bluuebunny/crossref_metadata_2025 huggingface dataset:
VALIDATION OF THEIN VITROINCUBATION OF EXTENSOR DIGITORUM LONGUS MUSCLE FROM MICE WITH A MATHEMATICAL MODEL
Authors: SOGAARD PETER , HARLÉN MIKAEL , LONG YUN CHAU , SZEKERES FERENC , BARNES BRIAN R. , CHIBALIN ALEXANDER V. , ZIERATH JULEEN R.
Published: September 2010

In vitro incubation of tissues; in particular, skeletal muscles from rodents, is a widely-used experimental method in diabetes research. This experimental method has previously been validated, both experimentally and theoretically. However, much of the method's experimental data remains unclear, including the high-rate of lactate production and the lack of an observable increase in glycogen content, within a given time. The predominant hypothesis explaining the high-rate of lactate production is that this phenomenon is dependent on a mechanism in glycolysis that works as a safety valve, producing lactate when glucose uptake is super-physiological. Another hypothesis is that existing anoxia forces more ATP to be produced from glycolysis, leading to an increased lactate concentration. The lack of an observable increase in glycogen content is assumed to be dependent on limitations in sensitivity of the measuring method used. We derived a mathematical model to investigate which of these hypotheses is most likely to be correct. Using our model, data analysis indicates that the in vitro incubated muscle specimens, most likely are sensing the presence of existing anoxia, rather than an overflow in glycolysis. The anoxic milieu causes the high lactate production. The model also predicts an increased glycogenolysis. After mathematical analyses, an estimation of the glycogen concentration could be made with a reduced model. In conclusion, central anoxia is likely to cause spatial differences in glycogen concentrations throughout the entire muscle. Thus, data regarding total glycogen levels in the incubated muscle do not accurately represent the entire organ. The presented model allows for an estimation of total glycogen, despite spatial differences present in the muscle specimen.
IMPULSIVE CONTROL OF AN INTEGRATED PEST MANAGEMENT MODEL WITH DISPERSAL BETWEEN PATCHES
Authors: GEORGESCU PAUL , DIMITRIU GABRIEL , SINCLAIR ROBERT
Published: September 2010

We consider a two-patch SI model of integrated pest management with dispersal of both susceptible and infective pests between patches. A biological control, consisting of the periodic release of infective pests and a chemical control, consisting of periodic and impulsive pesticide spraying, are employed in order to maintain the size of the pest population below an economically acceptable level. It is assumed that the spread of the disease which is inflicted on the pest population through the use of the biological control is characterized by a nonlinear force of infection expressed in an abstract form. A sufficient condition for the local stability of the susceptible pest-eradication periodic solution is found using Floquet theory for periodic systems of ordinary differential equations, an analysis of the influence of dispersal between patches being performed for several particular cases. Our numerical simulations indicate that an increase in the amount but not in the frequency of pesticide use may not result in control. We also show that patches which are stable in isolation can be destabilized by dispersal between patches.
Perinatal lipid nutrition alters early intestinal development and programs the response to experimental colitis in young adult rats
Authors: Innis Sheila M. , Dai Chuanbin , Wu Xiujuan , Buchan Alison M. J. , Jacobson Kevan
Published: September 2010

The long-chain polyunsaturated n-6 and n-3 fatty acids are essential nutrients in membrane biogenesis and regulate gene expression via their eicosanoid metabolites. We investigated whether the n-6 and n-3 fatty acid supply as determined by maternal diet alters colonic phospholipid fatty acids, intestinal morphology, and epithelial barrier permeability during milk feeding with lasting effect on mucosal responsiveness to dinitrobenzene sulfonic acid (DNBS)-induced colitis in young adulthood. Female rats were fed diets with 20% energy from safflower oil (SO) or canola oil (CO), or 8% fish oil (FO) plus 2% SO (10% FO) or 18% FO plus 2% SO (20% FO) throughout gestation and lactation and offspring weaned to a standard diet at 21 days of age. At 15 days of age, pups in the 20% and 10% FO groups had lower 20:4n-6 and higher 20:5n-3 and 22:6n-3 in colon phospholipids ( P < 0.01), shorter crypts ( P < 0.05), and higher paracellular permeability than SO or CO groups. At 3 mo of age, male offspring in the FO groups showed lasting reduction of crypt depth and a heightened inflammatory response to DNBS. We demonstrate that early decreased colon 20:4n-6 with increased n-3 fatty acids impairs intestinal barrier development and sensitizes the colon response to inflammatory insults later in life.
Mechanisms underlying gut dysfunction in a murine model of chronic parasitic infection
Authors: Motomura Yasuaki , Khan Waliul I. , El-Sharkawy Rami T. , Verma-Gandhu Monica , Grencis Richard K. , Collins Stephen M.
Published: September 2010

Irritable bowel syndrome (IBS) is common in countries where chronic parasitic infestations are endemic. However, the relationship between parasitic infection and IBS is not clear. The aim of this study was to examine whether chronic parasitic infection is accompanied by gut dysfunction and whether the continued presence of the parasite is required for the maintenance of the dysfunction. We used chronic Trichuris muris infection in Th1-biased susceptible AKR mice to evaluate this relationship. AKR mice were infected with T. muris and were euthanized on various days postinfection (pi) to examine worm burden, muscle function, and immune and inflammatory responses. Mice were treated with the anthelmintic oxantel pamoate to assess the effect of eradication of infection on muscle function. Infection resulted in persistence of the parasite, elevated IFN-γ, and increased MPO activity evident at 45 days pi. This was accompanied by a reduction in muscle contractility and excitatory innervation. Whereas parasite eradication at 7 days pi normalized IFN-γ and muscle contractility, eradication at 28 days pi failed to normalize muscle contractility. Administration of dexamethasone after parasite eradication normalized all parameters. Anthelmintic treatment improved histology except for eosinophils, which were normalized by subsequent dexamethasone therapy. Persistent gut dysfunction is independent of the continued presence of the parasite and is maintained by inflammatory process that includes eosinophils. Thus data in this preclinical model suggest that parasitic infection could be a cause of IBS, and the lack of symptomatic improvement following eradication is insufficient evidence to refute a causal relationship between the infection and IBS.
Transcardiac gradients of circulating apelin: extraction by normal hearts vs. release by hearts failing due to pressure overload
Authors: Helske Satu , Kovanen Petri T. , Lommi Jyri , Turto Heikki , Kupari Markku
Published: September 2010

