bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells
Authors: Xu Qin , Ohara Noriyuki , Liu Jin , Nakabayashi Koji , DeManno Deborah , Chwalisz Kristof , Yoshida Shigeki , Maruo Takeshi
Published: July 2007

A recent clinical trial (Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. Fertil Steril 87: 1399–1412, 2007) has demonstrated that the selective progesterone receptor modulator asoprisnil efficiently causes the shrinkage of uterine leiomyoma. The present study was conducted to examine whether asoprisnil elicits endoplasmic reticulum (ER) stress-induced apoptosis in cultured human uterine leiomyoma cells. After subculture in phenol red-free DMEM supplemented with 10% FBS for 120 h, cultured cells were stepped down to serum-free conditions with or without graded concentrations of asoprisnil. ER stress-associated and apoptosis-related proteins were assessed by reverse transcription-PCR analysis or Western blot analysis. RNA interference of growth-arrest- and DNA-damage-inducible gene 153 ( GADD153) was performed using small interfering RNA. Terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end labeling (TUNEL)-positive rates were assessed by TUNEL assay. Compared with untreated control cultures, treatment with 10−7 M asoprisnil significantly ( P < 0.05) increased the protein contents of ubiquitin at 2 h and phospho-double-stranded RNA-activated protein kinase-like ER kinase, phospho-eukaryotic initiation factor 2α, activating transcription factor 4, and glucose-regulated protein 78 kDa at 4 h, followed by the significant ( P < 0.05) increase in GADD153 protein content at 6 h and cleaved poly(adenosine 5′-diphosphate ribose)polymerase (PARP) at 8 h. RNA interference of GADD153 suppressed protein contents of asoprisnil-induced cleaved PARP, Bax, Bak, GADD34, and tribbles-related protein 3 (TRB3) and TUNEL-positive rate but attenuated asoprisnil-induced reduction in Bcl-2 protein content in cultured leiomyoma cells. These results suggest that asoprisnil elicits ER stress-induced apoptosis in cultured leiomyoma cells and that GADD153 plays a role in asoprisnil-induced apoptosis by modulating the Bcl-2 family of proteins, GADD34, and TRB3.
Pain sensations to the cold pressor test in normally menstruating women: comparison with men and relation to menstrual phase and serum sex steroid levels
Authors: Stening Kent , Eriksson Olle , Wahren LisKarin , Berg Göran , Hammar Mats , Blomqvist Anders
Published: July 2007

The role of gonadal hormones on pain sensations was investigated in normally menstruating women ( n = 16) using the cold pressor test. Tolerance time, pain threshold, and pain intensity were examined once a week during a 4-wk period, and serum concentrations of 17β-estradiol and progesterone were determined at each test session, which were classified into the early follicular phase, late follicular phase, early luteal phase, and late luteal phase, as determined by the first day of menses and the actual hormone levels recorded. A group of men ( n = 10) of the same age interval was examined for comparison. The data show that pain threshold was reduced during the late luteal phase compared with the late follicular phase, and hormone analyses showed significant positive correlation between the progesterone concentration and lowered pain threshold and increasing pain intensity. Hormone analysis also showed an interaction between S-estradiol and S-progesterone on pain intensity, demonstrating that the increased perceived pain intensity that was associated with high progesterone concentrations was significantly reduced with increasing levels of estradiol. While no statistically significant sex differences in pain measurements were found, women displayed much more pronounced, and statistically significant, session-to-session effects than men, with increased pain threshold and decreased pain intensity with each test session. Hence, these data suggest that the changes in the serum concentration of gonadal hormones that occur during the menstrual cycle influence pain sensations elicited by noxious tonic cold stimulation and show that adaptation to the cold pressor test may be sex dependent.
Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis
Authors: Chen Ping , Guo Austin M. , Edwards Paul A. , Trick Gary , Scicli A. Guillermo
Published: July 2007

We studied whether angiotensin II (ANG II) via superoxide may contribute to retinal leukostasis and thus to the pathogenesis of retinopathies. We studied: 1) whether intravitreal ANG II induces retinal leukostasis that is altered by antioxidants or by apocynin, a NAD(P)H oxidase inhibitor and 2) whether retinal leukostasis induced by diabetes in rats is also altered by these treatments. Rats were injected intravitreally with ANG II (20 μg in 2 μl), and divided into the following three groups: 1) untreated; 2) treated with tempol doses (∼3 mM/day) and N-acetylcysteine (NAC; ∼1 g·kg−1·day−1); and 3) treated with apocynin (∼2 mM/day), both in the drinking water. Rats with streptozotocin-induced diabetes were similarly treated. Leukostasis was evaluated 48 h after ANG II or 2 wk after diabetes induction. ANG II increased retinal leukostasis from 0.3 ± 0.5 to 3.7 ± 0.4 leukocytes/ mm2 ( P < 0.01), and these changes were markedly decreased by treatment with tempol + NAC or apocynin, and also by a blocking antibody against vascular endothelial growth factor given intravitreally ( P < 0.01). In addition, incubation of dihydroethidium-loaded retina sections with ANG II caused marked increase in superoxide formation. Compared with normal controls, retinal leukostasis in diabetic rats markedly increased from 0.2 ± 0.3 to 3.8 ± 0.1 leukocytes/mm2 ( P < 0.01). Diabetic retinal leukostasis was also decreased by treatment with tempol-NAC and normalized by apocynin. Thus increases in intravitreal ANG II can induce retinal leukostasis, which appears to be mediated via increasing superoxide generation by NAD(P)H oxidase, and by VEGF. The activity of NAD(P)H oxidase is required for leukostasis to occur in the diabetic retina.
Neurotrophic Factors Promote and Enhance Locomotor Recovery in Untrained Spinalized Cats
Authors: Boyce Vanessa S. , Tumolo Maureen , Fischer Itzhak , Murray Marion , Lemay Michel A.
Published: July 2007

