bluuebunny/crossref_metadata_2025 huggingface dataset:
Smooth Muscle Dysfunction in Resistance Arteries of the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα
Authors: Besnard Sandrine , Bakouche Joëlle , Lemaigre-Dubreuil Yolande , Mariani Jean , Tedgui Alain , Henrion Daniel
Published: July 2002

Retinoic acid receptor–related orphan receptor α (RORα) is a member of the nuclear receptor superfamily. The mouse mutant
staggerer
(sg/sg) carries a deletion within the RORα gene. RORα plays a major role in cellular differentiation during development and growth. In the present study, we found a lower mean arterial blood pressure in sg/sg than in +/+ mice (80.1±1.2 and 87.0±0.9 mm Hg, respectively;
P
<0.0002) and a smaller increase in blood pressure after in vivo injections of phenylephrine. To elucidate the mechanisms responsible for this phenotype, we investigated the vascular reactivity of large vessels (aorta and carotid arteries) and small resistance mesenteric arteries in response to mechanical forces or vasoactive agents. Arteries from sg/sg and +/+ mice were studied in vitro in arteriographs. Vascular responses of large vessels to all stimuli were similar in both groups. However, we found a markedly altered vascular function in mesenteric arteries from sg/sg mice. Flow-induced dilation, pressure-induced myogenic tone, responses to endothelium-dependent or -independent vasodilators, and responses to vasoconstrictors were significantly reduced in sg/sg compared with +/+ mice. We also determined by Western blot analysis the expression of smooth muscle (SM)-myosin, calponin, and heavy (h)-caldesmon, in large and small arteries of sg/sg and +/+ mice, and found a marked decrease in the expression of these contractile proteins in mesenteric arteries of sg/sg mice. Our findings provide the first evidence that functional RORα is required for normal contractile phenotype of smooth muscle cells (SMCs) in small resistance arteries and suggest that RORα might be involved in the differentiation of SMCs in mesenteric arteries.
Is the Association of National Institutes of Health Stroke Scale Scores and Acute Magnetic Resonance Imaging Stroke Volume Equal for Patients With Right- and Left-Hemisphere Ischemic Stroke?
Authors: Fink John N. , Selim Magdy H. , Kumar Sandeep , Silver Brian , Linfante Italo , Caplan Louis R. , Schlaug Gottfried
Published: July 2002

Background and Purpose

—

The National Institutes of Health Stroke Scale (NIHSS) is an established measure of neurological impairment; however, it can award more points for tests of presumed left-hemisphere function, such as language, than for tests of right-hemisphere function, such as neglect. This difference may be important if a low NIHSS score is used to exclude patients with right-hemisphere stroke from clinical trials or established treatments. The aim of this study was to investigate whether the relationship between acute NIHSS score and acute stroke volume as determined by acute diffusion- and perfusion-weighted MRI (DWI and PWI) differs between right- and left-sided stroke.

Methods

—

This was a retrospective study of 153 patients with acute stroke seen at Beth Israel Deaconess Medical Center between January 1995 and March 2000 who underwent an MRI examination and NIHSS within 24 hours of stroke onset. NIHSS score was recorded prospectively by the admitting stroke fellow at the time of acute presentation, immediately preceding imaging. Computerized volumetric analysis of the MRI lesions was performed by investigators blinded to clinical data.

Results

—

There were significant correlations between the acute NIHSS scores and acute DWI lesion volumes (
r
=0.48 right,
r
=0.58 left) and between acute NIHSS scores and perfusion-weight imaging hypoperfusion volumes (
r
=0.62 right,
r
=0.60 left). For patients with NIHSS scores of 0 to 5, the DWI volume of right cerebral lesions was greater than that of left-sided lesions (mean volume, 8.8 versus 3.2 cm
3
;
P
=0.04). Among patients with DWI lesions larger than the median volume (9 cm
3
), 8 of 37 with right-sided stroke had an NIHSS score of 0 to 5 compared with 1 of 39 patients with left-sided stroke (
P
=0.01). Multiple linear regression analysis revealed a significantly lower acute NIHSS on the right compared with the left side when adjusted for stroke volume on chronic T2 imaging (
P
=0.03).

Conclusions

—

Patients with right-sided stroke may have a low NIHSS score despite substantial DWI lesion volume. Acute imaging information, such as that available with multimodal MRI, may be useful to identify patients for inclusion in acute stroke protocols when there is clinical uncertainty about eligibility. Prospective evaluation of criteria incorporating acute imaging data is required.
Computed Tomography Angiography for the Evaluation of Carotid Atherosclerotic Plaque
Authors: Walker Leighton J. , Ismail Azam , McMeekin William , Lambert David , Mendelow A. David , Birchall Daniel
Published: July 2002

Background and Purpose

—

The goal of this study was to determine the efficacy of CT angiography for the characterization of plaque morphology and composition in carotid atherosclerotic disease.

Methods

—

Fifty-five patients undergoing carotid endarterectomy were imaged preoperatively with single-slice spiral CT angiography. One hundred sixty-five endarterectomy sections were examined histologically at selected levels through the distal common and proximal internal carotid arteries. Plaque density was measured (in Hounsfield units) on axial CT sections, and the presence or absence of ulceration was noted. These observations were compared with the histological findings at corresponding levels. Data were analyzed with 2-sample
t
tests and 1-way analysis of variance (ANOVA).

Results

—

ANOVA testing showed a statistically significant decrease in CT attenuation values with increasing plaque lipid but with a very high standard deviation of values. No other histological factor showed a statistically significant link with CT attenuation. Plaque ulceration was detected by CT with a sensitivity of 60% and a specificity of 74%.

