bluuebunny/crossref_metadata_2025 huggingface dataset:
ACE Inhibition Versus Angiotensin Type 1 Receptor Antagonism
Authors: Brown Nancy J. , Kumar Sandeep , Painter Corrie A. , Vaughan Douglas E.
Published: December 2002

ACE inhibition reduces plasminogen activator inhibitor-1 (PAI-1), a risk factor for myocardial infarction, whereas the effect of angiotensin receptor antagonism on PAI-1 is uncertain. The present study compares the time course of effects of ACE inhibition and angiotensin type 1 (AT
1
) receptor antagonism on morning plasma PAI-1 antigen. Blood pressure and endocrine, metabolic, and fibrinolytic variables were measured in 20 insulin-resistant (defined by fasting glucose >8.3 mmol/L, body mass index >28 kg/m
2
, or fasting serum triglyceride ≥2.8 mmol/L) hypertensive subjects (mean age, 47.9±2.1 years) (1) before and after 1 week of hydrochlorothiazide 12.5 mg/d, and (2) before and 1, 3, 4, and 6 weeks after addition of ramipril (escalated to 10 mg/d) or losartan (escalated to 100 mg/d). Hydrochlorothiazide decreased systolic (
P
=0.011) and diastolic (
P
=0.019) pressure. Ramipril (from 133.6±5.1/94.5±2.4 to 127.0±3.1/91.4±3.3 mm Hg) or losartan (from 137.0±3.9/93.1±2.9 to 123.7±2.6/86.4±2.1 mm Hg) further reduced systolic (
P
=0.009) and diastolic (
P
=0.037) pressure. The pressure effects of the 2 drugs were similar. Hydrochlorothiazide increased plasma PAI-1 (
P
=0.013) but not tissue-type plasminogen activator (tPA) (
P
=0.431) antigen. Addition of either ramipril or losartan significantly decreased plasma PAI-1 antigen (
P
=0.046). However, the effect of losartan on PAI-1 antigen was not sustained throughout the 6-week treatment period, such that there was a significant drug×time interaction (
P
=0.043). tPA antigen decreased during either ramipril or losartan (
P
=0.032), but tPA activity decreased only during losartan (
P
=0.018). Short-term interruption of the renin-angiotensin-aldosterone system by either ACE inhibition or AT
1
receptor antagonism decreases PAI-1 antigen, but the duration of this effect is greater for ACE inhibition than for AT
1
receptor antagonism.
Blunted Tubuloglomerular Feedback by Absence of Angiotensin Type 1A Receptor Involves Neuronal NOS
Authors: Ichihara Atsuhiro , Hayashi Matsuhiko , Koura Yukako , Tada Yuko , Sugaya Takeshi , Hirota Nobuhisa , Saruta Takao
Published: December 2002

To define the role of angiotensin type 1A (AT
1A
) receptor in modulating tubuloglomerular feedback signals and to determine its relationship to neuronal NO synthase (nNOS), the diameter of the afferent arterioles of wild-type and AT
1A
receptor–deficient mice was measured by the blood-perfused juxtamedullary nephron technique. The afferent arteriolar diameter of wild-type and AT
1A
receptor–deficient mice averaged 16.7±0.6 (n=9) and 16.8±0.7 μm (n=9), respectively. In the wild-type mice, addition of 10 μmol/L acetazolamide to the blood perfusate exerted a biphasic afferent arteriolar constriction, with the initial response and sustained response averaging 47.2±3.8% and 33.9±3.3%, respectively. In AT
1A
receptor–deficient mice, the initial response and sustained response averaged 51.6±3.6% and 9.5±1.3%, respectively, and the sustained response was significantly attenuated compared with that of wild-type mice. Inhibition of nNOS with 10 μmol/L
S
-methyl-
l
-thiocitrulline significantly decreased the afferent arteriolar diameter of AT
1A
receptor–deficient mice, from 15.1±1.2 to 5.0±0.3 μm (n=7), and the decrease was significantly greater than that observed in wild-type mice (from 15.9±1.2 to 10.6±1.3 μm; n=8). During nNOS inhibition, the initial and sustained afferent arteriolar constrictor responses to acetazolamide in wild-type mice averaged 54.4±6.4% and 44.8±11.3%; respectively, and were similar to those in AT
1A
receptor–deficient mice (53.2±6.4% and 59.5±4.4%, respectively). These results suggest that AT
1A
receptors enhance tubuloglomerular feedback–mediated afferent arteriolar constriction, at least in part, through reducing the counteracting modulation by nNOS.
Cyclooxygenase-2 Inhibition Attenuates Lipopolysaccharide-Induced Cardiovascular Failure
Authors: Höcherl Klaus , Dreher Franziska , Kurtz Armin , Bucher Michael
Published: December 2002

The present study aimed to determine the relevance of cyclooxygenase-2 (COX-2)–derived prostanoids for the adverse effects of lipopolysaccharides (LPSs) on cardiovascular function. For this goal, male Sprague-Dawley rats received a single intravenous dose of LPS (10 mg/kg) and were treated with different cyclooxygenase inhibitors. Injection of LPS caused a marked decrease of systolic arterial pressure, from 128 to 79 mm Hg, and a concomitant increase of heart rate, from 380 to 530 minutes
−1
. Both the decrease of systemic arterial pressure and the increase of heart rate induced by LPS were almost absent if the animals also received the COX-2 blocker rofecoxib (20 mg/kg), regardless whether the drug was given 1 hour before or 1 hour after LPS. Although plasma and organ levels of prostanoids were lowered by rofecoxib, the characteristic LPS-induced increases of NO synthase II and COX-2 gene expression, as well as of plasma and tissue nitrate/nitrite concentrations, were not affected by rofecoxib. Although rofecoxib treatment did also not change LPS-induced tissue cytokine concentrations, it markedly improved LPS-induced liver damage, as indicated by the decrease of transaminases. Moreover, the overall well-being of the LPS-injected animals improved on concomitant treatment with the COX-2 inhibitor. Taken together, our data suggest that COX-2–derived prostanoids are major mediators for the detrimental effects of LPS on cardiovascular and organ function.
Reactivity as a Predictor of Subsequent Blood Pressure
Authors: Knox Sarah S. , Hausdorff Jeff , Markovitz Jerome H.
Published: December 2002

