bluuebunny/crossref_metadata_2025 huggingface dataset:
HdaA, a Major Class 2 Histone Deacetylase of
Aspergillus nidulans
, Affects Growth under Conditions of Oxidative Stress
Authors: Tribus Martin , Galehr Johannes , Trojer Patrick , Brosch Gerald , Loidl Peter , Marx Florentine , Haas Hubertus , Graessle Stefan
Published: October 2005

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from the ε-amino group of distinct lysine residues in the amino-terminal tail of core histones. Since the acetylation status of core histones plays a crucial role in fundamental processes in eukaryotic organisms, such as replication and regulation of transcription, recent research has focused on the enzymes responsible for the acetylation/deacetylation of core histones. Very recently, we showed that HdaA, a member of the
Saccharomyces cerevisiae
HDA1-type histone deacetylases, is a substantial contributor to total HDAC activity in the filamentous fungus
Aspergillus nidulans.
Now we demonstrate that deletion of the
hdaA
gene indeed results in the loss of the main activity peak and in a dramatic reduction of total HDAC activity. In contrast to its orthologs in yeast and higher eukaryotes, HdaA has strong intrinsic activity as a protein monomer when expressed as a recombinant protein in a prokaryotic expression system. In vivo, HdaA is involved in the regulation of enzymes which are of vital importance for the cellular antioxidant response in
A. nidulans
. Consequently, Δ
hdaA
strains exhibit significantly reduced growth on substrates whose catabolism generates molecules responsible for oxidative stress conditions in the fungus. Our analysis revealed that reduced expression of the fungal catalase CatB is jointly responsible for the significant growth reduction of the
hdaA
mutant strains.
Prespore Cell Fate Bias in G
1
Phase of the Cell Cycle in
Dictyostelium discoideum
Authors: Chen Guokai , Kuspa Adam
Published: October 2005

By generating a population of
Dictyostelium
cells that are in the G
1
phase of the cell cycle we have examined the influence of cell cycle status on cell fate specification, cell type proportioning and its regulation, and terminal differentiation. The lack of observable mitosis during the development of these cells and the quantification of their cellular DNA content suggests that they remain in G
1
throughout development. Furthermore, chromosomal DNA synthesis was not detectable these cells, indicating that no synthesis phase had occurred, although substantial mitochondrial DNA synthesis did occur in prespore cells. The G
1
-phase cells underwent normal morphological development and sporulation but displayed an elevated prespore/prestalk ratio of 5.7 compared to the 3.0 (or 3:1) ratio normally observed in populations dominated by G
2
-phase cells. When migrating slugs produced by G
1
-phase cells were bisected, each half could reestablish the 5.7 (or 5.7:1) prespore/prestalk ratio. These results demonstrate that
Dictyostelium
cells can carry out the entire developmental cycle in the G
1
phase of the cell cycle and that passage from G
2
into G
1
phase is not required for sporulation. Our results also suggest that the population asymmetry provided by the distribution of cells around the cell cycle at the time of starvation is not strictly required for cell type proportioning. Finally, when developed together with G
2
-phase cells, G
1
-phase cells preferentially become prespore cells and exclude G
2
-phase cells from the prespore-spore cell population, suggesting that G
1
-phase cells have an advantage over G
2
-phase cells in executing the spore cell differentiation pathway.
KINETICS OF PHASE SEPARATION IN CONFINED GEOMETRIES
Authors: PURI SANJAY
Published: October 2005

We review analytical and numerical results for the kinetics of phase separation in confined geometries. It is often the case that a confining surface has a preferential attraction for one of the components of a segregating mixture. The equilibrium surface morphology is either partially wet or completely wet, depending on the strength of the surface potential. The dynamical interplay of wetting and phase separation is referred to as surface-directed spinodal decomposition (SDSD), and is of considerable technological importance. We discuss the modeling of SDSD at both the microscopic and coarse-grained levels. We also present results for SDSD in both semi-infinite and confined geometries.
THE GENERAL KONDO RESISTIVITY BY RENORMALIZED INFINITE SERIES METHOD (RISM)
Authors: KOO JE HUAN , CHO GUANGSUP
Published: October 2005

We investigate the Kondo resistivity using the perturbation methods. We calculate the resistivity above the Kondo temperature using an adjustable infinite series or series from log-function for uncrossed Kondo diagrams. We obtain the energy eigenvalue above the spin glass temperature using this RISM.
BOUNDARY PROBLEMS FOR THE GINZBURG–LANDAU EQUATION
Authors: CHIRON DAVID
Published: October 2005

We provide a study at the boundary for a class of equations including the Ginzburg–Landau equation as well as the equation of travelling waves for the Gross–Pitaevskii model. We prove Clearing-Out results and an orthogonal anchoring condition of the vortex on the boundary for the Ginzburg–Landau equation with magnetic field.
THE LYMPHATIC VASCULATURE: Recent Progress and Paradigms
Authors: Oliver Guillermo , Alitalo Kari
Published: October 2005

The field of lymphatic research has been recently invigorated by the identification of genes and mechanisms that control various aspects of lymphatic development. We are beginning to understand how, starting from a subgroup of embryonic venous endothelial cells, the whole lymphatic system forms in a stepwise manner. The generation of genetically engineered mice with defects in different steps of the lymphangiogenic program has provided models that are increasing our understanding of the lymphatic system in health and disease. This knowledge, in turn, should lead to the development of better diagnostic methods and treatments of lymphatic disorders and tumor metastasis.
EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I
Authors: Takaoka Munenori , Smith Caitlin E. , Mashiba Michael K. , Okawa Takaomi , Andl Claudia D. , El-Deiry Wafik S. , Nakagawa Hiroshi
Published: October 2005

