bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of esophageal contraction on esophageal wall blood perfusion
Authors: Mittal Ravinder K. , Bhargava Valmik , Lal Harshal , Jiang Yanfen
Published: September 2011

Myocardial blood flow occurs during the diastolic phase of the cardiac cycle, because myocardial contraction during the systolic phase impedes myocardial perfusion. Using laser Doppler perfusion technique, we studied the effect of esophageal contraction on the esophageal wall perfusion. Studies were conducted in rats. A laser Doppler probe was anchored to the esophageal wall, and wall perfusion was studied under various experimental conditions. Increase and decrease in the systemic blood pressure induced by different pharmacological agents was associated with the increase and decrease in the esophageal wall perfusion, respectively. Esophageal contractions induced by electrical stimulation of the vagus nerve and electrical stimulation of the muscle directly resulted in a reduction in the esophageal wall perfusion, in a dose-dependent fashion. Esophageal wall perfusion could be monitored by placing the Doppler probe on the esophageal mucosa or on the outside of the esophageal wall. Esophageal contraction impedes entry of blood into the esophageal wall. Future studies may investigate if ischemia of the esophageal wall induced by sustained esophageal contractions/esophageal spasm is the cause of esophageal pain symptoms in humans.
Plasma norepinephrine is an independent predictor of vascular endothelial function with aging in healthy women
Authors: Kaplon Rachelle E. , Walker Ashley E. , Seals Douglas R.
Published: September 2011

We tested the hypothesis that reductions in vascular endothelial function (endothelium-dependent dilation, EDD) with age are related to increases in sympathetic activity. Among 314 healthy men and women, age was inversely related to brachial artery flow-mediated dilation (FMD) ( r = −0.30, P < 0.001), a measure of EDD, and positively related to plasma norepinephrine concentrations (PNE), a marker of sympathetic activity ( r = 0.49, P < 0.001). Brachial FMD was inversely related to PNE in all subjects ( r = −0.25, P < 0.001) and in men ( n = 187, r = −0.17, P = 0.02) and women ( n = 127, r = −0.37, P < 0.001) separately. After controlling for PNE (multiple regression analysis), brachial FMD remained significantly related to age in all subjects ( r = −0.20, P < 0.001) and in men ( r = −0.23, P < 0.01), but not women ( r = −0.16, P = 0.06). Consistent with this, brachial FMD remained significantly related to PNE when controlling for age ( r = −0.24, P < 0.01) and menopause status ( r = −0.24, P < 0.01) in women. Indeed, PNE was the strongest independent correlate of brachial FMD in women after controlling for conventional cardiovascular disease risk factors ( r = −0.22, P = 0.01). This relation persisted in a subset of women ( n = 113) after further accounting for the effects of plasma oxidized low-density lipoprotein ( P < 0.05), a circulating marker of oxidative stress. Endothelium-independent dilation was not related to age in either men or women ( P > 0.05). These results provide the first evidence that EDD is inversely related to sympathetic activity, as assessed by PNE, among healthy adults varying in age. In particular, our findings suggest that sympathetic nervous system activity may be a key factor involved in the modulation of vascular endothelial function with aging in women.
Increased lipolysis but diminished gene expression of lipases in subcutaneous adipose tissue of healthy young males with intrauterine growth retardation
Authors: Højbjerre Lise , Alibegovic Amra C. , Sonne Mette P. , Dela Flemming , Vaag Allan , Bruun Jens M. , Stallknecht Bente
Published: September 2011

Intrauterine growth retardation (IUGR) is associated with a central fat distribution and risk of developing type 2 diabetes in adults when exposed to a sedentary Western lifestyle. Increased lipolysis is an early defect of metabolism in IUGR subjects, but the sites and molecular mechanisms involved are unknown. Twenty IUGR and 20 control (CON) subjects, aged 20–30 years, were studied before and after 10 days of bed rest using the glucose clamp technique combined with measurements of in vivo metabolism by microdialysis technique and blood flow by 133Xe washout technique in subcutaneous abdominal (SCAAT) and femoral (SCFAT) adipose tissue. Additionally, mRNA expression of lipases was evaluated in biopsies from SCAAT. Lipolysis in SCAAT was substantially higher in IUGR than in CON subjects despite markedly lower mRNA expression of lipases. Blood flow was higher in IUGR compared with CON in both SCAAT and SCFAT. Whole body insulin sensitivity did not differ between groups and decreased after bed rest. After bed rest, SCAAT lipolysis remained higher in IUGR compared with CON, and SCFAT lipolysis decreased in CON but not in IUGR. Prior to the development of whole body insulin resistance, young men with IUGR are characterized by increased in vivo adipose tissue lipolysis and blood flow with a paradoxically decreased expression of lipases compared with CON, and 10 days of physical inactivity underlined the baseline findings. Subjects with IUGR exhibit primary defects in adipose tissue metabolism.
Anandamide modulates carotid sinus nerve afferent activity via TRPV1 receptors increasing responses to heat
Authors: Roy Arijit , Mandadi Sravan , Fiamma Marie-Noelle , Rodikova Ekaterina , Ferguson Erin V. , Whelan Patrick J. , Wilson Richard J. A.
Published: September 2011

