bluuebunny/crossref_metadata_2025 huggingface dataset:
Anthropometric risk factors for patellar tendon injury among volleyball players
Authors: Malliaras P , Cook J L , Kent P M
Published: August 2006

Objective:Abnormal imaging in the patellar tendon reveals pathology that is often associated with knee pain. Anthropometric measures of body size and mass, such as height, weight and waist-to-hip ratio (WHR), have been individually associated with abnormal imaging. The aim of this study was to investigate the anthropometric factors that have the strongest relationship with abnormal imaging in volleyball players.

Methods:Height, weight, body mass index (BMI), waist girth, hip girth and WHR were measured in a cohort of 113 competitive volleyball players (73 men, 40 women). The univariate (ANOVA) and multivariable (discriminant function analysis) association between abnormal imaging and these anthropometric factors were investigated.

Results:No significant association was found in the female volleyball players. A significant univariate association was observed between abnormal imaging and heavier weight, greater BMI, larger waist and hip girth and larger WHR in the male volleyball players. Waist girth was the only factor that retained this association in a multivariable model (p<0.05).

Conclusions:Men with a waist girth greater than 83 cm seem to be at greater risk of developing patellar tendon pathology. There may be both mechanical and biochemical reasons for this increased risk.
Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2
Authors: Khare Sharad , Holgren Cory , Samarel Allen M.
Published: August 2006

Environmental factors, including dietary fats, are implicated in colonic carcinogenesis. Dietary fats modulate secondary bile acids including deoxycholic acid (DCA) concentrations in the colon, which are thought to contribute to the nutritional-related component of colon cancer risk. Here we demonstrate, for the first time, that DCA differentially regulated the site-specific phosphorylation of focal adhesion kinase (FAK). DCA decreased adhesion of HCA-7 cells to the substratum and induced dephosphorylation of FAK at tyrosine-576/577 (Tyr-576/577) and Tyr-925. Tyrosine phosphorylation of FAK at Tyr-397 remained unaffected by DCA stimulation. Interestingly, we found that c-Src was constitutively associated with FAK and DCA actually activated Src, despite no change in FAK-397 and an inhibition of FAK-576 phosphorylation. DCA concomitantly and significantly increased association of tyrosine phosphatase ShP2 with FAK. Incubation of immunoprecipitated FAK, in vitro, with glutathione- S-transferase-ShP2 fusion protein resulted in tyrosine dephosphorylation of FAK in a concentration-dependent manner. Antisense oligodeoxynucleotides directed against ShP2 decreased ShP2 protein levels and attenuated DCA-induced FAK dephosphorylation. Inhibition of FAK by adenoviral-mediated overexpression of FAK-related nonkinase and gene silencing of Shp2 both abolished DCA's effect on cell adhesion, thus providing a possible mechanism for inside-out signaling by DCA in colon cancer cells. Our results suggest that DCA differentially regulates focal adhesion complexes and that tyrosine phosphatase ShP2 has a role in DCA signaling.
Gastrin-releasing peptide mediates its morphogenic properties in human colon cancer by upregulating intracellular adhesion protein-1 (ICAM-1) via focal adhesion kinase
Authors: Taglia Lauren , Matusiak Damien , Matkowskyj Kristina A. , Benya Richard V.
Published: August 2006

Gastrin-releasing peptide (GRP) and its receptor (GRPR) act as morphogens when expressed in colorectal cancer (CRC), promoting the assumption of a better differentiated phenotype by regulating cell motility in the context of remodeling and retarding tumor cell metastasis by enhancing cell-matrix attachment. Although we have shown that these processes are mediated by focal adhesion kinase (FAK), the downstream target(s) of GRP-induced FAK activation are not known. Since osteoblast differentiation is mediated by FAK-initiated upregulation of ICAM-1 (Nakayamada S, Okada Y, Saito K, Tamura M, Tanaka Y. J Biol Chem 278: 45368–45374, 2003), we determined whether GRP-induced activation of FAK alters ICAM-1 expression in CRC and, if so, determined the contribution of ICAM-1 to mediating GRP's morphogenic properties. Caco-2 and HT-29 cells variably express GRP/GRPR. These cells only express ICAM-1 when GRPR are present. In human CRC, GRPR and ICAM-1 are only expressed by better differentiated tumor cells, with ICAM-1 located at the basolateral membrane. ICAM-1 expression was only observed subsequent to GRPR signaling via FAK. To study the effect of ICAM-1 expression on tumor cell motility, CRC cells expressing GRP, GRPR, and ICAM-1 were cultured in the presence and absence of GRPR antagonist or monoclonal antibody to ICAM-1. CRC cells engaged in directed motility in the context of remodeling and were highly adherent to the extracellular matrix, only in the absence of antagonist or ICAM-1 antibody. These data indicate that GRP upregulation of ICAM-1 via FAK promotes tumor cell motility and attachment to the extracellular matrix.
Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease
Authors: Künzli Beat M. , Berberat Pascal O. , Giese Thomas , Csizmadia Eva , Kaczmarek Elzbieta , Baker Colin , Halaceli Irfan , Büchler Markus W. , Friess Helmut , Robson Simon C.
Published: August 2006