IGF and EGF regulate various physiological and pathological processes. IGF binding protein (IGFBP)-3 regulates cell proliferation in IGF-dependent and -independent fashions. Recently, we identified IGFBP-3 as a novel EGF receptor (EGFR) downstream target molecule in primary and immortalized human esophageal epithelial cells, suggesting an interplay between the EGF and IGF signaling pathways. However, the regulatory mechanisms for IGFBP-3 expression and its functional role in esophageal cell proliferation remain to be elucidated. Herein, we report that IGFBP-3 mRNA and protein were induced upon growth factor deprivation in primary and immortalized human esophageal cells through mechanisms requiring p53-independent de novo mRNA transcription and protein synthesis. This occurred in the face of the activated phosphatidylinositol 3-OH-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. Secreted IGFBP-3 neutralized IGFs and prevented IGF-I receptor (IGF-IR) activation. In contrast, EGF suppressed IGFBP-3 mRNA and protein expression through activation of MAPK in an EGFR-tyrosine kinase-dependent manner to restore the cellular response to IGF-I. When stably overexpressed, wild-type IGFBP-3 but not I56G/L80G/L81G (GGG) mutant IGFBP-3, which has a reduced affinity to IGFs, prevented IGF-I from activating IGF-IR and Akt as well as stimulating cell proliferation. However, unlike other cell types where IGFBP-3 exerts antiproliferative effects, neither wild-type nor GGG mutant IGFBP-3 alone affected cell proliferation or EGFR activity. These results indicate that IGF signaling is subject to negative regulation through IGFBP-3 and positive regulation by EGF, the latter of which suppresses IGFBP-3. This provides a platform for understanding the novel cross talk between EGF- and IGF-mediated pathways.
Vascular injury response in mice is dependent on genetic background
Authors: Sindermann Jürgen R. , Köbbert Christiane , Skaletz-Rorowski Adriane , Breithardt Günter , Plenz Gabriele , March Keith L.
Published: October 2005

Mouse models are employed to unravel the pathophysiology of vascular restenosis. Although much effort has been spent on how to apply an adequate arterial injury, the influence of the genetic background of mice has not yet received sufficient consideration. The study presented herein was designed to demonstrate the influence of the mouse strain on vascular injury response. Mice of a defined background (50% 129 strain and 50% DBA strain) were backcrossed into either the 129 strain or the DBA strain. Male offspring were subjected to a femoral artery injury model by applying an electric current. Morphometric analysis revealed that backcrossing into the 129 strain resulted in a significant ( P < 0.001) 17-fold increase in neointima formation ( n = 17 mice) compared with backcrossing into the DBA strain ( n = 19). The values of neointima area were 9.18 × 103 ± 2.13 × 103 and 0.54 × 103 ± 0.39 × 103 μm2, respectively. In conjunction, the vessel wall area was enhanced by 1.8-fold ( P < 0.001). In contrast, no significant differences were found for the areas of the lumen and the tunica media. Similarly, a significant increase in neointima formation was also found for mice of pure 129 strain compared with pure DBA strain. The results underline the importance of the genetic background for studies on vascular injury response. Furthermore, because the mouse genome of the various strains is well defined, serial testing of the genetic background of mice will provide candidate genes and/or genetic modifiers controlling vascular injury response.
Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling
Authors: Voros Szilard , Yang Zequan , Bove Christina M. , Gilson Wesley D. , Epstein Frederick H. , French Brent A. , Berr Stuart S. , Bishop Sanford P. , Conaway Mark R. , Matsubara Hiroaki , Carey Robert M. , Kramer Christopher M.
Published: October 2005

The relative contribution of the angiotensin II type 1 and 2 receptors (AT1-R and AT2-R) in postmyocardial infarction (MI) remodeling remains incompletely understood. We studied five groups of C57Bl/6 mice after 1 h of left anterior descending artery occlusion-reperfusion: 1) wild type, untreated ( n = 12); 2) wild type, treated with the AT1-R blocker losartan (10–20 mg·kg−1·day−1 in drinking water) from day 1 to day 28 post-MI ( n = 10); 3) cardiac overexpression of the AT2-R [AT2-transgenic (TG); n = 14]; 4) AT2-TG treated with losartan ( n = 13); and 5) AT2-TG and null for the AT1a-R [AT2-TG/AT1 knockout (KO); n = 10]. Cardiac magnetic resonance imaging (CMR) measured ejection fraction and left ventricular end-diastolic and end-systolic volume (EDVI and ESVI) and mass indexed to weight on days 0, 1, 7, and 28 post-MI. Infarct size was measured on day 1 by late gadolinium-enhanced CMR. Regional myocyte hypertrophy and collagen content were measured on day 28 post-MI. Infarct size was similar among groups. Systolic blood pressure was lowest in AT2-TG/AT1KO. By day 28 post-MI, when corrected for baseline differences, EDVI and ESVI were higher and ejection fraction was lower in wild type than other groups. Ejection fraction was highest and EDVI and mass index were lowest in AT2-TG/AT1KO at day 28. The AT2-TG/AT1KO demonstrated less fibrosis in adjacent regions. Regional myocyte hypertrophy was similar in all groups. The AT1-R and AT2-R are intricately intertwined in post-MI remodeling. Pharmacological blockade of AT1-R is equivalent to AT2-R overexpression in attenuating post-MI remodeling. Genetic knockout of the AT1a-R is additive to AT2-R overexpression, due, at least in part, to blood pressure lowering.
Effects of selective inhibition of cytochrome P-450 ω-hydroxylases and ischemic preconditioning in myocardial protection
Authors: Nithipatikom Kasem , Endsley Michael P. , Moore Jeannine M. , Isbell Marilyn A. , Falck John R. , Campbell William B. , Gross Garrett J.
Published: October 2005

