bluuebunny/crossref_metadata_2025 huggingface dataset:
Blunted Fenfluramine-Evoked Prolactin Secretion in Hypertensive Rats
Authors: Stocker Sean D. , Muldoon Matthew F. , Sved Alan F.
Published: July 2003

Plasma prolactin (PRL) levels after acute administration of fenfluramine (FEN) have been used as a probe of brain serotonin activity. FEN-evoked increases in PRL levels inversely correlate with arterial blood pressure (ABP) in humans (Muldoon et al.
Hypertension
. 1998;32:972–975), thereby suggesting that brain serotonin activity may be reduced in hypertension. The present study sought to determine whether the relation between FEN-evoked PRL levels and ABP was present in two rat models of hypertension. Experiments were performed in awake male rats that were instrumented with femoral arterial and venous catheters 2 days before experiments. FEN (3.0 mg/kg IV) significantly increased plasma PRL levels in both spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY); however, FEN-evoked PRL levels were significantly lower in SHR compared with WKY, though baseline levels were similar between strains. Similar results were obtained in rats with chronic hypertension produced by figure-8 renal wrap plus contralateral nephrectomy. In contrast, the increase in PRL levels evoked by the serotonin receptor agonist m-CPP or the dopamine receptor antagonist eticlopride did not differ between SHR and WKY, indicating that PRL secretion is not generally blunted in chronic hypertensive rats. Furthermore, FEN-evoked PRL levels were not attenuated in rats made acutely hypertensive by an infusion of the α-adrenergic agonist phenylephrine. Thus, the present findings are consistent with the human data and suggest that chronic hypertension is associated with a presynaptic alteration in brain serotonin function.
Na
+
/Ca
2+
Exchanger
Authors: Unlap M. Tino , Bates Elizabeth , Williams Corey , Komlosi Peter , Williams Iantha , Kovacs Gergely , Siroky Brian , Bell P. Darwin
Published: July 2003

The Na
+
/Ca
2+
exchanger regulates intracellular calcium ([Ca
2+
]
i
), and attenuation of Na
+
/Ca
2+
exchange by oxidative stress might lead to dysregulation of [Ca
2+
]
i
. We have shown that the Na
+
/Ca
2+
exchanger differs functionally and at the amino acid level between salt-sensitive and salt-resistant rats. Therefore, the purpose of these studies was to determine how oxidative stress affects the activities of the 2 Na
+
/Ca
2+
exchangers that we cloned from mesangial cells of salt-resistant (RNCX) and salt-sensitive (SNCX) Dahl/Rapp rats. The effects of oxidative stress on exchanger activity were examined in cells expressing RNCX or SNCX by assessing
45
Ca
2+
uptake (reverse mode) and [Ca
2+
]
i
elevation (forward mode) in the presence and absence of H
2
O
2
and peroxynitrite. Our results showed that
45
Ca
2+
uptake in SNCX cells was attenuated at 500 and 750 μmol/L H
2
O
2
(63±12% and 25±7%, respectively; n=16) and at 50 and 100 μmol/L peroxynitrite (47±9% and 22±9%, respectively; n=16). In RNCX cells,
45
Ca
2+
uptake was attenuated at only 750 and 100 μmol/L H
2
O
2
and peroxynitrite (61±9% and 63±6%, respectively; n=16). In addition, the elevation in [Ca
2+
]
i
was greater in SNCX cells than in RNCX cells in response to 750 μmol/L H
2
O
2
(58±5.5 vs 17±4.1 nmol/L; n=13) and 100 μmol/L peroxynitrite (33±5 vs 11±6 nmol/L; n=19). The enhanced impairment of SNCX activity by oxidative stress might contribute to the dysregulation of [Ca
2+
]
i
that is found in this model of salt-sensitive hypertension.
Daily Life Blood Pressure Changes Are Steeper in Hypertensive Than in Normotensive Subjects
Authors: Mancia Giuseppe , Parati Gianfranco , Castiglioni Paolo , Tordi Roberto , Tortorici Elena , Glavina Fabio , Di Rienzo Marco
Published: July 2003

Target organ damage in hypertensive patients is related to their increased average blood pressure and greater 24-hour blood pressure variability. Whether the rate of blood pressure changes is also greater in hypertension, producing a greater stress on arterial walls, is not known, however. Our study aimed at addressing this issue by computer analysis of 24-hour ambulatory intra-arterial blood pressure recordings in 34 subjects (29 males), 13 normotensive subjects and 21 uncomplicated hypertensive subjects (mean age±SD, 40.4±11.8 years). The number, slope (mm Hg/s), and length (beats) of systolic blood pressure ramps of 3 or more consecutive beats characterized by a progressive increase (+) or reduction (−) in systolic blood pressure of at least 1 mm Hg per beat were computed for each hour and for the whole 24-hour period. Twenty-four-hour average systolic blood pressure was 112.9±2.1 and 159.4±5.7 mm Hg in normotensive and hypertensive subjects, respectively. Over the 24 hours, the number and length of systolic blood pressure ramps were similar in both groups, whereas the slope was markedly different (24-hour mean±SE slope, 4.80±0.30 in normotensives and 6.50±0.40 mm Hg/s in hypertensives,
P
<0.05). Ramp slope was not influenced by age or reflex pulse interval changes, but it was greater for higher ramp initial systolic blood pressure values. Thus, in daily life, hypertensive subjects are characterized by steeper blood pressure changes than normotensives, and this, regardless of the mechanisms, may have clinical implications, because it may be associated with greater traumatic effect on the vessel walls of hypertensive patients.
Urotensin II Acts Centrally to Increase Epinephrine and ACTH Release and Cause Potent Inotropic and Chronotropic Actions
Authors: Watson Anna M.D. , Lambert Gavin W. , Smith Kathryn J. , May Clive N.
Published: July 2003

