bluuebunny/crossref_metadata_2025 huggingface dataset:
Metoclopramide and Cellular Immune Functions during Polymicrobial Sepsis
Authors: Oberbeck R. , Schmitz D. , Wilsenack K. , Schüler M. , Pehle B. , Schedlowski M. , Exton M.S.
Published: March 2004

Metoclopramide (MCP) has been demonstrated to restore the depressed cellular immune function after hemorrhage by increasing the release of the immunomodulatory pituitary hormone prolactin. We investigated the effect of MCP on serum prolactin concentrations, on cellular immune functions (immune cell distribution, splenocyte proliferation, apoptosis and cytokine release) and on the survival 48 h after induction of a polymicrobial sepsis in mice. Administration of MCP increased circulating serum prolactin concentrations and splenocyte apoptosis rate and improved cellular cytokine release, but did not affect mortality of septic mice. We therefore conclude that administration of MCP modulated splenocyte apoptosis and cytokine release in a murine model of sepsis without an impact on the survival. Furthermore, this effect may be mediated by an increased endogenous prolactin release.
Hyaluronan-Based Antiadhesive Membrane Has No Major Effect on Intraperitoneal Growth of Colonic Tumour Cells
Authors: Sikkink C.J.J.M. , Postma V.A. , Reijnen M.M.P.J. , de Man B. , Bleichrodt R.P. , van Goor H.
Published: March 2004

Background: A relationship between post-surgical adhesion formation and peritoneal tumour implantation has been proposed. Hyaluronan (HA)-based agents reduce adhesion formation, but the effect on peritoneal tumour is not established. This study investigated the influence of a HA-containing agent on intraperitoneal tumour in an experimental model. Methods: 66 Balb/c mice underwent laparotomy and damage was inflicted to the parietal peritoneum. The animals were randomized into five groups. Groups 1 and 2 received HA-carboxymethylcellulose bioresorbable membrane and no treatment, respectively. Mice in groups 3–5 were injected intraperitoneally with 105 colon 26-B cells after the laparotomy. Treatment consisted of HA membrane, no HA agent and placement of HA membrane on the non-traumatized peritoneal wall, respectively. Animals were killed after 14 days; adhesions were scored in groups 1 and 2, and the tumour mass in groups 3–5. 45 Wag/Rij rats underwent the same procedures and treatment as mice in groups 3–5. In rats, 106 CC-531 cells were injected. Rats were killed after 3 weeks and the tumour mass was scored. Results: HA membrane resulted in a significant reduction of adhesions, but had no major effect on the intraperitoneal tumour mass in mice and rats. Conclusion: HA-carboxymethylcellulose bioresorbable membrane has no major effect on intraperitoneal tumour implantation and growth in an experimental model.
Functional Stereotactic Surgery for Treatment of Cervical Dystonia: Review of the Experience from the Lesional Era
Authors: Loher Thomas J. , Pohle Thomas , Krauss Joachim K.
Published: March 2004

Background: Functional stereotactic neurosurgery has been rediscovered as a powerful tool to treat various manifestations of medically refractory dystonia. The purpose of this study was to provide the first systematic review of previous experience with thalamic and basal ganglia surgery in the treatment of cervical dystonia (CD). Methods: A comprehensive review of the literature published between 1950 and 1990 was performed. In addition, data from an unpublished doctoral thesis on 162 patients with CD operated on by Mundinger between 1972 and 1986 were analyzed. Results: Overall, there is published documentation of experience with more than 300 patients with CD who underwent functional stereotactic surgery between the late 1950s and the early 1980s. In general, amelioration of CD was achieved in about 50–70% of patients in most studies. Bilateral surgery generally provided better outcomes than unilateral surgery. Postoperative benefit was reported to become evident only after a delay in several studies. Some reports demonstrated sustained benefit after follow-up of more than 5 years. Bilateral procedures, in particular bilateral thalamotomies, were clearly associated with a higher rate of postoperative side effects, such as dysarthria, dysphagia and ataxia, ranging from 20 to 70%. In the first decade after its introduction, thalamotomy was the preferred procedure. Later, the subthalamic area was targeted more frequently in order to affect pallidal outflow. Experience with targeting the pallidum proper was limited. Functional stereotactic surgery for CD was abandoned in the late 1970s for several reasons, including the general decline in movement disorder surgery at that time, the introduction of selective peripheral denervation and the widespread and beneficial use of botulinum toxin soon thereafter. Conclusions: Functional stereotactic surgery for treatment of CD has a rich history. There are several lessons to be learned from review of earlier experience. Contemporary techniques have led to a significant improvement in the benefit to risk ratio, in particular regarding bilateral surgery.
A Simple Method to Assess Accuracy of Deep Brain Stimulation Electrode Placement: Pre-Operative Stereotactic CT + Postoperative MR Image Fusion
Authors: Ferroli Paolo , Franzini Angelo , Marras Carlo , Maccagnano Elio , D’Incerti Ludovico , Broggi Giovanni
Published: March 2004

Objective: To describe a method for the measurement of the accuracy of deep brain stimulation (DBS) electrode placement with the use of image fusion technologies. Patients and Methods: Ten consecutive patients suffering from movement disorders underwent DBS electrode placement. Postoperative MR images were fused with the pre-operative stereotactic CT. The placement error in the anteroposterior, lateral and vertical planes was calculated. Results: The anteroposterior mean error ± SD was 0.61 ± 0.22 mm (range 0.2–0.9 mm). The lateral mean error ± SD was 0.65 ± 0.27 mm (range 0.2–2.2 mm). The vertical mean error ± SD was 0.82 ± 0.31 mm (range 0.3–1.6 mm). Conclusions: This technique provides a simple and precise method for the evaluation of the accuracy of DBS electrode placement.
Orbitofrontal Epilepsy: Electroclinical Analysis of Surgical Cases and Literature Review
Authors: Smith Joseph R. , Sillay Karl , Winkler Peter , King Don W. , Loring David W.
Published: March 2004

