bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-Brain Voxel-Based Correlation Analysis between Regional Cerebral Blood Flow and Intelligence Quotient Score in Parkinson’s Disease
Authors: Oishi Kenichi , Ogawa Masafumi , Oya Yasushi , Kawai Mitsuru
Published: October 2004

The correlation between regional cerebral blood flow (rCBF) and intelligence quotient (IQ) score was investigated in patients with Parkinson’s disease (PD) without severe dementia. We analyzed the 99mTc-ethyl cysteinate dimer single-photon emission computed tomography quantitative images and Revised Wechsler Adult Intelligence Scale scores of 44 PD patients using statistical parametric mapping. Verbal IQ positively correlated with rCBF in the right ventral striatum and the bilateral prefrontal cortex, performance IQ positively correlated with rCBF in the right operculum, insula and the left middle temporal gyrus, and full-scale IQ positively correlated with rCBF in the right operculum, insula and the ventral striatum. The identified areas may be functionally related to mild to moderate cognitive impairment in patients with PD.
Differential Regulation of 3-Beta-Hydroxysteroid Dehydrogenase and Vanilloid Receptor TRPV1 mRNA in Sensory Neurons by Capsaicin and NGF
Authors: Donnerer J. , Liebmann I. , Schicho R.
Published: October 2004

It was the aim of the present study to investigate by RT-PCR the regulation of the mRNA of the neurosteroid-synthesizing enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) and of the vanilloid receptor TRPV1 in dorsal root ganglia (DRGs) of rats during the process of capsaicin denervation of primary sensory neurons and the following regeneration. The expression of 3β-HSD in DRG was increased 3 days after the capsaicin treatment, and it remained at that level during a 22 day observation period. The expression of TRPV1, a specific marker of capsaicin-sensitive small sensory neurons connected to C- and Aδ-fibers, was markedly reduced 3 days after the capsaicin treatment. It slowly recovered during the 22 days observation period reaching almost control levels on day 22. When the capsaicin-treated rats received 5 intraplantar injections of nerve growth factor (NGF), the prototypical neurotrophin for capsaicin-sensitive neurons, on day 1, 2, 3, 5 and 6, both the 3β-HSD and the TRPV1 mRNA had returned to control levels at the time point 8 days after capsaicin. The present results demonstrate that both 3β-HSD and TRPV1 are markers for neurodegeneration and neuroregeneration in capsaicin-sensitive primary afferent neurons, and that NGF is an effective tool to induce recovery after peripheral nerve injury.
Atorvastatin and Simvastatin Decrease the Uptake of Acetylated Low-Density Lipoprotein by Human Monocytes
Authors: Tavridou Anna , Manolopoulos Vangelis G.
Published: October 2004

Several lines of evidence indicate that HMG-CoA reductase inhibitors, calcium channel blockers, and angiotensin-converting enzyme inhibitors exert anti-atherogenic effects in vitro and in vivo. In the present study, we determined the effect of members of the above classes of drugs on the uptake of modified low-density lipoprotein (LDL) by U937 cells (human monocytic cell line), a key event in the progression of atherosclerosis. U937 cells were treated with drugs and subsequently the uptake of fluorescent acetylated LDL was assessed by flow cytometry. The HMG-CoA reductase inhibitors, atorvastatin and simvastatin (1–30 µmol/l), but not calcium channel blockers or angiotensin-converting enzyme inhibitors, inhibited the uptake of modified LDL by monocytes. Therefore, atorvastatin and simvastatin may slow down the progression of atherosclerosis by inhibiting the formation of foam cells.
Effect of Potassium Channel and Cytochrome P450 Inhibition on Transient Hypotension and Survival during Lipopolysaccharide-Induced Endotoxic Shock in the Rat
Authors: Clayton Nicholas P. , LeDuc Barbara W. , Kelly Laurie J.
Published: October 2004

The purpose of this study was to determine whether inhibition of potassium channels or cytochrome P450 attenuates the transient phase of hypotension during endotoxic shock in vivo, and to determine whether these interventions improve the rate of survival. Male Sprague-Dawley rats were pretreated with saline (0.2 ml, i.v.), tetraethylammonium chloride (TEA 30 mg/kg; 0.2 ml, i.v.), proadifen (SKF-525 A; 50 mg/kg, i.p.) or ketoconazole (50 mg/kg, i.p.) and challenged with lipopolysaccharide (LPS; 20 mg/kg, i.p.). Changes in heart rate, mean (MAP), systolic (SP) and diastolic (DP) arterial pressures as well as survival rate were then monitored for 45 min. Potassium channel inhibition with TEA had no effect on LPS-induced hypotension at any time point compared with saline (maximal fall in MAP of 79 ± 18 and 80 ± 13 mm Hg, respectively). Pretreatment with proadifen or ketoconazole, inhibitors of cytochrome P450, significantly attenuated LPS-induced hypotension compared with saline (maximal fall in MAP of 34, 26 and 63% below baseline, respectively). This effect was evident in all arterial pressures measured, MAP, SP and DP. At 45 min, the survival rate in the saline group was 66%. Pretreatment with TEA significantly reduced survival rate to 50% and pretreatment with proadifen or ketoconazole improved survival to 100% (p < 0.05). These results suggest that an arachidonic acid metabolite produced by a cytochrome P450-catalyzed reaction may contribute to the transient phase of LPS-induced hypotension. However, these effects do not appear to be mediated through potassium channel activation.
Maternal and Fetal Blood Ammonia Concentrations in Normal Term Human Pregnancies
Authors: Jóźwik Maciej , Jóźwik Marcin , Pietrzycki Bartosz , Chojnowski Marcin , Teng Cecilia , Jóźwik Michał , Battaglia Frederick C.
Published: October 2004