This study investigated the association between cardiovascular reactivity and subsequent ambulatory blood pressure in 316 black and white men and women in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Cardiovascular laboratory reactivity was examined in subjects 20 to 33 years old, and ambulatory blood pressure and heart rate were measured 3 years later. Average ambulatory pressure during a 24-hour period was regressed separately on stress reactivity and standard covariate risk factors in each race/gender subgroup. Blacks had higher blood pressure and heart rates than whites, men had higher blood pressure than women, and women had higher heart rates than men. After controlling for age, baseline systolic pressure, familial history of hypertension, smoking, alcohol consumption, body mass index, and exercise, systolic blood pressure reactivity to star tracing and cold pressor stress were significantly associated with systolic ambulatory pressure in black men and women 3 years later (partial
r
=0.24 to 0.37). Heart rate reactivity to video challenge and star tracing were also significantly predictive of subsequent ambulatory heart rate in blacks. Diastolic star tracing reactivity was significantly associated with subsequent ambulatory blood pressure in black women (
r
=0.23), and diastolic reactivity to video and star tracing were significantly predictive of ambulatory diastolic pressure in white men (
r
=0.39). We conclude that hyperresponsivity to stress may be a risk factor for subsequent blood pressure elevation in blacks and may be one pathway leading to the higher prevalence of hypertension in blacks than in whites.
Increase in Cx45 Gap Junction Channels in Cerebral Smooth Muscle Cells from SHR
Authors: Li Xing , Simard J. Marc
Published: December 2002

We recently reported the novel finding of expression and function of connexin45 (Cx45) in cerebrovascular smooth muscle cells. We examined the hypothesis that Cx45 is altered in hypertension. Immunoblots for Cx45 showed a significant increase in Cx45 in cerebral arteries from adult spontaneously hypertensive rats (SHR) compared with adult Wistar-Kyoto (WKY) rats, with no difference in aorta or femoral artery. Patch-clamp of cerebral smooth muscle cells pairs from SHR versus WKY showed a significantly steeper voltage dependence of deactivation and partial block of junctional currents by quinine and by a peptide that interferes with docking of Cx45, consistent with dominance of functional Cx45 channels in SHR. We examined potential roles of blood pressure versus angiotensin in elevated Cx45 in SHR by measuring Cx45 protein in 4 groups: (1) long-term administration in Wistar rats of the nitric oxide synthase inhibitor L-NAME; (2) long-term administration in SHR of the ACE inhibitor captopril; (3) long-term administration in Wistar rats of angiotensin; and (4) exposure of basilar artery segments in organ culture to angiotensin. Blood pressure was significantly elevated in groups 1 and 3 and was normal in group 2. In groups 1, 2, and 4, there was no significant change in Cx45 protein. In group 3, there was a modest but insignificant increase in Cx45 protein but no change in voltage dependence of deactivation of junctional currents. Overall, our data show increased Cx45 in SHR that is unlikely to be due to either elevated blood pressure or to angiotensin. Relative dominance of Cx45 over Cx43 in cerebral vessels may predispose SHR to ischemic stroke.
Insulin Resistance But Not Inflammation Is Associated With Gestational Hypertension
Authors: Wolf Myles , Sandler Laura , Jimenez-Kimble Ricardo , Shah Anand , Ecker Jeffrey L. , Thadhani Ravi
Published: December 2002

Hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, are leading causes of pregnancy-associated morbidity. Although insulin resistance and inflammation contribute to preeclampsia, prospective data regarding mechanisms of gestational hypertension are sparse. We conducted a prospective, nested case-control study to test the hypotheses that insulin resistance, marked by reduced sex hormone–binding globulin (SHBG) levels, and inflammation, marked by increased C-reactive protein levels, are similarly associated with gestational hypertension. We measured first-trimester C-reactive protein and SHBG levels in 51 women who subsequently developed gestational hypertension and 102 randomly selected normotensive pregnant controls. Compared with controls, first-trimester SHBG levels were significantly reduced among women who later developed gestational hypertension (176±73 versus 203±79 nmol/L;
P
=0.03), but there was no difference in C-reactive protein levels. There was statistically significant interaction among nulliparity, first-trimester SHBG levels, and risk of gestational hypertension, such that increasing SHBG levels were associated with significantly reduced risk of gestational hypertension among nulliparous women (odds ratio, 0.64 per 50-nmol/L increase; 95% confidence interval, 0.46, 0.90;
P
<0.01) but not among multiparous women. This association remained significant after adjusting for potential confounders (odds ratio, 0.55; 95% confidence interval, 0.31, 0.98;
P
=0.04). We conclude that insulin resistance, but not inflammation, is an independent risk factor for gestational hypertension among nulliparous women. Furthermore, important mechanistic differences exist in the pathogenesis of gestational hypertension comparing nulliparous and multiparous women.
Ablation of NK1 Receptors in Rat Nucleus Tractus Solitarii Blocks Baroreflexes
Authors: Riley Jeffrey , Lin Li-Hsien , Chianca Deoclecio A. , Talman William T.
Published: December 2002

