick , Rafii Shahin , Mikawa Takashi , Edelberg Jay M.
Published: February 2004

The directed generation of cardiac myocytes from endogenous stem cells offers the potential for novel therapies for cardiovascular disease. To facilitate the development of such approaches, we sought to identify and exploit the pathways directing the generation of cardiac myocytes from adult rodent bone marrow cells (BMCs). In vitro cultures supporting the spontaneous generation of functional cardiac myocytes from murine BMCs demonstrated induced expression of platelet-derived growth factor (PDGF)-A and -B isoforms with α- and β-myosin heavy chains as well as connexin43. Supplementation of PDGF-AB speeded the kinetics of myocyte development in culture by 2-fold. In a rat heart, myocardial infarction pretreatment model PDGF-AB also promoted the derivation of cardiac myocytes from BMCs, resulting in a significantly greater number of islands of cardiac myocyte bundles within the myocardial infarction scar compared with other treatment groups. However, gap junctions were detected only between the cardiac myocytes receiving BMCs alone, but not BMCs injected with PDGF-AB. Echocardiography and exercise testing revealed that the functional improvement of hearts treated with the combination of BMCs and PDGF-AB was no greater than with injections of BMCs or PDGF-AB alone. These studies demonstrated that PDGF-AB enhances the generation of BMC-derived cardiac myocytes in rodent hearts, but suggest that alterations in cellular patterning may limit the functional benefit from the combined injection of PDGF-AB and BMCs. Strategies based on the synergistic interactions of PDGF-AB and endogenous stem cells will need to maintain cellular patterning in order to promote the restoration of cardiac function after acute coronary occlusion. The full text of this article is available online at http://circres.ahajournals.org.
Thromboxane A
2
Receptor Agonists Antagonize the Proangiogenic Effects of Fibroblast Growth Factor-2
Authors: Ashton Anthony W. , Cheng Yan , Helisch Armin , Ware J. Anthony
Published: February 2004

Thromboxane (TX) A
2
is released from multiple cell types and is a prime mediator of the pathogenesis of many vascular events, including angiogenesis. Endothelial cells express TXA
2
receptors (TP) but the effects of TP stimulation on angiogenesis remain controversial. In this study, we show that stimulation of endothelial cell TP impairs ligand-induced FGF receptor internalization and consequently abrogates FGF-2-induced endothelial cell migration in vitro and angiogenesis in vivo. Prevention of FGF-2-induced angiogenesis was associated with expression of the TPβ isoform. The deficit in FGFR1 internalization was mediated through activation of TPβ preventing the FGF-2-mediated decrease in p53 expression, thus enhancing thrombospondin-1 (TSP-1) release from EC and reducing FGFR1 internalization. Once released TSP-1 interacted with the α
v
β
3
integrin on the EC surface. On stimulation, FGFR1 and α
v
β
3
were found to associate in a complex. We determined that complex formation was important for receptor internalization as conditions that inhibit FGFR1 internalization, such as inappropriate ligation of α
v
β
3
by either TSP-1 or a neutralizing antibody, disrupted the complex. These results establish a novel role for isoform specific regulation of angiogenesis by TP, provide the first functional significance for the existence of two TP isoforms in humans, and clarify the mechanism by which TP signaling regulates FGFR1 kinetics and signaling.
Vasorelaxation by Red Blood Cells and Impairment in Diabetes
Authors: James Philip E. , Lang Derek , Tufnell-Barret Timothy , Milsom Alex B. , Frenneaux Michael P.
Published: February 2004