Background: The current evidence on the primary source of ammonia production in the human fetoplacental unit is potentially misleading. Objective: The aim of the present investigation was to determine the concentration of ammonia in human maternal and fetal blood at birth and to compare them with published data in late gestation sheep. Methods: In 12 normal human pregnancies, umbilical arterial and venous and maternal venous blood was sampled, and whole blood ammonia concentrations were measured. Data from 12 pregnant sheep and fetuses from our previous studies were utilized for comparison. Results: The human fetus at delivery has higher concentrations of ammonia (60–80 µM) than the late gestation fetal lamb (25–35 µM). In the human, the arterial umbilical ammonia concentration exceeds the venous umbilical concentration, indicating a net ammonia production by fetal tissues. In sheep, the venous umbilical ammonia concentration exceeds the arterial umbilical concentration, indicating the net placental ammonia production. Conclusions: In contrast to fetal lambs, human fetuses exhibit a net production of ammonia, which may reflect differences in biologic state or a species difference.
Association Between Elevated Liver Enzymes and C-Reactive Protein
Authors: Kerner Arthur , Avizohar Ophir , Sella Ron , Bartha Peter , Zinder Oren , Markiewicz Walter , Levy Yishai , Brook Gerald J. , Aronson Doron
Published: October 2004

Objective—

The objective of this study was to test whether the frequent association between liver enzyme elevations and various components of the metabolic syndrome is associated with higher C-reactive protein (CRP) levels.

Methods and Results—

Alanine aminotransferase (ALT), alkaline phosphatase (Alk-P), and high-sensitivity CRP were measured in 1740 subjects. Adjusted geometric mean CRP was calculated for subjects with normal and elevated ALT and for subjects with normal and elevated Alk-P, adjusting for age, sex, smoking, physical activity, body mass index, fasting glucose, triglycerides, the presence of hypertension and low HDL cholesterol, and use of aspirin or hormone replacement therapy. Adjusted CRP levels were higher in subjects with elevated ALT (2.21 versus 1.94 mg/L,
P
=0.028) or elevated Alk-P (2.58 versus 1.66 mg/L,
P
<0.0001). Logistic regression showed that compared with subjects with normal liver function tests, the adjusted odds for high-risk CRP (>3 mg/L) were significantly higher in subjects with elevated ALT (OR, 1.5; 95% CI, 1.2 to 1.9,
P
=0.002) or elevated Alk-P (OR, 2.1; 95% CI, 1.7 to 2.6,
P
<0.0001).

Conclusions—

Elevations of liver enzymes are associated with higher CRP concentrations. Hepatic inflammation secondary to liver steatosis is a potential contributor to the low-grade inflammation associated with the metabolic syndrome.
Bilirubin From Heme Oxygenase-1 Attenuates Vascular Endothelial Activation and Dysfunction
Authors: Kawamura Keiichi , Ishikawa Kazunobu , Wada Youichiro , Kimura Satoshi , Matsumoto Hayato , Kohro Takahide , Itabe Hiroyuki , Kodama Tatsuhiko , Maruyama Yukio
Published: October 2004

Objective—

Heme oxygenase-1 (HO-1), the rate-limiting enzyme of heme degradation, has recently been considered to have protective roles against various pathophysiological conditions. Since we demonstrated that HO-1 overexpression inhibits atherosclerotic formation in animal models, we examined the effect of HO modulation on proinflammatory cytokine production, endothelial NO synthase (eNOS) expression, and endothelium-dependent vascular relaxation responses.

Methods and Results—

After HO-1 induction by heme arginate (HA), vascular endothelial cell cultures were exposed to oxidized low-density lipoprotein (oxLDL) or tumor necrosis factor-α (TNF-α). HA pretreatment significantly attenuated the production of vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and macrophage colony-stimulating factor, suggesting that HO-1 induction attenuates proinflammatory responses. In addition, HO-1 overexpression also alleviated endothelial dysfunction as judged by restoration of attenuated eNOS expression after exposure to oxLDL and TNF-α. Importantly, impaired endothelium-dependent vascular relaxation responses in thoracic aortic rings from high-fat-fed LDL receptor knockout mice were also improved. These effects were observed by treatment with bilirubin not by carbon monoxide.

Conclusions—

These results suggest that the antiatherogenic properties of HO-1 may be mediated predominantly through the action of bilirubin by inhibition of vascular endothelial activation and dysfunction in response to proinflammatory stresses.
Effects of Cardiac Resynchronization on Disease Progression in Patients With Left Ventricular Systolic Dysfunction, an Indication for an Implantable Cardioverter-Defibrillator, and Mildly Symptomatic Chronic Heart Failure
Authors: Abraham William T. , Young James B. , León Angel R. , Adler Stuart , Bank Alan J. , Hall Shelley A. , Lieberman Randy , Liem L. Bing , O’Connell John B. , Schroeder John S. , Wheelan Kevin R.
Published: October 2004

Background—

The effects of cardiac resynchronization therapy (CRT) in patients with mildly symptomatic heart failure have not been fully elucidated.

