bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Biochemical Advances in White Matter Ischaemia
Authors: Alix James J.P.
Published: September 2006

Stroke is one of the leading causes of death and disability in the developed world and as a result is the focus of intensive research. Historically, investigators in the field have focused on the effects of energy deprivation on the neuronal population, but, in recent times, as imaging techniques have become more advanced, a greater appreciation of the extent of non-neuronal injury has emerged. Initial investigations into the pathophysiology of white matter ischaemia reported damage to central myelinated axons via reversal of the Na+-Ca2+ exchange protein due to Na+ loading and ischaemia-induced membrane depolarisation. The latter also gates voltage-sensitive Ca2+ channels that contribute to the Ca2+ overload both directly and indirectly via Ca2+ release from intracellular stores. Excitotoxicity, once thought the unfortunate preserve of neurons, also contributes to white matter damage via both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors. However, important physiological differences are apparent in these receptors when compared to those present at the synapse, leading researchers to ask whether the molecular diversity of glutamate receptors will provide successful therapeutic interventions in the future. This brief review aims to summarise recent progress in the field of white matter ischaemia.
Hypercalcaemia in Relapsed Medulloblastoma 8 Years Post-Diagnosis; Evidence to Support PTHrP Production by Medulloblastoma Cells
Authors: Dharmaraj P. , Ball S. , Johnstone H. , Bailey S. , Clifford S.C. , Hale J. , Cheetham T.D.
Published: September 2006

Background: A 19-year-old male presented with symptomatic hypercalcaemia as the first manifestation of relapsed metastatic medulloblastoma. Management at the time of the initial presentation 8 years earlier was with surgical excision and craniospinal radiotherapy. His biochemistry at the time of relapse and studies of medulloblastoma cell lines provide an insight into the pathogenesis of his hypercalcaemia. Methods: Parathyroid hormone-related protein (PTHrP) was measured by immunoradiometric assay in blood, and in conditioned and control media from three medulloblastoma cell lines following 72 h growth. Results: The histology at initial presentation (11 years of age) and at the time of relapse (with bone marrow infiltration and widespread bony metastases) demonstrated medulloblastoma. Ionised calcium concentrations at relapse were 2.89 mmol/l and serum PTHrP levels were increased at the same time (2.7 pmol/l; normal range: 0.7–1.8 pmol/l). There was evidence of PTHrP production by one cell line (MHH-MED-8A) while results for both other lines tested were below the limit of detection. Conclusions: Relapse 8 years after diagnosis is unusual in medulloblastoma and for this relapse to manifest as hypercalcaemia is also very uncommon. Our investigations suggest that the clinical picture was a reflection of PTHrP production by medulloblastoma cells.
A Girl with a Novel Splice Site Mutation in VDR Supports the Role of a Ligand-Independent VDR Function on Hair Cycling
Authors: Katavetin Paravee , Katavetin Pisut , Wacharasindhu Suttipong , Shotelersuk Vorasuk
Published: September 2006

Mutations in vitamin D receptor (VDR) cause hereditary vitamin D resistant rickets (HVDRR). We reported a Thai girl with HVDRR, presenting with an early onset of rickets and partial alopecia. She was a product of a consanguineous couple. Mutation analysis showed that she was homozygous for a novel splice site mutation of the VDR gene, 462 + 1 G → C, resulting in incorporation of the whole 254 bp of the intron 4 into its mRNA. The mutated protein is expected to contain no ligand-binding domain. The fact that she did not develop total alopecia despite of no VDR ligand-binding domain supports that VDR function on hair cycling is ligand independent.
Psychosocial Functioning, Self-Perception and Body Image and Their Auxologic Correlates in Growth Hormone and Oestrogen-Treated Young Adult Women with Turner Syndrome
Authors: Lagrou Katrien , Froidecoeur Christelle , Verlinde Francisca , Craen Margaretha , De Schepper Jean , François Inge , Massa Guy
Published: September 2006

Background: Few data are available on the psychosocial status of growth hormone (GH) and oestrogen treated women with Turner syndrome (TS). In this study, we evaluated psychosocial functioning, self-concept and body image in GH and oestrogen treated young adult women with TS and we studied the relationship with auxological parameters. Patients and Methods: Thirty women with TS (mean ± SD age: 22.1 ± 2.4 years), all treated with GH and oestrogens if indicated, and an age-matched reference group of 44 non-Turner female students (age: 20.5 ± 2.1 years) completed 3 questionnaires evaluating, respectively, behavioural and emotional problems (Young Adult Self Report), self-concept (Self Perception Profile for College Students) and body-image (Body Attitude Scale). Results: TS patients did not report more behavioural and emotional problems compared to the non-TS females except for attention problems; they even reported fewer problems on some subscales (somatic complaints, thought problems, delinquent behaviour). TS patients did not differ from the non-TS female group in their bodily satisfaction. TS patients, particularly patients with a 45,X karyotype, perceived themselves as less socially competent. BMI was significantly related to the appraisal score of the Body Attitude Scale, whereas height was not related to any of the evaluated psychosocial parameters. Conclusion: The psychosocial adaptation of young adult women with TS, diagnosed at an early age and treated during childhood with GH and oestrogens if indicated, appears to be quite satisfactory. Follow-up of adult TS patients should not neglect the problem of overweight and associated psychosocial consequences.
Effect of Reproductive Factors and Postmenopausal Hormone Use on the Risk of Amyotrophic Lateral Sclerosis
Authors: Popat Rita A. , Van Den Eeden Stephen K. , Tanner Caroline M. , Bernstein Allan L. , Bloch Daniel A. , Leimpeter Amethyst , McGuire Valerie , Nelson Lorene M.
Published: September 2006