In spinal cats, locomotor recovery without rehabilitation is limited, but weight-bearing stepping returns with treadmill training. We studied whether neurotrophins administered to the injury site also restores locomotion in untrained spinal cats and whether combining both neurotrophins and training further improves recovery. Ordinary rat fibroblasts or a mixture of fibroblasts secreting brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) (Fb-NTF) were grafted into T12 spinal transection sites. Cats with each type of transplant were divided into two groups: one receiving daily training and the other receiving no training. As expected, trained cats with/without neurotrophin-producing transplants could step on the treadmill. Untrained cats without neurotrophin-producing transplants could not locomote. However, untrained cats with neurotrophin-secreting transplants performed plantar weight-bearing stepping at speeds up to 0.8 m/s as early as 2 wk after transection. Locomotor capability and stance lengths in these animals were similar to those in animals receiving training alone, suggesting that administration of BDNF/NT-3 was equivalent to treadmill training in restoring locomotion in chronically spinalized cats. Cats receiving both interventions showed the greatest improvement in step length. Anatomical evaluation indicated that all transections were complete and that axons did not enter the cord caudal to the graft. Thus BDNF/NT-3 secreting fibroblasts were equivalent to training in their ability to engage the locomotor circuitry in chronic spinal cats. Furthermore, the rapid time-course of recovery and the absence of axonal growth through the transplants indicate that the restorative mechanisms were not related to supraspinal axonal growth. Finally, the results show that transplants beneficial in rodents are applicable to larger mammals.
Laparoscopically Guided Uterine Entry for Fetoscopy in Twin-to-Twin Transfusion Syndrome with Completely Anterior Placenta: A Novel Technique
Authors: Middeldorp Johanna M. , Lopriore Enrico , Sueters Marieke , Jansen Frank W. , Ringers Jan , Klumper Frans J.C.M. , Oepkes Dick , Vandenbussche Frank P.H.A.
Published: July 2007

Objective: Laser coagulationof anastomotic vessels on the placental surface is the treatment of choice in severe second trimester twin-to-twin transfusion syndrome (TTTS). This procedure is associated with technical difficulties when the placenta is located on the anterior side of the uterus. We describe a novel technique for fetoscopy in TTTS with completely anterior placenta where laparoscopy is used to guide safe percutaneous insertion of the fetoscope through the lateral abdominal wall and the dorsal side of the uterus. Methods: Prospective controlled series of 16 TTTS pregnancies with completely anterior placenta (study group) treated with this novel technique. Studied outcomes were technical result of the procedure and perinatal survival. Outcome in the study group was compared with outcome of 49 TTTS pregnancies treated with conventional percutaneous fetoscopic laser without laparoscopy, 9 of these with partially anterior placenta (control group A) and 40 with lateral or posterior placenta (control group B). Results: In the study group, the procedure-related complication rate was 25% (4/16). In 1 case, uterine entry of the fetoscope from the lateral abdominal wall was not possible due to complex bowel adhesions. In 3 patients, intra-amniotic haemorrhage occurred after fetoscopic entry, preventing complete laser coagulation of anastomoses. One of these patients required 2 units of blood transfusion. The procedure-related complication rate in control groups A and B was 22% (2/9) and 5% (2/40), respectively (intra-amniotic haemorrhage n = 3, severe leakage of amniotic fluid into the peritoneal cavity, n = 1). Perinatal survival in the study group, control group A and control group B was 63% (20/32), 78% (14/18) and 70% (56/80), respectively. Conclusion: Combined laparoscopy and fetoscopy is a novel technique that enables safe uterine entry and creates optimal visualisation for laser coagulation of inter-twin anastomoses in TTTS pregnancies with completely anterior placenta. The procedure-related complication rate and perinatal survival rate were similar compared to the conventional percutaneous technique. Procedure-related complications occur more often with partially or completely anterior placenta.
Successful Intrauterine Intracardiac Transfusion in Monochorionic Twins Affected by Parvovirus B19
Authors: von Kaisenberg Constantin S. , Grebe Sandra , Schleider Stephanie , Kühling-von Kaisenberg Heidi , Venhoff Lars , Meinhold-Heerlein Ivo
Published: July 2007