Cytochrome P-450 (CYP) ω-hydroxylases and their arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produce a detrimental effect on ischemia-reperfusion injury in canine hearts, and the inhibition of CYP ω-hydroxylases markedly reduces myocardial infarct size expressed as a percentage of the area at risk (IS/AAR, %). In this study, we demonstrated that a specific CYP ω-hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly reduced 20-HETE production during ischemia-reperfusion and reduced myocardial infarct size compared with control [19.5 ± 1.0% (control), 9.6 ± 1.5% (0.40 mg/kg DDMS), 4.0 ± 2.0% (0.81 mg/kg DDMS), P < 0.01]. In addition, 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (20-HEDE, a putative 20-HETE antagonist) significantly reduced myocardial infarct size from control [10.3 ± 1.3% (0.032 mg/kg 20-HEDE) and 5.9 ± 1.9% (0.064 mg/kg 20-HEDE), P < 0.05]. We further demonstrated that one 5-min period of ischemic preconditioning (IPC) reduced infarct size to a similar extent as that observed with the high doses of DDMS and 20-HEDE, and the higher dose of DDMS given simultaneously with IPC augmented the infarct size reduction [9.9 ± 2.8% (IPC) to 2.5 ± 1.4% (0.81 mg/kg DDMS), P < 0.05] to a greater degree than that observed with either treatment alone. These results suggest an important negative role for endogenous CYP ω-hydroxylases and their product, 20-HETE, to exacerbate myocardial injury in canine myocardium. Furthermore, for the first time, this study demonstrates that the effect of IPC and the inhibition of CYP ω-hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.
Rat pulmonary arterial smooth muscle myosin light chain kinase and phosphatase activities decrease with age
Authors: Belik J. , Kerc Ewa , Pato Mary D.
Published: October 2005

We and others have shown that the fetal pulmonary arterial smooth muscle potential for contraction and relaxation is significantly reduced compared with the adult. Whether these developmental changes relate to age differences in the expression and/or activity of key enzymes regulating the smooth muscle mechanical properties has not been previously evaluated. Therefore, we studied the catalytic activities and expression of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) catalytic (PP1cδ) and regulatory (MYPT) subunits in late fetal, early newborn, and adult rat intrapulmonary arterial tissues. In keeping with the greater force development and relaxation of adult pulmonary artery, Western blot analysis showed that the MLCK, MYPT, and PP1cδ contents increased significantly with age and were highest in the adult rat. In contrast, their specific activities (activity/enzyme content) were significantly higher in the fetal compared with the adult tissue. The fetal and newborn pulmonary arterial muscle relaxant response to the Rho-kinase inhibitor Y-27632 was greater than the adult tissue. In addition to the 130-kDa isoform of MLCK, we documented the presence of minor higher-molecular-weight embryonic isoforms in the fetus and newborn. During fetal life, the lung pulmonary arterial MLCK- and MLCP-specific activities are highest and appear to be related to Rho-kinase activation during lung morphogenesis.
Mechanisms of pulmonary edema clearance
Authors: Mutlu Gökhan M. , Sznajder Jacob I.
Published: October 2005

The mechanisms of pulmonary edema resolution are different from those regulating edema formation. Absorption of excess alveolar fluid is an active process that involves vectorial transport of Na+out of alveolar air spaces with water following the Na+osmotic gradient. Active Na+transport across the alveolar epithelium is regulated via apical Na+and chloride channels and basolateral Na-K-ATPase in normal and injured lungs. During lung injury, mechanisms regulating alveolar fluid reabsorption are inhibited by yet unclear pathways and can be upregulated by pharmacological means. Better understanding of the mechanisms that regulate edema clearance may lead to therapeutic interventions to improve the ability of lungs to clear fluid, which is of clinical significance.
Effect of chronic hyperghrelinemia on ingestive action of ghrelin
Authors: Wei Wei , Qi Xiang , Reed Jason , Ceci Jeff , Wang Hui-Qun , Wang Guiyun , Englander Ella W. , Greeley George H.
Published: October 2005

The stomach hormone ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Systemic administration of ghrelin will cause elevations in growth hormone (GH) secretion, food intake, adiposity, and body growth. Ghrelin also affects insulin secretion, gastric acid secretion, and gastric motility. Several reports indicate that repeated or continuous activation of GHS-R by exogenous GHSs or ghrelin results in a diminished GH secretory response. The purpose of this study was to examine the extent to which the acute stimulation of food intake by exogenous ghrelin is altered by chronic hyperghrelinemia in transgenic mice that overexpress the human ghrelin gene. The present findings show that the orexigenic action of exogenous ghrelin is not diminished by a chronic hyperghrelinemia and indicate that the food ingestive pathway of the GHS-R is not susceptible to desensitization. In contrast, the epididymal fat pad growth response, like the GH response, to exogenous ghrelin is blunted in ghrelin transgenic mice with chronic hyperghrelinemia.
Blockade of AT1 receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions
Authors: Sheriff Mohammed J. , Fontes Marco A. P. , Killinger Suzanne , Horiuchi Jouji , Dampney Roger A. L.
Published: October 2005