Clinical and electrographic data were reviewed on 2 of our patients with orbitofrontal epilepsy who were seizure free at 5-year follow-up, and on 2 similar patients from the literature. One of our patients was lesional, and the other was nonlesional. Interictal EEG discharges were lateralized to the side of invasively recorded orbitofrontal seizures in the nonlesional case. In this case, no clinical manifestations occurred until the orbitofrontal discharge had spread to the opposite orbitofrontal and both mesial temporal areas. Unresponsiveness or arrest of activity were the initial manifestations of complex partial seizures in both cases. The 2 cases from the literature with long-term seizure-free follow-up had little impairment of awareness and displayed vigorous motor automatisms. Interictal epileptiform activity was bifrontally synchronous in 1 case. Ipsilateral frontotemporal discharges were seen in both. Invasive ictal epileptiform activity appeared maximal in the ipsilateral orbitofrontal region in both patients. No consistent electrographic or clinical pattern characterized these 4 cases. Seizures of orbitofrontal origin may be characterized by either unresponsiveness associated with oroalimentary automatisms or limited alteration of awareness and associated with vigorous motor automatisms. Invasive monitoring of the orbitofrontal cortex should be considered in nonlesional cases with complex partial seizures that show nonlocalizing ictal patterns and interictal frontal or frontotemporal epileptiform discharges.
Epilepsy in Cortical Dysplasia: Factors Affecting Surgical Outcome
Authors: Fountas K.N. , King D.W. , Meador K.J. , Lee G.P. , Smith J.R.
Published: March 2004

Purpose: To determine the factors influencing the outcome of cortical dysplasia resection for medically refractory epilepsy. Material and Methods: 13 patients underwent craniotomy for resection of epileptogenic foci using electrographic and MRI guidance. All patients had had seizures for more than 2 years and were on 3 or more antiepileptic medications. Their preoperative evaluation included MRI, neuropsychological evaluation including the WADA test, video EEG monitoring and intraoperative electrocorticography. Invasive preoperative monitoring was employed in 8 cases. The Engel outcome classification system was used. The mean follow-up time was 60.1 months with a minimum follow-up of 24 months. Results: Postoperatively, all 6 patients younger than 18 years were seizure free. Among 7 patients older than 18 years, 6 were class II and 1 was class III. Based on their preoperative MRI studies, among the patients with abnormal studies, 2 were class I, 5 were class II and 1 was class III. Among patients with normal studies, 4 were class I and 1 class II. Regarding the ictal EEG findings, among patients with localizing findings, 4 were class I and 5 were class II. Among patients with no localization in their ictal EEG, 2 were class I, 1 class II and 1 class III. Regarding the invasive preoperative monitoring of the 7 patients with localizing findings, 5 were class I and 2 were class II. The only patient with nonlocalizing findings was class II. Finally, among the patients with no invasive preoperative monitoring, 3 were class I, 1 was class II and 1 was class III. Conclusion: Cortical resection is an effective treatment modality in patients with medically refractory epilepsy. In our series, the outcome was better in patients less than 18 years old and patients with normal preoperative MRI studies.
Stabilization Clamp for Insertion of Deep Brain Stimulation Electrodes: Technical Note
Authors: McNeely P. Daniel , Mendez Ivar , Hill Ron , Smith Steve W.
Published: March 2004

Background: Deep brain stimulation (DBS) electrodes are being implanted with increasing frequency for the management of movement disorders and chronic pain. Success with this neuro-augmentative technique requires accurate electrode lead placement. In order to enhance accuracy of final lead placement and ease of insertion, we describe a useful and reliable DBS electrode lead stabilization device developed and used at our centre. Materials and Methods: The DBS electrode stabilization device consists of a 2-clamp system designed to fit the Leksell stereotactic frame. The clamps work in series to secure the stereotactic lead at the time of its final positioning in the desired subcortical target without the need of fluoroscopic control. Results: The DBS electrode stabilization device has been used in 30 patients for 54 electrode implantations at our institution since 2000. Postoperative magnetic resonance imaging was performed in all cases and confirmed accurate placement of the electrodes. Conclusions: Accurate electrode lead placement is critical for the clinical efficacy of DBS systems. The simple and reliable stabilization device described here is easy to operate and enhances the final placement accuracy of DBS electrode leads.
A Retrospective Study of the Clinical Outcomes and Significant Variables in the Surgical Treatment of Temporal Lobe Tumor Associated with Intractable Seizures
Authors: Choi Jae Young , Chang Jin Woo , Park Yong Gou , Kim Tai Seung , Lee Byung In , Chung Sang Sup
Published: March 2004

A retrospective study was performed assessing the preoperative evaluation, and the postoperative outcomes in 35 patients with a temporal lobe tumor with intractable seizures who were treated by our neurosurgery service between October 1995 and December 1999. The mean age of the patients at the time of surgery was 27.9 years. The period of follow-up after surgery was a mean of 33.0 months. Of the study group of 35 patients, 27 (77.1%) became completely seizure free after surgery (class I), and 2 patients (5.7%) had no more than 2 seizures per year (class II). Worthwhile seizure control was achieved in 29 patients (82.8%). There was a statistical significance between the extent of tumor resection and favorable seizure outcome (p = 0.014). The most frequent histopathological diagnoses were classic epilepsy-associated ganglioglioma in 16 (45.7%) patients and low-grade astrocytoma in 10 (28.6%) patients. Complete resection of tumor was the most significant factor in obtaining a favorable seizure outcome.
Gamma Knife Radiosurgery for Trigeminal Neuralgia: Comparing the Use of a 4-mm versus Concentric 4- and 8-mm Collimators
Authors: Kanner Andrew A. , Neyman Gennady , Suh John H. , Weinhous Martin S. , Lee Shih-Yuan , Barnett Gene H.
Published: March 2004