Conclusions

—

Analysis of plaque attenuation with single-slice spiral CT does not give useful information concerning plaque composition. The predictive value of CT for the detection of plaque ulceration was moderate. Single-slice CT angiography is insufficiently robust to be a useful tool for the characterization of carotid plaque composition and morphology.
Persistent Defect in Transmitter Release and Synapsin Phosphorylation in Cerebral Cortex After Transient Moderate Ischemic Injury
Authors: Bolay Hayrunnisa , Gürsoy-Özdemir Yasemin , Sara Yildirim , Onur Rüstü , Can Alp , Dalkara Turgay
Published: July 2002

Background and Purpose

—

Synaptic transmission is highly vulnerable to metabolic perturbations. However, the long-term consequences of transient metabolic perturbations on synapses are not clear. We studied the long-lasting changes in synaptic transmission and phosphorylation of presynaptic proteins in penumbral cortical neurons after transient moderate ischemia.

Methods

—

Rats were subjected to 1 hour of middle cerebral artery occlusion. After reperfusion, electric activity of neurons in the peri-infarct region was recorded intracellularly and extracellularly in situ. Phosphorylation of synapsin-I and tyrosine residues was studied by immunohistochemistry.

Results

—

Neurons in the penumbra displayed no postsynaptic potentials 1 to 3 hours after recirculation. However, these cells were able to generate action potentials and were responsive to glutamate, suggesting that postsynaptic excitability was preserved but the synaptic transmission was blocked because of a presynaptic defect. The synaptic transmission was still depressed 24 hours after recirculation in neurons in the peri-infarct area that survived ischemia. The amount of immunoreactive synapsin-I, synaptophysin, and synaptotagmin was not appreciably changed for 72 hours after reperfusion. However, phosphorylation of synapsin-l was significantly decreased, whereas phosphotyrosine immunoreactivity was increased, suggesting a selective defect in synapsin-I phosphorylation.

Conclusions

—

These data demonstrate that synaptic transmission may be permanently impaired after transient moderate brain injury. Since postsynaptic excitability is preserved, the transmission failure is likely to be caused by presynaptic mechanisms, one of which may be impaired phosphorylation of presynaptic proteins.
Poststroke Fatigue
Authors: Glader Eva-Lotta , Stegmayr Birgitta , Asplund Kjell
Published: July 2002

Background and Purpose

—

Fatigue is common among stroke patients. This study determined the prevalence of fatigue among long-term survivors after stroke and what impact fatigue had on various aspects of daily life and on survival.

Methods

—

This study was based on Riks-Stroke, a hospital-based national register for quality assessment of acute stroke events in Sweden. During the first 6 months of 1997, 8194 patients were registered in Riks-Stroke, and 5189 were still alive 2 years after the stroke. They were followed up by a mail questionnaire, to which 4023 (79%) responded. Patients who reported that they always felt depressed were excluded.

Results

—

To the question, “Do you feel tired?” 366 (10.0%) of the patients answered that they always felt tired, and an additional 1070 (29.2%) were often tired. Patients who always felt tired were on average older than the rest of the study population (74.5 versus 71.5 years,
P
<0.001); therefore, all subsequent analyses were age adjusted. Fatigue was an independent predictor for having to move into an institutional setting after stroke. Fatigue was also an independent predictor for being dependent in primary activities of daily living functions. Three years after stroke, patients with fatigue also had a higher case fatality rate.

Conclusions

—

Fatigue is frequent and often severe, even late after stroke. It is associated with profound deterioration of several aspects of everyday life and with higher case fatality, but it usually receives little attention by healthcare professionals. Intervention studies are needed.
Changes in Blood Flow and Oxygen Metabolism During Visual Stimulation in Carotid Artery Disease
Authors: Yamauchi Hiroshi , Okazawa Hidehiko , Kishibe Yoshihiko , Sugimoto Kanji , Takahashi Masaaki
Published: July 2002

Background and Purpose

—

Severe atherosclerotic disease of the carotid arteries may affect perfusion in the posterior circulation according to the degree of collateral supply. The purpose of this study was to determine whether the responses of regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of oxygen (rCMR
o
2
) during neural stimulation are affected by the baseline perfusion or oxygen metabolism.

Methods

—

We used PET to measure rCBF, rCMR
o
2
, and regional oxygen extraction fraction (rOEF) in 13 patients with carotid artery steno-occlusive lesions at baseline and during visual stimulation. We examined whether the changes in CBF, CMR
o
2
, and OEF during visual stimulation were correlated with the baseline values of these parameters in the visual cortex.

Results

—

With visual stimulation, rCBF increased in all patients, whereas rCMR
o
2
showed variable changes. The baseline rCMR
o
2
value showed a positive relationship with the degree of rCBF increase and a negative relationship to the degree of rCMR
o
2
increase. rCMR
o
2
decreased in patients with relatively high baseline rCMR
o
2
values, resulting in dissociation of the rCMR
o
2
response from the rCBF response. The rCBF increase was large in the region with an increased baseline rOEF value. These variable changes in rCBF and rCMR
o
2
resulted in a significant correlation between the values of rCBF and rCMR
o
2
during visual stimulation in contrast to the lack of such a correlation at baseline.