Chronic inflammation, fibrosis, atrophy, malignant transformation, and thromboembolic events are hallmarks of chronic pancreatic disease. Extracellular nucleotides have been implicated as inflammatory mediators in many pathological situations. However, there are minimal data detailing expression of ectonucleotidases and type-2 purinergic receptors (P2R) in chronic pancreatitis and pancreatic cancer. We have therefore defined tissue distribution and localization of the CD39 family of ectonucleotidases and associated P2R in human disease. Transcripts of ectonucleotidases (CD39 and CD39L1) together with P2R (P2X7, P2Y2, and P2Y6) are significantly increased in both chronic pancreatitis and pancreatic cancer. CD39 and CD39L1 are preferentially associated with the vasculature and stromal elements in pathological tissues. P2X7mRNA upregulation was associated with chronic pancreatitis, and heightened protein expression was found to be localized to infiltrating cells. P2Y2was markedly upregulated in biopsies of pancreatic cancer tissues and expressed by fibroblasts adjacent to tumors. High-tissue mRNA levels of CD39 significantly correlated with better long-term survival after tumor resection in patients with pancreatic cancer. Heightened expression patterns and localization patterns of CD39, P2X7, and P2Y2infer associations with chronic inflammation and neoplasia of the pancreas. Our data suggest distinct roles for CD39 and P2-purinergic signaling in both tissue remodeling and fibrogenesis with respect to human pancreatic diseases.
The diastolic flow velocity-pressure gradient relation and dpv50to assess the hemodynamic significance of coronary stenoses
Authors: Marques Koen M. J. , van Eenige Machiel J. , Spruijt Hugo J. , Westerhof Nico , Twisk Jos , Visser Cees A. , Visser Frans C.
Published: August 2006

To evaluate the hemodynamic impact of coronary stenoses, the fractional (FFR) or coronary flow velocity reserve (CFVR) usually is measured. The combined measurement of instantaneous flow velocity and pressure gradient (v-dp relation) is rarely used in humans. We derived from the v-dp relation a new index, dpv50(pressure gradient at flow velocity of 50 cm/s), and compared the diagnostic performance of dpv50, CFVR, and FFR. Before coronary angiography was performed, patients underwent noninvasive stress testing. In all coronary vessels with an intermediate or severe stenosis, the flow velocity, aortic, and distal coronary pressure were measured simultaneously with a Doppler and pressure guidewire after induction of hyperemia. After regression analysis of all middiastolic flow velocity and pressure gradient data, the dpv50was calculated. With the use of the results of noninvasive stress testing, the dpv50cutoff value was established at 22.4 mmHg. In 77 patients, 124 coronary vessels with a mean 39% (SD 19) diameter stenosis were analyzed. In 43 stenoses, ischemia was detected. We found a sensitivity, specificity, and accuracy of 56%, 86%, and 76% for CFVR; 77%, 99%, and 91% for FFR; and 95%, 95%, and 95% for dpv50. To establish that dpv50is not dependent on maximal hyperemia, dpv50was recalculated after omission of the highest quartile of flow velocity data, showing a difference of 3%. We found that dpv50provided the highest sensitivity and accuracy compared with FFR and CFVR in the assessment of coronary stenoses. In contrast to CFVR and FFR, assessment of dpv50is not dependent on maximal hyperemia.
cGMP signals mainly through cAMP kinase in permeabilized murine aorta
Authors: Wörner René , Lukowski Robert , Hofmann Franz , Wegener Jörg W.
Published: August 2006