The role of ANG type 1 (AT1) receptors in the rostral ventrolateral medulla (RVLM) in the maintenance of sympathetic vasomotor tone in normotensive animals is unclear. In this study, we tested the hypothesis that AT1 receptors make a significant contribution to the tonic activity of presympathetic neurons in the RVLM of normotensive rats under conditions where the excitatory input to these neurons is enhanced, such as during systemic hypoxia. In urethane-anesthetized rats, microinjections of the AT1 receptor antagonist candesartan in the RVLM during moderate hypoxia unexpectedly resulted in substantial increases in arterial pressure and renal sympathetic nerve activity (RSNA), whereas under normoxic conditions the same dose resulted in no significant change in arterial pressure and RSNA. Under hypoxic conditions, and after microinjection of the GABAA receptor antagonist bicuculline in the RVLM, subsequent microinjection of candesartan in the RVLM resulted in a significant decrease in RSNA. In control experiments, bilateral microinjections in the RVLM of the compound [Sar1,Thr8]ANG II (sarthran), which decreases sympathetic vasomotor activity via a mechanism that is independent of AT1 receptors, significantly reduced arterial pressure and RSNA under both normoxic and hypoxic conditions. The results indicate that, at least under some conditions, endogenous ANG II has a tonic sympathoinhibitory effect in the RVLM, which is dependent on GABA receptors. We suggest that the net effect of endogenous ANG II in this region depends on the balance of both tonic excitatory and inhibitory actions on presympathetic neurons and that this balance is altered in different physiological or pathophysiological conditions.
Applicability of segmental bioelectrical impedance analysis for predicting trunk skeletal muscle volume
Authors: Ishiguro Noriko , Kanehisa Hiroaki , Miyatani Masae , Masuo Yoshihisa , Fukunaga Tetsuo
Published: October 2005

This study aimed to investigate the validity of using segmental bioelectrical impedance (BI) analysis for estimating skeletal muscle volume (MV) in the trunk, defined as the body segment from the acromion process to the greater trochanter. Using a magnetic resonance imaging (MRI) method, the trunk MV was determined in 28 men (19∼34 yr), divided into validation ( n = 20) and cross-validation ( n = 8) groups, and used as a reference (MVMRI). For BI measurements of the trunk, the source electrodes were placed at the dorsal surface of the third metacarpal bone of both hands and the dorsal surface of the third metatarsal bone of both feet, and the detector electrodes were placed at the acromion process of both shoulders and the greater trochanter of both femurs. Using this arrangement, the BI values of five parts of the trunk, both sides of the upper region, the middle region, and both sides of the lower region, were obtained and then used to calculate the whole trunk BI value and BI index (BI indexTR). In the validation group, a simple regression analysis of the relationship between BI indexTR and MVMRI showed a significant correlation between the two variables ( r = 0.884, P < 0.05) and produced a prediction equation with a SE of estimation of 1,020.3 cm3 (8.5%). In the validation and cross-validation groups, there were no significant differences between the measured and estimated MV without systematic errors. These findings indicate that the segmental BI analysis employed in the present study can be used to estimate trunk MV.
Vasoactive mediators and pulmonary hypertension after cigarette smoke exposure in the guinea pig
Authors: Wright Joanne L. , Tai Hsin , Churg Andrew
Published: October 2005

The pathogenesis of pulmonary hypertension in patients with chronic obstructive pulmonary disease is not understood. We have previously shown increased levels of mediators that control vasoconstriction (endothelin-1), vascular cell proliferation (endothelin-1 and vascular endothelial growth factor), and vasodilation (endothelial nitric oxide synthase) in the intrapulmonary arteries of animals exposed to cigarette smoke. To determine whether these mediators could be implicated in the structural remodeling of the arterial vasculature and increased pulmonary arterial pressure caused by chronic cigarette smoke exposure, guinea pigs were exposed to daily cigarette smoke for 6 mo. Pulmonary arterial pressures were measured. Intrapulmonary artery structure was analyzed by morphometry, artery mediator protein expression by immunohistochemistry, and artery mediator gene expression by laser capture microdissection and real-time RT-PCR. We found that the smoke-exposed animals developed increases in pulmonary arterial pressure and increased muscularization of the small pulmonary arteries. Gene expression and protein levels of all three mediators were increased, and pulmonary arterial pressure correlated both with the levels of mediator production and with the degree of arterial muscularization. We conclude that chronic smoke exposure produces increased vasoactive mediator expression in the small intrapulmonary arteries and that these mediators are associated with vascular remodeling as well as increased pulmonary arterial pressure. These findings support the idea that hypertension in chronic obstructive pulmonary disease is a result of direct cigarette smoke-mediated effects on the vasculature and suggest that interference with endothelin and VEGF production and activity or augmentation of nitric oxide levels may be beneficial.
Chlamydia pneumoniae
Burden in Carotid Arteries Is Associated With Upregulation of Plaque Interleukin-6 and Elevated C-Reactive Protein in Serum
Authors: Johnston S. Claiborne , Zhang Hui , Messina Louis M. , Lawton Michael T. , Dean Deborah
Published: October 2005

Objective—

Chlamydia pneumoniae
(Cpn) infection of vascular smooth muscle cells increases interleukin-6 (IL-6) secretion in vitro. In vivo, IL-6 stimulates liver C-reactive protein (CRP) production. Because serum levels of IL-6 and CRP are independent risk factors for stroke and myocardial infarction (MI), we investigated whether Cpn burden in carotid plaques might provide a link between plaque IL-6 expression and elevated serum levels of IL-6 and CRP.