Urotensin II is a small peptide whose receptor was recently identified in mammals as the orphan G protein–coupled receptor-14. The reported cardiovascular responses to systemic urotensin II administration are variable, and there is little detailed information on its central cardiovascular actions. We examined the cardiovascular and humoral actions of intracerebroventricular urotensin II (0.02 and 0.2 nmol/kg and vehicle) and intravenous urotensin II (2, 20, and 40 nmol/kg and vehicle) in conscious ewes previously surgically implanted with flow probes and intracerebroventricular guide tubes. Two hours after intracerebroventricular infusion of urotensin II (0.2 nmol/kg over 1 hour; n=5), heart rate (+56±13 beats per minute [bpm]),
dF
/
dt
(an index of cardiac contractility; +533±128 L · min
−1
· s
−1
), and cardiac output (+3.4±0.4 L/min) increased significantly compared with vehicle, as did renal, mesenteric, and iliac blood flows and conductances. Plasma epinephrine, adrenocorticotropic hormone, and glucose levels also increased dramatically (+753±166 pg/mL, +14.3±3.5 pmol/L, and +7.0±1.4 mmol/L, respectively). All of these variables remained elevated for up to 4 hours after infusion. In contrast, 1 hour after intravenous urotensin II (40 nmol/kg bolus; n=6), a sustained tachycardia (+25±8 bpm) ensued, but cardiac output, cardiac contractility, total peripheral conductance, and plasma glucose levels did not change significantly. In summary, this is the first study to show that urotensin II acts centrally to stimulate sympathoadrenal and pituitary-adrenal pathways, resulting in increased adrenocorticotropic hormone and epinephrine release and potent chronotropic and inotropic actions. In contrast, tachycardia was the only major response to intravenous urotensin II. These findings suggest that urotensin II is a novel stimulator of central pathways that mediate responses to alerting stimuli or stress.
NADPH Oxidase–Derived Superoxide Augments Endothelin-1–Induced Venoconstriction in Mineralocorticoid Hypertension
Authors: Li Lixin , Watts Stephanie W. , Banes Amy K. , Galligan James J. , Fink Gregory D. , Chen Alex F.
Published: July 2003

Deoxycorticosterone acetate (DOCA)–salt hypertension is characterized by low renin/angiotensin but increased arterial superoxide levels. We have recently reported that the arterial endothelin-1 (ET-1) level is increased, resulting in NADPH oxidase activation and superoxide generation. However, the effect of ET-1 on venous superoxide production and its relation to venoconstriction are unknown. The present study tested the hypotheses that ET-1 stimulates venous NADPH oxidase and superoxide via its ET
A
receptors, resulting in enhanced venoconstriction in DOCA-salt hypertensive rats. Treatment with ET-1 (0.01 to 1 nmol/L), but not the selective ET
B
receptor agonist sarafotoxin s6c, of vena cavas of normal rats concentration-dependently increased superoxide levels, an effect that was abolished by the selective ET
A
receptor antagonist ABT-627. Although the ET-1 level was not increased in the vena cava and plasma, both venous NADPH oxidase activity and superoxide levels were significantly higher in DOCA-salt compared with sham rats. Moreover, ET-1 treatment (10
−9
mol/L, 10 minutes) of isolated vena cavas further elevated superoxide levels in DOCA-salt rats only but not sham rats, an effect that was abrogated by the superoxide scavenger tempol. Similarly, ET-1–induced contractions of isolated vena cavas of DOCA-salt but not sham rats were significantly inhibited by tempol. The NADPH oxidase inhibitor apocynin significantly reduced superoxide levels in vena cavas of DOCA-salt rats and in ET-1–treated vena cavas of normal rats. Finally, in vivo ET
A
receptor blockade by ABT-627 significantly lowered venous superoxide levels and blood pressure in DOCA-salt but not sham rats. These results suggest that superoxide contributes to ET-1–induced venoconstriction through an elevated venous NADPH oxidase activity in mineralocorticoid hypertension.
Interaction Between
ACE
and
ADD1
Gene Polymorphisms in the Progression of IgA Nephropathy in Japanese Patients
Authors: Narita Ichiei , Goto Shin , Saito Noriko , Song Jin , Ajiro Junya , Sato Fuminori , Saga Daisuke , Kondo Daisuke , Akazawa Kohei , Sakatsume Minoru , Gejyo Fumitake
Published: July 2003

An interaction effect between the angiotensin-converting enzyme insertion/deletion (
ACE I/D
) and α-adducin (
ADD1
) Gly460Trp polymorphisms (
G460W
) on blood pressure regulation has recently been suggested, although its significance in the prognosis of renal function in IgA nephropathy (IgAN) has not been fully investigated. Therefore, we evaluated the clinical manifestations and renal prognosis in 276 Japanese patients with histologically proven IgAN with respect to their
ACE I/D
and
ADD1 G460W
polymorphisms. The prognosis of renal function was analyzed by Kaplan-Meier survival curves and multivariate Cox proportional-hazards regression models. Baseline data, including blood pressures, proteinuria, renal function, and incidence of hypertension, were similar for the different genotypes of
ACE
and
ADD1
. The individual genotypes taken alone were not associated with the progression of renal dysfunction. However, renal survival of patients with the
460WW
polymorphism of
ADD1
was significantly worse within the group with the
II
genotype of
ACE
(Kaplan-Meier, log rank test; χ
2
=6.062,
P
=0.0138) but not for those with other
ACE
genotypes. In the Cox proportional-hazards regression model with adjustment for clinical risk factors, including hypertension, proteinuria, and no administration of an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the
460WW
variant of
ADD1
was a highly significant and independent risk factor only for patients with the
ACE II
genotype, with a hazard ratio of 3.65 (
P
=0.0016), but not for those with other
ACE
genotypes (hazard ratio=0.65,
P
=0.2902). These findings suggest an interaction between
ACE
and
ADD1
polymorphisms not only on blood pressure regulation but also on the progression of renal dysfunction in patients with IgAN.
Attenuated Responses to Angiotensin II in Follitropin Receptor Knockout Mice, a Model of Menopause-Associated Hypertension
Authors: Javeshghani Danesh , Touyz Rhian M. , Sairam M. Ram , Virdis Agostino , Neves Mario Fritsch , Schiffrin Ernesto L.
Published: July 2003