Vascular dysfunction in diabetes is attributed to lack of bioavailable nitric oxide (NO) and is postulated as a primary cause of small vessel complications as a result of poor glycemic control. Although it has been proposed that NO is bound by red blood cells (RBCs) and can induce relaxation of blood vessels distal to its site of production in the normal circulation, the effect of RBC glycation on NO binding and relaxation of hypoxic vessels is unknown. We confirm RBC-induced vessel relaxation is inversely related to tissue oxygenation and is proportional to RBC
S
-nitrosohemoglobin (HbSNO) content (but not nitrosylhemoglobin content). We show more total NO bound inside highly glycated RBCs (0.0134 versus 0.0119 NO/Hb, respectively;
P
<0.05) although proportionally less HbSNO (0.0053 versus 0.0088 NO/Hb, respectively;
P
<0.05). We also show glycosylation impairs the vasodilator function of RBCs within a physiological range of tissue oxygenation. These findings may represent an important contribution to reduced NO bioavailability in the microvasculature in diabetes.
MMP-9 Polymorphisms Are Not Associated With Spontaneous Cervical Artery Dissection
Authors: Wagner Simone , Kluge Britta , Koziol James A. , Grau Armin J. , Grond-Ginsbach Caspar
Published: February 2004

Background and Purpose—

Cervical artery dissection (CAD) is a common cause of ischemic stroke in young adults. Alteration in the structure of the vascular extracellular matrix has been described in CAD. Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and can lead to vascular damage.

Methods—

We tested 2 different MMP-9 DNA polymorphisms, a CA repeat and a cytosine to thymidine transition in the promotor sequence, for frequency in 52 patients with CAD. We compared the results with those of 52 healthy controls.

Results—

No differences were found in the allelic distribution of either polymorphism.

Conclusions—

Alleles of these well-characterized functional polymorphisms of MMP-9 gene are not associated with structural alterations in the matrix of vessels of patients with CAD.
Transient Ischemic Attacks Before Ischemic Stroke: Preconditioning the Human Brain?
Authors: Wegener Susanne , Gottschalk Barbara , Jovanovic Verica , Knab René , Fiebach Jochen B. , Schellinger Peter D. , Kucinski Thomas , Jungehülsing Gerhard J. , Brunecker Peter , Müller Bianca , Banasik Anna , Amberger Nicola , Wernecke Klaus D. , Siebler Mario , Röther Joachim , Villringer Arno , Weih Markus
Published: February 2004

Background and Purpose—

We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain.

Methods—

Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA.

Results—

Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL;
P
=0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits.

Conclusions—

The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.
Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage
Authors: Sarrafzadeh Asita S. , Haux Daniel , Lüdemann Lutz , Amthauer Holger , Plotkin Michail , Küchler Ingeborg , Unterberg Andreas W.
Published: February 2004

Background and Purpose—

Cerebral microdialysis (MD) is discussed as a technique for detection of cerebral ischemia in subarachnoid hemorrhage; however, clinical data on cerebral blood flow (CBF) are limited in these patients. The main objective of this study was to investigate whether pathological MD parameters reflect a reduced regional CBF (rCBF) determined by
15
O-H
2
O PET.

Methods—

Thirteen subarachnoid hemorrhage patients (age, 48.7±15.0 years; World Federation of Neurological Surgeons grade 1 to 5) were studied. Extracellular glucose, lactate, lactate/pyruvate (L/P) ratio, glutamate, and glycerol levels were analyzed hourly. rCBF was determined in the volume of interest of the MD catheter and all vascular territories. MD values were correlated to rCBF on the day of PET. Then, MD concentrations of asymptomatic versus ischemic phases (3-day medians) were analyzed.

Results—

In symptomatic patients (n=10), rCBF was significantly lower compared with controls (n=3,
P
=0.048). Glutamate correlated best with rCBF (
r
=−0.66;
P
=0.014), followed by glycerol (
r
=−0.62;
P
=0.021). The L/P ratio was most sensitive (0.82) and specific (1.0) in indicating symptoms of ischemia, but only during longer periods of ischemia.