Objective: To examine the associations of reproductive factors and postmenopausal hormone use with the risk of amyotrophic lateral sclerosis (ALS) among women. Methods: This case-control study was conducted within the Kaiser Permanente Medical Care Program (KPMCP) of Northern California during the years 1996–2000. Among the 193 postmenopausal women, 62 were incident ALS cases and 131 were controls randomly selected from KPMCP members and frequency matched by age and respondent type (self versus proxy) to the cases. Statistical analyses were carried out using logistic regression. Results: Reproductive factors such as age at menarche, age at final menstrual period, parity, oral contraceptive use, and type of menopause (natural vs. hysterectomy with or without oophorectomy) were not associated with risk of ALS. Postmenopausal hormone use was positively, but not significantly, associated with the risk of ALS (adjusted OR 1.9, 95% CI 0.9–3.8). Conclusions: Reproductive factors were not associated with ALS risk. There is no evidence that suggests a protective effect of postmenopausal hormone use against the development of ALS. However, due to insufficient power, we cannot rule out a possible increase in ALS risk associated with postmenopausal hormone use.
Combined Work and Leisure Physical Activity and Risk of Stroke in Men and Women in the European Prospective Investigation into Cancer-Norfolk Prospective Population Study
Authors: Myint Phyo K. , Luben Robert N. , Wareham Nicholas J. , Welch Ailsa A. , Bingham Sheila A. , Day Nicholas E. , Khaw Kay-Tee
Published: September 2006

Most studies to date support a protective role of physical activity in reducing stroke risk. However, they were not able to take into account combined work and leisure activity. We prospectively followed up 22,602 men and women aged 40–79 years, who had no history of stroke and myocardial infarction at baseline, participating in the European Prospective Investigation into Cancer-Norfolk. Participants were categorized into four levels of physical activity based on a validated self-reported questionnaire, which assesses combined work and leisure activities, at baseline during the period from 1993 to 1997. Stroke incidence was ascertained by death certificate and hospital record linkage data up to 2004, average 8.6 years of follow-up. We used the Cox proportional hazards model. There were 361 incident strokes during follow-up (total person years = 195,092). After adjusting for age, sex, systolic blood pressure, body mass index, cholesterol, history of diabetes and smoking, men and women who were physically active were less likely to have a stroke (relative risk = 0.70, 95% CI: 0.49–0.99, p = 0.024) compared to those who were inactive. This highlights the fact that efforts to increase physical activity in both the work place and in leisure time should be encouraged.
Tetrahydrobiopterin and Cardiovascular Disease
Authors: Moens An L. , Kass David A.
Published: September 2006

Tetrahydrobiopterin (BH
4
) is an essential cofactor for the aromatic amino acid hydroxylases, which are essential in the formation of neurotransmitters, and for nitric oxide synthase. It is presently used clinically to treat some forms of phenylketonuria (PKU) that can be ameliorated by BH
4
supplementation. Recent evidence supports potential cardiovascular benefits from BH
4
replacement for the treatment of hypertension, ischemia-reperfusion injury, and cardiac hypertrophy with chamber remodeling. Such disorders exhibit BH
4
depletion because of its oxidation and/or reduced synthesis, which can result in functional uncoupling of nitric oxide synthase (NOS). Uncoupled NOS generates more oxygen free radicals and less nitric oxide, shifting the nitroso-redox balance and having adverse consequences on the cardiovascular system. While previously difficult to use as a treatment because of chemical instability and cost, newer methods to synthesize stable BH4 suggest its novel potential as a therapeutic agent. This review discusses the biochemistry, physiology, and evolving therapeutic potential of BH4 for cardiovascular disease.
Cholesteryl Ester Transfer Protein Decreases High-Density Lipoprotein and Severely Aggravates Atherosclerosis in
APOE*3-Leiden
Mice
Authors: Westerterp Marit , van der Hoogt Caroline C. , de Haan Willeke , Offerman Erik H. , Dallinga-Thie Geesje M. , Jukema J. Wouter , Havekes Louis M. , Rensen Patrick C.N.
Published: September 2006

Objective—

The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in
APOE*3-Leiden
(
E3L
) mice with a humanized lipoprotein profile.

Methods and Results—

E3L
mice were crossbred with human
CETP
transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (+43%;
P
<0.05). To evaluate the effects of CETP on the development of atherosclerosis, mice were fed a Western-type diet containing 0.25% cholesterol, leading to 4.3-fold elevated TC levels in both
E3L
and
CETP.E3L
mice (
P
<0.01). On both diets, CETP expression shifted the distribution of cholesterol from high-density lipoprotein (HDL) toward very-low-density lipoprotein (VLDL)/low-density lipoprotein (LDL). Moreover, plasma of
CETP.E3L
mice had reduced capacity (−39%;
P
<0.05) to induce SR-BI–mediated cholesterol efflux from Fu5AH cells than plasma of
E3L
mice. After 19 weeks on the Western-type diet,
CETP.E3L
mice showed a 7.0-fold increased atherosclerotic lesion area in the aortic root compared with
E3L
mice (
P
<0.0001).

