bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of short-term vibration and hypoxia during high-intensity cycling exercise on circulating levels of angiogenic regulators in humans
Authors: Suhr Frank , Brixius Klara , de Marées Markus , Bölck Birgit , Kleinöder Heinz , Achtzehn Silvia , Bloch Wilhelm , Mester Joachim
Published: April 2007

This study aimed to investigate the biological response to hypoxia as a stimulus, as well as exercise- and vibration-induced shear stress, which is known to induce angiogenesis. Twelve male cyclists (27.8 ± 5.4 yr) participated in this study. Each subject completed four cycle training sessions under normal conditions (NC) without vibration, NC with vibration, normobaric hypoxic conditions (HC) without vibration, and HC with vibration. Each session lasted 90 min, and sessions were held at weekly intervals in a randomized order. Five blood samples (pretraining and 0 h post-, 0.5 h post-, 1 h post-, and 4 h posttraining) were taken from each subject at each training session. Hypoxia was induced by a normobaric hypoxic chamber with an altitude of 2,500 m. The mechanical forces (cycling with or without vibration) were induced by a cycling ergometer. The parameters VEGF, endostatin, and matrix metalloproteinases (MMPs) were analyzed using the ELISA method. VEGF showed a significant increase immediately after the exercise only with exogenously induced vibrations, as calculated with separate ANOVA analysis. Endostatin increased after training under all conditions. Western blot analysis was performed for the determination of endostatin corresponding to the 22-kDa cleavage product of collagen XVIII. This demonstrated elevated protein content for endostatin at 0 h postexercise. MMP-2 increased in three of the four training conditions. The exception was NC with vibration. MMP-9 reached its maximum level at 4 h postexercise. In conclusion, the results support the contention that mechanical stimuli differentially influence factors involved in the induction of angiogenesis. These findings may contribute to a broader understanding of angiogenesis.
Temporal differences in the influence of ischemic factors and deformation on the metabolism of engineered skeletal muscle
Authors: Gawlitta Debby , Oomens Cees W. J. , Bader Dan L. , Baaijens Frank P. T. , Bouten Carlijn V. C.
Published: April 2007

Prolonged periods of tissue compression may lead to the development of pressure ulcers, some of which may originate in, for example, skeletal muscle tissue and progress underneath intact skin, representing deep tissue injury. Their etiology is multifactorial and the interaction between individual causal factors and their relative importance remain unknown. The present study addressed the relative contributions of deformation and ischemic factors to altered metabolism and viability. Engineered muscle tissue was prepared as previously detailed ( 14 ) and subjected to a combination of factors including 0% oxygen, lactic acid concentrations resulting in pH from 5.3 to 7.4, 34% compression, and low glucose levels. Deformation had an immediate effect on tissue viability {[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay}, which increased with time. By contrast, hypoxia evoked metabolic responses (glucose and lactate levels) within 24 h, but viability was only reduced after 48 h. In addition, lactic acidification downregulated tissue metabolism up to an acid concentration (∼23 mM) where metabolism was arrested and cell death enhanced. A similar tissue response was observed during glucose deprivation, which, at negligible concentration, resulted in both a cessation of metabolic activity and a reduction in cell viability. The combination of results suggests that in a short-term (<24 h) deformation, extreme acidification and glucose deprivation increased the level of cell death. By contrast, nonextreme acidification and hypoxia influenced tissue metabolism, but not the development of cell death. These data provide more insight into how compression-induced factors can lead to the onset of deep tissue injury.
Muscle Quality, Aerobic Fitness and Fat Mass Predict Lower-Extremity Physical Function in Community-Dwelling Older Adults
Authors: Misic Mark M. , Rosengren Karl S. , Woods Jeffrey A. , Evans Ellen M.
Published: April 2007

Background: Muscle mass, strength and fitness play a role in lower-extremity physical function (LEPF) in older adults; however, the relationships remain inadequately characterized. Objective: This study aimed to examine the relationships between leg mineral free lean mass (MFLMLEG), leg muscle quality (leg strength normalized for MFLMLEG), adiposity, aerobic fitness and LEPF in community-dwelling healthy elderly subjects. Methods: Fifty-five older adults (69.3 ± 5.5 years, 36 females, 19 males) were assessed for leg strength using an isokinetic dynamometer, body composition by dual energy X-ray absorptiometry and aerobic fitness via a treadmill maximal oxygen consumption test. LEPF was assessed using computerized dynamic posturography and stair ascent/descent, a timed up-and-go task and a 7-meter walk with and without an obstacle. Results: Muscle strength, muscle quality and aerobic fitness were similarly correlated with static LEPF tests (r range 0.27–0.40, p < 0.05); however, the strength of the independent predictors was not robust with explained variance ranging from 9 to 16%. Muscle quality was the strongest correlate of all dynamic LEPF tests (r range 0.54–0.65, p < 0.001). Using stepwise linear regression analysis, muscle quality was the strongest independent predictor of dynamic physical function explaining 29–42% of the variance (p < 0.001), whereas aerobic fitness or body fat mass explained 5–6% of the variance (p < 0.05) depending on performance measure. Conclusions: Muscle quality is the most important predictor, and aerobic fitness and fat mass are secondary predictors of LEPF in community-dwelling older adults. These findings support the importance of exercise, especially strength training, for optimal body composition, and maintenance of strength and physical function in older adults.
Temporal Relationship between Renal Cyst Development, Hypertension and Cardiac Hypertrophy in a New Rat Model of Autosomal Recessive Polycystic Kidney Disease
Authors: Phillips Jacqueline K. , Hopwood Deborah , Loxley Rhonda A. , Ghatora Kamaljit , Coombes Jason D. , Tan Ying Sin , Harrison Joanne L. , McKitrick Douglas J. , Holobotvskyy Vasyl , Arnolda Leonard F. , Rangan Gopala K.
Published: April 2007

