bluuebunny/crossref_metadata_2025 huggingface dataset:
Standard magnetic resonance-based measurements of the Pi→ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles
Authors: From Arthur H. L. , Ugurbil Kamil
Published: March 2011

Magnetic resonance spectroscopy-based magnetization transfer techniques (MT) are commonly used to assess the rate of oxidative (i.e., mitochondrial) ATP synthesis in intact tissues. Physiologically appropriate interpretation of MT rate data depends on accurate appraisal of the biochemical events that contribute to a specific MT rate measurement. The relative contributions of the specific enzymatic reactions that can contribute to a MT Pi→ATP rate measurement are tissue dependent; nonrecognition of this fact can bias the interpretation of MT Pi→ATP rate data. The complexities of MT-based measurements of mitochondrial ATP synthesis rates made in striated muscle and other tissues are reviewed, following which, the adverse impacts of erroneous Pi→ATP rate data analyses on the physiological inferences presented in selected published studies of cardiac and skeletal muscle are considered.
High-energy phosphate transfer in human muscle: diffusion of phosphocreatine
Authors: Gabr Refaat E. , El-Sharkawy AbdEl-Monem M. , Schär Michael , Weiss Robert G. , Bottomley Paul A.
Published: March 2011

The creatine kinase (CK) reaction is central to muscle energetics, buffering ATP levels during periods of intense activity via consumption of phosphocreatine (PCr). PCr is believed to serve as a spatial shuttle of high-energy phosphate between sites of energy production in the mitochondria and sites of energy utilization in the myofibrils via diffusion. Knowledge of the diffusion coefficient of PCr ( DPCr) is thus critical for modeling and understanding energy transport in the myocyte, but DPCr has not been measured in humans. Using localized phosphorus magnetic resonance spectroscopy, we measured DPCr in the calf muscle of 11 adults as a function of direction and diffusion time. The results show that the diffusion of PCr is anisotropic, with significantly higher diffusion along the muscle fibers, and that the diffusion of PCr is restricted to a ∼28-μm pathlength assuming a cylindrical model, with an unbounded diffusion coefficient of ∼0.69 × 10−3 mm2/s. This distance is comparable in size to the myofiber radius. On the basis of prior measures of CK reaction kinetics in human muscle, the expected diffusion distance of PCr during its half-life in the CK reaction is ∼66 μm. This distance is much greater than the average distances between mitochondria and myofibrils. Thus these first measurements of PCr diffusion in human muscle in vivo support the view that PCr diffusion is not a factor limiting high-energy phosphate transport between the mitochondria and the myofibrils in healthy resting myocytes.
17β-estradiol attenuates exercise-induced neutrophil infiltration in men
Authors: MacNeil Lauren G. , Baker Steven K. , Stevic Ivan , Tarnopolsky Mark A.
Published: March 2011

17β-estradiol (E2) attenuates exercise-induced muscle damage and inflammation in some models. Eighteen men completed 150 eccentric contractions after random assignment to placebo (Control group) or E2 supplementation (Experimental group). Muscle biopsies and blood samples were collected at baseline, following 8-day supplementation and 3 h and 48 h after exercise. Blood samples were analyzed for sex hormone concentration, creatine kinase (CK) activity and total antioxidant capacity. The mRNA content of genes involved in lipid and cholesterol homeostasis [forkhead box O1 (FOXO1), caveolin 1, and sterol regulatory element binding protein-2 (SREBP2)] and antioxidant defense (SOD1 and -2) were measured by RT-PCR. Immunohistochemistry was used to quantify muscle neutrophil (myeloperoxidase) and macrophage (CD68) content. Serum E2 concentration increased 2.5-fold with supplementation ( P < 0.001), attenuating neutrophil infiltration at 3 h ( P < 0.05) and 48 h ( P < 0.001), and the induction of SOD1 at 48 h ( P = 0.02). Macrophage density at 48 h ( P < 0.05) and SOD2 mRNA at 3 h ( P = 0.01) increased but were not affected by E2. Serum CK activity was higher at 48 h for both groups ( P < 0.05). FOXO1, caveolin 1 and SREBP2 expression were 2.8-fold ( P < 0.05), 1.4-fold ( P < 0.05), and 1.5-fold ( P < 0.001) and higher at 3 h after exercise with no effect of E2. This suggests that E2 attenuates neutrophil infiltration; however, the mechanism does not appear to be lesser oxidative stress or membrane damage and may indicate lesser neutrophil/endothelial interaction.
Attenuating effect of angiotensin-(1–7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-Ay/Ta mice
Authors: Moon Ju-Young , Tanimoto Mitsuo , Gohda Tomohito , Hagiwara Shinji , Yamazaki Takahiko , Ohara Ikko , Murakoshi Maki , Aoki Tatsuya , Ishikawa Yuji , Lee Sang-Ho , Jeong Kyung-Hwan , Lee Tae-Won , Ihm Chun-Gyoo , Lim Sung Jig , Tomino Yasuhiko
Published: March 2011