GMP affects vascular tone by multiple mechanisms, including inhibition of the Rho/Rho kinase-mediated Ca2+sensitization, a process identified as Ca2+desensitization. Ca2+desensitization is mediated probably by both cGMP- and cAMP-dependent protein kinases (cGKI and PKA). We investigate to which extent Ca2+desensitization is initiated by cGKI and PKA. cGMP/cAMP-induced relaxation was studied at constant [Ca2+] in permeabilized aortas from wild-type and cGKI-deficient mice. [Ca2+] increased aortic tone in the absence and presence of 50 μM GTPγS with EC50values of 160 and 30 nM, respectively. In the absence of GTPγS, the EC50for [Ca2+] was shifted rightward from 0.16 μM to 0.43 and 0.82 μM by 1 and 300 μM 8-bromo-cGMP (8-Br-cGMP), and to 8 μM by 10 μM Y-27632. Contractions induced by 300 nM [Ca2+] were relaxed by 8-Br-cGMP with an EC50of 2.6 μM. Surprisingly, [Ca2+]-induced contractions were also relaxed by 8-Br-cGMP in aortas from cGKI−/−mice (EC50of 19 μM). Western blot analysis of the vasodilator-stimulated phosphoprotein indicated “cross”-activation of PKA by 1 mM 8-Br-cGMP in aortic smooth muscle cells from cGKI−/−mice. Indeed, the PKA inhibitor peptide (PKI 5–24) completely abolished the relaxant effect of 8-Br-cGMP in muscles from cGKI−/−mice and to 65% in wild-type aortas. The thromboxane analogue U-46619 induced contraction at constant [Ca2+], which was only partially relaxed by 8-Br-cGMP but completely relaxed by Y-27632. The effect of 8-Br-cGMP on U-46619-induced contraction was attenuated by PKI 5–24. These results show that cGKI has only a small inhibitory effect on Ca2+sensitization in murine aortas.
Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemia-induced myocardial infarction via cardiac adrenergic neurons
Authors: Southerland E. M. , Milhorn D. M. , Foreman R. D. , Linderoth B. , DeJongste M. J. L. , Armour J. A. , Subramanian V. , Singh M. , Singh K. , Ardell J. L.
Published: August 2006

Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) mitigates transient ischemia-induced ventricular infarction and, if so, whether adrenergic neurons are involved in such cardioprotection. The hearts of anesthetized rabbits, subjected to 30 min of left anterior descending coronary arterial occlusion (CAO) followed by 3 h of reperfusion (control), were compared with those with preemptive SCS (starting 15 min before and continuing throughout the 30-min CAO) or reactive SCS (started at 1 or 28 min of CAO). For SCS, the dorsal C8-T2 segments of the spinal cord were stimulated electrically (50 Hz, 0.2 ms, 90% of motor threshold). For preemptive SCS, separate groups of animals were pretreated 15 min before SCS onset with 1) vehicle, 2) prazosin (α1-adrenoceptor blockade), or 3) timolol (β-adrenoceptor blockade). Infarct size (IS), measured with tetrazolium, was expressed as a percentage of risk zone. In controls exposed to 30 min of CAO, IS was 36.4 ± 9.5% (SD). Preemptive SCS reduced IS to 21.8 ± 6.8% ( P < 0.001). Preemptive SCS-mediated infarct reduction was eliminated by prazosin (36.6 ± 8.8%) and blunted by timolol (29.4 ± 7.5%). Reactive SCS did not reduce IS. SCS increased phosphorylation of cardiac PKC. SCS did not alter blood pressure or heart rate. We conclude that preemptive SCS reduces the size of infarcts induced by transient CAO; such cardioprotection involves cardiac adrenergic neurons.
In vivo gene delivery of HSP70i by adenovirus and adeno-associated virus preserves contractile function in mouse heart following ischemia-reperfusion
Authors: Belke Darrell D. , Gloss Bernd , Hollander John M. , Swanson Eric A. , Duplain Hervé , Dillmann Wolfgang H.
Published: August 2006