Activation of the renin-angiotensin system has been implicated in the development of hypertension in menopausal women. We investigated whether blood pressure is elevated and whether angiotensin II (Ang II)-induced vascular reactivity is increased in follitropin receptor knockout (FORKO) female mice. These mice are estrogen-deficient and have characteristics similar to postmenopausal women. Serum estradiol levels were significantly reduced in FORKO versus wild-type mice (1.4±0.2 versus 15±3 pg/mL,
P
<0.01). Blood pressure, measured by telemetry, was significantly increased in FORKO (120±2/92±2 mm Hg) compared with wild-type counterparts (110±1/85±2 mm Hg,
P
<0.05). Vascular dose responses to acetylcholine (endothelium-dependent dilation) and sodium nitroprusside (endothelium-independent dilation) were not different. Ang II–induced vasoconstriction was blunted in FORKO compared with wild-type mice (
P
<0.05). Media-to-lumen ratio was significantly increased in FORKO (6.2±0.5%) versus control mice (5.2±0.3%), indicating vascular remodeling. Aortic ·O
2
−
levels, NADH-inducible ·O
2
−
generation, and plasma levels of thiobarbituric acid reactive substances (TBARS), indexes of oxidative stress, were not significantly different between wild-type and FORKO mice. Vascular AT
1
receptor content, assessed by immunoblotting, was reduced by 40% in FORKO compared with wild-type mice (
P
<0.01). This was associated with decreased circulating Ang II levels in FORKO versus control mice. These data indicate that FORKO mice have increased blood pressure, vascular remodeling, and attenuated vascular responses to Ang II. Our findings suggest that vascular Ang II signaling is downregulated in female FORKO mice and that Ang II may not play an important role in blood pressure elevation in this model of menopause-associated hypertension.
PPARγ Inhibition of Cyclooxygenase-2, PGE
2
Synthase, and Inducible Nitric Oxide Synthase in Cardiac Myocytes
Authors: Mendez Mariela , LaPointe Margot C.
Published: July 2003

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They regulate lipid metabolism, glucose homeostasis, cell proliferation, and differentiation and modulate inflammatory responses. We examined whether PPARγ is functional in cultured neonatal ventricular myocytes and studied its role in inflammation. Western blots revealed PPARγ in myocytes. When myocytes were transfected with a PPAR response element reporter plasmid (PPRE-TK-luciferase), the PPARγ activator 15-deoxy-Δ
12,14
-prostaglandin J
2
(15dPGJ
2
) increased promoter activity, whereas cotransfection of a dominant negative PPARγ inhibited it. To determine the role of 15dPGJ
2
in expression of proinflammatory genes, we tested its effect on interleukin-1β induction of cyclooxygenase-2 (COX-2). 15dPGJ
2
decreased interleukin-1β stimulation of COX-2 by 40% and PGE
2
production by 73%. We next questioned whether 15dPGJ
2
was modulating the expression of inducible prostaglandin E
2
synthase (PGES) and found that it completely blocked interleukin-1β induction of PGES. Use of a second PPARγ agonist, troglitazone, and the selective PPARγ antagonist GW9662 demonstrated that the effects seen were PPARγ-dependent. In addition, we found that 15dPGJ
2
blocked interleukin-1β stimulation of inducible nitric oxide synthase (iNOS). We concluded that 15dPGJ
2
may play an anti-inflammatory role in a PPARγ-dependent manner, decreasing COX-2, PGES, and PGE
2
production, as well as iNOS expression.
Role of Crk-Associated Substrate in the Regulation of Vascular Smooth Muscle Contraction
Authors: Tang Dale D. , Tan Jian
Published: July 2003

A pool of actin monomers is induced to polymerize into actin filaments during contractile stimulation of smooth muscle. The inhibition of actin dynamics by actin polymerization inhibitors depresses active force generation in smooth muscle. In this study, we hypothesized that Crk-associated substrate plays a role in the regulation of contraction and actin dynamics in vascular smooth muscle. Antisense or sense oligodeoxynucleotides for Crk-associated substrate were introduced into carotid smooth muscle tissues by chemical loading. The treatment of smooth muscle strips with antisense oligodeoxynucleotides inhibited the expression of Crk-associated substrates; it did not influence the expression of actin, myosin heavy chain, and paxillin. Sense oligodeoxynucleotides did not affect the expression of these proteins in smooth muscle tissues. Force generation in response to stimulation with norepinephrine or KCl was significantly lower in antisense-treated muscle strips than in sense-treated strips or in muscle strips not treated with oligodeoxynucleotides. The downregulation of Crk-associated substrate did not attenuate increases in phosphorylation of the 20-kDa regulatory light chain of myosin in response to stimulation with norepinephrine. The increase in F-actin/G-actin ratio during contractile stimulation was significantly inhibited in antisense-treated smooth muscle strips. Contractile activation of smooth muscle increased the association of profilin with actin monomers; the depletion of Crk-associated substrate inhibited the increases in the profilin-actin complex in response to contractile stimulation. These results suggest that Crk-associated substrate is a necessary molecule of signaling cascades that regulate active force generation in smooth muscle. This molecule may regulate actin dynamics in smooth muscle in response to contractile stimulation.
Volume Status and Blood Pressure During Long-Term Hemodialysis
Authors: Chen Chen-Huan , Lin Yao-Ping , Yu Wen-Chung , Yang Wu-Chang , Ding Yu-An
Published: July 2003

