bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical Strength of the Isolated Carotid Artery in SHR
Authors: Cohuet Geraldine , Challande Pascal , Osborne-Pellegrin Mary , Arribas Silvia M. , Dominiczak Anna , Louis Huguette , Laurent Stéphane , Lacolley Patrick
Published: September 2007

We have previously reported an adaptation of arterial wall elasticity in spontaneously hypertensive rats (SHR) that involves an increase in both fibronectin/α5β1-integrin complexes and smooth-muscle elastic lamellae connections. We examined the mechanical strength (MS) of the carotid artery in relation to its elastic properties, its elastin/collagen content, and the structure of the internal elastic lamina. MS was defined as the in vitro intraluminal pressure and wall stress that produces rupture of the vascular wall. Intact carotid arteries from 3-month-old normotensive rats (Wistar-Kyoto, WKY) and SHR were cannulated on a specially designed device and adjusted to their in situ length. A slowly increasing static pressure was applied until wall rupture occurred to determine the static mechanical behavior and MS. Static elasticity was similar in SHR and WKY, as were the rupture pressure (2740±90 versus 2740±40 mm Hg) and wall stress at rupture (11.5±1.0 versus 12.8±0.4 MPa), indicating equivalent MS in both groups. Histological examination showed several wall ruptures and dissociation of lamellar units that did not differ significantly between the 2 groups. Confocal microscopy showed that the size of fenestrations of the internal elastic lamina and the fraction of area occupied by them were reduced 3-fold in SHR. We have demonstrated that static elasticity of the arterial wall and mechanical strength are similar in carotid arteries from SHR and WKY.
Enhanced Affective Startle Modulation in Salt-Sensitive Subjects
Authors: Buchholz Konrad , Schächinger Hartmut , Wagner Miriam , Schorr Ulrike , Sharma Arya Mitra , Deter Hans Christian
Published: September 2007

Salt-sensitive normotensive men exhibit an enhanced pressor response to mental stress. Although an enhanced pressor response is associated with higher affective startle modulation in men, an association between salt sensitivity of blood pressure and affective startle modulation has not been studied so far. We studied reactivity to mental stress and startle modulation in 14 salt-sensitive healthy white male students and 14 salt-resistant control subjects, who were well matched for age, body mass index, physical fitness, and family history of hypertension. Subjects performed a computerized information-processing task under time pressure (manometer test), while heart rate and blood pressure were continuously registered. In a separate session, subjects viewed a series of 42 pictures of the International Affective Picture System (IAPS), varying in pleasure and arousal, while acoustic startle probes were administered randomly, and electromyogram activity of the orbicular eye muscle was continuously recorded. Startle modulation was calculated as the difference between startle responses under negative and positive affective stimuli. In contrast to salt-resistant subjects, salt-sensitive subjects showed significantly enhanced startle amplitudes under negative stimuli and diminished amplitudes under positive stimuli. Thus, salt-sensitive subjects displayed a significantly higher startle modulation than did salt-resistant subjects (
P
<0.05). Subjective ratings of the presented IAPS pictures did not differ between the groups. The increased startle modulation of salt-sensitive subjects suggests an enhanced activity of the central nucleus of the amygdala. This enhanced central nervous responsiveness may contribute to higher sympathetic pressor reactivity and, thus, to the later development of hypertension in salt-sensitive individuals.
Physiological and Pathophysiological Functions of the AT2Subtype Receptor of Angiotensin II
Authors: Henrion Daniel , Kubis Nathalie , Lévy Bernard I.
Published: September 2007

Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT1R) and type 2 (AT2R). Whereas the key role of AT2R in the development of the embryo has been extensively studied, the role of AT2R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT2R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT2R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT2R-dependent dilation. Sometimes, such as in large renal arteries, AT2R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT2R stimulation may also have a role in shear stress–induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT2R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT1R blockade in patients, overstimulation of AT2R might be beneficial, given their potential vasodilator effect.

Concerning the possible role of AT2R in cardiovascular remodeling, the situation is more controversial. In vitro AT2R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT2R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT1R blockade, and thus AT2R overstimulation, require more in-depth analysis.
In Vivo 11β-HSD-2 Activity
Authors: Ferrari Paolo , Sansonnens Aurelie , Dick Bernhard , Frey Felix J.
Published: September 2007

