bluuebunny/crossref_metadata_2025 huggingface dataset:
A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus
Authors: Pagel-Langenickel Ines , Schwartz Daniel R. , Arena Ross A. , Minerbi Diane C. , Johnson D. Thor. , Waclawiw Myron A. , Cannon Richard O. , Balaban Robert S. , Tripodi Dorothy J. , Sack Michael N.
Published: September 2007

Skeletal muscle mitochondrial dysfunction is hypothesized to contribute to the pathophysiology of insulin resistance and Type 2 diabetes. Whether thiazolidinedione therapy enhances skeletal muscle mitochondrial function as a component of its insulin-sensitizing effect is unknown. To test this, we evaluated skeletal muscle mitochondria and exercise capacity in Type 2 diabetic subjects with otherwise normal cardiopulmonary function in response to rosiglitazone therapy. Twenty-three subjects were treated for 12 wk and underwent pre- and posttherapy metabolic stress testing and skeletal muscle biopsies. Rosiglitazone significantly ameliorated fasting glucose, insulin, and free fatty acid levels but did not augment the subjects' maximal oxygen consumption (V̇o2max) or their skeletal muscle mitochondrial copy number. The baseline V̇o2max correlated strongly with muscle mitochondrial copy number ( r = 0.56, P = 0.018, n = 17) and inversely with the duration of diabetes ( r = −0.67, P = 0.004, n = 23). Despite the global lack of effect of rosiglitazone-mediated insulin sensitization on skeletal muscle mitochondria, subjects with the most preserved functional capacity demonstrated some plasticity in their mitochondria biology as evidenced by an upregulation of electron transfer chain proteins and in citrate synthase activity. This study demonstrates that the augmentation of skeletal muscle mitochondrial electron transfer chain content and/or bioenergetics is not a prerequisite for rosiglitazone-mediated improved insulin sensitivity. Moreover, in diabetic subjects, V̇o2max reflects the duration of diabetes and skeletal muscle mitochondrial content. It remains to be determined whether longer-term insulin sensitization therapy with rosiglitazone will augment skeletal muscle mitochondrial bioenergetics in those diabetic subjects with relatively preserved basal aerobic capacity.
Triadin is a critical determinant of cellular Ca cycling and contractility in the heart
Authors: Kirchhefer Uwe , Klimas Jan , Baba Hideo A. , Buchwalow Igor B. , Fabritz Larissa , Hüls Marion , Matus Marek , Müller Frank U. , Schmitz Wilhelm , Neumann Joachim
Published: September 2007

Triadin is involved in the regulation of cardiac excitation-contraction coupling. However, the extent of its contribution to the regulation of sarcoplasmic reticulum (SR) Ca release remains unclear, because overexpression of triadin in single-transgenic mice was associated with the downregulation of its homologous protein, junctin. In the present study, this problem was circumvented by cross-breeding of mice with heart-directed overexpression of triadin and junctin (JxT). This resulted in a stable approximately threefold expression of total triadin but unchanged junctin protein. Transgenic mice exhibited cardiac hypertrophy and structural abnormalities of myofibrils. Measurement of cardiac function by echocardiography and edge detection in myocytes revealed an impaired relaxation in JxT mice. The stimulation of β-adrenergic receptors resulted in a depressed contractility and an impaired relaxation in catheterized hearts and myocytes of JxT mice. The use of a maximum stimulation frequency (5 Hz) was associated with both a lower shortening and relengthening in isolated myocytes of JxT mice. The contractile effects in JxT myocytes were paralleled by similar changes of the intracellular Ca concentration ([Ca]i) peak amplitude and Ca transient decay kinetics at basal conditions, under administration of isoproterenol, and with high-frequency stimulation. Finally, we found a higher caffeine-induced [Ca]ipeak amplitude in JxT myocytes. Our data show that the stable expression of triadin, independent of junctin expression, resulted in cardiac hypertrophy, prolonged basal relaxation, a depressed response to β-adrenergic agonists, and altered Ca transients. Thus the maintenance of triadin expression is essential for normal SR Ca cycling and contractile function.
Role of medullary GABA, opioids, and nociceptin in prolonged inhibition of cardiovascular sympathoexcitatory reflexes during electroacupuncture in cats
Authors: Tjen-A-Looi Stephanie C. , Li Peng , Longhurst John C.
Published: September 2007

Electroacupuncture (EA) causes prolonged suppression of reflex elevations in blood pressure for 1–2 h in anesthetized preparations. A long-loop pathway involving the arcuate nucleus (ARC), ventrolateral periaqueductal gray, and rostral ventrolateral medulla (rVLM) is involved in sympathoinhibitory cardiovascular EA effects. However, the mechanisms and locations of the prolonged EA inhibition are unknown. We hypothesized that this effect is mediated through a long-loop pathway involving opioid, nociceptin, and γ-aminobutyric acid (GABA) receptor activation in the rVLM. In anesthetized, ventilated cats application of bradykinin to the gallbladder every 10 min induced consistent reflex increases in blood pressure. Bilateral EA stimulation at the cardiovascular acupoints P5–6 overlying the median nerves reduced the reflex responses for at least 80 min. Bilateral blockade with kynurenic acid in the ARC 60 min after onset of EA inhibition reversed the cardiovascular response, suggesting a role for the ARC in the long-loop pathway during the prolonged inhibitory response. Unilateral microinjection with either an opioid or a GABAAantagonist in rVLM 50–60 min after the beginning of the EA response reversed EA inhibition of the cardiovascular excitatory reflex. Gabazine also reversed EA inhibition of cardiovascular premotor sympathetic rVLM neurons. Conversely, microinjection of a nociceptin/orphanin FQ peptide antagonist did not affect the prolonged inhibitory effect. Thus the ARC, an important component in the long-loop pathway in the EA cardiovascular response, is required for prolonged suppression of reflex cardiovascular excitatory responses by EA. Furthermore, in the rVLM, opioids and GABA, but not nociceptin, participate in the long-term EA-related inhibition of sympathoexcitatory cardiovascular responses.
Effect of pravastatin on sympathetic reinnervation in postinfarcted rats
Authors: Lee Tsung-Ming , Lin Mei-Shu , Chang Nen-Chung
Published: September 2007