The importance of volume status on blood pressure in hemodialysis patients has long been recognized. We hypothesized that the enhanced volume dependency of blood pressure is partly determined by ventricular stiffness at end systole. A total of 115 long-term hemodialysis patients were invited to receive a comprehensive, noninvasive cardiovascular examination. End-systolic elastance was determined by using a novel, noninvasive echo-Doppler technique. The positive ratios of the interdialytic systolic blood pressure change vs weight gain during the subsequent 25 hemodialysis sessions were averaged to obtain the volume sensitivity index (mm Hg/kg). The averaged interdialytic weight gain per fat-free mass was correlated significantly with averaged percent change in systolic blood pressure (
r
=0.45,
P
<0.001). The estimated end-systolic elastance at baseline was significantly correlated with subsequently observed volume sensitivity index (volume sensitivity index=[1.17×end-systolic elastance]+6.4;
r
=0.34,
P
=0.001). End-systolic elastance was also significantly correlated with various vascular function parameters, including effective arterial elastance (
r
=0.48,
P
<0.001), pulse wave velocity (
r
=0.30,
P
=0.001), carotid augmentation index (
r
=0.31,
P
<0.001), and aortic compliance (
r
=−0.49,
P
<0.001). The results suggest that end-systolic elastance, a direct measure of left ventricular mechanical properties at end systole, is coupled to arterial mechanical properties and predicts the extent of subsequent interdialytic systolic blood pressure rise relative to weight gain. Therefore, ventricular stiffness at end systole is a determinant of the enhanced volume sensitivity of blood pressure in hemodialysis patients.
Migration Inhibitory Factor Mediates Angiogenesis via Mitogen-Activated Protein Kinase and Phosphatidylinositol Kinase
Authors: Amin M. Asif , Volpert Olga V. , Woods James M. , Kumar Pawan , Harlow Lisa A. , Koch Alisa E.
Published: July 2003

In this study, we investigated the effects of migration inhibitory factor (rhMIF) on angiogenesis-related signaling cascades and apoptosis in human endothelial cells (ECs). We show that in vitro rhMIF induces migration and tube formation in Matrigel of human dermal microvascular endothelial cells (HMVECs), with potency comparable to that of basic fibroblast growth factor. In vivo, rhMIF induces angiogenesis in Matrigel plugs and in the corneal bioassay. Using panels of relatively specific kinase inhibitors, antisense oligonucleotides, and dominant-negative mutants, we show that mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) are critical for MIF-dependent HMVEC migration, whereas Src and p38 kinases are nonessential. Moreover, we demonstrate that rhMIF induces time-dependent increases in phosphorylation levels of MEK1/2, Erk1/2, and Elk-1, as well as PI3K, and its effector kinase, Akt, in HMVECs. Studies with dominant-negative mutants and antisense oligonucleotides corroborate these effects in HMVECs. Furthermore, we demonstrate that rhMIF-induced angiogenesis in the rat cornea in vivo and in the ex vivo endothelial cell morphogenesis assay is also MAPK- and PI3K-dependent. Our findings support a role for MIF as an angiogenic factor and provide a rationale for the use of MIF as a therapeutic inducer of neovascularization in the development of collateral circulation in coronary artery disease.
Homocysteine Mediated Expression and Secretion of Monocyte Chemoattractant Protein-1 and Interleukin-8 in Human Monocytes
Authors: Zeng Xiaokun , Dai Jing , Remick Daniel G. , Wang Xian
Published: July 2003

Homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are major chemokines for leukocyte trafficking and have been identified in atheromatous plaques. MCP-1 and IL-8 have been found to express mainly by macrophages in human lesion. We undertook this study to determine whether Hcy could induce the secretion of chemokines from human monocytes and, if so, to explore the mediating mechanism. We found that clinically relevant levels of Hcy (10 to 1000 μmol/L) increased the protein secretion and mRNA expression as well as activity of MCP-1 and IL-8 in cultured primary human monocytes. These effects of Hcy were primarily mediated by reactive oxygen species (ROS) through NAD(P)H oxidase, because Hcy could upregulate the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers, or NAD(P)H oxidase abolished Hcy-induced ROS production and MCP-1 and IL-8 secretion in these cells. Furthermore, the inhibitors of mitogen-activated protein kinase (p38 and extracellular signal-regulated kinase 1/2) and nuclear factor-κB or the activator of peroxisome proliferator-activated receptor γ (PPARγ) significantly decreased Hcy-induced MCP-1 and IL-8 secretion in these cells. These data indicate that pathophysiological levels of Hcy can alter human monocyte function by upregulating MCP-1 and IL-8 expression and secretion via enhanced formation of intracellular ROS originated from NAD(P)H oxidase source via calmodulin or protein kinase C signaling pathways and that Hcy-induced ROS subsequently activates mitogen-activated protein kinase (p38 and ERK1/2) and nuclear factor-κB in a PPARγ activator–sensitive manner. Thus, activation of PPARγ may become a therapeutic target for preventing Hcy-induced proatherogenic effects.
Circulating Vascular Progenitor Cells Do Not Contribute to Compensatory Lung Growth
Authors: Voswinckel Robert , Ziegelhoeffer Tibor , Heil Matthias , Kostin Sawa , Breier Georg , Mehling Tanja , Haberberger Rainer , Clauss Matthias , Gaumann Andreas , Schaper Wolfgang , Seeger Werner
Published: July 2003

