bluuebunny/crossref_metadata_2025 huggingface dataset:
Vigilant Vector: Heart-Specific Promoter in an Adeno-Associated Virus Vector for Cardioprotection
Authors: Phillips M. Ian , Tang Yi , Schmidt-Ott Kai , Qian Keping , Kagiyama Shuntaro
Published: July 2002

Repeated bouts of ischemia in the heart lead to fibrosis and eventually to heart failure. Although certain genes, such as SOD or hemoxygenase and antisense to AT
1
R, ACE, and (β
1
-AR can provide short-term protection of the heart from ischemia, there is no known mechanism for constantly responding to repeated incidences of ischemia. We hypothesized that a “vigilant vector,” designed to be expressed specifically in the heart and switch on therapeutic genes only during hypoxia, would provide cardioprotection. To attain cardiac specificity, we inserted an MLC2v promoter into an adeno-associated virus (AAV) designed to deliver AS to AT
1
R and gfp. In in vitro experiments in cardiomyocytes (H9C2 cells), the MLC2v-AAV-gfp drove gene expression in all cells at levels comparable to a cytomegalovirus (CMV) promoter. In in vivo experiments, the rAAV-MLC2v-gfp was injected intravenously into mice or rats. Green fluoresence protein (GFP) DNA was located in kidney, heart (right and left ventricle), lung, adrenal and spleen. GFP mRNA, however, was expressed only in the heart and absent in other tissues. To switch on the rAAV transgene during ischemia, we inserted a hypoxia response element (HRE). This upregulates transcription when O
2
levels are low. Thus, there are 4 components to the vigilant vector; a gene switch (HRE), a heart-specific promoter (MLC2v), a therapeutic gene (AS-AT
1
R) and a reporter gene (gfp). To silence or lower basal level of expression while retaining specificity, we have reduced the length of the MLC2v promoter from 3 kb to 1775 bp or 281 bp. The truncated promoter is equally effective in heart specific expression. Preliminary studies with the rAAV-HRE-gfp in vitro show an increased expression in 1% O
2
in 4 to 6 hours. By adding additional hypoxia-inducible factor (HIFα) (5 μg), the MLC2v-gfp expression is increased by 4-fold in 1% O
2
. Further amplification of the gene to 400-fold in 1% O
2
can be achieved with a double plasmid. The construct may serve as a prototype “vigilant vector” to switch on therapeutic genes in specific tissue with physiological signals.
Lacidipine Inhibits Adhesion Molecule and Oxidase Expression Independent of Blood Pressure Reduction in Angiotensin-Induced Vascular Injury
Authors: Park Joon-Keun , Fiebeler Anette , Muller Dominik N. , Mervaala Eero M.A. , Dechend Ralf , Abou-Rebyeh Faikah , Luft Friedrich C. , Haller Hermann
Published: July 2002

Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-κB transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II–dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (
P
<0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-κB and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-κB activation.
Hypertension Genetics, Single Nucleotide Polymorphisms, and the Common Disease:Common Variant Hypothesis
Authors: Doris Peter A.
Published: July 2002

The investigation of heritable susceptibility to disease is an effort to associate disease phenotype with underlying genotype. Such genotype:phenotype associations have been demonstrated for a large number of monogenetic disorders. The usual strategy has been to use linkage mapping in affected families to identify chromosomal loci from which candidate genes and genotypes can be tested for association with disease. This strategy has not been similarly successful for common heritable disease susceptibilities including hypertension that involve multiple genes and gene-environment interactions. Development of extensive collections of single nucleotide polymorphisms (SNPs) raises the possibility that these SNPs can be used as markers in genome-wide association mapping studies to identify hypertension susceptibility loci. In this approach, large numbers of markers are typed in cases and controls with the expectation that markers interrogating SNPs that are involved in inheritance of disease susceptibility will emerge through their association with this trait in the affected population. Essential hypertension is a common disorder. The term “common” has 2 implications: first, that the disease is prevalent; and, second, that it is widespread. Such frequency and distribution characteristics could arise if the susceptibility alleles for hypertension were prevalent in the founding population of contemporary human beings and became distributed with human global dispersal. This common disease:common variant concept is attractive because it suggests that the genetic heterogeneity underlying hypertension susceptibility could be relatively small. It also allows the possibility that nonrandom association of alleles (linkage disequilibrium, LD) can be used to reduce the number of SNP markers required to identify disease susceptibility alleles because a single marker can act as a surrogate for variation flanking it. The influence of a number of important factors on the detectability of hypertension susceptibility alleles by SNP mapping approaches is not yet fully defined. These factors include the locus and allelic diversity of hypertension, the weaker relationship (compared with Mendelian traits) between genotype and phenotype, the accuracy of high throughput genotyping techniques, the extensive role of nongenetic factors, and the extent and heterogenous nature of LD across the genome.
Nitric Oxide Blockade Enhances Renal Responses to Superoxide Dismutase Inhibition in Dogs
Authors: Majid Dewan S.A. , Nishiyama Akira
Published: July 2002