Apelin is a newly discovered inotropic peptide tentatively linked up with the pathophysiology of heart failure (HF). To further assess the role of apelin in HF, we measured its transcardiac arteriovenous gradients in patients with left ventricular pressure overload with or without HF and in patients with structurally normal hearts. Blood samples from the aortic root and coronary sinus were drawn from 49 adult patients undergoing preoperative cardiac catheterization for severe aortic valve stenosis (AS). Similar samples were taken from 12 control patients with structurally normal hearts undergoing electrophysiological studies. Plasma apelin was determined by enzyme immunoassay. In the control group, apelin decreased from a median of 0.39 (0.16–1.94) ng/ml in the aortic root to 0.18 (0.13–1.04) ng/ml in the coronary sinus ( P = 0.004). In AS patients free of HF ( n = 33), apelin concentration remained unaltered across the heart, but in those with HF ( n = 15) apelin rose from a median of 0.26 (0.20–0.82) ng/ml in the aorta to 0.45 (0.24–1.17) ng/ml in the coronary sinus ( P = 0.002). The transcardiac apelin gradients differed statistically highly significantly across the three groups ( P = 0.00005), and each of the two-group differences was also statistically significant ( P < 0.05). In conclusion, left ventricular pressure overload changes the transcardiac arteriovenous differences of circulating apelin. Although normal hearts extract apelin from the coronary blood, hearts failing due to left ventricular pressure overload release apelin into the circulation. Loss of cardiac apelin may be involved in the mechanisms of HF development in AS.
Effect of hypohydration and altitude exposure on aerobic exercise performance and acute mountain sickness
Authors: Castellani John W. , Muza Stephen R. , Cheuvront Samuel N. , Sils Ingrid V. , Fulco Charles S. , Kenefick Robert W. , Beidleman Beth A. , Sawka Michael N.
Published: September 2010

Hypoxia often causes body water deficits (hypohydration, HYPO); however, the effects of HYPO on aerobic exercise performance and prevalence of acute mountain sickness (AMS) at high altitude (ALT) have not been reported. We hypothesized that 1) HYPO and ALT would each degrade aerobic performance relative to sea level (SL)-euhydrated (EUH) conditions, and combining HYPO and ALT would further degrade performance more than one stressor alone; and 2) HYPO would increase the prevalence and severity of AMS symptoms. Seven lowlander men (25 ± 7 yr old; 82 ± 11 kg; mean ± SD) completed four separate experimental trials. Trials were 1) SL-EUH, 2) SL-HYPO, 3) ALT-EUH, and 4) ALT-HYPO. In HYPO, subjects were dehydrated by 4% of body mass. Subjects maintained hydration status overnight and the following morning entered a hypobaric chamber (at SL or 3,048 m, 27°C) where they completed 30 min of submaximal exercise immediately followed by a 30-min performance time trial (TT). AMS was measured with the Environmental Symptoms Questionnaire-Cerebral Score (AMS-C) and the Lake Louise Scoring System (LLS). The percent change in TT performance, relative to SL-EUH, was −19 ± 12% (334 ± 64 to 278 ± 87 kJ), −11 ± 10% (334 ± 64 to 293 ± 33 kJ), and −34 ± 22% (334 ± 64 to 227 ± 95 kJ), for SL-HYPO, ALT-EUH, and ALT-HYPO, respectively. AMS symptom prevalence was 2/7 subjects at ALT-EUH for AMS-C and LLS and 5/7 and 4/7 at ALT-HYPO for AMS-C and LLS, respectively. The AMS-C symptom severity score (AMS-C score) tended to increase from ALT-EUH to ALT-HYPO but was not significant ( P = 0.07). In conclusion, hypohydration at 3,048 m 1) degrades aerobic performance in an additive manner with that induced by ALT; and 2) did not appear to increase the prevalence/severity of AMS symptoms.
Sympathetic and cardiovascular responses to glossopharyngeal insufflation in trained apnea divers
Authors: Heusser Karsten , Dzamonja Gordan , Breskovic Toni , Steinback Craig D. , Diedrich André , Tank Jens , Jordan Jens , Dujic Zeljko
Published: September 2010

