bluuebunny/crossref_metadata_2025 huggingface dataset:
Vision of the Lynxes
Authors: Bignami Giovanni F.
Published: May 2003

The Eye of the Lynx
Galileo, His Friends, and the Beginnings of Modern Natural History. David Freedberg. University of Chicago, Chicago, 2003. 525 pp., illus. $50, £35.50. ISBN 0-226-26147-6.

In this lavishly illustrated volume, Freedberg discusses the activities and influences of the 17th-century Academy of Lincei-including the members involvement with Galileo, their "paper museum" (an attempt to compile of visual encyclopedia of the entire known world), their blending of what we currently recognize as science and the humanities, and their depictions of the previously invisible microscopic world.
Identification of a Subset of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus Strains Able To Exploit an Alternative Coreceptor on Untransformed Human Brain and Lymphoid Cells
Authors: Willey Samantha J. , Reeves Jacqueline D. , Hudson Richard , Miyake Koichi , Dejucq Nathalie , Schols Dominique , Clercq Erik De , Bell Jeanne , McKnight Áine , Clapham Paul R.
Published: May 2003

The chemokine receptors CCR5 and CXCR4 are the major coreceptors for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). At least 12 other chemokine receptors or close relatives support infection by particular HIV and SIV strains on CD4+transformed indicator cell lines in vitro.However, the role of these alternative coreceptors in vivo is presently thought to be insignificant. Infection of cell lines expressing high levels of recombinant CD4 and coreceptors thus does not provide a true indication of coreceptor use in vivo. We therefore tested primary untransformed cell cultures that lack CCR5 and CXCR4, including astrocytes and brain microvascular endothelial cells (BMVECs), for naturally expressed alternative coreceptors functional for HIV and SIV infection. An adenovirus vector (Ad-CD4) was used to express CD4 in CD4−astrocytes and thus confer efficient infection if a functional coreceptor is present. Using a large panel of viruses with well-defined coreceptor usage, we identified a subset of HIV and SIV strains able to infect two astrocyte cultures derived from adult brain tissue. Astrocyte infection was partially inhibited by several chemokines, indicating a role for the chemokine receptor family in the observed infection. BMVECs were weakly positive for CD4 but negative for CCR5 and CXCR4 and were susceptible to infection by the same subset of isolates that infected astrocytes. BMVEC infection was efficiently inhibited by the chemokine vMIP-I, implicating one of its receptors as an alternative coreceptor for HIV and SIV infection. Furthermore, we tested whether the HIV type 1 and type 2 strains identified were able to infect peripheral blood mononuclear cells (PBMCs) via an alternative coreceptor. Several strains replicated in Δ32/Δ32 CCR5 PBMCs with CXCR4 blocked by AMD3100. This AMD3100-resistant replication was also sensitive to vMIP-I inhibition. The nature and potential role of this alternative coreceptor(s) in HIV infection in vivo is discussed.
Multiple Epstein-Barr Virus Infections in Healthy Individuals
Authors: Walling Dennis M. , Brown Abigail L. , Etienne Wiguins , Keitel Wendy A. , Ling Paul D.
Published: May 2003

We employed a newly developed genotyping technique with direct representational detection of LMP-1 gene sequences to study the molecular epidemiology of Epstein-Barr virus (EBV) infection in healthy individuals. Infections with up to five different EBV genotypes were found in two of nine individuals studied. These results support the hypothesis that multiple EBV infections of healthy individuals are common. The implications for the development of an EBV vaccine are discussed.
History of the development of geriatric medicine in the UK
Authors: Barton A , Mulley G
Published: May 2003

In this review the development of the specialty of geriatric medicine in the UK is traced from its humble beginnings. Elderly medicine is now thriving and represents the largest group of physician members of the Royal Colleges of Physicians. Geriatric medicine is essentially about optimising the care and wellbeing of older people. A key component of this is teamwork. A successful service for old people depends on the skills of many people, including nurses, therapists, social workers, and others. The contributions made by nurses and other professionals have been immense, but space does not permit a historical review of their important role.
Prognostic Implication of Microvascular Invasion in Biochemical Failure in Patients Treated with Radical Prostatectomy
Authors: Ito Keiichi , Nakashima Jun , Mukai Makio , Asakura Hirotaka , Ohigashi Takashi , Saito Shiro , Tachibana Masaaki , Hata Jun-ichi , Murai Masaru
Published: May 2003

Introduction: Micrometastasis before radical prostatectomy (RP) is considered to be related to the biochemical failure after surgery in patients with prostate cancer. To predict the biochemical failure, we evaluated microvascular (lymphatic/vascular) invasion and other pathological findings as prognostic factors for biochemical failure after RP. Materials and Methods: Eighty-two men who underwent RPs and received neither preoperative nor postoperative adjuvant therapy were analyzed. Pathological findings of each patient were carefully reviewed to determine pathological factors predicting biochemical failure. The influence of pathological findings on the biochemical failure was evaluated. Results: The overall biochemically assessed disease-free survival rate was 55.7% at 3 years. By univariate analysis, Gleason sum, capsular penetration, and microvascular invasion were significantly associated with the rate of biochemical failure. Microvascular invasion was strongly correlated with Gleason sum, capsular penetration, surgical margin, perineural invasion, and pathological stage. By multivariate analysis, Gleason sum, capsular penetration, and microvascular invasion were independent predictors of biochemical failure. Conclusion: This study suggests that in addition to Gleason grade and capsular penetration, microvascular invasion is one of independent prognostic factors in patients with prostate cancer treated with RPs.
Detecting Metastatic Pelvic Lymph Nodes by 18F-2-Deoxyglucose Positron Emission Tomography in Patients with Prostate-Specific Antigen Relapse after Treatment for Localized Prostate Cancer
Authors: Chang Chao-Hsiang , Wu His-Chin , Tsai Jeffery J.P. , Shen Yeh-You , Changlai Sheng-Pin , Kao Albert
Published: May 2003