We assessed whether pravastatin attenuates cardiac sympathetic reinnervation after myocardial infarction through the activation of ATP-sensitive K+(KATP) channels. Epidemiological studies have shown that men treated with statins appear to have a lower incidence of sudden death than men without statins. However, the specific factor for this has remained disappointingly elusive. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to groups treated with either vehicle, nicorandil (a specific mitochondrial KATPchannel agonist), pinacidil (a nonspecific KATPchannel agonist), pravastatin, glibenclamide (a KATPchannel blocker), or a combination of nicorandil and glibenclamide, pinacidil and glibenclamide, or pravastatin and glibenclamide for 4 wk. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats at the remote zone compared with sham-operated rats (2.54 ± 0.17 vs. 1.26 ± 0.36 μg/g protein, P < 0.0001), consistent with excessive sympathetic reinnervation after infarction. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated factor 43, and neurofilament also confirmed the change of myocardial norepinephrine. This was paralleled by a significant upregulation of tyrosine hydroxylase protein expression and mRNA in vehicle-treated rats, which was reduced after the administration of either nicorandil, pinacidil, or pravastatin. Arrhythmic scores during programmed stimulation in vehicle-treated rats were significantly higher than those treated with pravastatin. In contrast, the beneficial effects of pravastatin were reversed by the addition of glibenclamide, implicating KATPchannels as the relevant target. The sympathetic reinnervation after infarction is modulated by the activation of KATPchannels. Chronic use of pravastatin after infarction, resulting in attenuated sympathetic reinnervation by the activation of KATPchannels, may modify the arrhythomogenic response to programmed electrical stimulation.
Effects of sex differences on constitutive nitric oxide synthase expression and activity in response to pressure overload in rats
Authors: Loyer Xavier , Oliviero Patricia , Damy Thibaud , Robidel Estelle , Marotte Françoise , Heymes Christophe , Samuel Jane-Lise
Published: September 2007

Clinical studies have documented sex differences in left ventricular (LV) hypertrophy patterns, but the mechanisms are so far poorly defined. This study aimed to determine whether 1) severe pressure overload altered expression and/or activity of cardiac constitutive nitric oxide synthase (NOS1 and NOS3) and 2) these changes were modulated according to sex. Analyses were performed 0.4–20 wk after thoracic aortic constriction (TAC) in male and female Wistar rats. Male rats with TAC exhibited early signs of cardiac dysfunction, as shown by echocardiographic and LV end-diastolic pressure measurements, whereas females with TAC exhibited higher LV hypertrophy (+96% vs. males at 20 wk; P < 0.05). After TAC, cardiac NOS1 expression was rapidly induced (0.4 wk) and stable afterward in males ( P < 0.05 vs. sham groups), whereas it was delayed in females. Accordingly, specific NOS1 activity was increased by 2 wk in male rats with TAC (+122%; P < 0.001 vs. sham groups) and only by 20 wk in females (+220%; P < 0.001 vs. sham groups). NOS1 activity was correlated with NOS1 level. Regarding cardiac NOS3, expression was unaffected by TAC, and the decrease in activity observed at early and late times in male and female rats with TAC, respectively, is shown to be related to NOS3 allosteric regulator caveolin-1 level. The data demonstrated a unique sex-dependent regulation of the constitutive NOSs in response to TAC in rats; such a difference might play a role in the sex-dependent adaptability of the heart in response to pressure overload.
Heme oxygenase-1 induction improves ischemic renal failure: role of nitric oxide and peroxynitrite
Authors: Salom Miguel G. , Nieto Cerón Susana , Rodriguez Francisca , Lopez Bernardo , Hernández Isabel , Gil Martínez José , Martínez Losa Adoración , Fenoy Francisco J.
Published: September 2007

The present study evaluated the effects of heme oxygenase-1 (HO-1) induction on the changes in renal outer medullary nitric oxide (NO) and peroxynitrite levels during 45-min renal ischemia and 30-min reperfusion in anesthetized rats. Glomerular filtration rate (GFR), outer medullary blood flow (OMBF), HO and nitric oxide synthase (NOS) isoform expression, and renal low-molecular-weight thiols (–SH) were also determined. During ischemia significant increases in NO levels and peroxynitrite signal were observed (from 832.1 ± 129.3 to 2,928.6 ± 502.0 nM and from 3.8 ± 0.7 to 9.0 ± 1.6 nA before and during ischemia, respectively) that dropped to preischemic levels during reperfusion. OMBF and –SH significantly decreased after 30 min of reperfusion. Twenty-four hours later, an acute renal failure was observed (GFR 923.0 ± 66.0 and 253.6 ± 55.3 μl·min−1·g kidney wt−1 in sham-operated and ischemic kidneys, respectively; P < 0.05). The induction of HO-1 (CoCl2 60 mg/kg sc, 24 h before ischemia) decreased basal NO concentration (99.7 ± 41.0 nM), although endothelial and neuronal NOS expression were slightly increased. CoCl2 administration also blunted the ischemic increase in NO and peroxynitrite (maximum values of 1,315.6 ± 445.6 nM and 6.3 ± 0.5 nA, respectively; P < 0.05), preserving postischemic OMBF and GFR (686.4 ± 45.2 μl·min−1·g kidney wt−1). These beneficial effects of CoCl2 on ischemic acute renal failure seem to be due to HO-1 induction, because they were abolished by stannous mesoporphyrin, a HO inhibitor. In conclusion, HO-1 induction has a protective effect on ischemic renal failure that seems to be partially mediated by decreasing the excessive production of NO with the subsequent reduction in peroxynitrite formation observed during ischemia.
Glutathione suppresses TGF-β-induced PAI-1 expression by inhibiting p38 and JNK MAPK and the binding of AP-1, SP-1, and Smad to the PAI-1 promoter
Authors: Vayalil Praveen K. , Iles Karen E. , Choi Jinah , Yi Ae-Kyung , Postlethwait Edward M. , Liu Rui-Ming
Published: September 2007