Conclusions—

rCBF correlates best with glutamate, followed by glycerol, whereas the L/P ratio is sensitive only after longer periods of ischemia. Clinically relevant regional metabolic derangements occur already above an rCBF of 20 mL·100 g
−1
·min
−1
. Future research should focus on identifying alternative causes of metabolic derangement in subarachnoid hemorrhage patients and optimal treatment management in these patients.
Comparison of Transcranial Brain Tissue Perfusion Images Between Ultraharmonic, Second Harmonic, and Power Harmonic Imaging
Authors: Shiogai Toshiyuki , Takayasu Natsuko , Mizuno Toshiki , Nakagawa Masanori , Furuhata Hiroshi
Published: February 2004

Background and Purpose—

To clarify optimal brain tissue perfusion images visualized by transcranial ultrasound harmonic imaging, we compared gray-scale integrated backscatter (IBS) images of new ultraharmonic imaging (UHI) and conventional second harmonic imaging (SHI) with power harmonic imaging (PHI) (harmonic B-mode with harmonic power Doppler images) in 10 patients with and 4 without a temporal skull.

Methods—

Using a SONOS 5500 (Philips), we evaluated transient response images taken after a bolus Levovist injection at a horizontal diencephalic plane via temporal windows. Based on transmitting/receiving frequencies (MHz), 4 imaging procedures using an S3 transducer (SHI2.6 [1.3/2.6], UHI [1.3/3.6], PHI2.6 [1.3/2.6], and PHI3.2 [1.6/3.2]) and 2 imaging procedures using an S4 transducer (SHI3.6 [1.8/3.6] and PHI3.6 [1.8/3.6]) were compared in terms of size and location, peak intensity (PI), contrast area demarcation, and background image quality.

Results—

In intact skull cases, gray-scale imaging tended to show larger contrast areas than PHI. A large contrast area was most frequently observed in SHI2.6 images, despite there being more high-PI cases in UHI. No contrast area with unclear background was observed in a few cases. In craniectomized cases, all contrast images tended to have large and high PI compared with the intact skull cases. PHI, particularly PHI3.6, demonstrated sharper demarcation and a clearer background than gray-scale imaging.

Conclusions—

Transcranial gray-scale SHI using a low receiving frequency of 2.6 MHz is the superior method. PHI identifies contrast area localization better than gray-scale imaging and is particularly suitable for intraoperative and postoperative cases.
Noninvasive Phenotypes of Atherosclerosis
Authors: Spence J. David , Hegele Robert A.
Published: February 2004

Background and Purpose—

Noninvasive measures of atherosclerosis, such as carotid intima-media thickness, total carotid plaque area, and carotid stenosis, probably represent different phenotypes with distinct determinants. For instance, total carotid plaque area may reflect atherosclerotic lesion size more closely than carotid stenosis, which instead may reflect hemodynamic compromise within the arterial lumen.

Methods—

In 1821 patients from a Premature Atherosclerosis Clinic, we studied determinants of total carotid plaque area and carotid stenosis as measured by ultrasound using multivariate regression analysis with traditional risk factors and some emerging risk factors.

Results—

Regression modeling showed that (1) traditional atherosclerosis risk factors were more strongly associated with total carotid plaque area than with carotid stenosis (
R
=0.53 and 0.13, respectively), and (2) individual risk factors had different relationships with total carotid plaque area and carotid stenosis. For instance, age accounted for 53% and 26% of the explained variance of total carotid plaque area and carotid stenosis, respectively. Female sex was inversely associated with total carotid plaque area but positively associated with carotid stenosis. Nontraditional risk variables such as plasma homocysteine had different associations with the 2 analytes.

Conclusions—

Total carotid plaque area and carotid stenosis had different associations with specific atherosclerosis risk factors. Thus, for future studies of the determinants of atherosclerosis, it is important to distinguish between different phenotypes and to appreciate that they will not necessarily have the same determinants.
Electrocardiographic Abnormalities and Serum Magnesium in Patients With Subarachnoid Hemorrhage
Authors: van den Bergh Walter M. , Algra Ale , Rinkel Gabriël J.E.
Published: February 2004

Background and Purpose—

ECG abnormalities and hypomagnesemia frequently occur after aneurysmal subarachnoid hemorrhage (SAH). Because hypomagnesemia is associated with several ECG abnormalities, we studied whether hypomagnesemia mediates ECG abnormalities after SAH.