Background/Methods: We have examined the hypothesis that cyst formation is key in the pathogenesis of cardiovascular disease in a Lewis polycystic kidney (LPK) model of autosomal-recessive polycystic kidney disease (ARPKD), by determining the relationship between cyst development and indices of renal function and cardiovascular disease. Results: In the LPK (n = 35), cysts appear at week 3 (1.1 ± 0.1 mm) increasing to week 24 (2.8 ± 2 mm). Immunostaining for nephron-specific segments indicate cysts develop predominantly from the collecting duct. Cyst formation preceded hypertension (160 ± 22 vs. Lewis control 105 ± 20 mm Hg systolic blood pressure (BP), n = 12) at week 6, elevated creatinine (109 ± 63 vs. 59 ± 6 µmol/l, n = 16) and cardiac mass (0.7 vs. 0.4% bodyweight, n = 15) at week 12, and left ventricular hypertrophy (2,898 ± 207 vs. 1,808 ± 192 µm, n = 14) at week 24 (all p ≤ 0.05). Plasma-renin activity and angiotensin II were reduced in 10- to 12-week LPK (2.2 ± 2.9 vs. Lewis 11.9 ± 4.9 ng/ml/h, and 25.0 ± 19.1 vs. 94.9 ± 64.4 pg/ml, respectively, n = 26, p ≤ 0.05). Ganglionic blockade (hexamethonium 3.3 mg/kg) significantly reduced mean BP in the LPK (52 vs. Lewis 4%, n = 9, p ≤ 0.05). Conclusion: Cyst formation is a key event in the genesis of hypertension while the sympathetic nervous system is important in the maintenance of hypertension in this model of ARPKD.
Sutureless Vascular Anastomoses by N-Butyl-2 Cyanoacrylate Adhesive: An Experimental Animal Study
Authors: Saba D. , Yilmaz M. , Yavuz H. , Noyan S. , Avci B. , Ercan A. , Ozkan H. , Cengiz M.
Published: April 2007

Background: The purpose of this animal study was to find out whether sutureless anastomoses using N-butyl-2-cyanoacrylate were effective in the suppression of neointimal hyperplasia or not. Material and Methods: Ten male adult mongrel dogs were used in this animal study. The animals were randomly divided into a control group (n = 5) and a study group (n = 5). The study group underwent sutureless anastomoses using N-buthyl-2-cyanoacrylate adhesive. Infrarenal aortoaortic graft was interposed using polytetrafluoroethylene. Results: In the study group, the mean intimal thickness at the proximal anastomosis was 27.4 ± 1.94 µm and 27.4 ± 1.51 µm at the distal anastomosis. In the control group, the mean intimal thickness was 138.4 ± 5.02 µm at the proximal anastomosis and 67.6 ± 6.42 µm at the distal anastomosis. Intimal thickness at the proximal and distal anastomoses in the control group was significantly (p < 0.001) greater than in the study group. Also, perianastomotic inflammation was more obvious in the control group compared to the study group (p < 0.01). Conclusion: Sutureless anastomoses using with N-butyl-2-cyanoacrylate adhesive might be a good alternative to conventional suture technique.
Surgical Treatment for Esophageal Cancer
Authors: Kato Hiroyuki , Fukuchi Minoru , Miyazaki Tatsuya , Nakajima Masanobu , Tanaka Naritaka , Inose Takanori , Kimura Hitoshi , Faried Ahmad , Saito Kana , Sohda Makoto , Fukai Yasuyuki , Masuda Norihiro , Manda Ryokuhei , Ojima Hitoshi , Tsukada Katsuhiko , Kuwano Hiroyuki
Published: April 2007

Esophageal cancer is one of the most difficult malignancies to cure. The prognosis remains unsatisfactory despite significant advances in surgical techniques and perioperative management. The optimal treatment strategy for localized esophageal cancer has not yet been established. Surgical resection remains the mainstay of treatment for esophageal cancer, and curative resection is the most important surgery. Extended esophagectomy with three-field lymphadenectomy provides the highest quality of tumor clearance and prolongation of patient survival. There has been intense effort in developing novel strategies to treat patients with resectable esophageal cancer. Various combined-modality approaches have been attempted to improve treatment outcomes. Definitive chemoradiotherapy has an impact on long-term survival in patients with resectable esophageal cancer. Accordingly, there are three main combined-modality approaches: esophagectomy with adjuvant chemotherapy or chemoradiotherapy; primary definitive chemoradiotherapy with or without salvage esophagectomy, and preoperative chemoradiotherapy followed by planned esophagectomy. Recently, owing to the remarkable advances in optical technology, minimally invasive esophagectomy using endoscopic instruments has been introduced into esophageal cancer surgery. This article reviews recent changes in the treatment of esophageal cancer surgery, and considers the role of esophagectomy.
Surgical Treatment of Advanced Gastric Cancer: Japanese Perspective
Authors: Sasako M. , Saka M. , Fukagawa T. , Katai H. , Sano T.
Published: April 2007