Objectives: To assess the possibility to correct for fetal anemia using an intracardiac approach in twin pregnancies affected by fetal Parvovirus B19 infection. Methods: A monochorionic twin pregnancy affected by fetal Parvovirus B19 infection and hydrops was treated using an intraabdominal approach and by intracardiac transfusions. Access to the umbilical cord was not possible. Results: In one fetus, hydrops resolved after intraabdominal transfusions, in the other however, hydrops was progressive. After intracardiac transfusions, both fetuses normalized. Conclusions: In multiple gestation affected by anemia, intracardiac transfusion is a possible and alternative technique, if access to the cord is impossible.
Utility of Doppler Echocardiography and Tissue Doppler Imaging in the Estimation of Diastolic Function in Heart Failure With Normal Ejection Fraction
Authors: Kasner Mario , Westermann Dirk , Steendijk Paul , Gaub Regina , Wilkenshoff Ursula , Weitmann Kerstin , Hoffmann Wolfgang , Poller Wolfgang , Schultheiss Heinz-Peter , Pauschinger Matthias , Tschöpe Carsten
Published: July 2007

Background—

Various conventional and tissue Doppler echocardiographic indexes were compared with pressure–volume loop analysis to assess their accuracy in detecting left ventricular (LV) diastolic dysfunction in patients with heart failure with normal ejection fraction (HFNEF).

Methods and Results—

Diastolic dysfunction was confirmed by pressure–volume loop analysis obtained by conductance catheter in 43 patients (19 men) with HFNEF. Their Doppler indexes were compared with those of 12 control patients without heart failure symptoms and with normal ejection fraction. Invasively measured indexes for diastolic relaxation (τ, dP/dt
min
), LV end-diastolic pressure, and LV end-diastolic pressure–volume relationship (stiffness, b [dP/dV], and stiffness constant, β) were correlated with several conventional mitral flow and tissue Doppler imaging indexes. Conventional Doppler indexes correlated moderately with the degree of LV relaxation index, τ (E/A:
r
=−0.36,
P
=0.013; isovolumic relaxation time:
r
=0.31,
P
=0.040) and b (deceleration time:
r
=0.39,
P
=0.012) but not with β, in contrast to the tissue Doppler imaging indexes E’/A’
lateral
(
r
=−0.37,
P
=0.008) and E/E’
lateral
(
r
=0.53,
P
<0.001). Diastolic dysfunction was detected in 70% of the HFNEF patients by mitral flow Doppler but in 81% and 86% by E’/A’
lateral
, and E/E’
lateral
, respectively.

Conclusions—

Of all echocardiographic parameters investigated, the LV filling index E/E’
lateral
was identified as the best index to detect diastolic dysfunction in HFNEF in which the diagnosis of diastolic dysfunction was confirmed by conductance catheter analysis. We recommend its use as an essential tool for noninvasive diagnostics of diastolic function in patients with HFNEF.
A Decade of Short-Term Outcomes in Post–Cardiac Surgery Ventricular Assist Device Implantation
Authors: Hernandez Adrian F. , Grab Joshua D. , Gammie James S. , O’Brien Sean M. , Hammill Bradley G. , Rogers Joseph G. , Camacho Margarita T. , Dullum Mercedes K. , Ferguson T. Bruce , Peterson Eric D.
Published: July 2007

Background—

Previous studies showed 75% mortality before hospital discharge in patients with a ventricular assist device (VAD) placed for post–cardiac surgery shock. We examined a large national clinical database to assess trends in the incidence of post–cardiac surgery shock requiring VAD implantation, survival rates, and risk factors for mortality.

Methods and Results—

We identified patients undergoing a VAD procedure after cardiac surgery at US hospitals participating in the Society of Thoracic Surgeons’ National Cardiac Database during the years 1995 to 2004. Baseline characteristics and operative outcomes were analyzed in 2.5-year increments. Logistic regression modeling was performed to provide risk-adjusted operative mortality and morbidity odds ratios. A total of 5735 patients had a VAD placed during the 10-year period (0.3% cardiac surgeries). Overall survival rate to discharge after VAD placement was 54.1%. With the earliest period (January 1995 through June 1997) used as reference, the mortality odds ratio declined to 0.72 (July 1997 through December 1999) and eventually to 0.41 (July 2002 through December 2004;
P
<0.0001). The combined mortality/morbidity odds ratio also declined, to 0.84 and 0.48 over identical periods (
P
<0.0001). Preoperative characteristics associated with increased mortality were urgency of procedure, reoperation, renal failure, myocardial infarction, aortic stenosis, female sex, race, peripheral vascular disease, New York Heart Association class IV, cardiogenic shock, left main coronary stenosis, and valve procedure (c index=0.755).

Conclusions—

After adjustment for clinical characteristics of patients requiring mechanical circulatory support, rates of survival to hospital discharge have improved dramatically. Insertion of a VAD for post–cardiac surgery shock is an important therapeutic intervention that can salvage most of these patients.
Soft Drink Consumption and Risk of Developing Cardiometabolic Risk Factors and the Metabolic Syndrome in Middle-Aged Adults in the Community
Authors: Dhingra Ravi , Sullivan Lisa , Jacques Paul F. , Wang Thomas J. , Fox Caroline S. , Meigs James B. , D’Agostino Ralph B. , Gaziano J. Michael , Vasan Ramachandran S.
Published: July 2007

Background—

Consumption of soft drinks has been linked to obesity in children and adolescents, but it is unclear whether it increases metabolic risk in middle-aged individuals.

