bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Expression Profiling in Hypertension Research
Authors: Pravenec Michal , Wallace Caroline , Aitman Timothy J. , Kurtz Theodore W.
Published: January 2003

Recent advances in molecular biology and technology have made it possible to monitor the expression levels of virtually all genes simultaneously. As the tools for gene expression profiling have become more widely available, the number of investigators applying this technology in hypertension research, as in other fields of biomedical research, has grown rapidly. At the same time, numerous articles have been published that discuss the technical aspects of gene profiling and its promise for advancing research on the pathogenesis and treatment of multiple clinical disorders. However, much of the research carried out with gene expression profiling has been of a correlational or descriptive nature, and the true value of this technology is unclear. Despite the initial wave of enthusiasm for gene expression profiling, its actual utility for studying multifactorial disorders like hypertension remains to be established. In this review, we offer a critical perspective on the use of gene expression profiling in hypertension research and discuss some emerging strategies for taking this technology beyond the limits of correlational and descriptive studies.
Asymmetry of Renal Blood Flow in Patients With Moderate to Severe Hypertension
Authors: van Onna Marieke , Houben Alphons J.H.M. , Kroon Abraham A. , Wierema Thomas K.A. , Koster Derk , van Engelshoven Jos M.A. , de Leeuw Peter W.
Published: January 2003

It is generally assumed that renal blood flow is symmetric in the absence of renal artery stenosis. The aim of the present study was to evaluate whether this is really the case. From a group of consecutive hypertensive patients who had undergone renal angiography, we selected those with patent renal arteries. In all of them selective renal blood flow (RBF) measurements (
133
Xenon washout technique) had been performed with blood sampling from aorta and both renal veins (n=148). Asymmetry of RBF, defined as ≥25% difference in RBF between left and right kidney, was present in 51% of the patients. Subjects with and without asymmetry did not differ in age, body mass index, blood pressure, creatinine clearance, renal volume, or activity of the renin-angiotensin system. The presence of asymmetry coincided with an increased rate of false-positive results on renal scintigraphy. Preliminary data suggest that there may be a relation between asymmetry and renal sympathetic nerve activity. This study demonstrates that asymmetry of RBF is a frequent finding in essential hypertension, which may confound the results of diagnostic tests for renal artery stenosis. Furthermore, the present results underscore the importance of studying the function of both kidneys separately, because it cannot be assumed that they are functionally equal.
Endothelin-1 Contributes to the Frank-Starling Response in Hypertrophic Rat Hearts
Authors: Piuhola Jarkko , Szokodi István , Kinnunen Pietari , Ilves Mika , deChâtel Rudolf , Vuolteenaho Olli , Ruskoaho Heikki
Published: January 2003

Endothelin-1 is involved in mechanical load–induced cardiac growth processes; it also has effects on contractility. The interaction of endothelin-1 and the Frank-Starling response is unknown. The present study aimed to characterize the role of endothelin-1 in the regulation of the Frank-Starling response, one of the major mechanisms regulating cardiac contractile force, in both normal and hypertrophied hearts. Nontransgenic rat hearts and hypertrophic hearts of hypertensive double transgenic rats harboring human angiotensinogen and renin genes were studied in a Langendorff isolated heart setup with a liquid-filled balloon inside the left ventricle used to measure contractile parameters. The rats were studied at compensated phase, before showing any signs of heart failure. Compensated hypertrophy in double transgenic rat hearts resulted in improved contractility at a given level of preload when compared with nontransgenic rat hearts. Hearts of both rat lines showed preserved Frank-Starling responses, that is, increased contractile function in response to increased end-diastolic pressure. The mixed endothelin A/B receptor antagonist bosentan attenuated the Frank-Starling response by 53% (
P
<0.01) in the double transgenic hearts but not in nontransgenic hearts. The diastolic parameters remained unaffected. The left ventricles of the double transgenic rat hearts showed an 82% higher level of endothelin type A receptor mRNA and a 25% higher level of immunoreactive endothelin-1 compared with nontransgenic rat hearts. The type 1 angiotensin II receptor antagonist CV-11974 had no significant effect on contractile function in response to load in either strain. These results show that endogenous endothelin-1 contributes to the Frank-Starling response in hypertrophied rat hearts by affecting systolic performance.
Enhancement of Ischemia-Induced Angiogenesis by eNOS Overexpression
Authors: Amano Katsuya , Matsubara Hiroaki , Iba Osamu , Okigaki Mitsuhiko , Fujiyama Soichiro , Imada Takanobu , Kojima Hiroyuki , Nozawa Yoshihisa , Kawashima Seinosuke , Yokoyama Mitsuhiro , Iwasaka Toshiji
Published: January 2003

