bluuebunny/crossref_metadata_2025 huggingface dataset:
Deficiency of Adrenomedullin Induces Insulin Resistance by Increasing Oxidative Stress
Authors: Shimosawa Tatsuo , Ogihara Takehide , Matsui Hiromitsu , Asano Tomoichiro , Ando Katsuyuki , Fujita Toshiro
Published: May 2003

Hypertension, insulin resistance, and obesity are common age-related metabolic disorders that are often associated with increased oxidative stress and the resultant vascular damage. Underlying mechanisms have been suggested, and age-related overproduction of oxidative stress is one possible candidate. Since we recently found a vasoactive peptide, adrenomedullin, to be an endogenous antioxidant that potently inhibits oxidative stress–induced vascular damage, in the current study we evaluated oxidative stress–induced changes in aged mice. Insulin sensitivities in young and aged adrenomedullin-deficient mice were measured by means of the hyperinsulinemic-euglycemic clamp method; insulin resistance was apparent in aged adrenomedullin-deficient mice with increased urinary excretion of 8-iso-prostaglandin F
2α
, a marker of oxidative stress, but not in young adrenomedullin-deficient mice. Concomitantly, only aged adrenomedullin-deficient mice not only showed increased production of muscular reactive oxygen species, as demonstrated by the electron spin resonance method, but also had significantly decreased insulin-stimulated glucose uptake into the soleus muscle associated with impairment of insulin signals such as insulin receptor substrate-1,2 and phosphatidylinositol-3 kinase activities. In turn, these abnormalities could be nearly reversed by either treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-
N
-oxyl, a membrane-permeable superoxide dismutase mimetic, or adrenomedullin supplementation. Evidence presented in this report suggests that age-related accumulation of oxidative stress is involved in blood pressure regulation and insulin resistance in aged adrenomedullin-deficient mice, and adrenomedullin is thus an endogenous substance counteracting oxidative stress–induced insulin resistance associated with aging.
Capillary Pressure in Subjects With Type 2 Diabetes and Hypertension and the Effect of Antihypertensive Therapy
Authors: Fegan P. Gerard , Tooke John E. , Gooding Kim M. , Tullett Jayne M. , MacLeod Kenneth M. , Shore Angela C.
Published: May 2003

Raised capillary pressure has been implicated in the formation of diabetic microangiopathy in type I diabetes, in which it is elevated in those with the earliest signs of diabetic kidney disease but remains normal in those without complications. In subjects with type 2 diabetes without complications, capillary pressure is normal, although alterations in the pressure waveforms suggested enhanced wave reflections. The nature of skin capillary pressure in subjects with type 2 diabetes and hypertension remains to be elucidated, as does the effect of blood pressure–lowering therapy on capillary pressure in these subjects. Three studies were performed in well-matched groups. First, capillary pressure was elevated in hypertensive subjects with type 2 diabetes compared with normotensive subjects with type 2 diabetes (20.2 [17.4 to 22.7] mm Hg versus 17.7 [16.1 to 18.9] mm Hg, respectively,
P
<0.03, Mann-Whitney
U
test). Second, no significant difference was detected between hypertensive subjects with type 2 diabetes and hypertensive subjects without type 2 diabetes (19.4 [15.8 to 21.3] mm Hg versus 17.2 [15.1 to 19.8] mm Hg, respectively,
P
=0.5, Mann-Whitney
U
test). Finally, patients with type 2 diabetes were recruited to a case-control study. Seven subjects received blood pressure–lowering therapy and 8 did not. Therapy reduced capillary pressure from 18.2 [15.8 to 20.1] mm Hg to 15.9 [15.4 to 17.0] mm Hg (
P
=0.024 ANOVA), in contrast to the lack of effect of time alone. Mean arterial pressure was reduced from 110 [102 to 115] mm Hg to 105 [101 to 111] mm Hg (
P
=0.006, ANOVA). These findings provide a plausible mechanism by which reducing arterial hypertension may reduce the risk of microangiopathy in type 2 diabetes.
Smooth Muscle α-Actin Gene Requires Two E-Boxes for Proper Expression In Vivo and Is a Target of Class I Basic Helix-Loop-Helix Proteins
Authors: Kumar Meena S. , Hendrix Jennifer A. , Johnson A. Daniel , Owens Gary K.
Published: May 2003

Changes in the differentiated state of smooth muscle cells (SMCs) play a key role in vascular diseases, yet the mechanisms controlling SMC differentiation are still largely undefined. We addressed the role of basic helix-loop-helix (bHLH) proteins in SMC differentiation by first determining the role of two E-box (CAnnTG) motifs, binding sites for bHLH proteins, in the transcriptional regulation of the SMC differentiation marker gene, smooth muscle α-actin (SM α-actin), in vivo. Mutation of one or both E-boxes significantly reduced the expression of a −2560- to 2784-bp SM α-actin promoter/LacZ reporter gene in vivo in transgenic mice. We then determined the potential role of class I bHLH proteins, E12, E47, HEB, and E2-2, in SM α-actin regulation. In cotransfection experiments, E12, HEB, and E2-2 activated the SM α-actin promoter. Activation by HEB and E2-2 was synergistic with serum response factor. Additionally, the dominant-negative/inhibitory HLH proteins, Id2, Id3, and Twist, inhibited both the E12 and serum response factor–induced activations of the SM α-actin promoter. Finally, we demonstrated that E2A proteins (E12/E47) specifically bound the E-box–containing region of the SM α-actin promoter in vivo in the context of intact chromatin in SMCs. Taken together, these results provide the first evidence of E-box–dependent regulation of a SMC differentiation marker gene in vivo in transgenic mice. Moreover, they demonstrate a potential role for class I bHLH factors and their inhibitors, Id and Twist, in SM α-actin regulation and suggest that these factors may play an important role in control of SMC differentiation and phenotypic modulation.
Protein Kinase Cε Interacts With and Inhibits the Permeability Transition Pore in Cardiac Mitochondria
Authors: Baines Christopher P. , Song Chang-Xu , Zheng Yu-Ting , Wang Guang-Wu , Zhang Jun , Wang Ou-Li , Guo Yiru , Bolli Roberto , Cardwell Ernest M. , Ping Peipei
Published: May 2003