Loss-of-function mutations or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) results in overstimulation of the mineralocorticoid receptor by cortisol and causes salt-sensitive hypertension. Traditionally, 11β-HSD-2 activity has been assessed by measurement of the urinary cortisol metabolite ratio (tetrahydrocortisol [THF]+5α-THF)/tetrahydrocortisone (THE). Recently, the ratio of urinary free glucocorticoids, UFF/UFE, has been suggested to be a more reliable parameter, an aspect that has not been investigated systematically. Steroid metabolites were measured repeatedly by gas chromatography–mass spectrometry in 20 healthy subjects at baseline and after 1 week each of a 30- or 180-mmol/d of sodium diet or 500 mg/d of glycyrrhetinic acid. Intraindividual coefficients of variation from 3 random urine collections for (THF+5α-THF)/THE and UFF/UFE ratios were 11±9% and 25±14% (
P
<0.001). (THF+5α-THF)/THE was more sensitive than UFF/UFE for detection of glycyrrhetinic acid–induced increases higher than the upper 95% confidence interval of the coefficient of variation of the corresponding ratio. Low- or high-salt diet did not alter either ratio. Mean (THF+5α-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects. Absolute glycyrrhetinic acid–related increase in (THF+5α-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects and correlated with changes in mean BP. Intraindividual variability of (THF+5α-THF)/THE is lower than that of UFF/UFE. The UFF/UFE ratio does not appear to be more sensitive than (THF+5α-THF)/THE for detection of decreased 11β-HSD-2 activity. The (THF+5α-THF)/THE ratio better discriminates between salt-sensitive and salt-resistant subjects. Together with BP responses to glycyrrhetinic acid, these findings support a pivotal role of 11β-HSD-2 in salt sensitivity.
Angiotensin II Type 2 Receptors and Cardiac Hypertrophy in Women With Hypertrophic Cardiomyopathy
Authors: Deinum Jaap , van Gool Jeanette M.G. , Kofflard Marcel J.M. , ten Cate Folkert J. , Danser A.H. Jan
Published: September 2007

The development of left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors such as angiotensin II. Angiotensin II mediates both trophic and antitrophic effects, via angiotensin II type 1 (AT1-R) and angiotensin II type 2 (AT2-R) receptors, respectively. Here we investigated the effect of the AT2-R gene A/C3123polymorphism, located in the 3′ untranslated region of exon 3, on left ventricular mass index (LVMI) in 103 genetically independent subjects with HCM (age, 12 to 81 years). LVMI and interventricular septum thickness were determined by 2D echocardiography. Extent of hypertrophy was quantified by a point score (Wigle score). Plasma prorenin, renin, and ACE were determined by immunoradiometric or fluorometric assays, and genotyping was performed by polymerase chain reaction. In men, no associations between AT2-R genotype and any of the measured parameters were observed, whereas in women, LVMI decreased with the number of C alleles (211±19, 201±18, and 152±10 g/m2in women with the AA, AC, and CC genotype, respectively;P=0.015). Similar C allele–related decreases in women were observed for interventricular septum thickness (P=0.13), Wigle score (P=0.05), plasma renin (P=0.03), and plasma prorenin (P=0.26). Multiple regression analysis revealed that the AT2-R C allele–related effect on LVMI (β=−30.7±11.1,P=0.010) occurred independently of plasma renin, the AT1-R gene A/C1166polymorphism, or the ACE gene I/D polymorphism. In conclusion, AT2-Rs modulate cardiac hypertrophy in women with HCM, independently of the circulating renin-angiotensin system. These data support the contention that AT2-Rs mediate antitrophic effects in humans.
Molecular Basis of Salt Sensitivity in Human Hypertension
Authors: Poch Esteban , González Daniel , Giner Vicente , Bragulat Ernesto , Coca Antonio , de la Sierra Alejandro
Published: September 2007

We analyzed the association between salt sensitivity in essential hypertension and 8 genetic polymorphisms in 6 genes of the renin-angiotensin aldosterone system. Seventy-one patients with essential hypertension were classified as salt sensitive or salt resistant by means of the 24-hour ambulatory blood pressure (BP) change to high salt intake. The polymorphisms evaluated correspond to the following genes: ACE (I/D), angiotensinogen (M235T), angiotensin II type 1 receptor (A1166C), 11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) (G534A), aldosterone synthase (C-344T and Intron 2 conversion), and the mineralocorticoid receptor (G3514C and A4582C); all were determined using standard polymerase chain reaction methods. Thirty-five patients (49%) were classified as salt sensitive. We analyzed the BP response to high salt intake among genotypes and found a significant association for ACE I/D and 11βHSD2 G534A polymorphisms. Patients homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake than did patients homozygous for the deletion allele (DD). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension was also significantly higher (
P
=0.003) in II (68%) and DI patients (59%) compared with DD hypertensives (19%). With respect to 11βHSD2 G534A, patients with the GG genotype had a significantly higher systolic BP increase with high salt intake than did GA patients. In addition, plasma renin activity suppression in response to high salt was significantly greater in GA patients than in GG patients. The prevalence of salt-sensitive hypertension was 14.3% in GA patients and 50.8% in GG patients (
P
=0.067). In conclusion, the I allele of ACE I/D polymorphism is significantly associated to salt-sensitive hypertension. The BP response to high salt intake was different among genotypes of ACE I/D and 11βHSD G534A, suggesting that these polymorphisms may be potentially useful genetic markers of salt sensitivity.
Modulation by 20-HETE of Phenylephrine-Induced Mesenteric Artery Contraction in Spontaneously Hypertensive and Wistar-Kyoto Rats
Authors: Zhang Fan , Wang Mong-Heng , Krishna U.Murali , Falck John R. , Laniado-Schwartzman Michal , Nasjletti Alberto
Published: September 2007