Abnormal respiratory chemosensitivity is implicated in recurrent apnea syndromes, with the peripheral chemoreceptors, the carotid bodies, playing a particularly important role. Previous work suggests that supraphysiological concentrations of the endocannabinoid endovanilloid and TASK channel blocker anandamide (ANA) excite carotid bodies, but the mechanism(s) and physiological significance are unknown. Given that carotid body output is temperature-sensitive, we hypothesized that ANA stimulates carotid body chemosensory afferents via temperature-sensitive vanilloid (TRPV1) receptors. To test this hypothesis, we used the dual-perfused in situ rat preparation to confirm that independent perfusion of carotid arteries with supraphysiological concentrations of ANA strongly excites carotid sinus nerve afferents and that this activity is sufficient to increase phrenic activity. Next, using ex vivo carotid body preparations, we demonstrate that these effects are mediated by TRPV1 receptors, not CB1 receptors or TASK channels: in CB1-null mouse preparations, ANA increased afferent activity across all levels of Po2, whereas in TRPV1-null mouse preparations, the stimulatory effect of ANA was absent. In rat ex vivo preparations, ANA's stimulatory effects were mimicked by olvanil, a nonpungent TRPV1 agonist, and suppressed by the TRPV1 antagonist AMG-9810. The specific CB1 agonist oleamide had no effect. Physiological levels of ANA had no effect alone but increased sensitivity to mild hyperthermia. AMG-9810 blocked ANA's effect on the temperature response. Immunolabeling and RT-PCR demonstrated that TRPV1 receptors are not expressed in carotid body glomus cells but reside in petrosal sensory afferents. Together, these results suggest that ANA plays a physiological role in augmenting afferent responses to mild hyperthermia by activating TRPV1 receptors on petrosal afferents.
Catechins attenuate eccentric exercise-induced inflammation and loss of force production in muscle in senescence-accelerated mice
Authors: Haramizu Satoshi , Ota Noriyasu , Hase Tadashi , Murase Takatoshi
Published: September 2011

Catechins have a great variety of biological actions. We evaluated the potential benefits of catechin ingestion on muscle contractile properties, oxidative stress, and inflammation following downhill running, which is a typical eccentric exercise, in senescence-accelerated prone mice (SAMP). Downhill running (13 m/min for 60 min; 16° decline) induced a greater decrease in the contractile force of soleus muscle and in Ca2+-ATPase activity in SAMP1 compared with the senescence-resistant mice (SAMR1). Moreover, compared with SAMR1, SAMP1 showed greater downhill running-induced increases in plasma CPK and LDH activity, malondialdehyde, and carbonylated protein as markers of oxidative stress; and in protein and mRNA expression levels of the inflammatory mediators such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in muscle. SAMP1 exhibited aging-associated vulnerability to oxidative stress and inflammation in muscle induced by downhill running. Long-term (8 wk) catechin ingestion significantly attenuated the downhill running-induced decrease in muscle force and the increased inflammatory mediators in both plasma and gastrocnemius muscle. Furthermore, catechins significantly inhibited the increase in oxidative stress markers immediately after downhill running, accompanied by an increase in glutathione reductase activity. These findings suggest that long-term catechin ingestion attenuates the aging-associated loss of force production, oxidative stress, and inflammation in muscle after exercise.
A Rare Complication of a Vaginal Breech Delivery
Authors: Vergers-Spooren H. C. , de Leeuw J. W.
Published: September 2011

Rectal lesions without anal sphincter trauma in childbirth are only sporadically described in literature. We describe the case of a 29-year-old primigravida who delivered a child in frank breech presentation. During the second stage of labour a foot presented transanally through a rectal laceration with intact anal sphincters. The laceration was repaired immediately after delivery in theatre. Follow-up visits showed a properly cured laceration and no complaints of incontinence or foul discharge.
Recto-Femoral Fistula Presenting as Emphysematous Cellulitis of the Knee: A Case Report & Literature Review
Authors: Karampinas P. K. , Evangelopoulos D. S. , Benetos I. S. , Kavroudakis E. , Vlamis J.
Published: September 2011

Purpose. The rectofemoral fistula represents a devastating complication of colorectal surgery. Its early diagnosis and treatment are critical to obtain a good patient outcome.Case Presentation. A 75-year-old Caucasian female patient presented with high fever, ileus, low back pain, sciatic nerve palsy, and infection of the right knee. After numerous surgical debridements and antibiotic therapies, a rectofemoral fistula was diagnosed.Conclusion. Increased doctors' alertness is mandatory for the early identification and surgical treatment of patients suffering from a rectofemoral fistula before the stage of diffuse infection has significantly decreases their postoperative morbidity and mortality.
Rapidly Progressive Lung Cysts and Pleural Effusion: A Case Report
Authors: Olsen Diana , Molloy Charlene , Sriram P. S.
Published: September 2011

Angiosarcoma is a rare but highly malignant tumor arising from vascular endothelial cells. Angiosarcoma commonly arises from the heart, liver, breast, and skin including the scalp. Angiosarcoma metastasizing to the lungs can present as either pneumothorax, hemothorax, or pleural effusions. They can rarely present as rapidly enlarging thin-walled pulmonary cysts. A review of the literature is included.
Management of a Type I Hypersensitivity Reaction to IV Etoposide in a Woman with a Yolk Sac Tumor: A Case Report
Authors: Starks David , Prinz Deborah , Armstrong Amy , Means Lindsay , Waggoner Steven , DeBernardo Robert
Published: September 2011

Type I hypersensitivity reactions to intravenous administration of etoposide are extremely rare. Etoposide is an essential component of several chemotherapy regimens used in gynecologic oncology, and discontinuation of this drug during a course of treatment should only be due to severe patient intolerance. We report the successful use of intravenous etoposide phosphate as a substitute drug in a patient with a yolk sac tumor who manifested a Type I hypersensitivity to intravenous etoposide. The patient ultimately completed all 4 cycles of bleomycin, etoposide, cisplatin (BEP) using etoposide phosphate as a substitute drug.
A Misleading Trismus
Authors: Galzerano A. , Sabatini E. , De Monte A. , Durì D.
Published: September 2011