To examine the potential role of superoxide anion (O
2
−
) and its interaction with NO in the regulation of renal hemodynamics and excretory function, we have evaluated the renal responses to enhancement in O
2
−
activity before and during NO synthase inhibition in anesthetized dogs (n=6). Intraarterial infusion of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DETC; 0.1 and 0.5 mg/kg per min) was made to enhance O
2
−
activity in the kidney. Cortical (CBF), medullary (MBF), and total renal blood flow (RBF) responses were assessed using laser-Doppler needle flow probes and an electromagnetic flow probe. DETC caused dose-dependent changes in renal parameters, which were recovered within 30 minutes after the termination of DETC infusion. The high-dose infusion of DETC for 25 minutes resulted in an increase of 29±10% in renal vascular resistance (control, 35.4±4.4 mm Hg/mL per min per g) and decreases of 21±5% in RBF (control, 3.5±0.5 mL/min per g), 20±5% in CBF, 21±7% in MBF, 62±11% in urine flow (control, 10.5±2.2 μL/min per g), and 47±11% in sodium excretion (control, 2.1±0.2 μmol/min per g), without a significant change (−10±6%) in glomerular filtration rate (control, 0.74±0.09 mL/min per g). During NO synthase inhibition with intraarterial administration of nitro-
l
-arginine (50 μg/kg per min), the same dose of DETC showed a greater increase in renal vascular resistance (73±15%) and reductions in RBF (39±4%), CBF (32±5%), MBF (34±6%), urine flow (78±5%), and sodium excretion (67±10%), with a marked reduction in glomerular filtration rate (59±7%). These data indicate that O
2
−
exerts renal vasoconstriction as well as antidiuretic and antinatriuretic effects. These responses are enhanced during NO synthase blockade, suggesting that NO serves a renoprotective effect against these action of O
2
−
.
Inhibition of the Hypothalamic Paraventricular Nucleus in Spontaneously Hypertensive Rats Dramatically Reduces Sympathetic Vasomotor Tone
Authors: Allen Andrew M.
Published: July 2002

Experimental evidence indicates that the hypothalamic paraventricular nucleus modulates sympathetic vasomotor tone and blood pressure and that this modulation is altered in some cardiovascular diseases. This study tested the hypothesis that this nucleus exerts a more significant tonic excitatory modulation of basal sympathetic vasomotor activity in spontaneously hypertensive rats. In anesthetized, artificially-ventilated rats, bilateral microinjections of the GABA
A
receptor agonist, muscimol (1 to 1.5 nmoles per side), into the paraventricular nucleus produced a depressor and sympathoinhibitory response that did not recover. When compared with normotensive rats, this response was more marked in spontaneously hypertensive rats, where lumbar sympathetic nerve discharge was reduced by 75±3% and mean arterial pressure fell from 119±7 mm Hg to 58±3 mm Hg. Blockade of excitatory and inhibitory amino acid receptors in the rostral ventrolateral medulla significantly attenuated this response. Microinjections of small volumes (<20 nL) of GABA were used to localize precisely the responsive region of the paraventricular nucleus. Unilateral injections of GABA into the dorsomedial cap of the paraventricular nucleus induced a brisk depressor (decrease of 42±4 mm Hg), sympathoinhibitory (decrease by 72±2%), and bradycardic (decrease of 77±16 bpm) response. The mechanisms underlying the sympathoinhibition after inactivation of the paraventricular nucleus are not elucidated, but evidence discussed suggests the involvement of a supracollicular sympathoinhibitory pathway. The results presented demonstrate that the paraventricular nucleus exerts a powerful, tonic effect on the control of sympathetic vasomotor tone under basal conditions in anesthetized rats and that this is enhanced in spontaneously hypertensive rats.
Chronic Cardiovascular and Renal Actions of Leptin
Authors: Carlyle Megan , Jones Oscar B. , Kuo Jay J. , Hall John E.
Published: July 2002

Abstract—

This study was designed to determine the role of changes in adrenergic activity in mediating the chronic cardiovascular, renal, and metabolic actions of leptin. Male Sprague-Dawley rats were implanted with catheters for mean arterial pressure (MAP) and heart rate (HR) measurements and IV infusions of either vehicle (n= 7) or α- and β-adrenergic receptor antagonists, terazosin and propranolol (10 mg/kg/d; n= 8) throughout the study. After control measurements, murine leptin was infused IV (1.0 μg/kg/min) for 7 days along with vehicle or adrenergic antagonists, followed by a 7-day recovery period. Leptin infusion significantly reduced food intake in control rats from 22.6±0.8 to 10.6±0.4 g/d and, in adrenergic blockade rats, from 22.6±0.8 to 13.2±0.8 g/d. Fasting plasma insulin decreased from 48±10 to 5±2 μU/mL in control rats and from 51±9 to 9±2 μU/mL in adrenergic blockade rats during leptin infusion. Leptin infusion did not significantly alter glomerular filtration rate in either group. MAP and HR increased by 6±1 mm Hg and 23±7 bpm after 7 days of leptin infusion in control rats. However, in adrenergic blockade rats, leptin infusion did not significantly alter MAP (−1±1 mm Hg) and decreased, rather than increased, HR (−23±8 bpm). These results indicate that leptin-induced increases in blood pressure and tachycardia are mediated by increased adrenergic activity and support the concept that leptin may be an important link between obesity, increased sympathetic activity, and hypertension. However, the chronic effects of leptin on insulin and glucose regulation do not appear to be altered by α- and β-adrenergic receptor blockade.
Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension
Authors: Banes Amy K.L. , Watts Stephanie W.
Published: July 2002