Small mesenteric arteries of spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY) were compared for the production of 20-HETE and the effects of 20-HETE andN-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS, 30 μmol/L), a 20-HETE synthesis inhibitor, on contractile responsiveness to phenylephrine (0.1 to 50.0 μmol/L). 20-HETE production was higher in vessels of SHR compared with WKY (1.34±0.16 versus 0.27±0.09 pmol/mg tissue,P<0.05). Phenylephrine elicited concentration-dependent vascular contraction; the Rmaxwas similar in vessels of SHR and WKY, but the former were more sensitive as denoted by the lower EC50(1.10±0.14 versus 1.89±0.33 μmol/L,P<0.05). DDMS caused a rightward shift in the concentration-response curve to phenylephrine, increasing (P<0.05) the EC50by 258% and 134% in vessels of SHR and WKY, respectively. In contrast, in DDMS-treated vessels, 20-HETE (0.01 to 10.0 μmol/L) caused a leftward shift in the phenylephrine concentration-response curve, decreasing (P<0.05) the EC50without affecting the Rmax. Importantly, the minimal concentration of 20-HETE that decreased the EC50of phenylephrine was much smaller in vessels of SHR that of WKY (0.01 versus 1.0 μmol/L). We conclude that 20-HETE increases the sensitivity of mesenteric arterial vessels to phenylephrine, vessels of SHR are more sensitive to this action of the eicosanoid than vessels of WKY, and vessels of SHR produce more 20-HETE than do vessels of WKY. Hence, 20-HETE of vascular origin may be a determinant of the increased reactivity to constrictor agonists in the vasculature of SHR.
Participation of the Hypothalamus-Hypophysis Axis in the Sympathetic Activation of Human Obesity
Authors: Grassi Guido , Seravalle Gino , Dell’Oro Raffaella , Turri Carlo , Pasqualinotto Lucia , Colombo Manuela , Mancia Giuseppe
Published: September 2007

Previous studies have shown that hypothalamic and hypophyseal factors are involved in the acute sympathoexcitation induced by a variety of laboratory stimuli. Whether a chronic condition of sympathetic activation, such as that characterizing human obesity, is also dependent on these factors has never been investigated. In 40 normotensive obese subjects ([mean±SEM] age, 39.1±0.8 years) we measured blood pressure (Finapres), heart rate (ECG), and postganglionic muscle sympathetic nerve activity (MSNA) (microneurography). In 20 subjects measurements were repeated, according to a double-blind randomized sequence, after a midnight oral dose of dexamethasone (1 mg) (n=10) or placebo (n=10), while in the remaining subjects they were performed again after 1 week of a daily evening oral administration of 1 mg of dexamethasone (n=10) or placebo (n=10). The same protocol was performed in 16 age-matched lean normotensives. In both groups acute dexamethasone administration markedly reduced plasma cortisol (radioimmunoassay), without affecting hemodynamic and neural variables. In contrast to the acute administration, in obese subjects prolonged dexamethasone administration, although not affecting blood pressure and heart rate, significantly reduced both plasma cortisol (from 16.0±1.3 to 0.7±0.1 μg/dL;
P
<0.01) and MSNA (from 59.5±2.8 to 39.6±2.9 bursts per 100 heartbeats;
P
<0.02; −33.1±4.1%). This was not the case in lean subjects, in which the dexamethasone-induced reduction in plasma cortisol was associated with a slight and nonsignificant MSNA decrease. In both lean and obese subjects, placebo administration caused no change in any variable. Thus, prolonged dexamethasone administration exerts in obese subjects marked sympathoinhibitory effects that are not detectable in lean individuals. This suggests that hypothalamic and hypophyseal factors substantially contribute to the sympathoexcitation of obesity.
Cardiac and Vascular Remodeling in Older Adults With Borderline Isolated Systolic Hypertension
Authors: Pini Riccardo , Cavallini M. Chiara , Bencini Francesca , Staglianò Loredana , Tonon Elisabetta , Innocenti Francesca , Baldereschi Giorgio , Marchionni Niccolò , Di Bari Mauro , Devereux Richard B. , Masotti Giulio , Roman Mary J.
Published: September 2007