Although functional coupling between protein kinase Cε (PKCε) and mitochondria has been implicated in the genesis of cardioprotection, the signal transduction mechanisms that enable this link and the identities of the mitochondrial proteins modulated by PKCε remain unknown. Based on recent evidence that the mitochondrial permeability transition pore may be involved in ischemia/reperfusion injury, we hypothesized that protein-protein interactions between PKCε and mitochondrial pore components may serve as a signaling mechanism to modulate pore function and thus engender cardioprotection. Coimmunoprecipitation and GST-based affinity pull-down from mouse cardiac mitochondria revealed interaction of PKCε with components of the pore, namely voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), and hexokinase II (HKII). VDAC1, ANT1, and HKII were present in the PKCε complex at ≈2%, ≈0.2%, and ≈1% of their total expression, respectively. Moreover, in vitro studies demonstrated that PKCε can directly bind and phosphorylate VDAC1. Incubation of isolated cardiac mitochondria with recombinant PKCε resulted in a significant inhibition of Ca
2+
-induced mitochondrial swelling, an index of pore opening. Furthermore, cardiac-specific expression of active PKCε in mice, which is cardioprotective, greatly increased interaction of PKCε with the pore components and inhibited Ca
2+
-induced pore opening. In contrast, cardiac expression of kinase-inactive PKCε did not affect pore opening. Finally, administration of the pore opener atractyloside significantly attenuated the infarct-sparing effect of PKCε transgenesis. Collectively, these data demonstrate that PKCε forms physical interactions with components of the cardiac mitochondrial pore. This in turn inhibits the pathological function of the pore and contributes to PKCε-induced cardioprotection.
The δ
C
Isoform of CaMKII Is Activated in Cardiac Hypertrophy and Induces Dilated Cardiomyopathy and Heart Failure
Authors: Zhang Tong , Maier Lars S. , Dalton Nancy D. , Miyamoto Shigeki , Ross John , Bers Donald M. , Brown Joan Heller
Published: May 2003

Recent studies have demonstrated that transgenic (TG) expression of either Ca
2+
/calmodulin-dependent protein kinase IV (CaMKIV) or CaMKIIδ
B
, both of which localize to the nucleus, induces cardiac hypertrophy. However, CaMKIV is not present in heart, and cardiomyocytes express not only the nuclear CaMKIIδ
B
but also a cytoplasmic isoform, CaMKIIδ
C
. In the present study, we demonstrate that expression of the δ
C
isoform of CaMKII is selectively increased and its phosphorylation elevated as early as 2 days and continuously for up to 7 days after pressure overload. To determine whether enhanced activity of this cytoplasmic δ
C
isoform of CaMKII can lead to phosphorylation of Ca
2+
regulatory proteins and induce hypertrophy, we generated TG mice that expressed the δ
C
isoform of CaMKII. Immunocytochemical staining demonstrated that the expressed transgene is confined to the cytoplasm of cardiomyocytes isolated from these mice. These mice develop a dilated cardiomyopathy with up to a 65% decrease in fractional shortening and die prematurely. Isolated myocytes are enlarged and exhibit reduced contractility and altered Ca
2+
handling. Phosphorylation of the ryanodine receptor (RyR) at a CaMKII site is increased even before development of heart failure, and CaMKII is found associated with the RyR in immunoprecipitates from the CaMKII TG mice. Phosphorylation of phospholamban is also increased specifically at the CaMKII but not at the PKA phosphorylation site. These findings are the first to demonstrate that CaMKIIδ
C
can mediate phosphorylation of Ca
2+
regulatory proteins in vivo and provide evidence for the involvement of CaMKIIδ
C
activation in the pathogenesis of dilated cardiomyopathy and heart failure.
Protein Kinase A Hyperphosphorylation Increases Basal Current but Decreases β-Adrenergic Responsiveness of the Sarcolemmal Na
+
-Ca
2+
Exchanger in Failing Pig Myocytes
Authors: Wei Shao-kui , Ruknudin Abdul , Hanlon Stephen U. , McCurley John M. , Schulze Dan H. , Haigney Mark C.P.
Published: May 2003

The sodium-calcium exchanger (NCX) protein is the major cardiac calcium extrusion mechanism and is upregulated in heart failure (HF). NCX expression level and functional activity as regulated by β-adrenergic receptor (β-AR) stimulation in swine with and without tachycardia-induced heart failure were studied. The Ni
2+
-sensitive NCX current was measured in myocytes from HF and control animals in the basal state or in the presence of isoproterenol, forskolin, 8-Br-cAMP, okadaic acid, or protein phosphatase type 1. Western blot analysis revealed a significant increase in both the 120-kDa (29%) and 80-kDa (69%) fragments in HF (
P
<0.05 versus control). Despite this modest increase in protein, the basal peak outward NCX current was increased almost 5-fold in HF (
P
<0.05 versus control). Stimulation with isoproterenol, however, increased the control currents to a significantly greater extent than HF (500% increase in control versus 100% increase in HF,
P
<0.01); peak stimulated current was not different in HF and control. This reduction in responsiveness to β-AR stimulation was refractory to forskolin, 8-Br-cAMP, or okadaic acid stimulation. In vitro protein kinase A back-phosphorylation revealed higher phosphorylation capacity of NCX protein in control versus HF, consistent with increased phosphorylation in vivo (hyperphosphorylation) in HF. Protein phosphatase type 1 exposure resulted in a significant reduction (73%) in peak basal current in HF (compared with no significant difference in controls), confirming that the increased basal NCX current in HF is predominately attributable to hyperphosphorylation. NCX expression and activity are thus increased in HF, although β-AR responsiveness is decreased because of NCX hyperphosphorylation.
Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases
Authors: Visse Robert , Nagase Hideaki
Published: May 2003

Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.
Frequency of Thrombolytic Therapy in Patients With Acute Ischemic Stroke and the Risk of In-Hospital Mortality
Authors: Heuschmann Peter U. , Berger Klaus , Misselwitz Bjoern , Hermanek Peter , Leffmann Carsten , Adelmann Michael , Buecker-Nott Hans-Joachim , Rother Joachim , Neundoerfer Bernhard , Kolominsky-Rabas Peter L.
Published: May 2003

Background and Purpose—

There is little information about early outcome after intravenous application of tissue-type plasminogen activator (tPA) for stroke patients treated in community-based settings. We investigated the association between tPA therapy and in-hospital mortality in a pooled analysis of German stroke registers.

Methods—

Ischemic stroke patients admitted to hospitals cooperating within the German Stroke Registers Study Group (ADSR) between January 1, 2000, and December 31, 2000, were analyzed. The ADSR is a network of regional stroke registers, combining data from 104 academic and community hospitals throughout Germany. Patients treated with tPA were matched to patients not receiving tPA on the basis of propensity scores and were analyzed with conditional logistic regression. Analyses were stratified for hospital experience with the administration of tPA.

Results—

A total of 13 440 ischemic stroke patients were included. Of these, 384 patients (3%) were treated with tPA. In-hospital mortality was significantly higher for patients treated with tPA compared with patients not receiving tPA (11.7% versus 4.5%, respectively;
P
<0.0001). After matching for propensity score, overall risk of inpatient death was still increased for patients treated with tPA (odds ratio [OR], 1.7; 95% CI, 1.0 to 2.8). Patients receiving tPA in hospitals that administered ≤5 thrombolytic therapies in 2000 had an increased risk of in-hospital mortality (OR, 3.3; 95% CI, 1.1 to 9.9). No significant influence of tPA use for risk of inpatient death was found in hospitals administering >5 thrombolytic treatments per year (OR, 1.3; 95% CI, 0.8 to 2.4).

Conclusions—

In-hospital mortality of ischemic stroke patients after tPA use varied between hospitals with different experience in tPA treatment in routine clinical practice. Our study suggested that thrombolytic therapy in hospitals with limited experience in its application increase the risk of in-hospital mortality.
Motor Cortex Organization After Stroke Is Related to Side of Stroke and Level of Recovery
Authors: Zemke Anna C. , Heagerty Patrick J. , Lee Christopher , Cramer Steven C.
Published: May 2003

Background and Purpose—

The present study hypothesized that side of stroke and level of recovery influence motor system organization after stroke.

Methods—

Functional MRI was performed on 14 control subjects and 21 patients with chronic stroke during index finger tapping (control subjects, right; patients, recovered side).

Results—

On functional MRI, stroke patients with right arm involvement showed (1) significantly smaller activation in contralateral motor cortexes compared with control subjects; (2) smaller ipsilateral (nonstroke) premotor and larger contralateral (stroke-side) sensorimotor activation compared with patients with left arm involvement, although electromyogram across groups was similar; and (3) 2.7-fold–larger contralateral sensorimotor cortex activation, ventrally, in those with full recovery compared with those with partial recovery, despite similar tapping force, frequency, range of motion, and electromyogram between groups. Supplementary motor area activation was unrelated to level of recovery.

Conclusions—

After stroke that causes mild to moderate initial impairment and mild residual hand weakness, cortical organization varies with side of injury and with final motor status. The findings may have implications for treatment after stroke.
Contribution of 5-Hydroxytryptamine
1B
Receptors and 20-Hydroxyeiscosatetraenoic Acid to Fall in Cerebral Blood Flow After Subarachnoid Hemorrhage
Authors: Cambj-Sapunar Liana , Yu Ming , Harder David R. , Roman Richard J.
Published: May 2003

Background and Purpose—

This study examined the interaction between 5-hydroxytryptamine
1B
(5-HT
1B
) receptors and 20-hydroxyeiscosatetraenoic acid (20-HETE) in contributing to the acute fall in regional cerebral blood flow (rCBF) after subarachnoid hemorrhage (SAH) in rats.

Methods—

The effects of intracisternal injection of 0.3 mL of arterial blood, artificial cerebrospinal fluid, and 5-HT on rCBF and the levels of 20-HETE and 5-HT in cerebrospinal fluid were measured in rats pretreated with vehicle, a 5-HT
1B
receptor antagonist (isamoltane hemifumarate), or an inhibitor of the synthesis of 20-HETE (HET0016). The effects of HET0016 and isamoltane on the vasoconstrictor response and changes in [Ca
2+
]
i
to 5-HT were also studied in middle cerebral arteries and vascular smooth muscle cells isolated from these vessels.

Results—

20-HETE and 5-HT levels in cerebrospinal fluid rose from 172±10 to 629±44 ng/mL and from 6±4 to 1163±200 nmol/mL, respectively, after SAH. rCBF fell by 30% 10 minutes after SAH, and it remained at this level for the next 2 hours. Blockade of 5-HT
1B
receptors prevented the sustained fall in rCBF seen after SAH. Intracisternal injection of 5-HT mimicked SAH by increasing 20-HETE levels in cerebrospinal fluid to 475±94 ng/mL and reducing rCBF by 30%. Blockade of the synthesis of 20-HETE with HET0016 prevented the fall in rCBF produced by 5-HT. Isamoltane and HET0016 reduced the vasoconstrictor response of isolated MCA to 5-HT by >60% and diminished the rise in [Ca
2+
]
i
produced by 5-HT in vascular smooth muscle cells isolated from these arteries.