Methods—

We prospectively studied a consecutive series of 62 patients admitted within 72 hours after aneurysmal SAH. A standard 12-lead ECG and serum magnesium measurement were routinely performed at admission. The relationship between serum magnesium and ECG abnormalities was assessed with linear regression analysis and the Mann-Whitney test in case of dichotomized ECG abnormalities.

Results—

Hypomagnesemia was present in 23 patients (37%), and 38 patients (61%) had a long QTc duration. Low serum magnesium was related to a long PR interval (
P
=0.001) and a shorter QTc interval (
P
=0.004). Adjustment for World Federation of Neurological Surgeons score, hydrocephalus, and the amount of cisternal and ventricular blood did not influence these relations.

Conclusions—

In patients with SAH, lower serum magnesium levels are related to less pronounced increase in the QTc interval. Although the direction of the relation was unexpected, decreased serum magnesium might be the missing link between SAH and ECG abnormalities.
Absence of Association Between Polymorphisms in the Hemostatic Factor Pathway Genes and Carotid Intimal Medial Thickness
Authors: Fox Caroline S. , Larson Martin G. , Corey Diane , Feng DaLi , Lindpaintner Klaus , Polak Joseph F. , Wolf Philip A. , D’Agostino Ralph B. , Tofler Geoffrey H. , O’Donnell Christopher J.
Published: February 2004

Background and Purpose—

Fibrinogen, plasminogen activator inhibitor-1, and other key proteins in the coagulation cascade have been implicated in the origin of cardiovascular disease. Polymorphisms in genes encoding these proteins have been associated with variability in plasma levels of these proteins. Carotid intimal medial thickness (IMT) is a heritable, quantitative measure of atherosclerosis that is predictive of subsequent myocardial infarction and stroke. We sought to test whether carotid IMT is associated with polymorphisms in several well-characterized genes in the hemostatic factor pathways.

Methods—

Here, 867 men and 911 women (mean age, 57 years) in the Framingham offspring cohort underwent B-mode carotid ultrasonography to determine the mean internal (ICA) and common carotid artery (CCA) IMT. Age-, sex-, and multivariable-adjusted linear regression was used to estimate the association of the following variants with log-transformed CCA and ICA IMT: factor V Leiden, factor VII Arg/Gln, fibrinogen
Hin
dIII β-148, plasminogen activator inhibitor-1 4G/5G, and the glycoprotein IIIa P
l
A2
polymorphism.

Results—

Mean ICA IMT was 0.58 mm; mean CCA IMT was 0.60 mm. There were no differences in ICA or CCA IMT by genotype for any of the candidate genes in unadjusted, age- or sex-adjusted, and multivariable-adjusted models.

Conclusions—

There is no evidence for an association between well-studied polymorphisms in the hemostatic factor genes and carotid IMT. Whether other common genetic variants in hemostatic factor genes are associated with subclinical atherosclerosis remains to be determined.
Serial Urinary 11-Dehydrothromboxane B2, Aspirin Dose, and Vascular Events in Blacks After Recent Cerebral Infarction
Authors: Bruno Askiel , McConnell Joseph P. , Cohen Stanley N. , Tietjen Gretchen E. , Wallis Roi Ann , Gorelick Philip B. , Bang Nils U.
Published: February 2004

Background and Purpose—

Incomplete platelet inhibition by aspirin (aspirin resistance) may be a reason for stroke recurrence in some patients. 11-Dehydrothromboxane B2 (11-DTB2) is a stable thromboxane A2 metabolite that reflects in vivo platelet activation. This pilot study was intended to evaluate the reproducibility of urinary 11-DTB2 over time and to look for evidence of aspirin resistance.

Methods—

All subjects were screened for the African American Antiplatelet Stroke Prevention Study (AAASPS) 7 to 90 days after noncardioembolic cerebral infarction. Of 83 subjects with at least 1 urine sample, 52 were enrolled in AAASPS (randomized to blinded treatment with aspirin 650 mg/d or ticlopidine 500 mg/d), and 31 were enrolled in an open-label antiplatelet therapy cohort. Subjects were followed up for 2 years, with 11-DTB2 measurements scheduled at baseline and 6, 12, and 24 months. Vascular events were cerebral infarction, myocardial infarction, or vascular death.

