bluuebunny/crossref_metadata_2025 huggingface dataset:
A spatial and temporal model of root cohesion in forest soils
Authors: Sakals M E , Sidle Roy C
Published: May 2004

Root cohesion is an important parameter governing slope stability in steep forested terrain. Forest harvesting impacts root cohesion, and although the temporal effects have been noted, this dynamic parameter is often assumed to be spatially uniform. A model was developed to simulate the variation in root cohesion on a hillslope resulting from various forest management treatments. The model combines physical data on the horizontal rooting distribution of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco var. menziesii) together with a temporal relation of root cohesion decay. Harvesting methods examined include clear-cutting, single-tree selection cutting, and strip-cutting. Model outputs are analysed qualitatively for regions of root cohesion minima and quantitatively for the average root cohesion within the simulated hillslope. A selection cutting simulation maintained the highest average root cohesion value, decreasing to only 81% of the preharvest condition. In contrast, the minimum root cohesion following clear-cutting declined to 38% of the preharvest value. Selection and strip-cutting scenarios resulted in smaller areas of reduced root cohesion that were adjacent to areas with high root cohesion. Such partial cutting methods shorten the period of reduced root cohesion following timber harvesting compared with clear-cutting.
Modulatory effects of acid-sensing ion channels on action potential generation in hippocampal neurons
Authors: Vukicevic Marija , Kellenberger Stephan
Published: May 2004

Extracellular acidification has been shown to generate action potentials (APs) in several types of neurons. In this study, we investigated the role of acid-sensing ion channels (ASICs) in acid-induced AP generation in brain neurons. ASICs are neuronal Na+ channels that belong to the epithelial Na+ channel/degenerin family and are transiently activated by a rapid drop in extracellular pH. We compared the pharmacological and biophysical properties of acid-induced AP generation with those of ASIC currents in cultured hippocampal neurons. Our results show that acid-induced AP generation in these neurons is essentially due to ASIC activation. We demonstrate for the first time that the probability of inducing APs correlates with current entry through ASICs. We also show that ASIC activation in combination with other excitatory stimuli can either facilitate AP generation or inhibit AP bursts, depending on the conditions. ASIC-mediated generation and modulation of APs can be induced by extracellular pH changes from 7.4 to slightly <7. Such local extracellular pH values may be reached by pH fluctuations due to normal neuronal activity. Furthermore, in the plasma membrane, ASICs are localized in close proximity to voltage-gated Na+ and K+ channels, providing the conditions necessary for the transduction of local pH changes into electrical signals.
Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-α-converting enzyme in human airway epithelial (NCI-H292) cells
Authors: Shao Matt X. G. , Nakanaga Takashi , Nadel Jay A.
Published: May 2004

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the U.S. Because cigarette smoking is so importantly implicated in the pathogenesis of COPD and because mucus hypersecretion plays such an important role in COPD, understanding of the mechanisms of smoking-induced mucus hypersecretion could lead to new therapies for COPD. Cigarette smoke causes mucin overproduction via EGF receptor (EGFR) in airway epithelial cells, but the cellular mechanism remains unknown. Airway epithelial cells contain EGFR proligands on their surfaces, which can be cleaved by metalloprotease and subsequently bind to EGFR resulting in mucin production. We hypothesize that TNF-α-converting enzyme (TACE) is activated by cigarette smoke, resulting in increased shedding of EGFR proligand, leading to EGFR phosphorylation and mucin induction in human airway epithelial (NCI-H292) cells. Here we show that cigarette smoke increases MUC5AC production in NCI-H292 cells, an effect that is prevented by an EGFR-neutralizing antibody and by specific knockdown of transforming growth factor-α (TGF-α) using small interfering RNA (siRNA) for TGF-α, implicating TGF-α-dependent EGFR activation in the responses. Cigarette smoke increases TGF-α shedding, EGFR phosphorylation, and mucin production, which are prevented by metalloprotease inhibitors (GM-6001 and TNF-α protease inhibitor-1) and by specific knockdown of TACE with TACE siRNA, implicating TACE in smoking-induced responses. Furthermore, pretreatment with antioxidants prevents smoking-induced TGF-α shedding and mucin production, suggesting that reactive oxygen species is involved in TACE activation. These results implicate TACE in smoking-induced mucin overproduction via the TACE-proligand-EGFR signal pathway in NCI-H292 cells.
Constitutive roles for inducible genes: evidence for the alteration in expression of the induciblehsp70gene in Antarctic notothenioid fishes
Authors: Place Sean P. , Zippay Mackenzie L. , Hofmann Gretchen E.
Published: May 2004

Previous research on the Antarctic notothenioid fish Trematomus bernacchii demonstrated the loss of the heat shock response (HSR), a classical cellular defense mechanism against thermal stress, characterized by the rapid synthesis of heat shock proteins (Hsps). In the current study, we examined potential mechanisms for the apparent loss of the HSR in Antarctic notothenioids and, in addition, compared expression patterns of two genes from the 70-kDa Hsp family ( hsc71 and hsp70) in tissues from T. bernacchii to expression patterns in tissues of two closely related temperate notothenioid fishes from New Zealand, Bovichtus variegatus and Notothenia angustata. The results showed that transcript for both the constitutive and inducible genes in the Hsp70 gene family were expressed in detectable levels in all three species. However, only the cold-temperate New Zealand fishes displayed the ability to upregulate the inducible transcript, hsp70. Although hsp70 was present in detectable levels in several tissues of the Antarctic notothen T. bernacchii, in vitro thermal stresses failed to produce a significant increase in mRNA levels. In all species, the expression of the constitutive transcript hsc71 was variable and nonresponsive to temperature increases, even at temperatures as high as 10°C above the ecologically relevant range for the species under study. Field-collected tissues from T. bernacchii (sampled immediately after capture) indicated that hsp70 mRNA was expressed at high levels in field-acclimatized fishes. Thus upregulation of molecular chaperones suggested that low-temperature stress may be significantly denaturing to cellular proteins in Antarctic fish, an observation that was supported by elevated levels of ubiquitin-conjugated protein.
Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O2−and is diminished by a high-salt diet
Authors: Varela Marisela , Herrera Marcela , Garvin Jeffrey L.
Published: May 2004