Aim: To evaluate whether positron emission tomography (PET) with 18F-2-deoxyglucose (FDG) can detect pelvic lymph node metastases in prostate cancer patients who had elevated serum prostate-specific antigen (PSA) levels after treatment. Methods: Twenty-four patients with a rising serum PSA level after treatment for localized prostate cancer were examined with FDG-PET before pelvic lymph node dissection. All patients had negative findings on whole body bone scan and equivocal pelvic computed tomography (CT) results. The results of FDG-PET were then compared to the histology of the pelvic lymph nodes obtained at surgery. Results: Lymph node metastases were detected by histopathological examination in 16/24 (66.7%) patients. At the sites with histopathologically proven metastases, increased FDG uptake was found in 12/16 (75.0%) patients. In addition, there were 4 patients with false-negative results, but no patient with a false-positive result on FDG-PET images. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FDG-PET in detecting metastatic pelvic lymph nodes were 75.0, 100.0, 83.3, 100.0, and 67.7%, respectively. Conclusions: These results suggest that FDG-PET may be a valuable diagnostic tool in the staging of pelvic lymph nodes in patients with PSA relapse after treatment of localized prostate cancer when the whole body bone scan is negative and pelvic CT findings are equivocal.
Pressure Wave Reflection Assessed From the Peripheral Pulse
Authors: Millasseau Sandrine C. , Patel Sundip J. , Redwood Simon R. , Ritter James M. , Chowienczyk Philip J.
Published: May 2003

Synthesis of the aortic pressure waveform by application of a transfer function to the radial pulse allows the estimation of aortic systolic blood pressure and aortic augmentation index, an index of pressure wave reflection derived from the early systolic component of the waveform. The accuracy of this approach for determining the aortic augmentation index has been questioned, however, and it may be possible to derive similar information without using a transfer function. We compared aortic systolic blood pressure and the aortic augmentation index obtained from carotid and radial arteries with the use of transfer functions. We examined the correlation between the aortic augmentation index and a radial augmentation index obtained without use of a transfer function. Arterial tonometry (Sphygmocor) was performed in 84 subjects including healthy volunteers (n=30), subjects with essential hypertension (n=30), and patients with coronary artery disease (n=24). Effects of nitroglycerine and norepinephrine on aortic and radial augmentation index were examined in 12 healthy volunteers. Values of aortic systolic pressure obtained from radial and carotid arteries by using transfer functions were in acceptable agreement (
R
=0.98, difference=−0.9±4.6 mm Hg; mean±SD, n=84), but those of aortic augmentation index differed especially in control subjects (
R
=0.47, difference=−3.8±12.4%). Aortic augmentation index was, however, closely correlated with radial augmentation index (
R
=0.96, n=84). Nitroglycerine and norepinephrine produced parallel changes in the aortic and radial augmentation index. Our findings question the use of a transfer function to obtain the aortic augmentation index but suggest that similar information on central pressure wave reflection can be obtained directly from the radial pulse.
Cardiac Hypertrophy and Microvascular Deficit in Kinin B2 Receptor Knockout Mice
Authors: Maestri Roberta , Milia Anna Franca , Salis Maria Bonaria , Graiani Gallia , Lagrasta Costanza , Monica Manuela , Corradi Domenico , Emanueli Costanza , Madeddu Paolo
Published: May 2003

Experimental and clinical evidence suggests kinin involvement in adaptive myocardial growth. Kinins are growth-inhibitory to cardiomyocytes. Knockout of kinin B2 receptor (B2R) signaling causes dilated and failing cardiomyopathy in 129/J mice, and a 9-bp deletion polymorphism of human B2R is associated with reduced receptor expression and exaggerated left ventricular growth response to physical stress. We reasoned that genetic background and aging may significantly influence the impact of B2R mutation on cardiac phenotype. The theory was challenged in C57BL/6 mice, a strain that naturally differs from the 129/J strain, carrying 1 instead of 2 renin genes. C57BL/6 B2R knockouts (B2R-KO) showed higher blood pressure and heart rate levels (
P
<0.05) compared with wild-type controls (WT) at all ages examined. At 12 months, left ventricular contractility and diastolic function were mildly altered (
P
<0.05) and histological and morphological analyses revealed ventricular hypertrophy and cardiomyocyte enlargement in B2R-KO (
P
<0.01). Reparative fibrosis was enhanced by 208% and capillary density reduced by 38% (
P
<0.01). Functional and structural alterations induced by B2R deletion in C57BL/6 mice were less severe than those reported previously in the 129/J strain. We conclude that interaction of B2R signaling with other genetic determinants influences aging-related changes in myocardial structure and function. These findings may help us understand the role of kinins in the development of cardiac failure.
Racial Differences in the Prevalence of Hypertensive Retinopathy
Authors: Wong Tien Yin , Klein Ronald , Duncan Bruce B. , Nieto F. Javier , Klein Barbara E.K. , Couper David J. , Hubbard Larry D. , Sharrett A. Richey
Published: May 2003