Results—

Despite considerable individual up or down fluctuations, the median 11-DTB2 change did not significantly differ from zero in any of the subgroups. However, in 6 subjects with a 4-fold decrease in aspirin dose from 1300 to 325 or 81 mg/d, the 11-DTB2 level increased from 611 to 1881 pg/mg creatinine (
P
=0.06). Vascular events occurred in 7 of 61 aspirin-treated subjects, and 11-DTB2 levels did not correlate with the events.

Conclusions—

Fluctuations in urinary 11-DTB2 after cerebral infarction in blacks do not correlate with changes in aspirin doses, except perhaps when the dose changes by a factor of 4 or more. A larger study is needed to look further for aspirin resistance.
Prehospital Delay After Acute Stroke in Kaohsiung, Taiwan
Authors: Chang Ku-Chou , Tseng Mei-Chiun , Tan Teng-Yeow
Published: February 2004

Background and Purpose—

Successful acute stroke intervention depends on early hospital presentation. Our study aimed to examine the extent of and factors associated with prehospital delays after acute stroke in Taiwan, where people are new to thrombolytic therapy for stroke.

Methods—

Data were prospectively collected from 196 patients admitted with acute stroke who presented to the emergency department (ED) of the study hospital within 48 hours of symptom onset before intravenous recombinant tissue plasminogen activator was approved. Prehospital delay was defined as time from symptom onset to the ED arrival. Univariate and multivariable regression analyses were conducted to evaluate factors influencing delay in ED presentation and delay in decision to seek medical help.

Results—

The median interval between symptom onset and decision to seek medical contact was 90 minutes; the median interval between symptom onset and ED arrival was 335 minutes. The time from symptom onset to first call for medical help accounted for 45% (95% confidence interval, 41 to 50) of the prehospital delay. Advanced age delayed the decision to seek medical help, whereas stroke severity reduced the risk for this delay.

Conclusions—

The time interval between symptom onset and the decision to call for medical care is far from optimal and is the underlying cause of prolonged prehospital delay. Educational efforts to reduce extent of delay are urgently needed.
Lesion Location and Poststroke Depression
Authors: Bhogal Sanjit K. , Teasell Robert , Foley Norine , Speechley Mark
Published: February 2004

Background—

It has been hypothesized that poststroke depression (PSD) results from left hemisphere lesions. However, attempts to systematically review the data investigating lesion location and PSD have yielded conflicting results. We sought to investigate the methodological differences across the literature studying the relationship between lesion location and PSD.

Summary of Review—

A MEDLINE literature search to retrieve articles investigating the association between PSD and lesion location was performed. Information sought included source population of samples, definition of depression, standardized measurement of stroke and depression, blinding, time since stroke onset, and study design. Odds ratios (ORs) and 95% CIs were calculated with the use of Review Manager and MetaView statistical software. Twenty-six original articles were reviewed. Much of the heterogeneity across studies reflected differences in methodology. The direction of association between left hemisphere lesion location and PSD varied depending on whether patients were sampled as inpatients (OR, 1.36; 95% CI, 1.05 to 1.76) or from the community (OR, 0.60; 95% CI, 0.39 to 0.92). Change in the direction of association was also observed across assessment interval from the acute stroke (OR, 2.14; 95% CI, 1.50 to 3.04) to the chronic stroke (OR, 0.53; 95% CI, 0.30 to 0.93) phase. Differences in the measurement of depression, study design, and presentations of results also may have contributed to the heterogeneity of the findings.