A high-salt diet enhances nitric oxide (NO)-induced inhibition of transport in the thick ascending limb (THAL). Long exposures to NO inhibit Na-K-ATPase in cultured cells. We hypothesized that NO inhibits THAL Na-K-ATPase after long exposures and a high-salt diet would augment this effect. Rats drank either tap water or 1% NaCl for 7–10 days. Na-K-ATPase activity was assessed by measuring ouabain-sensitive ATP hydrolysis by THAL suspensions. After 2 h, spermine NONOate (SPM; 5 μM) reduced Na-K-ATPase activity from 0.44 ± 0.03 to 0.30 ± 0.04 nmol Pi·μg protein−1·min−1in THALs from rats on a normal diet ( P < 0.03). Nitroglycerin also reduced Na-K-ATPase activity ( P < 0.04). After 20 min, SPM had no effect (change −0.07 ± 0.05 nmol Pi·μg protein−1·min−1). When rats were fed high salt, SPM did not inhibit Na-K-ATPase after 120 min. To investigate whether ONOO−formed by NO reacting with O2−was involved, we measured O2−production. THALs from rats on normal and high salt produced 35.8 ± 0.3 and 23.7 ± 0.8 nmol O2−·min−1·mg protein−1, respectively ( P < 0.01). Because O2−production differed, we studied the effects of the O2−scavenger tempol. In the presence of 50 μM tempol, SPM did not inhibit Na-K-ATPase after 120 min (0.50 ± 0.05 vs. 0.52 ± 0.07 nmol Pi·μg protein−1·min−1). Propyl gallate, another O2−scavenger, also prevented SPM-induced inhibition of Na-K-ATPase activity. SPM inhibited pump activity in tubules from rats on high salt when O2−levels were increased with xanthine oxidase and hypoxanthine. We concluded that NO inhibits Na-K-ATPase after long exposures when rats are on a normal diet and this inhibition depends on O2−. NO donors do not inhibit Na-K-ATPase in THALs from rats on high salt due to decreased O2−production.
The effect of high glucose and PPAR-γ agonists on PPAR-γ expression and function in HK-2 cells
Authors: Panchapakesan U. , Pollock C. A. , Chen X. M.
Published: May 2004

Peroxisome proliferator-activated receptor-γ (PPAR-γ) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. PPAR-γ in the human kidney has been described. However, the role of PPAR-γ in proximal tubular cells with respect to cell growth and inflammation in diabetic nephropathy is largely unknown. We evaluated the effect of high (30 mM) d-glucose, thiazolidinedione pioglitazone (10 μM), and the selective PPAR-γ agonist L-805645 (8 μM) on PPAR-γ expression, growth, and inflammatory parameters in the proximal tubular model of HK-2 cells. PPAR-γ was present in HK-2 cells and upregulated with 30 mM d-glucose to 177 ± 31.2% of control ( P < 0.05). PPAR-γ activation was induced by pioglitazone to a similar level to that observed by exposure to high glucose but maximally induced by the selective agonist L-805645. However, L-805645 reduced cell viability in both 5 and 30 mM d-glucose to 73.8 ± 3.1 and 77.6 ± 1.4% of control (both P < 0.0001). In parallel, thymidine incorporation was reduced with L-805645 in both 5 and 30 mM d-glucose to 33.3 ± 3.4 and 37.9 ± 2.2%, respectively (both P < 0.0001). Flow cytometry demonstrated increased apoptosis and G1phase arrest in association with an increase in p21cip1/waf1in cells exposed to L-805645. Exposure to 30 mM d-glucose did not significantly change AP-1 promoter activity (89.0 ± 5.5% of control); however, the addition of L-805645 significantly reduced it to 62.2 ± 2.7% of control ( P < 0.0001). Thirty nanomolar d-glucose induced transforming growth factor-β1to 137.7 ± 16.9% of control ( P < 0.05), and L-805645 was able to suppress this to 68.7 ± 5.7% of control ( P < 0.01 vs. d-glucose). Exposure to 30 mM d-glucose reduced monocyte chemoattractant protein 1 levels to 78.6 ± 7.1% ( P < 0.05) of control, with the reduction more marked in the presence of either pioglitazone ( P < 0.01) or L-805645 ( P < 0.01). In summary, high glucose upregulates PPAR-γ and when significantly induced demonstrates anti-proliferative and anti-inflammatory effects.
Adaptation to lengthening contraction-induced injury in mouse muscle
Authors: Ingalls Christopher P. , Wenke J. C. , Nofal Talal , Armstrong R. B.
Published: May 2004

Adaptations to repeated bouts of injury-inducing lengthening contractions were studied in mouse anterior crural muscles. Five bouts of 150 lengthening contractions were performed in vivo, with each bout separated by 2 wk of rest. Three primary observations were made. First, there was little, if any, attenuation in the immediate isometric torque losses after lengthening contractions at “physiological” stimulation frequencies (i.e., <125 Hz), although there was a pronounced decrease in torque loss at higher frequencies between the first and second bouts. Second, the immediate losses in strength that occurred after all five lengthening contraction bouts could be explained in part by excitation-contraction uncoupling. Third, the most important adaptation was a significant enhancement in the rate of recovery of strength after the lengthening contractions. It is probable that the accelerated rate of strength recovery resulted from the more rapid loss and subsequent recovery of myofibrillar protein observed after the fifth bout.
Effect of endurance training on muscle TCA cycle metabolism during exercise in humans
Authors: Howarth Krista R. , LeBlanc Paul J. , Heigenhauser George J. F. , Gibala Martin J.
Published: May 2004