Methods and Results—

We related the incidence of metabolic syndrome and its components to soft drink consumption in participants in the Framingham Heart Study (6039 person-observations, 3470 in women; mean age 52.9 years) who were free of baseline metabolic syndrome. Metabolic syndrome was defined as the presence of ≥3 of the following: waist circumference ≥35 inches (women) or ≥40 inches (men); fasting blood glucose ≥100 mg/dL; serum triglycerides ≥150 mg/dL; blood pressure ≥135/85 mm Hg; and high-density lipoprotein cholesterol <40 mg/dL (men) or <50 mg/dL (women). Multivariable models included adjustments for age, sex, physical activity, smoking, dietary intake of saturated fat, trans fat, fiber, magnesium, total calories, and glycemic index. Cross-sectionally, individuals consuming ≥1 soft drink per day had a higher prevalence of metabolic syndrome (odds ratio [OR], 1.48; 95% CI, 1.30 to 1.69) than those consuming <1 drink per day. On follow-up (mean of 4 years), new-onset metabolic syndrome developed in 765 (18.7%) of 4095 participants consuming <1 drink per day and in 474 (22.6%) of 2059 persons consuming ≥1 soft drink per day. Consumption of ≥1 soft drink per day was associated with increased odds of developing metabolic syndrome (OR, 1.44; 95% CI, 1.20 to 1.74), obesity (OR, 1.31; 95% CI, 1.02 to 1.68), increased waist circumference (OR, 1.30; 95% CI, 1.09 to 1.56), impaired fasting glucose (OR, 1.25; 95% CI, 1.05 to 1.48), higher blood pressure (OR, 1.18; 95% CI, 0.96 to 1.44), hypertriglyceridemia (OR, 1.25; 95% CI, 1.04 to 1.51), and low high-density lipoprotein cholesterol (OR, 1.32; 95% CI 1.06 to 1.64).

Conclusions—

In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors.
Laminin-α4 and Integrin-Linked Kinase Mutations Cause Human Cardiomyopathy Via Simultaneous Defects in Cardiomyocytes and Endothelial Cells
Authors: Knöll Ralph , Postel Ruben , Wang Jianming , Krätzner Ralph , Hennecke Gerrit , Vacaru Andrei M. , Vakeel Padmanabhan , Schubert Cornelia , Murthy Kenton , Rana Brinda K. , Kube Dieter , Knöll Gudrun , Schäfer Katrin , Hayashi Takeharu , Holm Torbjorn , Kimura Akinori , Schork Nicholas , Toliat Mohammad Reza , Nürnberg Peter , Schultheiss Heinz-Peter , Schaper Wolfgang , Schaper Jutta , Bos Erik , Hertog Jeroen Den , van Eeden Fredericus J.M. , Peters Peter J. , Hasenfuss Gerd , Chien Kenneth R. , Bakkers Jeroen
Published: July 2007

Background—

Extracellular matrix proteins, such as laminins, and endothelial cells are known to influence cardiomyocyte performance; however, the underlying molecular mechanisms remain poorly understood.

Methods and Results—

We used a forward genetic screen in zebrafish to identify novel genes required for myocardial function and were able to identify the lost-contact (
loc
) mutant, which encodes a nonsense mutation in the integrin-linked kinase (
ilk
) gene. This
loc/ilk
mutant is associated with a severe defect in cardiomyocytes and endothelial cells that leads to severe myocardial dysfunction. Additional experiments revealed the epistatic regulation between laminin-α4 (Lama4), integrin, and Ilk, which led us to screen for mutations in the human
ILK
and
LAMA4
genes in patients with severe dilated cardiomyopathy. We identified 2 novel amino acid residue–altering mutations (2828C>T [Pro943Leu] and 3217C>T [Arg1073X]) in the integrin-interacting domain of the
LAMA4
gene and 1 mutation (785C>T [Ala262Val]) in the
ILK
gene. Biacore quantitative protein/protein interaction data, which have been used to determine the equilibrium dissociation constants, point to the loss of integrin-binding capacity in case of the Pro943Leu (
K
d
=5±3 μmol/L) and Arg1073X LAMA4 (
K
d
=1±0.2 μmol/L) mutants compared with the wild-type LAMA4 protein (
K
d
=440±20 nmol/L). Additional functional data point to the loss of endothelial cells in affected patients as a direct consequence of the mutant genes, which ultimately leads to heart failure.

Conclusions—

This is the first report on mutations in the laminin, integrin, and ILK system in human cardiomyopathy, which has consequences for endothelial cells as well as for cardiomyocytes, thus providing a new genetic basis for dilated cardiomyopathy in humans.
Percutaneous Transarterial Aortic Valve Replacement in Selected High-Risk Patients With Aortic Stenosis
Authors: Webb John G. , Pasupati Sanjeevan , Humphries Karin , Thompson Christopher , Altwegg Lukas , Moss Robert , Sinhal Ajay , Carere Ronald G. , Munt Brad , Ricci Donald , Ye Jian , Cheung Anson , Lichtenstein Sam V.
Published: July 2007

Background—

Percutaneous aortic valve replacement represents an endovascular alternative to conventional open heart surgery without the need for sternotomy, aortotomy, or cardiopulmonary bypass.