Although borderline isolated systolic hypertension (ISH), defined as a blood pressure of 140 to 159/<90 mm Hg, is a proven cardiovascular risk factor, the major clinical trials on treatment of ISH have used a cutoff of 160 mm Hg. Moreover, no data exist on the cardiovascular modifications associated with borderline ISH. Therefore, we compared subjects with borderline ISH to subjects with diastolic hypertension (diastolic blood pressure ≥90 mm Hg) or ISH. Community-dwelling residents (age ≥65 years) of a small town in Italy (Dicomano) underwent extensive clinical examination, echocardiography, carotid ultrasonography, and applanation tonometry. Only untreated subjects were included in this analysis: 95 with diastolic hypertension, 87 with borderline ISH, and 43 with ISH. Despite lower systolic and mean pressures in borderline ISH, left ventricular mass was similar to that in diastolic hypertension. In univariate and multivariate analysis, pulse pressure but not systolic pressure was related to left ventricular mass. Borderline ISH subjects had a tendency to greater carotid cross-sectional area and stiffness index than did diastolic hypertensive subjects despite lower mean carotid pressure, whereas the number of atherosclerotic plaques was similar in the 2 groups. Pulse pressure but not systolic pressure was independently related to carotid remodeling. In our community-based, older population, individuals with borderline ISH had a similar prevalence of left ventricular hypertrophy and carotid atherosclerosis as that of subjects with diastolic hypertension, despite lower systolic and mean pressures. Among blood pressure values, pulse pressure was the single or strongest independent predictor of cardiovascular remodeling.
Omapatrilat Versus Lisinopril
Authors: Campese Vito M. , Lasseter Kenneth C. , Ferrario Carlos M. , Smith William B. , Ruddy Michael C. , Grim Clarence E. , Smith Ronald D. , Vargas Ramon , Habashy Michael F. , Vesterqvist Ole , Delaney Carol L. , Liao Wei-Chi
Published: September 2007

Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (
P
=0.008), ambulatory systolic blood pressure (
P
=0.004), and ambulatory mean arterial pressure (
P
=0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (
P
<0.001) increased urinary excretion of atrial natriuretic peptide over 0- to 24-hour (3.8-fold) and 12- to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (
P
<0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.
Effects of Race and Hypertension on Flow-Mediated and Nitroglycerin-Mediated Dilation of the Brachial Artery
Authors: Gokce Noyan , Holbrook Monica , Duffy Stephen J. , Demissie Serkalem , Cupples L.Adrienne , Biegelsen Elizabeth , Keaney John F. , Loscalzo Joseph , Vita Joseph A.
Published: September 2007

Black Americans have increased morbidity and mortality rates from cardiovascular disease, greater prevalence of hypertension, and altered responses to vasodilator medications compared with those of white Americans. Hypertension and black race have been linked to impaired vascular function in the microcirculation. To examine these effects and their interaction in the conduit vasculature, we examined vasomotor responses of the brachial artery by using high-resolution vascular ultrasound in 228 subjects (48% hypertensive, 54% black). Subjects had no history of diabetes mellitus and were matched for age and gender. Flow-mediated dilation (8.5±5.3% versus 11.7±6.3%,
P
<0.001) and nitroglycerin-mediated vasodilation (14.9±6.0 versus 18.5±7.8,
P
=0.003) were both impaired in hypertensive compared with normotensive individuals. Multivariate analysis identified higher systolic blood pressure (
P
=0.003) and larger baseline vessel (
P
<0.001) size as independent predictors of lower flow-mediated dilation. Race did not significantly influence flow-mediated dilation. In contrast, blacks had a greater vasodilator response to nitroglycerin compared with whites (17.7±7.5% versus 15.0±6.2%, respectively;
P
=0.02). By multivariate analysis, black race (
P
=0.004), smaller vessel size (
P
=0.001), lower serum glucose (
P
=0.02), lower systolic blood pressure (
P
=0.02), and lower serum total cholesterol (
P
=0.04) were independent predictors of higher nitroglycerin-mediated dilation. Thus, hypertension is associated with impaired NO–mediated vasodilation in the conduit brachial artery. Overall, race did not influence flow-mediated dilation, but black race was associated with an enhanced response to sublingual nitroglycerin. This later observation provides further evidence of racial differences in the responses to medical therapy that may be relevant to the treatment of patients with cardiovascular disease.
Angiotensin Type 2 Receptor-Mediated Hypotension in Angiotensin Type-1 Receptor-Blocked Rats
Authors: Carey Robert M. , Howell Nancy L. , Jin Xiao-Hong , Siragy Helmy M.
Published: September 2007