Previous studies have established a role for 5-hydroxytryptamine (5-HT)
2B
and 5-HT
1B
receptors in mediating enhanced contraction to serotonin (5-HT) in arteries from hypertensive deoxycorticosterone acetate (DOCA)-salt rats. To determine whether the observed increase in responsiveness was due to upregulation of 5-HT receptors, we used Western analysis to measure 5-HT
1B
and 5-HT
2B
receptor protein density. In endothelium-denuded aortas from hypertensive DOCA-salt rats (mean systolic blood pressure 192±6 mm Hg), 5-HT
1B
and 5-HT
2B
receptor proteins were upregulated ≈2-fold compared with the response in the aortas of sham-operated control rats (mean systolic blood pressure 119±2 mm Hg). Contraction to 5-HT
2B
receptor agonists was also enhanced in arteries from Wistar-Furth rats given DOCA and salt. This strain is relatively resistant to the hypertensive effects of DOCA and salt treatment. A common factor between the model of DOCA-salt hypertension and the DOCA-salt–treated Wistar-Furth rats is the presence of mineralocorticoids. Therefore, we tested the hypothesis that mineralocorticoids can upregulate 5-HT
1B
and 5-HT
2B
receptors. Aortas from normal Sprague-Dawley rats were incubated with aldosterone (100 nmol/L) for 8, 12, 24, and 48 hours. The expression of 5-HT
2B
and 5-HT
1B
receptor proteins was significantly increased (≈2- fold over vehicle treatment) by 8 hours. 5-HT
2B
and 5-HT
1B
receptors were upregulated by aldosterone in a concentration-dependent manner, and incubation with spironolactone (10 μmol/L) blocked this upregulation. These data support the conclusion that the increased expression of 5-HT
1B
and 5-HT
2B
receptors observed in arteries from DOCA-salt rats may be partially due to mineralocorticoids acting via the mineralocorticoid receptor to modulate gene expression.
Substance P in Subtotal Nephrectomy-Salt Hypertension
Authors: Katki Khurshed A. , Supowit Scott C. , DiPette Donald J.
Published: July 2002

We have previously demonstrated that calcitonin gene-related peptide (CGRP) plays a counterregulatory role in subtotal nephrectomy-salt (SN-salt) hypertension through an increase in vascular responsiveness to the dilator activity of this neuropeptide. Substance P (SP) is often co-localized with CGRP in perivascular sensory nerves. To determine the role and mechanism of action of SP in SN-salt hypertension, we induced hypertension in 4- to 6-week-old male Sprague-Dawley rats (n=8) by subtotal nephrectomy and 1% saline drinking water. Sham-operated rats were given either tap water (n=9) or 1% saline to drink (n=9). Eleven to 13 days after each protocol, all rats had intravenous (for drug administration) and arterial (for continuous monitoring of mean arterial pressure [MAP]) catheters surgically implanted and were studied in the conscious and unrestrained state. Baseline MAP was significantly elevated in the SN-salt rats (157±6 mm Hg) compared with tap water–fed controls (128±3 mm Hg) and 1% saline–fed controls (132±5 mm Hg). Vehicle administration did not alter the MAP in any group. In contrast, administration of spantide-II (0.2 μmol/L in saline), an SP receptor antagonist, significantly elevated the MAP in SN-salt rats (13.9±0.8 mm Hg) compared with the tap water (1.7±1.7 mm Hg) and 1% saline controls (2.0±1.9 mm Hg). SP mRNA and peptide levels in dorsal root ganglia were not significantly different between the 3 groups. Administration of exogenous SP (12 and 24 nmol · L
−1
· kg
−1
intravenously) resulted in a significantly greater decrease in MAP in the SN-salt rats compared with both control groups. Taken together, these data suggest that in SN-salt hypertension, SP plays a counterregulatory role in the absence of an increase in its neuronal expression, thereby suggesting that one possible mechanism of this compensatory vasodilator response is enhanced vascular reactivity to SP.
Pressure Promotes Angiotensin II–Mediated Migration of Human Coronary Smooth Muscle Cells Through Increase in Oxidative Stress
Authors: Yasunari Kenichi , Maeda Kensaku , Nakamura Munehiro , Yoshikawa Junichi
Published: July 2002

Angiotensin II–mediated oxidative stress may play a role in the pathogenesis of coronary atherosclerosis. We examined the effects of pressure on the angiotensin II–mediated increase in oxidative stress and migration of cultured human coronary smooth muscle cells (SMCs). Increased pressure (100 mm Hg) by helium gas for 48 hours increased angiotensin II–mediated oxidative stress as evaluated by flow cytometry and SMC migration (from 15.9±2.2 to 32.0±2.4 cells per 4 high-power fields,
P
<0.05; n=8). The pressure-induced increases in oxidative stress observed appear to involve phospholipase D (PLD) and protein kinase C (PKC), inasmuch as the indirect PLD inhibitor suramin, at 100 μmol/L, and the PKC inhibitor chelerythrine, at 1 μmol/L, completely blocked the increase in angiotensin II–mediated oxidative stress induced by pressure. Pressure-induced increase in angiotensin II–mediated oxidative stress was inhibited by diphenylene iodonium chloride, an NADPH oxidase inhibitor, by 79% (
P
<0.05, n=8). Losartan (1 μmol/L), its active metabolite E3174 (1 μmol/L), and the antioxidant
N
-acetylcysteine (100 mmol/L) but not PD123319 (1 μmol/L) also blocked pressure-induced increases in angiotensin II–mediated oxidative stress and SMC migration (
P
<0.05, n=8). These findings suggest a novel cellular mechanism whereby pressure regulates the angiotensin II–mediated migration of SMCs, possibly via angiotensin II type 1 receptors, and which involves PLD-mediated, PKC-mediated, and NADPH oxidase–mediated increases in oxidative stress.
Oxidative Stress in Leukocytes Is a Possible Link Between Blood Pressure, Blood Glucose, and C-Reacting Protein
Authors: Yasunari Kenichi , Maeda Kensaku , Nakamura Munehiro , Yoshikawa Junichi
Published: July 2002