ANG-(1–7) is associated with vasodilation and nitric oxide synthase stimulation. However, the role of ANG-(1–7) in type 2 diabetes mellitus is unknown. In this study, we examined the hypothesis that ANG-(1–7) attenuates ANG II-induced reactive oxygen species stress (ROS)-mediated injury in type 2 diabetic nephropathy of KK-Ay/Ta mice. KK-Ay/Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG II+ANG-(1–7) coinfusion group; and 4) ANG II+ANG-(1–7)+d-Ala7-ANG-(1–7) (A779) coinfusion group. In addition, primary mesangial cells were cultured and then stimulated with 25 mM glucose with or without ANG II, ANG-(1–7), and A779. The ANG II+ANG-(1–7) coinfusion group showed a lower urinary albumin/creatinine ratio increase than the ANG II group. ANG-(1–7) attenuated ANG II-mediated NAD(P)H oxidase activation and ROS production in diabetic glomeruli and mesangial cells. ANG II-induced NF-κB and MAPK signaling activation was also attenuated by ANG-(1–7) in the mesangial cells. These findings were related to improved mesangial expansion and to fibronectin and transforming growth factor-β1 production in response to ANG II and suggest that ANG-(1–7) may attenuate ANG II-stimulated ROS-mediated injury in type 2 diabetic nephropathy. The ACE2-ANG-(1–7)-Mas receptor axis should be investigated as a novel target for treatment of type 2 diabetic nephropathy.
Contribution of renal purinergic receptors to renal vasoconstriction in angiotensin II-induced hypertensive rats
Authors: Franco Martha , Bautista Rocio , Tapia Edilia , Soto Virgilia , Santamaría José , Osorio Horacio , Pacheco Ursino , Sánchez-Lozada L. Gabriela , Kobori Hiroyuki , Navar L. Gabriel
Published: March 2011

To investigate the participation of purinergic P2 receptors in the regulation of renal function in ANG II-dependent hypertension, renal and glomerular hemodynamics were evaluated in chronic ANG II-infused (14 days) and Sham rats during acute blockade of P2 receptors with PPADS. In addition, P2X1 and P2Y1 protein and mRNA expression were compared in ANG II-infused and Sham rats. Chronic ANG II-infused rats exhibited increased afferent and efferent arteriolar resistances and reductions in glomerular blood flow, glomerular filtration rate (GFR), single-nephron GFR (SNGFR), and glomerular ultrafiltration coefficient. PPADS restored afferent and efferent resistances as well as glomerular blood flow and SNGFR, but did not ameliorate the elevated arterial blood pressure. In Sham rats, PPADS increased afferent and efferent arteriolar resistances and reduced GFR and SNGFR. Since purinergic blockade may influence nitric oxide (NO) release, we evaluated the role of NO in the response to PPADS. Acute blockade with Nω-nitro-l-arginine methyl ester (l-NAME) reversed the vasodilatory effects of PPADS and reduced urinary nitrate excretion (NO2−/NO3−) in ANG II-infused rats, indicating a NO-mediated vasodilation during PPADS treatment. In Sham rats, PPADS induced renal vasoconstriction which was not modified by l-NAME, suggesting blockade of a P2X receptor subtype linked to the NO pathway; the response was similar to that obtained with l-NAME alone. P2X1 receptor expression in the renal cortex was increased by chronic ANG II infusion, but there were no changes in P2Y1 receptor abundance. These findings indicate that there is an enhanced P2 receptor-mediated vasoconstriction of afferent and efferent arterioles in chronic ANG II-infused rats, which contributes to the increased renal vascular resistance observed in ANG II-dependent hypertension.
TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injury
Authors: Andrade Edinéia Lemos , Forner Stefânia , Bento Allisson Freire , Leite Daniela Ferraz Pereira , Dias Marcos Antonio , Leal Paulo César , Koepp Janice , Calixto João B.
Published: March 2011

The ankyrin-repeat transient receptor potential 1 (TRPA1) has been implicated in pathological conditions of the bladder, but its role in overactive bladder (OAB) following spinal cord injury (SCI) remains unknown. In this study, using a rat SCI model, we assessed the relevance of TRPA1 in OAB induced by SCI. SCI resulted in tissue damage, inflammation, and changes in bladder contractility and in voiding behavior. Moreover, SCI caused upregulation of TRPA1 protein and mRNA levels, in bladder and in dorsal root ganglion (DRG; L6-S1), but not in corresponding segment of spinal cord. Alteration in bladder contractility following SCI was evidenced by enhancement in cinnamaldehyde-, capsaicin-, or carbachol-induced bladder contraction as well as in its spontaneous phasic activity. Of relevance to voiding behavior, SCI induced increase in the number of nonvoiding contractions (NVCs), an important parameter associated with the OAB etiology, besides alterations in other urodynamic parameters. HC-030031 (TRPA1 antagonist) treatment decreased the number and the amplitude of NVCs while the TRPA1 antisense oligodeoxynucleotide (AS-ODN) treatment normalized the spontaneous phasic activity, decreased the cinnamaldehyde-induced bladder contraction and the number of NVCs in SCI rats. In addition, the cinnamaldehyde-induced bladder contraction was reduced by exposure of the bladder preparations to HC-030031. The efficacy of TRPA1 AS-ODN treatment was confirmed by means of the reduction of TRPA1 expression in the DRG, in the corresponding segment of the spinal cord and in the bladder, specifically in detrusor muscle. The present data show that the TRPA1 activation and upregulation seem to exert an important role in OAB following SCI.
High-frequency, short-latency disinhibition bursting of midbrain dopaminergic neurons
Authors: Lobb Collin J. , Wilson Charles J. , Paladini Carlos A.
Published: March 2011