Transforming growth factor (TGF)-β upregulates plasminogen activator inhibitor type 1 (PAI-1) in a variety of cell types, and PAI-1 is considered to be an essential factor for the development of fibrosis. Our previous studies demonstrated that TGF-β decreased intracellular glutathione (GSH) content in murine embryonic fibroblasts (NIH/3T3 cells), whereas treatment of the cells with GSH, which restored intracellular GSH concentration, inhibited TGF-β-induced collagen accumulation by blocking PAI-1 expression and enhancing collagen degradation. In the present study, we demonstrate that GSH blocks TGF-β-induced PAI-1 promoter activity in NIH/3T3 cells, which is associated with an inhibition of TGF-β-induced JNK and p38 phosphorylation. Interestingly, although exogenous GSH does not affect phosphorylation and/or nuclear translocation of Smad2/3 and Smad4, it completely eliminates TGF-β-induced binding of transcription factors to not only AP-1 and SP-1 but also Smad cis elements in the PAI-1 promoter. Decoy oligonucleotides (ODN) studies further demonstrate that AP-1, SP-1, and Smad ODNs abrogate the inhibitory effect of GSH on TGF-β-induced PAI-1 promoter activity and inhibit TGF-β-induced expression of endogenous PAI-1. Furthermore, we show that GSH reduces TGF-β-stimulated reactive oxygen species (ROS) signal. Blocking ROS production with diphenyleneiodonium or scavenging ROS with a superoxide dismutase and catalase mimetic MnTBaP dramatically reduces TGF-β-induced p38 and JNK phosphorylation as well as PAI-1 gene expression. In composite, these findings suggest that GSH inhibits TGF-β-stimulated PAI-1 expression in fibroblasts by blocking the JNK/p38 pathway, probably by reducing ROS, which leads to an inhibition of the binding of transcription factors to the AP-1, SP-1, and Smad cis elements in the PAI-1 promoter.
Sterol response element binding protein and thyroid transcription factor-1 (Nkx2.1) regulateAbca3gene expression
Authors: Besnard Valérie , Xu Yan , Whitsett Jeffrey A.
Published: September 2007

The ATP-binding cassette (ABC) ABCA3 gene encodes a lipid transporter critical for surfactant function at birth. To identify transcription factors that regulate ABCA3 expression in the lung, we identified by bioinformatic and functional analyses two positive regulatory regions, located between bp −2591 and −1102 and bp −1102 and +11, relative to the exon 1 of the Abca3 gene promoter. The distal cassette contains consensus sequences predicting binding to lung transcription factors including FOXA2, CCAAT/enhancer binding protein-α (C/EBPα), GATA-6, thyroid transcription factor-1 (TTF-1 or Nkx2.1), and nuclear factor of activated T cells-c3 (NFATc3). The activity of the distal region from bp −2591 to −1102 was assessed in HeLa and mouse lung epithelial MLE-15 cells. FOXA2, C/EBPα, GATA-6, TTF-1, and NFATc3 increased the activity of the Abca3 luciferase construct in a dose-dependent manner. The distal cassette conferred activation by FOXA2, C/EBPα, GATA-6, TTF-1, and NFATc3 in a position- and orientation-independent manner, serving as an enhancer-like regulatory element. The proximal Abca3 promoter region contained multiple sterol responsive element (SRE) binding sites. SRE binding protein (SREBP)-1c significantly increased the activity of the Abca3 luciferase construct in a dose-dependent manner, whereas SREBP-1a and SREBP-2 did not influence the Abca3 promoter activity. Chromatin immunoprecipitation (ChIP) analyses demonstrated the binding of SREBP-1c, C/EBPα, and TTF-1 to their respective regulatory elements. Conditional deletion of SREBP cleavage-activating protein ( Scap) in respiratory epithelial cells in the mouse lung in vivo inhibited the expression of SREBPs in concert with Abca3. Abca3 gene expression is mediated by discrete cis-acting cassettes that mediate pulmonary cell- and lipid-sensitive pathways regulating surfactant homeostasis.
Caveolae facilitate muscarinic receptor-mediated intracellular Ca2+mobilization and contraction in airway smooth muscle
Authors: Gosens Reinoud , Stelmack Gerald L. , Dueck Gordon , Mutawe Mark M. , Hinton Martha , McNeill Karol D. , Paulson Angela , Dakshinamurti Shyamala , Gerthoffer William T. , Thliveris James A. , Unruh Helmut , Zaagsma Johan , Halayko Andrew J.
Published: September 2007