Glossopharyngeal insufflation (lung packing) is a common maneuver among experienced apnea divers by which additional air is pumped into the lungs. It has been shown that packing may compromise cardiovascular homeostasis. We tested the hypothesis that the packing-mediated increase in intrathoracic pressure enhances the baroreflex-mediated increase in muscle sympathetic nerve activity (MSNA) in response to an exaggerated drop in cardiac output (CO). We compared changes in hemodynamics and MSNA (peroneal microneurography) during maximal breath-holds without and with prior moderate packing (0.79 ± 0.40 liters) in 14 trained divers (12 men, 2 women, 26.7 ± 4.5 yr, body mass index 24.8 ± 2.4 kg/m2). Packing did not change apnea time (3.8 ± 1.0 vs. 3.8 ± 1.2 min), hemoglobin oxygen desaturation (−17.6 ± 12.3 vs. −18.7 ± 12.8%), or the reduction in CO (1 min: −3.65 ± 1.83 vs. −3.39 ± 1.96 l/min; end of apnea: −2.44 ± 1.33 vs. −2.16 ± 1.44 l/min). On the other hand, packing dampened the early, i.e., 1-min increase in mean arterial pressure (MAP, 1 min: 9.2 ± 8.3 vs. 2.4 ± 11.0 mmHg, P < 0.01) and in total peripheral resistance (relative TPR, 1 min: 2.1 ± 0.5 vs. 1.9 ± 0.5, P < 0.05) but it augmented the concomitant rise in MSNA (1 min: 28.0 ± 11.7 vs. 39.4 ± 12.7 bursts/min, P < 0.001; 32.8 ± 16.4 vs. 43.9 ± 14.8 bursts/100 heart beats, P < 0.01; 3.3 ± 2.1 vs. 4.8 ± 3.2 au/min, P < 0.05). We conclude that the early sympathoactivation 1 min into apnea after moderate packing is due to mechanisms other than excessive reduction in CO. We speculate that lower MAP despite increased MSNA after packing might be explained by vasodilator substances released by the lungs. This idea should be addressed in future studies.
Clenbuterol and formoterol decrease force production in isolated intact mouse skeletal muscle fiber bundles through a β2-adrenoceptor-independent mechanism
Authors: McCormick Cecilia , Alexandre Leo , Thompson Juliette , Mutungi Gabriel
Published: September 2010

Although the acute actions of short-acting β2-adrenoceptor agonists on force production in isolated mammalian skeletal muscle fibers have been the subject of a number of previous studies, those of long-acting β2-adrenoceptor agonists have never been investigated. Also, little is known about the cellular signal transduction events mediating their actions. Therefore, the primary aim of this study was to investigate the acute effects of treatment of mouse fast- and slow-twitch muscle fiber bundles with clenbuterol, formoterol, and salbutamol. Both clenbuterol and salbutamol increased the levels of cAMP in both fiber types, and this effect was reversed by ICI-118551. On the other hand, clenbuterol and formoterol decreased force production in both fiber types. They also increased the phosphorylation of phospholamban and β2-adrenoceptors in slow-twitch fiber bundles, and their effects were insensitive to propranolol, ICI-118551, and 14–22 amide. In contrast, salbutamol increased force production in both fiber types. It also increased the phosphorylation of β2-adrenoceptors in slow-twitch fibers only, but it had no effect on the phosphorylation of phospholamban in either fiber type. These effects were reversed by propranolol and ICI-118551 but not by 14–22 amide. Instead, 14–22 amide further potentiated the effects of salbutamol on force. In summary, long- and short-acting β2-adrenoceptor agonists have opposite effects on force production in isolated intact mouse skeletal muscle fiber bundles. From these results, we suggest that the acute actions of short-acting β2-adrenoceptor agonists on force production in mammalian skeletal muscles are mediated through the β2-adrenoceptor, whereas those of long-acting β2-adrenoceptor agonists are not.
Human aging and CD31+T-cell number, migration, apoptotic susceptibility, and telomere length
Authors: Kushner Erich J. , Weil Brian R. , MacEneaney Owen J. , Morgan Richard G. , Mestek Michael L. , Van Guilder Gary P. , Diehl Kyle J. , Stauffer Brian L. , DeSouza Christopher A.
Published: September 2010

CD31+T cells, or so-called “angiogenic T cells,” have been shown to demonstrate vasculoprotective and neovasculogenic qualities. The influence of age on CD31+T-cell number and function is unclear. We tested the hypothesis that circulating CD31+T-cell number and migratory capacity are reduced, apoptotic susceptibility is heightened, and telomere length is shortened with advancing age in adult humans. Thirty-six healthy, sedentary men were studied: 12 young (25 ± 1 yr), 12 middle aged (46 ± 1 yr), and 12 older (64 ± 2 yr). CD31+T cells were isolated from peripheral blood samples by magnetic-activated cell sorting. The number of circulating CD31+T cells (fluorescence-activated cell sorting analysis) was lower ( P < 0.01) in older (24% of CD3+cells) compared with middle-aged (38% of CD3+cells) and young (40% of CD3+cells) men. Migration (Boyden chamber) to both VEGF and stromal cell-derived factor-1α was markedly blunted ( P < 0.05) in cells harvested from middle-aged [306.1 ± 45 and 305.6 ± 46 arbitrary units (AU), respectively] and older (231 ± 65 and 235 ± 62 AU, respectively) compared with young (525 ± 60 and 570 ± 62 AU, respectively) men. CD31+T cells from middle-aged and older men demonstrated greater apoptotic susceptibility, as staurosporine-stimulated intracellular caspase-3 activation was ∼40% higher ( P < 0.05) than young. There was a progressive age-related decline in CD31+T-cell telomere length (young: 10,706 ± 220 bp; middle-aged: 10,179 ± 251 bp; and older: 9,324 ± 192 bp). Numerical and functional impairments in this unique T-cell subpopulation may contribute to diminished angiogenic potential and greater cardiovascular risk with advancing age.
Countermeasures against lumbar spine deconditioning in prolonged bed rest: resistive exercise with and without whole body vibration
Authors: Belavý Daniel L. , Armbrecht Gabriele , Gast Ulf , Richardson Carolyn A. , Hides Julie A. , Felsenberg Dieter
Published: September 2010