Conclusions

—

In patients with cerebrovascular disease, neural stimulation may induce variable changes in rCBF and rCMR
o
2
according to the baseline perfusion and oxygen metabolism.
Falls, Fractures, and Osteoporosis After Stroke
Authors: Poole Kenneth E.S. , Reeve Jonathan , Warburton Elizabeth A.
Published: July 2002

Background

—

Osteoporosis is a significant complication of stroke. The clinical course of hemiplegic stroke predisposes patients to disturbed bone physiology. Sudden immobility and unilateral loss of function unload the skeleton at key areas such as the affected hip. This is manifest by an early reduction in bone density at this site. Stroke patients may also have motor, sensory, and visual/perceptual deficits that predispose them to falls. These factors result in an early but sustained increase in hip fractures after stroke.

Summary of Comment

—

Potential bone loss is often overlooked in stroke treatment. Morbidity and mortality from hip fractures might be reduced by preventing bone loss at an early stage. In the crucial first year after stroke, bone loss seems to be due to accelerated resorption. Bisphosphonates are the drugs of choice in preventing osteoclastic bone resorption, but oral administration soon after stroke may be impractical. Potent new intravenous bisphosphonates have been used in postmenopausal women with osteoporosis with good preliminary results. Effective dosing regimens for osteoporosis have included a single annual or semiannual injection of bisphosphonate as well as weekly oral dosing. This article reviews the current literature on osteoporosis and hip fractures after stroke, making a case for a trial of intravenous bisphosphonates early after stroke.

Conclusions

—

Hip fracture after stroke is an increasingly recognized problem. Measures to prevent bone loss and preserve bone architecture have not been part of stroke management thus far. Because rapid bone loss is a risk factor for fracture, we believe that a randomized, placebo-controlled trial of intravenous bisphosphonates given in the early phase of stroke rehabilitation is indicated.
Sex Differences in US Mortality Rates for Stroke and Stroke Subtypes by Race/Ethnicity and Age, 1995–1998
Authors: Ayala Carma , Croft Janet B. , Greenlund Kurt J. , Keenan Nora L. , Donehoo Ralph S. , Malarcher Ann M. , Mensah George A.
Published: July 2002

Background and Purpose

—

Ischemic stroke accounts for 70% to 80% of all strokes, but intracerebral and subarachnoid hemorrhagic strokes have greater fatality. Age-standardized death rates from overall stroke are higher among men than women, but little is known about sex differences in stroke subtype mortality by race/ethnicity.

Methods

—

We analyzed 1995 to 1998 national death certificate data to compare sex-specific age-standardized death rates (per 100 000) for ischemic stroke (n=507 256), intracerebral hemorrhagic stroke (n=98 709), and subarachnoid hemorrhagic stroke (n=27 334) among whites, blacks, American Indians/Alaska Natives, Asians/Pacific Islanders, and Hispanics. We calculated rate ratios and 95% CIs comparing women with men within age and racial/ethnic groups.

Results

—

Age-specific rates of ischemic and intracerebral hemorrhagic stroke deaths were lower for women than for men aged 25 to 44 and 45 to 64 years but were higher for ischemic stroke among older women, aged ≥65 years. Only among whites did women have higher age-standardized rates of ischemic stroke. Age-standardized death rates for intracerebral hemorrhagic stroke among women were lower than or similar to those among men in all racial/ethnic groups. Women had higher risk of death from subarachnoid hemorrhagic; this sex differential increased with age.

Conclusions

—

The female-to-male mortality ratio differs for stroke subtypes by race/ethnicity and age. A primary public health effort should focus on increasing the awareness of stroke symptoms, particularly among people at high risk, to decrease delay in early detection and effective stroke treatment.
Regional Cerebral Blood Flow and Magnetic Resonance Spectroscopic Imaging Findings in Diaschisis From Stroke
Authors: Chu Wen-Jang , Mason Graeme F. , Pan Jullie W. , Hetherington Hoby P. , Liu Hong-Gang , San Pedro Elmer C. , Mountz James M.
Published: July 2002

Background and Purpose

—

This study evaluated blood flow and metabolite changes in cerebral diaschisis from internal capsule region infarction using regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) and
1
H magnetic resonance spectroscopic imaging (MRSI). We hypothesized that complementary measures of diaschisis effects in white matter (characterized by
1
H MRSI) and gray matter (characterized by changes in rCBF) can be measured and exhibit parallel changes.

Methods

—

Five stroke patients and 16 normal controls underwent Tc-99m hexamethylpropyleneamine-oxime brain SPECT and
1
H MRSI at 4.1 T. The metabolites
N
-acetyl aspartate (NAA) and creatine (Cr) were measured using
1
H MRSI. The tissue content was expressed as the percent of gray or white matter in each MRSI voxel to allow comparison of the differential effects of diaschisis in gray and white matter tissue types. The blood flow and metabolite changes were evaluated at superior cerebral regions distant from the stroke to allow a measure of diaschisis relatively unconfounded by their expected changes in the infarction region.

Results

—

The rCBF SPECT data in stroke patients showed a perfusion defect, with size ranging from 1.23 cc to 10.23 cc, in the region of cortical diaschisis.
1
H MRSI showed increased Cr/NAA ratios in regions of white matter diaschisis. There was a tendency for larger rCBF defect size to be associated with greater increases in Cr/NAA values in the same diaschitic cerebral hemisphere, ipsilateral to the infarction.