Because oxidative stress and inflammation are believed to play roles in the pathogenesis of cardiovascular diseases, oxidative stress in polymorphonuclear leukocytes (PMNs) and mononuclear cells (MNCs) has been measured. A total of 529 subjects participated this study. Intracellular oxidative stress in PMNs and MNCs was measured by gated flow cytometry using carboxyfluorescin diacetate bis-acetoxymethyl ester. C-reacting protein (CRP), insulin action (homeostasis model assessment), and traditional risk factors such as age, gender, body mass index, triglycerides, LDL cholesterol, HDL cholesterol, hemoglobin A
1c
, and mean blood pressure were also measured. Multiple regression analysis revealed a significant correlation between mean blood pressure and PMN oxidative stress (
r
=0.104,
P
=0.018). It also demonstrated a significant correlation between hemoglobin A
1c
and PMN oxidative stress (
r
=0.112,
P
=0.021). A significant correlation was also found between CRP and MNC oxidative stress (
r
=0.116,
P
=0.008) by multiple regression analysis. In patients with both hypertension and diabetes, both PMN and MNC oxidative stress was increased (n=21,
P
=0.022 and
P
=0.006). These results suggest that both hypertension and diabetes lead to increased oxidative stress of PMNs and MNCs, and that CRP is related to MNC oxidative stress.
Endothelial Nitric Oxide Synthase Lies Downstream From Angiotensin II–Induced Angiogenesis in Ischemic Hindlimb
Authors: Tamarat Radia , Silvestre Jean-Sébastien , Kubis Nathalie , Benessiano Joelle , Duriez Micheline , deGasparo Marc , Henrion Daniel , Levy Bernard I.
Published: July 2002

We assessed the role of angiotensin (Ang) II in ischemia-induced angiogenesis and analyzed the molecular pathways involved in such an effect. Ischemia was produced by unilateral artery femoral occlusion in control, in valsartan-treated (Ang II receptor type I antagonist, 20 mg/kg per day), in Ang II–treated (5 ng/kg per min), and in Ang II and valsartan–treated rats. After 28 days, angiogenesis was assessed by microangiography and capillary density measurement in hindlimbs. The ischemic/nonischemic leg ratio for angiographic score and capillary number increased by 2.6- and 2-fold, respectively, in Ang II–treated rats compared with controls (
P
<0.01). This was associated with an increase in vascular endothelial growth factor (VEGF; 1.6-fold) and endothelial NO synthase (eNOS; 1.8-fold) protein content within the ischemic leg, assessed by Western blot. Angiotensin type 1 receptor blockade and administration of VEGF neutralizing antibody (2.5 μg IP, twice a week) in Ang II–treated rats completely prevented such Ang II angiogenic effects. The key role of eNOS was then emphasized by using mice deficient in gene encoding for eNOS. In wild-type mice, Ang II (0.3 mg/kg per min) treatment increased by 1.7- and 1.6-fold the ischemic/nonischemic leg for angiographic score and blood perfusion (assessed by laser Doppler perfusion imaging) ratios, respectively (
P
<0.01). Conversely, no significant changes were observed in Ang II–treated mice deficient in gene encoding for eNOS. Subhypertensive dose of Ang II enhanced angiogenesis associated with tissue ischemia through angiotensin type 1 receptor activation that involved the VEGF/eNOS-dependent pathway.
Factors Related to the Occurrence of Microalbuminuria During Antihypertensive Treatment in Essential Hypertension
Authors: Redon Josep , Rovira Eduardo , Miralles Amparo , Julve Raul , Pascual Jose M.
Published: July 2002