We report the case of a 73-year-old women admitted to ICU with a diagnosis of tetanum supported by a mild trismus and treated with potentially unsafe drugs until the correct diagnosis was made.
Inhibition of Neurotensin Receptor 1 Selectively Sensitizes Prostate Cancer to Ionizing Radiation
Authors: Valerie Nicholas C.K. , Casarez Eli V. , DaSilva John O. , Dunlap-Brown Marya E. , Parsons Sarah J. , Amorino George P. , Dziegielewski Jaroslaw
Published: September 2011

Radiotherapy combined with androgen depletion is generally successful for treating locally advanced prostate cancer. However, radioresistance that contributes to recurrence remains a major therapeutic problem in many patients. In this study, we define the high-affinity neurotensin receptor 1 (NTR1) as a tractable new molecular target to radiosensitize prostate cancers. The selective NTR1 antagonist SR48692 sensitized prostate cancer cells in a dose- and time-dependent manner, increasing apoptotic cell death and decreasing clonogenic survival. The observed cancer selectivity for combinations of SR48692 and radiation reflected differential expression of NTR1, which is highly expressed in prostate cancer cells but not in normal prostate epithelial cells. Radiosensitization was not affected by androgen dependence or androgen receptor expression status. NTR1 inhibition in cancer cell–attenuated epidermal growth factor receptor activation and downstream signaling, whether induced by neurotensin or ionizing radiation, establish a molecular mechanism for sensitization. Most notably, SR48692 efficiently radiosensitized PC-3M orthotopic human tumor xenografts in mice, and significantly reduced tumor burden. Taken together, our findings offer preclinical proof of concept for targeting the NTR1 receptor as a strategy to improve efficacy and outcomes of prostate cancer treatments using radiotherapy. Cancer Res; 71(21); 6817–26. ©2011 AACR.
Contribution of Matrix Metalloproteinase-9 to Cerebral Edema and Functional Outcome following Experimental Subarachnoid Hemorrhage
Authors: Feiler Sergej , Plesnila Nikolaus , Thal Serge C. , Zausinger Stefan , Schöller Karsten
Published: September 2011

Background: Cerebral edema is an important risk factor for death and poor outcome following subarachnoid hemorrhage (SAH). However, underlying mechanisms are still poorly understood. Matrix metalloproteinase (MMP)-9 is held responsible for the degradation of microvascular basal lamina proteins leading to blood-brain barrier dysfunction and, thus, formation of vasogenic cerebral edema. The current study was conducted to clarify the role of MMP-9 for the development of cerebral edema and for functional outcome after SAH. Methods: SAH was induced in FVB/N wild-type (WT) or MMP-9 knockout (MMP-9–/–) mice by endovascular puncture. Intracranial pressure (ICP), regional cerebral blood flow (rCBF), and mean arterial blood pressure (MABP) were continuously monitored up to 30 min after SAH. Mortality was quantified for 7 days after SAH. In an additional series neurological function and body weight were assessed for 3 days after SAH. Subsequently, ICP and brain water content were quantified. Results: Acute ICP, rCBF, and MABP did not differ between WT and MMP-9–/– mice, while 7 days’ mortality was lower in MMP-9–/– mice (p = 0.03; 20 vs. 60%). MMP-9–/– mice also exhibited better neurological recovery, less brain edema formation, and lower chronic ICP. Conclusions: The results of the current study suggest that MMP-9 contributes to the development of early brain damage after SAH by promoting cerebral edema formation. Hence, MMP- 9 may represent a novel molecular target for the treatment of SAH.
Validation of a Compact Motion Sensor for the Measurement of Physical Activity in Patients with Chronic Obstructive Pulmonary Disease
Authors: Sugino Akihito , Minakata Yoshiaki , Kanda Masae , Akamatsu Keiichiro , Koarai Akira , Hirano Tsunahiko , Sugiura Hisatoshi , Matsunaga Kazuto , Ichinose Masakazu
Published: September 2011

Background: The DynaPort Activity Monitor (DAM) has been reported to be useful to evaluate the activity in healthy subjects and patients with chronic obstructive pulmonary disease (COPD). However, it is difficult to estimate the activity of COPD patients using DAM, because its battery works only for several hours and sensors should be worn at two parts of the body. A newly developed compact, single-position triaxial accelerometer (Actimarker) can measure the activity for >1 month, but has not been validated for COPD patients. Objectives: The validity of the Actimarker was evaluated in COPD patients. Methods: In study 1, the validity of the device was tested in 14 stable COPD patients by comparing it with DAM. In study 2, the influence of the weather on activity was examined. In study 3, the number of measurement days required to ensure repeatability was determined. Results: The durations of activity measured by the Actimarker and DAM were significantly correlated at intensity values ≧2.0, ≧2.5 and ≧3.0 METs. The duration of activity on rainy days was significantly shorter than that on non-rainy days. The values of intraclass correlation coefficients were >0.8 in 3-, 4- or 5-day measurements, and there was no systematic bias at any number of days or intensities with Bland-Altman plots. Conclusions: The validity of the Actimarker was confirmed, and repeatability was obtained when the data from at least 3 non-rainy weekdays were analyzed. Actimarker appears to be useful as a simplified method to evaluate the physical activity of COPD patients.
Fluoride Intake of Japanese Infants from Infant Milk Formula
Authors: Nohno K. , Zohoori F.V. , Maguire A.
Published: September 2011