The results of clinical trials regarding surgery of curable advanced gastric cancer and esophagogastric junction (EGJ) tumors are reviewed and summarized. Four clinical trials have evaluated D2 dissection for curable gastric cancer in the West. Two large trials in the UK and the Netherlands failed to prove the efficacy of D2 dissection. However, these trials had critical weak points. As they were carried out in a number of hospitals where there was no experience with this surgery, the quality of surgery and postoperative care were very poor making the hospital mortality unacceptably high. After these trials, an Italian group started a phase II study in 8 hospitals with a relatively high volume to confirm the safety of this procedure for Caucasians. They achieved 3% mortality, which was much smaller than that of even D1 in the former trials. These results first highlighted the importance of learning and hospital volume in D2 dissection. Survival results of the Dutch trial showed some difference between D1 and D2, but the difference was not statistically significant. This was attributed to the high hospital mortality and poor quality of surgery, especially low compliance of D2 and the high rate of extension of D1, making this comparison similar to that between D1.3 and D1.7. The results of the phase III study by the Italian group are awaited. Recently a Taiwanese trial proved the benefit of D2 dissection over D1 in a phase III trial. This was a single institutional trial with a sample size of 221 patients. The 5-year survival rate of D2 and D1 was 59.5 and 53.6%, respectively (p = 0.04). The Dutch trials for EGJ tumors showed a large difference in overall survival between the transthoracic and transhiatal approach for Siewert type 1 and 2 tumors, but this was not statistically significant, most likely due to the small sample size. In the subgroup analysis, they demonstrated that there was no survival difference in Siewert type 2 but a large difference in Siewert type 1. A Japanese study showed that there is no benefit to the thoraco-abdominal approach over the transhiatal approach for EGJ tumors whose invasion in the esophagus is 3 cm or less. These two trials clearly demonstrated that mediastinal dissection through a right thoracotomy is recommendable for Siewert type 1, while the transhiatal approach should be considered as standard for Siewert type 2.
Surgical Treatment for Liver Cancer
Authors: Miyazaki Masaru , Kimura Fumio , Shimizu Hiroaki , Yoshidome Hiroyuki , Ohtsuka Masayuki , Kato Atushi , Yoshitomi Hideyuki , Nozawa Satoshi , Furukawa Katsunori , Takeuchi Dan , Suda Kousuke , Yoshioka Isaku , Mituhashi Noboru
Published: April 2007

Surgical treatment of hepatocellular carcinoma (HCC) has developed remarkable for several reasons. The surgical mortality rates of patients with HCC after hepatectomy have decreased due to appropriate criteria for surgery, refined surgical techniques and improvement in the pre- and postoperative management. In preoperative management, refinements in liver function tests and strategies for esophageal varices, and the induction of preoperative portal vein embolization have contributed favorably to the outcome after hepatectomy for HCC. Furthermore, hepatectomy has been technically refined by various vascular control methods and liver transection devices based on the realization that surgical anatomical information also plays a major role in improving surgical outcome. Also concomitant splenectomy with hepatectomy might extend the criteria for surgery in HCC patients with hypersplenism. Therefore, hepatectomy is a safe therapeutic approach that could bring about a favorable outcome in patients with HCC. Nowadays transplantation is one of the therapeutic options for HCC patients, even in Japan. Herein the surgical treatment of HCC in Japan is reviewed and current issues in the surgical treatment of HCC are discussed.
Liver Transplantation for Hepatocellular Carcinoma
Authors: Sawada Tokihiko , Kubota Keiichi
Published: April 2007

Hepatocellular carcinoma (HCC) has been a major reason for liver transplantation (LT). Globally, LT for HCC is performed on the basis of the Milan criteria, and if performed within those criteria, then the outcome is not different from that of LT performed for other primary diseases. On the other hand, the scope of the Milan criteria covers only early-stage HCC, and many HCC patients do not meet the criteria even at the time of diagnosis. Therefore, over the last decade, efforts have been made to perform LT for patients whose clinical characteristics lie outside the Milan criteria. In Japan, more than 99% of LTs are living donor LTs (LDLTs) and more than 15% of LTs are performed in patients with HCC. The 1- and 3-year actual survival rates of LDLT for HCC in Japan are 82 and 79%, respectively. Efforts to extend the Milan criteria have also been made in Japan. To improve the outcome of LT for HCC, pre- and postoperative management of hepatitis B and hepatitis C, and immunosuppressant specific for this type of LT are still crucial issues. In this review, we provide an overview of current outcome, efforts to extend the Milan criteria, control of viral hepatitis, and immunosuppression for LT in patients with HCC.
Status of Surgical Treatment of Biliary Tract Cancer
Authors: Ishihara Shin , Miyakawa Shuichi , Takada Tadahiro , Takasaki Ken , Nimura Yuji , Tanaka Masao , Miyazaki Masaru , Nagakawa Takukazu , Kayahara Masato , Horiguchi Akihiko
Published: April 2007