Methods and Results—

The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) was a randomized, double-blind, parallel-controlled clinical trial of CRT in NYHA class II heart failure patients on optimal medical therapy with a left ventricular (LV) ejection fraction ≤35%, a QRS ≥130 ms, and a class I indication for an ICD. One hundred eighty-six patients were randomized: 101 to the control group (ICD activated, CRT off) and 85 to the CRT group (ICD activated, CRT on). End points included peak V̇
o
2
, V̇
e
/V̇
co
2
, NYHA class, quality of life, 6-minute walk distance, LV volumes and ejection fraction, and composite clinical response. Compared with the control group at 6 months, no significant improvement was noted in peak V̇
o
2
, yet there were significant improvements in ventricular remodeling indexes, specifically LV diastolic and systolic volumes (
P
=0.04 and
P
=0.01, respectively), and LV ejection fraction (
P
=0.02). CRT patients showed statistically significant improvement in V̇
e
/V̇
co
2
(
P
=0.01), NYHA class (
P
=0.05), and clinical composite response (
P
=0.01). No significant differences were noted in 6-minute walk distance or quality of life scores.

Conclusions—

In patients with mild heart failure symptoms on optimal medical therapy with a wide QRS complex and an ICD indication, CRT did not alter exercise capacity but did result in significant improvement in cardiac structure and function and composite clinical response over 6 months.
Gene Expression Profiling of Inflamed Human Endothelial Cells and Influence of Activated Protein C
Authors: Franscini Nicola , Bachli Esther B. , Blau Nenad , Leikauf Maria-Sybille , Schaffner Andreas , Schoedon Gabriele
Published: October 2004

Background—

During systemic inflammation, activation of vascular endothelium by proinflammatory cytokines leads to hypotension, microvascular thrombosis, and organ damage. Recent data suggest a link between coagulation and inflammation through the activated protein C (APC) pathway. We studied gene expression profiles in human coronary artery endothelial cells (HCAECs) exposed to proinflammatory stimuli and the influence of APC on expression of candidate genes regulated by these stimuli.

Methods and Results—

HCAECs were stimulated with interleukin-1β, interferon-γ, and tumor necrosis factor-α. In gene expression profiling, 400 of 8400 genes were regulated >2-fold. Verification of selected candidate genes was achieved by measuring expression of mRNA species by real-time polymerase chain reaction, cytokine secretion by ELISA, and metabolites of tetrahydrobiopterin (BH4) biosynthesis by high-performance liquid chromatography. BH4 synthesis, interleukin-6, interleukin-8, monocyte chemotactic protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were downregulated by APC at the transcriptional and protein level. Endothelial nitric oxide synthase, endothelial adhesion molecule, and vascular cell adhesion molecule-1 were not affected by APC. Activities of transcription factors c-Fos, FosB, and c-Rel were inhibited by APC in inflamed HCAECs.

Conclusions—

Our study revealed a novel antiinflammatory mechanism of APC-dependent gene regulation in HCAECs since c-Fos–dependent induction of MCP-1 and ICAM-1 was suppressed. APC downregulates expression and activity of genes related to inflammation, most pronounced under intermediate or mild inflammatory conditions.
Subclinical Coronary Atherosclerosis in Asymptomatic Filipino and White Women
Authors: Araneta Maria Rosario G. , Barrett-Connor Elizabeth
Published: October 2004

Background—

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in persons with type 2 diabetes mellitus (T2DM). Electron-beam computed tomography (EBCT) detects coronary artery calcium (CAC), a marker of atherosclerotic plaque. Few studies have described EBCT-defined CHD among ethnic minorities with elevated T2DM prevalence. The objective of this study was to compare EBCT-defined CAC in Filipino and white women without known cardiovascular disease.

Methods and Results—

Subjects were participants aged 55 to 78 years in the Rancho Bernardo Study (n=196) and the University of California at San Diego’s Filipino Women’s Health Study (n=181). Glucose, blood pressure, lipids, anthropometric measurements, and lifestyle factors were measured from 1995 to 1999. EBCT-defined CAC scores, visceral and subcutaneous fat, and statin use were assessed in 2001 to 2002. Compared with whites, Filipinas had a significantly higher prevalence of T2DM (32.6% versus 6.1%,
P
<0.001) and the metabolic syndrome (32.6% versus 13.8,
P
<0.001). Filipinas were younger (64.4 versus 66.7 years), had higher triglyceride levels (155 versus 135 mg/dL), had a higher ratio of total cholesterol to HDL cholesterol (4.3 versus 3.5), more frequently used statins (31% versus 19%), and had more visceral fat (69.4 versus 62.1 cm
3
) and lower HDL cholesterol levels (54 versus 66 mg/dL) than whites. Exercise frequency, body mass index, and waist girth did not differ by ethnicity. Nevertheless, extensive (CAC score ≥400; 9% versus 9%) and moderate (CAC score 150 to 399; 13% versus 11%) atherosclerotic plaque did not differ by ethnicity, even after adjustment for age, T2DM, hypertension, estrogen use, statin use, smoking, lipids, and visceral fat.

Conclusions—

Filipinas had no excess of subclinical atherosclerosis despite their significantly higher prevalence of T2DM, the metabolic syndrome, hypertension, and visceral adiposity.
From Mouse to Whale
Authors: Noujaim Sami F. , Lucca Elena , Muñoz Viviana , Persaud Dharmendra , Berenfeld Omer , Meijler Frits L. , Jalife José
Published: October 2004

Background—

On the ECG, the PR interval measures the time taken by an electrical impulse generated in the sinoatrial node to propagate from atria to ventricles. From mouse to whale, the PR interval increases ≈10
1
, whereas body mass (BM) augments ≈10
6
. Scaling of many biological processes (eg, metabolic rate, life span, aortic diameter) is described by the allometric equation
Y
=
Y
0
·
BM
b
, where
Y
is the biological process and
b
is the scaling exponent that is an integer multiple of 1/4. Hierarchical branching networks have been proposed to be the underlying mechanism for the 1/4 power allometric law.