It remains undetermined whether continuous endothelial nitric oxide (NO) overexpression exerts angiogenic action. We surgically induced hindlimb ischemia in transgenic mice overexpressing endothelial NO synthase in the endothelium (eNOS-Tg) and studied neocapillary formation, ischemia-induced vascular endothelial growth factor (VEGF) expression, cGMP accumulation, and Akt/PKB signaling. Laser Doppler imaging revealed a markedly increased recovery of blood perfusion in ischemic limbs of eNOS-Tg mice (44% increase) compared with that in wild-type mice. Angiography showed a marked increase in basal and ischemia-induced collateral vessel formation in eNOS-Tg mice. Basal capillary densities and tissue cGMP levels were increased in eNOS-Tg mice (1.8-fold and 1.6-fold versus wild-type mice, respectively). Ischemia-induced neocapillary formation and cGMP accumulation were markedly increased in eNOS-Tg mice (3.6-fold and 4.1-fold versus preischemia levels, respectively), whereas those in wild-type mice were much less (1.8-fold and 1.5-fold, respectively). Basal and time-dependent VEGF expression in ischemic muscles did not differ between eNOS-Tg and wild-type mice. Basal and VEGF-mediated Akt phosphorylation in aortas was similar between eNOS-Tg and wild-type mice. Aortic basal eNOS expression was increased 3.3-fold, and VEGF-mediated eNOS phosphorylation was markedly induced in aortas of eNOS-Tg compared with preischemia levels (4.2-fold), whereas much smaller changes were observed in wild-type mice (1.8-fold increase). Our study demonstrates that overexpression of eNOS protein causes a marked increase in neocapillary formation in response to tissue ischemia without affecting ischemia-induced VEGF expression or VEGF-mediated Akt phosphorylation.
Stroke in Black South African HIV-Positive Patients
Authors: Mochan Andre , Modi Mala , Modi Girish
Published: January 2003

Background and Purpose—

Stroke associated with HIV infection is poorly characterized. In this study we analyze the association in a black African population.

Methods—

The clinical, laboratory, and radiological characteristics of 35 hospital-based black South African, heterosexual, HIV-infected patients who did not abuse intravenous drugs and presented with strokes were prospectively studied. The patients were antiretroviral therapy naive. Patients with other intracranial space-occupying lesions were excluded from the study.

Results—

The age range was 20 to 61 years (mean, 32.1 years). There were 21 female and 14 male patients, with a female to male ratio of 1.5:1. Cerebral infarction occurred in 33 patients (94%) and intracerebral hemorrhage in 2 patients (6%). Underlying causes were identified in 30 of the 35 patients (86%) and included coagulopathies, meningitis, cardioembolism, and hypertension. The most common coagulopathy was protein S deficiency. No cause was found in 5 patients (14%).

Conclusions—

The results are similar to data from studies on young black African stroke patients who are HIV negative.
Performance of a Statistical Model to Predict Stroke Outcome in the Context of a Large, Simple, Randomized, Controlled Trial of Feeding
Authors:   The FOOD Trial Collaboration
Published: January 2003

Background and Purpose—

Statistical models to predict the outcome of stroke patients have several uses. Their utility depends on their predictive accuracy in patients other than those on whom they were developed (ie, external validity). We sought to test the external validity of some recently described models in patients enrolled in the FOOD (Feed Or Ordinary Diet) trial: a large randomized trial evaluating feeding policies in patients with stroke.

Methods—

The predictive variables were collected during a telephone call to randomize the patient a median of 5 days after stroke onset. Patients were followed up 6 months later to establish their survival, functional status, and residence. Charts were plotted to demonstrate the discrimination and calibration of the models.

Results—

The models performed well in the first 2955 patients enrolled and followed up in the FOOD trial. The area under the receiver operating characteristic curves varied between 0.78 and 0.81 (with 0.5 indicating no discrimination and 1.0 indicating perfect discrimination). The discrimination was marginally better for patients enrolled within the first day of stroke than later. The models tended to provide rather pessimistic predictions in all groups except those predicted to have a high likelihood of surviving free of dependency.

Conclusions—

As one might predict, the discriminatory power in the selected cohort of trial patients was marginally less good than in previously studied unselected cohorts used to test their external validity. These models provide a well-tested tool for stratification in trials, comparing outcomes in different cohorts and examining the additional predictive power of novel factors.
Cognitive Behavioral Psychotherapy for Depression Following Stroke
Authors: Lincoln N.B. , Flannaghan T.
Published: January 2003

Background and Purpose—

There is inconclusive evidence of the effectiveness of psychological interventions for depression after stroke. We report the results from a randomized controlled trial of cognitive behavioral therapy (CBT).

Methods—

Stroke patients admitted to hospital were invited to complete mood questionnaires 1, 3 and 6 months after stroke. Patients who were depressed were invited to take part in a trial and randomly allocated to receive CBT (n=39), an attention placebo intervention (n= 43), or standard care (n=41). Outcome assessments were undertaken at 3 and 6 months after recruitment, on the Beck Depression Inventory, Wakefield Depression Inventory, Extended Activities of Daily Living scale, London Handicap Scale, and a rating of satisfaction with care.

Results—

There were no significant differences between the groups in patients’ mood, independence in instrumental activities of daily living, handicap, or satisfaction with care.

Conclusions—

CBT in the treatment of depression following stroke was found to be ineffective in this study. However, because of the small sample size, method of recruitment, and selection criteria, further randomized trials are required.
New-Onset Fecal Incontinence After Stroke
Authors: Harari Danielle , Coshall Catherine , Rudd Anthony G. , Wolfe Charles D.A.
Published: January 2003

Background and Purpose—

Fecal incontinence (FI) is a common complication after stroke, yet epidemiological research into this distressing condition is limited. The purpose of this study was to describe the prevalence, natural history, associations, and impact of new-onset FI after stroke.

Methods—

Stroke patients in the community-based South London Stroke Register (January 1995 to 2000) without preexisting FI were characterized regarding bowel continence at 7 to 10 days, 3 months, and 1 and 3 years after stroke. FI was defined as any degree of bowel leakage.