Complete surgical resection of biliary tract carcinoma remains the best treatment. The Japanese Society of Biliary Surgery has organized a registry project and established a classification of biliary tract carcinoma. We report here the status of biliary surgery in Japan. For hilar bile duct carcinoma, major hepatectomy is needed to increase the resection rate, and total caudate lobectomy is required for curative resection. The 5-year survival rate was 39.1%. Middle and distal bile duct carcinomas were treated with pancreatoduodenectomy (PD) or pylorus-preserving PD (PPPD) or bile duct resection alone. The 5-year survival rate was 44.0%. The treatment of gallbladder carcinoma with pT1 lesions is cholecystectomy. The treatment of pT2 lesions is extended cholecystectomy or various hepatectomy with or without extrahepatic bile duct resection along with lymphadenectomy. Treatment of pT3 and pT4 lesions includes hepatectomy with or without bile duct resection, combined with vascular resection, extended lymphadenectomy, and autonomic nerve dissection. Several groups in Japan have performed hepatopancreatoduodenectomy. The 5-year survival rate of pT1, pT2, pT3, and pT4 were 93.7, 65.1, 27.3, and 13.8%. PD or PPPD is the standard operation for carcinoma of the papilla of Vater. The 5-year survival rate was 57.5%.
Dynamics of Glucocorticoid Receptor and Mineralocorticoid Receptor: Implications from Live Cell Imaging Studies
Authors: Nishi Mayumi , Kawata Mitsuhiro
Published: April 2007

Adrenal corticosteroids (cortisol in humans/corticosterone in rodents) readily enter the brain and exert markedly diverse effects, such as the stress response of target neural cells. These effects are regulated via two receptor systems, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), both of which are ligand-inducible transcription factors. It is generally accepted that GR and MR predominantly reside in the cytoplasm in the absence of corticosterone (CORT), and are quickly translocated into the nucleus upon binding CORT. Then these receptors form dimers to bind hormone-responsive elements and regulate the expression of target genes. Given the different actions of MR and GR in the central nervous system, it is important to elucidate how the trafficking of these receptors between the cytoplasm and nucleus and their interaction are regulated by ligands or other molecules to exert transcriptional activity. However, the precise mechanisms of these processes are still not completely clarified. To address these issues, we have tried to observe more dynamic subcellular trafficking processes in living cells by employing a green fluorescent protein. In this review, we describe our recent studies of corticosteroid receptor dynamics in living cells focusing on three points: (1) the effects of a ligand, corticosteroid; (2) the carrier molecules involved in active nuclear transport, importins, and (3) the possibility of heterodimer formation. These studies demonstrate that GR and MR were quickly translocated from the cytoplasm to the nucleus after CORT treatment by associating with importin molecules. GR and MR differed in their response to the concentration of CORT in neural cells and non-neural cells. In the nuclear region, we detected GR-MR heterodimers, which were affected by changes in CORT concentrations in response to various hormonal milieus such as circadian rhythm and stress.
Hepatitis C in Dialysed Patients – What Is the Current Optimal Treatment?
Authors: Kes Petar , Basic-Jukic Nikolina
Published: April 2007

Hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in the dialysis population. The problem is more pronounced after renal transplantation. It seems that immunosuppressive drugs facilitate HCV replication and accelerate hepatic lesions. Interferon is not recommended after renal transplantation because of the risk of acute rejection and graft dysfunction, and for this reason it is important to eradicate HCV RNA before transplantation. Prevention is the most important treatment measure. Good clinical practice together with screening of blood products and organs is of outstanding importance. Pegylated interferon (PEG-INF) and ribavirin are currently considered to be optimal therapy for HCV infection. Pegylation delays clearance of interferon, which leads to a more potent and longer antiviral effect. The two PEG-INF formulations (alfa-2a and alfa-2b) with different pharmacokinetic characteristics are currently available. Their clearance is reduced by almost 45% in patients with end-stage renal disease. Taken together with the high prevalence of adverse effects associated with the PEG-INF, an increased awareness of their use in dialysis patients is reasonable. There are few published studies on interferon and PEG-INF therapy in uremic patients. These studies confirm that the rate of response to different interferon formulations in dialysis is much higher than in the general population, but with a higher rate of adverse events. Ribavirin increases the response rate to treatment with PEG-INF. Great caution is warranted on its use in dialysis patients, whereas in patients with renal disease it accumulates and causes a dose-related haemolysis. Current results are encouraging but limited by a small number of patients and short follow-up. Multi-centre, controlled studies with longer follow-up are needed to establish an optimal protocol for the treatment of chronic HCV infection in dialysis patients.
The Effects of Psychological Intervention on Atopic Dermatitis
Authors: Chida Yoichi , Steptoe Andrew , Hirakawa Noriaki , Sudo Nobuyuki , Kubo Chiharu
Published: April 2007