During reinforcement and sequence learning, dopaminergic neurons fire bursts of action potentials. Dopaminergic neurons in vivo receive strong background excitatory and inhibitory inputs, suggesting that one mechanism by which bursts may be produced is disinhibition. Unfortunately, these inputs are lost during slice preparation and are not precisely controlled during in vivo experiments. In the present study we show that dopaminergic neurons can be shifted into a balanced state in which constant synaptic N-methyl-d-aspartate (NMDA) and GABAA conductances are mimicked either pharmacologically or using dynamic clamp. From this state, a disinhibition burst can be evoked by removing the background inhibitory conductance. We demonstrate three functional characteristics of network-based disinhibition that promote high-frequency, short-latency bursting in dopaminergic neurons. First, we found that increasing the total background NMDA and GABAA synaptic conductances increased the intraburst firing frequency and reduced its latency. Second, we found that the disinhibition burst is sensitive to the proportion of background inhibitory input that is removed. In particular, we found that high-frequency, short-latency bursts were enhanced by increasing the degree of disinhibition. Third, the time course over which inhibition is removed had a large effect on the burst, namely, that synchronous removal of weak inhibitory inputs produces bursts of high intraburst frequency and shorter latency. Our results suggest that fast, more precisely timed bursts can be evoked by complete and synchronous disinhibition of dopaminergic neurons in a high-conductance state.
Regulated Intramembrane Proteolysis: Signaling Pathways and Biological Functions
Authors: Lal Mark , Caplan Michael
Published: March 2011

Intramembrane cleavage of transmembrane proteins is a fundamental cellular process. Several enzymes capable of releasing domains of integral membrane proteins have been described. Transmembrane protein proteolytic cleavage is regulated and involved not only in degrading membrane spanning segments but also in generating messengers that elicit biological responses. This review examines the role of the released functional protein domain in signaling mechanisms regulating an array of cellular and physiological processes.
Spontaneous Neurotransmission: An Independent Pathway for Neuronal Signaling?
Authors: Kavalali Ege T. , Chung ChiHye , Khvotchev Mikhail , Leitz Jeremy , Nosyreva Elena , Raingo Jesica , Ramirez Denise M. O.
Published: March 2011

Recent findings suggest that spontaneous neurotransmission is a bona fide pathway for interneuronal signaling that operates independent of evoked transmission via distinct presynaptic as well as postsynaptic substrates. This article will examine the role of spontaneous release events in neuronal signaling by focusing on aspects that distinguish this process from evoked neurotransmission, and evaluate the mechanisms that may underlie this segregation.
Distinct TRAIL Resistance Mechanisms Can Be Overcome by Proteasome Inhibition but not Generally by Synergizing Agents
Authors: Menke Christina , Bin Lianghua , Thorburn Jacqueline , Behbakht Kian , Ford Heide L. , Thorburn Andrew
Published: March 2011

One impediment to the use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-targeted agents as antitumor drugs is the evolution of resistance, a common problem in cancer. On the contrary, many different kinds of drugs synergize with TRAIL in TRAIL-sensitive tumor cells, raising the question whether one can overcome resistance with the same drugs producing synergy. This is an important question, because recent clinical trials suggest that combination treatments with cytotoxic drugs and TRAIL receptor-targeted agents do not provide additional benefit compared with cytotoxic agents on their own. Such results might be expected if drug combinations that synergize in sensitive tumor cells but cannot overcome TRAIL resistance are used in patients whose tumors were not selected for retention of TRAIL sensitivity. We tested this idea by creating isogenic tumor cells with acquired TRAIL resistance or defined mechanisms of resistance that occur in human tumors and then comparing them to the TRAIL-sensitive parental cell line. Although diverse classes of anticancer drugs were all able to synergize with TRAIL in sensitive cells, most agents were unable to overcome resistance and there was no relationship between the amount of synergy seen with a particular agent and its ability to overcome acquired resistance. An important exception was proteasome inhibitors, which were, however, able to overcome diverse resistance mechanisms. Our findings suggest that one should select drugs for TRAIL receptor agonist combination therapy based not just on their ability to synergize, but rather on their ability to overcome resistance as well as synergize. Cancer Res; 71(5); 1883–92. ©2011 AACR.
Reduced VEGF Production, Angiogenesis, and Vascular Regrowth Contribute to the Antitumor Properties of Dual mTORC1/mTORC2 Inhibitors
Authors: Falcon Beverly L. , Barr Sharon , Gokhale Prafulla C. , Chou Jeyling , Fogarty Jennifer , Depeille Philippe , Miglarese Mark , Epstein David M. , McDonald Donald M.
Published: March 2011

The mammalian target of rapamycin (mTOR) pathway is implicated widely in cancer pathophysiology. Dual inhibition of the mTOR kinase complexes mTORC1 and mTORC2 decreases tumor xenograft growth in vivo and VEGF secretion in vitro, but the relationship between these two effects are unclear. In this study, we examined the effects of mTORC1/2 dual inhibition on VEGF production, tumor angiogenesis, vascular regression, and vascular regrowth, and we compared the effects of dual inhibition to mTORC1 inhibition alone. ATP-competitive inhibitors OSI-027 and OXA-01 targeted both mTORC1 and mTORC2 signaling in vitro and in vivo, unlike rapamycin that only inhibited mTORC1 signaling. OXA-01 reduced VEGF production in tumors in a manner associated with decreased vessel sprouting but little vascular regression. In contrast, rapamycin exerted less effect on tumoral production of VEGF. Treatment with the selective VEGFR inhibitor OSI-930 reduced vessel sprouting and caused substantial vascular regression in tumors. However, following discontinuation of OSI-930 administration tumor regrowth could be slowed by OXA-01 treatment. Combining dual inhibitors of mTORC1 and mTORC2 with a VEGFR2 inhibitor decreased tumor growth more than either inhibitor alone. Together, these results indicate that dual inhibition of mTORC1/2 exerts antiangiogenic and antitumoral effects that are even more efficacious when combined with a VEGFR antagonist. Cancer Res; 71(5); 1573–83. ©2011 AACR.
Ironing Out Cancer
Authors: Torti Suzy V. , Torti Frank M.
Published: March 2011