Inducible heat shock protein 70 (HSP70i) has been shown to exert a protective effect in hearts subjected to ischemia-reperfusion. Although studied in heat-shocked animals and in transgenic mice that constitutively overexpress the protein, the therapeutic application of the protein in the form of a viral vector-mediated HSP70i expression has not been widely examined. Accordingly, we have examined the effects of HSP70i delivered in vivo to the left ventricular free wall of the heart via viral gene therapy in mice. The affect of virally mediated HSP70i expression in preserving cardiac function following ischemia-reperfusion was examined after short-term expression (5-day adenovirus mediated) and long-term expression (8-mo adeno-associated virus mediated) in mice by subjecting ex vivo Langendorff perfused hearts to a regime of ischemia-reperfusion. Both vectors were capable of increasing HSP70i expression in the heart, and neither vector had any effect on cardiac function during aerobic (preischemic) perfusion when compared with corresponding controls. In contrast, both adenovirus-mediated and adeno-associated virus-mediated expression of HSP70i improved the contractile recovery of the heart after 120 min of reperfusion following ischemia. This study demonstrates the feasibility of using both short- and long-term expression of virally mediated HSP70i as a therapeutic intervention against cardiac ischemia-reperfusion injury.
Reduction in postsystolic wall thickening during late preconditioning
Authors: Monnet Xavier , Lucats Laurence , Colin Patrice , Derumeaux Geneviève , Dubois-Rande Jean-Luc , Hittinger Luc , Ghaleh Bijan , Berdeaux Alain
Published: August 2006

Brief coronary artery occlusion (CAO) and reperfusion induce myocardial stunning and late preconditioning. Postsystolic wall thickening (PSWT) also develops with CAO and reperfusion. However, the time course of PSWT during stunning and the regional function pattern of the preconditioned myocardium remain unknown. The goal of this study was to investigate the evolution of PSWT during myocardial stunning and its modifications during late preconditioning. Dogs were chronically instrumented to measure (sonomicrometry) systolic wall thickening (SWT), PSWT, total wall thickening (TWT = SWT + PSWT), and maximal rate of thickening (dWT/d tmax). Two 10-min CAO (circumflex artery) were performed 24 h apart ( day 0 and day 1, n = 7). At day 0, CAO decreased SWT and increased PSWT. During the first hours of the subsequent stunning, evolution of PSWT was symmetrical to that of SWT. At day 1, baseline SWT was similar to day 0, but PSWT was reduced (−66%), while dWT/d tmaxand SWT/TWT ratio increased (+48 and +14%, respectively). After CAO at day 1, stunning was reduced, indicating late preconditioning. Simultaneously vs. day 0, PSWT was significantly reduced, and dWT/d tmaxas well as SWT/TWT ratio were increased, i.e., a greater part of TWT was devoted to ejection. Similar decrease in PSWT was observed with a nonischemic preconditioning stimulus (rapid ventricular pacing, n = 4). In conclusion, a major contractile adaptation occurs during late preconditioning, i.e., the rate of wall thickening is enhanced and PWST is almost abolished. These phenotype adaptations represent potential approaches for characterizing stunning and late preconditioning with repetitive ischemia in humans.
Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition
Authors: Ono Norihiko , Hayashi Hideki , Kawase Ayaka , Lin Shien-Fong , Li Hongmei , Weiss James N. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: August 2006

Aging and glycolytic inhibition (GI) are known to alter intracellular calcium ion (Cai2+) handling in cardiac myocytes, causing early afterpotentials (EADs) and delayed afterpotentials. We hypothesized that aging and GI interact synergistically in intact hearts to generate EADs and triggered activity leading to atrial fibrillation (AF). We studied isolated and Langendorff-perfused hearts of young (age 3–5 mo, N = 8) and old (age 27–29 mo, N = 14) rats subjected to GI (0 glucose + 10 mmol/l pyruvate). Epicardial atrial activation maps were constructed using optical action potentials, while simultaneously monitoring Cai2+ by means of dual-voltage and calcium-sensitive fluorescent dyes. During GI, spontaneous AF occurred in 13 of 14 old but in no young rats. AF was initiated by EAD-induced triggered activity at the left atrial pulmonary vein junction (LA-PVJ). The triggered activity initially propagated as single wave front, but within 1 s degenerated into multiple wavelets. The EADs and triggered activity in the old atria were associated with significantly elevated diastolic Cai2+ levels at the LA-PVJ, where the time constant τ of the Cai2+ transient decline and action potential duration were significantly ( P < 0.01) prolonged compared with atrial sites 5 mm away from LA-PVJ. During GI and rapid atrial pacing, spatially discordant APD and Cai2+ transient alternans developed in the old but not young atria, leading to AF. Atria in old rats had significantly more fibrotic tissue than atria in young rats. We conclude that GI interacts with the aged and fibrotic atria to amplify Cai2+ handling abnormalities that facilitate EAD-mediated triggered activity and AF.
P2X1 receptors mediate sympathetic postjunctional Ca2+ transients in mesenteric small arteries
Authors: Lamont Christine , Vial C. , Evans R. J. , Wier W. G.
Published: August 2006