Methods and Results—

Consecutive patients undergoing elective carotid endarterectomy were studied. Serum levels of CRP and IL-6 were measured before surgery. Immunohistochemistry and real-time quantitative (k)RT-PCR were used to detect Cpn and the expression of IL-6 within carotid plaques. Cpn mRNA was present in 19 (37%) of 51 patients, suggesting viable infections. These patients had evidence for infection by PCR and immunohistochemistry. The Cpn burden, measured by real-time quantitative (k)-PCR using the number of organisms normalized against the number of eukaryotic cells in the tissue, was associated with plaque expression of IL-6 (Spearman
R
=0.55;
P
<0.0001), which was associated with serum levels of IL-6 (
R
=0.56;
P
<0.0001) and CRP (
R
=0.80;
P
<0.0001).

Conclusions—

IL-6 secretion in atherosclerotic plaques infected with Cpn could explain elevated serum inflammatory markers in individuals at risk for stroke and MI.
A Novel Inhibitor of Oxidosqualene:Lanosterol Cyclase Inhibits Very Low–Density Lipoprotein Apolipoprotein B100 (ApoB100) Production and Enhances Low-Density Lipoprotein ApoB100 Catabolism Through Marked Reduction in Hepatic Cholesterol Content
Authors: Telford Dawn E. , Lipson Sara M. , Barrett P. Hugh R. , Sutherland Brian G. , Edwards Jane Y. , Aebi Johannes D. , Dehmlow Henrietta , Morand Olivier H. , Huff Murray W.
Published: October 2005

Objective—

Inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), an enzyme in the cholesterol synthesis pathway, has the unique ability to inhibit cholesterol synthesis while simultaneously enhancing oxysterol synthesis. Our objectives were to determine, in vivo, if a novel OSC inhibitor reduced low-density lipoprotein (LDL) cholesterol and to define the mechanism(s) involved.

Methods and Results—

Miniature pigs received the OSC inhibitor RO0717625 or placebo and a diet containing fat (34% of energy) and 400 mg per day of cholesterol. Treatment decreased plasma total cholesterol (−20%) and LDL cholesterol (−29%). Apolipoprotein B (apoB) kinetic parameters were determined. Very low–density lipoprotein (VLDL) apoB pool size decreased 22% because of inhibition of VLDL production (−43%). LDL apoB pool size decreased 22% because of a 1.5-fold increase in fractional catabolic rate (FCR). The increased FCR was associated with a 2-fold increase in hepatic LDL receptor mRNA. Hepatic total and microsomal cholesterol were reduced by 16% and 27%, respectively. Plasma lathosterol concentrations decreased 57%, reflecting inhibition of hepatic cholesterol synthesis. Treatment reduced plasma plant sterols and decreased postprandial cholesterol transport in chylomicrons.

Conclusions—

A novel OSC inhibitor, RO0717625, decreased VLDL and LDL apoB100 through decreased VLDL production and enhanced LDL clearance. Thus, OSC represents a potential therapeutic target for dyslipidemia.
Smoking, Endothelial Function, and Rho-Kinase in Humans
Authors: Noma Kensuke , Goto Chikara , Nishioka Kenji , Hara Keiko , Kimura Masashi , Umemura Takashi , Jitsuiki Daisuke , Nakagawa Keigo , Oshima Tetsuya , Chayama Kazuaki , Yoshizumi Masao , Higashi Yukihito
Published: October 2005

Objective—

Smoking is associated with endothelial dysfunction and activated Rho-kinase in vascular smooth muscle cells (VSMCs) in humans. The purpose of this study was to elucidate the relationship between endothelial function and Rho-kinase activity in forearm VSMCs in healthy young men.

Methods and Results—

We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), fasudil, a Rho-kinase inhibitor, and sodium nitroprusside (SNP) in male smokers (n=10) and nonsmokers (n=14). FBF was measured by using a strain-gauge plethysmography. The vasodilatory effect of ACh was significantly smaller in smokers than that in nonsmokers. The vasodilatory effect of fasudil was significantly greater in smokers than that in nonsmokers. The vasodilatory effects of SNP in the 2 groups were similar. There was a significant correlation between the maximal FBF response to fasudil and that to ACh (
r
=−0.67;
P
<0.01). There was no significant correlation between the maximal FBF response to fasudil and that to SNP. The intra-arterial coinfusion of fasudil significantly increased the FBF response to ACh in smokers but not in nonsmokers. There were no significant differences between FBF response to fasudil alone and that in combination with
N
G
-monomethyl-
l
-arginine in smokers and in nonsmokers. The intra-arterial coinfusion ascorbic acid did not alter the FBF response to fasudil in both groups.

Conclusions—

These findings suggest that smoking is involved in not only endothelial dysfunction but also activation of Rho-kinase in VSMCs in forearm circulation, and that there is a significant correlation between endothelial function and Rho-kinase activity in VSMCs.
Hyperhomocystinemia Impairs Endothelial Function and eNOS Activity via PKC Activation
Authors: Jiang Xiaohua , Yang Fan , Tan Hongmei , Liao Dan , Bryan Robert M. , Randhawa Jaspreet K. , Rumbaut Rolando E. , Durante William , Schafer Andrew I. , Yang Xiaofeng , Wang Hong
Published: October 2005

Objective—A risk factor for cardiovascular disease, hyperhomocystinemia (HHcy), is associated with endothelial dysfunction. In this study, we examined the mechanistic role of HHcy in endothelial dysfunction.