Contractile responses of airway smooth muscle (ASM) determine airway resistance in health and disease. Caveolae microdomains in the plasma membrane are marked by caveolin proteins and are abundant in contractile smooth muscle in association with nanospaces involved in Ca2+homeostasis. Caveolin-1 can modulate localization and activity of signaling proteins, including trimeric G proteins, via a scaffolding domain. We investigated the role of caveolae in contraction and intracellular Ca2+([Ca2+]i) mobilization of ASM induced by the physiological muscarinic receptor agonist, acetylcholine (ACh). Human and canine ASM tissues and cells predominantly express caveolin-1. Muscarinic M3receptors (M3R) and Gαq/11cofractionate with caveolin-1-rich membranes of ASM tissue. Caveolae disruption with β-cyclodextrin in canine tracheal strips reduced sensitivity but not maximum isometric force induced by ACh. In fura-2-loaded canine and human ASM cells, exposure to methyl-β-cyclodextrin (mβCD) reduced sensitivity but not maximum [Ca2+]iinduced by ACh. In contrast, both parameters were reduced for the partial muscarinic agonist, pilocarpine. Fluorescence microscopy revealed that mβCD disrupted the colocalization of caveolae-1 and M3R, but [ N-methyl-3H]scopolamine receptor-binding assay revealed no effect on muscarinic receptor availability or affinity. To dissect the role of caveolin-1 in ACh-induced [Ca2+]iflux, we disrupted its binding to signaling proteins using either a cell-permeable caveolin-1 scaffolding domain peptide mimetic or by small interfering RNA knockdown. Similar to the effects of mβCD, direct targeting of caveolin-1 reduced sensitivity to ACh, but maximum [Ca2+]imobilization was unaffected. These results indicate caveolae and caveolin-1 facilitate [Ca2+]imobilization leading to ASM contraction induced by submaximal concentrations of ACh.
Transiently, paralleled upregulation of arginase and nitric oxide synthase and the effect of both enzymes on the pathology of asthma
Authors: Takemoto Kei , Ogino Keiki , Shibamori Masafumi , Gondo Toshikazu , Hitomi Yoshiaki , Takigawa Tomoko , Wang Da-Hong , Takaki Jiro , Ichimura Hiroshi , Fujikura Yoshihisa , Ishiyama Hironobu
Published: September 2007

Changes in the expression of arginase and their association with nitrosative stress were investigated using an asthmatic model previously established in NC/Nga mice with mite extract. Mite crude extract (100 μg/day) from Dermatophagoides farinae was administered intranasally for 5 consecutive days ( day 0–4), and a single challenge was performed on day 11. On day 12, upregulation of the mRNA expression of inducible types of nitric oxide synthase (iNOS) and increases in immunohistochemical staining for iNOS and nitrotyrosine were observed. However, the level of nitrite + nitrate was unchanged. An increase in enzymatic activity, upregulation of mRNA expression, and immunostaining for arginase I was detected in the lung tissue and serum. Moreover, increases in both arginase I and II were revealed by immunoblotting. Goblet cell hyperplasia in bronchial epithelial cells and increasing collagen synthesis around the bronchus were also observed. These results suggested that an increase in arginase may lead to decreased availability of arginine for nitric oxide synthase and may contribute to the remodeling of the lung.
Chronic paraplegia-induced muscle atrophy downregulates the mTOR/S6K1 signaling pathway
Authors: Dreyer Hans C. , Glynn Erin L. , Lujan Heidi L. , Fry Christopher S. , DiCarlo Stephen E. , Rasmussen Blake B.
Published: September 2007

Ribosomal S6 kinase 1 (S6K1) is a downstream component of the mammalian target of rapamycin (mTOR) signaling pathway and plays a regulatory role in translation initiation, protein synthesis, and muscle hypertrophy. AMP-activated protein kinase (AMPK) is a cellular energy sensor, a negative regulator of mTOR, and an inhibitor of protein synthesis. The purpose of this study was to determine whether the hypertrophy/cell growth-associated mTOR pathway was downregulated during muscle atrophy associated with chronic paraplegia. Soleus muscle was collected from male Sprague-Dawley rats 10 wk following complete T4–T5 spinal cord transection (paraplegic) and from sham-operated (control) rats. We utilized immunoprecipitation and Western blotting techniques to measure upstream [AMPK, Akt/protein kinase B (PKB)] and downstream components of the mTOR signaling pathway [mTOR, S6K1, SKAR, 4E-binding protein 1 (4E-BP1), and eukaryotic initiation factor (eIF) 4G and 2α]. Paraplegia was associated with significant soleus muscle atrophy (174 ± 8 vs. 240 ± 13 mg; P < 0.05). There was a reduction in phosphorylation of mTOR, S6K1, and eIF4G ( P < 0.05) with no change in Akt/PKB or 4E-BP1 ( P > 0.05). Total protein abundance of mTOR, S6K1, eIF2α, and Akt/PKB was decreased, and increased for SKAR ( P < 0.05), whereas 4E-BP1 and eIF4G did not change ( P > 0.05). S6K1 activity was significantly reduced in the paraplegic group ( P < 0.05); however, AMPKα2 activity was not altered (3.5 ± 0.4 vs. 3.7 ± 0.5 pmol·mg−1·min−1, control vs. paraplegic rats). We conclude that paraplegia-induced muscle atrophy in rats is associated with a general downregulation of the mTOR signaling pathway. Therefore, in addition to upregulation of atrophy signaling during muscle wasting, downregulation of muscle cell growth/hypertrophy-associated signaling appears to be an important component of long-term muscle loss.
Undercarboxylated Matrix GLA Protein Levels Are Decreased in Dialysis Patients and Related to Parameters of Calcium-Phosphate Metabolism and Aortic Augmentation Index
Authors: Hermans Marc M.H. , Vermeer Cees , Kooman Jeroen P. , Brandenburg Vincent , Ketteler Markus , Gladziwa Ulrich , Rensma Pieter L. , Leunissen Karel M.L. , Schurgers Leon J.
Published: September 2007