The neuropeptide substance P (SP) is found in vagal afferent nerves within the nucleus tractus solitarii, where it is released on stimulation of arterial baroreflexes. The neurokinin-1 receptors at which SP may act have been identified in the nucleus tractus solitarii, but there remains uncertainty if the neurons at which SP acts are critical to baroreflex transmission. By using SP conjugated with the toxin saporin, which kills the neurons at which SP may act, we sought to test the hypothesis that neurons expressing the neurokinin-1 receptor are critical to baroreflex transmission in the nucleus tractus solitarii. One and 2 weeks after injection of the toxin into the rat nucleus tractus solitarii, immunoreactivity for the neurokinin-1 receptor was lost. When the toxin had been injected bilaterally, the baroreflex gain was significantly reduced. Therefore, neurons that express SP receptors play a critical role in mediating baroreflexes through the nucleus tractus solitarii of rat.
Effect of AT
2
Receptor on Expression of AT
1
and TGF-β Receptors in VSMCs from SHR
Authors: Su Jin-Zi , Fukuda Noboru , Jin Xue-Qing , Lai Yi-Mu , Suzuki Ryo , Tahira Yoshiko , Takagi Hiroto , Ikeda Yukihiro , Kanmatsuse Katsuo , Miyazaki Hitoshi
Published: December 2002

We recently reported that overexpression of the angiotensin II type 2 (AT
2
) receptor downregulates the AT
1a
receptor through the bradykinin/NO pathway in a ligand-independent manner in vascular smooth muscle cells (VSMCs). In the present study, we investigated the effect of AT
2
receptor overexpression on the expression of the AT
1a
receptor and transforming growth factor-β (TGF-β) receptor subtypes in VSMCs from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Transfection of the AT
2
receptor gene downregulated expression of the AT
1a
receptor in VSMCs from WKY, but did not affect expression of the AT
1a
receptor in VSMCs from SHR. Transfection of the AT
2
receptor abolished DNA synthesis in response to angiotensin II in VSMCs from WKY; in VSMCs from SHR, basal DNA synthesis was suppressed, but DNA synthesis in response to Ang II was not altered. The NO substrate
l
-arginine augmented downregulation of the AT
1a
receptor in VSMCs from WKY, whereas it did not affect expression of the AT
1a
receptor in VSMCs from SHR. In response to AT
2
receptor transfection, expression of TGF-β type I receptor mRNA was suppressed significantly in VSMCs from WKY, whereas expression of TGF-β type I receptor was not altered in VSMCs from SHR. These results suggest that the AT
2
receptor downregulates AT
1a
and TGF-β type I receptors in normal VSMCs, but not in SHR-derived VSMCs. The lack of downregulation of the AT
1a
receptor may contribute, in part, to the exaggerated growth of VSMCs from SHR.
Localization of Sodium Channels in Intercalated Disks Modulates Cardiac Conduction
Authors: Kucera Jan P. , Rohr Stephan , Rudy Yoram
Published: December 2002

It is well known that the sodium current (
I
Na
) and the degree of gap-junctional electrical coupling are the key determinants of action potential (AP) conduction in cardiac tissue. Immunohistochemical studies have shown that sodium channels (NaChs) are preferentially located in intercalated disks (IDs). Using dual immunocytochemical staining, we confirmed the colocalization of NaChs with connexin43 in cultures of neonatal rat ventricular myocytes. In mathematical simulations of conduction using the Luo-Rudy dynamic model of the ventricular AP, we assessed the hypothesis that conduction could be modulated by the preferential localization of NaChs in IDs. Localization of
I
Na
at the ID caused a large negative potential in the intercellular cleft, which influenced conduction in two opposing ways, depending on the degree of electrical coupling: (1) for normal and moderately reduced coupling, the negative cleft potential led to a large overshoot of the transmembrane potential resulting in a decreased driving force for
I
Na
itself (self-attenuation), which slowed conduction; (2) for greatly reduced coupling (<10%), the negative cleft potential induced by
I
Na
in the prejunctional membrane led to suprathreshold depolarization of the postjunctional membrane, which facilitated and accelerated conduction. When cleft potential effects were not incorporated, conduction was not significantly affected by the ID localization of
I
Na
. By enhancing conduction through the establishment of cleft potentials, the localization of NaChs in IDs might protect the myocardium from conduction block, very slow conduction, and microreentry under conditions of greatly reduced coupling. Conversely, by supporting moderately slow conduction, this mechanism could also promote arrhythmias.
Long-Term Effects of Inflammation-Sensitive Plasma Proteins and Systolic Blood Pressure on Incidence of Stroke
Authors: Engström G. , Lind P. , Hedblad B. , Stavenow L. , Janzon L. , Lindgärde F.
Published: December 2002

Background and Purpose—

The present study investigated the relationships between inflammation-sensitive plasma proteins (ISPs) and systolic blood pressure (SBP), as well as the joint long-term effects of ISP and SBP on incidence of stroke.

Methods—

BP and 5 ISPs (fibrinogen, α1-antitrypsin, haptoglobin, ceruloplasmin, orosomucoid) were assessed in 6071 healthy men 28 to 61 years of age. All-cause mortality and incidence of stroke were monitored over a mean follow-up of 18.7 years in men defined by SBP (<120, 120 to 139, ≥140 mm Hg) and ISP (0 to 1 or 2 to 5 ISPs in the top quartile).