To evaluate the effect of short-duration, high-load resistive exercise, with and without whole body vibration on lumbar muscle size, intervertebral disk and spinal morphology changes, and low back pain (LBP) incidence during prolonged bed rest, 24 subjects underwent 60 days of head-down tilt bed rest and performed either resistive vibration exercise ( n = 7), resistive exercise only ( n = 8), or no exercise ( n = 9; 2nd Berlin Bed-Rest Study). Discal and spinal shape was measured from sagittal plane magnetic resonance images. Cross-sectional areas (CSAs) of the multifidus, erector spinae, quadratus lumborum, and psoas were measured on para-axial magnetic resonance images. LBP incidence was assessed with questionnaires at regular intervals. The countermeasures reduced CSA loss in the multifidus, lumbar erector spinae and quadratus lumborum muscles, with greater increases in psoas muscle CSA seen in the countermeasure groups ( P ≤ 0.004). There was little statistical evidence for an additional effect of whole body vibration above resistive exercise alone on these muscle changes. Exercise subjects reported LBP more frequently in the first week of bed rest, but this was only significant in resistive exercise only ( P = 0.011 vs. control, resistive vibration exercise vs. control: P = 0.56). No effect of the countermeasures on changes in spinal morphology was seen ( P ≥ 0.22). The results suggest that high-load resistive exercise, with or without whole body vibration, performed 3 days/wk can reduce lumbar muscle atrophy, but further countermeasure optimization is required.
Effects of postnatal smoke exposure on laryngeal chemoreflexes in newborn lambs
Authors: St-Hilaire Marie , Duvareille Charles , Avoine Olivier , Carreau Anne-Marie , Samson Nathalie , Micheau Philippe , Doueik Alexandre , Praud Jean-Paul
Published: September 2010

Laryngeal chemoreflexes (LCR), which are elicited by the contact of liquids such as gastric refluxate with laryngeal mucosa, may trigger some cases of sudden infant death syndrome. Indeed, while LCR in mature mammals consist of protective responses, previous animal data have shown that LCR in immature newborns can include laryngospasm, apnea, bradycardia, and desaturation. The present study was aimed at testing the hypothesis that postnatal exposure to cigarette smoke is responsible for enhancing cardiorespiratory inhibition observed with LCR. Eight lambs were exposed to cigarette smoke (20 cigarettes/day) over 16 days and compared with seven control lambs. Urinary cotinine/creatinine ratio was measured at a level relevant to previously published levels in infants. On days 15 and 16, 0.5 ml of HCl (pH 2), milk, distilled water, or saline was injected onto the larynx via a chronic supraglottal catheter during sleep. Results showed that exposure to cigarette smoke enhanced respiratory inhibition ( P < 0.05) and tended to enhance cardiac inhibition and decrease swallowing and arousal during LCR ( P < 0.1). Overall, these results were observed independently of the state of alertness and the experimental solution tested. In conclusion, 16-day postnatal exposure to cigarette smoke increases cardiorespiratory inhibition and decreases protective mechanisms during LCR in nonsedated full-term lambs.
ANCCA/ATAD2 Overexpression Identifies Breast Cancer Patients with Poor Prognosis, Acting to Drive Proliferation and Survival of Triple-Negative Cells through Control of B-Myb and EZH2
Authors: Kalashnikova Ekaterina V. , Revenko Alexey S. , Gemo Abigael T. , Andrews Nicolas P. , Tepper Clifford G. , Zou June X. , Cardiff Robert D. , Borowsky Alexander D. , Chen Hong-Wu
Published: September 2010

Chromatin coregulators are important factors in tumorigenesis and cancer progression. ANCCA is an AAA+ ATPase and a bromodomain-containing nuclear coactivator for the estrogen and androgen receptors that is crucial for assembly of chromatin-modifying complexes and proliferation of hormone-responsive cancer cells. In this study, we show that ANCCA is overexpressed in >70% of breast tumors and that its high protein level correlates well with tumor histologic grades (P < 0.0001), highlighting ANCCA as a prognostic factor for poor overall survival and disease recurrence. Strikingly, high-level ANCCA correlated with triple-negative tumors that represent highly aggressive disease. Analysis of ANCCA transcript levels in multiple expression profiles of breast cancer identified ANCCA as a common signature gene, indicating that elevated transcripts also strongly correlate with tumor metastasis and poor survival. Biological and mechanistic investigations revealed that ANCCA is crucial for proliferation and survival of triple-negative/basal-like cancer cells and that it controls the expression of B-Myb, histone methyltransferase EZH2, and an Rb-E2F core program for proliferation, along with a subset of key mitotic kinesins and cell survival genes (IRS2, VEGF, and Akt1). In particular, ANCCA overexpression correlated strongly with EZH2 in tumors. Our results suggest that ANCCA may integrate multiple oncogenic programs in breast cancer, serving in particular as a prognostic marker and a therapeutic target for triple-negative cancers. Cancer Res; 70(22); 9402–12. ©2010 AACR.
γ-Tocotrienol Inhibits Pancreatic Tumors and Sensitizes Them to Gemcitabine Treatment by Modulating the Inflammatory Microenvironment
Authors: Kunnumakkara Ajaikumar B. , Sung Bokyung , Ravindran Jayaraj , Diagaradjane Parmeswaran , Deorukhkar Amit , Dey Sanjit , Koca Cemile , Yadav Vivek R. , Tong Zhimin , Gelovani Juri G. , Guha Sushovan , Krishnan Sunil , Aggarwal Bharat B.
Published: September 2010