Conclusions—

CETP expression in
E3L
mice shifts the distribution of cholesterol from HDL to VLDL/LDL, reduces plasma-mediated SR-BI–dependent cholesterol efflux, and represents a clear pro-atherogenic factor in
E3L
mice. We anticipate that the
CETP.E3L
mouse will be a valuable model for the preclinical evaluation of HDL-raising interventions on atherosclerosis development.
Reduced Cardiac L-Type Ca
2+
Current in Ca
v
β
2
−/−
Embryos Impairs Cardiac Development and Contraction With Secondary Defects in Vascular Maturation
Authors: Weissgerber Petra , Held Brigitte , Bloch Wilhelm , Kaestner Lars , Chien Kenneth R. , Fleischmann Bernd K. , Lipp Peter , Flockerzi Veit , Freichel Marc
Published: September 2006

Cardiac myocyte contraction depends on transmembrane L-type Ca
2+
currents and the ensuing release of Ca
2+
from the sarcoplasmic reticulum. Here we show that these L-type Ca
2+
currents are essential for cardiac pump function in the mouse at developmental stages where the functional significance of the heart becomes imperative to blood flow and to the continuing growth and survival of the embryo. Disruption of the Ca
v
β
2
gene, which encodes for the predominant ancillary β subunit of cardiac Ca
2+
channels, resulted in diminished L-type Ca
2+
currents in cardiomyocytes of embryonic day 9.5 (E9.5). This led to a functionally compromised heart, causing defective remodeling of intra- and extraembryonic blood vessels and embryonic death following E10.5. The defects in vascular remodeling were also observed when the Ca
v
β
2
gene was selectively targeted in cardiomyocytes, demonstrating that they are secondary to cardiac failure rather than a result of the lack of Ca
v
β
2
proteins in the vasculature. Partial rescue of the Ca
2+
channel currents by a Ca
2+
channel agonist significantly postponed embryonic death in Ca
v
β
2
−/−
mice. Taken together, these data strongly support the essential role of L-type Ca
2+
channel activity in cardiomyocytes for normal heart development and function and that this is a prerequisite for proper maturation of the vasculature.
Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations
Authors: Picht Eckard , DeSantiago Jaime , Blatter Lothar A. , Bers Donald M.
Published: September 2006

Cardiac alternans are thought to be a precursor to life-threatening arrhythmias. Previous studies suggested that alterations in sarcoplasmic reticulum (SR) Ca
2+
content are either causative or not associated with myocyte Ca
2+
alternans. However, those studies used indirect measures of SR Ca
2+
. Here we used direct continuous measurement of intra-SR free [Ca
2+
] ([Ca
2+
]
SR
) (using Fluo5N) during frequency-dependent Ca
2+
alternans in rabbit ventricular myocytes. We tested the hypothesis that alternating [Ca
2+
]
SR
is required for Ca
2+
alternans. Amplitudes of [Ca
2+
]
SR
depletions alternated in phase with cytosolic Ca
2+
transients and contractions. Some cells showed clear alternation in diastolic [Ca
2+
]
SR
during alternans, with higher [Ca
2+
]
SR
before the larger SR Ca
2+
releases. However, the extent of SR Ca
2+
release during the small beats was smaller than expected for the modest decrease in [Ca
2+
]
SR
. In other cells, clear Ca
2+
alternans was observed without alternations in diastolic [Ca
2+
]
SR
. Additionally, alternating cells were observed, in which diastolic [Ca
2+
]
SR
fluctuations occurred interspersed by depletions in which the amplitude was unrelated to the preceding diastolic [Ca
2+
]
SR
. In all forms of alternans, the SR Ca
2+
release rate was higher during large depletions than during small depletions. Although [Ca
2+
]
SR
exerts major influence on SR Ca
2+
release, alternations in [Ca
2+
]
SR
are not required for Ca
2+
alternans to occur. Rather, it seems likely that some other factor, such as ryanodine receptor availability after a prior beat (eg, recovery from inactivation), is of greater importance in initiating frequency-induced Ca
2+
alternans. However, once such a weak SR Ca
2+
release occurs, it can result in increased [Ca
2+
]
SR
and further enhance SR Ca
2+
release at the next beat. In this way, diastolic [Ca
2+
]
SR
alternans can enhance frequency-induced Ca
2+
alternans, even if they initiate by other means.
Maternal Immunization Programs Postnatal Immune Responses and Reduces Atherosclerosis in Offspring
Authors: Yamashita Tomoya , Freigang Stefan , Eberle Claudia , Pattison Jennifer , Gupta Sachin , Napoli Claudio , Palinski Wulf
Published: September 2006

Maternal hypercholesterolemia during pregnancy increases offspring susceptibility to atherosclerosis by an oxidation-dependent mechanism. The present studies investigated whether maternal immunization with oxidized LDL (OxLDL) before pregnancy protects the fetus from atherogenic in utero programming by maternal hypercholesterolemia. Maternal immunization of NZW rabbits and LDL receptor–deficient mice indeed reduced atherosclerosis in adult offspring by up to 56%, but the protective effect could not be attributed to a reduction of fetal exposure to hypercholesterolemia alone, and even nonspecific immune stimulation with adjuvant only provided some protection. Unexpectedly, offspring of immunized mothers developed increased IgM antibodies to selective OxLDL epitopes and increased IgM-LDL immune complexes, compared with offspring of nonimmunized controls. Even naïve offspring of OxLDL-immunized mothers never exposed to postnatal hypercholesterolemia responded to a one-time OxLDL and KLH challenge with greater OxLDL-specific IgM responses, increased OxLDL-specific IgM-secreting B cells, and more IgM-LDL immune complexes. In contrast, maternal immunization with KLH, a T cell–dependent nonmammalian antigen, did not influence postnatal immune responses. Effects of maternal OxLDL-immunization on offspring B cells and selective antibodies were independent of transplacental passage of maternal immunoglobulins. Results show that maternal immunization with antigens prevalent in atherosclerotic lesions reduces atherogenesis in their offspring by mechanisms that include, but are not limited to, reduced fetal exposure to maternal hypercholesterolemia and lipid peroxidation. More importantly, they demonstrate in principle that maternal adaptive immunity to selective antigens influences postnatal B cell and antibody responses in offspring, and that modulation of in utero immune programming may influence immune-modulated diseases later in life.
Tissue-Specific Induction of Intestinal ABCA1 Expression With a Liver X Receptor Agonist Raises Plasma HDL Cholesterol Levels
Authors: Brunham Liam R. , Kruit Janine K. , Pape Terry D. , Parks John S. , Kuipers Folkert , Hayden Michael R.
Published: September 2006