The biological principles that underlie the induction and process of alveolization in the lung as well as the maintenance of the complex lung tissue structure are one of the major obstacles in pulmonary medicine today. Bone marrow–derived cells have been shown to participate in angiogenesis, vascular repair, and remodeling of various organs. We addressed this phenomenon in the lung vasculature of mice in a model of regenerative lung growth. C57BL/6 mice were transplanted with bone marrow from one of three different reporter gene–transgenic strains. flk-1
+/lacZ
mice, tie-2/lacZ transgenic mice (both exhibiting endothelial cell–specific reporter gene expression), and ubiquitously enhanced green fluorescent protein (eGFP)-expressing mice served as marrow donors. After hematopoietic recovery, compensatory lung growth was induced by unilateral pneumonectomy and led to complete restoration of initial lung volume and surface area. The lungs were consecutively investigated for bone marrow–derived vascular cells by lacZ staining and immunohistochemistry for phenotype identification of vascular cells. lacZ- or eGFP-expressing bone marrow–derived endothelial cells could not be found in microvascular regions of alveolar septa. Single eGFP-positive endothelial cells were detected in pulmonary arteries at very low frequencies, whereas no eGFP-positive vascular smooth muscle cells were observed. In conclusion, we demonstrate in a model of lung growth and alveolization in adult mice the absence of significant bone marrow–derived progenitor cell contribution to the concomitant vascular growth and remodeling processes.
Regulation of the Growth Arrest and DNA Damage-Inducible Gene 45 (GADD45) by Peroxisome Proliferator-Activated Receptor γ in Vascular Smooth Muscle Cells
Authors: Bruemmer Dennis , Yin Fen , Liu Joey , Berger Joel P. , Sakai Toshiyuki , Blaschke Florian , Fleck Eckart , Van Herle Andre J. , Forman Barry M. , Law Ronald E.
Published: July 2003

Peroxisome proliferator-activated receptor (PPAR) γ is activated by thiazolidinediones (TZDs), widely used as insulin-sensitizing agents for the treatment of type 2 diabetes. TZDs have been shown to induce apoptosis in a variety of mammalian cells. In vascular smooth muscle cells (VSMCs), proliferation and apoptosis may be competing processes during the formation of restenotic and atherosclerotic lesions. The precise molecular mechanisms by which TZDs induce apoptosis in VSMCs, however, remain unclear. In the present study, we demonstrate that the TZDs rosiglitazone (RSG), troglitazone (TRO), and a novel non-TZD partial PPARγ agonist (nTZDpa) induce caspase-mediated apoptosis of human coronary VSMCs. Induction of VSMC apoptosis correlated closely with an upregulation of growth arrest and DNA damage-inducible gene 45 (GADD45) mRNA expression and transcription, a well-recognized modulator of cell cycle arrest and apoptosis. Using adenoviral-mediated overexpression of a constitutively active PPARγ mutant and the irreversible PPARγ antagonist GW9662, we provide evidence that PPARγ ligands induce caspase-mediated apoptosis and GADD45 expression through a receptor-dependent pathway. Deletion analysis of the GADD45 promoter revealed that a 153-bp region between −234 and −81 bp proximal to the transcription start site, containing an Oct-1 element, was crucial for the PPARγ ligand–mediated induction of the GADD45 promoter. PPARγ activation induced Oct-1 protein expression and DNA binding and stimulated activity of a reporter plasmid driven by multiple Oct-1 elements. These findings suggest that activation of PPARγ can lead to apoptosis and growth arrest in VSMCs, at least in part, by inducing Oct-1–mediated transcription of GADD45. The full text of this article is available online at http://www.circresaha.org.
Angiotensin II Type 2 Receptor Inhibits Vascular Endothelial Growth Factor–Induced Migration and In Vitro Tube Formation of Human Endothelial Cells
Authors: Benndorf Ralf , Böger Rainer H. , Ergün Süleyman , Steenpass Anna , Wieland Thomas
Published: July 2003

Endothelial cell migration and tube formation in response to vascular endothelial growth factor (VEGF) play an important role in the process of angiogenesis. Recent data indicate that angiotensin type 2 (AT
2
) receptor stimulation is antiangiogenic. Therefore, we studied the effect of angiotensin II (Ang II) on VEGF-induced migration and in vitro tube formation of human endothelial cells. Ang II inhibited VEGF-induced migration of EA.hy926 cells, human coronary artery (HCA) and human dermal microvascular (HDM) endothelial cells (ECs) as well as tube formation by HDMECs. The AT
2
receptor antagonist PD123,319 but not the AT
1
receptor antagonist losartan blocked the inhibitory effect of Ang II. The inhibitory effect of Ang II on VEGF-induced migration of endothelial cells was mimicked by the specific AT
2
receptor agonist CGP-42112A. The phosphorylation of Akt and its downstream effector endothelial NO synthase (eNOS) is pivotal to VEGF-induced angiogenesis. We therefore investigated the effect of Ang II on VEGF-induced Akt and eNOS phosphorylation. Ang II diminished the VEGF-induced phosphorylation of Akt and eNOS in endothelial cells, whereas the autophosphorylation of VEGF receptors was unaffected. CGP-42112A again mimicked and PD123,319 but not losartan blocked the inhibitory effect of Ang II. Treatment of endothelial cells with pertussis toxin (PTX) totally abolished the AT
2
receptor–mediated inhibition of VEGF-induced endothelial cell migration and blocked the inhibition of Akt and eNOS phosphorylation. In conclusion, this study indicates that AT
2
receptor stimulation inhibits VEGF-induced endothelial cell migration and tube formation via activation of a PTX-sensitive G protein. These findings may explain the reported antiangiogenic properties of the AT
2
receptor.
Antiplatelet Therapy in Aneurysmal Subarachnoid Hemorrhage
Authors: Dorhout Mees Sanne M. , Rinkel Gabriel J.E. , Hop Jeannette W. , Algra Ale , van Gijn Jan
Published: July 2003

Background and Purpose—

Observational studies suggest that platelet inhibitors reduce the risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage and thereby have a beneficial effect on clinical outcome. Robust evidence, however, is lacking. We performed a systematic meta-analysis to determine whether antiplatelet therapy has a beneficial effect after SAH.