We tested the theory that links the capacity to perform prolonged exercise with the size of the muscle tricarboxylic acid (TCA) cycle intermediate (TCAI) pool. We hypothesized that endurance training would attenuate the exercise-induced increase in TCAI concentration ([TCAI]); however, the lower [TCAI] would not compromise cycle endurance capacity. Eight men (22 ± 1 yr) cycled at ∼80% of initial peak oxygen uptake before and after 7 wk of training (1 h/day, 5 days/wk). Biopsies (vastus lateralis) were obtained during both trials at rest, after 5 min, and at the point of exhaustion during the pretraining trial (42 ± 6 min). A biopsy was also obtained at the end of exercise during the posttraining trial (91 ± 6 min). In addition to improved performance, training increased ( P < 0.05) peak oxygen uptake and citrate synthase maximal activity. The sum of four measured TCAI was similar between trials at rest but lower after 5 min of exercise posttraining [2.7 ± 0.2 vs. 4.3 ± 0.2 mmol/kg dry wt ( P < 0.05)]. There was a clear dissociation between [TCAI] and endurance capacity because the [TCAI] at the point of exhaustion during the pretraining trial was not different between trials (posttraining: 2.9 ± 0.2 vs. pretraining: 3.5 ± 0.2 mmol/kg dry wt), and yet cycle endurance time more than doubled in the posttraining trial. Training also attenuated the exercise-induced decrease in glutamate concentration (posttraining: 4.5 ± 0.7 vs. pretraining: 7.7 ± 0.6 mmol/kg dry wt) and increase in alanine concentration (posttraining: 3.3 ± 0.2 vs. pretraining: 5.6 ± 0.3 mmol/kg dry wt; P < 0.05), which is consistent with reduced carbon flux through alanine aminotransferase. We conclude that, after aerobic training, cycle endurance capacity is not limited by a decrease in muscle [TCAI].
An iterative algorithm for generalized nonlinear variational inclusions with relaxed strongly accretive mappings in Banach spaces
Authors: Siddiqi A. H. , Ahmad Rais
Published: May 2004

We use Nadler′s theorem and the resolvent operator technique for
m‐accretive mappings to suggest an iterative algorithm for
solving generalized nonlinear variational inclusions with relaxed
strongly accretive mappings in Banach spaces. We prove the
existence of solutions for our inclusions without compactness
assumption and the convergence of the iterative sequences
generated by the algorithm in real Banach spaces. Some special
cases are also discussed.
Rank and k‐nullity of contact manifolds
Authors: Rukimbira Philippe
Published: May 2004

We prove that the dimension of the 1‐nullity distribution N(1)
on a closed Sasakian manifold M of rank l is at least equal
to 2l − 1 provided that M has an isolated closed
characteristic. The result is then used to provide some examples
of k‐contact manifolds which are not Sasakian. On a closed,
2n + 1‐dimensional Sasakian manifold of positive bisectional
curvature, we show that either the dimension of N(1)
is less
than or equal to n + 1 or N(1) is the entire tangent bundle
TM. In the latter case, the Sasakian manifold M is isometric
to a quotient of the Euclidean sphere under a finite group of
isometries. We also point out some interactions between
k‐nullity, Weinstein conjecture, and minimal unit vector fields.
Unique Morphology and Focal Adhesion Development of Valvular Endothelial Cells in Static and Fluid Flow Environments
Authors: Butcher Jonathan T. , Penrod Andrea M. , García Andrés J. , Nerem Robert M.
Published: May 2004

Background—The influence of mechanical forces on cell function has been well documented for many different cell types. Endothelial cells native to the aortic valve may play an important role in mediating tissue responses to the complex fluid environment, and may therefore respond to fluid flow in a different manner than more characterized vascular endothelial cells.

Methods and Results—Porcine endothelial cells of aortic and aortic valvular origin were subjected to 20 dynes/cm2steady laminar shear stress for up to 48 hours, with static cultures serving as controls. The aortic valve endothelial cells were observed to align perpendicular to flow, in direct contrast to the aortic endothelial cells, which aligned parallel to flow. Focal adhesion complexes reorganized prominently at the ends of the long axis of aligned cells. Valvular endothelial cell alignment was dependent on Rho-kinase signaling, whereas vascular endothelial cell alignment was dependent on both Rho-kinase and phosphatidylinositol 3-kinase signal pathways.

Conclusions—These differences in response to mechanical forces suggest a unique phenotype of valvular endothelial cells not mimicked by vascular endothelial cells, and could have implications for cardiovascular cell biology and cell-source considerations for tissue-engineered valvular substitutes.
Analysis of Apolipoprotein A5, C3, and Plasma Triglyceride Concentrations in Genetically Engineered Mice
Authors: Baroukh Nadine , Bauge Eric , Akiyama Jennifer , Chang Jessie , Afzal Veena , Fruchart Jean-Charles , Rubin Edward M. , Fruchart-Najib Jamila , Pennacchio Len A.
Published: May 2004

Objective—Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. These similar findings raised the issue of the relationship between these 2 genes and altered triglycerides.