Conclusions—

These results suggest that the release of 5-HT after SAH activates 5-HT
1B
receptors and the synthesis of 20-HETE and that 20-HETE contributes to the acute fall in rCBF by potentiating the vasoconstrictor response of cerebral vessels to 5-HT.
Chronic Treatment With a Low Dose of Lithium Protects the Brain Against Ischemic Injury by Reducing Apoptotic Death
Authors: Xu Jihong , Culman Juraj , Blume Annegret , Brecht Stephan , Gohlke Peter
Published: May 2003

Background and Purpose—

In vitro and in vivo studies have demonstrated neuroprotective actions of lithium. The present study investigated the effect of a low dose of lithium on infarct volume and neurological outcome as well as on apoptotic and inflammatory processes in rats exposed to focal ischemia.

Methods—

Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes followed by reperfusion. Lithium (1 mmol/kg) was given subcutaneously daily for 14 days before the onset of MCAO and 2 days thereafter. Blood parameters and cerebral blood flow were assessed before, during, and after MCAO. Rats were examined for neurological deficits 24 and 48 hours after MCAO. Two days after MCAO, the brains were removed for immunohistochemical evaluation of caspase-3, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL), activated microglia, and the expression of AP-1 proteins (c-Fos and c-Jun). Infarct volume was assessed by cresyl violet staining.

Results—

Pretreatment with lithium did not alter cerebral blood flow or blood parameters. Neurological deficits were significantly decreased in rats treated with lithium at 24 and 48 hours after ischemia. Infarct volume was reduced in rats treated with lithium at 48 hours after ischemia. Lithium significantly decreased the ischemia-induced caspase-3 immunoreactivity and TUNEL staining as well as the AP-1 protein expression in the penumbra of the ischemic cortex. No changes in activated microglia were observed.

Conclusions—

The present study demonstrates that chronic treatment with lithium at a low dose exhibits neuroprotection in transient focal cerebral ischemia. Antiapoptotic mechanisms are involved in the lithium-induced neuroprotective effects.
Hyperbaric Oxygen Reduces Neuronal Death and Improves Neurological Outcome After Canine Cardiac Arrest
Authors: Rosenthal Robert E. , Silbergleit Robert , Hof Patrick R. , Haywood Yolanda , Fiskum Gary
Published: May 2003

Background and Purpose—

Studies suggest that hyperbaric oxygen (HBO) is neuroprotective after experimental cerebral ischemia, but the mechanism is unknown. This study tested the hypotheses that postischemic HBO affords clinical and histopathological neuroprotection after experimental cardiac arrest and resuscitation (A/R) and that this neuroprotection results from improved cerebral oxygen metabolism after A/R.

Methods—

Anesthetized adult female beagles underwent A/R and randomization to HBO (2.7-atm absolute [ATA] for 60 minutes, 1 hour after A/R) or control (P
o
2
=80 to 100 mm Hg; 1 ATA). Animals underwent neurological deficit scoring (NDS) 23 hours after A/R. After euthanasia at 24 hours, neuronal death (necrotic and apoptotic) in representative animals was determined stereologically in hippocampus and cerebral neocortex. In experiment 2, arterial and sagittal sinus oxygenation and cerebral blood flow (CBF) were measured. Cerebral oxygen extraction ratio (ER
c
), oxygen delivery (D
o
2
c), and metabolic rate for oxygen (CMR
o
2
) were calculated (baseline and 2, 30, 60, 120, 180, 240, 300, and 360 minutes after restoration of spontaneous circulation).

Results—

NDS improved after A/R in HBO animals (HBO, 35±14; controls, 54±15;
P
=0.028). Histopathological examination revealed significantly fewer dying neurons in HBO animals; the magnitude of neuronal injury correlated well with NDS. HBO corrected elevations in ER
c
(peak, 60±14% for controls, 26±4% for HBO) but did not increase D
o
2
c or CMR
o
2
, which decreased ≈50% after A/R in both groups.

Conclusions—

HBO inhibits neuronal death and improves neurological outcome after A/R; the mechanism of HBO neuroprotection is not due to stimulation of oxidative cerebral energy metabolism.
Rapid Cerebral Ischemic Preconditioning in Mice Deficient in Endothelial and Neuronal Nitric Oxide Synthases
Authors: Atochin Dmitriy N. , Clark Jeffrey , Demchenko Ivan T. , Moskowitz Michael A. , Huang Paul L.
Published: May 2003

Background and Purpose—

The purpose of this study was to test the hypothesis that nitric oxide is required for preconditioning in an intact animal model of focal ischemia using neuronal and endothelial nitric oxide synthase (nNOS and eNOS) knockout mice.

Methods—

Cerebral blood flow was measured in wild-type, nNOS knockout, and eNOS knockout mice by hydrogen clearance (absolute) and laser Doppler flowmetry (relative). Mice were preconditioned by three 5-minute episodes of transient middle cerebral artery occlusion (MCAO) and subjected to permanent MCAO. Neurological deficit and infarct size were determined 24 hours later.

Results—

Although wild-type mice showed protection from ischemic preconditioning, neither eNOS nor nNOS knockout mice showed protection. Laser Doppler measurements indicated that the relative blood flow decreases in core ischemic areas were the same in all groups.