Methods—

We searched Medline and the Cochrane Library to identify all randomized controlled trials of antiplatelet drugs versus control and calculated relative risks with corresponding 95% confidence intervals (CIs) for poor outcome (dependence or death), the occurrence of DCI, and the occurrence of any intracranial hemorrhage.

Results—

We included 5 trials totaling 699 patients. The overall relative risk for poor outcome was 0.87 (95% CI, 0.65 to 1.17); for the occurrence of DCI (reported in 3 of the 5 studies), 0.65 (95% CI, 0.47 to 0.89); and for the occurrence of intracranial hemorrhage, 1.19 (reported in 4 of the 5 studies) (95% CI, 0.76 to 1.85).

Conclusions—

Our data indicate that antiplatelet drugs reduce the risk of DCI in patients with subarachnoid hemorrhage. A randomized clinical trial is warranted to assess the effect on overall outcome.
Prediction of Malignant Course in MCA Infarction by PET and Microdialysis
Authors: Dohmen Christian , Bosche Bert , Graf Rudolf , Staub Frank , Kracht Lutz , Sobesky Jan , Neveling Michael , Brinker Gerit , Heiss Wolf-Dieter
Published: July 2003

Background and Purpose—

To predict malignant course in patients with large middle cerebral artery (MCA) infarction, we combined PET imaging and neuromonitoring, including microdialysis.

Methods—

Thirty-four patients with stroke of >50% of the MCA territory in early cerebral CT scan were included. Probes for microdialysis and measurement of intracranial pressure and tissue oxygen pressure (Pt
o
2
) were placed into the ipsilateral frontal lobe. PET was performed with
11
C-flumazenil to assess CBF and irreversible neuronal damage.

Results—

PET measurements within 24 hours after stroke showed larger volumes of ischemic core (mean, 144.5 versus 62.2 cm
3
) and larger volumes of irreversible neuronal damage (157.9 versus 47.0 cm
3
) in patients with malignant course (ie, edema formation with midline shift) than in patients with benign course. Mean cerebral blood flow values within the ischemic core were significantly lower and the volume of the ischemic penumbra was smaller in the malignant than in the benign group. In patients with malignant course, cerebral perfusion pressure dropped to <50 to 60 mm Hg 22 to 72 hours (mean, 52.0 hours) after onset of symptoms; subsequently, Pt
o
2
dropped and glutamate increased, indicating secondary ischemia. Maximal changes in the monitored variables reached significant levels for glutamate, aspartate, GABA, glycerol, lactate-to-pyruvate ratio, hypoxanthine, intracranial pressure, cerebral perfusion pressure, and Pt
o
2
.

Conclusions—

PET allowed prediction of malignant MCA infarction within the time window suggested for hemicraniectomy. Neuromonitoring helped to classify the clinical courses by characterizing pathophysiological sequelae of malignant edema formation. In contrast to PET, however, it did not predict fatal outcome early enough for successful implementation of invasive therapies.
Human Neural Stem Cell Transplantation Promotes Functional Recovery in Rats With Experimental Intracerebral Hemorrhage
Authors: Jeong Sang-Wuk , Chu Kon , Jung Keun-Hwa , Kim Seung U. , Kim Manho , Roh Jae-Kyu
Published: July 2003

Background and Purpose—

Cell transplantation has been used to reduce behavioral deficit in cerebral ischemia. However, there is no report about cell transplantation in experimental intracerebral hemorrhage (ICH). We hypothesize that intravenously transplanted human neural stem cells (NSCs) can migrate and differentiate into neurons or glial cells, thereby improving functional outcome in ICH.

Methods—

Experimental ICH was induced by intrastriatal administration of bacterial collagenase in adult rats. One day after surgery, the rats were randomly divided into 2 groups to receive intravenously either immortalized
Lac z
–positive human NSCs (5×10
6
cells in 500 μL, n=12) or the same amount of saline (n=13). The animals were evaluated for 8 weeks with modified limb placing and rotarod tests. Transplanted NSCs were detected by X-gal histochemistry or β-gal immunohistochemistry with double labeling of GFAP, NeuN, neurofilament, or CNPase.

Results—

Intravenously transplanted NSCs migrated selectively to the perihematomal areas and differentiated into neurons (≈10% of β-gal
+
cells) and astrocytes (≈75%). The NSC-transplanted group showed better functional performance on rotarod test after 2 weeks and on modified limb placing test after 5 weeks compared with the control group (
P
<0.05), and these effects persisted for up to 8 weeks. There was no difference in the final hemispheric area between the 2 groups.

Conclusions—

Intravenously transplanted NSCs can enter the rat brain with ICH, survive, migrate, and improve functional recovery. Transplantation of human NSCs can be used to restore neurological deficits in experimental ICH.
Thirty-Year Projections for Deaths From Ischemic Stroke in the United States
Authors: Elkins Jacob S. , Johnston S. Claiborne
Published: July 2003

Background and Purpose—

The age adjustment of stroke mortality rates may obscure the impact of population changes on the total burden of disease. Deaths from ischemic stroke may rise unless future declines in stroke death rates offset the projected growth in high-risk populations.