This study aimed to measure the fluoride (F) content of all infant milk formulas (IMF) available for purchase in Japan and estimate the F exposure of infants whose primary source of nutrition is IMF when reconstituted with different F concentrations of water. Twenty-two commercially available IMFs were purchased from 6 manufacturers in Japan. These IMFs included 21 milk-based products and 1 soy-based product. Each IMF was reconstituted using distilled water and 0.13 µg F/ml fluoridated water according to the manufacturers’ instructions. The F concentrations in each sample were measured using the hexamethyldisiloxane diffusion technique and an F ion-selective electrode. The mean F concentration of all products was 0.41 (range 0.15–1.24) µg/g. There were no statistically significant differences among mean F concentrations of newborn milks, follow-on milks and other milks or among manufacturers. The mean F concentration of all products, when reconstituted with distilled water and 0.13 µg F/ml water, was 0.09 and 0.18 µg/ml, respectively. The mean F intake from IMF ranged from 0.039 to 0.134 mg/day with distilled water and from 0.078 to 0.258 mg/day with 0.13 µg/ml fluoridated water, respectively. These results suggested that F intake of infants from IMFs depended on the F concentration of added water, and therefore the risk of dental fluorosis for most Japanese infants would be small since most Japanese municipal water supplies are low in F. However, there was a possibility to exceed the tolerable upper intake level, even under the limit of the law, especially for infants within the first 5 months of life.
Causal Models for Investigating Complex Genetic Disease: II. What Causal Models Can Tell Us about Penetrance for Additive, Heterogeneity, and Multiplicative Two-Locus Models
Authors: Madsen Ann M. , Ottman Ruth , Hodge Susan E.
Published: September 2011

Background/Aims: Statistical geneticists commonly use certain two-locus penetrance models because these models are familiar and mathematically tractable. We investigate whether and under what circumstances these two-locus penetrance models correspond to models of causation. Methods: We describe a sufficient component cause model for a hypothetical disease with two genetic causes. We then use the potential outcomes framework to determine the expected two-locus penetrances from this causal model and contrast them with commonly used two-locus penetrance models (additive, heterogeneity, and multiplicative penetrance models, as formulated by Risch [Am J Hum Genet 1990;46:222–228]). Results: Conventional additive and multiplicative models can correspond to any two-locus causal model only when certain very specific algebraic relationships hold. The heterogeneity model corresponds to a two-locus causal model only if the model stipulates that no disease cases are caused by the combined presence of the causal genotypes at both loci (i.e. only when there is no causal gene-gene interaction). Hence the heterogeneity model provides a valid test of the null hypothesis of no gene-gene interaction, whereas the additive and multiplicative models do not. Conclusion: We suggest that causal principles should provide the basis for statistical modeling in genetics.
Is Confrontation Naming Performance in Alzheimer’s Disease the Nominal Linguistic Retrogenesis of Normal Development?
Authors: Kim HyangHee , Yoon Ji Hye , Lee Ji Eun , Baek Eun Jin , Sohn Young H. , Na Duk L.
Published: September 2011

We investigated confrontation naming performance of patients with Alzheimer’s disease (AD) and normal children (NC) to see if the nature of naming performance of AD patients is the reversal of that in normal development. Sixty items of the Boston Naming Test were given to 78 AD patients (and 40 age- and education-matched normal elderly) and 1,080 NC (3- to 14-year-olds). The analyses revealed that, firstly, the naming abilities of the AD patients demonstrated an inverse relationship with those of the NC. Secondly, from the clinical point of view, AD patients tended to lose vocabulary acquired later first while maintaining those acquired in earlier stages of development. Based on the findings, we claimed that this phenomenon was ‘a nominal retrogenesis’ in which ‘retrogenesis’ is ‘the process by which degenerative mechanisms reverse the order of acquisition in normal development’ as defined by Reisberg and colleagues.
Chitosan Nanoparticles Affect the Acid Tolerance Response in Adhered Cells of Streptococcus mutans
Authors: Neilands J. , Sutherland D. , Resin A. , Wejse P.L. , Chávez de Paz L.E.
Published: September 2011

In this study we evaluated the effect of chitosan nanoparticles on the acid tolerance response (ATR) of adhered Streptococcus mutans. An ATR was induced by exposing S. mutans to pH 5.5 for 2 h and confirmed by exposing the acid-adapted cells to pH 3.5 for 30 min, with the majority of cells appearing viable according to the LIVE/DEAD® technique. However, when chitosan nanoparticles were present during the exposure to pH 5.5, no ATR occurred as most cells appeared dead after the pH 3.5 shock. We conclude that the chitosan nanoparticles tested had the ability to hinder ATR induction in adhered S. mutans.
Relationship between the Effect of Dietary Fat on Swimming Endurance and Energy Metabolism in Aged Mice
Authors: Zhang Guihua , Shirai Nobuya , Suzuki Hiramitsu
Published: September 2011

Aim: The aim of this study was to investigate the effect of different dietary fats on alterations in endurance, energy metabolism, and plasma levels of interleukin-6 (IL-6) and minerals in mice. Method: Male mice (aged 58 weeks) were fed diets containing 6% safflower oil, fish oil, or lard for 12 weeks. Swimming time to exhaustion, energy metabolism, and plasma IL-6 levels were subsequently determined. Results: Mice fed safflower oil exhibited a marked increase in swimming time compared to the baseline level. Mice fed lard exhibited a significant decrease in swimming time, while mice on a fish oil diet exhibited a small decrease in swimming time. The final swimming time of mice fed safflower oil was significantly longer than that of animals fed lard. This improvement in endurance with dietary safflower oil was accompanied by decreased accumulation of lactate and less glycogen depletion during swimming. In the safflower oil group, muscle carnitine palmitoyltransferase activity increased significantly after swimming, while the plasma non-esterified fatty acid concentration decreased significantly. A trend to increased plasma IL-6 levels was observed in sedentary animals on a safflower oil diet compared to those on a lard diet. Conclusions: These results suggest that dietary safflower oil improves the swimming endurance of aged mice to a greater extent than lard, and that this effect appears to involve glycogen sparing through increased fatty acid utilization.
The Ratio of Adiponectin to HOMA as an Index of Metabolic Syndrome in Obese Women
Authors: de Luis Daniel Antonio , Aller Rocio , Izaola Olatz , Conde Rosa , Gonzalez Sagrado Manuel
Published: September 2011