New insights into the roles of proteins that regulate cellular iron in cancer growth, angiogenesis, and metastasis have recently emerged. Discoveries of the roles of ferroportin, hepcidin, lipocalin 2, and members of the six transmembrane epithelial antigen of the prostate (STEAP) and iron regulatory protein (IRP) families in cancer have provided specificity and molecular definition to the role of iron homeostasis in cancer growth and metastasis. A number of studies directly support a role of these proteins in modifying bioavailable iron, whereas other studies suggest that at least some of their effects are independent of their role in iron biology. Cancer Res; 71(5); 1511–4. ©2011 AACR.
Dynamic Expression of IL-6 Trans-Signalling Molecules in the Lungs of Preterm Baboons Undergoing Mechanical Ventilation
Authors: McGreal Eamon P. , Chakraborty Mallinath , Winter Vicki T. , Jones Simon A. , Coalson Jacqueline J. , Kotecha Sailesh
Published: March 2011

Background: Interleukin (IL)-6, when complexed with soluble IL-6 receptor (sIL-6R), has emerged as an important modulator of chemokine expression and leukocyte recruitment during inflammation and in this state can be specifically antagonised by soluble gp130 (sgp130). The expression of these modifiers of IL-6 activity during ventilator-induced inflammation remains poorly understood. Objectives: To ascertain the expression pattern of IL-6, sIL-6R and sgp130 in response to mechanical ventilation in the preterm neonatal lung and define its relationship to associated markers of inflammation. Methods: Inflammatory cell recruitment and expression of IL-6, sIL-6R, sgp130, IL-8 and monocyte chemotactic protein-1 (MCP-1) were quantified in tracheal aspirate fluid collected over a 14-day period from preterm (125 days) baboons undergoing mechanical ventilation. Results: Over the period of ventilation, the ratio of agonistic IL-6/sIL-6R increased 4.3-fold between days 3 and 10–11 (p < 0.01) while the ratio of antagonistic sgp130/IL-6 decreased 2.6-fold over the same period (p < 0.05). Over the same period, the relative numbers of neutrophils compared to mononuclear cells shifted from an excess of 1.8 on day 1 to 0.6 on day 14 (p < 0.01). Both IL-8 and MCP-1 were elevated between days 1 and 10–11 of ventilation (p < 0.01). Conclusions: In the ventilated preterm baboon lung, expression of sIL-6R and dynamic modulation of sgp130 expression appear to modulate the activity and inflammatory potential of IL-6.
Prognosis of a Normal Positron Emission Tomography 82Rb Myocardial Perfusion Imaging Study in Women with No History of Coronary Disease
Authors: Van Tosh Andrew , Supino Phyllis G. , Nichols Kenneth J. , Garza Dahlia , Horowitz Steven F. , Reichek Nathaniel
Published: March 2011

Objectives: Myocardial perfusion imaging (MPI) with positron emission tomography (PET) has advantages over single-photon emission computerized tomography, particularly for women. This investigation was undertaken to define the prognosis of a normal stress PET MPI study in women. Methods:The cohort comprised 457 women evaluated for suspected coronary artery disease (CAD) who had normal pharmacologic stress 82Rb PET MPI. No patient had clinically evident CAD. Kaplan-Meier estimates were used to determine death and initial nonfatal cardiac event rates over 7 years. Log rank tests were used to assess the relationship between baseline cardiac risk and events during follow-up, and to contrast survival in the cohort with age- and gender-matched US census comparators. Results: During follow-up, there were 11 deaths (all nonischemic), 3 nonfatal myocardial infarctions, 3 percutaneous coronary interventions and 1 coronary artery bypass operation. Average risks of death and initial nonfatal cardiac events were 0.72 and 0.47% per year, respectively. Cardiac events were associated with a history of diabetes (p < 0.0003) and a family history of CAD (p < 0.05). Conclusion: A normal cardiac PET study is associated with a very low rate of future cardiac events. Women with diabetes and a strong family history of CAD are more likely to sustain events and require close surveillance for the development of coronary disease.
Comparable Ten-Year Outcome in Hemodialysis Patients with Hepatitis C Virus and Hepatitis B Virus Coinfection and Single Hepatitis B Virus Infection
Authors: Lee Cheng-Chia , Li I-Jung , Chen Yung-Chang , Cheng Jen-Wei , Wu Hsin-Hsu , Weng Cheng-Hao , Fang Ji-Tseng , Tian Ya-Chung
Published: March 2011

Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection in comparison with single HBV infection causes more severe liver disease in nonuremic population. The long-term impact of HBV/HCV coinfection on severity of liver diseases and patient survival in hemodialysis patients is unclear. Forty-eight HBV-positive patients and 19 HBV/HCV-positive patients were followed up from February 1996 to September 2006. During 10-year follow-up, there was no difference in acute hepatitis episodes, abnormal serum alanine aminotransferase period, occurrence of cirrhosis and hepatocellular carcinoma, and patient survival between the two groups. The serum HBV DNA levels in HBV/HCV-positive patients were significantly lower than those in HBV-positive patients during the first 27-month follow-up. In conclusion, HCV infection suppresses the serum HBV DNA level in hemodialysis patients. Nevertheless, HBV/HCV coinfection in comparison with single HBV infection does not cause more severe liver diseases or reduce patient survival in hemodialysis patients during 10-year follow-up.
Prevalence, Predictors and Prognosis of Post-Stroke Hyperglycaemia in Acute Stroke Trials: Individual Patient Data Pooled Analysis from the Virtual International Stroke Trials Archive (VISTA)
Authors: Muir Keith W. , McCormick Michael , Baird Tracey , Ali Myzoon ,   On behalf of the VISTA Collaboration
Published: March 2011