Conclusion

—

Diaschisis ipsilateral to stroke in white matter can be characterized by
1
H MRSI, and diaschisis ipsilateral to stroke in cortical gray matter regions can be characterized by changes in rCBF. The tendency for greater reductions in cortical rCBF values to be associated with increased Cr/NAA values in the same diaschitic cerebral hemisphere implies that a relationship exists between rCBF reductions in gray matter and abnormal changes in white matter subservient to it.
Neuroprotective Effects of the Spin Trap Agent Disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate
N
-Oxide (Generic NXY-059) in a Rabbit Small Clot Embolic Stroke Model
Authors: Lapchak Paul A. , Araujo Dalia M. , Song Donghuan , Wei Jiandong , Zivin Justin A.
Published: July 2002

Background and Purpose

—

It has been proposed that the novel spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate
N
-oxide (NXY-059) may be useful in the treatment of ischemic stroke. However, there is little information concerning the neuroprotective properties of NXY-059 when administered after an embolic stroke. Moreover, there is no information available concerning the combination of NXY-059 with the only Food and Drug Administration–approved pharmacological agent for the treatment of acute stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on behavioral outcome after an embolic stroke when administered alone or in combination with tPA.

Methods

—

Male New Zealand White rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059G (100 mg/kg) was infused intravenously 5 minutes or 3 hours after embolization, whereas control rabbits received infusions of the saline vehicle. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes or 3 hours after embolization (3.3 mg/kg). In combination studies, NXY-059G was given 5 minutes after embolization, followed by the administration of tPA beginning either 60 minutes or 3 hours after embolization. Behavioral analysis was conducted 24 hours after embolization.

Results

—

In the vehicle control group, the ES
50
value (calculated as the amount of microclots [milligrams] that produce neurological dysfunction [impairment] in 50% of the rabbits within a specific treatment group) measured 24 hours after embolism was 1.04±0.31 mg, and this was increased by 153% to 2.54±0.72 mg if NXY-059G was administered beginning 5 minutes after embolization. However, if NXY-059G was administered beginning 3 hours after embolization, the ES
50
was 2.01±0.40 mg. The rabbits treated with tPA alone had an ES
50
of 2.64±0.66 or 0.63±0.35 mg if tPA administration started 60 minutes or 3 hours after embolization, respectively. If tPA was administered after NXY-059G (started at 5 minutes), the ES
50
values were 3.15±0.50 or 2.66±0.82 if tPA administration started 60 minutes or 3 hours after embolization, respectively.

Conclusions

—

This study suggests that NXY-059G is neuroprotective and can increase behavioral ratings if administered early after an embolic stroke. In addition, the study shows that NXY-059G can be used in combination with tPA without negative side effects. The drug combination can improve behavioral function and increase ES
50
values. However, during the short time course of the behavioral analysis, the combination was not statistically better than either drug alone.
Thrombolytic Therapy Within 3 to 6 Hours After Onset of Ischemic Stroke
Authors: Ringleb P.A. , Schellinger P.D. , Schranz C. , Hacke W.
Published: July 2002

Background

—

The use of recombinant tissue plasminogen activator (rtPA) within 3 hours after onset of an ischemic stroke is an established therapy. Because the use of intravenous rtPA beyond a time window of 3 hours after stroke onset is still a matter of debate, we sought to review the evidence for the use of thrombolytic therapy in a time window up to 6 hours after onset of symptoms of ischemic stroke.

Summary of Review

—

The meta-analyses of the major trials (National Institute of Neurological Disorders and Stroke rtPA Stroke Study, European Cooperative Acute Stroke Study [ECASS] I, ECASS II) showed a benefit of thrombolytic therapy with intravenous rtPA even within 6 hours after onset of symptoms of ischemic stroke. The rate of intracerebral hemorrhage was slightly increased in the 6-hour time window compared with the 3-hour time window (odds ratio, 3.23 versus 2.68), but this was without statistical significance because of wide confidence intervals. A positive effect of 37% relative odds reduction with the use of a dichotomization of ≤2 versus ≥3 on the modified Rankin Scale remains for rtPA treatment within 6 hours. However, the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) Study, in which a 3- to 5-hour time window was used, failed to show a benefit of rtPA. Still, when the results of ATLANTIS are included into meta-analyses such as the Cochrane Library, the positive effect of rtPA treatment in the 6-hour time window remains, with a “number needed to treat” value of 11. Treating patients only within a 3- to 6-hour time window would lead to a number needed to treat value of 25.

Conclusions

—

Consequently, from our point of view it appears unjustified to limit thrombolytic therapy to 3 hours. Because of lack of approvals for 3 to 6 hours, thrombolytic therapy within this time window should be done only as part of an institutional protocol after extensive information is obtained from the patient and the patient’s relatives. Better methods for patient selection are required; in particular, newer MRI techniques, such as diffusion- and perfusion-weighted imaging, can play a key role. The aim is to qualify and individualize the time window according to the findings in each patient’s imaging results rather than to use a strictly time-defined therapeutic window.
Cerebrovascular Reactivity to Acetazolamide and Outcome in Patients With Symptomatic Internal Carotid or Middle Cerebral Artery Occlusion
Authors: Ogasawara Kuniaki , Ogawa Akira , Yoshimoto Takashi
Published: July 2002

Background and Purpose

—

The present study prospectively evaluated relationships among baseline characteristics, cerebral hemodynamics, and outcome of patients with symptomatic major cerebral artery occlusion, by quantitative measurement of cerebral blood flow using xenon-133 (
133
Xe) inhalation and single-photon emission computed tomography (SPECT).

Methods

—

Regional cerebrovascular reactivity (rCVR) to acetazolamide was calculated at entry to the study using
133
Xe SPECT. Seventy consecutive patients aged less than 70 years with unilateral internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion were divided into 2 groups: normal or reduced rCVR, and prospectively followed up for a period of 24 months.