Background: Psychological interventions may be valuable in atopic dermatitis. We systematically reviewed and carried out a meta-analysis of randomized controlled trials of psychological interventions. Methods: Electronic searches and manual journal searches were carried out. Two coders independently coded study designs, participants, treatments and outcome characteristics of the studies meeting the selection criteria. Results: Eight journal articles published between 1986 and 2006 were included. Eight types of intervention were tested: aromatherapy, autogenic training, brief dynamic psychotherapy, cognitive-behavioral therapy, dermatological education and cognitive-behavioral therapy, habit reversal behavioral therapy, a stress management program, and structured educational programs. Effect sizes were computed as correlation coefficient (r), and random effects models were used in the analysis. For eczema severity, the average effect size for the 8 trials including 8 interventions was –0.367 [χ2(1) = 7.452, p = 0.006; 95% CI –0.579 to –0.108]. The average effect sizes on itching intensity (5 trials with 5 interventions) and scratching (5 trials with 4 interventions) were –0.805 [χ2(1) = 4.719, p = 0.030; 95% CI –0.971 to –0.108] and –0.620 [χ2(1) = 24.24, p < 0.0001; 95% CI –0.767 to –0.410], respectively. Conclusions: Although the present meta-analysis revealed that psychological interventions had a significant ameliorating effect on eczema severity, itching intensity and scratching in atopic dermatitis patients, a definite conclusion about their effectiveness seems premature. Accordingly, future studies should involve more sophisticated methodologies, use established measures of outcome variables, adjust for possible confounders between the intervention and control groups, and provide sufficient data to calculate the effect sizes for future meta-analyses.
Pulmonary Involvement in Behçet’s Disease
Authors: Uzun Oğuz , Erkan Levent , Akpolat Ilkser , Findik Serhat , Atıcı Atilla Güven , Akpolat Tekin
Published: April 2007

Background: Behçet’s disease (BD) is a multisystem vasculitis and pulmonary involvement in BD is reported to indicate poor prognosis and high mortality. Objectives: The aims of this study were to report on patients with pulmonary involvement and to discuss pulmonary artery thrombus and small-sized vasculitis associated with BD, with respect to previously published cases. Methods: Fifteen patients with BD and pulmonary involvement were included in this study. Massive hemoptysis was observed in all patients having pulmonary artery aneurysm (PAA). Results: Eleven patients had macroscopic pulmonary vascular disease (2 PAA, 3 PAA and thrombi and 6 only thrombi) and 3 patients had microscopic pulmonary vascular disease. The remaining patient had pulmonary cryptococcosis. Conclusions: Data regarding treatment and outcomes of patients having BD-related pulmonary emboli/infarct and small-sized vasculitis are limited. Pulmonary vasculitis affects different levels of the pulmonary artery in BD and should be classified as macroscopic and microscopic vascular disease. ‘Pulmonary artery thrombosis’ should be used instead of ‘pulmonary emboli’. Spiral CT angiography is the best radiological tool for evaluation of pulmonary problems in BD. Treatment of vasculitis should be based on the type of vascular disease and may vary among different types of vascular disease. Anticoagulation can be used in patients with microscopic vascular disease and nonaneurysmal macroscopic vascular disease. More studies are needed to clarify this issue.
Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart
Authors: Alcendor Ralph R. , Gao Shumin , Zhai Peiyong , Zablocki Daniela , Holle Eric , Yu Xianzhong , Tian Bin , Wagner Thomas , Vatner Stephen F. , Sadoshima Junichi
Published: April 2007

Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4- to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.
Adenovirus-Mediated Expression of Human Paraoxonase 3 Protects Against the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Ng Carey J. , Bourquard Noam , Hama Susan Y. , Shih Diana , Grijalva Victor R. , Navab Mohamad , Fogelman Alan M. , Reddy Srinivasa T.
Published: April 2007

Objective—

We have previously reported that human paraoxonase 3 (PON3) is an HDL-associated protein capable of preventing LDL oxidation in vitro. The objective of the present study was to determine whether elevated levels of human PON3 in mice could protect against the progression of atherosclerosis in vivo.

Methods and Results—

Twenty-six week-old apolipoprotein E–deficient mice were injected with 3×10
11
particles of adenovirus expressing either GFP alone (AdGFP) or together with human PON3 (AdPON3). Three weeks after injection, lesion area was significantly lower in AdPON3-treated mice compared with AdGFP controls. Serum from AdPON3 mice contained significantly lower levels of lipid hydroperoxides and exhibited an enhanced potential to efflux cholesterol from cholesterol-loaded macrophages. In addition, LDL was less susceptible to oxidation, whereas HDL was more capable of protecting against LDL oxidation. Exogenous human PON3 was not detected in the serum or HDL and more surprisingly we demonstrate that endogenous mouse PON3 is not associated with HDL, suggesting that the antioxidant function of PON3 is at the cellular level in mice.

Conclusions—

This study demonstrates for the first time that PON3 enhances the antiatherogenic capacity of serum and protects against the progression of atherosclerosis in vivo.
Formation of Extracellular Matrix-Digesting Invadopodia by Primary Aortic Smooth Muscle Cells
Authors: Furmaniak-Kazmierczak Emilia , Crawley Scott W. , Carter Rhonda L. , Maurice Donald H. , Côté Graham P.
Published: April 2007