Brief, spatially localized Ca2+ transients occur in the smooth muscle adjacent to perivascular nerves of small arteries during neurogenic contractions. We named these “junctional Ca2+ transients” (jCaTs) and postulated that they arose from Ca2+ entering smooth muscle cells through P2X1 receptors activated by neurally released ATP. Nevertheless, the lack of potent, subtype-selective P2X-receptor antagonists made determining the exact molecular identity of the channels difficult. Here we used small, pressurized mesenteric arteries from P2X1-receptor-deficient mice (KO) to test the hypothesis that jCaTs arise from Ca2+ entering the smooth muscle cell via P2X1 receptors. In wild-type (WT) arteries, confocal microscopy of fluo-4 fluorescence during electrical field stimulation (EFS) of perivascular sympathetic nerves revealed jCaTs in the smooth muscle cells adjacent to the perivascular nerves, similar to those reported previously in rat arteries, and α-latrotoxin (2.5 nM) markedly increased the frequency of “spontaneous” jCaTs. In the KO arteries, however, neither EFS nor α-latrotoxin elicited any jCaTs. A potent P2X-receptor agonist, α,β-methylene ATP (10.0 μM), elicited strong contractions and increased intracellular Ca2+ concentration in WT arteries but elicited neither in KO arteries. A biphasic vasoconstriction in response to EFS was observed in WT arteries. In KO arteries, however, the initial rapid, transient component of the biphasic vasoconstriction was absent. The data support the hypothesis that jCaTs represent Ca2+ that enters the smooth muscle cells through P2X1 receptors activated by neurally released ATP and that this Ca2+ is involved in the initial rapid component of the sympathetic neurogenic contraction.
Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction
Authors: Onai Yasuyuki , Suzuki Jun-ichi , Maejima Yasuhiro , Haraguchi Go , Muto Susumu , Itai Akiko , Isobe Mitsuaki
Published: August 2006

Several studies have demonstrated that NF-κB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-κB is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of IκB that acts via inhibition of IKK-β, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group ( P < 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV end-diastolic area: vehicle, 74.13 ± 3.57 mm2; IMD-0354, 55.00 ± 3.73 mm2; P < 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 ± 0.26; IMD-0354, 2.61 ± 0.24; P < 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 ± 14.87 pg/ml; IMD-0354, 110.75 ± 6.41 pg/ml; P < 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-β1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-κB activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI.
Evidence for the involvement of nitric oxide in A2Breceptor-mediated vasorelaxation of mouse aorta
Authors: Ansari Habib R. , Nadeem Ahmed , Talukder M. A. Hassan , Sakhalkar Shilpa , Mustafa S. Jamal
Published: August 2006

We have investigated the role of adenosine and its analogs on vasorelaxation of mouse aorta in intact endothelium with rank order of potency as follows: 5′- N-ethylcarboxamidoadenosine (NECA) > 2-chloroadenosine > adenosine ≫ CGS-21680, which is consistent with the profile of A2B-adenosine receptor (A2BAR). In endothelium-intact tissues, acetylcholine produced relaxation ranging from 65 to 80% in phenylephrine (PE, 10−7M)-precontracted mouse aorta, whereas no relaxation was observed in endothelium-denuded tissues. The A2BAR antagonist alloxazine (10−5M) shifted concentration-response curve for NECA (EC50= 0.005 × 10−5M) to the right with an EC50of 2.8 × 10−5M, demonstrating that this relaxation is partially dependent on functional endothelium mediated predominantly via A2BAR in this tissue. This conclusion was further supported by the following findings: 1) in the endothelium-intact mouse aorta, the EC50values for NECA and adenosine were found to be 0.05 and 1.99 × 10−4M, respectively; however, in denuded endothelium, these values were 0.098 and 3.55 × 10−4M, respectively; 2) NECA-induced relaxation was significantly blocked by NG-nitro-l-arginine methyl ester (l-NAME; 10−4M) in endothelium-intact tissues, which was reversed by pretreatment with l-arginine (10−4M), whereas no significant inhibition was found in endothelium-denuded tissues; 3) total nitrites and nitrates (NOx) in intact endothelium with l-NAME (10−4M) alone and in combination with l-arginine were 59% ( P < 0.05) and 96%, respectively, in comparison with control (PE + NECA); and 4) endothelial nitric oxide synthase gene expression was found to be 67% ( P < 0.05) less in endothelium-denuded as opposed to endothelium-intact mouse aorta. Thus these data demonstrate that adenosine-mediated vasorelaxation is partially dependent on A2BAR in mouse aorta.
Characteristics of myogenic tone in the rat ophthalmic artery
Authors: Ito Isamu , Jarajapu Yagna P. R. , Grant Maria B , Knot Harm J
Published: August 2006