Methods and Results—To address this issue, we generated independent lines of mice that either overexpressed (“double transgenic”) or completely lacked (“double knockout”) both apolipoprotein genes. We report that both “double transgenic” and “double knockout” mice display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the “double transgenic” mice are ≈500-fold lower than human ApoCIII levels, supporting ApoAV as a potent triglyceride modulator despite its low concentration.

Conclusions—Together, these data support thatAPOA5andAPOC3independently influence plasma triglyceride concentrations but in an opposing manner.
R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation
Authors: Slater Sadie C. , Koutsouki Evgenia , Jackson Christopher L. , Bush Raymond C. , Angelini Gianni D. , Newby Andrew C. , George Sarah J.
Published: May 2004

Objective—

Vascular smooth muscle cell (VSMC) proliferation is an important component of atherosclerosis, restenosis after angioplasty and stent placement, and vein graft failure. Outside-in signaling from the cadherin:β-catenin complex can increase transcription of the cell-cycle gene cyclin D1; however, its role in VSMC proliferation has only recently been considered.

Methods and Results—

We examined the involvement of R-cadherin and β-catenin in VSMC proliferation in balloon-injured carotid arteries in vivo and aortic rings in vitro. The number of medial VSMCs positive for R-cadherin was significantly reduced by 32%±5%, 52%±10%, and 23%±2% at 0.25, 24, and 48 hours after injury in vivo, respectively. These changes in cadherin expression coincided with the detection of nuclear β-catenin and elevated cyclin D1 expression. Furthermore, loss of R-cadherin expression was associated with medial VSMC proliferation. Inhibition of classical cadherin function with a HAV peptide and R-cadherin neutralizing antibodies significantly increased proliferation by 4.3±1.0-fold and 4.1±0.98-fold, and increased the number of cells with β-catenin in the nucleus and expressing cyclin D1 in aortic rings.

Conclusions—

These results suggest that R-cadherin expression and β-catenin signaling may be associated with increased cyclin D1 expression and VSMC proliferation and may therefore play an important role in vascular disease.
Effect of Obesity and Insulin Resistance on Myocardial Substrate Metabolism and Efficiency in Young Women
Authors: Peterson Linda R. , Herrero Pilar , Schechtman Kenneth B. , Racette Susan B. , Waggoner Alan D. , Kisrieva-Ware Zulia , Dence Carmen , Klein Samuel , Marsala JoAnn , Meyer Timothy , Gropler Robert J.
Published: May 2004

Background—

Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women.

Methods and Results—

We studied 31 young women (body mass index [BMI] 19 to 52 kg/m
2
); 19 were obese (BMI >30 kg/m
2
). Myocardial oxygen consumption (MV̇
o
2
) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/MV̇
o
2
. BMI correlated with MV̇
o
2
(
r
=0.58,
P
=0.0006), MFAUp (
r
=0.42,
P
<0.05), and efficiency (
r
=−0.40,
P
<0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with MFAUp (
r
=0.55,
P
<0.005), MFAU (
r
=0.62,
P
<0.001), and MFAO (
r
=0.58,
P
<0.005). A multivariate, stepwise regression analysis showed that BMI was the only independent predictor of MV̇
o
2
and efficiency (
P
=0.0005 and
P
<0.05, respectively). Glucose AUC was the only independent predictor of MFAUp, MFAU, and MFAO (
P
<0.05, <0.005, and <0.005, respectively).

Conclusions—

In young women, obesity is a significant predictor of increased MV̇
o
2
and decreased efficiency, and insulin resistance is a robust predictor of MFAUp, MFAU, and MFAO. This increase in fatty acid metabolism and decrease in efficiency is concordant with observations made in experimental models of obesity. These metabolic changes may play a role in the pathogenesis of decreased cardiac performance in obese women.
Neurological Events During Long-Term Mechanical Circulatory Support for Heart Failure
Authors: Lazar Ronald M. , Shapiro Peter A. , Jaski Brian E. , Parides Michael K. , Bourge Robert C. , Watson John T. , Damme Laura , Dembitsky Walter , Hosenpud Jeffrey D. , Gupta Lopa , Tierney Anita , Kraus Tonya , Naka Yoshifumi
Published: May 2004

Background—

Progression of heart failure can lead to cardiac transplantation, but when patients are ineligible, long-term mechanical circulatory support may improve survival. The REMATCH trial showed that left ventricular assist devices (LVADs) prolonged survival in patients with end-stage disease, but with a significant number of adverse events. We report on the neurological outcomes in the REMATCH trial.

Methods and Results—

We examined new neurological events in the 129 patients randomized to either LVAD placement (n=68) or medical management (n=61), classified as stroke, transient ischemic attack, toxic-metabolic encephalopathy, and other. There were 46 neurological events: 42 in 30 LVAD patients and 4 in 4 patients in the medical arm (χ
2
, 30/68 versus 4/61,
P
<0.001). Sixteen percent of the LVAD patients had a stroke, with a rate of 0.19 per year (95% CI, 0.10 to 0.33), many occurring in the postoperative period. The stroke rate in the medical arm was 0.052. A Kaplan-Meier survival analysis showed a 44% reduction in the risk of stroke or death in the LVAD group versus the optimal medical group (
P
=0.002). The mean interval from implantation to stroke was 221.8 days (±70.4 days). History of stroke, age, and sepsis were not stroke risk factors in the LVAD group.