Results—

Prevalence of poststroke FI was 30% (7 to 10 days), 11% (3 months), 11% (1 year), and 15% (3 years). One third of patients with FI at 3 months were continent by 1 year; conversely, 63% incontinent at 1 year had been continent at 3 months. Characteristics of 91 patients with FI and 755 without FI at 3 months were compared using multiple logistic regression. Acute stroke associations of neglect (adjusted odds ratio [OR], 1.9; 95% CI, 1.0 to 3.5) and initial urinary incontinence (OR, 6.2; 95% CI, 3.2 to 11.9) were no longer significant after adjustment for clinical factors at 3 months. Final independent associations were anticholinergic drug use (OR, 3.1; 95% CI, 1.1 to 10.2) and needing help with toilet use (OR, 3.5; 95% CI, 1.4 to 17.3). FI at 3 months increased the risk of long-term placement (28% vs 6%) and death within 1 year (20% vs 8%).

Conclusions—

New-onset FI in stroke survivors is common but may be transient. Modifiable risk factors for FI 3 months after stroke are constipating drug use and difficulty with toilet access, raising implications for developing treatment and prevention strategies.
Diagnostic Accuracy of Stroke Referrals From Primary Care, Emergency Room Physicians, and Ambulance Staff Using the Face Arm Speech Test
Authors: Harbison Joseph , Hossain Omar , Jenkinson Damian , Davis John , Louw Stephen J. , Ford Gary A.
Published: January 2003

Background and Purpose—

Timely referral of appropriate patients to acute stroke units is necessary for effective provision of skilled care. We compared the characteristics of referrals with suspected stroke to an academic acute stroke unit via 3 primary referral routes: ambulance paramedics using a rapid ambulance protocol and stroke recognition instrument, the Face Arm Speech Test; primary care doctors (PCDs); and emergency room (ER) referrals.

Methods—

Patient characteristics, final diagnosis, and admission delay were recorded in all suspected acute stroke referrals in a 6-month period.

Results—

Four hundred eighty-seven patients (356 strokes/transient ischemic attacks) were admitted by the 3 routes: 178 by ambulance, 216 by PCDs, and 93 through the ER. The proportion of nonstrokes admitted by each route was similar (23%, 29%, and 29%, respectively). Ambulance paramedics’ stroke diagnosis was correct in 144 of 183 (79%) stroke patients who initially presented to them. Thirty-nine of 66 strokes/transient ischemic attacks referred via ER were taken there following initial ambulance assessment. Compared with PCDs, paramedics referred more total anterior circulation (39% versus 14%,
P
<0.0001) and fewer lacunar strokes (14% versus 31%,
P
<0.001) and admitted more patients (46% versus 12%,
P
<0.01) within 3 hours of symptom onset. The most common nonstroke conditions were seizures, infections and confusion, cardiovascular collapse, and cerebral tumors. Paramedics admitted more patients with seizures.

Conclusions—

Misdiagnosis of stroke is common in the ER and by PCDs. Paramedics using the Face Arm Speech Test achieved high levels of detection and diagnostic accuracy of stroke.
Contrast Burst Depletion Imaging (CODIM)
Authors: Eyding Jens , Wilkening Wilko , Reckhardt Markus , Schmid Gebhard , Meves Saskia , Ermert Helmut , Przuntek Horst , Postert Thomas
Published: January 2003

Background and Purpose—

Established methods of ultrasonic perfusion imaging using a bolus application of echo contrast agent provide only qualitative data because of various physical phenomena. This study was intended to investigate whether a new ultrasound perfusion imaging method termed contrast burst depletion imaging (CODIM) may provide semiquantitative measures of parenchymal perfusion independent of examination depth and acoustic energy distribution.

Methods—

In a system with a constant concentration of contrast agent, analyzing the decrease in image intensity that occurs with microbubble-destructive imaging modes yields parameters that are considered to correlate with tissue perfusion. This method was first evaluated with a perfusion model that showed that the main resulting parameter “perfusion coefficient” (PC) is a monotonic nonlinear function of flow velocity. Seventeen human volunteers were then scanned according to this method with the use of 2 different contrast agents. Results were correlated with those from perfusion-weighted MRI examinations.

Results—

The PC did not show significant differences in gray matter areas (ranging from 1.466×10
−2
s
−1
to 1.641×10
−2
s
−1
) of the brain despite different insonation depths (eg, ipsilateral and contralateral thalamus). In contrast, white matter exhibited significantly lower perfusion values in both imaging modes (PC: 0.604×10
−2
s
−1
to 0.745×10
−2
s
−1
;
P
<0.05).

Conclusions—

CODIM is a promising new tool of imaging parenchymal (brain) perfusion in healthy persons. The method provides semiquantitative and depth-independent perfusion parameters and in this way overcomes the limitations of the perfusion methods using a bolus kinetic. Further investigations must be done to evaluate the potential of the method in patients with perfusion deficits.
In Vitro Measurement of Fluid-Induced Wall Shear Stress in Unruptured Cerebral Aneurysms Harboring Blebs
Authors: Tateshima Satoshi , Murayama Yuichi , Villablanca J. Pablo , Morino Taku , Nomura Kiyoe , Tanishita Kazuo , Viñuela Fernando
Published: January 2003

Background and Purpose—

Little attention has been focused on the role of fluid-induced wall shear stress in fully developed cerebral aneurysms. The purpose of this study is to evaluate the alternation and distribution of wall shear stress over 1 cardiac cycle in patients’ aneurysms.