Results

—

During the follow-up period, recurrent strokes occurred in 8 of the 23 patients with reduced rCVR at entry and in 3 of 47 patients with normal rCVR. Cumulative recurrence-free survival rates in all patients, and in each subgroup of patients with ICA or MCA occlusion and reduced rCVR on entry, were significantly lower than in those with normal rCVR (
P
=0.0030,
P
=0.0404, and
P
=0.0310, respectively; Kaplan-Meier analysis). Among the factors considered, only lower rCVR and resting regional cerebral blood flow values were significantly associated with the risk of stroke recurrence (
P
=0.0019 and
P
=0.0080, respectively; Cox regression multivariate analysis).

Conclusions

—

The present study demonstrated that reduced rCVR to acetazolamide as determined by
133
Xe SPECT is significantly associated with an increased risk of stroke recurrence in patients with symptomatic MCA or ICA occlusion.
Heritability of Carotid Artery Intima-Medial Thickness in Type 2 Diabetes
Authors: Lange Leslie A. , Bowden Donald W. , Langefeld Carl D. , Wagenknecht Lynne E. , Carr J. Jeffrey , Rich Stephen S. , Riley Ward A. , Freedman Barry I.
Published: July 2002

Background and Purpose

—

Carotid artery intima-medial thickness (IMT), a marker of subclinical atherosclerosis, is a strong predictor of subsequent cardiovascular morbidity. The role of genetic factors in thickening of the carotid wall remains largely unknown. We hypothesize that in families with multiple members having diabetes, carotid IMT is likely to be associated with both inherited and environmental factors.

Methods

—

To determine the extent of the familial aggregation of carotid IMT in the presence of type 2 diabetes, we studied 252 individuals with type 2 diabetes (mean age 60.6 years) from 122 families. Common carotid artery IMT was measured by high-resolution B-mode ultrasonography. Other measured factors included lipid levels, body mass index, fasting glucose, hemoglobin A
1c
, albumin/creatinine ratio, and self-reported medical history. Heritability estimates were obtained by using variance component methodology, as implemented in the SOLAR software package. Tests for association between carotid IMT and variables were performed by using mixed model analysis while accounting for the correlation due to family structure.

Results

—

The age-, sex-, and race-adjusted heritability estimate for carotid IMT was 0.32 (SE 0.17,
P
=0.02). Further adjustment for total cholesterol, hypertension status, and current smoking status resulted in a heritability estimate of 0.41 (SE 0.16,
P
=0.004). The strongest predictors of carotid IMT, after adjusting for age and sex, were ethnicity (African American versus white), total cholesterol, and smoking status.

Conclusions

—

These data provide empirical evidence that subclinical cardiovascular disease has a significant genetic component and merits a search for the genes involved in susceptibility to the atherosclerotic complications of diabetes.
Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons
Authors: Wang Xiaoying , Mori Tatsuro , Sumii Toshihisa , Lo Eng H.
Published: July 2002

Background and Purpose

—

Apoptotic-like pathways may contribute to brain cell death after intracerebral hemorrhage. In this study, we used a simplified in vitro model of hemoglobin neurotoxicity to map the caspase cascades involved and to document the role of oxidative stress.

Methods

—

Primary neuronal cultures were obtained from rat cerebral cortex and exposed to hemoglobin to induce cell death. Cytotoxicity was assessed via measurements of mitochondrial viability (MTT assay) and lactate dehydrogenase (LDH assay). Activation of caspase-3, -8, and -9 was measured by Western blot and enzyme activity assays. Various caspase inhibitors (zVADfmk, zDEVDfmk, zIETDfmk, and zLEHDfmk) were tested for neuroprotective efficacy. The role of oxidative stress was assessed with the use of U83836E as a potent scavenger of free radicals.

Results

—

Exposure of primary cortical neurons to hemoglobin induced a dose- and time-dependent cytotoxicity. Western blots showed upregulation of cleaved caspase-3. Enzyme assays showed an increase in caspase-9–like and caspase-3–like activity. However, caspase inhibition did not result in neuroprotection. In contrast, the free radical scavenger U83836E significantly reduced hemoglobin-induced neuronal death. Combination treatment with both U83836E and the broad spectrum caspase inhibitor zVADfmk did not yield additional protection.

Conclusions

—

Upstream and downstream caspases were upregulated after hemoglobin-induced neurotoxicity in vitro, but only an antioxidant approach with a potent free radical scavenger significantly improved neuronal survival. These data suggest that in addition to the activation of caspase cascades, parallel pathways of oxidative stress may predominate in this model of hemoglobin neurotoxicity.
Stroke Rehabilitation
Authors: Roth Elliot J. , Lovell Linda , Harvey Richard L. , Bode Rita K. , Heinemann Allen W.
Published: July 2002

Background and Purpose

—

The aim of this study was to investigate the associations between tracheostomies, enteral feeding tubes, and indwelling urinary catheters and functional outcome measures, incidence of medical complications, and resource use in an inpatient stroke rehabilitation program.

Methods

—

A cohort of 1553 patients consecutively admitted for inpatient stroke rehabilitation was studied. Demographic and stroke characteristics, impairment (National Institutes of Health Stroke Scale) and disability level (Functional Independence Measure [FIM]), preexisting medical conditions, and the presence of tracheostomies, enteral feeding tubes, and indwelling urinary catheters were recorded at admission. The occurrence of medical complications during rehabilitation, discharge disability level, length of rehabilitation stay, and rehabilitation hospital charges were recorded at discharge.