Objective: The aim of our study was to investigate the role of the ratio of adiponectin concentration to homeostasis model assessment insulin resistance (HOMA-IR) as a predictor of metabolic syndrome (MS) in obese subjects. Methods: We studied a population-based cross-sectional sample of 217 obese women. To estimate the prevalence of MS, the definitions of the Adult Treatment Panel III (ATP III) were considered. Results: The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve for the detection of each MS component on the basis of the ratio of the serum adiponectin concentration to HOMA-IR (A/H ratio) was higher than that for the detection based on serum adiponectin concentration (for central obesity: 0.722 vs. 0.316, for increased triglycerides: 0.579 vs. 0.500, for increased blood pressure: 0.573 vs. 0.493, and for elevated fasting plasma glucose: 0.718 vs. 0.465). The AUC of the ROC curve for the detection of MS on the basis of the A/H ratio was higher than that for the detection based on serum adiponectin concentration (0.700 vs. 0.481). Conclusion: The A/H ratio appears to provide a discriminatory marker for MS risk and some components of MS (central obesity, increased blood pressure and elevated fasting plasma glucose) in obese women.
Radiofrequency Ablation for the Treatment of Hepatocellular Carcinoma with Decompensated Cirrhosis
Authors: Wakuta Akiko , Nouso Kazuhiro , Kariyama Kazuya , Nishimura Mamoru , Kishida Masayuki , Wada Nozomu , Mizushima Takaaki , Higashi Toshihiro , Tanimoto Mitsune
Published: September 2011

Background: Radiofrequency ablation (RFA) is used to treat early-stage hepatocellular carcinoma (HCC), but is sometimes avoided in patients with decompensated liver cirrhosis because of the possible side effect of deterioration of liver function. Aims: In this study, we report the safety and effects of RFA for treating HCC patients with Child-Pugh B/C liver cirrhosis. Methods: Sixty-six consecutive HCC patients with Child-Pugh B/C cirrhosis, who were treated by RFA, were enrolled in this study. We analyzed patient outcomes, the complications of RFA, and changes in liver function and tumor markers. Results: Fifty-six patients were classified as Child-Pugh class B, and 10 were classified as class C. The overall survival rates in patients with Child-Pugh B and C cirrhosis were 82 and 83% at 1 year and 47 and 31% at 3 years, respectively. Serum total bilirubin (T.Bil), albumin, prothrombin time, ascites, and encephalopathy were unchanged at 1, 3, and 6 months after RFA in patients with Child-Pugh B cirrhosis; however, serum T.Bil levels increased significantly at 6 months after RFA in 6/10 (60%) patients with Child-Pugh C cirrhosis. Hemothorax and rupture of esophageal varices were observed in 2 patients; however, there were no complications related to poor liver function. Conclusion: RFA is a useful modality for treating HCC in patients with poor liver function such as Child-Pugh B and C, but careful monitoring after RFA must be needed.
Early-Onset Metabolic Syndrome in Prepubertal Obese Children and the Possible Role of Alanine Aminotransferase as Marker of Metabolic Syndrome
Authors: Calcaterra V. , Muratori T. , Klersy C. , Albertini R. , Caramagna C. , Brizzi V. , Larizza D.
Published: September 2011

Introduction: Obesity is often associated with increased serum alanine aminotransferase (ALT), and elevation of ALT is a marker of non-alcoholic fatty liver disease which is caused in part by insulin resistance, the essential characteristic of metabolic syndrome (MS). We evaluated the prevalence of MS in prepubertal obese children and the usefulness of ALT as an MS marker. Patients: 120 obese children (6.3 ± 1.6 years old) and 50 normal-weight controls (5.3 ± 2.0 years old) were included. Patients were classified as having MS if they met ≧3 of the following criteria: body mass index >97th percentile, triglycerides >95th percentile, high-density lipoprotein cholesterol <5th percentile, systolic (SBP) and/or diastolic (DBP) blood pressure >95th percentile, fasting blood glucose 100 mg/dl and/or impaired insulin sensitivity with homeostasis model assessment for insulin resistance >97.5th percentile. ALT levels were also evaluated. Results: MS occurred in 16.6% of obese patients. Significant differences were present in body mass index (p < 0.001), SBP (p = 0.002) and DBP (p < 0.001) between non-MS and MS obese patients; laboratory data, except total cholesterol, were significantly different in the two groups. The strongest association with MS (as evaluated by the c-statistic) was found for insulin and homeostasis model assessment for insulin resistance (c = 0.92 and 0.91, respectively); also, DBP and SBP showed good discrimination ability (c = 0.73 and 0.72, respectively). ALT levels in the MS group were higher than in the non-MS group (p = 0.02) and associated with MS (p = 0.001; c = 0.69). Conclusion: MS is a consequence of obesity already in very young children. Also, pathological serum ALT levels were significantly correlated with MS and might be considered a marker for defining MS, though confirmation in a longitudinal study is called for.
Selective Inhibition of Matrix Metalloproteinase-13 Increases Collagen Content of Established Mouse Atherosclerosis
Authors: Quillard Thibaut , Tesmenitsky Yevgenia , Croce Kevin , Travers Richard , Shvartz Eugenia , Koskinas Konstantinos C. , Sukhova Galina K. , Aikawa Elena , Aikawa Masanori , Libby Peter
Published: September 2011

Objective—

Evidence has linked collagen loss with the onset of acute coronary events. This study tested the hypothesis that selective matrix metalloproteinase-13 (MMP-13) collagenase inhibition increases collagen content in already established and nascent mouse atheromas.