Background: Post-stroke hyperglycaemia (PSH) is associated with higher mortality and dependence, but further data on predictors of PSH and its evolution over time are required. We examined the prevalence, predictors, and prognosis of acute PSH using data from well-characterised clinical trials in the VISTA database. Methods: Data were extracted for individual participants enrolled <24 h after stroke with ≧1 blood glucose readings documented. PSH was defined as glucose >7.0 mmol/l. Outcome measures were: (1) prevalence of PSH; (2) predictors of PSH by binary logistic regression; (3) mortality, and (4) favourable functional outcome [modified Rankin Scale (mRS) score <2] at day 90. Results: For 2,649 subjects treated at a median 5.5 h after admission, PSH was present in 1,126 (42.6%, 95% CI 40.7–44.5) on admission and within the first 48 h in 1,421 (53.7%, 95% CI 51.8–55.6). PSH developed between 24 and 48 h in 19.4% (95% CI 17.5–21.4) of initially normoglycaemic subjects. Admission and 48-hour PSH were predicted predominantly by a history of diabetes (for admission PSH: OR 7.40, 95% CI 5.60–9.79) and less clearly by stroke severity. Favourable outcome (mRS <2) at day 90 was less likely with PSH within the first 48 h, advanced age, and higher NIHSS score, and more likely with recombinant tissue plasminogen activator treatment. Conclusions: Over 40% of ischaemic stroke patients are hyperglycaemic on admission, and 20% of those who are initially normoglycaemic develop hyperglycaemia within 48 h. Diabetes is the strongest predictor of acute hyperglycaemia. Hyperglycaemia within the first 48 h is independently associated with higher mortality and poorer functional outcome, with an absolute increase of 12.9%.
Combined Effects of Smoking and Hypercholesterolemia on the Risk of Stroke and Coronary Heart Disease in Japanese: The Hisayama Study
Authors: Hata Jun , Doi Yasufumi , Ninomiya Toshiharu , Fukuhara Masayo , Ikeda Fumie , Mukai Naoko , Hirakawa Yoichiro , Kitazono Takanari , Kiyohara Yutaka
Published: March 2011

Background: Cigarette smoking is an established risk factor for stroke and coronary heart disease (CHD) in Western countries. However, it is uncertain whether or not smoking raises the risk of stroke in Japanese. We examined the influence of smoking on the development of stroke and CHD and the effects of interactions between smoking and hypercholesterolemia on these outcomes in a general Japanese population. Methods: A total of 2,421 community-dwelling Japanese individuals, aged 40–79 years, with no history of cardiovascular disease, were followed up for 14 years. Results: During the follow-up, 194 total stroke and 112 CHD events occurred. Compared with never smokers, the multivariate-adjusted hazard ratios for the occurrence of total stroke were 1.53 (95% confidence interval = 0.90–2.61) in former smokers, 1.90 (1.18–3.06) in current light smokers (<20 cigarettes/day) and 2.01 (1.11–3.65) in current heavy smokers (≧20 cigarettes/day). The multivariate-adjusted hazard ratios for the development of CHD were 1.10 (0.56–2.15), 1.88 (1.02–3.47) and 2.31 (1.17–4.57), respectively. In regard to stroke subtypes, current smoking was an independently significant risk factor for ischemic stroke and subarachnoid hemorrhage. Furthermore, the combination of smoking and hypercholesterolemia synergistically increased the risks of total stroke and CHD (all p for interaction <0.05). Conclusion: Our findings suggest that smoking raises the risks of ischemic stroke, subarachnoid hemorrhage and CHD occurrence in the Japanese population, and that this effect is strengthened by hypercholesterolemia.
Cost-Minimisation Analysis in First-Line Treatment of Metastatic Colorectal Cancer in France: XELOX versus FOLFOX-6
Authors: Perrocheau G. , Bennouna J. , Ducreux M. , Hebbar M. , Ychou M. , Lledo G. , Conroy T. , Dominguez S. , Faroux R. , Florentin V. , Douillard J.Y.
Published: March 2011

Objective: In a recent randomized study, we demonstrated that XELOX (oxaliplatin + oral capecitabine) was well tolerated and not inferior in terms of efficacy to the infusional FOLFOX-6 regimen in first-line treatment of metastatic colorectal cancer (mCRC). The objective of this additional analysis was to compare the cost of XELOX and FOLFOX-6. Methods: This cost-minimisation study took into account costs related to drug acquisition, hospital care for chemotherapy administration and for serious adverse event management. Hospital care costs were based on French ‘diagnosis-related group’ tariffs. Drug acquisition costs were drawn from French official sources. Analysis was performed from the French health insurance perspective. Results: Baseline characteristics of the 282 patients included (143 XELOX, 139 FOLFOX-6) were well balanced. Patients reported less and shorter hospitalisations (day and overnight hospital care) with XELOX: 6.4 ± 2.2 hospitalisations versus 9.7 ± 3.1 (p < 0.001); 11.4 ± 10.6 days versus 17.7 ± 11.8 (p < 0.001). Mean disease management cost per patient was significantly lower with XELOX (EUR 12,918 ± 5,075 vs. EUR 17,229 ± 8,665, p < 0.001). Conclusion: In the perspective of our analysis, taking into account hospitalisation and drug acquisition costs, the treatment of mCRC patients with XELOX in comparison to FOLFOX-6 significantly decreased the costs, as well as the mean overall hospitalisation length of stay.
Immunotherapy With Tolerogenic Apolipoprotein B-100–Loaded Dendritic Cells Attenuates Atherosclerosis in Hypercholesterolemic Mice
Authors: Hermansson Andreas , Johansson Daniel K. , Ketelhuth Daniel F.J. , Andersson John , Zhou Xinghua , Hansson Göran K.
Published: March 2011

Background—

Atherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic vascular inflammation with an autoimmune response to low-density lipoprotein components.