The objective of the study was to assess the factors related to the occurrence of microalbuminuria during the follow-up of a young adult group with essential hypertension that had not been previously treated. Normo-albuminuric essential hypertensives, <50 years old, who had not been previously treated with antihypertensive drugs and who did not have diabetes mellitus were included. After the initial evaluation, patients were treated using only nonpharmacological measures (n=62), β-blockers (n=38), ACE inhibitors (n=64), calcium channel blockers (n=8), and several classes (n=15). Measurements were taken for office blood pressure, biochemical profile, and 24-hour urinary albumin excretion at the beginning of the study and were measured yearly during an average of 2.7±1.2 years of follow-up. Among the 187 patients included, 22 (11,7%) developed microalbuminuria (progressors, 4.4/100 patients/y). No differences were present between progressors and those who remained normo-albuminuric (nonprogressors) in terms of age, gender, body mass index, disease duration, blood pressure values, biochemical profile, familial history of diabetes or hypertension, smoking habits, or the presence of EKG left ventricular hypertrophy. The group with the lowest progression rate was the patients treated with ACE inhibitors (n=5; 2.9/100 patients/y), followed by the diet group (n=5; 3.3/100 patients/y) and the β-blockers group (n=5; 4.1/100 patients/y). When we excluded patients treated with calcium channel blockers or those who changed over time between different classes of treatment, no significant differences in the incidence of microalbuminuria were observed among the groups. Progressors showed higher slopes of fasting glucose (4.78±11.4 versus 0.50±6.8 mg/y,
P
<0.02) and uric acid (0.58±0.93 versus 0.05±1.10 mg/y,
P
<0.03) compared with the slopes of nonprogressors. Both the slopes for glucose and systolic blood pressure over time were associated independently with the slope of the logarithm of urinary albumin excretion when adjusted for age, gender, and treatment groups. Cox proportional hazard model for progression of microalbuminuria showed that baseline urinary albumin excretion (risk ratio [RR]=1.06; confidence interval [CI] 95%, 1.01 to 1.11), slope for systolic blood pressure (RR=1.11; CI 95%, 1.03 to 1.20), and slope for glucose (RR=1.08; CI 95%, 1.03 to 1.14) were independently associated to the development of microalbuminuria. In conclusion, in a group of young adults with essential hypertension that had not been previously treated, the main factors influencing the occurrence of microalbuminuria during antihypertensive treatment were the values of microalbuminuria at baseline and the slopes for systolic blood pressure and fasting glucose.
Exaggerated Hypotensive Effect of Vascular Endothelial Growth Factor in Spontaneously Hypertensive Rats
Authors: Yang Renhui , Ogasawara Annie K. , Zioncheck Thomas F. , Ren Zhen , He Guo-Wei , DeGuzman Geralyn G. , Pelletier Nicolas , Shen Ben-Quan , Bunting Stuart , Jin Hongkui
Published: July 2002

Vascular endothelial growth factor (VEGF) induces hypotension in normotensive subjects, which is considered to be a major side effect for treatment of ischemic diseases. However, the hypotensive effect of VEGF has not been investigated in the setting of hypertension. This study determined effects of VEGF on hemodynamics, pharmacokinetics, and release of NO and prostaglandin I
2
(PGI
2
) in vivo and on vasorelaxation of mesentery artery rings in vitro in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Intravenous infusion of VEGF for 2 hours produced a dose-related decrease in arterial pressure, which was enhanced in conscious SHR compared with WKY (
P
<0.01), and an increase in heart rate in WKY but not in SHR. In response to similar doses of VEGF, compared with WKY, SHR had a higher plasma VEGF level and lower VEGF clearance (
P
<0.01). Circulating NO and PGI
2
levels after VEGF administration were not increased in SHR versus WKY, and VEGF-induced vasorelaxation was blunted in SHR versus WKY in vitro, suggesting endothelial dysfunction in SHR. One-week VEGF infusion also caused greater hypotension (
P
<0.05) in the absence of tachycardia in SHR compared with WKY controls. Thus, despite blunted vasorelaxation in vitro because of endothelial dysfunction, SHR exhibited exaggerated hypotension without tachycardia in response to VEGF, which was independent of NO and PGI
2
. The exaggerated hypotensive response to VEGF in SHR may be owing to impaired baroreflex function and reduced VEGF clearance. The data may also suggest that more caution should be taken when VEGF is administered in patients with hypertension.
Socioeconomic Trajectories and Incident Hypertension in a Biracial Cohort of Young Adults
Authors: Matthews Karen A. , Kiefe Catarina I. , Lewis Cora E. , Liu Kiang , Sidney Stephen , Yunis Carla
Published: July 2002

We assessed the impact of initial socioeconomic status and change in socioeconomic status across 10 years, ie, status trajectories, on the development of essential hypertension among black and white young men and women. Three thousand eight hundred twenty-seven normotensive individuals ages 18 to 30 years at study entry were followed for 10 years, with blood pressure, body mass index, and socioeconomic status characteristics measured at years 0, 2, 5, 7, and 10. Socioeconomic status trajectory measures were a new educational degree earned by year 10; difficulties paying for basics during years 2 to 10; and change in income category from year 5 to 10, defined in relation to year 0 status. Hypertension was defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or antihypertensive medication use at year 10. Reporting difficulties paying for basics at study entry (odds ratio=1.45, 95% confidence interval, 1.05 to 2.02) and continued difficulties during year 2 to 10 follow-up (odds ratio=1.62, 95% confidence interval, 1.04 to 2.53) were independently associated with incident hypertension, adjusted for race-gender group, body mass index, site, age, and initial systolic blood pressure. Decline in income from year 5 to 10 tended to be associated with hypertension,
P
=0.07, but a new educational degree after study onset was not. Socioeconomic trajectories are independently associated with incidence of hypertension. A dynamic index of socioeconomic status may be a useful concept in understanding the effects of socioeconomic status on the natural history of hypertension.
Correlates of Left Atrial Size in Hypertensive Patients With Left Ventricular Hypertrophy
Authors: Gerdts Eva , Oikarinen Lasse , Palmieri Vittorio , Otterstad Jan Erik , Wachtell Kristian , Boman Kurt , Dahlöf Björn , Devereux Richard B.
Published: July 2002