Purpose: Gamma knife (GK) radiosurgery for trigeminal neuralgia (TN) has been effective in 50–80% of cases when using a single 4-mm collimator and a maximum dose of 60–90 Gy. Attempting to improve the response rate by increasing the dose may lead to increased risk of facial numbness or disturbed sensation. Combined use of 4- and 8-mm collimators results in a larger target volume, which would potentially treat a larger region of the nerve without increasing the maximum dose. Materials and Methods: One hundred-one patients suffering from medically refractory TN were evaluated. Fifty-four were treated with a single shot using a 4-mm helmet and 47 with concentrically aimed, equally weighted 4- and 8-mm helmets. 75 Gy were prescribed to the 100% isodose line (using a 4-mm helmet output factor of 0.80) in all cases. The outcome was assessed by interview or outpatient visit. Results: An excellent/good response was seen in 57.8 vs. 71.4%, respectively, with a partial response of 13.3 vs. 2.3%, respectively (p > 0.05). Pain recurrence occurred in 28.6 vs. 23.2%, respectively (p > 0.05). Conclusion: The use of a combined concentric 4- and 8-mm collimator treatment for medically refractory TN at a maximum dose of 75 Gy does not improve outcome as compared with a single 4-mm collimator with an equivalent maximum dose.
Recurrent Subependymoma Treated with Radiosurgery
Authors: Ecker Robert D. , Pollock Bruce E.
Published: March 2004

Purpose: Subependymomas are rare, slow-growing intracranial neoplasms of the subependymal matrix. We document a successful case of radiosurgical treatment of a multiply recurrent subependymoma. Materials andMethods: A nineteen-year-old male developed a recurrent fourth ventricular subependymoma after 6 resections, fractionated radiation therapy (50.4 Gy) and chemotherapy. In addition, a lesion consistent with a cavernous malformation (CM) was noted adjacent to the tumor within the previously irradiated region. Results: Stereotactic radiosurgery was performed covering both the subependymoma and the presumed CM. Fifty-four months after radiosurgery, both lesions had decreased in size and the patient remained neurologically unchanged. Conclusions: Subependymoma may be added to the list of primary glial neoplasms that have been successfully managed with stereotactic radiosurgery. Also, we add a case of presumed CM following radiation therapy to the literature.
Myocardial Reinfarction in a Patient with Coronary Ectasia
Authors: Mrdović Igor , Jozić Tanja , Ašanin Milika , Peruničić Jovan , Ostojić Miodrag
Published: March 2004

A 47-year-old male patient was admitted to our Emergency Hospital’s coronary unit with an acute myocardial infarction, localized inferolaterally. He had been hospitalized 2 months before this occurrence because of persistent chest pain accompanied by elevation of the ST segment in precordial and inferior leads, for which he received thrombolytic therapy. Selective cardiac catheterization was then also effected, and showed diffuse ectasia of coronary arteries with no significant stenoses. Since streptokinase had been applied recently, the patient was given standard therapy as well as electroshocks because of chamber fibrillation. Two hours after admission, the infarct pain ceased and rapid ECG improvement occurred. Repeated coronarography showed a situation identical to the previous one. The patient was sent home to proceed with drug therapy.
Modulation of Cortisol Metabolism during Treatment of Acromegaly Is Independent of Body Composition and Insulin Sensitivity
Authors: Frajese Giovanni V. , Taylor Norman F. , Jenkins Paul J. , Besser G. Michael , Monson John P.
Published: March 2004

Objectives: The set point of cortisol-cortisone conversion is shifted in the direction of cortisone by the inhibition of the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) during adult GH replacement and in active acromegaly. Additionally, both fat mass and insulin may modulate 11β-HSD1 and are both influenced by changes in GH status. This study examined the relative direct contribution of GH/IGF1 in modulating cortisol metabolism. Methods: Overall cortisol/cortisone conversion (ratio of urine 11-hydroxy-/11-oxo-cortisol metabolites; Fm/Em), insulin sensitivity (homeostatic model assessment; HOMA %S) and fat mass (DXA) were examined in parallel in 6 patients (mean age 53 years, range 42–76; 4 males, 2 females) with previously untreated active acromegaly during 6 months of therapy with Sandostatin® LAR® (20–30 mg i.m. 4 weekly). All but 1 patient had normal ACTH reserve. Results: At baseline, Pearson correlation demonstrated an inverse relationship between serum GH (mean of a 5-point day curve) and Fm/Em (r = –0.83, p = 0.04) and a trend towards an inverse relationship between HOMA %S and Fm/Em (r = –0.79, p = 0.06) but no other patterns were evident. During the course of treatment, serum GH decreased from 9.9 ± 6.4 (mean ± SD) to 3.5 ± 3.1 ng/ml (p < 0.01) and serum IGF-1 from 785 ± 268 to 431 ± 156 ng/ml (p < 0.005). Fm/Em increased from 0.52 ± 0.1 to 0.75 ± 0.08 (p < 0.03) consistent with increased 11β-HSD1 activity. There were no significant changes in truncal fat percentage (33.0 ± 9.0 vs. 33.0 ± 8.2) or insulin sensitivity (HOMA %S: 37.1 ± 8.6 vs. 52.8 ± 33.7). Conclusions: Modulation of cortisol metabolism during treatment of active acromegaly is dependent on changes in GH/IGF-1 status and is not influenced by any individual change in body composition or insulin sensitivity.
Role of Angiotensin-Converting Enzyme and Neutral Endopeptidase in Flow-Dependent Remodeling
Authors: Korshunov Vyacheslav A. , Massett Michael P. , Carey Robert M. , Berk Bradford C.
Published: March 2004