Methods and Results—Through the use of 2 functional models, aortic rings and intravital video microscopy of the cremaster, we found that arterial relaxation in response to the endothelium-dependent vessel relaxant, acetylcholine or the nitric oxide synthase (NOS) activator (A23187), was significantly impaired in cystathionine β-synthase null (CBS−/−) mice. However, the vascular smooth muscle cell (VSMC) response to the nitric oxide (NO) donor (SNAP) was preserved in CBS−/−mice. In addition, superoxide dismutase and catalase failed to restore endothelium-dependent vasodilatation. Endothelial nitric oxide synthase (eNOS) activity was significantly reduced in mouse aortic endothelial cells (MAECs) of CBS−/−mice, as well as in Hcy-treated mouse and human aortic endothelial cells (HAECs). Hcy-mediated eNOS inhibition—which was not rescued by adenoviral transduction of superoxide dismutase and glutathione peroxidase, or by tetrahydrobiopterin, sepiapterin, and arginine supplementations in MAEC—was associated with decreased protein expression and increased threonine 495 phosphorylation of eNOS in HAECs. Ultimately, a protein kinase C (PKC) inhibitor, GF109203X (GFX), reversed Hcy-mediated eNOS inactivation and threonine 495 phosphorylation in HAECs.

Conclusions—These data suggest that HHcy impairs endothelial function and eNOS activity, primarily through PKC activation.
Calreticulin Destabilizes Glucose Transporter-1 mRNA in Vascular Endothelial and Smooth Muscle Cells Under High-Glucose Conditions
Authors: Totary-Jain Hana , Naveh-Many Tally , Riahi Yael , Kaiser Nurit , Eckel Jürgen , Sasson Shlomo
Published: October 2005

Substrate autoregulation of glucose transporter-1 (GLUT-1) mRNA and protein expression provides vascular endothelial and smooth muscle cells a sensitive mechanism to adapt their rate of glucose transport in response to changing glycemic conditions. Hyperglycemia-induced downregulation of glucose transport is particularly important in protecting these cells against an excessive influx of glucose and consequently increased intracellular protein glycation and generation of free radicals; both are detrimental in the development of vascular disease in diabetes. We aimed to investigate the molecular mechanism of high glucose–induced downregulation of GLUT-1 mRNA expression in primary bovine aortic vascular endothelial (VEC) and smooth muscle (VSMC) cell cultures. Using RNA mobility shift, UV cross-linking, and in vitro degradation assays, followed by mass-spectrometric analysis, we identified calreticulin as a specific destabilizing
trans
-acting factor that binds to a 10-nucleotide
cis
-acting element (CAE
2181-2190
) in the 3′-untranslated region of GLUT-1 mRNA. Pure calreticulin accelerated the rate of GLUT-1 mRNA-probe degradation in vitro, whereas overexpression of calreticulin in vascular cells decreased significantly the total cell content of GLUT-1 mRNA and protein. The expression of calreticulin was augmented in vascular cells exposed to high glucose in comparison with low-glucose conditions. Similarly, increased expression of calreticulin was observed in aortae of diabetic
Psammomys obesus
in comparison with normoglycemic controls. These data suggest that CAE
2181-2190
–calreticulin complex, which is formed in VSMC and VEC exposed to hyperglycemic conditions, renders GLUT-1 mRNA susceptible to degradation. This interaction underlies the process of downregulation of glucose transport in vascular cells under high-glucose conditions.
When a Parent Has a Stroke
Authors: Visser-Meily Anne , Post Marcel , Meijer Anne Marie , van de Port Ingrid , Maas Cora , Lindeman Eline
Published: October 2005

Background and Purpose—

The purpose of this research was to describe the clinical course of children’s functioning (depression, behavioral problems, and health status) during the first year after parental stroke and to determine which patient-, spouse-, or child-related factors at the start of inpatient rehabilitation can predict children’s functioning after parental stroke at 1-year poststroke.

Methods—

Interviews with 82 children (4 to 18 years of age) and their parents (n=55) shortly after admission to a rehabilitation center, 2 months after discharge from inpatient rehabilitation, and 1 year after stroke. Depression was assessed using the Children Depression Inventory, behavioral problems with the Child Behavior Check List, and health status with the Functional Status II. Potential predictors were gender and age (child), activities of daily living disability and communication ability (patient), and spouse’s depression and perception of the marital relationship.

Results—

At the start of the stroke patient’s rehabilitation, 54% of the children had ≥1 subclinical or clinical problems, which improved to 29% 1 year after stroke. Children’s functioning 1 year after stroke could best be predicted by their functioning at the start of rehabilitation. Spouse depression and perception of marital relationship were also significant predictors. A total of 28% to 58% of the variance in children’s functioning could be explained.

Conclusions—

Children’s functioning after parental stroke improved during the first year after stroke. Identifying children at risk for problems 1 year after stroke requires assessment of children’s functioning and the healthy spouse’s depressive symptoms and perception of the marital relationship at the start of rehabilitation. This demonstrates the need for a family-centered approach in stroke rehabilitation.
Poor Outcomes in Patients Who Do Not Receive Intravenous Tissue Plasminogen Activator Because of Mild or Improving Ischemic Stroke
Authors: Smith Eric E. , Abdullah Abdul R. , Petkovska Iva , Rosenthal Eric , Koroshetz Walter J. , Schwamm Lee H.
Published: October 2005

Background and Purpose—

Some patients with mild or improving ischemic stroke symptoms do not receive intravenous tissue plasminogen activator (tPA) because they look “too good to treat” (TGT); however, some have poor outcomes.