Methods and Results—

Transcatheter implantation of a balloon-expandable stent valve using a femoral arterial approach was attempted in 50 symptomatic patients with severe aortic stenosis in whom there was a consensus that the risks of conventional open heart surgery were very high. Valve implantation was successful in 86% of patients. Intraprocedural mortality was 2%. Discharge home occurred at a median of 5 days (interquartile range, 4 to 13). Mortality at 30 days was 12% in patients in whom the logistic European System for Cardiac Operative Risk Evaluation risk score was 28%. With experience, procedural success increased from 76% in the first 25 patients to 96% in the second 25 (
P
=0.10), and 30-day mortality fell from 16% to 8% (
P
=0.67). Successful valve replacement was associated with an increase in echocardiographic valve area from 0.6±0.2 to 1.7±0.4 cm
2
. Mild paravalvular regurgitation was common but was well tolerated. After valve insertion, there was a significant improvement in left ventricular ejection fraction (
P
<0.0001), mitral regurgitation (
P
=0.01), and functional class (
P
<0.0001). Improvement was maintained at 1 year. Structural valve deterioration was not observed with a median follow-up of 359 days.

Conclusion—

Percutaneous valve replacement may be an alternative to conventional open heart surgery in selected high-risk patients with severe symptomatic aortic stenosis.
Xenografted Adult Human Mesenchymal Stem Cells Provide a Platform for Sustained Biological Pacemaker Function in Canine Heart
Authors: Plotnikov Alexei N. , Shlapakova Iryna , Szabolcs Matthias J. , Danilo Peter , Lorell Beverly H. , Potapova Irina A. , Lu Zhongju , Rosen Amy B. , Mathias Richard T. , Brink Peter R. , Robinson Richard B. , Cohen Ira S. , Rosen Michael R.
Published: July 2007

Background—

Biological pacemaking has been performed with viral vectors, human embryonic stem cells, and adult human mesenchymal stem cells (hMSCs) as delivery systems. Only with human embryonic stem cells are data available regarding stability for >2 to 3 weeks, and here, immunosuppression has been used to facilitate survival of xenografts. The purpose of the present study was to determine whether hMSCs provide stable impulse initiation over 6 weeks without the use of immunosuppression, the “dose” of hMSCs that ensures function over this period, and the catecholamine responsiveness of hMSC-packaged pacemakers.

Methods and Results—

A full-length mHCN2 cDNA subcloned in a pIRES2-EGFP vector was electroporated into hMSCs. Transfection efficiency was estimated by GFP expression.
I
HCN2
was measured with patch clamp, and cells were administered into the left ventricular anterior wall of adult dogs in complete heart block and with backup electronic pacemakers. Studies encompassed 6 weeks.
I
HCN2
for all cells was 32.1±1.3 pA/pF (mean±SE) at −150 mV. Pacemaker function in intact dogs required 10 to 12 days to fully stabilize and persisted consistently through day 42 in dogs receiving ≥700 000 hMSCs (≈40% of which carried current). Rhythms were catecholamine responsive. Tissues from animals killed at 42 days manifested neither apoptosis nor humoral or cellular rejection.

Conclusions—

hMSCs provide a means for administering catecholamine-responsive biological pacemakers that function stably for 6 weeks and manifest no cellular or humoral rejection at that time. Cell doses >700 000 are sufficient for pacemaking when administered to left ventricular myocardium.
Apoptosis Signal-Regulating Kinase-1 Is Involved in Vascular Endothelial and Cardiac Remodeling Caused by Nitric Oxide Deficiency
Authors: Yamashita Takuro , Yamamoto Eiichiro , Kataoka Keiichiro , Nakamura Taishi , Matsuba Shinji , Tokutomi Yoshiko , Dong Yi-Fei , Ichijo Hidenori , Ogawa Hisao , Kim-Mitsuyama Shokei
Published: July 2007