Few population-based data support the hypothesis that hypertensive retinopathy is more common in African Americans than in whites. We examined racial differences in the prevalence of and risk factors for hypertensive retinopathy in a population-based sample of 1860 African Americans and 7874 white persons, aged 49 to 73 years, without diabetes. Retinal photographs were taken of one randomly selected eye and evaluated for the presence of retinopathy (flame and blot-shaped retinal hemorrhages, microaneurysms, and soft exudates) according to standardized protocols by graders masked to participant characteristics. The prevalence of retinopathy was 2 times higher in African Americans than in whites (7.7% versus 4.1%, age- and gender-adjusted odds ratio [OR] 2.03, 95% confidence intervals [CI] 1.65, 2.49). After controlling for 6-year mean arterial blood pressure, use of antihypertensive medications and left ventricular hypertrophy by ECG criteria, the excess prevalence of retinopathy in African Americans was reduced by 40% (adjusted OR 1.61, 95% CI 1.26, 2.06). Further adjustment for other vascular risk factors, common carotid artery intima-media thickness, and serum creatinine levels reduced the excess prevalence in African Americans by another 13% (adjusted OR 1.48, 95% CI 1.08, 2.03). We conclude that hypertensive retinopathy is twice as frequent in African Americans compared with whites without diabetes and that the excess prevalence of retinopathy in African Americans is associated with blood pressure and severity of hypertension.
Transactivation of KDR/Flk-1 by the B2 Receptor Induces Tube Formation in Human Coronary Endothelial Cells
Authors: Miura Shin-ichiro , Matsuo Yoshino , Saku Keijiro
Published: May 2003

Endothelial cells (ECs) are the critical cellular element responsible for postnatal angiogenesis. Vascular endothelial growth factor (VEGF) stimulates angiogenesis via the activation of kinase insert domain–containing receptor/fetal liver kinase-1 (KDR/Flk-1) in ECs. In addition, transactivation of KDR/Flk-1 by the bradykinin (BK) B2 receptor induces the activation of endothelial nitric oxide synthase (eNOS). These findings indicate that the precise role of BK in angiogenesis is likely to be more complex than initially thought, and it questions the importance of BK in angiogenic processes. Therefore, we examined whether transactivation by BK induced tube formation. We developed an in vitro model of human coronary artery EC (HCEC) tube formation on a matrix gel. We demonstrated that BK dose-dependently induced tube formation. Although a lower concentration of BK and VEGF did not separately induce tube formation, the formation was induced by a combination of lower concentrations of BK and VEGF, suggesting that VEGF and BK had a synergistic effect. The effect was blocked by a B2 receptor antagonist (HOE140) and specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NOS. In addition, BK induced tyrosine phosphorylation of the KDR/Flk-1 receptor, as did VEGF itself. The transactivation was also blocked by HOE140 and Tki. Our results showed that, in HCECs, stimulation of the B2 receptor leads to the transactivation of KDR/Flk-1, as well as to eNOS activation, which induces tube formation. To our knowledge, this is a novel mechanism in which transactivation of KDR/Flk-1 by a G protein–coupled receptor, B2 receptor, may be a potent signal for tube formation.
AT
1
Receptors in the RVLM Mediate Pressor Responses to Emotional Stress in Rabbits
Authors: Mayorov Dmitry N. , Head Geoffrey A.
Published: May 2003

In this study, we examined the role of angiotensin type 1 (AT
1
) receptors in the rostral ventrolateral medulla (RVLM) in mediating the pressor action of emotional stress in conscious rabbits. Rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the RVLM and an electrode for measuring renal sympathetic nerve activity (RSNA). Airjet stress evoked increases in arterial pressure, heart rate, and RSNA, which reached a maximum (+9±1 mm Hg, +20±5 beats/min, and +93±17%, respectively) in the first 2 minutes of stress exposure. Then RSNA rapidly returned to prestress values, while arterial pressure and heart rate remained close to the maximal level until the conclusion of the 7-minute airjet exposure. Microinjections of the nonselective angiotensin receptor antagonist sarile (0.5 nmol, n=8) or AT
1
receptor antagonists losartan (2 nmol, n=6) or candesartan (0.2 nmol, n=6) into the RVLM did not alter resting cardiovascular parameters. By contrast, the antagonists attenuated the sustained phase (4 to 7 minutes) of the pressor stress response by 55% to 89%. However, only sarile decreased the onset of this response. The antagonists affected neither the stress-induced tachycardia nor the pressor response to glutamate microinjections. Microinfusion of angiotensin II (4 pmol/min, n=8) into the RVLM did not change the pressor response to airjet stress but attenuated tachycardic response by 47%. Microinjections of vehicle did not alter the cardiovascular stress response. Sarile, losartan, and angiotensin II did not affect the sympathoexcitatory response to baroreceptor unloading. These results suggest that AT
1
receptors in the RVLM are important in mediating the pressor effects of emotional stress in conscious rabbits.
Effect of Low-Dose Perindopril/Indapamide on Albuminuria in Diabetes
Authors: Mogensen Carl Erik , Viberti Giancarlo , Halimi Serge , Ritz Eberhard , Ruilope Luis , Jermendy György , Widimsky Jiri , Sareli Pinchas , Taton Jan , Rull Juan , Erdogan Gürbüz , De Leeuw Pieter W. , Ribeiro Arthur , Sanchez Ramiro , Mechmeche Rachid , Nolan John , Sirotiakova Jana , Hamani Ahmed , Scheen André , Hess Bernhard , Luger Anton , Thomas Stephen M.
Published: May 2003