Invasion of the subendothelial space by vascular smooth muscle cells (VSMCs) contributes to the development and progression of diverse cardiovascular diseases. In this report we show that the expression of activated versions of Src, Cdc42 and Rac1, or a kinase-dead but open form of the p21-activated kinase (PAK1), induces primary rat aorta VSMCs to form extracellular matrix-degrading actin-rich protrusions that are morphologically similar to the invadopodia formed by highly invasive tumor cells. The matrix-degrading structures are enriched in known markers for invadopodia, including cortactin and tyrosine-phosphorylated cortactin and contain the matrix metalloproteinases MMP-9 and MT1-MMP and the urokinase plasminogen activator receptor (uPAR). In contrast to other cell types, invadopodia formation in VSMCs is only weakly supported by the phorbol ester PBDu. Invadopodia formation by Src was dependent on Cdc42, Rac, and ERK, but not on p38 MAPK. Invadopodia formation induced by kinase-dead PAK1 required Src and ERK activity and a direct interaction with the exchange factor PIX. VSMCs embedded in a three-dimensional collagen matrix formed actin- and cortactin-rich extensions that penetrated through holes in the matrix, suggesting that invadopodia-like structures are formed in a three-dimensional environment.
Low Density Lipoprotein Undergoes Oxidation Within Lysosomes in Cells
Authors: Wen Yichuan , Leake David S.
Published: April 2007

The oxidized low density lipoprotein (LDL) hypothesis of atherosclerosis proposes that LDL undergoes oxidation in the interstitial fluid of the arterial wall. We have shown that aggregated (vortexed) nonoxidized LDL was taken up by J774 mouse macrophages and human monocyte-derived macrophages and oxidized intracellularly, as assessed by the microscopic detection of ceroid, an advanced lipid oxidation product. Confocal microscopy showed that the ceroid was located in the lysosomes. To confirm these findings, J774 macrophages were incubated with acetylated LDL, which is internalized rapidly to lysosomes, and then incubated (chase incubation) in the absence of any LDL. The intracellular levels of oxysterols, measured by HPLC, increased during the chase incubation period, showing that LDL must have been oxidized inside the cells. Furthermore, we found that this oxidative modification was inhibited by lipid-soluble antioxidants, an iron chelator taken up by fluid-phase pinocytosis and the lysosomotropic drug chloroquine, which increases the pH of lysosomes. The results indicate that LDL oxidation can occur intracellularly, most probably within lysosomes.
Association Between Disability Measures and Healthcare Costs After Initial Treatment for Acute Stroke
Authors: Dawson Jesse , Lees Jennifer S. , Chang Tou-Pin , Walters Matthew R. , Ali Myzoon , Davis Stephen M. , Diener Hans-Christoph , Lees Kennedy R.
Published: April 2007

Background and Purpose—

The distribution of 3-month modified Rankin scale (mRS) scores has been used as an outcome measure in acute stroke trials. We hypothesized that hospitalization and institutional care home stays within the first 90 days after stroke should be closely related to 90-day mRS, that each higher mRS category will reflect incremental cost, and that resource use may be less clearly linked to the National Institutes of Health Stroke Scale (NIHSS) or Barthel index.

Methods—

We examined resource use data from the GAIN International trial comparing 90-day mRS with total length of stay in hospital or other institutions during the first 90 days. We repeated analyses using NIHSS and Barthel index scores. Relationships were examined by analysis of variance (ANOVA) with Bonferroni contrasts of adjacent score categories. Estimated costs were based on published Scottish figures.

Results—

We had full data from 1717 patients. Length of stay was strongly associated with final mRS (
P
<0.0001). Each mRS increment from 0 to 1–2 to 3–4 was significant (mean length of stay: 17, 25, 44, 58, 79 days;
P
<0.0005). Ninety-five percent confidence limits for estimated costs (£) rose incrementally: 2493 to 3412, 3369 to 4479, 5784 to 7008, 7300 to 8512, 10 095 to 11 141, 11 772 to 13 560, and 2623 to 3321 for mRS 0 to 5 and dead, respectively. Weaker relationships existed with Barthel and NIHSS.

Conclusions—

Each mRS category reflects different average length of hospital and institutional stay. Associated costs are meaningfully different across the full range of mRS outcomes. Analysis of the full distribution of mRS scores is appropriate for interpretation of treatment effects after acute stroke and more informative than Barthel or NIHSS end points.
The Virtual International Stroke Trials Archive
Authors: Ali Myzoon , Bath Philip M.W. , Curram John , Davis Stephen M. , Diener Hans-Christoph , Donnan Geoffrey A. , Fisher Marc , Gregson Barbara A. , Grotta James , Hacke Werner , Hennerici Michael G. , Hommel Marc , Kaste Markku , Marler John R. , Sacco Ralph L. , Teal Philip , Wahlgren Nils-Gunnar , Warach Steven , Weir Christopher J. , Lees Kennedy R.
Published: April 2007

Background and Purpose—

Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses.

Methods—

Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing.

Results—

Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on >15 000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69±12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials.

Conclusions—

This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning.
Predictive Variables for Mortality After Acute Ischemic Stroke
Authors: Carter Angela M. , Catto Andrew J. , Mansfield Michael W. , Bamford John M. , Grant Peter J.
Published: April 2007

Background and Purpose—

Stroke is a major healthcare issue worldwide with an incidence comparable to coronary events, highlighting the importance of understanding risk factors for stroke and subsequent mortality.

Methods—

In the present study, we determined long-term (all-cause) mortality in 545 patients with ischemic stroke compared with a cohort of 330 age-matched healthy control subjects followed up for a median of 7.4 years. We assessed the effect of selected demographic, clinical, biochemical, hematologic, and hemostatic factors on mortality in patients with ischemic stroke. Stroke subtype was classified according to the Oxfordshire Community Stroke Project criteria. Patients who died 30 days or less after the acute event (n=32) were excluded from analyses because this outcome is considered to be directly attributable to the acute event.