The type-2 (AT
2
) angiotensin (Ang) II receptor has been characterized as potentially counterregulatory to the actions of Ang II at its type-1 (AT
1
) receptor. We investigated the effects of Ang II and CGP-42112A (CGP), a selective peptide AT
2
receptor agonist, on blood pressure (BP) in rats with or without pharmacological blockade of the AT
1
receptor with losartan (LOS) or valsartan (VAL). In anesthetized rats (n=5 per group) receiving normal sodium intake, Ang II (200 pmol/kg per minute IV) alone increased BP from a control of 112±3 to 168±7 mm Hg (
P
<0.001) and LOS (30 mg/kg) alone decreased BP to 89±7 mm Hg (
P
<0.0001 from control). Ang II administered together with LOS decreased BP further to 71±4 mm Hg (
P
<0.00001 from control and LOS alone). AT
2
receptor antagonist PD 123,319 (PD) completely blocked the hypotensive response to LOS combined with Ang II (
P
=NS from control). In conscious rats (n=5 per group) receiving normal sodium intake, VAL (10 mg/kg) alone decreased BP from a control of 98±5 to 86±3 mm Hg (
P
<0.00001). Ang II combined with VAL induced a consistent, highly significant decline in BP for 6 days to a nadir of 69±3 mm Hg (
P
<0.01 versus daily VAL alone). PD completely blocked the chronic hypotensive response to the combination of Ang II and VAL to control levels before VAL administration. In another study in conscious rats (n=5 per group), CGP (70 μg/kg per minute) also decreased BP in VAL-treated conscious rats. BP was 119±3 mm Hg during the control period, decreased to 86±6 mm Hg during 3 days of VAL alone, (
P
<0.00001) and decreased further to 65±7 mm Hg (
P
<0.001 from daily VAL alone) with 7 days of CGP in the presence of VAL. In the absence of VAL, CGP decreased BP for 4 consecutive days, and this response was blocked by PD. Also, the CGP-induced decrease in BP over a 7-day period was blocked by
N
G
-nitro-
l
-arginine methyl ester, an inhibitor of NO synthase. The results strongly suggest that the AT
2
receptor induces a systemic vasodilator response mediated by NO that counterbalances the vasoconstrictor action of Ang II at the AT
1
receptor.
Endothelial Nitric Oxide Synthase Gene Polymorphism and Maternal Vascular Adaptation to Pregnancy
Authors: Savvidou Makrina D. , Vallance Patrick J.T. , Nicolaides Kypros H. , Hingorani Aroon D.
Published: September 2007

A common polymorphism of the endothelial NO synthase gene that predicts a Glu298Asp amino acid substitution in the mature protein has been associated with cardiovascular disorders in which NO bioactivity is impaired. However, the influence of this polymorphism on endothelial function is unknown. Healthy pregnancy is associated with enhanced endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery, a response mediated by NO. In this study, we investigated the effect of the endothelial NO synthase Glu298Asp polymorphism on endothelium-dependent vasodilation in early pregnancy, making the hypothesis that any genotype-dependent differences in NO generation would be more marked during pregnancy, when the production of NO is upregulated. FMD of the brachial artery was recorded during the first trimester in 139 healthy women with normal singleton pregnancies genotyped for the Glu298Asp variant of endothelial NO synthase. Maternal FMD exhibited a codominant inverse relation with the number of Asp298 alleles (
r
=−0.21,
P
=0.01). Among homozygotes for endothelial NO synthase Asp298, FMD (7.99±1.46%) was significantly lower than that observed among individuals homozygous for endothelial NO synthase Glu298 (10.12±3.44) (
P
=0.002). In a backward stepwise multiple regression analysis, vessel size (
P
<0.0001) and Glu298Asp polymorphism (
P
=0.01) were significantly and independently correlated with FMD. Our findings indicate that the endothelial NO synthase Glu298Asp polymorphism is associated with differences in endothelium-dependent dilation at 12-week gestation and are the first to implicate genetic factors in the normal vascular adaptation to pregnancy. They also provide a potential mechanism linking the endothelial NO synthase polymorphism with the development of cardiovascular disorders and have implications for understanding the genetic basis of preeclampsia.
Pressure-Altering Agents Affect Central Aortic Pressures More Than Is Apparent From Upper Limb Measurements in Hypertensive Patients
Authors: Vlachopoulos Charalambos , Hirata Kozo , O’Rourke Michael F.
Published: September 2007

The pressure pulse does not have the same amplitude in central and peripheral arteries, but it is amplified toward the periphery; the degree of this amplification depends principally on wave reflection. Despite the conventional clinical and epidemiological focus on peripheral pressures, the most physiologically relevant pressures for both cardiac and vascular effects are central pressures. The reflected wave contributes differently in the configuration of the peripheral and central pressure waveform. Therefore, we hypothesized that agents that alter wave reflections could have an unequal effect on central and peripheral pressures in hypertensive patients. Thus, the effect of caffeine was investigated in 10 hypertensive subjects according to a randomized, placebo-controlled, double-blind, crossover design. Central aortic pressures and wave reflection were assessed with applanation tonometry and pulse wave analysis. After caffeine, augmentation index and augmented pressure increased by 4.6%, (
P
<0.005) and 5.7 mm Hg (
P
<0.001), respectively, indicating increased effect of wave reflection from the periphery. The increase in aortic systolic pressure was greater compared with that in radial artery pressure at 30 minutes (25%) and marginally greater at 60 minutes (21%). Furthermore, the increase in aortic pulse pressure was greater at 30 and 60 minutes (34% and 40%, respectively). The intensified reflected wave after caffeine was largely responsible for the disparate effect between central and peripheral pressures by boosting the peak of the central and not of the peripheral waveform. This study shows that pressure-altering agents might affect central pressures more than is apparent from the corresponding upper limb values because of the concomitant changes in wave reflection.
Role of the Renin-Angiotensin System in Vascular Diseases
Authors: Ruiz-Ortega M. , Lorenzo O. , Rupérez M. , Esteban V. , Suzuki Y. , Mezzano S. , Plaza J.J. , Egido J.
Published: September 2007