Methods and Results—

We first derived analytically the allometric equation for the PR interval. We assumed that the heart behaves as a set of “fractal-like” networks that tend to minimize propagation time across the conducting system while ensuring a hemodynamically optimal atrioventricular activation sequence. Our derivation yielded the relationship
PR
∝
BM
1/4
. We subsequently obtained previously published values of PR interval, heart rate, and BM of 541 mammals representing 33 species. Double-logarithmic analysis demonstrates that PR interval increases as heart rate decreases, and both variables relate to BM following the 1/4 power law. Most important, the best fit for PR versus BM is described by the equation PR=53 · BM
0.24
. Hence, the empirically determined exponent (0.24) is close to 1/4, as predicted.

Conclusions—

We have demonstrated that the PR interval of mammals scales as the 1/4 power of the BM, following the universal law for allometric scaling to ensure an optimal atrioventricular activation sequence.
Arterial Neovascularization and Inflammation in Vulnerable Patients
Authors: Fleiner Michael , Kummer Marco , Mirlacher Martina , Sauter Guido , Cathomas Gieri , Krapf Reto , Biedermann Barbara C.
Published: October 2004

Background—

Atherosclerosis is complicated by cardiovascular events such as myocardial infarction, stroke, or peripheral arterial occlusive disease. Inflammation and pathological neovascularization are thought to precipitate plaque rupture or erosion, both causes of arterial thrombosis and cardiovascular events. We tested the hypothesis that arterial inflammation and angiogenic events are increased throughout the arterial tree in vulnerable patients, ie, in patients who suffered from cardiovascular events, compared with patients who never suffered from complications of atherosclerosis.

Methods and Results—

In a postmortem study, we quantified the inflammatory infiltrate and microvascular network in the arterial wall of iliac, carotid, and renal arteries. Tissue microarray technology was adapted to investigate full-thickness arterial sectors. We compared 22 patients with symptomatic atherosclerosis with 27 patients who never had suffered from any cardiovascular event. The absolute intimal macrophage content was 2- to 4-fold higher in vulnerable patients at all 3 arterial sites analyzed (
P
<0.05). Patients with symptomatic atherosclerosis had a denser network of vasa vasorum than patients with asymptomatic disease (33±2 versus 25±2 adventitial microvessels per 1 mm
2
;
P
=0.008). Hyperplasia of vasa vasorum was an early and macrophage infiltration was a late sign of symptomatic atherosclerosis.

Conclusions—

High intimal macrophage content and a hyperplastic network of vasa vasorum characterize vulnerable patients suffering from symptomatic atherosclerosis. These changes are uniformly present in different arterial beds and support the concept of symptomatic atherosclerosis as a panarterial disease.
Modulation of Doxorubicin-Induced Cardiac Dysfunction in Toll-Like Receptor-2–Knockout Mice
Authors: Nozaki Naoki , Shishido Tetsuro , Takeishi Yasuchika , Kubota Isao
Published: October 2004

Background—

Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and are involved in the responsiveness to pathogen-associated molecular patterns. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, which may contribute to congestive heart failure. Oxidative stress is one of the major factors in doxorubicin (Dox)-induced cardiac dysfunction. Thus, we hypothesized that TLRs contribute to the pathogenesis of Dox-induced cardiac dysfunction.

Methods and Results—

Cardiac dysfunction was induced by a single injection of Dox (20 mg/kg IP) into wild-type (WT) mice and TLR-2–knockout (KO) mice. Five days after Dox injection, left ventricular dimension at end-diastole was smaller and fractional shortening was higher in KO mice compared with WT mice (
P
<0.01). Nuclear factor-κB activation and production of proinflammatory cytokines after Dox were suppressed in KO mice compared with WT mice (
P
<0.01). The numbers of TUNEL-positive nuclei and Dox-induced caspase-3 activation were less in KO mice than in WT mice (
P
<0.01). Survival rate was significantly higher in KO mice than in WT mice 10 days after Dox injection (46% vs 11%,
P
<0.05).

Conclusions—

These findings suggest that TLR-2 may play a role in the regulation of inflammatory and apoptotic mediators in the heart after Dox administration.
Endothelium-Dependent Flow-Mediated Vasodilation of Systemic Arteries Is Impaired in Patients With Myocardial Virus Persistence
Authors: Vallbracht Katja B. , Schwimmbeck Peter L. , Kühl Uwe , Seeberg Bettina , Schultheiss Heinz-Peter
Published: October 2004

Background—

Myocardial virus persistence is frequently observed in patients with cardiomyopathy. Endothelial dysfunction in patients with cardiomyopathy is associated with inflammatory immunoresponses in myocardial biopsies. The aim of this study was to investigate the impact of myocardial virus persistence on endothelial function.