Omapatrilat inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). We compared the effects of omapatrilat (40 mg/kg/day, p.o.) to fosinopril (40 mg/kg/day, p.o.) on flow-induced vascular remodeling in New Zealand genetically hypertensive (GH) rats. Both drugs equally reduced blood pressure (BP) initially, but systolic BP and pulse pressure were reduced more by omapatrilat after 1 week. Carotid remodeling was induced by partial ligation of the left common carotid artery (LCA). There was little remodeling in untreated GH rats – measured as outer diameter to body weight (OD/BW vs. before ligation): 97 ± 1% of initial LCA (low flow) and 107 ± 3% of initial right common carotid artery (RCA, high flow). In contrast, OD/BW increased to 118 ± 5% (p < 0.05) of initial RCA after omapatrilat versus 108 ± 2% (p = 0.96) after fosinopril. The major change was increased RCA lumen area which was significantly larger in omapatrilat-treated animals (127% vs. control) than fosinopril-treated animals (103% vs. control). The increase in outward remodeling after omapatrilat treatment correlated weakly with vascular cGMP levels and decreased systolic BP. The results suggest that dual inhibition of NEP/ACE may have greater effects than ACE inhibition alone on vessel remodeling in hypertension.
Inward Remodeling of the Rabbit Aorta Is Blocked by the Matrix Metalloproteinase Inhibitor Doxycycline
Authors: Courtman David W. , Franco Christopher D. , Meng Qinghe , Bendeck Michelle P.
Published: March 2004

Constrictive arterial remodeling accounts for a significant proportion of lumen loss in atherosclerotic progression and postangioplasty stenosis. Recent research suggests that constrictive remodeling is mediated by turnover of the extracellular matrix. We hypothesized that remodeling could be attenuated by treatment with the safe, effective matrix metalloproteinase (MMP) inhibitor doxycycline. Female rabbit abdominal aortas were denuded using a 4-Fr balloon embolectomy catheter, and reinjured 3 weeks later. Treatment with 30 mg/kg/day doxycycline was begun the day before the second injury. At 6 weeks after injury, lumen area measured 13.1 ± 1.2 mm2 in controls compared to 17.5 ± 1.6 mm2 in doxycycline-treated rabbits (p = 0.05). At 4 days after injury, MMP-2 activity was increased compared to uninjured controls, but doxycycline treatment reduced MMP-2 activity. Doxycycline treatment also inhibited fibrillar collagen deposition in the intima by 87% as detected by polarized light microscopy. Doxycycline was an effective inhibitor of constrictive arterial remodeling in the rabbit aorta. Treatment reduced MMP activity and attenuated the deposition of extracellular matrix particularly in the intima.
Changes in Activity of Plasma Thrombin Activatable Fibrinolysis Inhibitor in Pregnancy
Authors: Watanabe Takashi , Minakami Hisanori , Sakata Yoichi , Matsubara Shigeki , Sato Ikuo , Suzuki Mitsuaki
Published: March 2004

The thrombin activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis. Changes in the concentration of plasma TAFI molecules that are present and functional after activation by thrombin-thrombomodulin complex (TAFI activity) during pregnancy have not previously been studied, and we therefore conducted a present prospective study. Plasma TAFI activity was assayed in 15 healthy non-pregnant women and 176 healthy pregnant women at various stages of gestation. TAFI activity was higher in pregnant than in non-pregnant women. TAFI activity seemed to increase progressively until around 20 weeks of gestation, then maintained a moderately elevated level until delivery, and promptly decreased after delivery.
Lack of an Association between Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Ischaemic Stroke
Authors: Karagiannis Asterios , Balaska Katerina , Tziomalos Konstantinos , Tokalaki-Nikolaidou Laokratia , Papayeoryiou Athanasios , Zamboulis Chrysanthos
Published: March 2004

Background and Purpose: Numerous factors have been reported to influence the pathogenesis of stroke. The angiotensin I-converting enzyme (ACE) gene is a candidate gene for atherosclerotic-related diseases. In the present study, the association between the polymorphism of the ACE gene and ischaemic stroke was investigated. Methods: Using polymerase chain reaction techniques, 100 patients (48 males, age 69.3 ± 9.7 years) with cerebral infarction and 100 age- and sex-matched controls were divided into the following three ACE genotypes [deletion (D) and insertion (I)]: II, ID and DD. Results: There was no evidence of any association between the ACE gene polymorphism and the presence of ischaemic stroke (odds ratio 0.874, 95% confidence interval 0.386–1.973). Conclusions: The DD genotype in the human ACE gene does not appear to be a risk factor for ischaemic stroke. Further evaluation in a larger population study is required to examine the possibility of an increased risk of ischaemic stroke in DD homozygotes.
Endothelial Progenitor Cells: More Than an Inflammatory Response?
Authors: Rabelink Ton J. , de Boer Hetty C. , de Koning Eelco J.P. , van Zonneveld Anton-Jan
Published: March 2004

The formation of new capillaries (angiogenesis) may be of clinical importance in facilitating reperfusion and regeneration of hibernating cardiac tissue after myocardial infarction and in microvascular ischemia. Evidence is accumulating that as part of the response to hypoxia, bone marrow-derived circulating endothelial progenitor cells (CEPs) are mobilized and subsequently differentiate into proper endothelial cells. There are also indications that such CEPs can facilitate endothelial repair and angiogenesis in vivo. It is not clear yet, however, whether these CEPs are essential for these adaptive processes or what the relative contribution of CEP is compared with that of other mononuclear inflammatory cells that are mobilized to areas of ischemia. Moreover, there are still many uncertainties about how cardiovascular risk factors alter CEP function. Particularly when therapeutically mobilizing CEPs, a further understanding of this issue is essential to assess the risk of potentially harmful side effects of altered CEP function.
Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis
Authors: Kawashima Seinosuke , Yokoyama Mitsuhiro
Published: March 2004