Conclusions—

Neither eNOS nor nNOS knockout mice show protection from rapid ischemic preconditioning, suggesting that nitric oxide may play a role in the molecular mechanisms of protection.
Seasonal Variation in Stroke in the Hunter Region, Australia
Authors: Wang Yang , Levi Christopher R. , Attia John R. , D’Este Catherine A. , Spratt Neil , Fisher Janet
Published: May 2003

Background and Purpose—

Seasonal variation in stroke has long been recognized. To date, there are minimal published data on seasonal variations in rates of stroke and subsequent case fatality in the Southern Hemisphere. The aim of this study was to examine stroke seasonality through the use of data from a hospital-based stroke register in the Hunter Region of New South Wales, Australia.

Methods—

From July 1, 1995, to June 30, 2000, 3803 stroke events were registered in residents of the Hunter Region, New South Wales, Australia. We analyzed the trend of seasonal and monthly stroke attack rates and case-fatality rates using Poisson regressions with age and sex as covariates.

Results—

Stroke attack rates were highest in the winter and lowest in the summer. From February (summer) to July (winter), there was a significant trend in increasing stroke attack rates (rate ratio, 1.07; 95% confidence interval, 1.05 to 1.10;
P
<0.001). This increase was seen mainly in those ≥65 years of age. Case-fatality rates showed similar trends with a 1- to 2-month lag compared with attack rates.

Conclusions—

There is an increase in stroke attack rates and case-fatality rate from summer to winter in the Hunter Region, Australia. These trends are similar to those found in the Northern Hemisphere.
Ethanol Plus Caffeine (Caffeinol) for Treatment of Ischemic Stroke
Authors: Aronowski Jaroslaw , Strong Roger , Shirzadi Ali , Grotta James C.
Published: May 2003

Background and Purpose—

Ethanol and caffeine are 2 common psychoactive dietary components. We have recently shown that low-dose ethanol plus caffeine results in a 70% to 80% reduction of infarct volume after reversible common carotid/middle cerebral artery (CCA/MCA) occlusion in rats. The combination (caffeinol) was effective after either oral pretreatment or intravenous administration starting up to 2 hours after stroke onset. Ethanol alone aggravated ischemic damage, while caffeine alone was without effect. Daily caffeinol for 2 weeks before ischemia eliminated the neuroprotection seen with acute treatment (tolerance). The purpose of our present study was to further characterize the properties of caffeinol as a possible treatment for ischemic stroke.

Methods—

The transient CCA/MCA occlusion model was used in all experiments. Five sets of experiments were conducted (1) to test the effectiveness of various doses of ethanol (0.2 to 0.65 g/kg) and caffeine (3 to 10 mg/kg) in the caffeinol mixture; (2) to test whether the neuroprotective dose of caffeinol can improve behavioral dysfunction; (3) to test whether chronic ethanol or caffeine before ischemia will affect efficacy of caffeinol treatment; (4) to test whether the protective effect of caffeinol can be improved by pairing it with 35°C hypothermia; and (5) to test whether caffeinol affects frequency of hemorrhage after administration of recombinant tissue plasminogen activator (rtPA) in ischemic animals.

Results—

Doses as low as 0.2 g/kg of ethanol and 6 mg/kg of caffeine in the caffeinol were effective in reducing cortical infarct volume and behavioral dysfunction after transient CCA/MCA occlusion. Daily exposure to ethanol but not caffeine before CCA/MCA occlusion eliminated the therapeutic efficacy of acute caffeinol treatment, similar to the tolerance observed after chronic exposure to caffeinol. The therapeutic effect of caffeinol could be further improved by pairing it with mild intraischemic hypothermia, and caffeinol did not increase hemorrhagic infarction when given in combination with rtPA.

Conclusions—

Low doses of caffeinol, equivalent to no more than 2 to 3 cups of strong coffee and 1 cocktail, are consistently and highly neuroprotective, are well tolerated, can be added to other therapies to increase the effect of each, and do not interfere with or complicate rtPA therapy. Caffeinol is an appropriate candidate for clinical trial in stroke patients, although it may be less effective in patients with regular alcohol intake.
Duplex Ultrasound and Magnetic Resonance Angiography Compared With Digital Subtraction Angiography in Carotid Artery Stenosis
Authors: Nederkoorn Paul J. , van der Graaf Yolanda , Hunink M.G. Myriam
Published: May 2003

Background and Purpose—

The purpose of this work was to review and compare published data on the diagnostic value of duplex ultrasonography (DUS), MR angiography (MRA), and conventional digital subtraction angiography (DSA) for the diagnosis of carotid artery stenosis.

Methods—

We performed a systematic review of published studies retrieved through PUBMED, from bibliographies of review papers, and from experts. The English-language medical literature was searched for studies that met the selection criteria: (1) The study was published between 1994 and 2001; (2) MRA and/or DUS was performed to estimate the severity of carotid artery stenosis; (3) DSA was used as the standard of reference; and (4) the absolute numbers of true positives, false negatives, true negatives, and false positives were available or derivable for at least one definition of disease (degree of stenosis).

Results—

Sixty-three publications on duplex, MRA, or both were included in the analysis, yielding the test results of 64 different patient series on DUS and 21 on MRA. For the diagnosis of 70% to 99% versus <70% stenosis, MRA had a pooled sensitivity of 95% (95% CI, 92 to 97) and a pooled specificity of 90% (95% CI, 86 to 93). These numbers were 86% (95% CI, 84 to 89) and 87% (95% CI, 84 to 90) for DUS, respectively. For recognizing occlusion, MRA yielded a sensitivity of 98% (95% CI, 94 to 100) and a specificity of 100% (95% CI, 99 to 100), and DUS had a sensitivity of 96% (95% CI, 94 to 98) and a specificity of 100% (95% CI, 99 to 100). A multivariable summary receiver-operating characteristic curve (ROC) analysis for diagnosing 70% to 99% stenosis demonstrated that the type of MR scanner predicted the performance of MRA, whereas the presence of verification bias predicted the performance of DUS. For diagnosing occlusion, no significant heterogeneity was found for MRA; for DUS, the presence of verification bias and type of DUS scanner were explanatory variables. MRA had a significantly better discriminatory power than DUS in diagnosing 70% to 99% stenosis (regression coefficient, 1.6; 95% CI, 0.37 to 2.77). No significant difference was found in detecting occlusion (regression coefficient, 0.73; 95% CI, −2.06 to 3.51).