Methods and Results—

In 124 patients with suspected cardiomyopathy, myocardial biopsies were examined for virus persistence (by polymerase chain reaction) and inflammation (by immunohistology). Endothelial function of the radial artery was examined by high-resolution ultrasound. Diameter changes in response to reactive hyperemia (flow-mediated dilation [FMD]) compared with glycerol trinitrate (GTN-MD) were measured. Mean age of the patients (55 men, 69 women) was 45±13 years; ejection fraction was 57±17%. In 73 patients, adenovirus, enterovirus, parvovirus, or HHV6 virus (V) was detected; in 51, no virus was detected. FMD was significantly impaired in patients with myocardial virus persistence compared with control subjects (Co): FMD-V, 3.38±2.67%; FMD-Co, 7.34±3.44 (
P
<0.001). In 86 patients, myocardial inflammation was confirmed (Inf). Of those, 57 had virus, and 29 did not. FMD was significantly impaired in patients with virus compared with controls: FMD-Inf-V, 3.24±2.66%; FMD-Inf-Co, 6.07±3.00 (
P
<0.001). In 38 patients, immunohistology of the myocardial biopsies was normal (Co); of those, 16 had virus, and 22 did not. FMD was impaired in patients with virus compared with control subjects: FMD-Co-V, 3.88±2.72%; FMD-Co-Co, 9.00±3.32% (
P
<0.001). Endothelium-independent vasodilation (GTN-MD) was not significantly affected.

Conclusions—

Myocardial virus persistence is associated with endothelial dysfunction. Endothelial dysfunction in patients with myocardial virus persistence can occur independently of endothelial activation or myocardial inflammation but is more pronounced in patients with concurrent inflammation.
Heart Rate Recovery and Impact of Myocardial Revascularization on Long-Term Mortality
Authors: Chen Michael S. , Blackstone Eugene H. , Pothier Claire E. , Lauer Michael S.
Published: October 2004

Background—

Although heart rate recovery (HRR) predicts mortality after exercise testing, its ability to identify patients likely to benefit after revascularization is unknown. We sought to determine whether HRR can identify patients likely to have improved survival after revascularization.

Methods and Results—

A total of 8861 patients undergoing treadmill nuclear or echocardiographic testing were divided into early revascularization (percutaneous coronary intervention or bypass surgery within 3 months) and non–early revascularization groups. Prespecified subgroup analysis was performed based on the presence or absence of ischemia, normal or impaired functional capacity, and normal or abnormal HRR. The primary end point was all-cause mortality. Early revascularization occurred in 552 patients. We propensity-matched 508 early revascularization patients to 508 non–early revascularization patients on the basis of 48 possible confounders. This constituted the present study cohort. During 8-year follow-up, 232 patients died. Overall, revascularization was associated with a slight but not significant decrease in mortality (hazard ratio [HR] 0.80, 95% CI 0.62 to 1.03). A significant decrease in mortality after revascularization was present in patients with imaging evidence of stress-induced ischemia (HR 0.62, 95% CI 0.44 to 0.87). Ischemic patients with normal HRR had significantly lower mortality with revascularization (HR 0.55, 95% CI 0.34 to 0.90), whereas ischemic patients with abnormal HRR did not (HR 0.78, 95% CI 0.47 to 1.29); however, the test for interaction between these 2 groups was not significant (
P
=0.34).

Conclusions—

In patients with imaging evidence of myocardial ischemia, an abnormal HRR is associated with a nonsignificant trend toward blunting the survival improvement associated with early revascularization. HRR does not appear to identify patients likely to have a survival benefit.
Potassium Chloride Supplementation Diminishes Platelet Reactivity in Humans
Authors: Kimura Masayuki , Lu Xiaobin , Skurnick Joan , Awad Girgis , Bogden John , Kemp Francis , Aviv Abraham
Published: October 2004

The prevalence of occlusive stroke is inversely correlated with potassium intake. We explored the hypothesis that a high potassium intake attenuates platelet reactivity, as expressed in ADP-evoked platelet aggregation. We studied healthy men (n=31) and women (n=42), blacks (n=33) and whites (n=40). In this cohort, we supplemented the habitual intake of 17 men and 21 women with 60 mmol KCl/70 kg body weight per day for 3 days and maintained 14 men and 21 women on their habitual intake. We then compared the change in ADP concentration causing 50% of the maximal initial rate (EC
50
) of platelet aggregation in the potassium-supplemented versus control groups. Potassium supplementation attenuated platelet reactivity, expressed by an increase in EC
50
of platelet aggregation (
P
=0.0005), which was primarily attributable to an increase in EC
50
in whites (
P
=0.0004). Urinary potassium excretion was significantly lower in blacks than in whites under basal conditions and after potassium supplementation. We conclude that potassium supplementation diminishes platelet reactivity, a phenomenon that provides a link between platelet biology and occlusive stroke.
Vanilloid Receptor TRPV1, Sensory C-Fibers, and Vascular Autoregulation
Authors: Scotland Ramona S. , Chauhan Sharmila , Davis Clare , De Felipe Carmen , Hunt Stephen , Kabir Jahangir , Kotsonis Peter , Oh Uhtaek , Ahluwalia Amrita
Published: October 2004