Results—

SBP and diastolic BP were significantly and positively associated with the number of ISPs in the top quartile. As expected, elevated SBP was associated with an increased incidence of stroke. Among men with SBP ≥140 mm Hg, there were, however, significant differences between those with high and low ISP levels. After risk factor adjustment, men with SBP ≥140 mm Hg and high ISP levels had a relative risk of stroke of 4.3 (95% CI, 2.3 to 7.8) compared with men with SBP <120 mm Hg and low ISP levels. In the absence of high ISP levels, the risk associated with SBP ≥140 was 2.5 (95% CI,1.4 to 4.6). Men with high ISP levels had a significantly increased risk of stroke also after exclusion of the events from the first 10 years of follow-up.

Conclusions—

High ISP levels are associated with elevated BP. These proteins are associated with an increased risk of stroke among men with high BP and provide information on stroke risk even after many years of follow-up.
Addressing the Heterogeneity of the Ischemic Stroke Phenotype in Human Genetics Research
Authors: Meschia James F.
Published: December 2002

Background and Purpose—

Many investigators have approached ischemic stroke as a complex phenotype by dividing the ischemic stroke population into distinct subtypes. The purpose of this study was to review systematically the methods used to subtype ischemic stroke in recent genetic studies.

Methods—

The MEDLINE database was searched for articles pertaining to research on the genetics of human ischemic stroke published from January 2000 through January 2002. Abstracts and full-length reports were then sequentially screened to select articles pertaining to original case-control or cohort studies.

Results—

The initial search yielded 153 publications. Of 41 relevant articles, ischemic stroke was subtyped in 25 (61%). The most common standard subtyping system was the Cerebrovascular Classification of Diseases III system (9 articles). Of the subtyping systems used, 3 had previously published interrater reliability. The subtyping system was reported to have been prespecified in 1 study. Four articles reported using central adjudication. Two articles reported that the person doing the subtyping was blinded to genotype, and 2 reported that the person doing the genotyping was blinded to the patient’s subtype status.

Conclusions—

When investigators subtyped ischemic stroke, they typically used either nonstandard classification systems or systems of undetermined reliability. Important methodological issues, including blinding and prespecification of the classification system, were rarely reported. Advances in methodology and scientific reporting standards would foster identification of subtype-specific genetic risk factors.
Treadmill Training With Partial Body Weight Support and an Electromechanical Gait Trainer for Restoration of Gait in Subacute Stroke Patients
Authors: Werner C. , von Frankenberg S. , Treig T. , Konrad M. , Hesse S.
Published: December 2002

Background and Purpose—

The purpose of this study was to compare treadmill and electromechanical gait trainer therapy in subacute, nonambulatory stroke survivors. The gait trainer was designed to provide nonambulatory subjects the repetitive practice of a gait-like movement without overexerting therapists.

Methods—

This was a randomized, controlled study with a crossover design following an A-B-A versus a B-A-B pattern. A consisted of 2 weeks of gait trainer therapy, and B consisted of 2 weeks of treadmill therapy. Thirty nonambulatory hemiparetic patients, 4 to 12 weeks after stroke, were randomly assigned to 1 of the 2 groups receiving locomotor therapy every workday for 15 to 20 minutes for 6 weeks. Weekly gait ability (functional ambulation category [FAC]), gait velocity, and the required physical assistance during both kinds of locomotor therapy were the primary outcome measures, and other motor functions (Rivermead motor assessment score) and ankle spasticity (modified Ashworth score) were the secondary outcome measures. Follow-up occurred 6 months later.

Results—

The groups did not differ at study onset with respect to the clinical characteristics and effector variables. During treatment, the FAC, gait velocity, and Rivermead scores improved in both groups, and ankle spasticity did not change. Median FAC level was 4 (3 to 4) in group A compared with 3 (2 to 3) in group B at the end of treatment (
P
=0.018), but the difference at 6-month follow up was not significant. The therapeutic effort was less on the gait trainer, with 1 instead of 2 therapists assisting the patient at study onset. All but seven patients preferred the gait trainer.

Conclusions—

The newly developed gait trainer was at least as effective as treadmill therapy with partial body weight support while requiring less input from the therapist. Further studies are warranted.
Altered Calcium Dynamics Do Not Account for Attenuation of Endothelium-Derived Hyperpolarizing Factor–Mediated Dilations in the Female Middle Cerebral Artery
Authors: Golding Elke M. , Ferens Dorota M. , Marrelli Sean P.
Published: December 2002

Background and Purpose—

The contribution of endothelium-derived hyperpolarizing factor (EDHF) to ATP-mediated dilations is significantly attenuated in the rat middle cerebral artery of intact and estrogen-treated ovariectomized (OVX) females compared with males and vehicle-treated OVX females. Since an increase in endothelial calcium appears to be a critical prerequisite in the EDHF response, we tested the hypothesis that endothelial cell intracellular calcium ([Ca
2+
]
i
) fails to reach sufficient levels to elicit robust EDHF-mediated dilations in females and that this effect is mediated by estrogen.

Methods—

Vascular diameter and [Ca
2+
]
i
were measured concomitantly in perfused middle cerebral artery segments with the use of videomicroscopy and fura 2 fluorescence, respectively.

Results—

In the presence of
N
G
-nitro-
l
-arginine methyl ester and indomethacin, the dilation to 10
−5
mol/L ATP was significantly reduced (
P
<0.05) in intact females (42±8%; n=6) and estrogen-treated OVX females (25±6%; n=9) compared with intact males (89±5%; n=6) and vehicle-treated OVX females (92±2%; n=7). Contrary to our initial hypothesis, endothelial cell [Ca
2+
]
i
increased to comparable levels in intact females (461±116 nmol/L), estrogen-treated OVX females (417±50 nmol/L), intact males (421±77 nmol/L), and vehicle-treated OVX females (530±92 nmol/L). In response to luminal ATP (10
−5
mol/L), smooth muscle cell [Ca
2+
]
i
decreased to a greater degree in males (37±4%; n=8) compared with females (21±5%; n=7) and in vehicle-treated OVX females (18±7%; n=7) compared with estrogen-treated OVX females (3±5%; n=9).