Conclusions—

These results suggest that MRA has a better discriminatory power compared with DUS in diagnosing 70% to 99% stenosis and is a sensitive and specific test compared with DSA in the evaluation of carotid artery stenosis. For detecting occlusion, both DUS and MRA are very accurate.
Effects of Admission Hyperglycemia on Stroke Outcome in Reperfused Tissue Plasminogen Activator–Treated Patients
Authors: Alvarez-Sabín José , Molina Carlos A. , Montaner Joan , Arenillas Juan F. , Huertas Rafael , Ribo Marc , Codina Agusti , Quintana Manuel
Published: May 2003

Background and Purpose—

We sought to investigate the impact of hyperglycemia before reperfusion on long-term outcome in patients treated with intravenous tissue plasminogen activator (tPA).

Methods—

Of 268 consecutive patients with a nonlacunar middle cerebral artery (MCA) stroke evaluated at <3 hours after onset, 73 (27.2%) received intravenous tPA. Serum glucose was determined at baseline before tPA administration. Hyperglycemia was defined as a glucose level >140 mg/dL. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours. Transcranial Doppler monitoring of recanalization and reocclusion was conducted during the first 24 hours. Total infarct volume was measured on CT at day 5 to 7. Modified Rankin Scale was used to assess outcome at 3 months.

Results—

Median NIHSS score was 17. At baseline, 31 patients (42.5%) were hyperglycemic and 42 (57.5%) normoglycemic. Early reperfusion (<6 hours) occurred in 43 patients (58.9%). Admission blood glucose correlated negatively with the degree of neurological improvement at 24 hours in reperfused (
r
=−0.43;
P
=0.019) but not in nonreperfused (
r
=−0.20;
P
=0.21) tPA-treated patients. Increased age (
P
=0.014), history of diabetes mellitus (
P
=0.043), admission glucose >140 mg/dL (
P
=0.002), and early reocclusion (
P
=0.004) were factors associated with poor outcome among reperfused patients. A logistic regression modeling revealed that only admission glucose value >140 mg/dL (odds ratio, 8.4; 95% CI, 1.76 to 40.02;
P
=0.005) emerged as an independent predictor of poor outcome despite tPA-induced recanalization. In patients with 6-hour persistent MCA occlusion, baseline NIHSS score >15 points (
P
=0.011) and proximal MCA occlusion (
P
=0.039) were variables associated with poor outcome on univariate analysis. In a logistic regression model, only NIHSS score >15 points (odds ratio, 11.9; 95% CI, 1.48 to 97.1;
P
=0.032) remained as an independent predictor of poor outcome and functional dependence at 3 months in nonreperfused tPA-treated patients.

Conclusions—

Hyperglycemia before reperfusion may in part counterbalance the beneficial effect of early restoration of blood flow, which translates into a worse outcome in hyperglycemic patients despite tPA-induced recanalization.
Silent Brain Infarcts and White Matter Lesions Increase Stroke Risk in the General Population
Authors: Vermeer Sarah E. , Hollander Monika , van Dijk Ewoud J. , Hofman Albert , Koudstaal Peter J. , Breteler Monique M.B.
Published: May 2003

Background and Purpose—

Silent brain infarcts and white matter lesions are associated with an increased risk of subsequent stroke in minor stroke patients. In healthy elderly people, silent brain infarcts and white matter lesions are common, but little is known about their relevance. We examined the risk of stroke associated with these lesions in the general population.

Methods—

The Rotterdam Scan Study is a population-based prospective cohort study among 1077 elderly people. The presence of silent brain infarcts and white matter lesions was scored on cerebral MRI scans obtained from 1995 to 1996. Participants were followed for stroke for on average 4.2 years. We estimated the risk of stroke in relation to presence of brain lesions with Cox proportional hazards regression analysis.

Results—

Fifty-seven participants (6%) experienced a stroke during follow-up. Participants with silent brain infarcts had a 5 times higher stroke incidence than those without. The presence of silent brain infarcts increased the risk of stroke >3-fold, independently of other stroke risk factors (adjusted hazard ratio 3.9, 95% CI 2.3 to 6.8). People in the upper tertile of the white matter lesion distribution had an increased stroke risk compared with those in the lowest tertile (adjusted hazard ratio for periventricular lesions 4.7, 95% CI 2.0 to 11.2 and for subcortical lesions 3.6, 95% CI 1.4 to 9.2). Silent brain infarcts and severe white matter lesions increased the stroke risk independently of each other.

Conclusion—

Elderly people with silent brain infarcts and white matter lesions are at a strongly increased risk of stroke, which could not be explained by the major stroke risk factors.
Factors Influencing Outcome and Treatment Effect in PROACT II
Authors: Wechsler Lawrence R. , Roberts Robin , Furlan Anthony J. , Higashida Randall T. , Dillon William , Roberts Heidi , Rowley Howard A. , Pettigrew L. Creed , Callahan Alfred S. , Bruno Askiel , Fayad Pierre , Smith Wade S. , Firszt Carolyn M. , Schulz Gregory A.
Published: May 2003

Background and Purpose—

The PROACT II study demonstrated a significant benefit from treatment with intra-arterial pro-urokinase (r-proUK) in patients with middle cerebral artery occlusion treated within 6 hours of stroke onset. The purpose of the current study was to examine baseline factors to determine predictors of good outcome and response to treatment.