Methods—

A middle cerebral artery aneurysm and a basilar tip aneurysm with localized outpouching (blebs) in their domes were selected for this study. With the use of a stereo lithography machine, geometrically realistic aneurysm models were created on the basis of 3-dimensional CT angiograms. In vitro shearing velocity measurement was conducted with the use of laser-Doppler velocimetry at multiple points on the aneurysmal wall to calculate the value of wall shear stress. The wall shear stress was documented at multiple points in the aneurysm inflow zone, dome, and outflow zone.

Results—

Distribution of wall shear stress was not uniform in the aneurysm walls, and particular regions were exposed to relatively high wall shear stress. The wall shear stress changed dynamically throughout 1 cardiac cycle at the point where a high value of wall shear stress was noted. The blebs of both aneurysms were exposed to high wall shear stress. Unlike previous reports in which an ideal spherical aneurysm model was used, the aneurysm inflow zone was not exposed to high shear stress.

Conclusions—

In vitro aneurysm models based on the patients’ angiograms allowed us to conduct a more realistic evaluation of wall shear stress in the aneurysms harboring blebs. These results provide us with further indications of the correlation of wall shear stress with the natural history of cerebral aneurysms.
Inherited Thrombophilic Disorders in Young Adults With Ischemic Stroke and Patent Foramen Ovale
Authors: Pezzini Alessandro , Del Zotto Elisabetta , Magoni Mauro , Costa Angelo , Archetti Silvana , Grassi Mario , Akkawi Nabil Maalikjy , Albertini Alberto , Assanelli Deodato , Vignolo Luigi Amedeo , Padovani Alessandro
Published: January 2003

Background and Purpose—

The pathogenic link between patent foramen ovale (PFO) and stroke remains unknown in most cases. We investigated the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study.

Methods—

We investigated 125 consecutive subjects (age, 34.7±7.3 years) with ischemic stroke and 149 age- and sex-matched control subjects. PFO was assessed in all patients with transcranial Doppler sonography with intravenous injection of agitated saline according to a standardized protocol. Genetic analyses for the factor V (FV)
G1691A
mutation, the prothrombin (PT)
G20210A
variant, and the
TT
677 genotype of methylenetetrahydrofolate reductase (
MTHFR
) were performed in all subjects.

Results—

A pathogenic role of PFO was presumed in 36 patients (PFO+). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFO−). The PT
G20210A
variant was more frequent in the PFO+ group compared with control subjects and the PFO− group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO−, 11% versus 1.1%; 95% CI, 1.09 to 109;
P
=0.047). A similar distribution was observed for subjects carrying either the PT
G20210A
variant or the FV
G1691A
mutation (PFO+ versus control subjects, 19.4% versus 5.3%; 95% CI, 0.08 to 0.75; PFO+ versus PFO−, 19.4% versus 3.3%; 95% CI, 1.45 to 26.1;
P
=0.021). Combined thrombophilic defects were observed in 3 subjects of the PFO+ group, in 2 control subjects (8.3% versus 1.3%; 95% CI, 0.01 to 0.66;
P
=0.015), and in 0 subjects in the PFO− group. A trend toward a difference in the frequency of the FV
G1691A
mutation between PFO+ and control subjects was found after bivariate analysis (11% versus 3.3%;
P
=0.068) but not after multinomial logistic regression analysis. No significant association was found in the distribution of the
TT MTHFR
genotype in the 3 groups.

Conclusions—

In young adults, the PT
G20210A
variant and, to a lesser extent, the FV
G1691A
mutation may represent risk factors for PFO-related cerebral infarcts. A role of systemic thrombophilic disorders in the pathogenesis of this specific subtype of stroke may be hypothesized.
Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage
Authors: Mayer Stephan A.
Published: January 2003

Background—

Intracerebral hemorrhage (ICH) causes higher morbidity and mortality than other forms of stroke and has no proven effective treatment. Hematoma volume is a powerful predictor of outcome after ICH.

Summary of Review—

Historically, ICH bleeding was considered to be a monophasic event that stopped quickly as a result of clotting and tamponade by surrounding brain tissue. More recently, prospective and retrospective CT-based studies have demonstrated that hematoma growth occurs in up to 38% of patients initially scanned within 3 hours of onset and in 16% scanned between 3 and 6 hours, even in the absence of coagulopathy. Progressive bleeding of this type has been associated with contrast extravasation on CT angiography and poor outcome after early (<4 hours) surgical clot evacuation. On the basis of these observations, it is plausible that ultra-early hemostatic therapy given in the emergency setting might reduce ICH volume in some patients and improve outcome. Among candidate agents for this indication, the most promising is recombinant activated factor VIIa, which promotes local hemostasis at sites of vascular injury in both coagulopathic and normal patients.

Conclusions—

Ultra-early hemostatic therapy, given within 3 to 4 hours of onset, may potentially arrest ongoing bleeding and minimize hematoma growth after ICH. Given the current lack of effective therapy for ICH, clinical trials testing this treatment approach are justified.
Incidence and Outcome of Multiple Intracranial Aneurysms in a Defined Population
Authors: Kaminogo Makio , Yonekura Masahiro , Shibata Shobu
Published: January 2003

Background and Purpose—

Proportions of patients with single and multiple aneurysms among patients suffering from subarachnoid hemorrhage (SAH) are not well established. We evaluated these proportions and the differences in outcome between SAH patients with a single aneurysm and those with multiple aneurysms in a defined population.