Microalbuminuria in diabetes is a risk factor for early death and an indicator for aggressive blood pressure (BP) lowering. We compared a combination of 2 mg perindopril/0.625 mg indapamide with enalapril monotherapy on albumin excretion rate (AER) in patients with type 2 diabetes, albuminuria, and hypertension in a 12-month, randomized, double-blind, parallel-group international multicenter study. Four hundred eighty-one patients with type 2 diabetes and hypertension (systolic BP ≥140 mm Hg, <180 mm Hg, diastolic BP <110 mm Hg) were randomly assigned (age 59±9 years, 77% previously treated for hypertension). Results from 457 patients (intention-to-treat analysis) were available. After a 4-week placebo period, patients with albuminuria >20 and <500 μg/min were randomly assigned to a combination of 2 mg perindopril/0.625 mg indapamide or to 10 mg daily enalapril. After week 12, doses were adjusted on the basis of BP to a maximum of 8 mg perindopril/2.5 mg indapamide or 40 mg enalapril. The main outcome measures were overnight AER and supine BP. Both treatments reduced BP. Perindopril/indapamide treatment resulted in a statistically significant higher fall in both BP (−3.0 [95% CI −5.6, −0.4],
P
=0.012; systolic BP −1.5 [95% CI −3.0, −0.1] diastolic BP
P
=0.019) and AER −42% (95% CI −50%, −33%) versus −27% (95% CI −37%, −16%) with enalapril. The greater AER reduction remained significant after adjustment for mean BP. Adverse events were similar in the 2 groups. Thus, first-line treatment with low-dose combination perindopril/indapamide induces a greater decrease in albuminuria than enalapril, partially independent of BP reduction. A BP-independent effect of the combination may increase renal protection.
An Acyl-CoA Synthetase Gene Family in Chromosome 16p12 May Contribute to Multiple Risk Factors
Authors: Iwai Naoharu , Mannami Toshifumi , Tomoike Hitonobu , Ono Koh , Iwanaga Yoshitaka
Published: May 2003

We recently reported that genetic polymorphisms of SAH, an acyl-CoA synthetase for fatty acids, might contribute to multiple risk factors, especially hypertriglyceridemia. There are at least 4 members in this SAH gene family,
SAH
,
MACS1
,
MACS2
, and
MACS3
, and these 4 members are clustered in human Ch16p12. It is possible either that the previously observed associations were due to linkage disequilibrium with truly important polymorphisms in other members of the SAH gene family or that other polymorphisms in this gene family may also influence multiple risk factors. Thus, we performed association studies between genetic polymorphisms in this
SAH
region and multiple risk factors, using a large cohort representing the general population in Japan. The L513S polymorphism in
MACS2
was shown to significantly influence the triglyceride level and the waist-to-hip ratio. The previously observed associations between an
SAH
polymorphism and the waist-to-hip ratio appear to be due to linkage disequilibrium with the L513S polymorphism. Haplotype analysis indicated that a haplotype defined by the I/D polymorphism of
SAH
and the L513S polymorphism in
MACS2
was highly significantly associated with the triglyceride level. This study confirmed the importance of this chromosomal region in the pathogenesis of hypertriglyceridemia and visceral obesity.
Hypotension and Reduced Catecholamines in Neuropeptide Y Transgenic Rats
Authors: Michalkiewicz Mieczyslaw , Knestaut Kriss M. , Bytchkova Elena Yu. , Michalkiewicz Teresa
Published: May 2003

The neurons that control blood pressure express neuropeptide Y. Administered centrally, this neuropeptide reduces blood pressure and anxiety, together with lowering sympathetic outflow. The generation of neuropeptide Y transgenic rats overexpressing this peptide, under its natural promoter, has allowed us to examine the role of endogenous neuropeptide Y in the long-term control of blood pressure by the sympathetic nervous system. This study tested a hypothesis that endogenous neuropeptide Y acts to reduce blood pressure and catecholamine release. Blood pressure was measured by radiotelemetry in conscious male transgenic and nontransgenic littermates (control). Novel cage with cold water and forced swimming were used as stressors. Catecholamines were determined in 24-hour urine (baseline) and plasma (cold water stress) by a radioenzymatic assay. Blood pressures in baseline and during the stresses were significantly reduced in the transgenic rats. The lower blood pressure was associated with reduced catecholamines, lower decrease in pressure after autonomic ganglionic blockade, and increased longevity. Data obtained through the use of this transgenic rat model support and extend the evidence for the previously postulated sympatholytic and hypotensive effects of neuropeptide Y and provide novel evidence for an important physiological role of endogenous peptide in blood pressure regulation. As indicated by the increased longevity of these rats, in long-term regulation, these buffering actions of neuropeptide Y may have important cardiovascular protective effects against sympathetic hyperexcitation.
Altered Renal Handling of Sodium in Human Hypertension
Authors: Strazzullo Pasquale , Galletti Ferruccio , Barba Gianvincenzo
Published: May 2003