Long-term treatment with

N
ω

-nitro-
l
-arginine methylester (
l
-NAME), an NO synthase inhibitor, induces hypertension and cardiovascular injury. However, its precise mechanism is unknown. Using apoptosis signal-regulating kinase-1 (ASK1)–deficient mice, we investigated the role of ASK1 in cardiovascular injury caused by
l
-NAME treatment.
l
-NAME was orally administered to ASK1-deficient and C57BL/6J (wild) mice for 8 weeks.
l
-NAME treatment increased blood pressure of wild and ASK1-deficient mice to a similar extent, indicating no role of ASK1 in NO-deficient hypertension.
l
-NAME treatment significantly impaired acetylcholine-induced carotid arterial relaxation in wild mice (
P
<0.01), being associated with the decreased endothelial NO synthase (eNOS) activity (
P
<0.01) and the increased disruption of eNOS dimer (
P
<0.01), whereas these changes by
l
-NAME were substantially attenuated in ASK1-deficient mice. Thus, ASK1 is involved in the impairment of vascular endothelial function by reducing eNOS activity and disrupting eNOS dimer.
l
-NAME treatment increased vascular reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and superoxide in wild mice to a greater extent than in ASK1 deficient mice.
l
-NAME treatment in wild mice caused cardiac hypertrophy, myocyte apoptosis, macrophage infiltration, coronary arterial remodeling, interstitial fibrosis, and the expression of monocyte chemoattractant protein-1 and transforming growth factor-β1, whereas these cardiac changes by
l
-NAME were absent in ASK1-deficient mice. Cardiac reduced nicotinamide-adenine dinucleotide phosphate oxidase activation and superoxide elevation by
l
-NAME were much less in ASK1-deficient mice than in wild mice. Our work provided the first evidence that ASK1 is implicated in vascular endothelial dysfunction and cardiovascular remodeling induced by NO deficiency by regulating eNOS and reduced nicotinamide-adenine dinucleotide phosphate oxidase.
Aldosterone Suppresses Insulin Signaling Via the Downregulation of Insulin Receptor Substrate-1 in Vascular Smooth Muscle Cells
Authors: Hitomi Hirofumi , Kiyomoto Hideyasu , Nishiyama Akira , Hara Taiga , Moriwaki Kumiko , Kaifu Kumiko , Ihara Genei , Fujita Yoshiko , Ugawa Toyomu , Kohno Masakazu
Published: July 2007

Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using
3
H-labeled 2-deoxy-
d
-glucose uptake. Aldosterone (1–100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 μmol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 μmol/L; n=4). Treatment with antioxidants,
N
-acetylcysteine (10 mmol/L), or ebselen (40 μmol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 μmol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 μmol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.
Training-Induced Pressure Fall in Spontaneously Hypertensive Rats Is Associated With Reduced Angiotensinogen mRNA Expression Within the Nucleus Tractus Solitarii
Authors: Felix Jorge Vinicius Cestari , Michelini Lisete Compagno
Published: July 2007

Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with
35
S-oligodeoxynucleotide probes for angiotensinogen [Aogen] and angiotensin II type 1 [AT
1A
] receptors). Resting arterial pressure and heart rate were higher in SHR
S
(177±2 mm Hg, 357±12 bpm versus 121±1 mm Hg, 320±9 bpm in WKY
S
;
P
<0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (−10%) in both groups. Training-induced blood pressure fall (−6.3%) was observed only in SHR
T
. In SHR
S
(versus WKY
S
) AT
1A
and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of +67% and +41% for AT
1A
and Aogen, respectively;
P
<0.05) but unchanged in the gracilis nucleus. Training did not change AT
1A
expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHR
T
(
P
<0.05 versus SHR
S
, with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (y=5.95x +41;
r
=0.55;
P
<0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure.
Cold War Legacies: The Migration and Transformation of Popular/Unpopular Culture
Authors: Chapman Roger
Published: July 2007

This article reviews two recent collections of essays that focus on the role of popular culture in the Cold War. The article sets the phenomenon into a wide international context and shows how American popular culture affected Europe and vice versa. The essays in these two collections, though divergent in many key respects, show that culture is dynamic and that the past as interpreted from the perspective of the present is often reworked with new meanings. Understanding popular culture in its Cold War context is crucial, but seeing how the culture has evolved in the post-Cold War era can illuminate our view of its Cold War roots.
“Pearl Harbor in Reverse” Moral Analogies in the Cuban Missile Crisis
Authors: Tierney Dominic
Published: July 2007

During the 1962 Cuban missile crisis, the argument that U.S. air strikes against Soviet missile sites in Cuba would be morally analogous to the Japanese surprise attack on Pearl Harbor in 1941 had a major impact on policymaking. The invocation of this analogy contributed to President John F. Kennedy's decision to forgo an immediate attack on the missiles and to start instead with a naval blockade of the island. The “Pearl Harbor in reverse” argument is an example of an important phenomenon that has received little attention in foreign policy analysis—the moral analogy. Fusing together elements of moral and analogical thinking, the moral analogy can be a powerful force in shaping policy preferences, as it was in October 1962.
The Missiles of November, December, January, February…: The Problem of Acceptable Risk in the Cuban Missile Crisis Settlement
Authors: Coleman David G.
Published: July 2007

This article examines how the Kennedy administration assessed the risk posed by Soviet short-range missiles in Cuba and the associated combat troops, particularly in the months after the peak of the Cuban missile crisis. The issue had a strong domestic political subtext that played out for months. Missiles in Cuba had been a topic of discussion well before the dramatic events of October 1962, and the dispute about them dragged on well past the famous “thirteen days.” Many studies assume a final resolution to the crisis that did not actually exist. The evidence from this period indicates that domestic political considerations were a fundamental factor in Kennedy's decision-making and apparently induced him to take a slightly harder line in the post-crisis negotiations with the Soviet Union than he otherwise might have. But the evidence also suggests that Kennedy was more willing than some of his advisers and many Congressional critics to accept a degree of permanent military risk in Cuba.
Sino-Cuban Relations during the Early Years of the Castro Regime, 1959–1966
Authors: Cheng Yinghong
Published: July 2007