Methods—

We selected from the baseline clinical, radiologic, and angiographic data variables that considered possibly related to outcome. A univariate analysis was performed to examine the association between these baseline factors and good outcome, defined as a modified Rankin scale score ≤2. A multivariate model then selected the most important variables independently influencing prognosis. A risk score for each patient was constructed on the basis of the patient’s individual values for each independent variable. Patients were stratified into risk quartiles based on their risk scores, and an odds ratio for each risk quartile was calculated. The treatment effects of each quartile were compared.

Results—

In the univariate analysis, screening National Institutes of Health stroke scale (NIHSS) score and age were strongly associated with good outcome. The multivariate model selected age, NIHSS score, and CT hypodensity as the most important prognostic variables. Dividing patients into quartiles based on risk scores achieved a uniform gradient of probability of good outcomes. A trend toward benefit of r-proUK treatment was seen in all risk quartiles, and no differential treatment effect was observed across risk groups.

Conclusions—

There was no evidence of differential effect of r-proUK across subgroups of patients stratified by risk.
Dexmedetomidine and Meperidine Additively Reduce the Shivering Threshold in Humans
Authors: Doufas Anthony G. , Lin Chun-Ming , Suleman Mohammad-Irfan , Liem Edwin B. , Lenhardt Rainer , Morioka Nobutada , Akça Ozan , Shah Yunus M. , Bjorksten Andrew R. , Sessler Daniel I.
Published: May 2003

Background and Purpose—

Hypothermia might prove to be therapeutically beneficial in stroke victims; however, even mild hypothermia provokes vigorous shivering. Meperidine and dexmedetomidine each linearly reduce the shivering threshold (triggering core temperature) with minimal sedation. We tested the hypothesis that meperidine and dexmedetomidine synergistically reduce the shivering threshold without producing substantial sedation or respiratory depression.

Methods—

We studied 10 healthy male volunteers (18 to 40 years) on 4 days: (1) control (no drug); (2) meperidine (target plasma level 0.3 μg/mL); (3) dexmedetomidine (target plasma level 0.4 ng/mL); and (4) meperidine plus dexmedetomidine (target plasma levels of 0.3 μg/mL and 0.4 ng/mL, respectively). Lactated Ringer’s solution (≈4°C) was infused through a central venous catheter to decrease tympanic membrane temperature by ≈2.5°C/h; mean skin temperature was maintained at 31°C. An increase in oxygen consumption >25% of baseline identified the shivering threshold. Sedation was evaluated by using the Observer’s Assessment of Sedation/Alertness scale. Two-way repeated-measures ANOVA was used to identify interactions between drugs. Data are presented as mean±SD;
P
<0.05 was statistically significant.

Results—

The shivering thresholds on the study days were as follows: control, 36.7±0.3°C; dexmedetomidine, 36.0±0.5°C (
P
<0.001 from control); meperidine, 35.5±0.6°C (
P
<0.001); and meperidine plus dexmedetomidine, 34.7±0.6°C (
P
<0.001). Although meperidine and dexmedetomidine each reduced the shivering threshold, their interaction was not synergistic but additive (
P
=0.19). There was trivial sedation with either drug alone or in combination. Respiratory rate and end-tidal P
co
2
were well preserved on all days.

Conclusions—

Dexmedetomidine and meperidine additively reduce the shivering threshold; in the small doses tested, the combination produced only mild sedation and no respiratory toxicity.
Beta Radiation and Inhibition of Recanalization After Coil Embolization of Canine Arteries and Experimental Aneurysms
Authors: Raymond Jean , Leblanc Philippe , Morel François , Salazkin Igor , Gevry Guylaine , Roorda Sjoerd
Published: May 2003

Background and Purpose—

Beta radiation prevents recanalization after coil embolization. We sought to determine the effects of varying coil caliber, length, activity of
32
P per centimeter of coil or per volume, and spatial distribution of coils on recanalization.

Methods—

We studied the angiographic evolution of 81 canine maxillary, cervical, and vertebral arteries implanted with a variety of nonradioactive (n=29 arteries) or radioactive (n=52) devices. We compared 1- or 2-caliber 0.015 or 0.010 coils ion-implanted or not with 3 different activity levels (0.05 to 0.08, 0.06 to 0.12, 0.18 to 0.32 μCi/cm) of
32
P and totaling 4, 8, and 16 cm in length for the same arterial volume. We also compared inhibition of recanalization by beta radiation delivered by stents, after coil occlusion proximal to or within the stent, with that delivered by coils placed within nonradioactive stents. We finally studied the angiographic evolution of canine lateral wall carotid aneurysms treated with 1 or 2 stents of various activity levels positioned inside the parent artery across the neck. Animals were killed at 4 and 12 weeks for macroscopic photography and pathological examination.

Results—

All arteries (29 of 29) occluded with nonradioactive devices were recanalized, while 49 of 52 arteries (94%) implanted with
32
P devices were occluded at 4 weeks. All aneurysms treated with stents, radioactive or not, demonstrated residual filling of the sac or of channels leading to the aneurysms at follow-up angiography at 4 weeks.