Results

—

Compared with patients with no medical tubes, patients with 3 medical tubes had significantly higher National Institutes of Health Stroke Scale scores, lower admission and discharge FIM scores, reduced FIM efficiency scores (average FIM score change per day), and twice the number of medical complications. Patients with 3 medical tubes stayed 28 days longer in acute hospitalization and 20 days longer in rehabilitation compared with patients with no medical tubes. The presence of even a single medical tube was associated with longer length of stay, more medical complications during rehabilitation, and greater disability level at discharge.

Conclusions

—

The presence of ≥1 medical tubes is associated with more severe and disabling strokes, an increased number of medical complications, longer acute and rehabilitation hospitalizations, and greater resource use.
Increased Plasma C-Reactive Protein in Familial Hypoalphalipoproteinemia
Authors: Sampietro Tiziana , Bigazzi Federico , Dal Pino Beatrice , Fusaro Simone , Greco Francesco , Tuoni Mario , Bionda Alberto
Published: July 2002

Background
—

HDL molecules have an established role in the regression processes of atherosclerosis as well as a putative role as antiinflammatory agents. Our study investigated whether familial hypoalphalipoproteinemia, a genetic form of dyslipidemia characterized by very low HDL levels, might be associated with increased inflammation markers such as C-reactive protein.

Methods and Results
—

A total of 50 subjects with hypoalphalipoproteinemia (age, 53.1±16.7 years) were compared with 64 healthy controls (age, 51.9±12.4 years). Apart from significantly lower values of HDL cholesterol (30.2±4.0 versus 52.5±12.7 mg/dL,
P
<0.0001) and apolipoprotein AI (113.3±20.0 versus 155.4±24.9 mg/dL,
P
<0.0001) and higher levels of triglycerides (141.3±62.9 versus 73.5±39.9 mg/dL,
P
<0.0001), patients did not show different plasma values of total cholesterol and LDL cholesterol when compared with healthy controls (181.5±36.6 versus 186.3±32.6 mg/dL; 123.0±31.5 versus 119.1±30.3 mg/dL). CRP plasma values were significantly higher in patients than in controls (median 0.34 [range 0.02 to 4.66] versus 0.07 [0.02 to 0.85] mg/dL,
P
<0.0001). In the patient group, CRP values were significantly higher in subjects with angiographically documented coronary atherosclerotic disease than in those without. Moreover, CRP concentrations were inversely correlated with both HDL cholesterol (
r
= −0.44,
P
=0.0006) and apolipoprotein AI (
r
= −0.45,
P
=0.0006) values.

Conclusions
—

Elevation of C-reactive protein values in familial hypoalphalipoproteinemia, in the absence of signs and symptoms of local or systemic inflammation or systemic or recurrent disease, may suggest an upregulation of proinflammatory mechanisms, which is further exacerbated by the presence of coronary atherosclerotic disease.
Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats
Authors: Michelakis Evangelos D. , McMurtry M. Sean , Wu Xi-Chen , Dyck Jason R.B. , Moudgil Rohit , Hopkins Teresa A. , Lopaschuk Gary D. , Puttagunta Lakshmi , Waite Ross , Archer Stephen L.
Published: July 2002

Background
—

Chronic hypoxic pulmonary hypertension (CH-PHT) is associated with suppressed expression and function of voltage-gated K
+
channels (Kv) in pulmonary artery (PA) smooth muscle cells (SMCs) and a shift in cellular redox balance toward a reduced state. We hypothesized that dichloroacetate (DCA), a metabolic modulator that can shift redox balance toward an oxidized state and increase Kv current in myocardial cells, would reverse CH-PHT.

Methods and Results
—

We studied 4 groups of rats: normoxic, normoxic+DCA (DCA 70 mg · kg
−1
· d
−1
PO), chronically hypoxic (CH), and CH+DCA. CH and CH+DCA rats were kept in a hypoxic chamber (10% Fi
o
2
) for 2 to 3 weeks. DCA was given either at day 1 to prevent or at day 10 to reverse CH-PHT. We used micromanometer-tipped catheters and measured hemodynamics in closed-chest rats on days 14 to 18. CH+DCA rats had significantly reduced pulmonary vascular resistance, right ventricular hypertrophy, and PA remodeling compared with the CH rats. CH inhibited
I
K
, eliminated the acute hypoxia–sensitive
I
K
, and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 μmol/L) increased
I
K
in CH-PASMCs. In a mammalian expression system, DCA activated Kv2.1 by a tyrosine kinase–dependent mechanism. When given long-term, DCA partially restored
I
K
and Kv2.1 expression in PASMCs without altering right ventricular pyruvate dehydrogenase activity, suggesting that the beneficial effects of DCA occur by nonmetabolic mechanisms.

Conclusions
—

DCA both prevents and reverses CH-PHT by a mechanism involving restoration of expression and function of Kv channels. DCA has previously been used in humans and may potentially be a therapeutic agent for pulmonary hypertension.
Decreased Cardiac Expression of Vascular Endothelial Growth Factor and Its Receptors in Insulin-Resistant and Diabetic States
Authors: Chou Eva , Suzuma Izumi , Way Kerrie J. , Opland Darren , Clermont Allen C. , Naruse Keiko , Suzuma Kiyoshi , Bowling Nancy L. , Vlahos Chris J. , Aiello Lloyd Paul , King George L.
Published: July 2002

Background

—

Inadequate angiogenic response to ischemia in the myocardium of diabetic patients could result in poor collateral formation. Yet, excessive neovascularization in the retina causes proliferative diabetic retinopathy. Since vascular endothelial growth factor (VEGF) is the major angiogenic factor expressed in response to hypoxia, we have characterized expression of VEGF and its receptors in retina, renal glomeruli, aorta, and myocardium in insulin-resistant and diabetic states.