Conclusions—

Fewer than half of the patients in the LVAD group had a neurological event, and there were few neurological deaths. Survival analysis combining stroke or death demonstrated a significant benefit for long-term circulatory support with an LVAD over medical therapy. Future trials will need to address prospectively all neurological outcomes, including neurocognitive function, and the role of long-term neuroprotection.
Growth Hormone Replacement Decreases Plasma Levels of Matrix Metalloproteinases (2 and 9) and Vascular Endothelial Growth Factor in Growth Hormone–Deficient Individuals
Authors: Randeva Harpal S. , Lewandowski Krzysztof C. , Komorowski Jan , Murray Robert D. , O’Callaghan Chris J. , Hillhouse Edward W. , Stepien Henryk , Shalet Stephen M.
Published: May 2004

Background—

Matrix metalloproteinases (MMP) are implicated in cardiovascular disease. Growth hormone (GH) deficiency is associated with increased cardiovascular mortality. We assessed whether GH replacement, in GH-deficient adults, has any effect on plasma levels of MMP-2 and MMP-9 and on vascular endothelial growth factor (VEGF), known to activate MMPs.

Methods and Results—

The study comprised 66 GH-deficient adults, 37.8±14.7 years of age (37 female). Plasma MMP-2 and MMP-9, VEGF, and insulin-like growth factor-1 (IGF-1) were measured at baseline (V
1
), at 12 months (V
2
), and at 24 months of GH treatment (V
3
). IGF-1 levels rose under GH replacement (mean±SD): V
1
, 151.6±91.9 μg/mL; V
2
, 270.2±114.8 μg/mL; and V
3
, 266.2±109.8 (V
1
versus V
2
;
P
<0.001: V
2
versus V
3
;
P
=0.76). MMP-9 exhibited the most pronounced and sustained decline from 1248.0±651.1 ng/mL at V
1
, 949.2±457.7 ng/mL at V
2
, and 760.8±386.1 ng/mL at V
3
(
P
<0.001 at all time points). A similar pattern was detected for VEGF levels: 358.5±209.0 pg/mL at V
1
, 310.6±225.7 pg/mL at V
2
(
P
<0.001), and 283.7±202.7 pg/mL at V
3
(V
2
versus V
3
;
P
=0.005). MMP-2 demonstrated a significant decline initially from V
1
to V
2
(1134.4±217.8 ng/mL versus 1074.5±203.0 ng/mL, respectively;
P
=0.031), reaching a plateau at V
3
(1072.3±220.2 ng/mL) (V
2
versus V
3
;
P
=0.93). A negative relation existed between MMP-9 versus IGF-1 and MMP-2 versus IGF-1 (
P
<0.001 and
P
=0.007, respectively) as well as between VEGF and IGF-1 (
P
<0.001).

Conclusions—

These changes in MMPs and VEGF may contribute to the anticipated reduction in vascular mortality in hypopituitary adults receiving GH replacement.
Acceleration of the Healing Process and Myocardial Regeneration May Be Important as a Mechanism of Improvement of Cardiac Function and Remodeling by Postinfarction Granulocyte Colony–Stimulating Factor Treatment
Authors: Minatoguchi Shinya , Takemura Genzou , Chen Xue-Hai , Wang Ningyuan , Uno Yoshihiro , Koda Masahiko , Arai Masazumi , Misao Yu , Lu Chuanjiang , Suzuki Koji , Goto Kazuko , Komada Ai , Takahashi Tomoyuki , Kosai Kenichiro , Fujiwara Takako , Fujiwara Hisayoshi
Published: May 2004

Background—

We investigated whether the improvement of cardiac function and remodeling after myocardial infarction (MI) by granulocyte colony–stimulating factor (G-CSF) relates to acceleration of the healing process, in addition to myocardial regeneration.

Methods and Results—

In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 μg · kg
−1
· d
−1
of human recombinant G-CSF (G) was injected subcutaneously from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction, and thicker infarct-LV wall were seen in G at 3 months after MI. At 2, 7, and 14 days and 3 months after MI, necrotic tissue areas were 14.2±1.5/13.4±1.1, 0.4±0.1/1.8±0.5*, 0/0, and 0/0 mm
2
· slice
−1
· kg
−1
, granulation areas 0/0, 4.0±0.7/8.5±1.0*, 3.9±0.8/5.7±0.7,* and 0/0 mm
2
· slice
−1
· kg
−1
, and scar areas 0/0, 0/0, 0/0, and 4.2±0.5/7.9±0.9* mm
2
· slice
−1
· kg
−1
in G and S, respectively (*
P
<0.05, G versus S). Clear increases of macrophages and of matrix metalloproteinases (MMP) 1 and 9 were seen in G at 7 days after MI. This suggests that G accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs. Meanwhile, surviving myocardial tissue areas within the risk areas were significantly increased in G despite there being no difference in LV weight, LV wall area, or cardiomyocyte size between G and S. Confocal microscopy revealed significant increases of cardiomyocytes with positive 3,3,3′,3′-tetramethylindocarbocyanine perchlorate and positive troponin I in G, suggesting enhanced myocardial regeneration by G.

Conclusions—

The acceleration of the healing process and myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.
Thioredoxin-Interacting Protein Controls Cardiac Hypertrophy Through Regulation of Thioredoxin Activity
Authors: Yoshioka Jun , Schulze P. Christian , Cupesi Mihaela , Sylvan Jeremy D. , MacGillivray Catherine , Gannon Joseph , Huang Hayden , Lee Richard T.
Published: May 2004

Background—

Although cellular redox balance plays an important role in mechanically induced cardiac hypertrophy, the mechanisms of regulation are incompletely defined. Because thioredoxin is a major intracellular antioxidant and can also regulate redox-dependent transcription, we explored the role of thioredoxin activity in mechanically overloaded cardiomyocytes in vitro and in vivo.