Methods and Results—

To dampen the inflammatory component of atherosclerosis, we injected hypercholesterolemic huB100
tg
×
Ldlr
−/−
mice (mice transgenic for human apolipoprotein B100 [ApoB100] and deficient for the low-density lipoprotein receptor) intravenously with dendritic cells (DCs) that had been pulsed with the low-density lipoprotein protein ApoB100 in combination with the immunosuppressive cytokine interleukin-10. DCs treated with ApoB100 and interleukin-10 reduced proliferation of effector T cells, inhibited production of interferon-γ, and increased de novo generation of regulatory T cells in vitro. Spleen cells from mice treated with DCs plus ApoB100 plus interleukin-10 showed diminished proliferative responses to ApoB100 and significantly dampened T-helper 1 and 2 immunity to ApoB100. Spleen CD4
+
T cells from these mice suppressed activation of ApoB100-reactive T cells in a manner characteristic of regulatory T cells, and mRNA analysis of lymphoid organs showed induction of transcripts characteristic of these cells. Treatment of huB100
tg
×
Ldlr
−/−
mice with ApoB100-pulsed tolerogenic DCs led to a significant (70%) reduction of atherosclerotic lesions in the aorta, with decreased CD4
+
T-cell infiltration and signs of reduced systemic inflammation.

Conclusions—

Tolerogenic DCs pulsed with ApoB100 reduced the autoimmune response against low-density lipoprotein and may represent a novel possibility for treatment or prevention of atherosclerosis.
Effect of Weight Gain on Cardiac Autonomic Control During Wakefulness and Sleep
Authors: Adachi Taro , Sert-Kuniyoshi Fatima H. , Calvin Andrew D. , Singh Prachi , Romero-Corral Abel , van der Walt Christelle , Davison Diane E. , Bukartyk Jan , Konecny Tomas , Pusalavidyasagar Snigdha , Sierra-Johnson Justo , Somers Virend K.
Published: March 2011

Obesity has been associated with increased cardiac sympathetic activation during wakefulness, but the effect on sleep-related sympathetic modulation is not known. The aim of this study was to investigate the effect of fat gain on cardiac autonomic control during wakefulness and sleep in humans. We performed a randomized, controlled study to assess the effects of fat gain on heart rate variability. We recruited 36 healthy volunteers, who were randomized to either a standardized diet to gain ≈4 kg over 8 weeks followed by an 8-week weight loss period (n=20) or to serve as a weight-maintainer control (n=16). An overnight polysomnogram with power spectral analysis of heart rate variability was performed at baseline, after weight gain, and after weight loss to determine the ratio of low-frequency to high-frequency power and to examine the relationship between changes in heart rate variability and changes in insulin, leptin, and adiponectin levels. Mean weight gain was 3.9 kg in the fat gain group versus 0.1 kg in the maintainer group. Low frequency/high frequency increased both during wakefulness and sleep after fat gain and returned to baseline after fat loss in the fat gain group and did not change in the control group. Insulin, leptin, and adiponectin also increased after fat gain and fell after fat loss, but no clear pattern of changes was seen that correlated consistently with changes in heart rate variability. Short-term fat gain in healthy subjects is associated with increased cardiac sympathetic activation during wakefulness and sleep, but the mechanisms remain unclear.
Augmented Rififylin Is a Risk Factor Linked to Aberrant Cardiomyocyte Function, Short-QT Interval and Hypertension
Authors: Gopalakrishnan Kathirvel , Morgan Eric E. , Yerga-Woolwine Shane , Farms Phyllis , Kumarasamy Sivarajan , Kalinoski Andrea , Liu Xiaochen , Wu Jian , Liu Lijun , Joe Bina
Published: March 2011

Using congenic strains of the Dahl salt-sensitive (S) rat introgressed with genomic segments from the normotensive Lewis rat, a blood pressure quantitative trait locus was previously mapped within 104 kb on chromosome 10. The goal of the current study was to conduct extensive phenotypic studies and to further fine-map this locus. At 14 weeks of age, the blood pressure of the congenic rats fed a low-salt diet was significantly higher by 47 mm Hg (
P
<0.001) compared with that of the S rat. A time-course study showed that the blood pressure effect was significant from very young ages of 50 to 52 days (13 mm Hg;
P
<0.01). The congenic strain implanted with electrocardiography transmitters demonstrated shorter-QT intervals and increased heart rate compared with S rats (
P
<0.01). The average survival of the congenic strain was shorter (134 days) compared with the S rat (175 days;
P
<0.0007). The critical region was narrowed to <42.5 kb containing 171 variants and a single gene, rififylin. Both the mRNA and protein levels of rififylin were significantly higher in the hearts of the congenic strain. Overexpression of rififylin is known to delay endocytic recycling. Endocytic recycling of fluorescently labeled holotransferrin from cardiomyocytes of the congenic strain was slower than that of S rats (
P
<0.01). Frequency of cardiomyocyte beats in the congenic strain (62±9 bpm) was significantly higher than that of the S rat (24±6 bpm;
P
<0.001). Taken together, our study provides evidence to suggest that early perturbations in endocytic recycling caused by the overexpression of
Rffl
is a novel physiological mechanism potentially underlying the development of hypertension.
Distinct Endothelium-Derived Hyperpolarizing Factors Emerge In Vitro and In Vivo and Are Mediated in Part via Connexin 40–Dependent Myoendothelial Coupling
Authors: Boettcher Markus , de Wit Cor
Published: March 2011