Methods and Results

—

The expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, in the myocardium was decreased significantly by 40% to 70% in both diabetic and insulin-resistant nondiabetic rats. Twofold reductions in VEGF and VEGF-R2 were observed in ventricles from diabetic patients compared with nondiabetic donors. In contrast, expression of VEGF and its receptors were increased 2-fold in retina and glomeruli from diabetic or insulin-resistant rats. Insulin treatment of diabetic rats normalized changes in both cardiac and microvascular tissues. Insulin increased VEGF mRNA expression in cultured rat neonatal cardiac myocytes.

Conclusions

—

The results documented for the first time that differential regulation of VEGF and its receptors exist between microvascular and cardiac tissues, which can be regulated by insulin. These results provide a potential explanation for concomitant capillary leakage and neovascularization in the retina and inadequate collateral formation in the myocardium of insulin-resistant and diabetic patients.
Simple Scoring Scheme for Calculating the Risk of Acute Coronary Events Based on the 10-Year Follow-Up of the Prospective Cardiovascular Münster (PROCAM) Study
Authors: Assmann Gerd , Cullen Paul , Schulte Helmut
Published: July 2002

Background

—

The absolute risk of an acute coronary event depends on the totality of risk factors exhibited by an individual, the so-called global risk profile. Although several scoring schemes have been suggested to calculate this profile, many omit information on important variables such as family history of coronary heart disease or LDL cholesterol.

Methods and Results

—

Based on 325 acute coronary events occurring within 10 years of follow-up among 5389 men 35 to 65 years of age at recruitment into the
Pro
spective
Ca
rdiovascular
Mü
nster (PROCAM) study, we developed a Cox proportional hazards model using the following 8 independent risk variables, ranked in order of importance: age, LDL cholesterol, smoking, HDL cholesterol, systolic blood pressure, family history of premature myocardial infarction, diabetes mellitus, and triglycerides. We then derived a simple point scoring system based on the β-coefficients of this model. The accuracy of this point scoring scheme was comparable to coronary event prediction when the continuous variables themselves were used. The scoring system accurately predicted observed coronary events with an area under the receiver-operating characteristics curve of 82.4% compared with 82.9% for the Cox model with continuous variables.

Conclusions

—

Our scoring system is a simple and accurate way of predicting global risk of myocardial infarction in clinical practice and will therefore allow more accurate targeting of preventive therapy.
Morphological Predictors of Arterial Remodeling in Coronary Atherosclerosis
Authors: Burke Allen P. , Kolodgie Frank D. , Farb Andrew , Weber Deena , Virmani Renu
Published: July 2002

Background

—

Although arterial remodeling in atherosclerotic arteries affects luminal patency, the role of plaque components has not been systematically studied.

Methods and Results

—

Coronary segments (n=2885) were harvested from the hearts of 36 patients who died of severe coronary artery disease after perfusion fixation. Remodeling was determined by morphometric analysis of 657 sections selected as reference segments and 1318 segments with atheromatous plaques. Atherosclerotic plaques were identified as fibroatheroma, thin-cap fibroatheroma, intraplaque hemorrhage with or without rupture or erosion, or total occlusion. Plaque components consisted of calcification, lipid core, macrophage burden, and fibrosis. There was no correlation between plaque area and lumen size in proximal arteries, unlike middle and distal segments, which demonstrated a significant correlation. Marked expansion of the internal elastic lamina (IEL) occurred in plaque hemorrhages with or without and thin-cap fibroatheroma (vulnerable plaque), whereas in erosions and total occlusions there was shrinkage of the IEL. Macrophage burden, lipid core size, calcium (in fibrous plaque and lipid core), and medial atrophy were all associated with positive remodeling; fibrous areas, however, were negatively associated with remodeling.

Conclusions

—

Inflammation, calcification, and medial thinning are primary determinants of positive remodeling, which appears to be a feature of plaque instability.
Oral Administration of an Apo A-I Mimetic Peptide Synthesized From D-Amino Acids Dramatically Reduces Atherosclerosis in Mice Independent of Plasma Cholesterol
Authors: Navab Mohamad , Anantharamaiah G.M. , Hama Susan , Garber David W. , Chaddha Manjula , Hough Greg , Lallone Roger , Fogelman Alan M.
Published: July 2002

When apolipoprotein A-I mimetic peptides synthesized from either D- or L-amino acids were given orally to LDL receptor-null mice, only the peptide synthesized from D-amino acids was stable in the circulation and enhanced the ability of HDL to protect LDL against oxidation. The peptide synthesized from L-amino acids was rapidly degraded and excreted in the urine. When a peptide synthesized from D-amino acids (D-4F) was administered orally to LDL receptor-null mice on a Western diet, lesions decreased by 79%. When added to the drinking water of apoE-null mice, D-4F decreased lesions by approximately 75% at the lowest dose tested (0.05 mg/mL). The marked reduction in lesions occurred independent of changes in total plasma or HDL-cholesterol.
Tissue Doppler Echocardiographic Evidence of Reverse Remodeling and Improved Synchronicity by Simultaneously Delaying Regional Contraction After Biventricular Pacing Therapy in Heart Failure
Authors: Yu Cheuk-Man , Chau Elaine , Sanderson John E. , Fan Katherine , Tang Man-Oi , Fung Wing-Hong , Lin Hong , Kong Shun-Ling , Lam Yui-Ming , Hill Michael R.S. , Lau Chu-Pak
Published: July 2002

Background
—

Biventricular pacing has been proposed to improve symptoms and exercise capacity in patients with advanced heart failure and wide electrocardiographic wave complexes. This study investigated the effect of biventricular pacing on reverse remodeling and the underlying mechanisms.