Background: Vascular calcifications are related to cardiovascular mortality and morbidity in dialysis patients. Limited data exist on the role of calcification inhibitors, such as matrix-carboxyglutamic acid protein (MGP) in dialysis patients. Methods: In 120 dialysis patients and 41 age-matched healthy controls, circulating undercarboxylated (uc) MGP levels were measured with a novel ELISA-based competitive assay. The association between ucMGP levels and determinants of bone mineral metabolism, including the calcification inhibitor fetuin-A, was studied. Moreover, the relation between ucMGP levels and arterial stiffness was investigated. Results: The ucMGP level was significantly lower in dialysis patients compared to controls (173 ± 70 vs. 424 ± 126 nmol/l; p < 0.0001). After adjustment for age, sex and duration of dialysis an independent negative association between time-averaged phosphate levels [regression coefficient β with 95% confidence interval = –64 (–107 to –21)] and a positive association between serum ucMGP and fetuin-A [131 (55–208)] was observed. Duration of dialysis was inversely correlated with ucMGP (r = –0.24, p = 0.007). ucMGP levels were not related to high-sensitivity C-reactive protein or time-averaged calcium levels. After adjustment for age, sex, cardiovascular disease, diabetes, height and mean arterial pressure, ucMGP level was negatively associated with the aortic augmentation index [–0.036 (–0.061 to –0.010)] but not with pulse wave velocity or pulse pressure. Conclusion: Significantly lower serum ucMGP levels were observed in dialysis patients compared to healthy controls. ucMGP levels were inversely associated with phosphate and positively associated with serum fetuin-A levels. Furthermore, ucMGP levels were inversely associated with the aortic augmentation index. These data suggest that low ucMGP levels may be a marker of active calcification.
Sudden Cardiac Death in the United States, 1989 to 1998
Authors: Zheng Zhi-Jie , Croft Janet B. , Giles Wayne H. , Mensah George A.
Published: September 2007

Background

Sudden cardiac death (SCD) is a major clinical and public health problem.

Methods and Results

United States (US) vital statistics mortality data from 1989 to 1998 were analyzed. SCD is defined as deaths occurring out of the hospital or in the emergency room or as “dead on arrival” with an underlying cause of death reported as a cardiac disease (ICD-9 code 390 to 398, 402, or 404 to 429). Death rates were calculated for residents of the US aged ≥35 years and standardized to the 2000 US population. Of 719 456 cardiac deaths among adults aged ≥35 years in 1998, 456 076 (63%) were defined as SCD. Among decedents aged 35 to 44 years, 74% of cardiac deaths were SCD. Of all SCDs in 1998, coronary heart disease (ICD-9 codes 410 to 414) was the underlying cause on 62% of death certificates. Death rates for SCD increased with age and were higher in men than women, although there was no difference at age ≥85 years. The black population had higher death rates for SCD than white, American Indian/Alaska Native, or Asian/Pacific Islander populations. The Hispanic population had lower death rates for SCD than the non-Hispanic population. From 1989 to 1998, SCD, as the proportion of all cardiac deaths, increased 12.4% (56.3% to 63.9%), and age-adjusted SCD rates declined 11.7% in men and 5.8% in women. During the same time, age-specific death rates for SCD increased 21% among women aged 35 to 44 years.

Conclusions

SCD remains an important public health problem in the US. The increase in death rates for SCD among younger women warrants additional investigation.
Role of Inducible Nitric Oxide Synthase in the Pulmonary Vascular Response to Birth-Related Stimuli in the Ovine Fetus
Authors: Rairigh Robyn L. , Parker Thomas A. , Ivy D. Dunbar , Kinsella John P. , Fan I-Da , Abman Steven H.
Published: September 2007

Abstract
—To determine whether type II nitric oxide synthase (NOS II) contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) at birth, we studied the effects of selective NOS II antagonists
N
-(3-aminomethyl) benzylacetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselective NOS antagonist, nitro-
l
-arginine (L-NA), during mechanical ventilation with low F
io
2
(<10%), high F
io
2
(100%), and inhaled NO (20 ppm) in 23 near-term fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (
P
<0.05). In control animals, ventilation with low and high F
io
2
decreased PVR by 62% and 85%, respectively. Treatment with AG and 1400W attenuated the fall in PVR by 50% during ventilation with low and high F
io
2
(control versus treatment,
P
<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high F
io
2
to a similar degree as the NOS II antagonists. To test the selectivity of the NOS II antagonists, we studied the effects of acetylcholine and inhaled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not after treatment with nonselective NOS blockade with L-NA. In contrast, the response to inhaled NO was similar between treatment groups. We conclude that selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II activity contributes to NO-mediated pulmonary vasodilation at birth. We additionally speculate that stimulation of the airway epithelium by rhythmic distension and increased F
io
2
may activate NOS II release at birth.
Phosphorylation of Thr
495
Regulates Ca
2+
/Calmodulin-Dependent Endothelial Nitric Oxide Synthase Activity
Authors: Fleming Ingrid , Fisslthaler Beate , Dimmeler Stefanie , Kemp Bruce E. , Busse Rudi
Published: September 2007