Conclusions—

Several key initiatives should be addressed before future research is undertaken, including the development of a comprehensive measure of PSD, optimal poststroke assessment intervals, and determination of a representative population reference.
Endothelial Nitric Oxide Gene Haplotypes and Risk of Cerebral Small-Vessel Disease
Authors: Hassan A. , Gormley K. , O’Sullivan M. , Knight J. , Sham P. , Vallance P. , Bamford J. , Markus H.
Published: February 2004

Background and Purpose—

Genetic influences are important in multifactorial cerebral small-vessel disease (SVD) and may act via endothelial dysfunction. Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) is a key mediator of endothelial function. We determined the role of 3 potentially functional eNOS polymorphisms (T-786C, intron 4ab, G894T) located toward the 5′ flanking end of the gene as risk factors for SVD and different SVD subtypes: isolated lacunar infarction (n=137) and ischemic leukoaraiosis (n=160).

Methods—

Three hundred patients with SVD and 600 community controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction fragment digestion. Nitrate (NO
x
) levels were determined in a subgroup by use of a Griess method. Polymorphisms were tested individually and in combination with haplotype analysis.

Results—

The intron 4a variant was protective against SVD. This effect was confined to isolated lacunar infarction (odds ratio, 0.55; 95% confidence interval, 0.35 to 0.86;
P
=0.01). Haplotypes encountered were significantly different in this subtype compared with controls (
P
=0.001), with the -786C promoter/intron 4a combination particularly underrepresented. NO
x
levels were associated with the T-786C locus (
P
=0.03) but only in the presence of the intron 4a allele (
P
=0.07 for interaction).

Conclusions—

The intron 4ab insertion/deletion genotype was associated with isolated lacunar infarction. Haplotype and functional studies suggested that the protective effect of the 4a variant could be mediated through changes in eNOS promoter activity and increased NO levels. The specific association with isolated symptomatic lacunar infarction and not ischemic leukoaraiosis may reflect different etiopathogeneses of the 2 subtypes. Lack of NO could predispose to localized microatheroma in proximal arterioles rather than diffuse arteriosclerosis affecting distal perforating vessels.
Value of Routine Holter Monitoring for the Detection of Paroxysmal Atrial Fibrillation in Patients With Cerebral Ischemic Events
Authors: Schaer B.A. , Zellweger M.J. , Cron T.A. , Kaiser C.A. , Osswald S.
Published: February 2004

Background and Purpose—

Holter monitoring for the detection of paroxysmal atrial fibrillation (PAF) is a routine procedure after cerebral ischemic events, although its value is unknown. The aim of this study was to evaluate the incidence of PAF and its impact on drug treatment modifications in this population.

Methods—

Retrospective evaluation of all Holter ECGs in patients with cerebral ischemic events was done. Chart analysis with regard to drug treatment modification and cardiovascular drug therapy was performed in all patients.

Results—

Between January 2000 and December 2002, 425 hospitalized patients (median age, 68 years) had routine Holter ECG after a cerebral ischemic event. PAF was diagnosed in 9 patients (2.1%): in 2, oral anticoagulation was contraindicated; 1 had severe carotid stenosis as an additional risk factor; 1 had PAF but was on oral anticoagulation for basilar thrombosis; 2 had had PAF before and were on aspirin; and 3 had a new diagnosis of PAF. The last 5 patients were put on oral anticoagulation. Thus, routine Holter ECG resulted in drug treatment modification in only 5 of 425 patients (1.2%).

Conclusions—

PAF in cerebral ischemic event patients has a low incidence and, if diagnosed, rarely leads to drug modification. Therefore, routine Holter monitoring for PAF screening is not recommended in this patient population.
Rasch Analysis of Combining Two Indices to Assess Comprehensive ADL Function in Stroke Patients
Authors: Hsueh I-Ping , Wang Wen-Chung , Sheu Ching-Fan , Hsieh Ching-Lin
Published: February 2004

Background and Purpose—To justify the summation of scores representing comprehensive activities of daily living (ADL) function, a Rasch analysis was performed to examine whether items of the Barthel Index (BI), assessing ADL, and items of the Frenchay Activities Index (FAI), assessing instrumental ADL, contribute jointly to a single, unidimensional construct in stroke patients living in the community. The number of scoring points of both indices was examined for their usefulness in discerning the various ability levels of ADL in these patients.

Methods—A total of 245 patients at 1 year after stroke participated in this study. The BI and FAI were administered to the patient and/or the patient’s main caregiver by interview.