Methods—

Between 1989 and 1998, 2037 patients (age, 20 to 89 years) with ruptured intracranial aneurysm were treated in 11 hospitals in Nagasaki Prefecture. Multiple aneurysms were found in 361 of these patients. Age- and sex-specific incidences of ruptured aneurysm per 100 000 people were calculated.

Results—

For both single and multiple aneurysms, the incidences were significantly higher in women than in men 60 to 69 and 70 to 79 years of age. In every age category except 80 to 89 years, the frequency of multiple aneurysms was higher in women than in men. The overall frequency of multiple aneurysms was 20.2% in women, which was significantly higher than the 12.4% in men (
P
<0.0001). In patients 70 to 89 years of age, outcome was significantly worse (in terms of surgical complications) in patients with multiple aneurysms (12.1%) than in patients with a single aneurysm (6.0%).

Conclusions—

Among all patients with SAH, women ≥50 years of age outnumber other age and sex categories. Female sex itself is also associated with an increased rate of multiple aneurysms among SAH patients. Among the elderly ≥70 years of age, prognosis is less favorable for SAH patients with multiple aneurysms than for those with a single aneurysm.
Plasma Metalloproteinase-9 Concentration Predicts Hemorrhagic Transformation in Acute Ischemic Stroke
Authors: Castellanos Mar , Leira Rogelio , Serena Joaquín , Pumar José M. , Lizasoain Ignacio , Castillo José , Dávalos Antoni
Published: January 2003

Background and Purpose—

Matrix metalloproteinase-9 (MMP-9) activity has been associated with hemorrhagic transformation (HT) in experimental models of cerebral ischemia. Our aim was to investigate the relationship between MMP-9 concentrations in blood within 24 hours of stroke onset and subsequent HT of cerebral infarction.

Methods—

We studied 250 patients with a hemispheric ischemic stroke of 7.8±4.5 hours’ duration. Early CT signs of cerebral infarction were evaluated on admission. The HT and infarct volume were analyzed from the CT performed on days 4 through 7. MMP-9 levels were determined by enzyme-linked immunosorbent assay in blood samples obtained on admission.

Results—

HT was observed in 38 patients (15.2%): 24 (63.2%) had a hemorrhagic infarction, and 14 (36.8%) had a parenchymal hematoma. A total of 108 patients (43%) received anticoagulants before the second CT scan. Systolic and diastolic blood pressures, body temperature, frequency of early CT signs of ischemia (92% versus 22%), and treatment with anticoagulants (79% versus 37%) were significantly higher in the group with HT (
P
<0.001). Mean infarct volume was 126±60 cm
3
in the HT group and 90±68 cm
3
in the group without HT (
P
=0.003). Median (quartiles) plasma MMP-9 concentrations were higher in the HT group (193 [163, 213] versus 62 [40, 93] ng/mL,
P
<0.001), even in the 24 patients seen within 3 hours of symptom onset (
P
=0.014). MMP-9 levels ≥140 ng/mL had a positive and negative predictive value of HT of 61% and 97%, respectively. MMP-9 ≥140 ng/mL was associated with HT (odds ratio, 12; 95% confidence interval, 3 to 51;
P
<0.001) after adjustment for potential confounders and final infarct volume.

Conclusions—

High plasma MMP-9 concentration in the acute phase of a cerebral infarct is an independent biochemical predictor of HT in all stroke subtypes.
Differential Regulation of Thrombospondin-1 and Thrombospondin-2 After Focal Cerebral Ischemia/Reperfusion
Authors: Lin Teng-nan , Kim Gyoeng-Moon , Chen Jean-Ju , Cheung Wai-Mui , He Yong Y. , Hsu Chung Y.
Published: January 2003

Background and Purpose—

Angiogenesis occurs after cerebral ischemia, and the extent of angiogenesis has been correlated with survival in stroke patients. However, postischemic angiogenesis is short-lived and may be completely terminated within a few weeks after ischemic insult. The molecular mechanism underlying the dissolution of postischemic angiogenic processes is poorly understood. Although the expression of angiogenic genes has been studied in ischemic stroke models, the activation of angiostatic genes after cerebral ischemia has not been investigated. Thrombospondin (TSP)-1 and TSP-2 are naturally occurring angiostatic factors, which inhibit angiogenesis in vivo. The aim of the present study was to explore the expression of TSP-1 and TSP-2 in relation to the evolution of angiogenic process in a focal ischemia model in rats.

Methods—

Rats underwent cortical ischemia in the middle cerebral artery territory for 60 minutes and reperfusion for up to 2 weeks. Northern and Western blot analysis were used to study the temporal profile of TSP-1 and TSP-2 expression at the mRNA and protein level, respectively. In situ hybridization and immunohistochemical studies were used to examine the spatial expression patterns. Double immunostaining was applied to define the cellular origins of TSP-1 and TSP-2.

Results—

A biphasic expression of TSP-1 was noted after ischemia, peaking at 1 and 72 hours. Endothelial cells in the leptomeninges were the only source of the first TSP-1 peak, whereas endothelial, glial, neuronal, and macrophage cells contributed to the second peak of TSP-1 expression. TSP-2 expression occurred much later and in a monophasic manner, peaking 2 weeks after ischemia. TSP-2 immunoreactivity was observed in endothelial, neuronal, and macrophage, but not glial, cells. TSP-1 was expressed before the peak of angiogenesis, whereas robust TSP-2 expression occurred at the peak of angiogenesis and continued into the period when angiogenesis had completely resolved.