Conclusions—

Our data suggest that loss of a factor coupling EDHF to reduction of ionized smooth muscle cell [Ca
2+
]
i
accounts for the attenuated EDHF-mediated dilations in the female middle cerebral artery.
Low Concentration of Serum Total Cholesterol Is Associated With Multifocal Signal Loss Lesions on Gradient-Echo Magnetic Resonance Imaging
Authors: Lee Seung-Hoon , Bae Hee-Joon , Yoon Byung-Woo , Kim Ho , Kim Dong-Eog , Roh Jae-Kyu
Published: December 2002

Background and Purpose—

Multifocal signal loss lesions (MSLLs) on T2*-weighted gradient-echo (GE) MRI are believed to be microbleeds histopathologically. Previous epidemiological studies suggested that low serum cholesterol is associated with the increased risk of intracerebral hemorrhage. We investigated risk factors of MSLLs and the relationship between lipid profiles and MSLLs on GE-MRI.

Methods—

We included consecutively 172 patients who underwent brain MRI. MSLLs on GE-MRI were counted by 2 neurologists separately and graded by consensus. The concentrations of lipid profiles were categorized as quartiles, and the MSLLs were graded as absent (total count, 0), mild (1 to 2), moderate (3 to 10), and severe (>10).

Results—

The mean concentrations of total cholesterol and low-density lipoprotein cholesterol were significantly lower in patients with a severe degree of MSLLs than in those without MSLL (
P
<0.05). By multivariate analysis, MSLLs were significantly correlated with hypertension (odds ratio [OR], 3.42; 95% CI, 1.17 to 9.97), leukoaraiosis (OR, 4.62; 95% CI, 2.87 to 7.41), the lowest quartile of serum total cholesterol (<4.27 mmol/L; OR, 10.91; 95% CI, 3.98 to 25.57), and the highest quartile of high-density lipoprotein (>1.47 mmol/L; OR, 3.5; 95% CI, 1.45 to 8.29).

Conclusions—

Our results suggest that both the lipid profile levels and the severity of hypertension may be closely associated with MSLLs on GE-MRI.
Delayed Argatroban Treatment Reduces Edema in a Rat Model of Intracerebral Hemorrhage
Authors: Kitaoka Takuji , Hua Ya , Xi Guohua , Hoff Julian T. , Keep Richard F.
Published: December 2002

Background and Purpose—

Studies indicate that thrombin plays an important role in intracerebral hemorrhage (ICH)–induced edema formation. Although thrombin is produced as the blood clots, it may be bound to fibrin and only gradually released from the clot. The time window for administration of a thrombin inhibitor to reduce ICH-induced edema is unknown. Whether this time window extends beyond the period when a thrombin inhibitor might exacerbate rebleeding is also unknown.

Methods—

This study examines (1) whether argatroban, an inhibitor of both free and fibrin-bound thrombin, can reduce edema formation after intracerebral infusion of 100 μL of blood in the rat; (2) the therapeutic time window for argatroban; and (3) whether argatroban promotes rebleeding in a model in which ICH was induced by intracerebral injection of collagenase.

Results—

Intracerebral infusion of blood caused a marked increase in perihematomal water content. Intracerebral injection of argatroban 3 hours after ICH caused a significant reduction in edema measured at 48 hours (80.9±1.0% versus 82.6±0.8%;
P
<0.01). The systemic administration of high-dose argatroban (0.9 mg/h) starting 6 hours after ICH also significantly reduced edema (80.3±1.1% versus 82.0±1.3% in vehicle controls;
P
<0.05). There was no protection when the onset of argatroban administration was delayed to 24 hours after ICH or if a lower dose of argatroban (0.3 mg/h) was used. Argatroban did not increase collagenase-induced hematoma volume when given into the clot after 3 hours or given systemically at 6 hours.

Conclusions—

Our data suggest that argatroban may be an effective therapy for ICH-induced edema.
Amitriptyline in the Prophylaxis of Central Poststroke Pain
Authors: Lampl Christian , Yazdi Kambiz , Röper Christoph
Published: December 2002

Background and Purpose—

We performed a double-blind, placebo-controlled study to investigate the effectiveness of amitriptyline for the prophylactic treatment of patients with acute thalamic stroke in preventing central poststroke pain.

Methods—

Subject received, in a randomized sequence, either amitriptyline titrated from 10 to 75 mg in extended-release form or placebo over a therapy period of 365 days. We documented the time when pain developed; the intensity, type, site, and distribution of pain; and the presence/absence and type of allodynia.

Results—

Thirty-nine patients (23 women and 16 men; age range, 36 to 68 years) with central poststroke pain participated. The placebo group showed a pain rate of 21% within 1 year after the diagnosis of thalamic stroke compared with 17% in the group under prophylactic treatment with amitriptyline. Average (SE) time to pain was 318 (23) days for patients in the placebo group and 324 (24) days for patients in the amitriptyline group.

Conclusions—

With the achieved sample sizes of this study and a pain rate of approximately 21% in the placebo group, any near-perfect pain protection would have been detected. Near-perfect pain protection, in this context, refers to pain in <2.4% of the recruited patients treated with amitriptyline or in approximately 89% of placebo-treated patients. Larger studies are recommended to test the hypothesis that prophylactic amitriptyline reduces but does not completely prevent central poststroke pain.
Dynamic Changes in Cerebral Blood Flow and Angiogenesis After Transient Focal Cerebral Ischemia in Rats
Authors: Lin Teng-Nan , Sun Shu-Wei , Cheung Wai-Mui , Li Fuhai , Chang Chen
Published: December 2002

Background and Purpose—

Angiogenesis occurs after cerebral ischemia, but the relationship between angiogenesis and cerebral hemodynamic change is unknown. The aim of the present study was to investigate the relationship between ischemia-induced angiogenesis and hemodynamics in a well-defined 3-vessel occlusion model of the rat by using diffusion- (DWI), perfusion-, and T2-weighted MRI (T2WI).