A pathogenic role of the kidney in hypertension has been strongly supported by experimental studies by Guyton and Dahl since the 1960s. In the early 1980s, de Wardener and MacGregor proposed that in hypertensive patients the ability of the kidneys to excrete a sodium load could be genetically impaired. Since then, “sodium-sensitive” hypertension has been the object of numerous studies, mostly on animal models because of the difficulty to investigate the renal handling of sodium in humans. More recently, considerable progress in this field has been made thanks to the in vivo study of segmental renal tubular function by the clearance of lithium and to the growing knowledge of the genetics of renal tubular sodium transport systems. The scope of this review is to briefly review the most relevant information gathered by the investigation of segmental renal tubular sodium handling in humans as related to blood pressure regulation and hypertension. In aggregate, the results of these studies strongly support the association between altered renal sodium handling and high blood pressure and suggest a causal role of genetic, nutritional, metabolic, and neurohormonal factors. All of these factors, alone or in combination, may be able to impair the normal renal tubular sodium handling and influence blood pressure homeostasis. The paradigm of the pathogenic role of the kidney in hypertension is thus relentlessly shifting toward the definition of inherited as well as acquired renal tubular defects and molecular alterations, providing a plausible explanation for the alteration in blood pressure levels.
Skeletal Muscle Arteriolar Reactivity in SS.BN13 Consomic Rats and Dahl Salt-Sensitive Rats
Authors: Drenjancevic-Peric Ines , Frisbee Jefferson C. , Lombard Julian H.
Published: May 2003

Previous studies have demonstrated that angiotensin II is a crucial factor in maintaining normal vascular reactivity. In this study, we tested the hypothesis that altered reactivity to vasoactive stimuli in Dahl salt-sensitive (S) rats on a high salt diet could be prevented by introgression of chromosome 13 from the normotensive Brown Norway strain, which carries a normally functioning renin gene. Dahl S and consomic SS.BN13 rats were fed a low salt (0.4%) or high salt diet (4%) for 4 to 6 days or 4 weeks. Arteriolar responses to elevated superfusion solution PO
2
, acetylcholine, and sodium nitroprusside were assessed by videomicroscopy in the cremaster muscle. Arteriolar dilation to sodium nitroprusside was normal in both strains. Arteriolar constriction to elevated PO
2
was enhanced in Dahl S and SS.BN13 rats on a high salt diet compared with responses in rats on a low salt diet. Arterioles of Dahl S rats on a high salt diet had an impaired dilation to acetylcholine, whereas dilator responses to acetylcholine were restored in SS.BN13 rats regardless of elevated salt intake. These data suggest that (1) restitution of normal renin control mechanisms by chromosomal transfer contributes to the recovery of dilator responses in SS.BN13 rats versus Dahl S rats but does not affect constrictor responses to oxygen, and (2) factors in the Dahl S genetic background contribute to an enhanced sensitivity of arterioles to elevated PO
2
independent of elevated blood pressure.
Smoking Activates Rho-Kinase in Smooth Muscle Cells of Forearm Vasculature in Humans
Authors: Noma Kensuke , Higashi Yukihito , Jitsuiki Daisuke , Hara Keiko , Kimura Masashi , Nakagawa Keigo , Goto Chikara , Oshima Tetsuya , Yoshizumi Masao , Chayama Kazuaki
Published: May 2003

Previous studies have shown that smoking is strongly associated with atherosclerosis and coronary vascular disease. Rho-kinase plays an important role in various cellular functions associated with atherosclerosis and hypertension. However, there is no information on the relationship between smoking and Rho-kinase activity in humans. The purpose of this study was to determine the Rho-kinase activity in forearm vascular smooth muscle cells (VSMCs) in healthy young male smokers. We evaluated the forearm blood flow (FBF) responses to fasudil (3, 10, and 30 μg/min for 5 minutes), a Rho-kinase inhibitor, or sodium nitroprusside (0.75, 1.5, and 3.0 μg/min for 5 minutes) in current smokers (n=8) and nonsmokers (n=8). FBF was measured with a strain-gauge plethysmograph. The vasodilatory effect of fasudil was significantly greater in smokers than in nonsmokers (14.9±3.5 versus 10.5±3.6 mL/min per 100 mL tissue;
P
<0.01). The FBF responses to sodium nitroprusside were similar in the 2 groups (34.7±10.4 versus 33.2±10.2 mL/min per 100 mL tissue;
P
=0.78). These findings suggest that smoking activates Rho-kinase in forearm VSMCs but does not alter the vasodilatory effect induced by exogenous nitric oxide in forearm VSMCs in healthy young men.
Effects of the Selective Aldosterone Blocker Eplerenone Versus the Calcium Antagonist Amlodipine in Systolic Hypertension
Authors: White William B. , Duprez Daniel , St Hillaire Richard , Krause Scott , Roniker Barbara , Kuse-Hamilton Janice , Weber Michael A.
Published: May 2003

Eplerenone is a highly selective aldosterone blocker, which is under development for the treatment of hypertension and heart failure. To assess its usefulness in older patients with systolic hypertension and widened pulse pressure, we compared the effects of eplerenone with amlodipine, on clinic blood pressure (BP) and pulse pressure and in a subset of the patients, ambulatory BP, vascular compliance, and urinary albumin excretion. The study involved 269 patients ≥50 years of age who were randomly assigned to either eplerenone (50 to 200 mg daily) or amlodipine (2.5 to 10 mg daily) in a double-blind titration to effect design. After 24 weeks of therapy, reductions in clinic systolic BP were similar for both treatments (eplerenone, −20.5±1.1 mm Hg; amlodipine, −20.1±1.1 mm Hg). Reductions in clinic diastolic BP were modestly larger on amlodipine (−6.9±0.7 mm Hg) compared with eplerenone (−4.5±0.7 mm Hg) (
P
=0.014). Pulse pressure was also reduced similarly from baseline by the 2 treatment groups (eplerenone, −15.9 mm Hg versus amlodipine, −13.4 mm Hg,
P
=0.07). Changes from baseline in pulse wave velocity after 24 weeks of therapy were statistically similar for eplerenone and amlodipine. In patients with microalbuminuria at baseline (>30 mg albumin/g creatinine), eplerenone reduced the urinary albumin/creatinine ratio by 52% compared with a reduction of 10% by amlodipine (
P
=0.04). Thus, eplerenone was as effective as amlodipine in lowering systolic BP and pulse pressure as well as pulse wave velocity in older patients with widened pulse pressure hypertension. Furthermore, eplerenone reduced microalbuminuria to a greater extent than amlodipine in this older patient group.
PDE5 Inhibitor Sildenafil Citrate Augments Endothelium-Dependent Vasodilation in Smokers
Authors: Kimura Masashi , Higashi Yukihito , Hara Keiko , Noma Kensuke , Sasaki Satoshi , Nakagawa Keigo , Goto Chikara , Oshima Tetsuya , Yoshizumi Masao , Chayama Kazuaki
Published: May 2003