Methods and Results—

Overexpression of thioredoxin induced protein synthesis in cardiomyocytes (127±5% of controls,
P
<0.01). Overexpression of thioredoxin-interacting protein (Txnip), an endogenous thioredoxin inhibitor, reduced protein synthesis in response to mechanical strain (89±5% reduction,
P
<0.01), phenylephrine (80±3% reduction,
P
<0.01), or angiotensin II (80±4% reduction,
P
<0.01). In vivo, myocardial thioredoxin activity increased 3.5-fold compared with sham controls after transverse aortic constriction (
P
<0.01). Aortic constriction did not change thioredoxin expression but reduced Txnip expression by 40% (
P
<0.05). Gene transfer studies showed that cells that overexpress Txnip develop less hypertrophy after aortic constriction than control cells in the same animals (28.1±5.2% reduction versus noninfected cells,
P
<0.01).

Conclusions—

Thus, even though thioredoxin is an antioxidant, activation of thioredoxin participates in the development of pressure-overload cardiac hypertrophy, demonstrating the dual function of thioredoxin as both an antioxidant and a signaling protein. These results also support the emerging concept that the thioredoxin inhibitor Txnip is a critical regulator of biomechanical signaling.
Role of Hypothalamic Melanocortin 3/4-Receptors in Mediating Chronic Cardiovascular, Renal, and Metabolic Actions of Leptin
Authors: da Silva Alexandre A. , Kuo Jay J. , Hall John E.
Published: May 2004

The present study examined whether blockade of melanocortin receptors subtypes 3 and 4 (MC3/4-R) inhibits chronic cardiovascular and dietary responses to leptin infusion. A cannula was placed in the lateral ventricle of male Sprague-Dawley rats for chronic intracerebroventricular (ICV) infusion via osmotic minipump, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 h/d and IV infusions. After a 5-day control period, rats received (1) 0.9% saline vehicle ICV for 12 days plus leptin (1 μg/kg per minute IV, n=5) during the final 7 days; (2) MC3/4-R antagonist SHU-9119 (1 nmol/h ICV) for 12 days plus leptin (1 μg/kg per minute IV, n=6) during the final 7 days; and (3) SHU-9119 (1 nmol/h ICV, n=8) for 12 days. Leptin infusion in vehicle-treated rats caused a small increase in MAP (5±1 mm Hg) despite reduced food intake (23±1 to 10±1 g/d) and decreased body weight (−6%±1%). SHU-9119 infusion completely prevented the cardiovascular and dietary actions of leptin, leading to increased food intake (23±1 to 49±4 g/d) and body weight (+30%±2%), markedly decreased HR (−77±9 bpm), and caused a decrease in MAP (−6±1 mm Hg). Similar results were observed when SHU-9119 was infused alone in vehicle-treated rats. Leptin decreased plasma insulin to 30% of control values, an effect that was also abolished by SHU-9119 treatment, which caused a 5-fold increase in plasma insulin concentration. Thus, MC3/4-R antagonism completely blocked the chronic cardiovascular, satiety, and metabolic effects of leptin, suggesting that the hypothalamic melanocortin system plays an important role in mediating these actions of leptin.
Role of Osteopontin in Cardiac Fibrosis and Remodeling in Angiotensin II-Induced Cardiac Hypertrophy
Authors: Matsui Yutaka , Jia Nan , Okamoto Hiroshi , Kon Shigeyuki , Onozuka Hisao , Akino Masatoshi , Liu Lizhi , Morimoto Junko , Rittling Susan R. , Denhardt David , Kitabatake Akira , Uede Toshimitsu
Published: May 2004

Osteopontin (OPN) is upregulated in several experimental models of cardiac fibrosis and remodeling. However, its direct effects remain unclear. We examined the hypothesis that OPN is important for the development of cardiac fibrosis and remodeling. Moreover, we examined whether the inhibitory effect of eplerenone (Ep), a novel aldosterone receptor antagonist, was mediated through the inhibition of OPN expression against cardiac fibrosis and remodeling. Wild-type (WT) and OPN-deficient mice were treated with angiotensin II (Ang II) for 4 weeks. WT mice receiving Ang II were divided into 2 groups: a control group and an Ep treatment group. Ang II treatment significantly elevated blood pressure and caused cardiac hypertrophy and fibrosis in WT mice. Ep treatment and OPN deficiency could reduce the Ang II-induced elevation of blood pressure and ameliorate the development of cardiac fibrosis, whereas Ep-only treatment abolished the development of cardiac hypertrophy. Most compelling, the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and subsequent left ventricular dilatation in Ang II-treated OPN-deficient mice. These results suggest that OPN has a pivotal role in the development of Ang II-induced cardiac fibrosis and remodeling. Moreover, the effect of Ep on the prevention of cardiac fibrosis, but not cardiac hypertrophy, might be partially mediated through the inhibition of OPN expression.
Hypoadiponectinemia Is an Independent Risk Factor for Hypertension
Authors: Iwashima Yoshio , Katsuya Tomohiro , Ishikawa Kazuhiko , Ouchi Noriyuki , Ohishi Mitsuru , Sugimoto Ken , Fu Yuxiao , Motone Masaharu , Yamamoto Kouichi , Matsuo Akiko , Ohashi Koji , Kihara Shinji , Funahashi Tohru , Rakugi Hiromi , Matsuzawa Yuji , Ogihara Toshio
Published: May 2004