Atherosclerosis is associated with an impairment of endothelium-dependent relaxations, which represents the reduced bioavailability of nitric oxide (NO) produced from endothelial NO synthase (eNOS). Among various mechanisms implicated in the impaired EDR in atherosclerosis, superoxide generated from dysfunctional eNOS has attracted attention. Under conditions in which vascular tissue levels of tetrahydrobiopterin (BH4), a cofactor for NOS, are deficient or lacking, eNOS becomes dysfunctional and produces superoxide rather than NO. Experimental studies in vitro have revealed that NO from eNOS constitutes an anti-atherogenic molecule. A deficiency of eNOS was demonstrated to accelerate atherosclerotic lesion formation in eNOS knockout mice. In contrast, eNOS overexpression with hypercholesterolemia may promote atherogenesis via increased superoxide generation from dysfunctional eNOS. Thus, eNOS may have 2 faces in the pathophysiology of atherosclerosis depending on tissue BH4 metabolisms. An improved understanding of tissue BH4 metabolisms in atherosclerotic vessels is needed, which would help in developing new strategies for the inhibition and treatment of atherosclerosis.
C-Reactive Protein Is Associated With Arterial Stiffness in Apparently Healthy Individuals
Authors: Yasmin  , McEniery Carmel M. , Wallace Sharon , Mackenzie Isla S. , Cockcroft John R. , Wilkinson Ian B.
Published: March 2004

Objective—

C-reactive protein (CRP) levels predict outcome in healthy individuals and patients with atherosclerosis. Arterial stiffness also independently predicts all-cause and cardiovascular mortality and may be involved in the process of atherosclerosis. The aim of this study was to investigate the relationship between stiffness and inflammation in a cohort of healthy individuals.

Methods and Results—

Pulse wave velocity (PWV) and blood pressure were assessed in 427 individuals. Subjects with cardiovascular disease, diabetes, hypercholesterolemia and those using medication were excluded. CRP correlated with age, mean arterial pressure (MAP), brachial and aortic PWV, and pulse pressures. In multiple regression models, aortic PWV correlated independently with age, CRP, male gender, and MAP (
R
2
=0.593;
P
<0.001). CRP was also independently associated with brachial PWV. Aortic augmentation index correlated with age, gender, MAP, and inversely with heart rate and height, but not with CRP (
R
2
=0.794;
P
<0.001). Aortic, carotid, and brachial pulse pressures were also independently associated with CRP levels.

Conclusion—

Aortic and brachial PWV, and pulse pressure, relate to levels of inflammation in healthy individuals, suggesting that inflammation may be involved in arterial stiffening. Anti-inflammatory strategies may, therefore, be of benefit in reducing arterial stiffness and thus cardiovascular risk, especially in patients with premature arterial stiffening.
HDL
3
Induces Cyclooxygenase-2 Expression and Prostacyclin Release in Human Endothelial Cells Via a p38 MAPK/CRE-Dependent Pathway: Effects on COX-2/PGI-Synthase Coupling
Authors: Norata G.D. , Callegari E. , Inoue H. , Catapano A.L.
Published: March 2004

Objective—

In endothelial cells, cyclooxygenase-1 (COX-1) and COX-2 both contribute to prostacyclin production. Recent findings suggest that COX-2 contributes significantly to systemic prostacyclin synthesis in humans; whether COX-2 inhibition is related to an increased cardiovascular risk is undergoing debate. HDLs have been shown to increase prostacyclin synthesis, thus in the present study we investigated the molecular mechanisms involved in this effect in endothelial cells.

Methods and Results—

HDL
3
(30 μg/mL) induced COX-2 expression in a time- and dose-dependent manner. COX-2 was found mainly in the perinuclear area where it co-localizes with PGI synthase. Transient transfection experiments showed that CRE is required for HDL-induced COX-2 transcription, and we demonstrated that p38 MAPK activation by HDL
3
is involved in COX-2 mRNA transcription and stabilization. As a consequence of COX-2-induction by HDL
3
prostacyclin production increased, incubation with a COX-2 selective inhibitor blocked this effect. Moreover, HDL
3
increased caveolin-1 phosphorylation, thus promoting PGI-synthase shuttling from the membrane to the perinuclear area.

Conclusion—

We conclude that in endothelial cells, HDL modulates COX-2/PGI-S activity via both p38 MAPK-dependent COX-2 mRNA stability and transcription and both caveolin-1–dependent PGI-synthase shuttling and COX-2 coupling. The understanding of these mechanisms may provide new insights into the antiatherogenic role of HDL.
Modulation of PPARα Expression and Inflammatory Interleukin-6 Production by Chronic Glucose Increases Monocyte/Endothelial Adhesion
Authors: Srinivasan Suseela , Hatley Melissa E. , Reilly Kelly B. , Danziger Eric C. , Hedrick Catherine C.
Published: March 2004

Objective—

We have previously reported increased monocyte adhesion to human aortic endothelial cells (HAECs) cultured in 25 mmol/L glucose (HG) compared with normal glucose (NG) (5.5 mmol/L). In this study, we explored mechanisms that contribute to increased monocyte adhesion by elevated glucose.