Smoking is associated with endothelial dysfunction. The purpose of this study was to determine the effect of sildenafil, an inhibitor of phosphodiesterase type 5 (PDE5), on endothelial function in smokers. We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after oral sildenafil administration (100 mg) with a strain-gauge plethysmograph in 10 young healthy male smokers and 10 young healthy male nonsmokers. FBF response to ACh was lower in smokers than in nonsmokers. The vasodilatory effects of SNP were similar in both groups. Sildenafil increased the FBF response to ACh from 9.3±2.0 to 12.5±3.5 mL/min per 100 mL tissue in smokers and from 12.6±5.6 to 19.6±8.4 mL/min per 100 mL tissue in nonsmokers, and it increased the response to SNP from 13.3±3.9 to 15.1±4.3 mL/min per 100 mL tissue in smokers and from 14.8±5.2 to 18.4±6.0 mL/min/100 mL tissue in nonsmokers (
P
<0.05 for all). The ratio of maximal ACh-stimulated FBF expressed as a ratio of maximal SNP-stimulated FBF significantly increased after administration of sildenafil in both groups. Infusion of
N
G
-monomethyl-
l
-arginine, a nitric oxide synthase inhibitor, abolished sildenafil-induced augmentation of the FBF response to ACh in both groups. The findings suggest that endothelial function is impaired in smokers compared with that in nonsmokers, that inhibition of PDE5 by sildenafil significantly increases nitric oxide-mediated vasodilation, and that the activities of PDE5 in smokers and nonsmokers may be similar.
Antioxidant Activities and Oxidative Stress Byproducts in Human Hypertension
Authors: Redón Josep , Oliva Maria R. , Tormos Carmen , Giner Vicente , Chaves Javier , Iradi Antonio , Sáez Guillermo T.
Published: May 2003

The objective was to study oxidative status, antioxidant activities, and reactive oxygen species byproducts in whole blood and mononuclear peripherals cells and their relationship with blood pressure. Sixty-six hypertensive patients and 16 normotensive volunteers as a control group were studied. In both, whole blood and peripheral mononuclear cells oxidized/reduced glutathione ratio and malondialdehyde was significantly higher, and the activity of superoxide dismutase, catalase, and glutathione peroxidase was significantly lower in hypertensive patients when compared with normal subjects. The content of damaged base 8-oxo-2′-deoxyguanosine in nuclear and mitochondrial deoxyribonucleoproteins of hypertensive subjects was also significantly higher than that of the normotensive control subjects. No differences in these measurements were found among hypertensive subjects grouped in tertiles of 24-hour average mean blood pressure or between “white-coat” and established hypertensive subjects. Furthermore, no relationship was observed between the average of 24-hour mean blood pressure and oxidized/reduced glutathione ratio, reactive oxygen species byproducts, malondialdehide, or genomic 8-oxo-2′-deoxyguanosine. In whole blood and in mononuclear cells from hypertensive subjects, there was an increase in oxidative stress and a reduction in the activity of antioxidant mechanisms that appeared to be independent of the blood pressure values.
Associations Between Hypertension and Genes in the Renin-Angiotensin System
Authors: Zhu Xiaofeng , Chang Yen-Pei C. , Yan Denise , Weder Alan , Cooper Richard , Luke Amy , Kan Donghui , Chakravarti Aravinda
Published: May 2003

The genes of the renin-angiotensin system have been subjected to intense molecular scrutiny in cardiovascular disease studies, but their contribution to risk is still uncertain. In this study, we sampled 192 African American and 153 European American families (602 and 608 individuals, respectively) to evaluate the contribution of variations in genes that encode renin-angiotensin system components of susceptibility to hypertension. We genotyped 25 single-nucleotide polymorphisms in the renin-angiotensin system genes
ACE
,
AGT
,
AGTR1
, and
REN
. The family-based transmission/disequilibrium test was performed with each single-nucleotide polymorphism and with the multilocus haplotypes. Two individual single-nucleotide polymorphisms were significantly associated with hypertension among African Americans, and this result persisted when both groups were combined. The associations were confirmed in haplotype analysis for
REN
,
AGTR1
, and
ACE
in African Americans. Consistent but less significant evidence was found in European Americans. We also randomly sampled unrelated individuals across families to obtain 84 cases and 108 controls among the African Americans and 41 cases and 113 controls in the European Americans. Single-nucleotide polymorphism and haplotype analyses again showed consistent, albeit weaker, results. Thus, in this biracial population sample, we find evidence that interindividual variation in the renin-angiotensin system genes contributes to hypertension risk.
Enhanced Smooth Muscle Cell Coverage of Microvessels Exposed to Increased Hemodynamic Stresses In Vivo
Authors: Van Gieson Eric J. , Murfee Walter L. , Skalak Thomas C. , Price Richard J.
Published: May 2003