Results—

Patients with ischemic stroke were at more than 3-fold increased risk of death compared with the age-matched control cohort. In multivariate analyses, age, stroke subtype, atrial fibrillation, and previous stroke/transient ischemic attack were predictive of mortality in patients with ischemic stroke. Albumin and creatinine and the hemostatic factors von Willebrand factor and β-thromboglobulin were also predictive of mortality in patients with ischemic stroke after accounting for demographic and clinical variables.

Conclusions—

The results indicate that subjects with acute ischemic stroke are at increased risk of all-cause mortality. Advancing age, large-vessel stroke, atrial fibrillation, and previous stroke/transient ischemic attack predict mortality; and analysis of albumin, creatinine, von Willebrand factor, and β-thromboglobulin will aid in the identification of patients at increased risk of death after stroke.
High-Sensitivity C-Reactive Protein Is Not Associated With Carotid Intima-Media Progression
Authors: Lorenz Matthias W. , Karbstein Peter , Markus Hugh S. , Sitzer Matthias
Published: April 2007

Background and Purpose—

It is unclear whether elevated serum C-reactive protein (CRP) is causal to the initiation and progression of atherosclerosis. We undertook a prospective longitudinal cohort study to address this question.

Methods—

In a population-based sample of 3122 subjects, we measured carotid intima media thickness (IMT) at baseline and after 3 years and surveyed clinical events. Associations between baseline high-sensitivity CRP (hs-CRP) and baseline IMT, and IMT progression were determined before and after controlling for vascular risk factors. The relationship between baseline IMT and clinical events during follow up was determined.

Results—

All vascular risk factors were significantly associated with hs-CRP (
P
<0.001). Hs-CRP was significantly associated with baseline IMT in all carotid segments (
P
<0.001), but this association was no longer significant after controlling for age, gender, and cardiovascular risk factors. Hs-CRP was not related to individual IMT progression. Interactions between hs-CRP and body mass index, HbA1c, or blood pressure showed no association with IMT progression. Baseline hs-CRP was related to the risk of clinical events (myocardial infarction or stroke or death, hazard ratio of 1.22 per mg/L hs-CRP increase, 95% CI: 1.07 to 1.39,
P
=0.004, adjusted for age and gender), but this association was not significant after controlling for age, gender, and cardiovascular risk factors (1.59, 95% CI: 0.96 to 2.64,
P
=0.072).

Conclusions—

Our results suggest that hs-CRP is not an independent causal factor for the initiation and progression of early atherosclerotic changes of the carotid arteries. Univariate associations between hs-CRP and IMT were largely explained by confounding by age, gender, and cardiovascular risk factors.
Impairment of Cerebral Perfusion and Infarct Patterns Attributable to Vasospasm After Aneurysmal Subarachnoid Hemorrhage
Authors: Weidauer Stefan , Lanfermann Heinrich , Raabe Andreas , Zanella Friedhelm , Seifert Volker , Beck Jürgen
Published: April 2007

Background and Purpose—

The objective of this study was to investigate disturbance of perfusion and infarct patterns attributable to cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH).

Methods—

One hundred seventeen patients with aneurysmal SAH specifically selected at high risk for CVS were enrolled in this prospective study. One hundred twelve patients underwent surgical (n=63) or endovascular (n=59) therapy. For assessment of CVS, relative diameter changes of proximal and distal vessel segments on follow-up angiography at day 7±3 after SAH were analyzed in relation to baseline measurements, and cerebral circulation times were measured. Postprocedure MRI was undertaken selectively at four time points: within 3 days, between days 4 and 6, day 7 to 14, and day 15 to 28 from onset of SAH, including perfusion- and diffusion-weighted images. Procedure-related lesions were excluded and CVS-associated infarct patterns analyzed.

Results—

Occurrence of angiographic CVS was as high as 87.5% between days 7 and 14 and 52.5% showed new infarcts. Eighty-one percent of the infarcts were related to severe CVS (vascular narrowing >66%) and significant (
P
<0.001) cerebral circulation times prolongation of 8.47±2.25 seconds (time-to-peak delay on perfusion-weighted image: 6.52±4.75 seconds), 16% were associated with moderate CVS (34% to 66% vascular narrowing; cerebral circulation times prolongation: 4.72±0.66 seconds). Besides territorial (47%), lacunar (20%), and watershed infarcts (26%), in 7%, band-like cortical lesions developed without evidence for severe CVS.

Conclusions—

CVS after SAH may involve the complete arterial system from the circle of Willis up to the distal vessel segments. Depending on the variable types of collateral flow, location of affected vessels segments as well as the degree of CVS may induce different infarct patterns.
Brain Atrophy Is Related to Lacunar Lesions and Tissue Microstructural Changes in CADASIL
Authors: Jouvent Eric , Viswanathan Anand , Mangin Jean-François , O’Sullivan Mike , Guichard Jean-Pierre , Gschwendtner Andreas , Cumurciuc Rodica , Buffon Frédérique , Peters Nils , Pachaï Chahin , Bousser Marie-Germaine , Dichgans Martin , Chabriat Hugues
Published: April 2007

Background and Purpose—Cerebral atrophy has been recently recognized as a key marker of disease progression in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The contribution of subcortical cerebral lesions in this process remains undetermined. The aim of this study was to investigate the relationships between cerebral volume and different types of subcortical MRI lesions in CADASIL.