ABCA1 controls the rate-limiting step in HDL particle formation and is therefore an attractive molecular target for raising HDL levels and protecting against atherosclerosis. Intestinal ABCA1 significantly and independently contributes to plasma HDL cholesterol levels in mice, suggesting that induction of intestinal ABCA1 expression may raise plasma HDL cholesterol levels. We evaluated the ability of a synthetic Liver X Receptor (LXR) agonist, GW3965, to raise plasma HDL cholesterol levels in control mice and mice with liver- or intestinal-specific deletion of the
Abca1
gene. Oral treatment with GW3965 increased the expression of ABCA1 by ≈6-fold (
P
=0.004) as well as other LXR target genes in the intestines of mice, with no change in the hepatic expression of these genes. This resulted in a significant ≈48% elevation of plasma HDL cholesterol levels in wild-type mice (
P
<0.01) with no change in plasma triglycerides. A similar increase in HDL cholesterol was observed in mice lacking hepatic ABCA1, indicating that the increase in plasma HDL cholesterol was independent of hepatic ABCA1. This effect was completely abrogated in mice lacking intestinal ABCA1. These data indicate that intestinal ABCA1 may be an attractive therapeutic target for raising HDL levels while avoiding the hepatic lipogenesis and hypertriglyceridemia typical of systemic LXR activation.
Feasibility of Acute Clinical Trials During Aerial Interhospital Transfer
Authors: Leira Enrique C. , Lamb Diane L. , Nugent Andrew S. , Ahmed Azeemuddin , Grimsman Karla J. , Clarke William R. , Adams Harold P.
Published: September 2006

Background and Purpose—

In rural America, patients are often first seen at a small community hospital and then transferred to a tertiary care center by helicopter for further care. If acute clinical research were feasible during the aerial interhospital transport, more patients might be enrolled in trials at a critical earlier stage.

Methods—

Prospective data were collected for all aerial transfers of a university-based helicopter service from April 2005 to January 2006. Flight nurses were educated about stroke research and offered certification and participation. Data collected included patient characteristics and the availability of relatives to provide surrogate consent.

Results—

All 12 flight nurses completed the institutional review board certification requirements and collected data on 215 transfers. Sixty-one patients had acute stroke or myocardial events (MIs). The median time from symptom onset to helicopter arrival at an outside hospital was 213 minutes (range, 90 to 2135) for ischemic stroke (n=12), 186 (45 to 1332) for intracranial hemorrhage (n=28), and 157 (47 to 1044) for MI (n=21). A relative was available in >74% of those transfers. A trial with a 4-hour window would permit enrollment of 67% of the ischemic strokes, 82% of intracranial hemorrhage cases, and 76% of MI patients.

Conclusions—

Clinical trials are feasible during aerial interhospital transport of patients. Flight nurses became successful investigators in clinical research and were exposed to potentially eligible patients with the ability to consent either directly or through surrogates. This approach could improve current clinical trial recruitment in rural areas, as well as permit testing of inflight ancillary interventions to improve outcome during patient transport.
Long-Term Cognitive Transitions, Rates of Cognitive Change, and Predictors of Incident Dementia in a Population-Based First-Ever Stroke Cohort
Authors: Srikanth Velandai K. , Quinn Stephen J. , Donnan Geoffrey A. , Saling Michael M. , Thrift Amanda G.
Published: September 2006

Background and Purpose—

There are few data on long-term cognitive outcomes after first-ever stroke. We aimed to study long-term cognitive transitions, rates of cognitive change, and factors associated with incident dementia and cognitive impairment–no dementia (CIND) 2 years after first-ever stroke.

Methods—

A population-based cohort of incident first-ever stroke cases (n=99; mean age, 69.9 years) and an age- and sex-matched comparison group (nonstrokes, n=99) were followed up for 2 years by 3 serial examinations. Rates of cognitive change were compared by repeated-measures analyses. Factors associated with incident dementia and CIND at 2 years were determined by multinomial logistic regression.

Results—

Significant stroke×time interactions were present for all cognitive domains, with stroke cases showing a greater rate of decline compared with nonstrokes. Stroke recurrence during follow-up was responsible for significantly greater global decline. Strokes with recurrence (
P
=0.02), age (
P
=0.004), and baseline cognitive impairment (
P
<0.001) were independently associated with incident dementia at 2 years. Strokes without recurrence (
P
=0.008), age (
P
=0.001), and baseline cognitive impairment (
P
<0.001) were independently associated with CIND at 2 years.