Methods and Results
—

Twenty-five patients with NYHA class III to IV heart failure and electrocardiographic wave complex duration >140 ms receiving biventricular pacing therapy were assessed serially up to 3 months after pacing and when pacing was withheld for 4 weeks. Tissue Doppler echocardiography was performed using a 6-basal, 6-mid segmental model to assess the time to peak sustained systolic contraction (T
S
). There was significant improvement of ejection fraction, dP/dt, and myocardial performance index; decrease in mitral regurgitation, left ventricular (LV) end-diastolic (205±68 versus 168±67 mL,
P
<0.01) and end-systolic volume (162±54 versus 122±42 mL,
P
<0.01); and improved 6-minute hall-walk distance and quality of life score after pacing for 3 months. The mechanisms of benefits were as follows: (1) improved LV synchrony, as evident by homogeneous delay of T
S
to a timing close to the latest (usually the lateral) segment abolishing the intersegmental difference in T
S
and decreasing the standard deviation of T
S
within the left ventricle (37.7±10.9 versus 29.3±8.3 ms,
P
<0.05); (2) improved interventricular synchrony; and (3) shortened isovolumic contraction time (122±57 versus 82±36 ms,
P
<0.05) but increased diastolic filling time. These benefits are pacing dependent, because withholding the pacing resulted in varying speeds in the loss of cardiac improvements.

Conclusions
—

Biventricular pacing reverses LV remodeling and improves cardiac function. Improvement of LV mechanical synchrony seems to be the predominant mechanism.
Augmented Expression of Neuronal Nitric Oxide Synthase in the Atria Parasympathetically Decreases Heart Rate During Acute Myocardial Infarction in Rats
Authors: Takimoto Yoshihito , Aoyama Takeshi , Tanaka Koichi , Keyamura Reiko , Yui Yoshiki , Sasayama Shigetake
Published: July 2002

Background
—

Nitric oxide (NO) synthesized within sinoatrial cells recently has been shown to participate in the autonomic control of heart rate. We hypothesized that NO in the neuronal cells in the heart was increased and parasympathetically regulated heart rate after myocardial infarction (MI).

Methods and Results
—

We examined heart rate dynamics and neuronal NO synthase (nNOS) expression and activities in the atria of rats with MI 1, 3, 7, and 14 days after MI (n=7 to 22 for each group). Both the mRNA levels of nNOS in the atria determined by competitive reverse transcriptase-polymerase chain reaction and the protein levels determined by Western blotting were significantly increased compared with controls 1, 3, and 7 days after MI. nNOS activity in the atria 1 day after infarction was also increased in MI rats. nNOS immunoreactivity was observed in nerve fibers in the atria. After infusion of a specific inhibitor of nNOS and iNOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM) (50 mg/kg IV), heart rate was significantly (
P
<0.01) increased in MI rats compared with controls 1, 3, and 7 days after MI. The iNOS-specific inhibitor, 1400W (10 mg/kg SC), did not significantly affect the heart rate in rats with MI. The effect of TRIM was abolished by pretreatment with
l
-arginine (25 mg/kg IV) or by parasympathetic blockade with atropine but not by propranolol. There was a strong correlation (
r
=0.837,
P
<0.0001) between the nNOS protein expression and heart rate change after TRIM infusion.

Conclusions
—

These results indicate that increased nNOS parasympathetically decreased heart rate via the production of NO in rats with acute MI.
Overexpression of the Serine Elastase Inhibitor Elafin Protects Transgenic Mice From Hypoxic Pulmonary Hypertension
Authors: Zaidi Syed H.E. , You Xiao-Mang , Ciura Sorana , Husain Mansoor , Rabinovitch Marlene
Published: July 2002

Background
—

Increased serine elastase activity has been implicated in the vascular remodeling associated with chronic hypoxia-related pulmonary hypertension in rats.

Methods and Results
—

In this study we determined the time course of hypoxia-induced serine elastase activity in the murine lung and related this to initiation of a proteolytic cascade characterized by an increase in matrix metalloproteinases (MMPs). We then used transgenic mice in which overexpression of the selective serine elastase inhibitor elafin was targeted to the cardiovascular system to determine whether upregulation of a naturally occurring serine elastase inhibitor suppresses MMPs and the hemodynamic and structural response to chronic hypoxia (air at 380 mm Hg). In nontransgenic but not in elafin-transgenic mice, we documented a transient increase in serine elastase activity after 12 hours of hypoxic exposure attributed to a 30-kDa protein as determined by elastin zymography and fluorophosphonate/fluorophosphate-biotin labeling. Two days after hypoxia, the pro-forms of MMP-2 and MMP-9 were induced in the nontransgenic mice, but MMP-9 was suppressed in elafin-transgenic mice. Acute hypoxic vasoconstriction was similar in nontransgenic and elafin-transgenic littermates. Chronic hypoxia for 26 days resulted in >1-fold increase in right ventricular pressure (
P
<0.004) in nontransgenic compared with control or elafin-transgenic littermates. In the latter mice, normalization of the right ventricular pressure was associated with reduced muscularization and preservation of the number of distal vessels (
P
<0.04 for both comparisons).

Conclusions
—

Modulation of the severity of chronic hypoxia-induced pulmonary vascular disease could be a function of endogenously expressed serine elastase inhibitors.