Adiponectin is one of the key molecules in the metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and coronary artery disease. Genetic investigation has revealed that 2 polymorphisms (I164T and G276T) are related to adiponectin concentration and diabetes. To examine whether adiponectin affects hypertension genetically or biologically, we performed a case-control study. A total of 446 diagnosed cases of hypertension (HT) in men and 312 normotensive (NT) men were enrolled in this study. Plasma adiponectin concentration was measured using an enzyme-linked immunosorbent assay system. Single nucleotide polymorphisms were determined by TaqMan polymerase chain reaction method. After adjustment for confounding factors, adiponectin concentration was significantly lower in HT (HT: 5.2±0.2 μg/mL; NT: 6.1±0.2 μg/mL;
P
<0.001). Furthermore, multiple regression analysis indicated that hypoadiponectinemia was an independent risk factor for hypertension (
P
<0.001). Blood pressure was inversely associated with adiponectin concentration in normotensives regardless of insulin resistance. In subjects carrying the TC genotype of the I164T polymorphism, adiponectin concentration was significantly lower (TC: 2.6±0.9 μg/mL; TT: 5.5±0.1 μg/mL;
P
<0.01), and most of them had hypertension. In contrast, the G276T polymorphism was not associated with adiponectin concentration or hypertension. In conclusion, hypoadiponectinemia is a marker for predisposition to hypertension in men.
PPARγ Agonists Ameliorate Endothelial Cell Activation via Inhibition of Diacylglycerol–Protein Kinase C Signaling Pathway
Authors: Verrier Emily , Wang Lijun , Wadham Carol , Albanese Nathaniel , Hahn Chris , Gamble Jennifer R. , Chatterjee V. Krishna K. , Vadas Mathew A. , Xia Pu
Published: May 2004

Subject—

Peroxisome proliferator-activated receptor (PPAR)-γ agonists are emerging as potential protectors against inflammatory cardiovascular diseases including atherosclerosis and diabetic complications. However, their molecular mechanism of action within vasculature remains unclear. We report here that PPARγ agonists, thiazolidinedione class drugs (TZDs), or 15-deoxy-
Δ12,14
-prostaglandin J
2
(15d-PGJ2) were capable of activating diacylglycerol (DAG) kinase (DGK), resulting in attenuation of DAG levels and inhibition of protein kinase C (PKC) activation. The PPARγ agonist-induced DGK was completely blocked by a dominant-negative mutant of PPARγ, indicating an essential receptor-dependent action. Importantly, the suppression of DAG-PKC signaling pathway was functional linkage to the anti-inflammatory properties of PPARγ agonists in endothelial cells (EC), characterized by the inhibition of proinflammatory adhesion molecule expression and adherence of monocytes to the activated EC induced by high glucose. These findings thus demonstrate a novel molecular action of PPARγ agonists to suppress the DAG-PKC signaling pathway via upregulation of an endogenous attenuator, DGK.
Chronic Production of Angiotensin IV in the Brain Leads to Hypertension That Is Reversible With an Angiotensin II AT1 Receptor Antagonist
Authors: Lochard Nadheige , Thibault Gaétan , Silversides David W. , Touyz Rhian M. , Reudelhuber Timothy L.
Published: May 2004

Angiotensin IV (Ang IV) is a metabolite of the potent vasoconstrictor angiotensin II (Ang II). Because specific binding sites for this peptide have been reported in numerous tissues including the brain, it has been suggested that a specific Ang IV receptor (AT4) might exist. Bolus injection of Ang IV in brain ventricles has been implicated in learning, memory, and localized vasodilatation. However, the functions of Ang IV in a physiological context are still unknown. In this study, we generated a transgenic (TG) mouse model that chronically releases Ang IV peptide specifically in the brain. TG mice were found to be hypertensive by the tail-cuff method as compared with control littermates. Treatment with the angiotensin-converting enzyme inhibitor captopril had no effect on blood pressure, but surprisingly treatment with the Ang II AT1 receptor antagonist candesartan normalized the blood pressure despite the fact that the levels of Ang IV in the brains of TG mice were only 4-fold elevated over the normal endogenous level of Ang peptides. Calcium mobilization assays performed on cultured CHO cells chronically transfected with the AT1 receptor confirm that low-dose Ang IV can mobilize calcium via the AT1 receptor only in the presence of Ang II, consistent with an allosteric mechanism. These results suggest that chronic elevation of Ang IV in the brain can induce hypertension that can be treated with angiotensin II AT1 receptor antagonists.
Paired-Related Homeobox Gene
Prx1
Is Required for Pulmonary Vascular Development
Authors: Ihida-Stansbury Kaori , McKean David M. , Gebb Sarah A. , Martin James F. , Stevens Troy , Nemenoff Raphael , Akeson Ann , Vaughn Jessica , Jones Peter Lloyd
Published: May 2004

Herein, we show that the paired-related homeobox gene,
Prx1
, is required for lung vascularization. Initial studies revealed that Prx1 localizes to differentiating endothelial cells (ECs) within the fetal lung mesenchyme, and later within ECs forming vascular networks. To begin to determine whether Prx1 promotes EC differentiation, fetal lung mesodermal cells were transfected with full-length Prx1 cDNA, resulting in their morphological transformation to an endothelial-like phenotype. In addition, Prx1-transformed cells acquired the ability to form vascular networks on Matrigel. Thus, Prx1 might function by promoting pulmonary EC differentiation within the fetal lung mesoderm, as well as their subsequent incorporation into vascular networks. To understand how Prx1 participates in network formation, we focused on tenascin-C (TN-C), an extracellular matrix (ECM) protein induced by Prx1. Immunocytochemistry/histochemistry showed that a TN-C–rich ECM surrounds Prx1-positive pulmonary vascular networks both in vivo and in tissue culture. Furthermore, antibody-blocking studies showed that TN-C is required for Prx1-dependent vascular network formation on Matrigel. Finally, to determine whether these results were relevant in vivo, we examined newborn
Prx1
–wild-type (+/+) and
Prx1
-null (−/−) mice and showed that Prx1 is critical for expression of TN-C and lung vascularization. These studies provide a framework to understand how Prx1 controls EC differentiation and their subsequent incorporation into functional pulmonary vascular networks.
Dementia After Stroke
Authors: Ivan Cristina S. , Seshadri Sudha , Beiser Alexa , Au Rhoda , Kase Carlos S. , Kelly-Hayes Margaret , Wolf Philip A.
Published: May 2004

Background and Purpose—

Identification of risk factors for dementia after stroke is best performed in comparison with stroke-free controls, because older subjects at high risk for stroke also have a substantial risk of dementia in the absence of stroke. Previous case-control studies were hospital-based. We used a nested case-control design to prospectively evaluate these risk factors in the community-based Framingham Study cohort.