Abstract
—The activity of the endothelial nitric oxide synthase (eNOS) can be regulated independently of an increase in Ca
2+
by the phosphorylation of Ser
1177
but results only in a low nitric oxide (NO) output. In the present study, we assessed whether the agonist-induced (Ca
2+
-dependent, high-output) activation of eNOS is associated with changes in the phosphorylation of Thr
495
in the calmodulin (CaM)-binding domain. eNOS Thr
495
was constitutively phosphorylated in porcine aortic endothelial cells and was rapidly dephosphorylated after bradykinin stimulation. In the same cells, bradykinin enhanced the phosphorylation of Ser
1177
, which was maximal after 5 minutes, and abolished by the CaM-dependent kinase II (CaMKII) inhibitor KN-93. Bradykinin also enhanced the association of CaMKII with eNOS. Phosphorylation of Thr
495
was attenuated by the protein kinase C (PKC) inhibitor Ro 31-8220 and after PKC downregulation using phorbol 12-myristate 13-acetate. The agonist-induced dephosphorylation of Thr
495
was completely Ca
2+
-dependent and inhibited by the PP1 inhibitor calyculin A. Little CaM was bound to eNOS immunoprecipitated from unstimulated cells, but the agonist-induced dephosphorylation of Thr
495
enhanced the association of CaM. Mutation of Thr
495
to alanine increased CaM binding to eNOS in the absence of cell stimulation, whereas the corresponding Asp
495
mutant bound almost no CaM. Accordingly, NO production by the Ala
495
mutant was more sensitive to Ca
2+
/CaM than the aspartate mutant. These results suggest that the dual phosphorylation of Ser
1177
and Thr
495
determines the activity of eNOS in agonist-stimulated endothelial cells. Moreover, the dephosphorylation of Thr
495
by PP1 precedes the phosphorylation of Ser
1177
by CaMKII. The full text of this article is available at http://www.circresaha.org.
Vascular Morphogenesis and Remodeling in a Human Tumor Xenograft
Authors: Patan Sybill , Tanda Shigeru , Roberge Sylvie , Jones Rosemary C. , Jain Rakesh K. , Munn Lance L.
Published: September 2007

To determine mechanisms of blood vessel formation and growth in solid tumors, we used a model in which LS174T human colon adenocarcinomas are grown in the isolated ovarian pedicle of nude mice. Reconstruction of 3500 histological serial sections demonstrated that a new vascular network composed of venous-venous loops of varying sizes grows inside the tumor from the wall of the adjacent main vein. Loops elongate and remodel to establish complex loop systems. The mechanisms of loop formation and remodeling correspond to intussusceptive microvascular growth (IMG). In the tissue surrounding the tumor segmentation, another mechanism of IMG is prevalent in venous vessels. Comparison to vascular morphogenesis in the ovariectomized pedicle not only confirms the existence of corresponding mechanisms in both systems, but also reveals numerous sprouts that are superimposed onto loop systems and pathological deviations of loop formation, remodeling, and segmentation in the tumor. These pathological mechanisms interfere with vessel patency that likely cause heterogenous perfusion and hypoxia thus perpetuating angiogenesis. Blood vessel formation based on IMG was also detected in a large thrombus that completely occluded a part of an ovarian artery branch.
cAMP Response Element-Binding Protein Mediates Thrombin-Induced Proliferation of Vascular Smooth Muscle Cells
Authors: Tokunou Tomotake , Ichiki Toshihiro , Takeda Kotaro , Funakoshi Yuko , Iino Naoko , Takeshita Akira
Published: September 2007

Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. Although recent reports have suggested that cAMP response element-binding protein (CREB) is necessary for the survival of neuronal cells, the role of CREB in VSMC proliferation is not determined. We examined the role of CREB in thrombin-induced VSMC proliferation and the effect of thrombin on phosphorylation of CREB at Ser133, which is a critical marker for activation by Western blot analysis. Thrombin induced phosphorylation of CREB in a dose-dependent manner. An oligopeptide, SFLLRN, which activates the thrombin receptor, also induced the phosphorylation of CREB. Inhibition of extracellular signal-regulated protein kinase or inhibition of p38 mitogen-activated protein kinase suppressed the thrombin-induced CREB phosphorylation. Inhibition of the epidermal growth factor receptor by AG1478 also inhibited the thrombin-induced CREB phosphorylation. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced c-
fos
mRNA expression and incorporation of [
3
H]thymidine and [
3
H]leucine. These results suggest that CREB-dependent gene transcription plays a critical role in thrombin-induced proliferation and hypertrophy of VSMCs. Transactivation of the epidermal growth factor receptor and 2 mitogen-activated protein kinase pathways are involved in this process. CREB may be a novel transcription factor mediating the vascular remodeling process induced by thrombin.
Effects of Alcohol Reduction on Blood Pressure
Authors: Xin Xue , He Jiang , Frontini Maria G. , Ogden Lorraine G. , Motsamai Oaitse I. , Whelton Paul K.
Published: September 2007