Myogenic constriction describes the innate ability of resistance arteries to constrict in response to elevations in intraluminal pressure and is a fundamental determinant of peripheral resistance and, hence, organ perfusion and systemic blood pressure. However, the receptor/cell-type that senses changes in pressure on the blood vessel wall and the pathway that couples this to constriction of vascular smooth muscle remain unclear. In this study, we show that elevation of intraluminal transmural pressure of mesenteric small arteries in vitro results in a myogenic response that is profoundly suppressed following ablation of sensory C-fiber activity (using in vitro capsaicin desensitization resulted in 72.8±10.3% inhibition, n=8;
P
<0.05). Activation of C-fiber nerve endings by pressure was attributable to stimulation of neuronal vanilloid receptor, TRPV1, because blockers of this channel, capsazepine (71.9±11.1% inhibition, n=9;
P
<0.001) and ruthenium red (46.1±11.7% inhibition, n=4;
P
<0.05), suppressed the myogenic constriction. In addition, this C-fiber dependency is likely related to neuropeptide substance P release and activity because blockade of tachykinin NK
1
receptors (66.3±13.7% inhibition, n=6;
P
<0.001), and not NK2 receptors (n=4, NS), almost abolished the myogenic response. Previous studies support a role for 20-hydroxyeicosatetraenoic acid (20-HETE) in myogenic constriction responses; herein, we show that 20-HETE–induced constriction of mesenteric resistance arteries is blocked by capsazepine. Together, these results suggest that elevation of intraluminal pressure is associated with generation of 20-HETE that, in turn, activates TRPV1 on C-fiber nerve endings resulting in depolarization of nerves and consequent vasoactive neuropeptide release. These findings identify a novel mechanism contributing to Bayliss’ myogenic constriction and highlights an alternative pathway that may be targeted in the therapeutics of vascular disease, such as hypertension, where enhanced myogenic constriction plays a role in the pathogenesis.
Caveolae Localize Protein Kinase A Signaling to Arterial ATP-Sensitive Potassium Channels
Authors: Sampson Laura J. , Hayabuchi Yasunobu , Standen Nick B. , Dart Caroline
Published: October 2004

Arterial ATP-sensitive K
+
(K
ATP
) channels are critical regulators of vascular tone, forming a focal point for signaling by many vasoactive transmitters that alter smooth muscle contractility and so blood flow. Clinically, these channels form the target of antianginal and antihypertensive drugs, and their genetic disruption leads to hypertension and sudden cardiac death through coronary vasospasm. However, whereas the biochemical basis of K
ATP
channel modulation is well-studied, little is known about the structural or spatial organization of the signaling pathways that converge on these channels. In this study, we use discontinuous sucrose density gradients and Western blot analysis to show that K
ATP
channels localize with an upstream signaling partner, adenylyl cyclase, to smooth muscle membrane fractions containing caveolin, a protein found exclusively in cholesterol and sphingolipid-enriched membrane invaginations known as caveolae. Furthermore, we show that an antibody against the K
ATP
pore-forming subunit, Kir6.1 co-immunoprecipitates caveolin from arterial homogenates, suggesting that Kir6.1 and caveolin exist together in a complex. To assess whether the colocalization of K
ATP
channels and adenylyl cyclase to smooth muscle caveolae has functional significance, we disrupt caveolae with the cholesterol-depleting agent, methyl-β-cyclodextrin. This reduces the cAMP-dependent protein kinase A–sensitive component of whole-cell K
ATP
current, indicating that the integrity of caveolae is important for adenylyl cyclase–mediated channel modulation. These results suggest that to be susceptible to protein kinase A–dependent activation, arterial K
ATP
channels need to be localized in the same lipid compartment as adenylyl cyclase; the results also provide the first indication of the spatial organization of signaling pathways that regulate K
ATP
channel activity.
Calcium Dynamics in Cortical Astrocytes and Arterioles During Neurovascular Coupling
Authors: Filosa Jessica A. , Bonev Adrian D. , Nelson Mark T.
Published: October 2004

Neuronal activity in the brain is thought to be coupled to cerebral arterioles (functional hyperemia) through Ca
2+
signals in astrocytes. Although functional hyperemia occurs rapidly, within seconds, such rapid signaling has not been demonstrated in situ, and Ca
2+
measurements in parenchymal arterioles are still lacking. Using a laser scanning confocal microscope and fluorescence Ca
2+
indicators, we provide the first evidence that in a brain slice preparation, increased neuronal activity by electrical stimulation (ES) is rapidly signaled, within seconds, to cerebral arterioles and is associated with astrocytic Ca
2+
waves. Smooth muscle cells in parenchymal arterioles exhibited Ca
2+
and diameter oscillations (“vasomotion”) that were rapidly suppressed by ES. The neuronal-mediated Ca
2+
rise in cortical astrocytes was dependent on intracellular (inositol trisphosphate [IP
3
]) and extracellular voltage-dependent Ca
2+
channel sources. The Na
+
channel blocker tetrodotoxin prevented the rise in astrocytic [Ca
2+
]
i
and the suppression of Ca
2+
oscillations in parenchymal arterioles to ES, indicating that neuronal activity was necessary for both events. Activation of metabotropic glutamate receptors in astrocytes significantly decreased the frequency of Ca
2+
oscillations in parenchymal arterioles. This study supports the concept that astrocytic Ca
2+
changes signal the cerebral microvasculature and indicate the novel concept that this communication occurs through the suppression of arteriolar [Ca
2+
]
i
oscillations and corresponding vasomotion. The full text of this article is available online at http://circres.ahajournals.org.
Angiotensin II Impairs Neurovascular Coupling in Neocortex Through NADPH Oxidase–Derived Radicals
Authors: Kazama Ken , Anrather Josef , Zhou Ping , Girouard Helene , Frys Kelly , Milner Teresa A. , Iadecola Costantino
Published: October 2004