Pancreatic cancers generally respond poorly to chemotherapy, prompting a need to identify agents that could sensitize tumors to treatment. In this study, we investigated the response of human pancreatic cells to γ-tocotrienol (γ-T3), a novel, unsaturated form of vitamin E found in palm oil and rice bran oil, to determine whether it could potentiate the effects of gemcitabine, a standard of care in clinical treatment of pancreatic cancer. γ-T3 inhibited the in vitro proliferation of pancreatic cancer cell lines with variable p53 status and potentiated gemcitabine-induced apoptosis. These effects correlated with an inhibition of NF-κB activation by γ-T3 and a suppression of key cellular regulators including cyclin D1, c-Myc, cyclooxygenase-2 (COX-2), Bcl-2, cellular inhibitor of apoptosis protein, survivin, vascular endothelial growth factor (VEGF), ICAM-1, and CXCR4. In an orthotopic nude mouse model of human pancreatic cancer, p.o. administration of γ-T3 inhibited tumor growth and enhanced the antitumor properties of gemcitabine. Immunohistochemical analysis indicated a correlation between tumor growth inhibition and reduced expression of Ki-67, COX-2, matrix metalloproteinase-9 (MMP-9), NF-κB p65, and VEGF in the tissue. Combination treatment also downregulated NF-κB activity along with the NF-κB–regulated gene products, such as cyclin D1, c-Myc, VEGF, MMP-9, and CXCR4. Consistent with an enhancement of tumor apoptosis, caspase activation was observed in tumor tissues. Overall, our findings suggest that γ-T3 can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing NF-κB–mediated inflammatory pathways linked to tumorigenesis. Cancer Res; 70(21); 8695–705. ©2010 AACR.
A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer
Authors: Jiang Feng , Todd Nevins W. , Li Ruiyun , Zhang Howard , Fang HongBin , Stass Sanford A.
Published: September 2010

Non–small cell lung cancer (NSCLC) is the leading cause of cancer death. Early detection of NSCLC will improve its outcome. We previously identified genetic signatures whose genomic copy number aberrations were associated with early stage NSCLC. Here, we aimed to develop a panel of genes that could be detected in sputum for NSCLC early detection. We first optimized a panel of genes by using an in situ minichip for measuring changes of the signatures in sputum of a case–control cohort of 49 NSCLC patients, 49 patients with chronic obstructive pulmonary disease (COPD), and 49 healthy smokers. We then validated the genes in an independent cohort of 69 NSCLC patients and 65 noncancer subjects. The results were compared with those of sputum cytology. Fifteen genes showed significant differences of their copy number changes in sputum between NSCLC and both COPD and healthy subjects. A logistic regression model with the best prediction was built on the basis of 6 genes, ENO1, FHIT, HYAL2, SKP2, p16, and 14–3-3zeta. The composite of the 6 genes produced 86.7% sensitivity and 93.9% specificity in distinguishing stage I NSCLC patients from the noncancer individuals. Furthermore, the genes had higher sensitivity (86.9%) in identification of squamous cell carcinoma (SCC) than in adenocarcinoma of the lungs (80.8%; P < 0.05). Validation of the genes in the independent cohort confirmed their diagnostic power that also showed higher accuracy for lung SCCs than for sputum cytology. The gene panel could provide sputum-based markers that have the potential to improve early detection of lung SCCs. Cancer Prev Res; 3(12); 1571–8. ©2010 AACR.
Ketorolac plus Tobramycin/Dexamethasone versus Tobramycin/Dexamethasone after Uneventful Phacoemulsification Surgery: A Randomized Controlled Trial
Authors: Chatziralli Irini P. , Papazisis Leonidas , Sergentanis Theodoros N.
Published: September 2010

Background/Aims: To evaluate the benefit of adding a nonsteroid agent to an antibiotic/steroid combination after uneventful phacoemulsification, adopting a weekly follow-up, to gain insight into the optimal duration of postoperative treatment and to examine whether risk factors for inflammation exist. Methods: Patients were randomized to (i) tobramycin 0.3%-dexamethasone 0.1%, 1 drop q.i.d. (n = 72), and (ii) a combination of tobramycin 0.3%-dexamethasone 0.1%, 1 drop q.i.d., plus ketorolac tromethamine 0.5%, 1 drop t.i.d. (n = 73). On days 7, 14, 21 and 28, the frequency of inflammation-related signs (corneal edema, conjunctival hyperemia, anterior chamber or Tyndall reaction) as well as best-corrected visual acuity (BCVA) were measured. On day 21, logistic regression was performed to evaluate risk factors for inflammation. Results: The frequency of inflammation-related signs did not differ between the 2 groups at any time point, neither did BCVA. On day 21, pseudoexfoliation was associated with the presence of any inflammation-related sign (OR = 4.5; 95% CI: 1.2–16.0; p = 0.022). No evidence of clinically significant cystoid macular edema became evident in either group. Conclusion: The addition of ketorolac did not seem to offer any additional benefit in terms of inflammation-related signs. Four weeks appeared as an adequate treatment interval. Special attention should be paid to patients with pseudoexfoliation.
Ranibizumab Treatment for Choroidal Neovascularization from Causes Other than Age-Related Macular Degeneration and Pathological Myopia
Authors: Carneiro Angela M. , Silva Rufino M. , Veludo Maria J. , Barbosa Augusto , Ruiz-Moreno José M. , Falcão Manuel S. , Brandão Elisete M. , Falcão-Reis Fernando M.
Published: September 2010