The renin-angiotensin system (RAS) has emerged as one of the essential links in the pathophysiology of vascular disease. Angiotensin (Ang) II, the main peptide of the RAS, was considered as a vasoactive hormone, but in the past years, this view has been modified to a growth factor that regulates cell proliferation/apoptosis and fibrosis. Recently, this view has been enlarged with a novel concept: Ang II participates in the inflammatory response, acting as a proinflammatory mediator. In resident vascular cells, Ang II produces chemokines, cytokines, and adhesion molecules, which contribute to the migration of inflammatory cells into the tissue injury. Ang II is also a chemotactic and mitogenic factor for mononuclear cells. The molecular mechanisms of Ang II–induced vascular damage are mediated by the activation of transcription factors, redox signaling systems, and production of endogenous growth factors. In addition, other components of the RAS could also be involved in the pathogenesis of cardiovascular diseases. The Ang II degradation product Ang III shares some of its properties with Ang II, including chemotaxis and production of growth factors and chemokines. All these data clearly demonstrate that Ang II is a true cytokine, show the complexity of the RAS in pathological processes, and provide some mechanistic responses of the beneficial effects of the treatment with RAS blockers in cardiovascular diseases.
Noninvasive Cardiac Monitoring for Detecting Paroxysmal Atrial Fibrillation or Flutter After Acute Ischemic Stroke
Authors: Liao Joy , Khalid Zahira , Scallan Ciaran , Morillo Carlos , O’Donnell Martin
Published: September 2007

Background and Purpose—

Identifying paroxysmal atrial fibrillation/flutter is an essential part of the etiological workup of patients with ischemic stroke. However, there is controversy in the literature regarding the use of noninvasive cardiac rhythm monitoring with previous reviews reporting a low detection rate with routine monitoring. We performed a systematic review to determine the frequency of occult atrial fibrillation/flutter detected by noninvasive methods of continuous cardiac monitoring after acute ischemic stroke or transient ischemic attack.

Methods—

Studies were identified from comprehensive searches of PubMed, EMBASE, Science Citation Index, and bibliographies of relevant articles. Only English language articles were included. Randomized controlled trials and prospective cohort studies of consecutive patients with acute ischemic stroke that fulfilled predefined criteria were eligible. Two authors conducted searches and abstracted data from eligible studies independently.

Results—

Sixty studies were deemed potentially eligible. After application of eligibility criteria, 5 studies (736 participants) were included in the analysis. All studies evaluated Holter monitoring; 2 also evaluated event loop recording. In studies that evaluated Holter monitoring (588 participants), new atrial fibrillation/flutter was detected in 4.6% (95% CI: 0% to 12.7%) of consecutive patients with ischemic stroke. Duration of monitoring ranged from 24 to 72 hours. Two studies (140 participants) evaluated event loop recorders after Holter monitoring. New atrial fibrillation/flutter was detected in 5.7% and 7.7% of consecutive patients in these 2 studies.

Conclusions—

Screening consecutive patients with ischemic stroke with routine Holter monitoring will identify new atrial fibrillation/flutter in approximately one in 20 patients. Although based on limited data, extended duration of monitoring may improve the detection rate. Further research is required before definitive recommendations can be made.
Timing of Recanalization After Microbubble-Enhanced Intravenous Thrombolysis in Basilar Artery Occlusion
Authors: Pagola Jorge , Ribo Marc , Alvarez-Sabín José , Lange Marcos , Rubiera Marta , Molina Carlos A.
Published: September 2007

Background and Purpose—

Information about early recanalization of basilar artery occlusion after systemic tissue plasminogen activator remains unknown. We aimed to determine the timing of recanalization in basilar artery occlusion treated with systemic thrombolysis, microbubbles, and continuous transcranial Doppler monitoring.

Methods—

We studied 20 patients with <12 hours basilar artery occlusion treated with intravenous tissue plasminogen activator, 2 hours continuous ultrasound, and 3 boluses of microbubbles. Transcranial Doppler assessed recanalization at different time points. Outcome was assessed using the National Institutes of Health Stroke Scale and modified Rankin scale. Patients were considered to be independent if modified Rankin scale score was <3 at 90 days.

Results—

Median admission National Institutes of Health Stroke Scale was 18.5 (interquartile range 16 to 26.5) and median time to treatment was 180 minutes (range, 80 to 720 minutes). Rate of complete recanalization raised progressively: at 1 hour 10%, at 2 hours 20%, at 6 hours 35%, and at 24 hours 50%. In 10 patients (50%), no recanalization was observed at 24 hours. Median discharge National Institutes of Health Stroke Scale was 14 (interquartile range 1 to 30). Degree of National Institutes of Health Stroke Scale improvement was related to time of recanalization: median discharge National Institutes of Health Stroke Scale—1 for recanalization between 0 and 6 hours, 11 for recanalization between 6 and 24 hours, and 30 if no recanalization occurred (
P
=0.002). At 3 months, mortality was 35%. Only one patient (10%) who recanalized within 24 hours died as compared with 60% of nonrecanalizers (
P
=0.029). Rate of independent patients progressively decreased as time to recanalization increased (
P
=0.006).