Conclusions—

Robust expression of TSP-1 and TSP-2, 2 major angiostatic factors, was noted in the ischemic brain with different temporal expression profiles from different cellular origins. The expression of these angiostatic factors, especially TSP-2, likely contributes to the spontaneous resolution of postischemic angiogenesis. Further studies are needed to explore the molecular mechanisms that regulate the balance of angiogenic and angiostatic factors in the ischemic brain.
Reperfusion Differentially Induces Caspase-3 Activation in Ischemic Core and Penumbra After Stroke in Immature Brain
Authors: Manabat C. , Han B.H. , Wendland M. , Derugin N. , Fox C.K. , Choi J. , Holtzman D.M. , Ferriero D.M. , Vexler Z.S.
Published: January 2003

Background and Purpose—

Different strategies for neuroprotection of neonatal stroke may be required because the developing brain responds differently to hypoxia-ischemia than the mature brain. This study was designed to determine the role of caspase-dependent injury in the pathophysiology of pure focal cerebral ischemia in the immature brain.

Methods—

Postnatal day 7 rats were subjected to permanent or transient middle cerebral artery (MCA) occlusion. Diffusion-weighted MRI was used during occlusion to noninvasively map the evolving ischemic core. The time course of caspase-3 activation in ischemic brain tissue was determined with the use of an Asp-Glu-Val-Asp-aminomethylcoumarin cleavage assay. The anatomy of caspase-3 activation in the ischemic core and penumbra was mapped immunohistochemically with an anti–activated caspase-3 antibody in coronal sections that matched the imaging planes on diffusion-weighted MRI.

Results—

A marked increase in caspase-3 activity occurred within 24 hours of reperfusion after transient MCA occlusion. In contrast, caspase-3 activity remained significantly lower within 24 hours of permanent MCA occlusion. Cells with activated caspase-3 were prominent in the penumbra beginning at 3 hours after reperfusion, while a more delayed but marked caspase-3 activation was observed in the ischemic core by 24 hours after reperfusion.

Conclusions—

In the neonate, caspase-3 activation is likely to contribute substantially to cell death not only in the penumbra but also in the core after ischemia with reperfusion. Furthermore, persistent perfusion deficits result in less caspase-3 activation and appear to favor caspase-independent injury.
Predicting Outcome in Ischemic Stroke
Authors: Johnston Karen C. , Connors Alfred F. , Wagner Douglas P. , Haley E. Clarke
Published: January 2003

Background—

Six multivariable models predicting 3-month outcome of acute ischemic stroke have been developed and internally validated previously. The purpose of this study was to externally validate the previous models in an independent data set.

Summary of Report—

We predicted outcomes for 299 patients with ischemic stroke who received placebo in the National Institute of Neurological Disorders and Stroke rt-PA trial. The model equations used 6 acute clinical variables and head CT infarct volume at 1 week as independent variables and 3-month National Institutes of Health Stroke Scale, Barthel Index, and Glasgow Outcome Scale as dependent variables. Previously developed model equations were used to forecast excellent and devastating outcome for subjects in the placebo tissue plasminogen activator data set. Area under the receiver operator characteristic curve was used to measure discrimination, and calibration charts were used to measure calibration. The validation data set patients were more severely ill (National Institutes of Health Stroke Scale and infarct volume) than the model development subjects. Area under the receiver operator characteristic curves demonstrated remarkably little degradation in the validation data set and ranged from 0.75 to 0.89. Calibration curves showed fair to good calibration.

Conclusions—

Our models have demonstrated excellent discrimination and acceptable calibration in an external data set. Development and validation of improved models using variables that are all available acutely are necessary.
Angiographic Dilatation and Branch Extension of the Anterior Choroidal and Posterior Communicating Arteries Are Predictors of Hemorrhage in Adult Moyamoya Patients
Authors: Morioka Motohiro , Hamada Jun-Ichiro , Kawano Takayuki , Todaka Tatemi , Yano Shigetoshi , Kai Yutaka , Ushio Yukitaka
Published: January 2003

Background and Purpose—

The cause of intracranial bleeding in moyamoya disease patients is still unknown. To identify factors that contribute to bleeding, we assessed the angiographic findings of moyamoya disease patients.

Methods—

We examined angiograms obtained from 107 moyamoya patients; 70 manifested ischemic and 37 had hemorrhagic lesions. Patients with intracerebral aneurysms or both hemorrhagic and ischemic lesions in the same cerebral hemisphere were not included. Patients were divided into those <20 years of age (n=47) and those ≥20 years of age (n=60). The right and left hemispheres in each patient were individually classified as hemorrhagic, ischemic, or asymptomatic. Each hemisphere was assessed for dilatation and branch extension of the anterior choroidal artery (AChA) and posterior communicating artery (P-CoM) and for the degree of proliferation of basal moyamoya vessels. These data were then statistically analyzed for correlation with intracranial bleeding events.

Results—

The degree of proliferation of basal moyamoya vessels was not statistically correlated with hemorrhagic events. On the other hand, there was a correlation between hemorrhage and dilatation and abnormal branching of the AChA. In 27 of 37 hemorrhagic hemispheres (73.0%), this artery was dilated, and its abnormal branches served as collateral supply vessels to other regions. This phenomenon was observed in 4 of 5 hemorrhagic hemispheres from young patients; it was noted in fewer than one third of ischemic and asymptomatic hemispheres from this age group. Similarly, 71.9% of hemorrhagic hemispheres from adult patients manifested AChA dilatation and branching, and the difference between hemorrhagic hemispheres and those that were ischemic or asymptomatic was statistically significant (
P
<0.01). Although the incidence of dilatation and abnormal branching of the P-CoM was relatively low in hemorrhagic hemispheres from adult patients (18.8%), it was significantly higher than in the ischemic and asymptomatic hemispheres from this age group. Using dilatation and abnormal branching of the AChA and/or P-CoM as assessment criteria, we obtained high specificity (86.4%) and sensitivity (84.4%) for hemorrhagic events in adult moyamoya patients.