Methods—

We retrospectively analyzed data from a prospective single-center study between 2002 and 2004. TGT patients were those arriving within 3 hours of symptom onset and not treated with intravenous tPA solely because of mild or improving symptoms.

Results—

Of 128 patients presenting within 3 hours, 41 (34%) were not given tPA because of mild or improving stroke. Of the TGT patients, 11 of 41 (27%) died or were not discharged home because of neurological worsening (n=6) or persistent “mild” neurological deficit (n=5). No single variable at presentation was associated with death or lack of home discharge. There were 10 of 41 TGT patients (24%) who had ≥4-point improvement in National Institutes of Health Stroke Scale score before tPA decision; these patients were more likely to have subsequent neurological worsening (relative risk, 4.1, 95% CI, 1.1 to 15.4;
P
=0.05).

Conclusion—

A substantial minority of patients deemed too good for intravenous tPA were unable to be discharged home. A re-evaluation of the stroke severity criteria for tPA eligibility may be indicated.
Independent Meeting Planners
Authors: Toh Rex S. , Dekay C. Frederick , Yates Barbara
Published: October 2005

Corporations and associations have outsourced meeting-planning functions to third-party planners, who are independent contractors. While the corporations and associations remain responsible for the meetings’ content, independent planners typically handle all other details, in particular, finding venues and negotiating contracts. Most of an independent planner’s business depends on a reputation for fair dealing, referrals, and continued relationships. Thus, the best planners are careful to ensure that all parties are aware of all contract provisions, including those for commissions. Planners also ensure that the hotels treat meeting clients fairly when not all rooms in the block are picked up and it is necessary to invoke attrition clauses.
Managing Tourism Crises
Authors: Plog Stanley C.
Published: October 2005

The world of Lily Shum, formerly with Hong Kong Tourism Board, involves finding ways to draw people to Hong Kong. Complications are many, particularly since most obstacles to attracting travelers are beyond her control. Nevertheless, she has overcome many challenges—including Severe Acute Respiratory Syndrome—to keep Hong Kong in the forefront as a travel destination.
Lessons from Hong Kong
Authors: Tang Fang-Fang , Xi Yanping
Published: October 2005

The example of the Hong Kong Tourism Board demonstrates both the effective approaches for marketing a destination and the pitfalls of straying too far from the core marketing function. In particular, the experience of the Hong Kong Tourism Board is contrasted with that of tourism boards in cities in mainland China. The mainland boards’ energies are sidetracked by such functions as ensuring that hotels’ star ratings are correct, which absorb resources that should be used for promotion.
The Effects of Augmentation with Swine Small Intestine Submucosa on Tendon Healing under Tension
Authors: Schlegel Theodore F. , Hawkins Richard J. , Lewis Chad W. , Motta Tatiana , Turner A. Simon
Published: October 2005

Background

Rotator cuff failure after surgery may be attributed to inferior tissue healing properties that result from repetitive cyclic loading during early rehabilitation. Enhancing the biological healing process may reduce the incidence of failures after rotator cuff repairs.

Hypothesis

Augmentation of rotator cuff tissue using swine small intestine submucosa in a sheep model will improve the rate and quality of tissue repair.

Study Design

Controlled laboratory study.

Methods

We resected and reattached 26 sheep infraspinatus tendons under tension, with 13 animals receiving a small intestine submucosa patch (augmented group). Animals were sacrificed at 12 weeks, and biomechanical testing and histologic evaluation were performed. Biomechanical testing was completed in 10 tendons from each group. Specimens were loaded to failure at a constant displacement to obtain the load deformation curve used to calculate load to failure and stiffness of the healed bone-tendon interface. Histologic testing addressed tissue healing at the bone-tendon interface.

Results

The load-to-failure data did not indicate a significant difference between the augmented and nonaugmented groups (1252 ± 402 N vs 985 ± 459 N, respectively; P >. 05). However, the augmented group had significantly better stiffness than the nonaugmented group (215 ± 44 N/mm vs 154 ± 63 N/mm, respectively; P =. 03). Histologic data revealed that the infraspinatus tendon in all specimens inserted into the bone through a zone of fibrocartilage, although none of the patches were intact.

Conclusion

Although there were no differences in the load-to-failure data between the 2 groups, the statistically significant improvement in stiffness for the augmented group is clinically relevant. Stiffness is the biomechanical parameter representing the tissue response to subdestructive loads seen with early rehabilitation. Augmenting the repair with a collagen matrix improved the early healing characteristics of the repair construct.

Clinical Relevance

Enhancing the biological process of tendon healing under tension by using a collagen matrix patch may improve the ultimate success of rotator cuff repair.
Femoral Press-Fit Fixation Technique in Anterior Cruciate Ligament Reconstruction Using Bone-Patellar Tendon-Bone Graft
Authors: Pavlik Attila , Hidas Péter , Tállay András , Toman József , Berkes István
Published: October 2005

Background

The security of the graft fixation is an important factor of anterior cruciate ligament reconstruction, especially in the early postoperative period.

Hypothesis

The femoral press-fit fixation technique is a safe, alternative technique for the fixation of the bone-patellar tendon-bone graft.