Results—The initial Rasch analysis indicated that the middle scoring points for many items of the BI and FAI could be collapsed to allow only dichotomous response categories. All but 2 items of the FAI, social occasions and walking outside, fitted the model’s expectations rather well. These 2 items were excluded from further analysis. A factor analysis performed on the residuals of the Rasch-transformed scores recovered no dominant component. These results indicate that the combined 23 dichotomous items of the BI and FAI assess a single unidimensional ADL function.

Conclusions—A clinically useful assessment of the comprehensive ADL function of patients at or later than 1 year after stroke can be obtained by combining the items of the BI and FAI (excluding 2 FAI items) and simplifying the responses into dichotomous categories. It is also demonstrated that the items of the new scale measure comprehensive ADL function as a single unidimensional construct when assessed at 1 year after stroke.
Lateral and Medial Medullary Infarction
Authors: Kameda W. , Kawanami T. , Kurita K. , Daimon M. , Kayama T. , Hosoya T. , Kato T.
Published: February 2004

Background and Purpose—

No large-scale study has ever compared the clinical and radiological features of lateral medullary infarction (LMI) and medial medullary infarction (MMI). The aim of this study was to investigate them through the use of cooperatively collected cases.

Methods—

Medical information on all patients from 1996 to 2000 with medullary infarction (MI) proven by brain MR images at 35 stroke centers in the Tohoku district, Japan, was collected, and their clinical and radiological features were analyzed.

Results—

A total of 214 cases of MI were registered. They included 167 cases (78%) of LMI, 41 (19%) of MMI, and 6 (3%) of LMI plus MMI. The mean age of onset and the male-to-female ratio were 60.7 years and 2.7:1 in LMI and 65.0 years and 3.6:1 in MMI, respectively. The middle medulla was most frequently affected in LMI, and the upper medulla was most frequently affected in MMI. Dissection of the vertebral artery was observed in 29% of LMI and 21% of MMI. Prognosis, assessed by the Barthel Index, was favorable in both LMI and MMI. Diabetes mellitus was more frequently associated with MMI than with LMI.

Conclusions—

The present study surveyed a large number of MI cases and revealed that (1) the mean age of onset of MMI is higher than that of LMI, (2) the dissection of the vertebral artery is an important cause not only of LMI but also of MMI, and (3) diabetes mellitus is frequently associated with MMI.
Silent Brain Infarcts in Patients With Manifest Vascular Disease
Authors: Giele Janneke L.P. , Witkamp Theo D. , Mali Willem P.T.M. , van der Graaf Yolanda
Published: February 2004

Background and Purpose—

Silent infarcts are frequently found on MRIs of brains of healthy elderly persons (aged >60 years). The purpose of this study was to investigate the prevalence and determinants of silent infarcts in a population of patients with clinically manifest vascular disease.

Methods—

To detect silent infarcts, MR images were made in 308 participants of the Second Manifestations of ARTerial disease (SMART) study (mean age, 58 years) without prior stroke or transient ischemic attack. These are patients referred to the University Medical Center Utrecht because of atherosclerotic vascular disease. Risk factors were assessed by questionnaire and by physical, ultrasonographic, and laboratory examinations.

Results—

Silent infarcts were found in 51 patients (17%). Most infarcts (62%) were located in white matter, 20% in basal ganglia, 14% in brain stem and cerebellum, and 4% in cortical area. Categorical determinants for presence of silent infarct(s) that remained (borderline) significant after adjustment for age were hypertension (odds ratio [OR]=2.2; 95% CI, 1.2 to 4.2), abdominal aortic aneurysm (OR=2.4; 95% CI, 0.9 to 6.4), severe renal failure (OR=7.3; 95% CI, 2.1 to 25.2), and hyperhomocysteinemia (OR=2.6; 95% CI, 1.1 to 5.9).

Conclusions—

Patients with manifest vascular disease are at risk for silent infarcts at a younger age. In particular, patients with the aforementioned risk factors should be considered for treatment or (secondary) prevention.