Angiotensin II (Ang II) exerts detrimental effects on cerebral circulation, the mechanisms of which have not been elucidated. In particular, Ang II impairs the increase in cerebral blood flow (CBF) produced by neural activity, a critical mechanism that matches substrate delivery with energy demands in brain. We investigated whether Ang II exerts its deleterious actions by activating Ang II type 1 (AT
1
) receptors on cerebral blood vessels and producing reactive oxygen species (ROS) through NADPH oxidase. Somatosensory cortex CBF was monitored in anesthetized mice by laser-Doppler flowmetry. Ang II (0.25 μg/kg per minute IV) attenuated the CBF increase produced by mechanical stimulation of the vibrissae. The effect was blocked by the AT
1
antagonist losartan and by ROS scavenger superoxide dismutase or tiron and was not observed in mice lacking the gp91
phox
subunit of NADPH oxidase or in wild-type mice treated with the NADPH oxidase peptide inhibitor gp91ds-tat. Ang II increased ROS production in cerebral microvessels, an effect blocked by the ROS scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin and by the NADPH oxidase assembly inhibitor apocynin. Ang II did not increase ROS production in gp91-null mice. Double-label immunoelectron microscopy demonstrated that AT
1
and gp91
phox
immunoreactivities were present in endothelium and adventitia of neocortical arterioles. Collectively, these findings suggest that Ang II impairs functional hyperemia by activating AT
1
receptors and inducing ROS production via a gp91
phox
containing NADPH oxidase. The data provide the mechanistic basis for the cerebrovascular dysregulation induced by Ang II and suggest novel therapeutic strategies to counteract the effects of hypertension on the brain.
Modulation of Cardiac Gap Junction Expression and Arrhythmic Susceptibility
Authors: Danik Stephan B. , Liu Fangyu , Zhang Jie , Suk H. Jacqueline , Morley Gregory E. , Fishman Glenn I. , Gutstein David E.
Published: October 2004

Connexin43 (Cx43), the predominant ventricular gap junction protein, is critical for maintaining normal cardiac electrical conduction, and its absence in the mouse heart results in sudden arrhythmic death. The mechanisms linking reduced Cx43 abundance in the heart and inducibility of malignant ventricular arrhythmias have yet to be established. In this report, we investigate arrhythmic susceptibility in a murine model genetically engineered to express progressively decreasing levels of Cx43. Progressively older cardiac-restricted Cx43 conditional knockout (CKO) mice were selectively bred to produce a heart-specific Cx43-deficient subline (“O-CKO” mice) in which the loss of Cx43 in the heart occurs more gradually. O-CKO mice lived significantly longer than the initial series of CKO mice but still died suddenly and prematurely. At 25 days of age, cardiac Cx43 protein levels decreased to 59% of control values (
P
<0.01), but conduction velocity was not significantly decreased and no O-CKO mice were inducible into sustained ventricular tachyarrhythmias. By 45 days of age, cardiac Cx43 abundance had decreased in a heterogeneous fashion to 18% of control levels, conduction velocity had slowed to half of that observed in control hearts, and 80% of O-CKO mice were inducible into lethal tachyarrhythmias. Enhanced susceptibility to induced arrhythmias was not associated with altered invasive hemodynamic measurements or changes in ventricular effective refractory period. Thus, moderately severe reductions in Cx43 abundance are associated with slowing of impulse propagation and a dramatic increase in the susceptibility to inducible ventricular arrhythmias.
Image Representation by Complex Cell Responses
Authors: Wundrich Ingo J. , Malsburg Christoph von der , Würtz Rolf P.
Published: October 2004

We present an analysis of the representation of images as the magnitudes of their transform with complex-valued Gabor wavelets. Such a representation is a model for complex cells in the early stage of visual processing and of high technical usefulness for image understanding, because it makes the representation insensitive to small local shifts. We show that if the images are band limited and of zero mean, then reconstruction from the magnitudes is unique up to the sign for almost all images.
Maximum Likelihood Estimation of a Stochastic Integrate-and-Fire Neural Encoding Model
Authors: Paninski Liam , Pillow Jonathan W. , Simoncelli Eero P.
Published: October 2004

We examine a cascade encoding model for neural response in which a linear filtering stage is followed by a noisy, leaky, integrate-and-fire spike generation mechanism. This model provides a biophysically more realistic alternative to models based on Poisson (memoryless) spike generation, and can effectively reproduce a variety of spiking behaviors seen in vivo. We describe the maximum likelihood estimator for the model parameters, given only extracellular spike train responses (not intracellular voltage data). Specifically, we prove that the log-likelihood function is concave and thus has an essentially unique global maximum that can be found using gradient ascent techniques. We develop an efficient algorithm for computing the maximum likelihood solution, demonstrate the effectiveness of the resulting estimator with numerical simulations, and discuss a method of testing the model's validity using time-rescaling and density evolution techniques.
A Way to Overcome the Methodological Vicissitudes Involved in Researching Subjectivity
Authors: Giorgi Amedeo
Published: October 2004

Four research strategies currently employed by mainstream psychologists in researching the experiences and behaviors of human subjects are criticized for diminishing the presence of subjectivity. Two perspectives that tend to exaggerate subjectivity are also criticized. A balanced approach to subjectivity is offered that: (1) acknowledges a theoretical perspective that recognizes that there are invisible or nonsensorial characteristics of subjectivity that have to be theoretically appropriated, and (2) that emphasizes the intersubjective dimension as being critical for properly assessing a balanced approach to human subjectivity. A subject-dependent perspective that can efface its own interests is the attitude that is required for the achievement of objectivity.
Protocol Analysis of Couples' Self-reports of Wife Assault: Preliminary Findings
Authors: Campbell Kathryn , Casoni Dianne
Published: October 2004