Methods—

Using data on ischemic stroke mortality from the National Center of Health Statistics for 1979 to 1998, we fit a logistic model to predict changes in stroke death rates as a function of time for each of 42 sex-race-age groups. Using population projections from the US Census Bureau, we then calculated the expected number of deaths in the United States from ischemic stroke over the next 30 years on the basis of age, sex, and race.

Results—

Models generally fit historical data well (median
R
2
=0.81; interquartile range, 0.43 to 0.97) and consistently predicted small declines in future death rates. The total predicted number of stroke deaths increased by 98% from 139 000 in 2002 to 275 000 in 2032, whereas the total US population was projected to increase by only 27% in the same period. The largest percentage increases in stroke deaths were predicted to occur in blacks (134%) and nonwhite, nonblack races (221%).

Conclusions—

If recent trends in ischemic stroke mortality continue, increases in US stroke deaths will outpace overall population growth, with a doubling in deaths over the next 30 years.
Collateral Circulation
Authors: Liebeskind David S.
Published: July 2003

Background—

The collateral circulation plays a pivotal role in the pathophysiology of cerebral ischemia. Current knowledge of the collateral circulation remains sparse, largely because of prior limitations in methods for evaluation of these diminutive routes of cerebral blood flow.

Summary of Review—

Anatomic descriptions of the collateral circulation often focus on more proximal anastomoses at the circle of Willis, neglecting secondary collateral pathways provided by leptomeningeal vessels. Pathophysiological recruitment of collateral vessels likely depends on the temporal course of numerous compensatory hemodynamic, metabolic, and neural mechanisms. Subsequent endurance of these protective vascular pathways may determine the severity of ischemic injury. Characterization of the collateral circulation with advanced neuroimaging modalities that provide angiographic information and perfusion data may elucidate critical determinants of collateral blood flow. Such information on the status of the collateral circulation may be used to guide therapeutic interventions. Prognostication and risk stratification may also be improved by routine evaluation of collateral blood flow.

Conclusions—

Contemporary understanding of the collateral circulation may be greatly enhanced through further refinement of neuroimaging modalities that correlate angiographic findings with perfusion status, providing the basis for future therapeutic and prognostic applications.
The Failing Male God: Emasculation, Death and Other Accidents in the Ancient Mediterranean World
Authors: Casadio Giovanni
Published: July 2003

The purpose of this paper is threefold. Starting from a new analysis of some selected sources but also from a reappraisal of the highlights of scholarly literature, it aims to reassess the category of the Mediterranean "dying and rising gods," or "deities subject to vicissitude." A first conclusion is that in spite of past and present criticism this category holds it own and is still valuable for the work of the historian of religions. Secondly it is argued that an evaluation of some significant details in the parallel stories of Attis, Adonis, Osiris (and, mutatis mutandis, those of Dionysus and Mithras) demonstrates that deep-seated human urges may determine the formation of recurring mythical motifs. In order to clarify the background of this process, some Freudian formulas (the castration complex, the fear of death vs. the fear of castration) may be put to the test and yield profitable results. Another, "meta-critical" implication of this discussion is that our ways of collecting data, making comparisons, and suggesting solutions may be deeply conditioned by personal concerns.
The Power of the Impure: Transgression, Violence and Secrecy in Bengali Śākta Tantra and Modern Western Magic
Authors: Urban Hugh
Published: July 2003

Since their first encounter with the complex body of texts and traditions called "Tantras," Western scholars have been simultaneously repulsed and horrified, yet also tantalized and titillated by the deliberate use of normally impure and defiling substances in Tantric practice. Yet, with a few exceptions, they have made little headway in interpreting the deeper religious and social role of impurity, either in Tantric ritual or in the history of religions generally. This paper compares the role of ritual impurity and transgression in two very different traditions, widely separated both historically and geographically: the Śākta school of Tantra in Bengal (focusing on the 16th century brāhman, Kr⊡nānanda Āgamavāgīśa) and modern Western magic (focusing on Aleister Crowley and the Ordo Templi Orientis). Specifically, I look closely at the manipulation of impure bodily substances—such as blood, semen and vaginal fluids—in sexual rituals and animal sacrifice. By playing off of these two examples in a kind of metaphoric juxtaposition, I hope to shed some new light on the role of impurity, transgression and secrecy in both cases and also in the comparative study of religion as a whole. Adapting some insights from Georges Bataille and Michel Foucault, I argue that the ritual use of impurity has much larger social and political implications, as a means of harnessing the tremendous power that flows through the physical universe, the human body and the social body alike.
Ethnohermeneutics and Worldview Analysis in the Study of Hopi Indian Religion
Authors: Geertz Armin
Published: July 2003

Ethnohermeneutics grew out of the ethnosciences' emphasis on discourse analysis, componential analysis and cultural grammar. Ethnohermeneutics as interpreted in this article closely follows developments in symbolic anthropology, cognitive anthropology and semiotics. Ethnohermeneutics attempts to locate the scholar and the people under study in each their own network of discourses, traditions, texts and meanings in the context of their social and intellectual circumstances. The result is a third perspective whereby the frames of reference of the scholar and the people under study are transcended. In this article, four functions of this approach are illustrated in relation to the study of Hopi Indian religion.
FURTHER UNNOTICED POINTS IN THE TEXT OF THE NEW TESTAMENT
Authors: Ross J.M.
Published: July 2003