Methods—

Rats were subjected to 60 minutes of transient middle cerebral artery occlusion or sham operation. DWI and T2WI were used to characterize the extent of the ischemic lesion from 4.5 hours to 14 days after reperfusion. A flow-sensitive alternating inversion recovery method and dynamic susceptibility contrast MRI were used to evaluate the temporal changes in relative cerebral blood flow (CBF) and cerebral blood volume (CBV), respectively. Rats were randomly selected and killed at each time point for investigation of vascular density and for hematoxylin-eosin staining.

Results—

Ischemic lesions developed in the ipsilateral cortex, as demonstrated by DWI and T2WI. CBF was significantly increased in the ipsilateral cortex, especially in the cortical outer layer from day 1 to day 14, and peaked on day 7 (
P
<0.05), while CBV was significantly increased on day 7 (
P
<0.01). The vascular density on the ipsilateral brain surface was gradually increased from day 1 to day 5, peaked on day 7, and then decreased on day 14. Histology study showed pannecrosis in the cortex from day 1 to day 5 and partial liquefaction of the necrotic tissues on days 7 and 14.

Conclusions—

A delayed increase in both CBF and CBV is documented in the ipsilateral cortex after transient focal brain ischemia, and such an increase may be associated with angiogenesis.
Cerebral Capillary Endothelial Cell Mitogenesis and Morphogenesis Induced by Astrocytic Epoxyeicosatrienoic Acid
Authors: Zhang Chenyang , Harder David R.
Published: December 2002

Background and Purpose—

Epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 epoxygenation of arachidonic acid. We have previously demonstrated that astrocyte-conditioned medium induced mitogenesis in brain capillary endothelial cells. The goals of the present studies are to further define the mechanism through which this can occur and to confirm that EETs are derived from astrocytes, through which astrocytic activity can regulate cerebral angiogenesis in response to neuronal activation.

Methods—

Astrocytes and cerebral capillary endothelial cells in primary cultures were cocultured to examine the interaction of the 2 cell types. We used multiple immunohistochemical techniques to characterize the multicellular nature of the capillaries, which is not simply an artifact related to the culture conditions. The mitogenic effect of EETs was determined by
3
H-thymidine incorporation and cell proliferation assay. Endothelial tube formation was examined in vitro and in vivo with the use of a reconstituted basement membrane (Matrigel) assay.

Results—

In cocultures of astrocytes and capillary endothelium, we observed morphological changes in both cell types such that each assumed certain physiological characteristics, ie, endothelial networks and astrocytes with “footlike” projections as well as intermittent gap junctions forming within the endothelial cells. EETs from astrocytes as well as synthetic EETs promoted mitogenesis of endothelial cells, a process sensitive to inhibition of tyrosine kinase with genistein. Treatments with exogenous EETs were sufficient for endothelial cells to differentiate into capillary-like structures in culture as well as in vivo in a Matrigel matrix.

Conclusions—

The 2 major conclusions from these data are that astrocytes may play an important role in regulating angiogenesis in the brain and that cytochrome P450–derived EETs from astrocytes are mitogenic and angiogenic.
Endogenous Dopamine Amplifies Ischemic Long-Term Potentiation via D1 Receptors
Authors: Saulle Emilia , Centonze Diego , Martín Ana B. , Moratalla Rosario , Bernardi Giorgio , Calabresi Paolo
Published: December 2002

Background and Purpose—

Several observations indicate that, during energy deprivation, endogenous dopamine may become neurotoxic. Accordingly, the nucleus striatum is a preferential site of silent infarcts in humans, and experimental ischemia caused by homolateral carotid occlusion selectively damages this dopamine-enriched brain area. In an attempt to clarify how dopamine takes part in ischemia-induced neuronal damage, we performed in vitro electrophysiological recordings from neurons of the nucleus striatum.

Methods—

Intracellular recordings with sharp microelectrodes were performed from corticostriatal slices. Slices were obtained from both rats and wild-type and dopamine D1 receptor-lacking mice. In some experiments, the striatum was unilaterally denervated by injecting the dopamine-specific neurotoxin 6-hydroxydopamine in the homolateral substantia nigra. Dopamine agonists and antagonists, as well as drugs targeting the intracellular cascade coupled to dopamine receptor stimulation, were applied at known concentrations.

Results—

Manipulation of the dopamine system failed to affect the membrane depolarization of striatal neurons exposed to combined oxygen and glucose deprivation of short duration, but it reduced the amplitude of postischemic long-term potentiation (LTP) expressed at corticostriatal synapses. In particular, pharmacological blockade or genetic inactivation of D1/cAMP/protein kinase A pathway prevented the long-term increase of the excitatory postsynaptic potential (EPSP) amplitude caused by a transient ischemic episode, while it failed to prevent the increase of the EPSP half-decay coupled to ischemic LTP.