Conclusions—

Recurrent stroke contributes importantly to global cognitive decline after a first-ever stroke. Secondary stroke prevention will be important in ameliorating dementia related to stroke. Mechanisms underlying the progression of early cognitive impairment to dementia in stroke patients need further investigation.
Long-Term Changes of Functional MRI–Based Brain Function, Behavioral Status, and Histopathology After Transient Focal Cerebral Ischemia in Rats
Authors: Sicard Kenneth M. , Henninger Nils , Fisher Marc , Duong Timothy Q. , Ferris Craig F.
Published: September 2006

Background and Purpose—

The relation between recovery of brain function and neurological status after clinical and experimental cerebral ischemia is incompletely characterized. We assessed the evolution of ischemic injury, behavioral status, and brain activity at acute to chronic periods after transient middle cerebral artery occlusion (tMCAO) in rats.

Methods—

Male Sprague-Dawley rats were subjected to 20-minute tMCAO (n=10) or sham operation (n=10). Sensorimotor behavioral testing and multimodal (diffusion, perfusion, T2, and functional) MRI, as well as postmortem hematoxylin-eosin staining, were performed before and up to 21 days after tMCAO. MRI and histological parameters were evaluated in 5 regions of interest within the sensorimotor network. Diffusion, perfusion, and T2 lesion volumes were calculated according to previously established viability thresholds.

Results—

Diffusion and perfusion lesions were present during occlusion but disappeared completely and permanently within 30 minutes after reperfusion, with no T2 lesions seen. Functional MRI and behavioral deficits did not normalize until 1 and 21 days after tMCAO, respectively. Histology demonstrated selective neuronal cell death at 7 and 21 days after reperfusion.

Conclusions—

Twenty-minute tMCAO produced distinct changes on multimodal MRI, histology, and behavioral parameters acutely and chronically. Normal findings on MRI after transient ischemia may not indicate normal tissue status, as behavioral and histological anomalies remain. Behavioral dysfunction persisting long after the recovery of MRI parameters may relate to the subtle neuronal damage seen on histology. Together, these results may help explain unremitting neurological deficits in stroke or transient ischemic attack patients with normal MRI findings.
Safety of Cerebral Digital Subtraction Angiography in Children
Authors: Burger Ingrid M. , Murphy Kieran J. , Jordan Lori C. , Tamargo Rafael J. , Gailloud Philippe
Published: September 2006

Background and Purpose—

Catheter-based cerebral angiography remains an important diagnostic tool in the pediatric population, particularly considering the currently growing interest in diagnosing and treating cerebrovascular disorders in children. There are no recent estimates of the complication rate associated with modern diagnostic digital subtraction angiography (DSA) in the pediatric population. The purpose of this study was to estimate the rate of complications occurring during cerebral angiography in children.

Methods—

Data from 241 consecutive pediatric cerebral angiograms performed at a single institution were entered into an institutional review board–approved database. Information on patient demographics, DSA indication, neurovascular diagnosis, and intra procedural and postprocedural complications was collected.

Results—

Our population included 115 boys and 90 girls, with age ranging from 1 week to 18 years (mean±SD, 12±5 years). All angiograms were technically successful. No intraprocedural complication was noted; in particular, there was no occurrence of iatrogenic vessel injury (dissection) and no transient or permanent neurological deficit secondary to a thromboembolic event. One child with a complex dural arteriovenous fistula experienced a fatal intracranial rehemorrhage secondary to a posterior fossa varix rupture 3 hours after completion of an uneventful diagnostic angiogram. The rates of intraprocedural and postprocedural complications were therefore 0.0% (95% CI, 0.0% to 1.4%) and 0.4% (95% CI, 0.012% to 2.29%), respectively.

Conclusions—

The rate of immediate complications occurring during diagnostic cerebral angiography in children is very low. No intraprocedural complication was documented in the reported series. DSA performed by experienced angiographers is a safe procedure that can provide critical diagnostic information.
Effects of Cerebral Ischemia on Evoked Cerebral Blood Oxygenation Responses and BOLD Contrast Functional MRI in Stroke Patients
Authors: Murata Yoshihiro , Sakatani Kaoru , Hoshino Tatsuya , Fujiwara Norio , Kano Tsuneo , Nakamura Shin , Katayama Yoichi
Published: September 2006

Background and Purpose—

To evaluate the mechanisms of failure of blood oxygenation level–dependent (BOLD) imaging in stroke, we compared the evoked cerebral blood oxygenation (CBO) responses and activation volumes (AVs) of BOLD functional MRI (fMRI) in chronic stroke patients with moderate and severe cerebral ischemia.

Methods—

We measured the evoked CBO responses in the primary sensorimotor cortex (PSMC) by means of near-infrared spectroscopy during contralateral motor tasks. We compared the AV of BOLD-functional MRI in the PSMC on the nonlesion and lesion sides. Single-photon emission computed tomography was used to classify ischemic status as moderate (slight reduction of regional cerebral blood flow and cerebrovascular reserve capacity [CVRC]) or severe (marked reduction of regional cerebral blood flow and CVRC; ie, misery perfusion).

Results—

In age-matched controls, deoxyhemoglobin concentration decreased with concomitant increases in oxyhemoglobin and total hemoglobin concentrations during activation. The PSMC on the nonlesion side exhibited a normal CBO response pattern. On the lesion side, moderate cerebral ischemia did not affect the CBO response pattern, but severe cerebral ischemia caused an increase of deoxyhemoglobin during the task, associated with increases of oxyhemoglobin and total hemoglobin. Moderate cerebral ischemia induced only a slight reduction of the AV on the lesion side; however, severe cerebral ischemia markedly reduced the AV on the lesion side. The BOLD signal did not change in some areas of the PSMC on the lesion side in severe cerebral ischemia, whereas it tended to decrease in other areas during the tasks.