China's relations with Cuba in the first half of the 1960s—when the Sino-Soviet split was rapidly intensifying—were important to both Beijing and Havana as well as to the world Communist movement. The Sino-Cuban relationship during this period moved from one of intimate comradeship to deterioration and finally a bitter separation. Although Fidel Castro's ties with Mao Zedong survived the immediate start of the Sino-Soviet rift, Castro's dependence on the Soviet Union ultimately doomed his courtship of China. Castro's vehemently anti-Chinese speech in March 1966 marked the end of Sino-Cuban amity. The Sino-Cuban case sheds valuable light on the tensions that bedeviled the international Communist movement after the Sino-Soviet divide flared to the surface.
Neural Substrates of Dynamic Object Occlusion
Authors: Shuwairi Sarah M. , Curtis Clayton E. , Johnson Scott P.
Published: July 2007

In everyday environments, objects frequently go out of sight as they move and our view of them becomes obstructed by nearer objects, yet we perceive these objects as continuous and enduring entities. Here, we used functional magnetic resonance imaging with an attentive tracking paradigm to clarify the nature of perceptual and cognitive mechanisms subserving this ability to fill in the gaps in perception of dynamic object occlusion. Imaging data revealed distinct regions of cortex showing increased activity during periods of occlusion relative to full visibility. These regions may support active maintenance of a representation of the target's spatiotemporal properties ensuring that the object is perceived as a persisting entity when occluded. Our findings may shed light on the neural substrates involved in object tracking that give rise to the phenomenon of object permanence.
The Development of Control Processes Supporting Source Memory Discrimination as Revealed by Event-related Potentials
Authors: de Chastelaine Marianne , Friedman David , Cycowicz Yael M.
Published: July 2007

Improvement in source memory performance throughout childhood is thought to be mediated by the development of executive control. As postretrieval control processes may be better time-locked to the recognition response rather than the retrieval cue, the development of processes underlying source memory was investigated with both stimulus- and response-locked event-related potentials (ERPs). These were recorded in children, adolescents, and adults during a recognition memory exclusion task. Green- and red-outlined pictures were studied, but were tested in black outline. The test requirement was to endorse old items shown in one study color (“targets”) and to reject new items along with old items shown in the alternative study color (“nontargets”). Source memory improved with age. All age groups retrieved target and nontarget memories as reflected by reliable parietal episodic memory (EM) effects, a stimulus-locked ERP correlate of recollection. Response-locked ERPs to targets and nontargets diverged in all groups prior to the response, although this occurred at an increasingly earlier time point with age. We suggest these findings reflect the implementation of attentional control mechanisms to enhance target memories and facilitate response selection with the greatest and least success, respectively, in adults and children. In adults only, response-locked ERPs revealed an early-onsetting parietal negativity for nontargets, but not for targets. This was suggested to reflect adults' ability to consistently inhibit prepotent target responses for nontargets. The findings support the notion that the development of source memory relies on the maturation of control processes that serve to enhance accurate selection of task-relevant memories.
Visual Recognition and Inference Using Dynamic Overcomplete Sparse Learning
Authors: Murray Joseph F. , Kreutz-Delgado Kenneth
Published: July 2007

We present a hierarchical architecture and learning algorithm for visual recognition and other visual inference tasks such as imagination, reconstruction of occluded images, and expectation-driven segmentation. Using properties of biological vision for guidance, we posit a stochastic generative world model and from it develop a simplified world model (SWM) based on a tractable variational approximation that is designed to enforce sparse coding. Recent developments in computational methods for learning overcomplete representations (Lewicki & Sejnowski, 2000; Teh, Welling, Osindero, & Hinton, 2003) suggest that overcompleteness can be useful for visual tasks, and we use an overcomplete dictionary learning algorithm (Kreutz-Delgado, et al., 2003) as a preprocessing stage to produce accurate, sparse codings of images.

Inference is performed by constructing a dynamic multilayer network with feedforward, feedback, and lateral connections, which is trained to approximate the SWM. Learning is done with a variant of the back-propagation-through-time algorithm, which encourages convergence to desired states within a fixed number of iterations. Vision tasks require large networks, and to make learning efficient, we take advantage of the sparsity of each layer to update only a small subset of elements in a large weight matrix at each iteration. Experiments on a set of rotated objects demonstrate various types of visual inference and show that increasing the degree of overcompleteness improves recognition performance in difficult scenes with occluded objects in clutter.
Visual Remapping by Vector Subtraction: Analysis of Multiplicative Gain Field Models
Authors: Cassanello Carlos R. , Ferrera Vincent P.
Published: July 2007

Saccadic eye movements remain spatially accurate even when the target becomes invisible and the initial eye position is perturbed. The brain accomplishes this in part by remapping the remembered target location in retinal coordinates. The computation that underlies this visual remapping is approximated by vector subtraction: the original saccade vector is updated by subtracting the vector corresponding to the intervening eye movement. The neural mechanism by which vector subtraction is implemented is not fully understood. Here, we investigate vector subtraction within a framework in which eye position and retinal target position signals interact multiplicatively (gain field). When the eyes move, they induce a spatial modulation of the firing rates across a retinotopic map of neurons. The updated saccade metric can be read from the shift of the peak of the population activity across the map. This model uses a quasi-linear (half-rectified) dependence on the eye position and requires the slope of the eye position input to be negatively proportional to the preferred retinal position of each neuron. We derive analytically this constraint and study its range of validity. We discuss how this mechanism relates to experimental results reported in the frontal eye fields of macaque monkeys.
Representations of Space and Time in the Maximization of Information Flow in the Perception-Action Loop
Authors: Klyubin Alexander S. , Polani Daniel , Nehaniv Chrystopher L.
Published: July 2007

Sensor evolution in nature aims at improving the acquisition of information from the environment and is intimately related with selection pressure toward adaptivity and robustness. Our work in the area indicates that information theory can be applied to the perception-action loop.