Conclusions—

The present data suggest that endogenous dopamine, via D1 receptors, selectively facilitates the expression of ischemic LTP on the AMPA-mediated component of the EPSPs, while it does not alter the expression of this form of synaptic plasticity on the
N
-methyl-
d
-aspartate-mediated component of corticostriatal synaptic potentials. Understanding the cellular and molecular mechanisms of ischemia-triggered excitotoxicity offers hope for the development of specific treatments able to interfere with this pathological process.
Cryptogenic Stroke in Relation to Genetic Variation in Clotting Factors and Other Genetic Polymorphisms Among Young Men and Women
Authors: Austin Harland , Chimowitz Marc I. , Hill Holly A. , Chaturvedi Seemant , Wechsler Lawrence R. , Wityk Robert J. , Walz Elizabeth , Wilterdink Janet L. , Coull Bruce , Sila Cathy A. , Mitsias Panos , Evatt Bruce , Hooper W. Craig
Published: December 2002

Background and Purpose—

The purpose of the present study was to compare the prevalences of genetic polymorphisms in persons with cryptogenic stroke with those among stroke patients with evidence of large-artery occlusive disease or an unequivocal cardioembolic source (noncryptogenic stroke).

Methods—

We compared the prevalences of genetic polymorphisms thought to be related to thrombi formation in young stroke patients with evidence of large-artery occlusive disease or an unequivocal cardioembolic source (noncryptogenic stroke; controls; n=79) with those in young stroke patients without such sources (cryptogenic stroke; cases; n=67). Common variations in the genes encoding factor V, prothrombin, angiotensin I–converting enzyme, 5,10-methylenetetrahydrofolate reductase, endothelial cell nitric oxide synthase, tissue plasminogen activator, plasminogen activator inhibitor–1, and fibrinogen were evaluated. We also compared the allele prevalence of these genes among all stroke patients with those among a large pool of historical controls assayed for these genes.

Results—

None of these genetic polymorphisms was statistically significantly related to cryptogenic stroke. With respect to a comparison of all ischemic stroke with historical controls, only the prevalence of tissue plasminogen activator D allele among stroke subjects was statistically significantly higher than that of the historical controls (
P
=0.0014).

Conclusions—

These findings generally do not support the hypothesis that genes associated with a prothrombotic state are risk factors among a subgroup of young people with stroke of undetermined cause. Except for the D tissue plasminogen activator allele, the findings also indicated that these genetic factors are unrelated, or only weakly related, to all ischemic stroke.
To What Extent Should Quality of Care Decisions Be Based on Health Outcomes Data?
Authors: Samsa Gregory , Oddone Eugene Z. , Horner Ronnie , Daley Jennifer , Henderson William , Matchar David B.
Published: December 2002

Background and Purpose—

Most quality improvement methods implicitly assume that facilities with high complication rates are likely to have substandard processes of care, a stable characteristic that, in the absence of intervention, will persist over time. We assessed the extent to which this holds true for carotid endarterectomy.

Methods—

Using data from the Department of Veterans Affairs National Surgical Quality Improvement Project, we classified facilities on the basis of 30-day complications of carotid endarterectomy (stroke, myocardial infarction, death) during 1994 to 1995 (period 1, n=3389) and then compared these groups of facilities for complication rates during 1996 to 1997 (period 2, n=4453).

Results—

Despite wide variation in facility-specific complication rates, the correlation between rates in periods 1 and 2 was low (Spearman correlation coefficient, 0.04;
P
=0.01) Facility-specific rates did not show greater correlation when we examined only facilities with higher volumes patients in different clinical categories (asymptomatic, transient ischemic attack, stroke). Comorbid illness profiles were similar between the 2 time periods.

Conclusions—

Most of the facility-specific differences in complication rates in period 1 were not maintained into period 2. Many apparent quality improvement problems may not be as large as they first appear, especially when based on few complications per facility. The inability, in practice, to estimate complication rates at a high degree of precision is a fundamental difficulty for clinical policy making regarding procedures with complication rates such as carotid endarterectomy.
Thrombolytic Treatment of Clot Embolism in Rat
Authors: Niessen Frank , Hilger Thomas , Hoehn Mathias , Hossmann Konstantin-A.
Published: December 2002

Background and Purpose—

We sought to test the hypothesis that intra-arterial recombinant tissue plasminogen activator (rtPA) treatment of thromboembolic stroke is more efficient than intravenous application.

Methods—

Rats were embolized by intracarotid injection of autologous fibrin-rich blood clots. One hour later rtPA (10 mg/kg) was infused either intravenously (n=8) or intra-arterially (n=8). Control rats (n=8) received intra-arterial infusion of saline. Treatment was monitored by MR perfusion-weighted imaging and apparent diffusion coefficient (ADC) imaging, and outcome was evaluated by comparing incidence of hemorrhages and lesion volumes of ATP and pH.

Results—

Clot embolism led to a decline of perfusion-weighted imaging signal intensity in the middle cerebral artery territory to <40% of control. Both intra-arterial and intravenous treatment significantly improved blood flow in cerebral cortex but not in caudate putamen. In untreated animals, ATP and pH lesion volumes were 510.3±94.5 and 438.6±39.2 mm
3
at 7 hours after clot embolism, respectively. Both intravenous and intra-arterial rtPA treatment produced hemorrhagic complications but reduced ATP lesion size to 296.2±136.1 and 370.3±103.7 mm
3
and reduced pH lesion size to 263.3±114.6 and 303.3±103.0 mm
3
, respectively (
P
<0.05 for untreated versus treated rats; no difference between intravenous and intra-arterial treatment). ADC imaging revealed that lesion reduction was due to inhibition of infarct growth but not to reversal of primary injury.