Sixteen Canadian men and women, part of eight intact couples who had experienced severe and recurrent wife assault, were interviewed individually regarding their worst experience of violence. The self-reports of both spouses of one of these couples is presented and analyzed with a view towards isolating the emerging constituents of their narratives. Additionally, preliminary findings resulting from the analysis of all of the couple's self-reports are presented in the second part of the paper. A gendered reconstruction of their narratives emerges that mirrors the different positions men and women hold in experiences of wife assault. Finally, the main constituents derived from all the participant's selfreports are analyzed and discussed.
The International Criminal Tribunal for Rwanda: A Paper Umbrella in the Rain? Initial Pitfalls and Brighter Prospects
Authors: Maogoto Jackson Nyamuya
Published: October 2004

The tragedy which befell Rwanda in 1994 deserves a special place in the bloodstained pages of history. The Rwandan genocide merits distinction primarily because of its shocking ef ficiency, its scale and its proportional dimensions among the victim population. The Security Council's resolution establishing the ICTR articulates a set of decisions, assumptions, wishes, and objectives. Primarily, the States that voted in favour of the creation of the ICTR indicated that the root of the problem was

individual violations

of international criminal law. Only one State that voted for the resolution did not equate

ipso facto

ICTR actions with justice. That State considered the ICTR only one of the many tasks at hand for the international community. The ICTR was merely a vehicle of justice, 'but it is hardly designed as a vehicle for reconciliation . . . Reconciliation is a much more complicated process' (Czech Republic). Interestingly, Rwanda, which voted against the resolution, spoke of the problem in terms of a

culture of impunity

. The UN paid little to no heed to the subtle, but extremely different way in which the problem was characterized and the implications this would have on the type of tool needed to deal with that problem.
A Framework for Measuring Supercomputer Productivity
Authors: Snir Marc , Bader David A.
Published: October 2004

We propose a framework for measuring the productivity of high performance computing (HPC) systems, based on common economic definitions of productivity and on utility theory. We discuss how these definitions can capture essential aspects of HPC systems, such as the importance of time-to-solution and the trade-off between programming time and execution time. Finally, we outline a research program that would lead to the definition of effective productivity metrics for HPC that fit within the proposed framework.
Reterritorialization and Whispers From the Walls
Authors: Way Jennifer
Published: October 2004

According to Kellie Jones, reterritorialization involves ‘recapturing one’s (combined and various) history, much of which has been dismissed as an insignificant footnote to the dominant culture’. In this essay, I bring artist and photography scholar Deborah Willis’s use of Jones’s concept of reterritorialization to bear on Whispers from the Walls, an installation that Whitfield Lovell created at the University of North Texas Art Gallery in 1999. Chiefly, I explore what kinds and whose histories Whispers from the Walls engaged. In particular, I emphasize contributions that the photographs Lovell studied to create the installation and the objects he included therein made to recovering histories.
Human Well-Being and Social Structures
Authors: Gough Ian
Published: October 2004

There exists a contradiction between the domination of postmodernism and cultural relativism in intellectual life and the universalism and globalism dominant in the real world of institutions and politics. In this topsy-turvy world, core values and needs are relative and local, while means and policies are global and universal. This article contributes to those challenging this world-view. The first part looks at human well-being and contrasts the intellectual case for a universalist understanding of all people’s capabilities and the case for localism, respect for people’s values and knowledges, before exploring theoretical attempts to reconcile the two. The second part turns to the world of institutions and structures. It considers ideas of globalization as a universal trajectory before moving on to defend multi-level and middle-range frameworks. The article concludes by arguing for a clearer distinction between universal needs, local need satisfiers and subjective understandings, together with a comparative middle-range theory to explain contemporary success and failure in improving human well-being.
Universal and Local Understanding of Poverty in Peru
Authors: Altamirano TeóFilo , Copestake James , Figueroa Adolfo , Wright-Revolledo Katie
Published: October 2004

The purpose of this survey of the literature on poverty in Peru is to contribute to universal and interdisciplinary understanding, while at the same time giving due weight to discipline-specific contributions. The first three sections review relevant literature on Peru by economists, social anthropologists and sociologists. The strict positivism of much economic literature renders it susceptible to neglect power relations and assume a benign and universal process of modernization. Anthropologists have revealed the importance of local cultural identity, but at the risk of downplaying universal dimensions of well-being. Sociologists struggle to reconcile a universal analysis of class structure with renewed emphasis on individual and collective agency in adversity. The last section puts forward an integrating theoretical framework centred on the concepts of inclusion and exclusion. In contrast to the ‘tragic optimism’ of Sender this theory of social exclusion can best be summed up as ‘constructive pessimism’.
Cleanness, Pollution and Disgust in Modern Industrial Societies
Authors: Neves Livia Martins Pinheiro
Published: October 2004

The concept of pollution has long been central to theoretical discussions within the traditional anthropological literature. However, this has mainly been within the context of primitive or developing societies and largely concerned the links between pollution and religion and the sacred. In this article, I re-examine the importance that the concept of pollution has for modern industrial societies. I take as my ethnographic reference Brazil, with specific focus on cleaning and laundering practices. Besides being an important criterion in the organization of everyday life, the criterion of pollution has been very resilient to technological changes. Although modern industrial products are available to Brazilian women, these products do not replace pollution criteria with practical and efficient criteria. On the contrary, the use of domestic technologies has helped to refine the concept of ‘pollution’, introducing new forms of classification and separation.