Conclusions—

In adult moyamoya patients, dilatation and abnormal branching of the AChA and/or P-CoM are strong predictors of hemorrhagic events.
Autoregulatory Response and CO
2
Reactivity of the Basilar Artery
Authors: Park Cheol Wan , Sturzenegger Mathias , Douville Colleen M. , Aaslid Rune , Newell David W.
Published: January 2003

Background and Purpose—

Transcranial Doppler has been extensively used to measure cerebrovascular control mechanisms, including autoregulation in humans and in patients with cerebrovascular diseases. There have been sufficient reports on the measurement of normal autoregulatory response (AR) and CO
2
reactivity (CR) of the middle cerebral artery (MCA) but few reports of these indices for the basilar artery (BA). We measured AR and CR in the BA in healthy volunteers to determine normal values and compared them with simultaneous measurements made in the MCA.

Methods—

Sixteen normal subjects were enrolled. Time-averaged mean velocities of maximum blood flow in the BA and MCA were continuously and simultaneously monitored by using transcranial Doppler along with continuous measurement of mean arterial blood pressure (MABP). Values were obtained during rest, alterations of end-tidal Pa
co
2
(ETCO
2
), and acute decrease and recovery of MABP. AR was evaluated by using the thigh cuff method and graded by the standard dynamic autoregulatory index (ARI), with values between 0 and 9. CR was measured as percentage change in time-averaged mean velocity per mm Hg ETCO
2
.

Results—

The mean age of 16 subjects was 27.38±8.50 years. Average baseline values for MABP and ETCO
2
were 82.29±7.10 and 42.75±3.77 mm Hg, respectively. Mean ARI was 4.62±1.26 for the BA and was 4.77±1.23 for the MCA (n=15) (
P
=0.598). Average CR was 2.54±0.39%/mm Hg ETCO
2
for the BA and 2.51±0.29%/mm Hg ETCO
2
for the MCA (n=16) (
P
=0.686).

Conclusions—

Our study demonstrates that ARI and CR values for the BA are similar to those for the MCA.
Risk of Fatal Stroke in Patients With Treated Familial Hypercholesterolemia
Authors: Huxley R.R. , Hawkins M.H. , Humphries S.E. , Karpe F. , Neil H.A.W.
Published: January 2003

Background and Purpose—

Although it is recognized that in heterozygous familial hypercholesterolemia, large extracranial carotid vessels are affected by atherosclerosis, the risk of fatal stroke after treatment with cholesterol-lowering therapy remains uncertain. The goal of this study was to determine the risk of fatal stroke in patients with treated familial hypercholesterolemia.

Methods—

A cohort of 1405 men and 1466 women with definite or possible heterozygous familial hypercholesterolemia was recruited from 21 outpatient lipid clinics in the United Kingdom. Patients were followed up prospectively from 1980 to 1998 for 22 992 person-years for a median duration of 7.9 years (interquartile range, 4.9 to 12.0 years). The mortality rate was calculated, and the standardized mortality ratio for men and women 20 to 79 years of age was derived from the ratio of the observed deaths to the number expected in the general population of England and Wales (standardized mortality ratio=100 for the standard population).

Results—

A total of 169 deaths occurred; 9 (5.3%) were a result of stroke. The mortality rate from stroke was 0.39 per 1000 person-years (95% confidence interval, 0.18 to 0.74), and the standardized mortality ratio for fatal stroke was nonsignificantly lower than in the general population (79; 95% CI, 36 to 150).

Conclusions—

The results suggest that patients with treated familial hypercholesterolemia are not at increased risk of fatal stroke. However, the possibility cannot be excluded that untreated individuals are at increased risk, which would be consistent with the evidence that familial hypercholesterolemia is a panvascular disease.
Adaptive Noninvasive Assessment of Intracranial Pressure and Cerebral Autoregulation
Authors: Schmidt Bernhard , Czosnyka Marek , Raabe Andreas , Yahya Hilal , Schwarze Jens Jürgen , Sackerer Dieter , Sander Dirk , Klingelhöfer Jürgen
Published: January 2003

Background and Purpose—

A mathematical model has previously been introduced to estimate noninvasively intracranial pressure (nICP). In the present multicenter study, we investigated the ability of model to adapt to the state of cerebral autoregulation (SCA). This modification was intended to improve the quality of nICP estimation and noninvasive assessment of pressure reactivity of the cerebrovascular system.

Methods—

We studied 145 patients after severe head injuries or stroke. All patients had direct ICP, arterial blood pressure (ABP), and transcranial Doppler middle cerebral artery blood flow velocity (FV) monitored. The SCA was assessed by moving correlation (Mx index) of cerebral perfusion pressure (CPP=ABP−ICP) and cerebral blood flow velocity and correlation of ABP and ICP (PRx index). nICP was calculated from ABP and FV waveforms. When nICP was used instead of ICP, the SCA was continuously estimated, and the model was dynamically adapted to the SCA.