This letter studies the perception-action loop of agents, which is modeled as a causal Bayesian network. Finite state automata are evolved as agent controllers in a simple virtual world to maximize information flow through the perception-action loop. The information flow maximization organizes the agent's behavior as well as its information processing. To gain more insight into the results, the evolved implicit representations of space and time are analyzed in an information-theoretic manner, which paves the way toward a principled and general understanding of the mechanisms guiding the evolution of sensors in nature and provides insights into the design of mechanisms for artificial sensor evolution.
Computational Properties of Networks of Synchronous Groups of Spiking Neurons
Authors: Dayhoff Judith E.
Published: July 2007

We demonstrate a model in which synchronously firing ensembles of neurons are networked to produce computational results. Each ensemble is a group of biological integrate-and-fire spiking neurons, with probabilistic interconnections between groups. An analogy is drawn in which each individual processing unit of an artificial neural network corresponds to a neuronal group in a biological model. The activation value of a unit in the artificial neural network corresponds to the fraction of active neurons, synchronously firing, in a biological neuronal group. Weights of the artificial neural network correspond to the product of the interconnection density between groups, the group size of the presynaptic group, and the postsynaptic potential heights in the synchronous group model. All three of these parameters can modulate connection strengths between neuronal groups in the synchronous group models. We give an example of nonlinear classification (XOR) and a function approximation example in which the capability of the artificial neural network can be captured by a neural network model with biological integrate-and-fire neurons configured as a network of synchronously firing ensembles of such neurons. We point out that the general function approximation capability proven for feedforward artificial neural networks appears to be approximated by networks of neuronal groups that fire in synchrony, where the groups comprise integrate-and-fire neurons. We discuss the advantages of this type of model for biological systems, its possible learning mechanisms, and the associated timing relationships.
Asymptotic Behavior and Synchronizability Characteristics of a Class of Recurrent Neural Networks
Authors: Cebulla Christof
Published: July 2007

We propose an approach to the analysis of the influence of the topology of a neural network on its synchronizability in the sense of equal output activity rates given by a particular neural network model. The model we introduce is a variation of the Zhang model. We investigate the time-asymptotic behavior of the corresponding dynamical system (in particular, the conditions for the existence of an invariant compact asymptotic set) and apply the results of the synchronizability analysis on a class of random scale free networks and to the classical random networks with Poisson connectivity distribution.
Judicial Law-Making and the Developing Order of the Oceans
Authors: Harrison James
Published: July 2007

This article explores the powers of courts and tribunals in developing the legal order of the oceans. It is generally accepted that the rules of treaty interpretation allow courts to look beyond the strict con fines of a treaty to other sources of evidence. Such an approach allows an evolutionary interpretation which takes into account the contemporaneous views of the parties. In practice, courts and tribunals have adopted a pragmatic approach to the interpretation of the 1982 Law of the Sea Convention in light of other rules of international law. By doing so, they promote flexibility in the Convention regime, albeit at the risk of undermining the transparency and legitimacy of their decisions. In the context of the applicable law, the 1982 Convention seeks to safeguard itself against change by asserting priority over other sources of law. From a practical perspective, the role of courts in developing the Convention is limited by the fact that few decisions have come before the courts to date. Thus, it is clear that courts by themselves cannot provide a satisfactory mechanism for change in the legal order of the oceans.
Development of a Versatile Kinetic Monte Carlo Code to Simulate Physical Processes in Thin Film Nucleation and Growth
Authors: Han Xuetian , McAfee Richard , Yang Judith C.
Published: July 2007

Thin film development and nanoscale oxidation studies have been of great interest recent years. Nucleation rate theory[1‐3] has been successfully used to describe metal heteroepitaxy [4] and qualitatively explained the initial stage of oxidation behavior[5]. To further quantitative understanding of these nano‐scale processes and the morphology evolution in general gas‐metal reactions and thin film development, a powerful simulation tool is urgently needed. The Thin Film Oxidation (TFOx) model is an atomistic Kinetic Monte Carlo (KMC) model, which has been developed of this purpose. The TFOx model includes all of the relevant microscopic processes in thin film growth. It simulates various steps and phenomenon during thin film development, which includes deposition, decomposition, adatom diffusion, nucleation, adatom desorption, island growth and et.al. TFOx has a large amount of input parameters compared to other KMC models to assure the realistic and accuracy, which also makes itself a versatile tool of studying the thin film development. Some application of TFOx in simulating the Cu (100) oxidation behavior will also be discussed in this paper.