Aim: Evaluation of safety and efficacy of intravitreal ranibizumab in the treatment of choroidal neovascularization (CNV) secondary to causes other than age-related macular degeneration (AMD) or pathological myopia (PM). Methods: Retrospective and multicentric analysis of 21 eyes with CNV. Nine eyes had angioid streaks, 5 inflammatory chorioretinal diseases, 3 central serous chorioretinopathy and 4 idiopathic CNV. Follow-ups lasted ≧3 months. Best-corrected visual acuity (BCVA), ocular coherence tomography (OCT) and fundus examination were assessed monthly. Results: Sixteen eyes (76%) completed 180 days of follow-up. Overall BCVA increased by +9.8 letters with treatment (p = 0.015). Visual acuity improvements ≧15 letters occurred in 43%. A significant reduction in OCT central thickness was observed. No cases of severe visual acuity loss, systemic or ocular side effects were registered. Conclusion: Short-term results of intravitreal ranibizumab for CNV unrelated to AMD or PM are encouraging. This treatment may constitute the only option for some of these patients.
Nationwide Population-Based Epidemiologic Study of Huntington’s Disease in Taiwan
Authors: Chen Yen-Yu , Lai Chien-Hsu
Published: September 2010

Background: The purpose of this study is to investigate the epidemiology and medical expenses of Huntington’s disease (HD) in Taiwan. Methods: Cases of HD were identified from the National Health Insurance Research Database with corresponding International Classification of Diseases, Ninth Revision (ICD-9) code 333.4 from January 2000 to December 2007. Age- and sex-specific incidences were estimated by dividing the incidence number by population data obtained from the Department of Statistics, Ministry of the Interior. Results: During the study period, 182 cases were identified, including 81 males and 101 females. The average annual incidence rate was 0.1 per 100,000. The age-specific incidence peaked in the 40–49 age group in men (0.23 per 100,000 per year) and in the 50–59 age group in women (0.24 per 100,000 per year). The incidence rate was only 0.01 per 100,000 per year in those under 20 years of age. The prevalence was 0.42 per 100,000 in 2007. Conclusions: This is the first population-based epidemiologic study on HD in Taiwan. The incidence rates and prevalence were much lower than those of Caucasians although the age distribution was similar.
Amplification of Minute Amounts of Oral Bacterial DNA for Real-Time Quantitative PCR Analysis
Authors: Wolff D. , Staehle H.J. , Wolff B.
Published: September 2010

Background: High-throughput technologies for typing caries or health-associated bacterial populations including PCR, DNA microarrays and next-generation sequencing techniques require significant amounts of bacterial DNA. In clinical settings, the amount of sampled DNA is often limited and amplification is therefore essential. Protocols should be able to reproducibly amplify sequences in order to maintain initial sequence ratios and should not bias the representation of particular DNA sequence types. Methods: A linear amplification protocol using DNA polymerase I was modified to permit the amplification and subsequent analysis of small amounts of bacterial DNA. The protocol was tested on human oral bacterial biofilms from different sources, including carious dentine and plaque, and compared to amplification by degenerate PCR of 16S rDNA sequences. Real-time quantitative PCR of 24 bacterial species was used as a readout system to test amplified DNA against unamplified DNA. Results: The amplification protocol reliably yielded 5–10 µg DNA from as little as 12.5 ng of template DNA. Correlation coefficients between real-time quantitative PCR results from amplified and unamplified DNA were between 0.78 and 0.98. Conclusion: The optimized protocol consistently produced amplification products from minute amounts of bacterial DNA from caries and plaque; the amplification products are suitable for downstream genetic analyses.
Risk of Arterial Cardiovascular Diseases in Patients with Multiple Sclerosis: A Population-Based Cohort Study
Authors: Christiansen Christian Fynbo , Christensen Steffen , Farkas Dóra Körmendiné , Miret Montserrat , Sørensen Henrik Toft , Pedersen Lars
Published: September 2010

Background: Patients with multiple sclerosis (MS) may have a higher risk of cardiovascular diseases (CVD) than the general population, but data are limited. Methods: We conducted a population-based cohort study involving Danish citizens diagnosed with MS (n = 13,963) from 1977 to 2006 and an age- and sex-matched population cohort (n = 66,407) using data on MS, arterial CVD and comorbidity from the Danish National Registry of Patients. We calculated the risk of arterial CVD for all subjects and computed adjusted incidence rate ratios (IRRs). Results: During the first year of follow-up, the risk of myocardial infarction (MI) was 0.2% among patients with MS (adjusted IRR = 1.84; 95% confidence interval, CI: 1.28–2.65, compared with population cohort members), whereas the 1-year risk of overall stroke was 0.3% (adjusted IRR = 1.96; 95% CI: 1.42–2.71). IRRs were 1.92 (95% CI: 1.27–2.90) for heart failure and 0.77 (95% CI: 0.42–1.39) for atrial fibrillation/flutter. During the subsequent 2–30 years of follow-up, IRRs remained elevated for overall stroke (1.23; 95% CI: 1.10–1.38) and heart failure (1.53; 95% CI: 1.37–1.71) but decreased for acute MI (1.10; 95% CI: 0.97–1.24). Conclusion: In this Danish cohort, the risk of CVD among MS patients was low, but greater than that in the general population, particularly in the short term.
The Act of Voluntary Wheel Running Reverses Dietary Hyperphagia and Increases Leptin Signaling in Ventral Tegmental Area of Aged Obese Rats
Authors: Shapiro Alexandra , Cheng Kit-Yan , Gao Yongxin , Seo Dong-oh , Anton Steve , Carter Christy S. , Zhang Yi , Tumer Nihal , Scarpace Philip J.
Published: September 2010