Methods and Results—

In vitro and in situ experiments documented the selectivity and efficacy of an orally available MMP-13 inhibitor (MMP13i-A). In vivo observations monitored macrophage accumulation and MMP-13 activity using molecular imaging. After 10 weeks of MMP13i-A treatment, apolipoprotein E–deficient mice with evolving or established lesions exhibited reduced MMP-13 activity without affecting macrophage content, measured either by intravital microscopy or fluorescence reflectance imaging. Histological analysis indicated that MMP13-iA did not affect plaque size or macrophage or smooth muscle cell accumulation. Administration of MMP13i-A to mice with evolving or established atheromas substantially increased plaque interstitial collagen content in the intima and locally in the fibrous cap, compared with vehicle-treated controls. Analysis of collagen revealed thicker collagen fibers within the plaques of treated groups.

Conclusion—

Pharmacological MMP-13 inhibition yields collagen accumulation in plaques (a feature associated in humans with resistance to rupture), even in established plaques. This study, of considerable clinical relevance, furnishes new mechanistic insight into regulation of the plaque's extracellular matrix and validates molecular imaging for studying plaque biology.
Reduced Vascular Nitric Oxide–cGMP Signaling Contributes to Adipose Tissue Inflammation During High-Fat Feeding
Authors: Handa Priya , Tateya Sanshiro , Rizzo Norma O. , Cheng Andrew M. , Morgan-Stevenson Vicki , Han Chang-Yeop , Clowes Alexander W. , Daum Guenter , O'Brien Kevin D. , Schwartz Michael W. , Chait Alan , Kim Francis
Published: September 2011

Objective—

Obesity is characterized by chronic inflammation of adipose tissue, which contributes to insulin resistance and diabetes. Although nitric oxide (NO) signaling has antiinflammatory effects in the vasculature, whether reduced NO contributes to adipose tissue inflammation is unknown. We sought to determine whether (1) obesity induced by high-fat (HF) diet reduces endothelial nitric oxide signaling in adipose tissue, (2) reduced endothelial nitric oxide synthase (eNOS) signaling is sufficient to induce adipose tissue inflammation independent of diet, and (3) increased cGMP signaling can block adipose tissue inflammation induced by HF feeding.

Methods and Results—

Relative to mice fed a low-fat diet, an HF diet markedly reduced phospho-eNOS and phospho-vasodilator-stimulated phosphoprotein (phospho-VASP), markers of vascular NO signaling. Expression of proinflammatory cytokines was increased in adipose tissue of eNOS−/− mice. Conversely, enhancement of signaling downstream of NO by phosphodiesterase-5 inhibition using sildenafil attenuated HF-induced proinflammatory cytokine expression and the recruitment of macrophages into adipose tissue. Finally, we implicate a role for VASP, a downstream mediator of NO-cGMP signaling in mediating eNOS-induced antiinflammatory effects because VASP−/− mice recapitulated the proinflammatory phenotype displayed by eNOS−/− mice.

Conclusion—

These results imply a physiological role for endothelial NO to limit obesity-associated inflammation in adipose tissue and hence identify the NO-cGMP-VASP pathway as a potential therapeutic target in the treatment of diabetes.
HCN3 Contributes to the Ventricular Action Potential Waveform in the Murine Heart
Authors: Fenske Stefanie , Mader Robert , Scharr Andreas , Paparizos Christos , Cao-Ehlker Xiaochun , Michalakis Stylianos , Shaltiel Lior , Weidinger Martha , Stieber Juliane , Feil Susanne , Feil Robert , Hofmann Franz , Wahl-Schott Christian , Biel Martin
Published: September 2011

Rationale:

The hyperpolarization-activated current I
h
that is generated by hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) plays a key role in the control of pacemaker activity in sinoatrial node cells of the heart. By contrast, it is unclear whether I
h
is also relevant for normal function of cardiac ventricles.

Objective:

To study the role of the HCN3-mediated component of ventricular I
h
in normal ventricular function.

Methods and Results:

To test the hypothesis that HCN3 regulates the ventricular action potential waveform, we have generated and analyzed a HCN3-deficient mouse line. At basal heart rate, mice deficient for HCN3 displayed a profound increase in the T-wave amplitude in telemetric electrocardiographic measurements. Action potential recordings on isolated ventricular myocytes indicate that this effect was caused by an acceleration of the late repolarization phase in epicardial myocytes. Furthermore, the resting membrane potential was shifted to more hyperpolarized potentials in HCN3-deficient mice. Cardiomyocytes of HCN3-deficient mice displayed approximately 30% reduction of total I
h
. At physiological ionic conditions, the HCN3-mediated current had a reversal potential of approximately −35 mV and displayed ultraslow deactivation kinetics.

Conclusions:

We propose that HCN3 together with other members of the HCN channel family confer a depolarizing background current that regulates ventricular resting potential and counteracts the action of hyperpolarizing potassium currents in late repolarization. In conclusion, our data indicate that HCN3 plays an important role in shaping the cardiac action potential waveform.
Phosphodiesterase 4D Regulates Baseline Sarcoplasmic Reticulum Ca
2+
Release and Cardiac Contractility, Independently of L-Type Ca
2+
Current
Authors: Beca Sanja , Helli Peter B. , Simpson Jeremy A. , Zhao Dongling , Farman Gerrie P. , Jones Peter P. , Tian Xixi , Wilson Lindsay S. , Ahmad Faiyaz , Chen S.R. Wayne , Movsesian Matthew A. , Manganiello Vincent , Maurice Donald H. , Conti Marco , Backx Peter H.
Published: September 2011

Rationale:

Baseline contractility of mouse hearts is modulated in a phosphatidylinositol 3-kinase-γ–dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticulum (SR) calcium ATPase type 2a (SERCA2a).