The endothelium-derived hyperpolarizing factor (EDHF) contributes critically to the regulation of vascular tone. Its dependency on direct signaling through myoendothelial gap junctions composed of connexins (Cx) is controversially discussed. We studied the impact of Cx40 in EDHF-type dilations in vivo and in vitro (wire and pressure myography) in small arteries (A. gracilis) using different Cx40-deficient mouse models. Acetylcholine induced prominent EDHF-type dilations (inhibition of NO synthase and cyclooxygenase) of ≈90%(maximum effect) in wild-type and Cx40-deficient vessels (Cx40
−/−
) in vitro under isobaric conditions. In contrast, under isometric conditions, EDHF-type relaxations were nearly abrogated in Cx40
−/−
(9±3%) but only slightly reduced in wild-type vessels (45±4%;
P
<0.05). Vessels expressing Cx45 instead of Cx40 exhibited similarly reduced relaxations (13±1%), demonstrating that Cx45 cannot replace Cx40 functionally. The necessity of Cx40 in EDHF-type dilations under isometric conditions was verified by the attenuation in vessels being specifically deficient for Cx40 in endothelial cells (Cx40
fl
:TIE2-Cre: 17±3%; Cx40-floxed controls: 67±6%;
P
<0.05). Nevertheless, EDHF-type dilations were Cx40 independent when studied isobarically. The EDHF-type dilation in vivo resembled the isobaric situation, being virtually Cx40 independent and similar powerful. Distinct EDHF mechanisms can be distinguished by their Cx40 dependency. A powerful EDHF is present in vivo and in vitro under isobaric conditions but is lacking in wire myography (isometric conditions). Herein, a less potent EDHF depends on Cx40 and may represent signaling through myoendothelial gap junctions. We suggest that distinct EDHFs (even in the same artery) explain partially the controversy on the role of myoendothelial gap junctions in EDHF signaling.
In Silico Evolution of Early Metabolism
Authors: Ullrich Alexander , Rohrschneider Markus , Scheuermann Gerik , Stadler Peter F. , Flamm Christoph
Published: March 2011

We developed a simulation tool for investigating the evolution of early metabolism, allowing us to speculate on the formation of metabolic pathways from catalyzed chemical reactions and on the development of their characteristic properties. Our model consists of a protocellular entity with a simple RNA-based genetic system and an evolving metabolism of catalytically active ribozymes that manipulate a rich underlying chemistry. Ensuring an almost open-ended and fairly realistic simulation is crucial for understanding the first steps in metabolic evolution. We show here how our simulation tool can be helpful in arguing for or against hypotheses on the evolution of metabolic pathways. We demonstrate that seemingly mutually exclusive hypotheses may well be compatible when we take into account that different processes dominate different phases in the evolution of a metabolic system. Our results suggest that forward evolution shapes metabolic network in the very early steps of evolution. In later and more complex stages, enzyme recruitment supersedes forward evolution, keeping a core set of pathways from the early phase.
An Artificial Life View of the Collatz Problem
Authors: Sayama Hiroki
Published: March 2011

This letter presents a new, artificial-life-based view of the Collatz problem, a well-known mathematical problem about the behavior of a series of positive integers generated by a simple arithmetical rule. The Collatz conjecture asserts that this series always falls into a 4 → 2 → 1 cycle regardless of its initial values. No formal proof has been given yet. In this letter, the behavior of the series is considered an ecological process of artificial organisms (1s in bit strings). The Collatz conjecture is then reinterpreted as the competition between population growth and extinction. This new interpretation has made it possible to analytically calculate the growth and extinction speeds of bit strings. The results indicate that the extinction is always faster than the growth, providing an ecological explanation for the conjecture. Future research directions are also suggested.
School Choice and the Branding of Catholic Schools
Authors: Trivitt Julie R. , Wolf Patrick J.
Published: March 2011

How useful are “corporate brands” in markets? In theory, brands convey reliable information, providing consumers with shortcuts to time-consuming provider searches. We examine the usefulness of a corporate brand when parental school choice is expanded through K–12 tuition scholarships. Specifically, we evaluate whether Catholic schools carry an identifiable education brand (1) preferred even by non-Catholics, (2) for reasons connected to the brand, (3) signaling largely accurate information resulting in an enduring “match” of school characteristics to student needs, and (4) leading to exit from the program when a Catholic school fails to meet consumers' brand expectations. We test these hypotheses using attitudinal and behavioral data from a scholarship program in Washington, DC. The results largely confirm our hypotheses about the Catholic school brand being attractive, familiar, generally accurate, and, when not accurate, an instigator of programmatic attrition—results that speak to enduring policy issues involving school choice.
What Do AEFA Members Say? Summary of Results of an Education Finance and Policy Survey
Authors: Stiefel Leanna , Schwartz Amy Ellen , Rotenberg Anne
Published: March 2011

In the spring of 2008 the authors surveyed members of the American Education Finance Association (AEFA) to gain insight into their views on education policy issues. The results summarize opinions of this broad group of education researchers and practitioners, providing AEFA members and education leaders with access to views that may be helpful as they consider policies to analyze or pursue. This article reports the results in six areas of current policy interest. How should education aid be distributed? Is school choice a good thing? Does school finance reform work? What has accountability wrought? Can school policies close the black-white achievement gap? And how should teachers be compensated? Our findings identify areas of substantial agreement as well as areas where there is disagreement. For example, there is considerable agreement that state and federal governments should provide additional funding for disadvantaged students but disagreement on how to measure school finance adequacy.
Some Issues in the Study of Language Contact
Authors: Winford Donald
Published: March 2011