Study Design

Case series; Level of evidence, 4.

Methods

Between January 1, 1998, and June 30, 2002, 285 patients, with a mean age of 29.1 years, underwent operation and observation in our department. All patients had arthroscopic anterior cruciate ligament reconstruction using bone-patellar tendon-bone graft with femoral press-fit and tibial interference screw fixation. The mean follow-up period was 35.8 months (range, 24-77 months). During each patient's evaluation, a physical examination, a subjective evaluation, the International Knee Documentation Committee and Lysholm scores, KT-1000 arthrometer testing, and radiological evaluation were performed. The paired Student t test or X2 test was used for statistical analysis.

Results

According to the International Knee Documentation Committee score, 241 patients (85%) had good (46 normal and 195 nearly normal) results, whereas 39 patients had abnormal and 5 patients had severely abnormal overall results. The preoperative mean Lysholm score was 63.5 ± 12.7 points. At the final examination, the mean value was 93.5 ± 7.8 points (P <. 01). One hundred ninety-seven athletes could return to their previous sports activity level, whereas 13 patients gave up their sports career. The KT-1000 arthrometer results showed a side-to-side difference of 1.91 ± 2.1 mm at the maximum manual strength tests.

Conclusion

The femoral press-fit fixation is an alternative fixation method for the bone-patellar tendon-bone graft and provides good stability for the anterior cruciate ligament reconstruction. The use of press-fit fixation technique avoids most interference screw or other hardware-induced complications at the femoral side.
Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo
Authors: Gil M. Pilar , Salomon Rachelle , Louten Jennifer , Biron Christine A.
Published: October 2005

Type 1 interferons (IFNs) are induced in vivo, administered therapeutically, and potential targets for amelioration of autoimmune diseases. The cytokines mediate profound antiproliferative effects. Signal transducer and activator of transcription 1 (STAT1)-dependent signaling pathways are required for inhibition of proliferation, and viral infections can elicit high levels of type 1 IFNs as well as total STAT1 protein expression. Thus, a mechanism must be in place to help antigen-specific T cells overcome IFN-induced inhibition of proliferation. The studies reported here demonstrate that total CD8 T-cell proliferation in the presence of IFNs, ex vivo in response to cytokines and in vivo during viral infection, is inhibited through a STAT1-dependent mechanism. In contrast, major proportions of antigen-specific CD8, but not CD4, T cells are rendered less sensitive to this inhibition, express lower endogenous levels of total STAT1, and are selectively proliferating in the presence of type 1 IFN, at key times after viral challenge. Taken together, these novel results show that differential STAT1 expression is used by the immune system to modify cytokine-mediated effects on T-cell expansion and have implications for the consequences of therapeutic intervention in cytokine function.
Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells
Authors: Coenen Jeroen J. A. , Koenen Hans J. P. M. , van Rijssen Esther , Hilbrands Luuk B. , Joosten Irma
Published: October 2005

The immunosuppressive drugs rapamycin and cyclosporin A (CsA) are widely used to prevent allograft rejection. Moreover, they were shown to be instrumental in experimental models of tolerance induction. However, it remains to be elucidated whether these drugs have an effect on the CD4+CD25+ regulatory T-cell (TREG) population, which plays an important role in allograft tolerance. Recently, we reported that alloantigen-driven expansion of human CD4+CD25+ TREGs gives rise to a distinct highly suppressive CD27+TREG subset next to a moderately suppressive CD27-TREG subset. In the current study we found that rapamycin and CsA do not interfere with the suppressive activity of human naturally occurring CD4+CD25+ T cells. However, in contrast to CsA, rapamycin preserved the dominance of the potent CD27+TREG subset over the CD27-TREG subset after alloantigen-driven expansion of CD4+CD25+ TREGs in vitro. Accordingly, CD4+CD25+ TREGs cultured in the presence of rapamycin displayed much stronger suppressive capacity than CD4+CD25+ TREGs cultured in the presence of CsA. In addition, CD4+CD25+ TREG cells cultured in the presence of rapamycin, but not CsA, were able to suppress ongoing alloimmune responses. This differential effect of rapamycin and CsA on the CD27+TREG subset dominance may favor the use of rapamycin in tolerance-inducing strategies.
Sequential heart and autologous stem cell transplantation for systemic AL amyloidosis
Authors: Gillmore Julian D. , Goodman Hugh J. , Lachmann Helen J. , Offer Mark , Wechalekar Ashutosh D. , Joshi Jayshree , Pepys Mark B. , Hawkins Philip N.
Published: October 2005

Extensive cardiac amyloid deposition in systemic AL amyloidosis is associated with a grave prognosis. Heart transplantation is rarely performed because of the systemic and progressive nature of the disease. Patients with severe cardiac amyloid infiltration are ineligible for the preferred treatment of melphalan chemotherapy with stem cell transplantation (SCT) rescue because of the high risk for treatment-related mortality. Heart transplantation followed by SCT was performed in 5 patients with AL amyloidosis and predominant cardiomyopathy. Patients were followed up for a median of 95 months (range, 37-118 months) from diagnosis. At censor, 3 of 5 patients were well without evidence of intracardiac or extracardiac amyloid accumulation, and median overall survival by Kaplan-Meier estimate was not reached. Two patients died of progressive amyloidosis 33 and 90 months after heart transplantation after relapse of their underlying plasma cell dyscrasia. Heart transplantation followed by SCT is feasible in selected patients with cardiac AL amyloidosis and may confer substantial survival benefit.