Methods and Results—

We found that HAECs cultured in HG have increased production of the chemokine interleukin-6 (IL-6). We examined whether IL-6 directly modulated monocyte adhesion to EC. Inhibition of IL-6 using a neutralizing antibody significantly reduced glucose-mediated monocyte adhesion by 50%, and addition of IL-6 directly to human EC stimulated monocyte adhesion. PPARα has been reported to negatively regulate expression of IL-6 in vascular cells, so we examined PPARα-associated signaling in EC. A known PPARα agonist, Wy14,643, prevented glucose-mediated IL-6 production by EC and reduced glucose-mediated monocyte adhesion by 40%. HG-cultured HAEC had a 50% reduction in expression of PPARα compared with control EC. Primary aortic EC isolated from PPARα knockout (KO) mice showed increased monocyte adhesion compared with EC isolated from control mice. PPARα KO EC also had increased production of IL-6. Finally, we measured IL-6 levels in diabetic db/db mice and found significant 6-fold elevations in IL-6 levels in db/db EC.

Conclusions—

These data indicate that IL-6 production is increased in diabetes and contributes to early vascular inflammatory changes. PPARα protects EC from glucose-mediated monocyte adhesion, in part through regulation of IL-6 production.
Effects of Exogenous and Endogenous Natriuretic Peptides on Forearm Vascular Function in Chronic Heart Failure
Authors: Schmitt Matthias , Gunaruwan Prasad , Payne Nicola , Taylor Justin , Lee Leong , Broadley Andrew J.M. , Nightingale Angus K. , Cockcroft John R. , Struthers Allan D. , Tyberg John V. , Frenneaux Michael P.
Published: March 2004

Objective—

Natriuretic peptides (NPs) reduce central venous pressure in patients with chronic heart failure (cHF) despite attenuation of arterial, renal, and humoral effects. This suggests a preserved venodilator response. This study had 4 aims: to compare the venodilator effects of human NPs in patients with cHF; to assess the contribution of basal ANP and BNP levels to regulation of forearm vascular volume (FVV); to test the hypothesis that venous ANP responsiveness is preserved in cHF; and to assess the involvement of endothelial nitric oxide-synthase (eNOS) in NP-induced vascular effects.

Methods and Results—

Venous and arterial forearm vascular responses to incremental intra-arterial doses of ANP, Urodilatin, BNP, CNP, or the ANP receptor antagonist A71915 were studied in 53 patients and 11 controls. ANP receptor antagonism reduced FVV by 4.4%±1.2% (
P
<0.05). The forearm blood flow (FBF) response to ANP was significantly blunted in patients versus controls (
P
<0.01), whereas FVV increased similarly in both groups (maximum 14.7% and 13.4%, both
P
<0.001). The eNOS blockade reduced ANP-induced FBF changes in controls but not in patients (
P
<0.05), whereas similar reductions in FVV changes were seen in groups (both
P
<0.001).

Conclusions—

In cHF venous, but not arterial, ANP responsiveness is preserved. Arterial endothelial dysfunction may contribute to NP resistance.
l
-Arginine Transport in the Human Coronary and Peripheral Circulation
Authors: Miner S.E.S. , Al-Hesayen A. , Kelly S. , Benson T. , Thiessen J.J. , Young V.R. , Parker J.D.
Published: March 2004

Background—

Nitric oxide synthase (NOS) uses arginine for the production of nitric oxide (NO). High intracellular concentrations of arginine suggest that NOS activity should be independent of plasma arginine supply. However, under certain conditions, increased plasma arginine concentrations appear to be associated with increased NOS activity. The purpose of this study was to explore arginine transport within the human coronary and peripheral circulation

Methods and Results—

Mass-labeled
15
N
2
-arginine was infused to steady state before cardiac catheterization in 31 patients. After diagnostic angiography, a catheter was placed in the coronary sinus. The transcardiac concentration gradient (aorta−coronary sinus) of
15
N
2
-arginine was used as a measure of arginine transport at baseline and during infusions of acetylcholine and
N
G
-monomethyl-
l
-arginine (L-NMMA). No gradient was detected at rest. During the infusion of acetylcholine, a significant gradient was detected (2.5±1.2 μmol/L,
P
=0.01) corresponding to a fractional extraction of 11.7±7.5%. This is consistent with in vitro studies that suggest that stimulation of NOS induces arginine transport. During the infusion of L-NMMA, the concentration of
15
N
2
-arginine increased in the coronary sinus, producing a gradient of −3.9±1.3 μmol/L (
P
=0.0002), corresponding to a fractional production of 20.5±5.0%. This is consistent with in vitro studies that suggest that L-NMMA induces the efflux of arginine from the cell to the extracellular space via transporter-mediated transstimulation.

Conclusions—

The use of steady-state
15
N
2
-arginine to examine transorgan
l
-arginine gradients represents a novel tool for the study of
l
-arginine transport and the mechanisms of endothelial and NOS dysfunction.
Ultrafine Particles Exert Prothrombotic but Not Inflammatory Effects on the Hepatic Microcirculation in Healthy Mice In Vivo
Authors: Khandoga Andrej , Stampfl Andreas , Takenaka Shinji , Schulz Holger , Radykewicz Roman , Kreyling Wolfgang , Krombach Fritz
Published: March 2004

Background—

Air pollution episodes are strongly associated with increased cardiovascular morbidity and mortality. The effect of ultrafine particles (UFPs), when translocated after inhalation, on the microcirculation of extrapulmonary organs remains unclear.

Methods and Results—

In C57BL/6 mice, either carbon black UFPs (1×10
7
and 5×10
7
) or vehicle was infused intra-arterially. Two hours after infusion, platelet- and leukocyte-endothelial cell interactions, sinusoidal perfusion, endothelial fibrin(ogen) deposition, and phagocytic activity of Kupffer cells were analyzed by intravital video fluorescence microscopy in the liver microvasculature. Expression of fibrin(ogen), von Willebrand factor (vWF), and P-selectin on hepatic endothelium was determined by immunostaining. Apoptotic cells were quantified in TUNEL-stained tissue sections. Application of UFPs caused significantly enhanced platelet accumulation on endothelium of postsinusoidal venules and sinusoids in healthy mice. UFP-induced platelet adhesion was not preceded by platelet rolling but was strongly associated with fibrin deposition and an increase in vWF expression on the endothelial surface. In contrast, inflammatory parameters such as the number of rolling/adherent leukocytes, P-selectin expression/translocation, and the number of apoptotic cells were not elevated 2 hours after UFP exposure. In addition, UFPs did not affect sinusoidal perfusion and Kupffer cell function.