The pressure-induced constriction in the rat ophthalmic artery was characterized. Ophthalmic arteries were isolated, cannulated in an arteriograph, and pressurized. Arteries developed 25% constriction at 70 mmHg of intraluminal pressure. Arteries maintained almost similar diameter over the range of pressures 50–210 mmHg, and forced dilatation was observed at pressures >210 mmHg. Denudation of endothelium increased the sensitivity of arteries to pressure-induced constriction, and significantly higher myogenic tone was observed in the pressure range of 10–100 mmHg. Indomethacin and cyclooxygenase-2 inhibition by SC-236 decreased myogenic tone, whereas cyclooxygenase-1 inhibition by SC-560 potentiated myogenic tone in a lower concentration range and decreased at a higher concentration. Pressure-induced constriction was completely blocked by 1 μM nifedipine. Phospholipase C inhibition by 6 μM U-73122 decreased myogenic tone by 39%, whereas PKC inhibitor GF-109203X (3 μM) had no effect. Constriction to phenylephrine was significantly decreased by U-73122 (1 μM) and GF-109203X (3 μM) at an intraluminal pressure of 10 mmHg. Rho-kinase inhibition by Y-27632 (30 μM) and HA-1077 (30 μM) decreased myogenic tone by 75% and 73%, respectively, and 1 μM Y-27632 significantly decreased myogenic tone developed in response to graded increases in pressure. These results suggest that rat ophthalmic artery has an efficient pressure-dependent autoregulatory function that is modulated by endothelium. Contribution of phospholipase C-activation to myogenic tone is minimal, whereas Rho-kinase activation plays a predominant role in the myogenic reactivity in this artery.
Nicotine: the link between cigarette smoking and the progression of renal injury?
Authors: Jaimes Edgar A. , Tian Run-Xia , Raij Leopoldo
Published: August 2006

Cigarette smoke (CS) is the most important source of preventable morbidity and mortality in the United States. Recent clinical studies have suggested that, in addition to being a major cardiovascular risk factor, CS promotes the progression of kidney disease. The mechanisms by which CS promotes the progression of chronic kidney disease have not been elucidated. Here we demonstrate for the first time that human mesangial cells (MCs) are endowed with the nicotinic ACh receptors (nAChRs) α4, α5, α7, β2, β3, and β4. Studies performed in other cell types have shown that these nAChRs are ionotropic receptors that function as agonist-regulated Ca2+channels. Nicotine induced MC proliferation in a dose-dependent manner. At 10−7M, a concentration found in the plasma of active smokers, nicotine induced MC proliferation [control, 1,328 ± 50 vs. nicotine, 2,761 ± 90 counts/minute (cpm); P < 0.05] and increased the synthesis of fibronectin (50%), a critical matrix component involved in the progression of chronic kidney disease. We and others have shown that, in response to PKC activation, MC synthesize reactive oxygen species (ROS) via NADPH oxidase. In the current studies we demonstrate that PKC inhibition as well as diphenyleneiodonium and apocynin, two inhibitors of NADPH oxidase, prevented the effects of nicotine on MC proliferation and fibronectin production, hence establishing ROS as second messengers of the actions of nicotine. Furthermore, nicotine increased the production of ROS as assessed by 2′,7′-dichlorofluorescein diacetate fluorescence [control, 184.4 ± 26 vs. nicotine, 281.5 ± 26 arbitrary fluorescence units (AFU); n = 5 experiments, P < 0.05]. These studies unveil previously unrecognized mechanisms that indict nicotine, a component of CS, as an agent that may accelerate and promote the progression of kidney disease.
Oxidative stress reversibly inactivates myocardial enzymes during cardiac arrest
Authors: Sharma Arti B. , Sun Jie , Howard Linda L. , Williams Arthur G. , Mallet Robert T.
Published: August 2006