Conclusions—

Misery perfusion caused a marked reduction of the AV on BOLD imaging, associated with an increase of deoxyhemoglobin concentration during activation. BOLD-fMRI investigations of stroke patients should be performed while giving consideration to baseline circulatory status. Functional near-infrared spectroscopy could be an alternative means to assess the CVRC.
Stroke Among Patients With Dizziness, Vertigo, and Imbalance in the Emergency Department
Authors: Kerber Kevin A. , Brown Devin L. , Lisabeth Lynda D. , Smith Melinda A. , Morgenstern Lewis B.
Published: September 2006

Background and Purpose—

Dizziness, vertigo, and imbalance are common presenting symptoms in the emergency department. Stroke is a leading concern even when these symptoms occur in isolation. The objective of the present study was to determine the “real-world” proportion of stroke among patients presenting to the emergency department with these dizziness symptoms (DS).

Methods—

From a population-based study, patients >44 years of age presenting with DS to the emergency department, or directly admitted to the hospital, were identified. Demographics, the frequency of new cerebrovascular events, and the frequency of isolated DS (ie DS with no other stroke screening term or accompanying neurologic signs or symptoms) were assessed. Multivariable logistic regression was used to evaluate the association of age, gender, ethnicity, and isolated DS with stroke/transient ischemic attack (TIA). The association of the presenting symptoms with stroke/TIA was also assessed.

Results—

Stroke/TIA was diagnosed in 3.2% (53 of 1666) of all patients with DS. Only 0.7% (9 of 1297) of those with isolated DS had a stroke/TIA. Patients with stroke/TIA were slightly older than those without stroke/TIA (69.3±11.7 vs 65.3±12.9,
P
=0.02). Male gender was associated with stroke/TIA, whereas isolated DS was negatively associated with stroke/TIA. Patients with imbalance (dizziness as referent) were more likely to have stroke/TIA.

Conclusions—

The proportion of cerebrovascular events in patients presenting with dizziness, vertigo, or imbalance is very low. Isolated dizziness, vertigo, or imbalance strongly predicts a noncerebrovascular cause. The symptom of imbalance is a predictor of stroke/TIA.
Adeno-Associated Viral Vector-Mediated Hypoxia-Inducible Vascular Endothelial Growth Factor Gene Expression Attenuates Ischemic Brain Injury After Focal Cerebral Ischemia in Mice
Authors: Shen Fanxia , Su Hua , Fan Yongfeng , Chen Yongmei , Zhu Yiqian , Liu Weizhong , Young William L. , Yang Guo-Yuan
Published: September 2006

Background and Purpose—

Exogenous delivery of vascular endothelial growth factor gene (VEGF) may provide a useful approach to the treatment of brain ischemia. We investigated the use of a hypoxia-responsive element to control VEGF expression given for neuroprotection.

Methods—

Three groups (n=36) of mice received AAVH9-VEGF, AAVH9-lacZ, or saline injection. Five days after gene transfer, the mice underwent 45 minutes of transient middle cerebral artery occlusion (tMCAO) followed by 1 to 7 days of reperfusion. Infarct volume was determined using cresyl violet staining; neuronal injury was examined using TUNEL, cleaved caspase-3, and fluoro-Jade B staining.

Results—

Hypoxia-inducible factor-1 (HIF-1) was overexpressed after tMCAO in the ischemic hemisphere in the brain. Expression of lacZ, mediated by AAV-lacZ, was seen before and after tMCAO; however, AAVH9-lacZ-mediated lacZ expression was detected only after tMCAO. Infarct volume was smaller in the AAVH9-VEGF-transduced group compared with AAVH9-lacZ and saline groups (55% reduction,
P
<0.05) with reduced TUNEL (29±5% and 30±7% versus 12±3%,
P
<0.05), cleaved caspase-3 (20±3% and 21±5% versus 13±4%,
P
<0.05) and fluoro-Jade B (23±3% and 24±5% versus 12±5%,
P
<0.05) -positive neurons, respectively.

Conclusion—

Exogenous expression of VEGF through AAVH9-VEGF gene transfer 5 days before the onset of ischemia provides neuroprotection. Hypoxia-responsive element is a viable strategy of restricting VEGF expression to areas of ischemia to minimize adverse effects of therapy on adjacent normal parenchyma.
Impact of Stroke on Health-Related Quality of Life in the Noninstitutionalized Population in the United States
Authors: Xie Jipan , Wu Eric Q. , Zheng Zhi-Jie , Croft Janet B. , Greenlund Kurt J. , Mensah George A. , Labarthe Darwin R.
Published: September 2006

Background and Purpose—

Stroke is a major cause of long-term disability in the United States. This study examined the national impact of stroke on health-related quality of life (HRQoL) and disparities in HRQoL across different demographic groups.

Methods—

Combined 2000 and 2002 Medical Expenditure Panel Survey data were used, which include quality-of-life measures based on the short-form generic measures (SF-12) and the EuroQol Group measures (EQ-5D index and EQ VAS) for 39 680 adults aged >18 years. Stratified analysis and ordinary least square regressions were used to compare HRQoL scores between stroke and nonstroke populations.

Results—

The study included 1040 noninstitutionalized stroke survivors. After adjustment for sociodemographics, risk factors, and comorbidities, stroke survivors had statistically significantly lower mean scores for mental health (−4.1%), physical health (−7.9%), health utility (−6.9%), and self-rated health (−7.2%) (all
P
<0.01). In general, stroke did not affect differences in HRQoL among age or gender groups. However, racial and ethnic disparities in HRQoL were greater among stroke survivors than nonstroke individuals, particularly in health utility scores for black vs white participants (−0.06 in stroke survivors and −0.02 in the nonstroke population,
P
<0.01) and Hispanic versus non-Hispanic participants (−0.11 in stroke survivors and −0.01 in the nonstroke population).