Conclusions—

UFPs induce platelet accumulation in the hepatic microvasculature of healthy mice that is associated with prothrombotic changes on the endothelial surface of hepatic microvessels. Accumulation of particles in the liver exerts a strong procoagulatory impact but does not trigger an inflammatory reaction and does not induce microvascular/hepatocellular tissue injury.
Differential Effect of Urotensin II on Vascular Tone in Normal Subjects and Patients With Chronic Heart Failure
Authors: Lim Melissa , Honisett Suzy , Sparkes Christopher D. , Komesaroff Paul , Kompa Andrew , Krum Henry
Published: March 2004

Background—

Urotensin II (U-II) is a novel vasoactive peptide that also has direct hypertrophic and profibrotic effects on the myocardium. Upregulation of U-II and its receptor has been observed within the heart of patients with chronic heart failure (CHF). Furthermore, plasma levels of U-II have been found to be elevated in some but not all studies in such patients. However, the functional consequences of activation of the U-II system in patients with CHF, assessed by direct administration of exogenous U-II, have not been previously determined.

Methods and Results—

We compared the effect of iontophoresed U-II on skin microvascular tone in normal subjects and patients with CHF, assessed with the use of laser Doppler velocimetry. U-II mediated a dose-dependent vasodilator response in normal subjects (baseline, 137.9±52; U-II, 10
−12
mol/L, 145±134; U-II, 10
−9
mol/L, 712±179; U-II, 10
−7
mol/L, 943±139 arbitrary flux units [AFUs],
P
<0.0001). In contrast, a dose-dependent vasoconstrictor response was observed in patients with CHF (baseline, 336.1±129; U-II, 10
−12
mol/L, 317±131; U-II, 10
−9
mol/L, 129±137; U-II, 10
−7
mol/L, 22.4±130 AFUs,
P
<0.05). Differences in flow between normal subjects and patients with CHF were significant overall (
P
<0.001, 2-way ANOVA) and at the U-II 10
−9
mol/L and U-II 10
−7
mol/L dose level by Student’s unpaired
t
test (
P
<0.05,
P
<0.0001, respectively). In contrast, there was no significant difference between baseline blood flux and any dose of U-II in either group (or between groups) when the opposite polarity was applied.

Conclusions—

In addition to direct effects on the myocardium, U-II may contribute to the increased peripheral vascular tone that is characteristic of human CHF. The present observations support the contention that the U-II system may be a potentially important target for pharmacological blockade in the treatment of this condition.
Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease
Authors: Casas Juan P. , Bautista Leonelo E. , Humphries Steve E. , Hingorani Aroon D.
Published: March 2004

Background—

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may influence the risk of ischemic heart disease (IHD), but data from published studies with individually low statistical power are conflicting. To evaluate the role of polymorphisms in the eNOS gene in IHD, we considered all available studies in a meta-analysis.

Methods and Results—

Case-control studies evaluating the association between the Glu298Asp, −786T>C, and intron-4 polymorphisms and IHD were searched in MEDLINE and EMBASE up to January 2003. The principal prior hypothesis was that homozygosity for eNOS Asp298, the −786C allele in the promoter, or the intron-4 (
a
allele) would be associated with an increased risk of IHD. Data were available for 9867 cases and 13 161 controls from 26 studies. Homozygosity for the Asp298 was associated with an increased risk of IHD (OR, 1.31; 95% CI, 1.13 to 1.51). Although there was significant heterogeneity among studies of Asp298 (
P
Het
=0.0002), which was largely accounted for by a single study, the increase in risk was still significant after exclusion of that study from analysis. Homozygosity for the intron-4
a
allele was also significantly associated with higher risk of IHD (OR, 1.34; 95% CI, 1.03 to 1.75). However, no significant association was found with the −786C allele (OR, 1.06; 95% CI, 0.89, 1.25).

Conclusions—

Individuals homozygous for the Asp298 and intron-4
a
alleles of eNOS are at moderately increased risk of IHD. These findings support the proposal that common genetic variations in the eNOS gene contribute to atherosclerosis susceptibility, presumably by effects on endothelial NO availability.
Percutaneous Coronary Angioplasty Compared With Exercise Training in Patients With Stable Coronary Artery Disease
Authors: Hambrecht Rainer , Walther Claudia , Möbius-Winkler Sven , Gielen Stephan , Linke Axel , Conradi Katrin , Erbs Sandra , Kluge Regine , Kendziorra Kai , Sabri Osama , Sick Peter , Schuler Gerhard
Published: March 2004

Background—

Regular exercise in patients with stable coronary artery disease has been shown to improve myocardial perfusion and to retard disease progression. We therefore conducted a randomized study to compare the effects of exercise training versus standard percutaneous coronary intervention (PCI) with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion, cost-effectiveness, and frequency of a combined clinical end point (death of cardiac cause, stroke, CABG, angioplasty, acute myocardial infarction, and worsening angina with objective evidence resulting in hospitalization).