Alcohol drinking has been associated with increased blood pressure in epidemiological studies. We conducted a meta-analysis of randomized controlled trials to assess the effects of alcohol reduction on blood pressure. We included 15 randomized control trials (total of 2234 participants) published before June 1999 in which alcohol reduction was the only intervention difference between active and control treatment groups. Using a standard protocol, information on sample size, participant characteristics, study design, intervention methods, duration, and treatment results was abstracted independently by 3 investigators. By means of a fixed-effects model, findings from individual trials were pooled after results for each trial were weighted by the inverse of its variance. Overall, alcohol reduction was associated with a significant reduction in mean (95% confidence interval) systolic and diastolic blood pressures of −3.31 mm Hg (−2.52 to −4.10 mm Hg) and −2.04 mm Hg (−1.49 to −2.58 mm Hg), respectively. A dose-response relationship was observed between mean percentage of alcohol reduction and mean blood pressure reduction. Effects of intervention were enhanced in those with higher baseline blood pressure. Our study suggests that alcohol reduction should be recommended as an important component of lifestyle modification for the prevention and treatment of hypertension among heavy drinkers.
Poisonous Effects of Asteroid Impacts or Nuclear Explosions in the Western Regions of the Black Sea
Authors: Badescu Viorel
Published: September 2007

The impact of an asteroid or a very large nuclear explosion in the Black Sea may cause a poisonous hydrogen sulfide gas release into the atmosphere. Some effects of this phenomenon on the western Black Sea coasts are evaluated in this paper. Two simple models are proposed to describe the generation of the H2S cloud. The wind speed plays an important role in H2S cloud dynamics. The land surface area covered by the H2S cloud generated by a 1000-m-sized asteroid during the run-in ranges between about 4480 and 9600 km2. This may affect up to 230 000 people. In the case of a 70-m-sized asteroid, the cloud covers between 70 and 210 km2 of land. This may affect between about 1600 and 5100 people. The evaluations do not include the population of the towns on the seashore and may be a few times underestimated for some particular wind directions. These effects are briefly compared with more usual effects associated with asteroids impacting the sea, such as shock waves and tsunamis. Nuclear explosions of 1 and 50 Mton TNT may be assimilated to the impact by asteroids of about 33- and 120-m diameter, respectively.
The Turbulent Oscillator: A Mechanism of Low-Frequency Variability of the Wind-Driven Ocean Gyres
Authors: Berloff P. , Hogg A. Mc C. , Dewar W.
Published: September 2007

Intrinsic low-frequency variability is studied in the idealized, quasigeostrophic, midlatitude, wind-driven ocean gyres operating at large Reynolds number. A robust decadal variability mode driven by the transient mesoscale eddies is found and analyzed. The variability is a turbulent phenomenon, which is driven by the competition between the eddy rectification process and the potential vorticity anomalies induced by changes of the intergyre transport.
Three-Dimensional Tidal Flow in an Elongated, Rotating Basin
Authors: Winant Clinton D.
Published: September 2007

The three-dimensional tidal circulation in an elongated basin of arbitrary depth is described with a linear, constant-density model on the f plane. Rotation fundamentally alters the lateral flow, introducing a lateral recirculation comparable in magnitude to the axial flow, as long as friction is not too large. This circulation is due to the imbalance between the cross-channel sea level gradient, which is in near-geostrophic balance with the Coriolis acceleration associated with the vertically averaged axial flow, and the Coriolis acceleration associated with the vertically sheared axial flow. During flood condition, for example, the lateral Coriolis acceleration near the surface exceeds the pressure gradient, tending to accelerate the lateral flow, while the converse is true near the bottom. As a result, with rotation, fluid parcels tend to corkscrew into and out of the basin in a tidal period. The axial flow is only weakly modified by rotation. When friction is small, the axial velocity is uniform in each section, except in a narrow bottom boundary layer where it decreases to zero. The boundary layer thickness increases with friction, so that with moderate or large friction, axial velocities are sheared from bottom to surface. When friction is large, the local and Coriolis accelerations are both small and the dynamics are governed by a balance between friction and the pressure gradient.
Impact of Labrador Sea Convection on the North Atlantic Meridional Overturning Circulation
Authors: Pickart Robert S. , Spall Michael A.
Published: September 2007

The overturning and horizontal circulations of the Labrador Sea are deduced from a composite vertical section across the basin. The data come from the late-spring/early-summer occupations of the World Ocean Circulation Experiment (WOCE) AR7W line, during the years 1990–97. This time period was chosen because it corresponded to intense wintertime convection—the deepest and densest in the historical record—suggesting that the North Atlantic meridional overturning circulation (MOC) would be maximally impacted. The composite geostrophic velocity section was referenced using a mean lateral velocity profile from float data and then subsequently adjusted to balance mass. The analysis was done in depth space to determine the net sinking that results from convection and in density space to determine the diapycnal mass flux (i.e., the transformation of light water to Labrador Sea Water). The mean overturning cell is calculated to be 1 Sv (1 Sv ≡ 106 m3 s−1), as compared with a horizontal gyre of 18 Sv. The total water mass transformation is 2 Sv. These values are consistent with recent modeling results. The diagnosed heat flux of 37.6 TW is found to result predominantly from the horizontal circulation, both in depth space and density space. These results suggest that the North Atlantic MOC is not largely impacted by deep convection in the Labrador Sea.
Are Less-Involved Voters the Key to Win Elections?
Authors: De Sio Lorenzo
Published: September 2007

The literature highlights how different individual levels of political interest and knowledge matter for political attitudes and behavior. A logical-quantitative voting model is thus proposed for a two-party system, based on voters' left—right ideological positions and their degree of political involvement. The model hypothesizes that although more involved voters generally behave in accordance with their ideological orientation, those who are less involved do not. Moreover, the latter tend to be more undecided and therefore likely to be more strongly influenced by campaign activities. This model is then applied to survey data regarding the 2001 Italian general elections. Results confirm the hypotheses and show that the most competitive area is ideologically a narrow centrist area for very involved citizens, becoming wider as the level of involvement decreases. Separate analyses are carried out for different geopolitical areas of the country, with results fitting the political history of these areas.
Political Leadership and the Emergence of Radical Mass Movements in Democracy
Authors: Pappas Takis S.
Published: September 2007