Conclusions—

In acute basilar artery occlusion, endovenous tissue plasminogen activator, microbubbles, and continuous ultrasound leads to early recanalization in a significant number of patients and this is associated with favorable outcome. Immediate intravenous tissue plasminogen activator treatment should be the first therapeutic option in these patients.
Accurate Liquid Water Path Retrieval from Low-Cost Microwave Radiometers Using Additional Information from a Lidar Ceilometer and Operational Forecast Models
Authors: Gaussiat Nicolas , Hogan Robin J. , Illingworth Anthony J.
Published: September 2007

Water clouds have an important impact on the radiative balance of the earth. The use of ground-based dual-frequency microwave radiometers to derive both liquid water path (LWP) and water vapor path (WVP) is well established, but uncertainties over the dry, water vapor, and liquid water absorption coefficients and the radiometric calibration can lead to errors in the retrieved LWP. A method in which additional information from a lidar ceilometer is used to identify the presence of liquid water clouds and their altitude is described. When such clouds are absent, the radiometric calibrations of the two frequencies are optimally adjusted so that the retrieved LWP is forced to zero; when they are present the calibrations are interpolated from the nearest clear-sky periods before and after, and the temperature of the cloud is used to refine the liquid water absorption coefficient (with the temperature profile taken from a forecast model). This procedure is insensitive to the choice of absorption model, removes the troublesome negative values of LWP that can be retrieved, and provides more accurate values of low LWP in thin clouds. Analysis shows that LWP as low as 10 g m−2 can be reliably retrieved, 90% of the time the error being less than 50%, and for LWP greater than 20 g m−2 the error is less than 10%. An additional advantage is that the retrieval can tolerate uncertainties in the various absorption coefficients and is unaffected by slow drifts in brightness temperature errors of up to 5 K. Previous techniques have required that these temperatures be accurate to 0.5 K or better, which entails careful calibration and can be quite difficult to achieve.
Analysis of Abnormal Wave Records by the Hilbert–Huang Transform Method
Authors: Veltcheva Albena D. , Soares C. Guedes
Published: September 2007

The Hilbert–Huang transform method is used in this work to analyze wave records from the North Sea, which include abnormal waves. The analysis of the characteristics of abnormal waves is based on the local decomposition of wave data by using the intrinsic mode functions. The variations of amplitude of intrinsic mode functions around the time of the occurrence of abnormal waves are examined in order to investigate the contribution of different intrinsic mode functions on the abnormal waves’ profile, in an attempt to find relationships between them. The changes of local frequency of each intrinsic mode function in the vicinity of abnormal waves are examined. The essential nonlinearity of abnormal waves is considered as intrawave frequency modulation, a variation of the instantaneous frequency within one oscillation cycle. The Hilbert spectrum is used as a detector of abnormal waves.
Surface Salinity Measurements—COSMOS 2005 Experiment in the Bay of Biscay
Authors: Reverdin G. , Boutin J. , Lourenco A. , Blouch P. , Rolland J. , Niiler P. P. , Scuba W. , Rios A. F.
Published: September 2007

Sea surface salinity (SSS) data were collected in the Bay of Biscay between April and November 2005. The major source of data is 15 surface drifters deployed during the COSMOS experiment in early April and early May 2005 [12 from the Scripps Instution of Oceanography (SIO) and 3 from METOCEAN]. This is complemented by thermosalinograph (TSG) data from four French research vessels and four merchant vessels, from salinity profiles collected by Argo profiling floats and CTD casts, and from surface samples during two cruises. Time during the two cruises was dedicated to direct inspection of the drifters, recovering some, and providing validation data. This dataset provides a unique opportunity to estimate the accuracy of the SSS data and to evaluate the long-term performance of the drifter salinities. Some of the TSG SSS data were noisy, presumably from bubbles. The TSG data from the research vessels needed to be corrected from biases, which are very commonly larger than 0.1 pss-78 (practical salinity scale), and which in some instances evolved quickly from day to day. These corrections are only available when samples were collected or ancillary data are available (e.g., from CTD profiles). The resulting accuracy of the corrected TSG dataset, which varies strongly in time, is discussed. The surface drifter SSS data presented anomalous daytime values during days with strong surface warming. These data had to be excluded from the dataset. The drifter SSS presented initial biases in the range 0.009 to −0.026 pss-78. The (usually) negative bias increased by an average of −0.007 pss-78 during the average 65-day period before the COSMOS-2 cruise on 22–27 June. High chlorophyll derived from satellite ocean color, and therefore high density of phytoplanktonic cells, is observed in Medium Resolution Imaging Spectrometer (MERIS)/Moderate Resolution Imaging Spectroradiometer (MODIS) composites during part of the period, in particular in late April or early May. No correlation was found between the change in bias and the estimated surface chlorophyll. Evolution during the following summer months is harder to ascertain. For three buoys, there is little change in bias, but for two others, there could have been an increase in bias by up to 0.03 or 0.04 pss-78 during July–August. Seven drifters were recovered in the autumn, which provide recovery or postrecovery estimates of the biases, suggesting in three cases (out of seven) a large (0.02–0.03 pss-78) increase in bias during the autumn months, but no significant increase for the other four drifters.
Multiple‐Dose Pharmacokinetics and Safety of Desloratadine in Subjects With Moderate Hepatic Impairment
Authors: Gupta Samir K. , Kantesaria Bhavna , Wang Zaiqi
Published: September 2007