Conclusions—

Stroke significantly impairs HRQoL in the United States. The findings suggest that racial and ethnic disparities in HRQoL among stroke survivors are more pronounced than in the nonstroke population. The burden of nonfatal stroke, especially among racial and ethnic minorities, should be recognized more widely.
Should Spectrophotometry Be Used to Identify Xanthochromia in the Cerebrospinal Fluid of Alert Patients Suspected of Having Subarachnoid Hemorrhage?
Authors: Perry Jeffrey J. , Sivilotti Marco L.A. , Stiell Ian G. , Wells George A. , Raymond Jenny , Mortensen Melodie , Symington Cheryl
Published: September 2006

Background and Purpose—

The absence of xanthochromia in the cerebrospinal fluid (CSF) is often used to exclude subarachnoid hemorrhage (SAH). Authorities advocate spectrophotometry to measure xanthochromia, but most North American hospitals use visual inspection. We studied the diagnostic accuracy of spectrophotometry for SAH, and its potential impact on current practice.

Methods—

This was a prospective cohort study comparing the diagnostic accuracy of tests. The study was set in 3 university-affiliated tertiary care emergency departments. We enrolled consecutive neurologically intact adults with nontraumatic headache undergoing lumbar puncture (LP) to rule out SAH. CSF was centrifuged, frozen and analyzed later in batch. SAH was defined by (1) subarachnoid blood on CT, (2) >5×10
6
red blood cells/L in the final CSF tube and positive angiography, or (3) visible xanthochromia in CSF and positive angiography. All subjects lacking a normal CT and LP were telephoned at 30 days.

Results—

We enrolled 220 patients (mean age 42±16 years; CT rate 87.7%; angiography rate 5.9%). Two SAHs were identified: 1 with red blood cells without xanthochromia in the CSF and 1 with visibly xanthochromic CSF. The specificity of xanthochromia was 97% (95% CI: 92% to 99%) for visual inspection, but as low as 29% (95% CI: 23% to 35%) for 2 of the spectrophotometric definitions. Introducing spectrophotometry could lead to angiography in as many as 11% to 71% of patients undergoing LP.

Conclusions—

Spectrophotometric definitions of xanthochromia have only moderate to low specificity for SAH. Using spectrophotometry could increase angiography rates, thereby identifying more incidental aneurysms, increasing patient anxiety and exposing patients to unnecessary surgical or investigational complications without benefit.
Discontinuation of Statin Treatment in Stroke Patients
Authors: Endres Matthias , Laufs Ulrich
Published: September 2006

Background and Purpose—

Statins reduce the risk for myocardial infarctions and stroke which may in part depend on cholesterol-independent (pleiotropic) vasoprotective effects. Here, we review evidence to suggest that the abrupt discontinuation of statin medication exerts negative vascular effects in patients with acute vascular events.

Summary of Review—

It is increasingly recognized that statins (HMG-CoA reductase inhibitors) exert rapid cholesterol-independent effects. Cessation of statin treatment confers overshoot activation of heterotrimeric G-proteins Rho and Rac causing production of reactive oxygen species and suppression of NO bioavailability. In humans, discontinuation of statin therapy leads to a proinflammatory, prothrombotic state with impaired endothelium function. In patients with acute coronary syndromes, abrupt discontinuation of statin therapy significantly increases morbidity and mortality, whereas in stable vascular patients discontinuation may be safe. Recent prospective data indicated that the cessation of statin medication in acute ischemic stroke patients confers a significantly higher likelihood of early neurological deterioration and poor outcome.

Conclusions—

We propose that in all acute ischemic stroke patients chronically treated with statins before the event, treatment should be continued and the patient should receive medication at the day of the stroke.
Transesophageal Echocardiography Is Superior to Transthoracic Echocardiography in Management of Patients of Any Age With Transient Ischemic Attack or Stroke
Authors: de Bruijn Sebastiaan F.T.M. , Agema Willem R.P. , Lammers Gert Jan , van der Wall Ernst E. , Wolterbeek Ron , Holman Eduard R. , Bollen Edward L.E.M. , Bax Jeroen J.
Published: September 2006

Background and Purpose—

The merits of transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) in the management of transient ischemic attack (TIA) and stroke patients remains matter of debate.

Methods—

Two hundred and thirty-one consecutive patients with a recent TIA or stroke for which no definite cause and indication for anticoagulation was assessed after standardized work-up underwent TTE and TEE. Echocardiographic findings were categorized into minor and major risk factors.

Results—

A potential cardiac source of embolism was detected in 55% (127/ 231) of the patients by echocardiography, in 39% (90/231) only identified on TEE. Major risk factors, with an absolute indication for oral anticoagulation, were detected in 20% (46/231) of the patients, in 16% (38/231) of all patients identified on TEE only. A thrombus in the left atrial appendage was the most common major risk factor (38 patients, 16%). The presence of major risk factors was independent of age (χ
2
=1.48;
P
=0.224). The difference in proportions of cardiac sources detected in favor of TEE was highly significant in both patients ≤45 years of age (10/39,
P
=0.002) and in those >45 years of age (80/192;
P
<0.004).