The perception of liberal democracy as a solidly institutionalized system in which opposition forces moderately compete with legitimate authority is so fixed that people are often surprised when mass radicalism emerges. Why, when, and how do radical mass movements emerge in pluralist (or semipluralist) political systems? The article, by linking radical action at the mass level with strategic choices at the elite level, argues in favor of an explanation based on symbolic framing processes. Radical mass action is best explained by the symbolic-cum-strategic action of individual political entrepreneurs employing specific frames to mobilize large masses of people. The argument is empirically clarified by the examination of three cases in which mass radicalism occurred in recent decades (Greece, Yugoslavia, Venezuela) and is then counterfactually tested in six cases of nonoccurrence (Spain, Portugal, Bulgaria, Romania, Colombia, Ecuador). The present analysis also points to a novel theorization of political charisma and charismatic leadership.
End-of-Life Content in Comprehensive Cancer Control Plans: A Systematic Review
Authors: Theis Kristina A. , Rao Jaya K. , Anderson Lynda A. , Thompson PerStephanie M.
Published: September 2007

A recent project to deFine public health priorities For end oF liFe (EOL) recommends incorporating EOL principles in all state/territory/tribe Comprehensive Cancer Control (CCC) Plans. The degree to which EOL content is currently included in CCC Plans was assessed through a systematic review oF CCC Plans, examining keywords, deFinitions, topics, data, goals, and strategies. Forty-Five plans (42 state, 3 tribal) were eligible. Forty-one CCC Plans (91%) included the keyword “end-oF-liFe.” EOL goals were most oFten categorized as use oF care, access to care, and awareness oF EOL issues among patients/public and providers. The top EOL strategies were research, provider education, and patient/public education. The results establish a baseline oF EOL content in CCC Plans and should help improve assistance in Future CCC planning eFForts.
Mini-Suffering State Examination Scale: Possible Key Criterion for 6-Month Survival and Mortality of Critically Ill Dementia Patients
Authors: Zvi Aminoff Bechor
Published: September 2007

Six months of survival as a key criterion is extremely important for decision making in enrollment of critically ill patients to palliative settings. This was a prospective cohort study with 6 months of follow-up during a 24-month period performed in the Division of Geriatric Medicine in a tertiary general hospital. One-hundred three consecutively admitted, bedridden patients with end-stage dementia were evaluated. The Mini-Suffering State Examination scale was performed. Interrelations between the Mini-Suffering State Examination score at admission and 6-month survival and mortality were evaluated. A significant difference was proven among survival curves of subgroups of patients according to the mini scores (0-3, 4-6, 7-10). Survival was shorter and mortality higher in patients with a high Mini-Suffering State Examination score, as shown by the Kaplan-Meier method using the log rank ( P = .001) and Breslow tests ( P = .001). The Mini-Suffering State Examination scale is useful for predicting the last 6 months of survival and mortality of end-stage dementia patients.
Incidence and Management of Phantom Limb Pain According to World Health Organization Analgesic Ladder in Amputees of Malignant Origin
Authors: Mishra Seema , Bhatnagar Sushma , Gupta Deepak , Diwedi Alok
Published: September 2007

Antidepressants and anticonvulsants are currently considered to be the drug treatment of choice for neuropathic pain. Opioids are effective in relieving neuropathic pain, including phantom pain in the early postoperative course. The present study of 42 cancer patients with limb amputation was conducted to determine the incidence of phantom limb pain and phantom sensation and to test the utility of the World Health Organization 3-step analgesic ladder in phantom limb pain management. Patients were monitored monthly for the first 2 months postoperatively and every 2 months thereafter for 2 years. The World Health Organization analgesic ladder was followed for pain management. The patients complaining of phantom sensation, phantom pain, and stump pain decreased from 69%, 60%, and 31%, respectively, at 1 month to 32%, 32%, and 5%, at the end of 2 years with the addition of opioids. The World Health Organization analgesic ladder played significant role in phantom limb pain management.
Needs of Elderly Patients in Palliative Care
Authors: Wijk Helle , Grimby Agneta
Published: September 2007

A pilot study on elderly patients' end-of-life needs was performed at a Swedish geriatric palliative ward. Thirty patients (15 men and 15 women; mean age, 79 years) with a primary diagnosis of cancer and admitted for palliative care were interviewed by a nurse using semistructured interviews. The study included demographic data, physical and psychologic status, and naming and ranking of individual needs. Elimination of physical pain was ranked as the primary need of half of the patients. Only when pain was eliminated or absent did other important needs (psychological, social, spiritual) appear frequently.
Does the Messenger Matter? Candidate-Media Agenda Convergence and Its Effects on Voter Issue Salience
Authors: Hayes Danny
Published: September 2007

Though research has shown that candidates and the media can influence the importance voters ascribe to political issues, little work has sought to test the interactive agenda-setting effects of each—in particular, to determine whether the ability of candidates to set the public's agenda depends on the media's willingness to reflect their issue emphases. Using an experiment conducted during the early stages of the 2006 Texas gubernatorial election, the author shows that candidate attempts to influence voter issue salience are most effective when the media focus on the same topics. The findings suggest the value for candidates of enlisting the news media in helping to pass their messages along and serve as a point of departure for more work on the influence of candidate-media agenda convergence.