Desloratadine, a nonsedating histamine H1‐receptor antagonist, is metabolized to 3‐hydroxy (3‐OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3‐OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3‐OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6‐ to 6.5‐fold greater than in other subjects with normal liver function. Eleven treatment‐related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.
Optimal Adaptive Design in Clinical Drug Development: A Simulation Example
Authors: Maloney Alan , Karlsson Mats O. , Simonsson Ulrika S. H.
Published: September 2007

The objective of this article is to demonstrate optimal adaptive design as a methodology for improving the performance of phase II dose‐response studies. Optimal adaptive design uses both information prior to the study and data accrued during the study to continuously update and refine the study design. Dose‐response models include linear, log‐linear, 4‐parameter sigmoidal Emax, and exponential models. Where the response has both a placebo effect and plateau at higher doses, only the 4‐parameter sigmoidal Emaxmodel behaves acceptably and hence is used to illustrate the methodology. Across 13 hypothetical dose‐response scenarios considered, it was shown that the capability of the adaptive designs to “learn” the true dose response resulted in performances up to 180% more efficient than the best fixed optimal designs. This work exposes the common misconception that adaptive designs are somehow “risky.” As shown in this simple simulation example, the converse is true. Adaptive designs perform extremely well both when prior information is accurate and inaccurate. This leads to improved dose‐response models and dose selection in phase III. This benefits sponsors, regulators, and subjects alike by reducing sample size, increasing information, and providing better dose guidance.
Causes of Dissolution Among Spanish Nonprofit Associations
Authors: Fernandez Juan J.
Published: September 2007

Voluntary associations play increasingly important roles in many industrialized societies. However, little is still known about why they die. This article attempts to fill this gap. It reconstructs the history of 41 closed Spanish voluntary associations of Madrid's metropolitan area through archival research and semistructured interviews to define the causes of their dissolutions. The conclusions indicate that the majority of the organizations dissolved due to mission completion (particularly goal fulfillment) and resource insufficiency. This article also uses central predictions of new institutionalism, population ecology, and resource dependence theories and shows that these three models provide valuable insights to account for these dissolutions. As each theory respectively predicts, those organizations with lower sociopolitical legitimacy, that were younger and smaller, or that were funded by only one source dissolved younger.
Mentoring for Doctoral Student Praxis-Centered Learning: Creating a Shared Culture of Intellectual Aspiration
Authors: Stephenson Max , Christensen Rachel
Published: September 2007

This article explores the potential of doctoral student mentoring programs to serve as one bridge in the academic—practitioner divide in nonprofit education. This disconnect manifests itself in critiques regarding the marginalization of practitioners and lack of knowledge sharing. The article examines the potential role of nonprofit doctoral student mentoring as a possible avenue for addressing the divide by developing the intellectual capacities of graduates to interact effectively in both the academic and practitioner domains. It stresses the importance of a particular form of mentoring and its ties to multiple, reinforcing opportunities for students if analytical, praxis-centered capacities are to be successfully developed. Ultimately, this article aims to stimulate discussion on the role and forms of mentoring of scholars who must develop praxis capacities rather than to offer definitive evidence of the superiority of one or another approach of ensuring that result.
Titanium in quartz as a record of ultrahigh-temperature metamorphism: the granulites of Karur, southern India
Authors: Sato K. , Santosh M.
Published: September 2007

The occurrence is reported of spectacular oriented needles of rutile within quartz veins and pods in granulite-facies rocks that have undergone partial melting under ultrahigh-temperature (UHT) conditions in the Karur region in southern India. Laser Raman spectroscopy and electron microprobe analysis confirm that (1) the mineral inclusions within quartz are pure rutiles, and (2) a secondcategory of quartz contains pure hematite inclusions. The rutile never coexists with the hematite inside the same quartz specimens. Fluidinclusions in the quartz are characterized as a CO2+ H2O mixture. Application of two geothermometric calibrations utilizing Ti in quartz yields minimum estimates of ~1190ºC, suggesting the formation of the rutile-quartz under UHT metamorphic condition. It is proposed that such Ti-rich quartz segregations couldbe another indicator for extreme crustal metamorphism at very high temperatures.