Results—

High and moderate correlations between invasively (Mx, PRx) and noninvasively (nMx, nPRx) estimated autoregulation indexes were observed (Mx:
R
=0.90,
P
<0.001; PRx:
R
=0.62,
P
<0.001). Values of Mx and nMx indicated contradictory SCA in 4 of 167 evaluated recordings; values of PRx and nPRx were contradictory in 27 recordings. When the model was adapted to the SCA, the mean error of ICP estimation decreased significantly (
P
<0.005).

Conclusions—

Continuous adaptation of the model to SCA improves the accuracy of noninvasive estimation of ICP and ICP dynamics. The same model provides a noninvasive and continuous assessment of SCA.
Evaluation of a Stroke Family Support Organiser
Authors: Lincoln Nadina B. , Francis Valerie M. , Lilley Steven A. , Sharma Jagdish C. , Summerfield Maggi
Published: January 2003

Background and Purpose—

There is inconclusive evidence of the effectiveness of the Stroke Family Support Organiser (FSO) service. We report the results from a randomized controlled trial of the service.

Methods—

Stroke patients admitted to hospital and their informal caregivers were randomly allocated to receive the FSO service (n=126) or standard care (n=124). Outcome assessments were undertaken 4 and 9 months after recruitment with the General Health Questionnaire 12, Carer Strain Index, Barthel Index, Extended Activities of Daily Living scale, and a specially designed questionnaire to determine knowledge of stroke and satisfaction with services.

Results—

There were no significant differences between groups in patients’ mood and independence in personal or instrumental activities of daily living or caregivers’ mood, strain, or independence. Patients in the intervention group were significantly more knowledgeable about whom to contact for stroke information, reducing the risk of stroke, practical help, community services, and emotional support. Patients in the intervention group were also significantly more satisfied with the stroke information received. Caregivers in the intervention group were significantly more knowledgeable about whom to contact for information on stroke, reducing the risk of stroke, community services, and emotional support. Caregivers in the intervention group were also significantly more satisfied with stroke information.

Conclusions—

The FSO service had no significant effect on mood, independence in activities of daily living, or reduction in caregiver strain, but it did increase knowledge of stroke and satisfaction with that knowledge. The results may not be representative of all FSO services, and the sample was small relative to the heterogeneity of the participants. However, results suggest that the policies and training procedures of FSOs need to be evaluated to ensure that a cost-effective service is being provided to stroke patients and their caregivers.
Poor Outcome After First-Ever Stroke
Authors: Appelros Peter , Nydevik Ingegerd , Viitanen Matti
Published: January 2003

Background and Purpose—

The purpose of this study was to define predictors of poor outcome after a first-ever stroke. We studied risk factors and stroke severity at baseline in relationship to death, dependency, and stroke recurrence within a year after the event.

Methods—

The study included a community-based cohort of first-ever stroke patients. Subarachnoid hemorrhage was not included. All patients (n=377) were subjected to investigations regarding risk factors. Stroke severity was evaluated with the National Institutes of Health Stroke Scale, and dependency was defined according to the modified Rankin Scale. Multivariate regression models were used to analyze predictors of survival, dependency, and stroke recurrence. The following independent variables were used: age, sex, cohabitation status, cigarette smoking, dementia, hypertension, ischemic heart disease, heart failure, atrial fibrillation, diabetes mellitus, transitory ischemic attack, peripheral atherosclerosis, and stroke severity.

Results—

The 1-year mortality was 33%. After 1 year, 37% of the survivors were dependent; 9% of survivors had a recurrent stroke within a year. Dementia, age, stroke severity, and atrial fibrillation were associated with death within a year. Dependency was associated with age, stroke severity, and heart failure. Stroke recurrence was predicted by age and dementia.

Conclusions—

In addition to age and stroke severity, heart diseases and dementia before the stroke seem to have an impact on mortality and recurrence after 1 year. Finding and, when possible, treating these prestroke conditions may affect stroke morbidity and mortality favorably.
Admitting Acute Ischemic Stroke Patients to a Stroke Care Monitoring Unit Versus a Conventional Stroke Unit
Authors: Sulter Geert , Elting Jan Willem , Langedijk Marc , Maurits Natasha M. , De Keyser Jacques
Published: January 2003

Background and Purpose—

Pathophysiological considerations and observational studies indicate that elevated body temperature, hypoxia, hypotension, and cardiac arrhythmias in the acute phase of ischemic stroke may aggravate brain damage and worsen outcome.

Methods—

Both units were organized with the same standard care and multidisciplinary approach to nursing and rehabilitation. A blinded observer assessed functional outcome at 3 months with the modified Rankin scale (mRS) and Barthel Index (BI). End points were (1) poor outcome, defined as either mRS ≥4 or BI <60 or the need for institutional care and (2) mortality.

Results—

Fifty-four patients meeting the inclusion criteria were randomized. The groups were well matched for baseline characteristics, stroke subtype, stroke severity, vascular risk factors, and prognostic factors. Poor outcome was seen in 7 (25.9%) patients in the SCMU group and in 13 (48.1%) in the SU group (
P
=0.16). Mortality was lower in the SCMU group than in the SU group (1 [3.7%] vs 7 [25.9%]; odds ratio, 0.11 [95% CI, 0.02 to 0.96],
P
=0.05).

Conclusions—

This pilot study suggests that admission of acute stroke patients to an SCMU may reduce mortality and poor outcome. A larger trial is required to confirm these findings.