Objective:

The goal of this study was to determine whether PDE4D regulates basal cardiac contractility.

Methods and Results:

At 10 to 12 weeks of age, baseline cardiac contractility in PDE4D-deficient (PDE4D
−/−
) mice was elevated mice in vivo and in Langendorff perfused hearts, whereas isolated PDE4D
−/−
cardiomyocytes showed increased whole-cell Ca
2+
transient amplitudes and SR Ca
2+
content but unchanged L-type calcium current, compared with littermate controls (WT). The protein kinase A inhibitor
R
p
-adenosine-3′,5′ cyclic monophosphorothioate (R
p
-cAMP) lowered whole-cell Ca
2+
transient amplitudes and SR Ca
2+
content in PDE4D
−/−
cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca
2+
transients, or SR Ca
2+
content in PDE4D
−/−
preparations but increased these parameters in WT myocardium to levels indistinguishable from those in PDE4D
−/−
. The functional changes in PDE4D
−/−
myocardium were associated with increased PLN phosphorylation but not cardiac ryanodine receptor phosphorylation. Rolipram increased PLN phosphorylation in WT cardiomyocytes to levels indistinguishable from those in PDE4D
−/−
cardiomyocytes. In murine and failing human hearts, PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor.

Conclusions:

PDE4D regulates basal cAMP levels in SR microdomains containing SERCA2a-PLN, but not L-type Ca
2+
channels or ryanodine receptor. Because whole-cell Ca
2+
transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.
Diastolic Carotid Artery Wall Shear Stress Is Associated With Cerebral Infarcts and Periventricular White Matter Lesions
Authors: Mutsaerts Henri J.M.M. , Palm-Meinders Inge H. , de Craen Anton J.M. , Reiber Johan H.C. , Blauw Gerard J. , van Buchem Mark A. , van der Grond Jeroen , Box Frieke M.A.
Published: September 2011

Background and Purpose—

Low wall shear stress (WSS) is an early marker in the development of vascular lesions. The present study aims to assess the relationship between diastolic and systolic WSS in the internal carotid artery and periventricular (PWML), deep white matter lesions, and cerebral infarcts (CI).

Methods—

Early, mid, and late diastolic and peak systolic WSS were derived from shear rate obtained by gradient echo phase contrast magnetic resonance sequences multiplied by individually modeled viscosity.

PWML, deep white matter lesions, and CI were derived from proton density (PD), T2, and fluid attenuated inversion recovery (FLAIR) MRI in 329 participants (70–82 years; PROSPER baseline). Analyses were adjusted, if appropriate, for age, gender, intracranial volume, and multiple cardiovascular risk factors.

Results—

Mid-diastolic WSS was significantly correlated with the presence of PWML (B=−10.15;
P
=0.006) and CI (B=−2.06;
P
=0.044), but not with deep white matter lesions (B=−1.30;
P
=0.050; adjusted for age, gender, WML, and intracranial volume). After adjustment for cardiovascular risk factors, these correlations weakened but remained significant. Systolic WSS was not correlated with any of the cerebrovascular parameters.

Conclusions—

This study is the first to our knowledge to present a cross-sectional correlation between carotid artery WSS and cerebrovascular pathology such as PWML and CI in a large population. Furthermore, it shows that diastolic hemodynamics may be more important than systolic or mean hemodynamics. Future studies exploring vascular hemodynamic damage should focus on diastolic WSS.
Transient Cognitive Impairment in TIA and Minor Stroke
Authors: Pendlebury Sarah T. , Wadling Sarah , Silver Louise E. , Mehta Ziyah , Rothwell Peter M.
Published: September 2011

Background and Purpose—

Acute cognitive impairment and delirium occur after major stroke and are associated with poor cognitive outcome. We conducted a population-based study to determine whether transient cognitive impairment (TCI) is seen acutely after cerebral transient ischemic attack (TIA) or minor stroke, and whether it predicts long-term cognitive decline.

Methods—

Mini-mental-state examination was performed in consecutive testable patients with TIA or minor stroke (National Institutes of Health Stroke Scale ≤3) seen acutely (1–7 days) in the Oxford Vascular Study (2002–2005) versus after 7 days, and in referrals seen acutely who had a subsequent noncerebrovascular diagnosis. We defined TCI as a baseline Mini-mental-state examination score ≥2 points below the 1-month follow-up score, and identified cognitive impairment (Montreal Cognitive Assessment [MoCA] <26/30) and severe dementia at 1-, 2-, and 5-year follow-up.

Results—

In 280 TIA and minor stroke patients (mean age/SD 73.5/11.8 years), TCI was more frequent in those seen at 1 to 7 days (80/206; 38.9%) versus later (14/74; 19%;
P
=0.002) or in noncerebrovascular patients (10/47; 21%;
P
=0.004). TCI was associated with acute confusion (OR, 5.5; 95% CI, 2.5–11.7;
P
<0.0001), acute infarct on computed tomography (OR, 2.0; 1.2–3.5;
P
=0.01), and with residual focal deficits (OR,1.94; 1.13–3.34;
P
=0.01). However, it was still seen acutely in those whose focal deficits had resolved by time of assessment (41/120; 34%). Although patients with TCI had similar Mini-mental-state examination score by 1 month compared with those without TCI, their 5-year risks of cognitive impairment (OR, 4.3; 1.2–15.7;
P
=0.03) and severe dementia (OR, 4.9; 1.0–25.8;
P
=0.05) were increased.