During vascular remodeling in adult organisms, new capillary growth is often coupled with the adaptation of arterioles and venules, a process that requires the recruitment and differentiation of precursor cells into smooth muscle. We studied the in vivo adaptation of microvessels in the presence of elevated pressure and circumferential wall stress using a ligation strategy for mesenteric microvascular networks. Acute pressure increases of 42.6±18% and 17.1±2.3% were respectively elicited in the 25- to 30-μm-diameter venules and arterioles supplying the networks. Wall shear rates were not significantly changed; however, diameters were increased in >10-μm-diameter venules and >20-μm-diameter arterioles. Smooth muscle cell contractile phenotype was determined in all microvessels by observing the expression of smooth muscle myosin heavy chain (SM-MHC; a marker of fully differentiated smooth muscle) and smooth muscle α-actin (a marker for all smooth muscle, including immature smooth muscle of fibroblast/pericyte lineage). The ratio of SM-MHC positive vessel length to smooth muscle α-actin–positive vessel length increased >2-fold after 5 and 10 days of the ligation treatment. Smooth muscle proliferation was studied by bromodeoxyuridine incorporation, and the increase in SM-MHC–labeled microvessel length density was accompanied by no measurable change in proliferation of SM-MHC–labeled cells 5 and 10 days after ligation. These results indicate that after a period of 5 or 10 days, mesenteric microvessels <40 μm in diameter exposed to elevated pressure and wall strain exhibit an enhanced coverage of mature, fully differentiated smooth muscle cells.
Defective Sorting to Secretory Vesicles in Trans-Golgi Network Is Partly Responsible for Protein C Deficiency
Authors: Naito Masao , Mimuro Jun , Endo Hitoshi , Madoiwa Seiji , Ogata Kyo-ichi , Kikuchi Jiro , Sugo Teruko , Yasu Takanori , Kariya Yusei , Hoshino Yuichi , Sakata Yoichi
Published: May 2003

Three thrombophilic patients with protein C (PC) deficiency were found to have independent mutations in the PC gene. These mutations resulted in single amino acid substitutions of R169W, R352W, and G376D in the affected PC molecules. These abnormal PC molecules were expressed in CHO-K1 cells in the presence or absence of vitamin K, and their synthesis, posttranslational modification, and secretion were studied. PC G376D was not secreted from the cells and was gradually degraded inside the cells. There was partial secretion of PC R169W and PC R352W, but most of these molecules were not secreted but were degraded intracellularly. On the basis of pulse-chase, immunofluorescence, and endo-β-
N
-acetylglucosaminidase H digestion experiments, the majority of wild-type PC molecules localize not in the Golgi apparatus but in the rough endoplasmic reticulum inside the cells. This suggests that wild-type PC molecules are secreted immediately after γ-carboxylation and modification at the Golgi apparatus. In contrast, the mutant PC molecules were retained inside the cells even after modification of oligosaccharides at the trans-Golgi apparatus, which was probably due to impaired conformation of the abnormal molecules. Data suggest that these abnormal PC molecules were not sorted to secretory vesicles in the trans-Golgi network because of conformational defects in addition to the transport defect from the rough endoplasmic reticulum to the Golgi apparatus and were degraded inside the cells, thereby resulting in a PC deficiency in the affected patients.
Crosstalk Between Voltage-Independent Ca
2+
Channels and L-Type Ca
2+
Channels in A7r5 Vascular Smooth Muscle Cells at Elevated Intracellular pH
Authors: Poteser Michael , Wakabayashi Ichiro , Rosker Christian , Teubl Margot , Schindl Rainer , Soldatov Nikolai M. , Romanin Christoph , Groschner Klaus
Published: May 2003

This study was designed to investigate the role of voltage-independent and voltage-dependent Ca
2+
channels in the Ca
2+
signaling associated with intracellular alkalinization in A7r5 vascular smooth muscle cells. Extracellular administration of ammonium chloride (20 mmol/L) resulted in elevation of intracellular pH and activation of a sustained Ca
2+
entry that was inhibited by 2-amino-ethoxydiphenyl borate (2-APB, 200 μmol/L) but not by verapamil (10 μmol/L). Alkalosis-induced Ca
2+
entry was mediated by a voltage-independent cation conductance that allowed permeation of Ca
2+
(P
Ca
/P
Na
≈6), and was associated with inhibition of L-type Ca
2+
currents. Alkalosis-induced inhibition of L-type Ca
2+
currents was dependent on the presence of extracellular Ca
2+
and was prevented by expression of a dominant-negative mutant of calmodulin. In the absence of extracellular Ca
2+
, with Ba
2+
or Na
+
as charge carrier, intracellular alkalosis failed to inhibit but potentiated L-type Ca
2+
channel currents. Inhibition of Ca
2+
currents through voltage-independent cation channels by 2-APB prevented alkalosis-induced inhibition of L-type Ca
2+
currents. Similarly, 2-APB prevented vasopressin-induced activation of nonselective cation channels and inhibition of L-type Ca
2+
currents. We suggest the existence of a pH-controlled Ca
2+
entry pathway that governs the activity of smooth muscle L-type Ca
2+
channels due to control of Ca
2+
/calmodulin-dependent negative feedback regulation. This Ca
2+
entry pathway exhibits striking similarity with the pathway activated by stimulation of phospholipase-C–coupled receptors, and may involve a similar type of cation channel. We demonstrate for the first time the tight functional coupling between these voltage-independent Ca
2+
channels and classical voltage-gated L-type Ca
2+
channels.
Conducting Stroke Research With an Exception From the Requirement for Informed Consent
Authors: Bateman Brian T. , Meyers Philip M. , Schumacher H. Christian , Mangla Sundeep , Pile-Spellman John
Published: May 2003

Background—

Obtaining viable informed consent from stroke patients for participation in clinical trials of acute stroke therapies is often problematic because of patients’ neurological deficits. Furthermore, obtaining permission from surrogates is often not possible or not legally permissible.