To test the hypothesis that exercise increases central leptin signaling, and thus reduces dietary weight gain in an aged obese model, we assessed the effects of voluntary wheel running (WR) in 23-month-old F344×BN rats fed a 60% high-fat (HF) diet for 3 months. After 2 months on the HF diet, half of the rats were provided access to running wheels for 2 weeks while the other half remained sedentary. Following the removal of the wheels, physical performance was evaluated, and 4 weeks later leptin signaling was assessed in hypothalamus and VTA after an acute bout of WR. Introduction of a HF diet led to prolonged hyperphagia (63.9 ± 7.8 kcal/day on chow diet vs. 88.1 ± 8.2 kcal/day on high-fat diet (when food intake stabilized), p < 0.001). As little as 9 (ranging to 135) wheel revolutions per day significantly reduced caloric consumption of HF food (46.8 ± 11.2 kcal/day) to a level below that on chow diet (63.9 ± 7.8 kcal/day, p < 0.001). After 2 weeks of WR, body weight was significantly reduced (7.9 ± 2.1% compared with prerunning weight, p < 0.001), and physical performance (latency to fall from an incline plane) was significantly improved (p = 0.04). WR significantly increased both basal (p = 0.04) and leptin-stimulated (p = 0.001) STAT3 phosphorylation in the ventral tegmental area (VTA), but not in the hypothalamus. Thus, in aged dietary obese rats, the act but not the extent of voluntary WR is highly effective in reversing HF consumption, decreasing body weight, and improving physical performance. It appears to trigger a response that substitutes for the reward of highly palatable food that may be mediated by increased leptin signaling in the VTA.
Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease
Authors: Waterworth Dawn M. , Ricketts Sally L. , Song Kijoung , Chen Li , Zhao Jing Hua , Ripatti Samuli , Aulchenko Yurii S. , Zhang Weihua , Yuan Xin , Lim Noha , Luan Jian'an , Ashford Sofie , Wheeler Eleanor , Young Elizabeth H. , Hadley David , Thompson John R. , Braund Peter S. , Johnson Toby , Struchalin Maksim , Surakka Ida , Luben Robert , Khaw Kay-Tee , Rodwell Sheila A. , Loos Ruth J.F. , Boekholdt S. Matthijs , Inouye Michael , Deloukas Panagiotis , Elliott Paul , Schlessinger David , Sanna Serena , Scuteri Angelo , Jackson Anne , Mohlke Karen L. , Tuomilehto Jaako , Roberts Robert , Stewart Alexandre , Kesäniemi Y. Antero , Mahley Robert W. , Grundy Scott M. ,   Wellcome Trust Case Control Consortium, McArdle Wendy , Cardon Lon , Waeber Gérard , Vollenweider Peter , Chambers John C. , Boehnke Michael , Abecasis Gonçalo R. , Salomaa Veikko , Järvelin Marjo-Riitta , Ruokonen Aimo , Barroso Inês , Epstein Stephen E. , Hakonarson Hakon H. , Rader Daniel J. , Reilly Muredach P. , Witteman Jacqueline C.M. , Hall Alistair S. , Samani Nilesh J. , Strachan David P. , Barter Philip , van Duijn Cornelia M. , Kooner Jaspal S. , Peltonen Leena , Wareham Nicholas J. , McPherson Ruth , Mooser Vincent , Sandhu Manjinder S.
Published: September 2010

Objective—

Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.

Methods and Results—

We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10
−8
to 3.1×10
−10
). These include a potentially functional SNP in the
SLC39A8
gene for HDL-C, an SNP near the
MYLIP/GMPR
and
PPP1R3B
genes for LDL-C, and at the
AFF1
gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the
CELSR2
,
APOB
,
APOE-C1-C4-C2
cluster,
LPL
,
ZNF259-APOA5-A4-C3-A1
cluster and
TRIB1
loci were also associated with CAD risk (probability values, 1.1×10
−3
to 1.2×10
−9
).

Conclusion—

We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
Plasma Phospholipid Transfer Protein Deficiency in Mice Is Associated With a Reduced Thrombotic Response to Acute Intravascular Oxidative Stress
Authors: Desrumaux Catherine , Deckert Valérie , Lemaire-Ewing Stéphanie , Mossiat Claude , Athias Anne , Vandroux David , Dumont Laure , Monier Serge , Pais de Barros Jean-Paul , Klein Alexis , De Maistre Emmanuel , Blache Denis , Beley Alain , Marie Christine , Garnier Philippe , Lagrost Laurent
Published: September 2010

Objective—

Earlier in vitro studies suggested a putative role for the plasma phospholipid transfer protein (PLTP) in the modulation of blood coagulation. The effect of PLTP expression on blood coagulation under both basal and oxidative stress conditions was compared here in wild-type and PLTP-deficient (PLTP−/−) mice.

Methods and Results—

Under basal conditions, PLTP deficiency was associated with an extended tail bleeding time despite a significant depletion of vascular α-tocopherol content and an impairment of endothelial function. When acute oxidative stress was generated in vivo in the brain vasculature, the steady state levels of oxidized lipid derivatives, the extent of blood vessel occlusion, and the volume of ischemic lesions were more severe in wild-type than in PLTP−/− mice.

Conclusion—

In addition to its recognized hyperlipidemic, proinflammatory, and proatherogenic properties, PLTP increases blood coagulation and worsens the extent of ischemic lesions in response to acute oxidative stress. Thus, PLTP arises here as a cardiovascular risk factor for the late thrombotic events occurring in the acute phase of atherosclerosis.
Dyslipidemia of Mothers With Familial Hypercholesterolemia Deteriorates Lipids in Adult Offspring
Authors: van der Graaf Anouk , Vissers Maud N. , Gaudet Daniel , Brisson Diane , Sivapalaratnam Suthesh , Roseboom Tessa J. , Jansen Angelique C.M. , Kastelein John J.P. , Hutten Barbara A.
Published: September 2010

Objective—

It is unknown whether elevated maternal low-density lipoprotein cholesterol (LDL-C) levels lead to dyslipidemia in the offspring. Because this could have important consequences for cardiovascular prevention in mother and child, we explored the relationship between maternal familial hypercholesterolemia (FH) and lipids in adult offspring.