Professor J.K. Elliott (Leeds/UK) writes: J.M. Ross contributed many articles to the religious and academic press for over fifty years including three in this journal: "Some Unnoticed Points in the Text of the New Testament" (25 [1983] 59- 72), "Another Look at Mark 8:36" (29 [1987] 97-99) and "The Extra Words in Acts 18:21" (34 [1992] 247-9). These and his other text-critical notes are regularly to be seen referred to in commentaries and elsewhere in the literature. Mr. Ross died aged 88 in 1997. I have inherited his unpublished textual papers, from which a selection of eighteen further "Points" is edited here as a sequel to his 1983 article. This article appears with the approval of his family. John MacDonald Ross was a rara avis in the text-critical field, being a selfconfessed amateur. Having graduated in Greats (classics) at Oxford, he worked as a civil servant in the British Home Office (the interior ministry) and before his retirement was decorated as Commander of the British Empire for his services to the Crown. His hobby of text-critical studies was recognised by his election to the exclusive academic society Studiorum Novi Testamenti Societas, at the annual meetings of which he attended the textual criticism seminars. His published textual notes are modelled on the taut reporting style in B.M. Metzger, A Textual Commentary on the Greek New Testament (London/New York, 1971; Stuttgart, 21994). In editing these notes I have maintained this style: further treatment of all the issues would of course require fuller cross-references to other authorities and a greater discussion of alternative solutions, but Ross has the happy knack of spotlighting the essentials in many a complex text-critical crux and wrestles to achieve a resolution that betrays an essentially commonsense approach. We may not always agree with all his arguments but he often succeeds in making us revisit and appraise many an 'unnoticed' point.
THE SHAPE OF A MIRACLE STORY A RESPECTFUL ANALYSIS OF JOHN 4:43-54
Authors: Sibinga Joost Smit
Published: July 2003

As the evangelist's literary technique requires, this article studies the narrative in John 4:43-54 starting from a count of the number of syllables (= s.) and words (= w.) of its parts. In toto the story uses 450 s. in 222 w. Essentially, a central part vv. 48-52 (of 168 s. in 84 w.) is framed by vv. 46c47 and vv. 53-54 (each 75 s.). This central section supplements the introductory vv. 43-46b (132 s.). A pattern of 132 + 318 = 450 s. emerges, and the number 318, TIH, may well have to be interpreted in accordance with Barn. 9:8: "Here you have Jesus and his cross symbolized".
ΝΟΜΟΣ (ΤΩΝ) ΕΡΓΩΝ AND ΝΟΜΟΣ ΠΙΣΤΕΩΣ THE PAULINE RHETORIC AND THEOLOGY OF ΝΟΜΟΣ
Authors: Ito Akio
Published: July 2003

Since Paul intended his epistles to be read aloud to the congregation from the beginning to the end without going back and forth, they must have made some sense to the audience at the first reading. However, this does not deny that deeper meanings are hidden beneath the surface meaning. A superficial reading and the in-depth theological reading must be compatible and complementary. From this perspective this essay attempts to resolve the debate on the meaning of the ν μοσ π στεωσ and ν μοσ (τ ν) ργων in Rom. 3:27, whether they refer to the law in a general sense or the Torah.
A TOUCH OF CONDEMNATION IN A WORD OF EXHORTATION: APOCALYPTIC LANGUAGE AND GRAECO-ROMAN RHETORIC IN HEBREWS 6:4-12
Authors: Nongbri Brent
Published: July 2003

We propose that the author of Hebrews employs threats of eternal condemnation using words and imagery familiar from apocalyptic literature, particularly 4 Ezra, to evoke a specific kind of fear in his audience. The audience members should, rather than fearing the reproach of society, have angst for falling away from the community, which in our author's eyes, is an offense for which no repentance is available. To effectively bring about such fear, these threats, contrary to the assertions of many recent commentators, must be real and must concern genuine believers. The author of Hebrews uses this severe language, however, in good rhetorical fashion, following his threats with words of consolation to encourage his audience members to stand fast in their marginalized community.
THE TESTIMONY RESEARCH OF JAMES RENDEL HARRIS
Authors: Falcetta Alessandro
Published: July 2003

This article is a survey of the research carried out by James Rendel Harris on testimonia. It takes into account published and unpublished material written during a period of about fifty years (1884-1933). This survey permits the correction of current opinions about his work, including those referring to the question of only one original written testimony collection. It also shows that Harris' research was to a large extent independent of previous scholarship and that it influenced several aspects of subsequent testimony and, more in general, New Testament scholarship.
Life Course Factors Associated With Suicidal Behaviors in Young People
Authors: Beautrais Annette L.
Published: July 2003

This article reviews the major life course factors and processes associated with the development of suicidal behaviors in young people. Key issues examined include (a) the spectrum of suicidal behaviors in young people; (b) changing risks of suicidal behavior during childhood, adolescence, and young adulthood; and (c) key risk and protective factors. It is concluded that suicidal tendencies are frequently the culmination of adverse life course sequences that involve multiple risk factors. Future research priorities include a focus on (a) greater understanding of the role of genetic and biologic factors in the development of suicidal behaviors, (b) exploration of factors that may protect young people against suicidal behaviors, and (c) evaluation of public health and clinical programs designed to minimize risk of suicidal behaviors in young people.
Family Factors in Youth Suicidal Behaviors
Authors: Wagner Barry M. , Silverman Mary Alice C. , Martin Catherine E.
Published: July 2003

Research is reviewed on family risk factors for youth suicidal behaviors. Both fatal and nonfatal suicidal behaviors have been linked consistently to negative parent-child relationships (e.g., high conflict, low closeness), child maltreatment, residing with less than two biological parents, and family history of affective and antisocial disorders. Parental separation/divorces and family history of suicidal behavior and alcohol/substance abuse are more strongly associated with completed suicide than with other suicidal symptoms, but family systems problems (such as low cohesion and adaptability) and insecure parent-child attachments are more consistently associated with nonfatal suicidal symptoms than completed suicide. Future research will benefit from attending to the temporal sequencing of putative risk factors and suicidal symptoms and from greater use of observational methods and parental reports.