Methods—

We compared 212 subjects who were free of dementia in January 1982 and sustained a first stroke after this date, with 1060 age- and sex-matched, stroke- and dementia-free controls. We calculated 10-year risks of dementia (by
Diagnostic and Statistical Manual of Mental Disorders
, Volume IV criteria) developing in cases and controls and also estimated the hazard ratios within subgroups defined by exposure to various demographic factors (age, gender, education), stroke-related features (right or left hemisphere, stroke type, second stroke), stroke risk factors (hypertension, diabetes, atrial fibrillation, smoking) and apolipoprotein E genotype.

Results—

Dementia developed in 19.3% of cases and 11.0% of controls. Baseline stroke doubled the risk of dementia (hazard ratio [HR]: 2.0; 95% confidence interval [CI]: 1.5 to 3.1) and adjustment for age, sex, education, and exposure to individual stroke risk factors did not diminish the risk (HR: 2.4; 95% CI: 1.6 to 3.7). The HR was higher in younger subjects (age younger than 80 years [HR: 2.6; 95% CI: 1.5 to 4.5]), apolipoprotein E 3/3 homozygotes (HR: 3.4; 95% CI: 2.0 to 5.8), and high school graduates (HR: 2.4; 95% CI: 1.5 to 3.9).

Conclusion—

Stroke increases a subject’s risk of dementia as compared with age- and sex-matched controls. Primary and secondary prevention of stroke should significantly decrease the risk of all dementia.
Internal Carotid Artery Occlusive Disease and Polymorphisms of Fractalkine Receptor CX3CR1
Authors: Ghilardi Giorgio , Biondi Maria Luisa , Turri Olivia , Guagnellini Emma , Scorza Roberto
Published: May 2004

Background and Purpose—

Fractalkine (FKN), a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1. The polymorphisms V249I and T280M affect receptor expression and function. The role of FKN in atherosclerosis has been recently demonstrated. The aim of this study was to investigate a possible association between CX3CR1 polymorphisms and increased risk of internal carotid artery (ICA) occlusive disease.

Methods—

We studied 108 patients consecutively recruited for ICA occlusive disease, 84 of whom underwent operation for carotid endarterectomy, and 204 subjects without ICA occlusive disease (controls). Polymorphic genotypes were determined by polymerase chain reaction and sequencing analysis.

Results—

The adjusted odds ratio (OR) associated with the presence of the M280 (TM+MM versus TT genotype) was 0.55 (95% CI: 0.29 to 0.99;
P
=0.037). Therefore, this allele is associated with a reduced risk of ICA occlusive disease. No significant differences were observed in I249 distribution. The frequency of I249 allele was significantly higher in cases of hard plaques, which are considered more stable than soft ones (OR: 0.38; 95% CI: 0.13 to 1.05;
P
=0.037). Multiple logistic regression analysis using the common risk factors and the I249 and M280 allele variants revealed that the M280 allele was an independent risk factor for ICA stenosis (
P
=0.047).

Conclusion—

The results show that the CX3CR1 M280 is an independent genetic risk factor for ICA occlusive disease and that I249 is involved in the stability of carotid plaques. Even if obtained from a relatively limited patient series, these results might have relevant implications for treatment of ICA stenosis and possibly prevention of carotid related stroke. Further prospective cross-sectional studies are needed to confirm these results.
Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses
Authors: Milligan Donald W. , Fernandes Savio , Dasgupta Ranjit , Davies Faith E. , Matutes Estella , Fegan Christopher D. , McConkey Christopher , Child J. Anthony , Cunningham David , Morgan Gareth J. , Catovsky Daniel ,   for the National Cancer Research Institute (NCRI) Haematological Studies Group
Published: May 2004

We have assessed autologous stem cell transplantation after treatment with fludarabine in previously untreated patients with chronic lymphocytic leukemia (CLL). This study is the first to enroll previously untreated patients and follow them prospectively. The initial response rate to fludarabine was 82% (94 of 115 patients). Stem cell mobilization was attempted in 88 patients and was successful in 59 (67%). Overall 65 of 115 patients (56%) entered into the study proceeded to autologous transplantation. The early transplant-related mortality rate was 1.5% (1 of 65 patients). The number of patients in complete remission after transplantation increased from 37% (24 of 65) to 74% (48 of 65), and 26 of 41 patients (63%) who were not in complete remission at the time of their transplantation achieved a complete remission after transplantation. The 5-year overall and disease-free survival rates from transplantation were 77.5% (CI, 57.2%-97.8%) and 51.5% (CI, 33.2%-69.8%), respectively. None of the variables examined at study entry were found to be predictors of either overall or disease-free survival. Sixteen of 20 evaluable patients achieved a molecular remission on a polymerase chain reaction (PCR) for immunoglobulin heavy-chain gene rearrangements in the first 6 months following transplantation. Detectable molecular disease by PCR was highly predictive of disease recurrence. It is of concern that 5 of 65 (8%) patients developed posttransplant acute myeloid leukemia/myelodysplastic syndrome. (Blood. 2005;105:397-404)