Methods and Results—

In a large cohort of both Dutch and Canadian origin, we compared lipid profiles between patients, aged 18 to 85 years, who inherited FH maternally (n=1069) and those who inherited FH paternally (n=1270). This relationship was evaluated using multivariate regression analyses. Levels of total cholesterol (TC), LDL-C, and apolipoprotein B 100 (ApoB100) were significantly elevated in patients who inherited FH maternally compared with patients who inherited FH paternally (adjusted differences in TC: 0.156 mmol/L,
P
=0.037; LDL-C: 0.187 mmol/L,
P
=0.012; ApoB: 0.064 g/L,
P
=0.022).

Conclusion—

Our data show that maternal hereditary hypercholesterolemia slightly increases TC, LDL-C, and ApoB levels in their offspring later in life. Although the molecular mechanisms underlying these observations still require elucidation, our data suggest that maternal hypercholesterolemia during pregnancy may program lipid metabolism to a certain extent in the fetus.
Evidence for Active Regulation of Pro-Osteogenic Signaling in Advanced Aortic Valve Disease
Authors: Miller Jordan D. , Weiss Robert M. , Serrano Kristine M. , Castaneda Lauren E. , Brooks Robert M. , Zimmerman Kathy , Heistad Donald D.
Published: September 2010

Objective—

To test the hypothesis that valvular calcium deposition, pro-osteogenic signaling, and function can be altered in mice with advanced aortic valve disease.

Methods and Results—

“Reversa” mice were given a Western-type diet for 12 months and screened for the presence of aortic valve stenosis. Mice with advanced valve disease were assigned to 1 of 2 groups: (1) those with continued progression for 2 months and (2) those with regression for 2 months, in which lipid lowering was accomplished by a genetic switch. Control mice were normocholesterolemic for 14 months. Mice with advanced valve disease had massive valvular calcification that was associated with increases in bone morphogenetic protein signaling, Wnt/β-catenin signaling, and markers of osteoblastlike cell differentiation. Remarkably, reducing plasma lipids with a genetic switch dramatically reduced markers of pro-osteogenic signaling and significantly reduced valvular calcium deposition. Nevertheless, despite a marked reduction in valvular calcium deposition, valve function remained markedly impaired. Phosphorylated Smad2 levels and myofibroblast activation (indexes of profibrotic signaling) remained elevated.

Conclusion—

Molecular processes that contribute to valvular calcification and osteogenesis remain remarkably labile during the end stages of aortic valve stenosis. Although reductions in valvular calcium deposition were not sufficient to improve valvular function in the animals studied, these findings demonstrate that aortic valve calcification is a remarkably dynamic process that can be modified therapeutically, even in the presence of advanced aortic valve disease.
Nuclear Factor κB–Mediated Transactivation of Telomerase Prevents Intimal Smooth Muscle Cell From Replicative Senescence During Vascular Repair
Authors: Bu De-xiu , Johansson Maria E. , Ren Jingyi , Xu Da-wei , Johnson F. Brad , Edfeldt Kristina , Yan Zhong-qun
Published: September 2010

Objective—

To gain insights into mechanisms by which intimal hyperplasia interferes with the repair process by investigating expression and function of the catalytic telomerase reverse transcriptase (TERT) subunit after vascular injury.

Methods and Results—

Functional telomerase is essential to the replicative longevity of vascular cells. We found that TERT was de novo activated in the intima of injured arteries, involving activation of the nuclear factor κB pathway. Stimulation of the isolated intimal smooth muscle cell (SMC) by basic fibroblast growth factor or tumor necrosis factor α resulted in increased TERT activity. This depends on the activation of c-Myc signaling because mutation of the E-box in the promoter or overexpression of mitotic arrest deficient 1 (MAD1), a c-Myc competitor, abrogated the transcriptional activity. Inhibition of nuclear factor κB in both intimal SMCs and the injured artery attenuated TERT transcriptional activity through reduction of c-Myc expression. Pharmacological blockade of TERT led to SMC senescence. Finally, depletion of telomerase function in mice resulted in severe intimal SMC senescence after vascular injury.

Conclusion—

These results support a model in which vascular injury induces de novo expression of TERT in intimal SMCs via activation of nuclear factor κB and upregulation of c-Myc. The resumed TERT activity is critical for intimal hyperplasia.
Perivascular Adipose Tissue–Derived Complement 3 Is Required for Adventitial Fibroblast Functions and Adventitial Remodeling in Deoxycorticosterone Acetate–Salt Hypertensive Rats
Authors: Ruan Cheng-Chao , Zhu Ding-Liang , Chen Qi-Zhi , Chen Jing , Guo Shu-Jie , Li Xiao-Dong , Gao Ping-Jin
Published: September 2010

Objective—

To examine the role of perivascular adipose tissue (PVAT)–derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo.

Methods and Results—

PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by α-smooth muscle–actin induction. We identified the secretome of PVAT by liquid chromatography–tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium–induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in deoxycorticosterone acetate–salt hypertensive rats.

Conclusion—

PVAT-derived C3 stimulated AF migration and differentiation via the c-Jun N-terminal kinase pathway. PVAT-derived C3 may contribute to adventitial remodeling in a deoxycorticosterone acetate–salt hypertensive model.