Conclusions—

TCI is a manifestation of TIA and minor stroke, and may persist beyond resolution of focal symptoms. Our findings have implications for definitions in TIA and minor stroke and suggest that cognitive fragility may be revealed by minor cerebrovascular events.
Antithrombotic Therapy Use at Discharge and 1 Year in Patients With Atrial Fibrillation and Acute Stroke
Authors: Lopes Renato D. , Shah Bimal R. , Olson DaiWai M. , Zhao Xin , Pan Wenqin , Bushnell Cheryl D. , Peterson Eric D.
Published: September 2011

Background and Purpose—

Current American Heart Association/American Stroke Association guidelines identify warfarin use as a class IA indication in patients with atrial fibrillation (AF) and ischemic stroke (IS) or transient ischemic attack (TIA). However, few studies have examined factors associated with long-term antithrombotic therapy use in IS/TIA patients with AF.

Methods—

We utilized the Get With The Guidelines–Stroke national quality improvement registry and the Adherence eValuation After Ischemic Stroke Longitudinal (AVAIL) Registry to examine patterns of antithrombotic use at discharge and at 12 months in IS/TIA patients with AF. A multivariate logistic regression model was developed to identify predictors of warfarin use in this patient population at 12 months.

Results—

Of the 2460 IS/TIA patients, 291 (11.8%) had AF, of which 5.5% of patients were discharged on aspirin alone, 49.1% on warfarin alone, 1.4% on clopidogrel alone, 34.7% on warfarin plus aspirin, 2.1% on aspirin plus clopidogrel, and 1.0% on aspirin plus clopidogrel plus warfarin. Paradoxically, there was a decrease in the rate of warfarin use in patients with a CHADS
2
score >3. The only factor associated with warfarin use at 12-month follow-up was male gender (adjusted odds ratio, 2.27; confidence interval, 1.22–4.35;
P
=0.01).

Conclusions—

Overall, the use of warfarin therapy is high at discharge in IS/TIA patients with AF; however, there was a decrease in the rate of warfarin use in patients with a CHADS
2
score >3. Compared to women, men were more likely to be on warfarin at 1 year after the index stroke event. Therefore, opportunities exist to improve antithrombotic use in all IS/TIA patients with AF.
Short-Term Effect of Atorvastatin on Carotid Artery Elasticity
Authors: Ratchford Elizabeth V. , Gutierrez Jose , Lorenzo Dalia , McClendon Mark S. , Della-Morte David , DeRosa Janet T. , Elkind Mitchell S.V. , Sacco Ralph L. , Rundek Tatjana
Published: September 2011

Background and Purpose—

Few studies have examined the early effects of statins on carotid artery elasticity, a potential surrogate marker of cardiovascular risk. This study examined the short-term effects of atorvastatin 80 mg daily on carotid elasticity measured by high-resolution B-mode ultrasound.

Methods—

The study included 40 stroke-free and statin-naive subjects older than age 45 (mean age, 70±7 years; 55% men; 64% Caribbean-Hispanic). Outcome measures included carotid stiffness indices at 14 and 30 days after initiation of treatment. The systolic and diastolic diameters of the right common carotid artery were averaged from multiple B-mode imaging frames. Absolute and relative changes of strain [(systolic diameter−diastolic diameter)/diastolic diameter], stiffness (β) [ln (systolic/diastolic blood pressure)/strain], and distensibility (1/β adjusted for wall thickness) from baseline were compared by the repeated measures
t
test and were considered significant at α=0.05.

Results—

Baseline mean stiffness was 0.08 (95% confidence interval [CI], 0.06–0.10). It significantly decreased at day 30 to 0.05 (CI, 0.04–0.06;
P
<0.01). Mean baseline distensibility was 15.25 (CI, 13.18–17.32), increasing significantly at day 30 to 17.23 (CI, 14.01–20.45;
P
<0.05). An improvement in distensibility of ≥10% from baseline was observed in 29 (73%) subjects. Changes in stiffness and distensibility were maximal among subjects with baseline low-density lipoprotein levels <130 mg/dL.

Conclusions—

Short-term treatment with high-dose atorvastatin was associated with improvement in the carotid elasticity metrics. Carotid artery elasticity measured by B-mode ultrasound is a simple noninvasive measure of arterial wall function and may be a useful surrogate end point in clinical trials targeting individuals at increased risk for atherosclerosis.
Fish Consumption and the Risk of Stroke
Authors: Larsson Susanna C. , Orsini Nicola
Published: September 2011

Background and Purpose—

Fish consumption has been postulated to reduce the risk of stroke. We conducted a dose–response meta-analysis to summarize the evidence from prospective studies regarding the association between fish consumption and stroke risk.

Methods—

Pertinent studies were identified by searching Embase and PubMed through May 2011 and by reviewing the references of retrieved articles. We included prospective studies that reported relative risks with 95% CIs of stroke for ≥3 categories of fish consumption. Results were combined using a random-effects model.

Results—

Fifteen prospective studies, with 9360 stroke events among 383 838 participants, were included. An increment of 3 servings/week in fish consumption was associated with a 6% reduction in risk of total stroke (relative risk, 0.94; 95% CI, 0.89–0.99) without heterogeneity among studies (
P
=0.15,
I
2
=25.7%). Among 9 studies with results for stroke subtypes, the relative risks were 0.90 (95% CI, 0.84–0.97) for ischemic stroke and 0.90 (95% CI, 0.76–1.06) for hemorrhagic stroke.

Conclusions—

These findings indicate that fish consumption is weakly inversely associated with the risk of stroke.