Conclusions—

This study documents reduction of injury by rtPA treatment but does not reveal a difference between intra-arterial and intravenous application. Our data do not support an advantage of intra-arterial thrombolysis.
Prospective, Randomized, Double-Blind Trial Investigating the Effect of Doxycycline on Matrix Metalloproteinase Expression Within Atherosclerotic Carotid Plaques
Authors: Axisa Benedict , Loftus Ian M. , Naylor A. Ross , Goodall Steven , Jones Louise , Bell Peter R.F. , Thompson Matthew M.
Published: December 2002

Background and Purpose—

Elevated levels of matrix metalloproteinases (MMPs), particularly MMP-1 and MMP-9, have been implicated in plaque rupture. It has been suggested that inhibition of MMPs may stabilize vulnerable atherosclerotic plaques and improve clinical outcome. The aim of the study was to investigate the ability of doxycycline, a nonspecific MMP inhibitor, to reduce MMP concentration in carotid atheroma.

Methods—

The study design was a prospective, double-blind randomized trial. One hundred patients requiring carotid endarterectomy were randomized to receive 200 mg/d doxycycline or placebo for 2 to 8 weeks before surgery. During endarterectomy, carotid plaques were retrieved. The concentrations of MMPs and doxycycline were determined in the atherosclerotic tissue by enzyme-linked immunosorbent assay and high-performance liquid chromatography, respectively. Clinical events were recorded, as was the rate of preoperative embolization (transcranial Doppler).

Results—

Analysis of endarterectomized specimens demonstrated a mean doxycycline concentration of 6.0 μg/g wet weight in treated patients. Administration of doxycycline significantly reduced the concentration of MMP-1 in carotid plaques from a mean of 14.8 to 10.3 ng/100g wet weight (
P
=0.038). This difference was due to decreased MMP-1 transcript (
P
<0.001). There was no difference in any other MMP (MMP-2, -3, or -9) or tissue inhibitor of matrix metalloproteinases–1 or –2.

Conclusions—

Doxycycline penetrated atherosclerotic plaques with acceptable tissue levels. This resulted in a reduction in MMP-1 concentration because of decreased expression.
Association Between Behavior-Dependent Cardiovascular Risk Factors and Asymptomatic Carotid Atherosclerosis in a General Population
Authors: Luedemann Jan , Schminke Ulf , Berger Klaus , Piek Marion , Willich Stefan N. , Döring Angela , John Ulrich , Kessler Christof
Published: December 2002

Background and Purpose—

Physical inactivity and unfavorable dietary and lifestyle patterns are related to cardiovascular disease and premature death. Their relationship to atherosclerosis of the carotid arteries and subsequent stroke is unclear. The objective of this study was to investigate the association between those behavioral cardiovascular risk factors and asymptomatic atherosclerosis of the carotid arteries in a population of former East Germany.

Methods—

The Study of Health in Pomerania (SHIP) is a cross-sectional survey in northeast Germany. In 1632 individuals aged 45 to 70 years, high-resolution B-mode ultrasound was used to assess the mean intima-media thickness of the right and left common carotid arteries. Carotid plaques and stenosis were recorded. Physical activity, dietary patterns, and cardiovascular risk factors were assessed in interviews with the use of standardized scales. Physically active participants with optimal dietary patterns were classified in the optimal lifestyle group, and those inactive with unfavorable diet were classified in the unfavorable group.

Results—

After adjustment for sex and age, significant decreasing trends were found for both intima-media thickness and severe asymptomatic atherosclerosis from unfavorable to optimal lifestyle patterns in never smokers but not in smokers. Regression analysis revealed an increased risk of severe asymptomatic atherosclerosis in subjects with an unfavorable lifestyle pattern compared with those with an optimal pattern (odds ratio 2.68; 95% CI, 1.13 to 6.37), following a significant linear trend.

Conclusions—

Physical activity and optimal diet are associated with reduced risk of early atherosclerosis in subjects who never smoked, while no benefit of an otherwise optimal lifestyle is observed in smokers.
Cerebral Autoregulation Under Moderate Hypothermia in Patients With Acute Stroke
Authors: Georgiadis D. , Schwarz S. , Evans D.H. , Schwab S. , Baumgartner R.W.
Published: December 2002

Background and Purpose—

We undertook this study to examine the integrity of cerebral autoregulation in patients with acute ischemic stroke treated with moderate hypothermia (33°C).

Methods—

Fourteen patients, aged 58±11 years, with an acute anterior circulation infarction and National Institutes of Health Stroke Scale score >15 were evaluated. Patients received catecholamines (norepinephrine) via continuous intravenous infusion and were mechanically ventilated. Alpha-stat was used for pH maintenance. Arterial pressure (AP) and intracranial pressure (ICP) were invasively monitored. Flow velocity in the middle cerebral artery (MCA) supplying the unaffected hemisphere was continuously monitored. Instantaneous maximum flow velocity (V
max
MCA), ICP, and AP were simultaneously recorded in real time. Mean values of V
max
MCA (V
mean
MCA) and AP (MAP) were calculated over 1 minute. Static cerebral autoregulation (sCA) was calculated as sCA=(%ΔCVR/%ΔMAP)×100% (where %ΔCVR is an estimate of percent change in cerebrovascular resistance). An sCA value of 0% indicates absent autoregulation, and a value of 100% indicates perfect autoregulation. Autoregulation is considered impaired when sCA values are <40%. MAP changes were produced by increasing the rate of the norepinephrine infusion. Six patients were examined under both normothermic and hypothermic conditions, while 8 were examined only under hypothermia.

Results—

The induced MAP increase was 22±7 mm Hg (minimum 13, maximum 40 mm Hg). Mean sCA was 64±16% (minimum 40%, maximum 100%). No effect of moderate hypothermia on sCA or V
mean
MCA was evident in any of the 6 serially examined patients. Normocapnia was observed in all cases.

Conclusions—

sCA appears intact under moderate hypothermia with the use of alpha-stat for pH maintenance.