Conclusions—

The recanalization process found in the canine arterial occlusion model is minimally affected by coil caliber, number, and length or packing density. Beta radiation reliably inhibits this process, but thrombosis is an essential condition for the efficacy of a radioactive coil strategy.
Prospective, Population-Based Detection of Intracranial Vascular Malformations in Adults
Authors: Al-Shahi Rustam , Bhattacharya Jo J. , Currie David G. , Papanastassiou Vakis , Ritchie Vaughn , Roberts Richard C. , Sellar Robin J. , Warlow Charles P.
Published: May 2003

Background and Purpose—

Intracranial vascular malformations (IVMs) are an important cause of intracranial hemorrhage, epilepsy, and long-term disability in adults. There are no published prospective, population-based studies dedicated to the detection of any type of IVM (cavernous malformations, venous malformations, and arteriovenous malformations [AVMs] of the brain or dura). Therefore, we established the Scottish Intracranial Vascular Malformation Study (SIVMS) to monitor detection and long-term prognosis of people with IVMs.

Methods—

We used multiple overlapping sources of case ascertainment to identify adults (aged ≥16 years) with a first-ever-in-a-lifetime diagnosis of any type of IVM made between January 1, 1999, and December 31, 2000, while resident in Scotland (mid-1999 adult population estimate 4 110 956).

Results—

Of 418 notifications to SIVMS, 190 adults (45%) were included, 181 (95%) of whom were deemed to harbor a definite IVM after review of diagnostic brain imaging and/or reports of autopsy/surgical excision pathology. The crude detection rate (per 100 000 adults per year) was 2.27 (95% CI, 1.96 to 2.62) for all IVMs, 1.12 (95% CI, 0.90 to 1.37) for brain AVMs, 0.56 (95% CI, 0.41 to 0.75) for cavernous malformations, 0.43 (95% CI, 0.31 to 0.61) for venous malformations, and 0.16 (95% CI, 0.08 to 0.27) for dural AVMs.

Conclusions—

In addition to providing data on the public health importance and comparative epidemiology of IVMs, continuing recruitment and follow-up of this prospective, population-based cohort will provide estimates of IVM prognosis.
MTHFR Gene Polymorphism as a Risk Factor for Silent Brain Infarcts and White Matter Lesions in the Japanese General Population
Authors: Kohara Katsuhiko , Fujisawa Michiko , Ando Fujiko , Tabara Yasuharu , Niino Naoakira , Miki Tetsuro , Shimokata Hiroshi
Published: May 2003

Background and Purpose—

Silent brain infarcts (SBI) and white matter lesions are relatively common neuroimaging findings, especially in the elderly population. The genetic background for SBI and white matter lesions in a large Japanese general population was investigated.

Methods—

Subjects were recruited from participants in the National Institute for Longevity Sciences, Longitudinal Study of Aging. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation and brain MRI examination were performed in 1721 subjects free of any history of stroke. SBI and white matter lesions were diagnosed from MRI findings.

Results—

Of 1721 MRI examinations, SBI was observed in 178 (10.3%). The prevalence of SBI and white matter lesions increased with age. The prevalence of SBI was significantly higher in subjects with the MTHFR TT genotype compared with the TC+CC genotype (14.6% versus 9.5%; 42 of 288 versus 136 of 1433; χ
2
=6.71;
P
=0.010). The stage of white matter lesions was not significantly different. In subjects ≥60 years of age (n=849), the prevalence of SBI was significantly higher in TT than TC+CC (27.7% versus 16.6%; 36 of 130 versus 119 of 719; χ
2
=9.16;
P
=0.002). The prevalence of moderately advanced white matter lesions was also significantly higher in TT than TC+CC (60.7% versus 49.0%; 79 of 130 versus 352 of 719; χ
2
=9.16;
P
=0.002). After correction for other risk factors, the MTHFR TT genotype was independently associated with SBI (odds ratio [OR], 1.72; 95% CI, 1.10 to 2.68;
P
=0.018) and moderately advanced white matter lesions (OR, 1.58; 95% CI, 1.07 to 2.33;
P
=0.02).

Conclusions—

These findings indicate that the MTHFR TT genotype is an independent risk factor for SBI and white matter lesions in the general Japanese population, especially in elderly subjects.
Pre- and In-Hospital Delays From Stroke Onset to Intra-arterial Thrombolysis
Authors: Nedeltchev Krassen , Arnold Marcel , Brekenfeld Caspar , Isenegger Jörg , Remonda Luca , Schroth Gerhard , Mattle Heinrich P.
Published: May 2003

Background and Purpose—

Thrombolysis for treatment of acute ischemic stroke should be administered as fast as possible after symptom onset. The aim of this study was to examine, in our tertiary care center, the time intervals preceding intra-arterial thrombolysis in order to accelerate and optimize the management of acute strokes.

Methods—

Between January 1, 2000, and April 30, 2002, 597 patients with acute stroke were admitted to our stroke center. One hundred forty-eight patients underwent diagnostic arteriography, and 100 (16.8%) received intra-arterial thrombolysis. For all patients, we prospectively recorded and analyzed the time of symptom onset, admission, CT and/or MRI scan, diagnostic arteriography, and, if performed, intra-arterial thrombolysis.

Results—

The mean time to arrival in the emergency department was 99 minutes for patients who were admitted directly (Bern patients), 127 minutes for those who were referred from community hospitals without a CT scanner (non-Bern/−CT patients), and 210 minutes for patients from hospitals with imaging facilities (non-Bern/+CT patients). The mean delay from symptom onset to treatment was 234 minutes for Bern patients, 269 minutes for non-Bern/−CT patients, and 302 minutes for non-Bern/+CT patients. The patients from the last group needed longer to receive intra-arterial thrombolysis than did patients who were admitted directly (
P
=0.002) or who were transferred from a hospital without a CT scanner (
P
=0.03).

Conclusions—

This prospective study indicates that direct referral without prior imaging at community hospitals shortens the time until intra-arterial thrombolysis. In addition, our in-hospital delay preceding intra-arterial thrombolysis is longer than the delays reported for intravenous thrombolysis and indicates potential for improvement.