Left ventricular hypertrophy has been suggested to mediate the relation between hypertension and left atrial enlargement, with associated risks of atrial fibrillation and stroke. However, less is known about correlates of left atrial size in hypertensive patients with left ventricular hypertrophy. We assessed left atrial size by echocardiography in 941 hypertensive patients, age 55 to 80 (mean, 66) years, with electrocardiographic left ventricular hypertrophy at baseline in the Losartan Intervention For Endpoint reduction in hypertension study. Enlarged left atrial diameter (women, >3.8 cm; men, >4.2 cm) was present in 56% of women and 38% of men (
P
<0.01). Compared with the 512 patients with normal left atrial size, the 429 patients with enlarged left atrium more often had mitral regurgitation, atrial fibrillation, and echocardiographic left ventricular hypertrophy. They also had higher age, systolic blood pressure, pulse pressure, weight, body mass index, left ventricular internal chamber dimension, stroke volume, and mass and lower relative wall thickness and ejection fraction (all,
P
<0.05). In logistic regression analysis, left atrial enlargement was related to left ventricular hypertrophy and eccentric geometry; greater body mass index, systolic blood pressure, and age; female gender; mitral regurgitation; and atrial fibrillation (all,
P
<0.05). Thus, left atrial size in hypertensive patients with electrocardiographic left ventricular hypertrophy is influenced by gender, age, obesity, systolic blood pressure, and left ventricular geometry independently of left ventricular mass and presence of mitral regurgitation or atrial fibrillation.
Regulation and Localization of HSP70 and HSP25 in the Kidney of Rats Undergoing Long-Term Administration of Angiotensin II
Authors: Ishizaka Nobukazu , Aizawa Toru , Ohno Minoru , Usui Shin-ichi , Mori Ichiro , Tang Shiow-Shih , Ingelfinger Julie R. , Kimura Satoshi , Nagai Ryozo
Published: July 2002

Various renal insults result in induction of heat shock protein (HSP) expression within the kidney. Some of the HSPs induced in that manner are postulated to have renoprotective effects via either chaperoning actions or antioxidative properties. We have previously reported that long-term angiotensin (Ang) II administration induces the expression of renal HSP32, also known as heme oxygenase-1 (HO-1). Here, we investigated the regulation of expression and localization of other HSPs, including HSP70, HSP25, and αB-crystallin, in the kidney of rats undergoing long-term administration of Ang II (0.7 mg · kg
−1
· d
−1
). Immunoblot analysis demonstrated that Ang II increased renal expression of HSP70 and HSP25, as well as HO-1, but that expression of αB-crystallin was unaffected by this treatment. The Ang II–induced increase in renal HSP70 and HSP25 was dependent on the angiotensin type 1 receptor activation but not on hypertension per se. Immunohistochemistry revealed that HSP70 and HSP25 were expressed in the medullar regions and in the renal arterial wall in the kidney of control rats. After Ang II infusion, signals for HSP70, HSP25, and HO-1 proteins increased in intensity in the endothelium and medial smooth muscle of the renal artery. In addition, all of these HSPs were induced in proximal renal tubular epithelial cells from the same segments, suggesting that similar mechanisms are responsible for upregulating these HSPs. Our data show that Ang II infusion induces renal HSP70 and HSP25, as well as HO-1, and that Ang II can induce expression of these HSPs in renal cells in a pressor-independent manner.
Sabotaging the Peace: The Politics of Extremist Violence
Authors: Kydd Andrew , Walter Barbara F.
Published: July 2002

Why are extremists able to sabotage peace processes in some cases but not others? And under what conditions will the public respond to such provocation and return to unpopular wars? We seek to show that extremist violence is not indiscriminate or irrational as many people have assumed but quite strategic. We argue that extremist violence intentionally plays on the uncertainty that exists between the more moderate groups who are attempting to negotiate a peace agreement. Using a game-theoretic model of the interaction of extremist violence and mistrust, we identify the conditions under which extremists will succeed and fail. We find that extremists are most likely to succeed in derailing a peace process when the targeted side believes that opposition moderates are strong. At these times, the public perceives moderates as best able to control and suppress extremists within their own ranks. When moderates are viewed as weak and unable to crack down on extremists, terrorism is more likely to fail. We discuss this finding, as well as a number of additional implications of the model, in connection with the Israeli–Palestinian case.
Democratic Transitions, Institutional Strength, and War
Authors: Mansfield Edward D. , Snyder Jack
Published: July 2002

The relationship between democratization and war has recently sparked a lively debate. We find that transitions from autocracy that become stalled prior to the establishment of coherent democratic institutions are especially likely to precipitate the onset of war. This tendency is heightened in countries where political institutions are weak and national officials are vested with little authority. These results accord with our argument that elites often employ nationalist rhetoric to mobilize support in the populist rivalries of the poorly-institutionalized democratizing state but then get caught up in the belligerent politics that this process eventually unleashes. In contrast, we find that transitions that quickly culminate in a fully coherent democracy are much less perilous. Further, our results refute the view that transitional democracies are merely the targets of attack due to their temporary weakness: in fact, they tend to be the initiators of war. We also refute the view that any regime change is likely to precipitate the outbreak of war: transitions toward democracy are significantly more likely to generate hostilities than transitions toward autocracy.
In View of Ratification: Governmental Preferences and Domestic Constraints at the Amsterdam Intergovernmental Conference
Authors: Hug Simon , König Thomas
Published: July 2002