This paper provides an overview of various approaches to contact-induced change, and assesses their contribution to a unified theory of the processes involved in such change, and the outcomes they produce. I argue that clarification of the terminology and classifications we apply to contact languages can lead to better understanding of the types of contact languages, and the kinds of process that produce them. I further suggest that van Coetsem's framework offers a more uniform terminology and classification, and that it clarifies the distinction between the two major transfer types involved in contact induced change – borrowing via recipient language agentivity, and imposition via source language agentivity. Failure to distinguish these two mechanisms accurately has negative implications for our understanding of the processes by which various contact languages are created. I apply this model to two broad categories of contact languages, bilingual mixed languages, and creoles, and I argue that the differences in transfer type identified by Van Coetsem correspond to differences in the language production processes underlying the two broad types of contact-induced change. Finally, I suggest that psycholinguistic models of language or speech production can contribute significantly to our understanding of the different processes involved in the creation of different types of contact languages.
Apprendre une langue et devenir bilingue : un eclairage acquisitionniste sur les contacts de langues
Authors: Py Bernard
Published: March 2011

Il est ici proposé une synthèse de la problématique acquisitionniste confrontée à la réalité du bilinguisme et du contact des langues dans le cadre d'apprentissages formels et informels appréhendés en situation. Une question fondamentale : « Comment devient-on bilingue lorsqu'on est immergé dans une communauté alloglotte ou diglossique particulière, que l'on y pratique la communication bilingue ou exolingue et qu'on y occupe une position socioculturelle déterminée ? ». A partir de là, il s'agit de dépasser les notions abstraites d'exposition à la langue cible et de système qui ne prennent pas en compte les circonstances et la contextualisation de l'acquisition ; de mettre l'accent sur la pertinence de l'asymétrie de la communication exolingue. On développe alors une réflexion sur la dynamique de l'apprenant qui décontextualise les données linguistiques auxquelles il est confronté afin de constituer un ensemble de ressources stabilisées, fonctionnalisables à toutes fins utiles dans les contextes d'usage. Cela conduit à mettre en question l'intérêt de la notion de compétence, et le bilinguisme se définit alors autrement : par un accès à des ressources (issues de deux langues) actualisables dans des contextes sociaux particuliers.
Language Contact and Deliberate Change
Authors: Thomason Sarah
Published: March 2011

This paper explores the process of "negotiation", whereby speakers of two or more languages converge on a partially or entirely shared linguistic system. This process is surely unconscious in many or most instances, but sometimes speakers are aware of what they are doing as they "negotiate" the linguistic outcome of language contact. I provide evidence for the latter assertion, and discuss the difficulties inherent in any attempt to generalize about conscious vs. unconscious negotiation. I also contrast the process of negotiation with some other views of linguistic convergence. Finally, summarizing previous results, I argue that the existence of deliberate contact-induced (and other) linguistic change vitiates all efforts to achieve a deterministic predictive theory of contact-induced language change.
Layered, zippered and buttoned: the importation of Hebrew into "Dos Yidishe Vort"
Authors: Newman Zelda Kahan
Published: March 2011

This paper examines the ways in which Biblical, rabbinic and the Hebrew of modern Israel are imported into the Yiddish publication Dos Yidishe Vort. Three strategies are examined. The first strategy, "layering", occurs when the imported Hebrew elements appear without their connective tissue. We examine the cases when this can be done easily. The second strategy, "zippering", occurs when there is a 1:1 alignment between the morphemes of the two languages. In such cases, a text can, and does, slip easily from one language to the other. The third strategy, "buttoning", occurs when the host language incorporates the foreign elements by creating a structure that "nativizes" the foreign element and thereby draws it into the host language. This productive process sometimes stretches and sometimes shrinks the original material.
Langues en contact : l'expression contact comme révélatrice de la dynamique des langues. Persistance et intérêt de la métaphore
Authors: Tabouret-Keller Andrée
Published: March 2011

L'usage du terme contact se maintient depuis quatre siècles : ses emplois se diversifient de même que la référence généralement implicite à ce qui fait contact, par quoi ça passe et qu'est-ce que ça produit ? est-ce que ces questions sont valables pour ces objets particuliers que sont le langage et les langues ? La première partie de ce texte a pour objet une esquisse historique de la notion de contact, la seconde examine un certain nombre de problèmes résultant des emplois du trio de métaphores contact, évolution du langage et dynamique des langues Cet examen conduit à dégager des questions concernant le rapport entre déterminismes biologiques et facteurs sociaux, l'hétérogénéité des contraintes fonctionnelles du langage et celle des temporalités. L'idéal d'un modèle unique est vain, la complexité et l'hétérogénéité des langues et de leurs réalités langagières entraînent l'élaboration de modèles de portée relative en rapport avec des niveaux d'abstraction variables.
Relabelling: A Major Process in Language Contact
Authors: Lefebvre Claire
Published: March 2011

The problem of language contact may be taken up from two opposite angles: the processes at work in language contact situations or the language contact varieties. In this paper, I look at contact phenomena from the former angle. I focus on one process: relabelling, a mental operation that consists in assigning a lexical entry of a given language, L1, a new label taken from another language, L2. The aim of this paper is threefold: first, to assess the extent of relabelling across language contact situations; second, to assess the extent of relabelling across lexicons; and third, to assess the possibility of relabelling in cases of agglutinative languages. The approach taken in this paper highlights the importance of the process of relabelling in a variety of language contact situations. Furthermore, it makes it possible to analyse in a unified way the contribution of a single process to the makeup of various language varieties arising in different contact situations, and thus to link a number of contact phenomena and situations that would otherwise remain separate.