Summary of Review—

In 1996 the Food and Drug Administration and Department of Health and Human Services published regulations that allow investigators to conduct emergency research without patient consent under a narrowly defined set of circumstances. We review requirements of these regulations, paying particular attention to how they may be applied in a clinical trial of an acute stroke therapy.

Conclusions—

Acute stroke researchers should consider conducting clinical trials with an exception from the informed consent requirement permitted by this law.
Potassium Channel Blockers Attenuate Hypoxia- and Ischemia-Induced Neuronal Death In Vitro and In Vivo
Authors: Wei Ling , Yu Shan Ping , Gottron Frank , Snider B. Joy , Zipfel Gregory J. , Choi Dennis W.
Published: May 2003

Background and Purpose—

In light of recent evidence suggesting that an upregulation of K
+
efflux mediated by outward delayed rectifier (
I
K
) channels promotes central neuronal apoptosis, we sought to test the possibility that blockers of
I
K
channels might be neuroprotective against hypoxia/ischemia-induced neuronal death.

Methods—

Membrane currents were recorded with the use of patch clamp recordings in cultured murine cortical neurons. Protective effects of K
+
channel blockers were examined in rats subjected to transient middle cerebral artery occlusion followed by 14-day reperfusion.

Results—

The K
+
channel blocker tetraethylammonium (TEA) (5 mmol/L) selectively blocked
I
K
without affecting
N
-methyl-
d
-aspartate receptor–mediated current or voltage-gated Ca
2+
currents. Both TEA and a lipophilic K
+
channel blocker, clofilium, attenuated neuronal apoptosis induced by hypoxia in vitro and infarct volume induced by ischemia in vivo.

Conclusions—

These data are consistent with the idea that K
+
channel–mediated K
+
efflux may contribute to ischemia-triggered apoptosis and suggest that preventing excessive K
+
efflux through K
+
channels may constitute a therapeutic approach for the treatment of stroke.
Early Assessments of Dysphagia and Aspiration Risk in Acute Stroke Patients
Authors: Ramsey Deborah J.C. , Smithard David G. , Kalra Lalit
Published: May 2003

Background and Purpose—

Dysphagia is common after stroke and is a marker of poor prognosis. Early identification is important. This article reviews the merits and limitations of various assessment methods available to clinicians.

Methods—

An electronic database search was performed of MEDLINE, EMBASE, and the Cochrane database using such terms as stroke, aspiration, dysphagia, and assessment; extensive manual searching of articles was also conducted.

Results—

Bedside tests are safe, relatively straightforward, and easily repeated but have variable sensitivity (42% to 92%), specificity (59% to 91%), and interrater reliability (κ=0 to 1.0). They are also poor at detecting silent aspiration. Videofluoroscopy gives anatomic and functional information and allows testing of therapeutic techniques. However, swallowing is assessed under ideal conditions that are different from clinical settings, and reliability is often poor (κ=0 to 0.75) in the absence of assessor training. Fiberoptic endoscopy allows swallow assessment and sensory testing but requires specialized staff and equipment. Oxygen desaturation during swallowing may be predictive of aspiration (sensitivity, 73% to 87%; specificity, 39% to 87%) but is more useful in combination with bedside testing than in isolation. Other methods of swallow testing are invasive and require specialized staff and equipment.

Conclusions—

Although bedside tests remain an important early screening tool for dysphagia and aspiration risk, further refinements are needed to improve their accuracy.
Sex Differences in Carotid Endarterectomy Outcomes
Authors: Kapral Moira K. , Wang Hua , Austin Peter C. , Fang Jiming , Kucey Daryl , Bowyer Beverley , Tu Jack V.
Published: May 2003

Background and Purpose—

The existing literature provides conflicting evidence on surgical risks of carotid endarterectomy in women compared with men. We used data from a large population-based carotid surgery registry to determine whether sex differences exist in the risk of perioperative complications from carotid endarterectomy.

Methods—

We analyzed data from the Ontario Carotid Endarterectomy Registry, which contains data on all patients who underwent carotid endarterectomy in the province of Ontario between 1994 and 1997. We compared the risk of death or stroke at 30 days in women and men and used multivariate analyses to adjust for age, comorbid conditions, and surgical factors. Secondary analyses compared the risks of death and/or stroke in women and men at 2 years after surgery.

Results—

The study sample consisted of 6038 patients (35% women). The risks of perioperative stroke or death were not significantly different in women compared with men (adjusted hazard ratio, 1.10; 95% CI, 0.90 to 1.35). The combined risk of stroke or death at 2 years after surgery was also similar in women and men (adjusted hazard ratio, 1.05; 95% CI, 0.92 to 1.21). However, women were more likely to have a stroke (adjusted hazard ratio, 1.26; 95% CI, 1.05 to 1.51) and less likely to die (adjusted hazard ratio, 0.82; 95% CI, 0.68 to 0.99) within 2 years after surgery.

Conclusions—

Perioperative complication rates from carotid endarterectomy are similar in women and men. Women should not be discouraged from carotid endarterectomy solely on the basis of surgical risks.