The bargaining product of the Amsterdam Intergovernmental Conference—the Amsterdam Treaty—dwindled down the draft proposal to a consensus set of all fifteen member states of the European Union (EU). Using the two-level concept of international bargains, we provide a thorough analysis of how this consensus set was reached by issue subtraction with respect to domestic ratification constraints. Drawing on data sets covering the positions of all negotiating actors and ratifying national political parties, we first highlight the differences in the Amsterdam ratification procedures in the fifteen member states of the EU. This analysis allows us to compare the varying ratification difficulties in each country. Second, our empirical analysis of the treaty negotiations shows that member states excluded half of the Amsterdam bargaining issues to secure a smooth ratification. Because member states with higher domestic ratification constraints performed better in eliminating uncomfortable issues at the Amsterdam Intergovernmental Conference, issue subtraction can be explained by the extent to which the negotiators were constrained by domestic interests.
Figure—Ground Segregation in a Recurrent Network Architecture
Authors: Roelfsema Pieter R. , Lamme Victor A. F. , Spekreijse Henk , Bosch Holger
Published: July 2002

Here we propose a model of how the visual brain segregates textured scenes into figures and background. During texture segregation, locations where the properties of texture elements change abruptly are assigned to boundaries, whereas image regions that are relatively homogeneous are grouped together. Boundary detection and grouping of image regions require different connection schemes, which are accommodated in a single network architecture by implementing them in different layers. As a result, all units carry signals related to boundary detection as well as grouping of image regions, in accordance with cortical physiology. Boundaries yield an early enhancement of network responses, but at a later point, an entire figural region is grouped together, because units that respond to it are labeled with enhanced activity. The model predicts which image regions are preferentially perceived as figure or as background and reproduces the spatio-temporal profile of neuronal activity in the visual cortex during texture segregation in intact animals, as well as in animals with cortical lesions.
Neural Differentiation of Lexico-Syntactic Categories or Semantic Features? Event-Related Potential Evidence for Both
Authors: Kellenbach Marion L. , Wijers Albertus A. , Hovius Marjolijn , Mulder Juul , Mulder Gijsbertus
Published: July 2002

Event-related potentials (ERPs) were used to investigate whether processing differences between nouns and verbs can be accounted for by the differential salience of visual-perceptual and motor attributes in their semantic specifications. Three subclasses of nouns and verbs were selected, which differed in their semantic attribute composition (abstract, high visual, high visual and motor). Single visual word presentation with a recognition memory task was used. While multiple robust and parallel ERP effects were observed for both grammatical class and attribute type, there were no interactions between these. This pattern of effects provides support for lexical—semantic knowledge being organized in a manner that takes account both of category-based (grammatical class) and attribute-based distinctions.
The Timing of Action-Monitoring Processes in the Anterior Cingulate Cortex
Authors: Veen Vincent van , Carter Cameron S.
Published: July 2002

The anterior cingulate cortex (ACC) has been shown to respond to conflict between simultaneously active, incompatible response tendencies. This area is active during high-conflict correct trials and also when participants make errors. Here, we use the temporal resolution of high-density event-related potentials (ERPs) in combination with source localization to investigate the timing of ACC activity during conflict and error detection. We predicted that the same area of the ACC is active prior to high-conflict correct responses and following erroneous responses. Dipole modeling supported this prediction: The frontocentral N2, occurring prior to the response on correct conflict trials, and the ERN, occurring immediately following error responses, could both be modeled as having a generator in the caudal ACC, suggesting the same process to underlie both peaks. Modeling further suggested that the rostral area of the ACC was also active following errors, but later in time, contributing to the error positivity (P E), and peaking at 200–250 msec following the ERN peak. Despite the inherent limitations of source localization, these data may begin to shed light on the timing of action-monitoring processes. First, the time course of caudal ACC activity follows the time course as predicted by the conflict theory of this region. Second, caudal ACC activity might be temporally dissociated from rostral ACC activity during error trials, which possibly reflects a separate, affective component of the evaluative functions of the ACC.
Sustained Mnemonic Response in the Human Middle Frontal Gyrus during On-Line Storage of Spatial Memoranda
Authors: Leung H.-C. , Gore J. C. , Goldman-Rakic P. S.
Published: July 2002

The mapping of cognitive functions to neural systems is a central goal of cognitive neuroscience. On the basis of homology with lesion and physiological studies in nonhuman primates, Brodmann's area (BA) 46/9 in the middle frontal gyrus (MFG) has been proposed as the cortical focus for both the storage as well as processing components of working memory in the human brain, but the evidence on the segregation of these components and their exact areal localization has been inconsistent. In order to study this issue and increase the temporal resolution of functional mapping, we disambiguated the storage component of working memory from sensory and motor responses by employing functional magnetic resonance imaging (fMRI) in spatial delayed-response (DR) tasks with long delay intervals and different conditions of demand. We here show that BA 46 can support a sustained mnemonic response for as long as 24 sec in a high-demand task and the signal change in this area exceeded that in the other prefrontal areas examined. Our findings support a conservation of functional architecture between human and nonhuman primate in showing that the MFG is prominently engaged in the storage of spatial information.
Virtual Reality and Driving: The Road to Better Assessment for Cognitively Impaired Populations
Authors: Schultheis Maria T. , Mourant Ronald R.
Published: July 2002