Methods—Demographic, clinical, and laboratory data from 147 patients with CADASIL recruited from a prospective cohort study were analyzed. Validated methods were used to determine the ratio of brain volume to intracranial cavity volume (brain parenchymal fraction [BPF]), volume of white matter hyperintensities, volume of lacunar lesions, number of cerebral microhemorrhages, and mean apparent diffusion coefficient. Associations between BPF, clinical scales, and the different subcortical MRI markers were tested.

Results—BPF obtained in 129 patients was significantly associated with the Mattis dementia rating scale (P<0.0001), Mini-Mental State Examination (P=0.002), and modified Rankin scale (P<0.0001) after adjustment for age and sex. Multiple linear regression modeling showed that BPF was independently associated with mean apparent diffusion coefficient (P<0.0001), volume of lacunar lesions (P=0.004), and age (P<0.0001), accounting for 46% of the observed variance in BPF but not with volume of white matter hyperintensities or number of microhemorrhages.

Conclusions—In association with age, mean apparent diffusion coefficient and volume of lacunar lesions are strong and independent MRI predictors of BPF, a key marker of cognitive and motor disability in CADASIL. These results suggest brain atrophy is related to remote and/or diffuse consequences of both lacunar lesions and widespread microstructural alterations within the brain outside lacunar lesions.
Adipophilin Expression Is Increased in Symptomatic Carotid Atherosclerosis
Authors: Nuotio Krista , Isoviita Pia M. , Saksi Jani , Ijäs Petra , Pitkäniemi Janne , Sonninen Riitta , Soinne Lauri , Saimanen Eija , Salonen Oili , Kovanen Petri T. , Kaste Markku , Lindsberg Perttu J.
Published: April 2007

Background and Purpose—

Adipophilin is an adipose differentiation–related protein expressed in lipid-containing cells. Using DNA microarray analysis, we previously found the adipophilin gene (
ADFP
) to be overexpressed in symptomatic carotid plaques (CP). This led us to further examine the role of adipophilin in carotid atherosclerosis relative to symptom status.

Methods—

Ninety-eight high-grade (>70%) CPs were obtained in carotid endarterectomy. The relative expression of
ADFP
mRNA was measured by quantitative real-time RT-PCR, and the relative amount of adipophilin protein was quantified with Western blotting. Detailed topographical correlations with extravasated red blood cells and extracellular cholesterol crystals were obtained by means of immunohistochemistry.

Results—

The relative expression of
ADFP
mRNA was increased in symptomatic compared with asymptomatic CPs at both the mRNA level (1.82±0.19[SE] versus 1.25±0.15,
P
=0.012) and the protein level (1.04±0.23 versus 0.46±0.14,
P
=0.043). Adipophilin colocalized with macrophage foam cells, extravasated red blood cells (
P
<0.0001), and cholesterol crystals (
P
<0.0001), and its expression associated with macroscopic ulceration of CP (
P
<0.0001).

Conclusions—

Intraplaque hemorrhages may contribute to intracellular lipid accumulation and consequent adipophilin expression. Because adipophilin blocks cholesterol efflux from lipid-laden cells, they may die and develop a necrotic lipid core, thereby destabilizing the plaque.
Arterial Baroreflex
Authors: Liu Ai-Jun , Ma Xiu-Juan , Shen Fu-Ming , Liu Jian-Guo , Chen Hong , Su Ding-Feng
Published: April 2007

Background and Purpose—

Arterial baroreflex is one of the most important mechanisms in the regulation of cardiovascular activities. Arterial baroreflex function can be expressed as baroreflex sensitivity (BRS). The present study was designed to test 2 hypotheses: (1) BRS is a new independent predictor for the incidence of stroke in hypertension, and (2) restoration of BRS can prevent stroke in hypertension.

Methods—

First, 82 stroke-prone spontaneously hypertensive rats (SHR-SP) aged 28 to 30 weeks were used. After measuring blood pressure and BRS, the survival time was observed. Second, 12 SHR-SP aged 8 months were used. Blood pressure and BRS were determined separately before and after intragastric administration of ketanserin (0.3 and 3.0 mg/kg). Third, SHR-SP aged 5 months were treated with ketanserin for 12 weeks (0.3 mg and 3.0 mg/kg per day). At the end of the treatment, blood pressure and BRS were determined and the end-organ damage was evaluated. Last, SHR-SP aged 3 months were treated with ketanserin (0.3 and 3.0 mg/kg per day) for life and the survival time was recorded.

Results—

Stroke was significantly delayed in rats with high BRS than those with low BRS (time to 50% death was 1.47-fold longer than low BRS group;
P
<0.01). Ketanserin of 3.0 mg/kg per day decreased blood pressure and enhanced BRS, whereas 0.3 mg/kg per day only enhanced the BRS. Fatal stroke incidences were markedly reduced by treatment with both doses (
P
<0.0001 versus control group).

Conclusions—

The present study provides evidence that BRS is an independent predictor for stroke in hypertension. Restoration of BRS may be a new strategy for the prevention of stroke.