Conclusions—

TEE proved superior to TTE for identification of a cardiac embolic source in patients with TIA or stroke without pre-existent indication or contraindication for anticoagulation. In patients with normal TTE, a cardiac source of embolism was detected by TEE in ≈40% of patients, independent of age. More than 1 of 8 patients of any age with normal TTE revealed a major cardiac risk factor on TEE, in whom anticoagulation is warranted.
Increased Balloon-Induced Inflammation, Proliferation, and Neointima Formation in Apolipoprotein E (
ApoE
) Knockout Mice
Authors: Matter Christian M. , Ma Liming , von Lukowicz Tobias , Meier Patricia , Lohmann Christine , Zhang Dongming , Kilic Ülkan , Hofmann Eugen , Ha Suk-Woo , Hersberger Martin , Hermann Dirk M. , Lüscher Thomas F.
Published: September 2006

Background and Purpose—

The pathophysiology of vascular lesions after balloon angioplasty remains poorly understood. A major limitation of most experimental studies in this regard is that injury was assessed in healthy arteries. Our aim was to study the effects of hypercholesterolemia in a mouse vascular injury model that mimics human balloon angioplasty.

Methods—

Carotid balloon distension was performed in wild-type (WT) mice on a normal diet (ND), in apolipoprotein E–deficient (
ApoE
−/−
) mice on ND and in
ApoE
−/−
mice fed a high cholesterol diet (CD).

Results—

Medial cell death (TUNEL) was elevated in all mice at 1 hour and 1 day after angioplasty without differences between the groups. We found enhanced intimal inflammation (%CD45-positive cells) and vascular cell adhesion molecule-1 expression at 7 days (
P
<0.05; n≥4) as well as increased proliferation rates (BrdU-index) in
ApoE
−/−
CD at 7 and 28 days postinjury (
P
<0.05; n≥5). Four weeks after injury, these events led to enhanced neointima in
ApoE
−/−
CD compared with WT ND mice (intima/media,
P
<0.001; n≥8). The amount of lesion formation paralleled the incremental increase in total plasma cholesterol in WT ND,
ApoE
−/−
ND and
ApoE
−/−
CD (
P
<0.01).

Conclusions—

Carotid balloon distension injury in
ApoE
−/−
mice on CD induced enhanced inflammation and proliferation leading to increased neointima. Further applications of this microballoon catheter in genetically modified mice will provide opportunities to elucidate molecular mechanisms of vascular lesion formation in a model that reflects clinical balloon angioplasty. This know-how may pave the way to catheter-based interventions of human microvessels in the peripheral or cerebral circulation.
On the Analysis and Interpretation of Outcome Measures in Stroke Clinical Trials
Authors: Koziol James A. , Feng Anne C.
Published: September 2006

Background and Purpose—

A variety of primary end points have been used in acute stroke trials. We focus on the modified Rankin Scale, a reliable and valid ordinal outcome measure that assesses disability on a 7-point scale.

Methods—

We provide an abbreviated discussion of analytical methods for ordinal scales, and related effect size measures; we illustrate these methods and their interpretation with outcome data from the SAINT I study of NXY-059 in acute ischemic stroke.

Results—

The nonparametric Mann-Whitney statistic provides a straightforward method for analysis of the modified Rankin Scale, and incorporates associated measures of effect size. These measures are directly related to the concepts of Number Needed to Treat and Number Needed to Harm.

Conclusions—

Our re-examination of the outcome data from the SAINT I study provides little evidence for the purported efficacy of NXY-059. More broadly, analysis and interpretation of ordinal outcome scales based on ascribed numerical values to the steps of the scale should be done cautiously. Statistical treatment of multiple primary outcome measures in acute stroke clinical trials should be established before analysis. Lastly, conflating statistical and clinical significance should be avoided.
Plasma Fibrinogen Concentrations and Risk of Stroke and Its Subtypes Among Japanese Men and Women
Authors: Sato Shinichi , Iso Hiroyasu , Noda Hiroyuki , Kitamura Akihiko , Imano Hironori , Kiyama Masahiko , Ohira Tetsuya , Okada Takeo , Yao Masayuki , Tanigawa Takeshi , Yamagishi Kazumasa , Nakamura Masakazu , Naito Yoshihiko , Shimamoto Takashi
Published: September 2006

Background and Purpose—

We aimed to examine the impact of fibrinogen concentrations on the incidence of stroke.

Methods—

We examined the association between fibrinogen and risk of total stroke and stroke subtypes in an 11-year prospective study of 4608 men and 7589 women aged 40 to 79 years with no history of stroke and/or coronary heart disease. The analysis was repeated, stratified by smoking status, to examine whether the association between fibrinogen and stroke was modified by smoking.

Results—

There were 317 incident total strokes comprising 103 hemorrhagic strokes (70 intraparenchymal hemorrhages [22.1% of strokes], 33 subarachnoid hemorrhages [10.4%]), 206 ischemic strokes (65.0%), and 8 strokes of undetermined type (2.5%). The multivariable hazard ratio (95% CI) for the highest versus lowest fibrinogen quartiles after adjustment for age, sex, area, and known cardiovascular risk factors was 2.5 (1.3 to 5.0),
P
<0.01, for hemorrhagic stroke and 3.2 (1.4 to 7.4),
P
<0.01, for intraparenchymal hemorrhage. There was no positive association of fibrinogen with risk of ischemic stroke or subarachnoid hemorrhage. Among never-smokers, the multivariable hazard ratio (95% CI) for the highest versus lowest fibrinogen quartiles was 3.5 (1.3 to 9.3),
P
=0.01, for hemorrhagic stroke and 4.4 (1.3 to 15.2),
P
=0.02, for intraparenchymal hemorrhage.

Conclusions—

High plasma fibrinogen concentration can be a predictor for risk of intraparenchymal hemorrhage.