Individuals with cognitive impairments can be faced with difficulties that may challenge their ability to drive an automobile, and this impairment is often very disruptive to vocational, social, and domestic activities. Rehabilitation specialists are often given the task of determining capacity to drive. However, traditional assessment methods are fraught with various limitations, including dependence on subjective interpretation of behaviors, nonstandardized procedures, and few ecologically valid measures. A virtual reality-based driving-assessment system (VR-DAS) offers the opportunity to overcome many of the limitations of current methodologies. Specifically, a VR-DAS permits the development of relevant driving scenarios that can provide objective and quantifiable measures of driving behaviors, allowing for increasing standardization and consistency of protocols. VR-DAS also allows for the creation of realistic and interactive driving scenarios at varying levels of challenge and complexity. When coupled with the immersive features offered through a headmounted display (HMD), the VR-DAS may allow drivers to experience the sense of real-life driving, resulting in behavior and responsiveness that may be more predictive of actual driving ability. To examine these potential benefits and the validity of a VR-DAS, a collaborative study is presently being conducted, comparing VR-DAS performance and actual behind-the-wheel performance in adults with acquired brain injury (such as traumatic brain injury and stroke).
A Wearable Attitude-Measurement System Using a Fiberoptic Gyroscope
Authors: Sawada Keiichi , Okihara Masayuki , Nakamura Shigeru
Published: July 2002

An attitude-measurement system (TISS-5-40) has been developed to achieve a wearable sensor for individuals. This equipment is one of the inertial sensor systems having three fiberoptic gyroscopes and three accelerometers. Heading stability of 1 deg./hr. (1σ) and attitude accuracy of ±0.5 deg. have been demonstrated. At present, some of the attitude-measurement Systems have been applied in the field of mixed-reality technology, and the users confirm and report its effectiveness (Hara, Anabuki, Satoh, Yamamoto, & Tamura, 2000).
EyeTap Devices for Augmented, Deliberately Diminished, or Otherwise Altered Visual Perception of Rigid Planar Patches of Real-World Scenes
Authors: Mann Steve , Fung James
Published: July 2002

Diminished reality is as important as augmented reality, and both are possible with a device called the Reality Mediator. Over the past two decades, we have designed, built, worn, and tested many different embodiments of this device in the context of wearable computing. Incorporated into the Reality Mediator is an “EyeTap” system, which is a device that quantifies and resynthesizes light that would otherwise pass through one or both lenses of the eye(s) of a wearer. The functional principles of EyeTap devices are discussed, in detail. The EyeTap diverts into a spatial measurement system at least a portion of light that would otherwise pass through the center of projection of at least one lens of an eye of a wearer. The Reality Mediator has at least one mode of operation in which it reconstructs these rays of light, under the control of a wearable computer system. The computer system then uses new results in algebraic projective geometry and comparametric equations to perform head tracking, as well as to track motion of rigid planar patches present in the scene. We describe how our tracking algorithm allows an EyeTap to alter the light from a particular portion of the scene to give rise to a computer-controlled, selectively mediated reality. An important difference between mediated reality and augmented reality includes the ability to not just augment but also deliberately diminish or otherwise alter the visual perception of reality. For example, diminished reality allows additional information to be inserted without causing the user to experience information overload. Our tracking algorithm also takes into account the effects of automatic gain control, by performing motion estimation in both spatial as well as tonal motion coordinates.
A Transparent, Interactive Software Environment for Communicating Life‐Cycle Assessment Results: An Application to Residential Windows
Authors: Norris Gregory A. , Yost Peter
Published: July 2002

Life‐cycle assessments (LCAs) can be used to support the selection of environmentally preferable building materials. But the dominance of the usage phase in the life cycle of building materials represents a special challenge for two reasons. First, many aspects of a building material's usage phase can be context specific. Second, the LCA outcome may rest on a building material's service life, a parameter for which there is typically insufficient information for proper determination. For example, in the selection of a window, important usagephase, context‐specific factors that could be determinant include lo‐cation/climate, heating‐system characteristics (efficiency and fuel), and product durability. A prototype software tool, the Life Cycle Explorer, has been developed that enables decision makers to assess the relative importance of literally dozens of such influential parameters in determining the outcomes of LCA evaluations for building components. The software employed by the Life Cycle Explorer permits extensive layering while maintaining ease of browsing, with the intent of accessibility to both the layperson and the expert. An initial application of the tool addressed residential window selection; the design principles of the software are relevant to the communication phase of a wide variety of LCA and industrial‐ecologyrelated modeling projects.
Beyond Pollution Havens
Authors: Wheeler David
Published: July 2002

Poor countries suffer from serious environmental damage, and much more pollution control is justifiable. Weak regulation is partly to blame, but the evidence suggests that it reflects a general development problem, not deliberate creation of “pollution havens” to promote investment and trade. Aid from the OECD countries can help reduce pollution in poor countries by promoting better public information about polluters, stronger regulatory institutions, and more explicit attention to environmental risks in large projects. However, attempts to enforce OECD-level regulatory standards through general trade and aid sanctions are both regressive and useless: regressive because they penalize workers in poor countries by reducing opportunities for jobs and higher wages; useless because governments of low-income countries can not deliver on promises of OECD-level regulation, even if they wish to do so.