Methods and Results—

A total of 101 male patients aged ≤70 years were recruited after routine coronary angiography and randomized to 12 months of exercise training (20 minutes of bicycle ergometry per day) or to PCI. Cost efficiency was calculated as the average expense (in US dollars) needed to improve the Canadian Cardiovascular Society class by 1 class. Exercise training was associated with a higher event-free survival (88% versus 70% in the PCI group,
P
=0.023) and increased maximal oxygen uptake (+16%, from 22.7±0.7 to 26.2±0.8 mL O
2
/kg,
P
<0.001 versus baseline,
P
<0.001 versus PCI group after 12 months). To gain 1 Canadian Cardiovascular Society class, $6956 was spent in the PCI group versus $3429 in the training group (
P
<0.001).

Conclusions—

Compared with PCI, a 12-month program of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event-free survival and exercise capacity at lower costs, notably owing to reduced rehospitalizations and repeat revascularizations.
Distinct Subcellular Localization of Different Sodium Channel α and β Subunits in Single Ventricular Myocytes From Mouse Heart
Authors: Maier Sebastian K.G. , Westenbroek Ruth E. , McCormick Kimberly A. , Curtis Rory , Scheuer Todd , Catterall William A.
Published: March 2004

Background—

Voltage-gated sodium channels composed of pore-forming α and auxiliary β subunits are responsible for the rising phase of the action potential in cardiac muscle, but their localizations have not yet been clearly defined.

Methods and Results—

Immunocytochemical studies show that the principal cardiac α subunit isoform Na
v
1.5 and the β2 subunit are preferentially localized in intercalated disks, identified by immunostaining of connexin 43, the major protein of cardiac gap junctions. The brain α subunit isoforms Na
v
1.1, Na
v
1.3, and Na
v
1.6 are preferentially localized with β1 and β3 subunits in the transverse tubules, identified by immunostaining of α-actinin, a cardiac z-line protein. The β1 subunit is also present in a small fraction of intercalated disks. The recently cloned β4 subunit, which closely resembles β2 in amino acid sequence, is also expressed in ventricular myocytes and is localized in intercalated disks as are β2 and Na
v
1.5.

Conclusions—

Our results suggest that the primary sodium channels present in ventricular myocytes are composed of Na
v
1.5 plus β2 and/or β4 subunits in intercalated disks and Na
v
1.1, Na
v
1.3, and Na
v
1.6 plus β1 and/or β3 subunits in the transverse tubules.
Time Delay to Treatment and Mortality in Primary Angioplasty for Acute Myocardial Infarction
Authors: De Luca Giuseppe , Suryapranata Harry , Ottervanger Jan Paul , Antman Elliott M.
Published: March 2004

Background—

Although the relationship between mortality and time delay to treatment has been demonstrated in patients with acute ST-segment elevation myocardial infarction (STEMI) treated by thrombolysis, the impact of time delay on prognosis in patients undergoing primary angioplasty has yet to be clarified. The aim of this report was to address the relationship between time to treatment and mortality as a continuous function and to estimate the risk of mortality for each 30-minute delay.

Methods and Results—

The study population consisted of 1791 patients with STEMI treated by primary angioplasty. The relationship between ischemic time and 1-year mortality was assessed as a continuous function and plotted with a quadratic regression model. The Cox proportional hazards regression model was used to calculate relative risks (for each 30 minutes of delay), adjusted for baseline characteristics related to ischemic time. Variables related to time to treatment were age >70 years (
P
<0.0001), female gender (
P
=0.004), presence of diabetes mellitus (
P
=0.002), and previous revascularization (
P
=0.035). Patients with successful reperfusion had a significantly shorter ischemic time (
P
=0.006). A total of 103 patients (5.8%) had died at 1-year follow-up. After adjustment for age, gender, diabetes, and previous revascularization, each 30 minutes of delay was associated with a relative risk for 1-year mortality of 1.075 (95% CI 1.008 to 1.15;
P
=0.041).

Conclusions—

These results suggest that every minute of delay in primary angioplasty for STEMI affects 1-year mortality, even after adjustment for baseline characteristics. Therefore, all efforts should be made to shorten the total ischemic time, not only for thrombolytic therapy but also for primary angioplasty.
Autologous Bone-Marrow Mononuclear Cell Implantation Improves Endothelium-Dependent Vasodilation in Patients With Limb Ischemia
Authors: Higashi Yukihito , Kimura Masashi , Hara Keiko , Noma Kensuke , Jitsuiki Daisuke , Nakagawa Keigo , Oshima Tetsuya , Chayama Kazuaki , Sueda Taijiro , Goto Chikara , Matsubara Hiroaki , Murohara Toyoaki , Yoshizumi Masao
Published: March 2004

Background—

Patients with limb ischemia were associated with endothelial dysfunction. The purpose of this study was to determine whether autologous bone-marrow mononuclear cell (BM-MNC) implantation improves endothelial dysfunction in patients with limb ischemia.

Methods and Results—

We evaluated the leg blood flow (LBF) response to acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after BM-MNC implantation in 7 patients with limb ischemia. LBF was measured with a mercury-filled Silastic strain-gauge plethysmograph. The number of BM-MNCs implanted into ischemic limbs was 1.6×10
9
±0.3×10
9
. The number of CD34
+
cells included in the implanted BM-MNCs was 3.8×10
7
±1.6×10
7
. BM-MNC implantation improved the ankle-brachial pressure index (0.33±0.21 to 0.39±0.17,
P
=0.06), transcutaneous oxygen pressure (28.4±11.5 to 36.6±5.2 mm Hg,
P
=0.03), and pain-free walking time (0.8±0.6 to 2.9±2.2 minutes,
P
=0.02). After BM-MNC implantation, LBF response to ACh was enhanced (19.3±6.8 versus 29.6±7.1 mL/min per 100 mL;
P
=0.002). The vasodilatory effect of SNP was similar before and after BM-MNC implantation.

Conclusions—

These findings suggest that BM-MNC implantation augments endothelium-dependent vasodilation in patients with limb ischemia.