Oxidative stress during cardiac arrest may inactivate myocardial enzymes and thereby exacerbate ischemic derangements of myocardial metabolism. This study examined the impact of cardiac arrest on left ventricular enzymes. Beagles were subjected to 5 min of cardiac arrest and 5 min of open-chest cardiac compressions (OCCC) before epicardial direct current countershocks were applied to restore sinus rhythm. Glutathione/glutathione disulfide redox state (GSH/GSSG) and a panel of enzyme activities were measured in snap-frozen left ventricle. To test whether oxidative stress during arrest inactivated the enzymes, metabolic (pyruvate) or pharmacological ( N-acetyl-l-cysteine) antioxidants were infused intravenously for 30 min before arrest. During cardiac arrest, activities of phosphofructokinase, citrate synthase, aconitase, malate dehydrogenase, creatine kinase, glucose-6-phosphate dehydrogenase, and glutathione reductase fell by 56, 81, 55, 34, 42, 55, and 45%, respectively, coincident with 50% decline in GSH/GSSG. OCCC effected full recovery of glutathione reductase and partial recovery of citrate synthase and aconitase, in parallel with GSH/GSSG. Phosphofructokinase, malate dehydrogenase, creatine kinase, and glucose-6-phosphate dehydrogenase recovered only after cardioversion. Antioxidant pretreatments augmented phosphofructokinase, aconitase, and malate dehydrogenase activities before arrest and enhanced these activities, as well as those of citrate synthase and glucose-6-phosphate dehydrogenase, during arrest. In conclusion, cardiac arrest reversibly inactivates several important myocardial metabolic enzymes. Antioxidant protection of these enzymes implicates oxidative stress as a principal mechanism of enzyme inactivation during arrest.
Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells
Authors: McWhinnie Ralph , Pechkovsky Dmitri V. , Zhou Danyi , Lane David , Halayko Andrew J. , Knight Darryl A. , Bai Tony R.
Published: August 2006

Endothelin-1 (ET-1), a G protein-coupled receptor-activating peptide, is increased in airway epithelium, plasma, and bronchoalveolar lavage fluid of asthmatic patients. We hypothesized that ET-1 may contribute to the increased airway smooth muscle mass found in severe asthma by inducing hypertrophy and inhibiting apoptosis of smooth muscle cells. To investigate this hypothesis, we determined that treatment of primary human bronchial smooth muscle cells with ET-1 dose dependently [10−11-10−7M] inhibited the apoptosis induced by serum withdrawal. ET-1 treatment also resulted in a significant increase in total protein synthesis, mediated through both ETAand ETBreceptors, cell size, as well as increased expression of myosin heavy chain, α-smooth muscle actin, and calponin. ET-1-induced hypertrophy was accompanied by activation of JAK1/STAT-3 and MAPK1/2 (ERK1/2) cell signaling pathways. Inhibition of JAK1/STAT-3 pathways by piceatannol or ERK1/2 by the MAPK/ERK kinase 1/2 inhibitor U0126 blunted the increase in total protein synthesis. The hypertrophic effect of ET-1 was equivalent to that of the gp130 cytokine oncostatin M and greater than that induced by cardiotrophin-1. ET-1 induced release of IL-6 but not IL-11, leukemia inhibitory factor, oncostatin M, or cardiotrophin-1, although treatment of cells with IL-6 alone did not induce hypertrophy. These results suggest that ET-1 is a candidate mediator for the induction of increased smooth muscle mass in asthma and identify signaling pathways activated by this mediator.
Calcium transient evoked by nicotine in isolated rat vagal pulmonary sensory neurons
Authors: Xu Jennings , Yang Wenbin , Zhang Guangfan , Gu Qihai , Lee Lu-Yuan
Published: August 2006

It has been shown that inhaled cigarette smoke activates vagal pulmonary C fibers and rapidly adapting receptors (RARs) in the airways and that nicotine contained in the smoke is primarily responsible. This study was carried out to determine whether nicotine alone can activate pulmonary sensory neurons isolated from rat vagal ganglia; the response of these neurons was determined by fura-2-based ratiometric Ca2+imaging. The results showed: 1) Nicotine (10−4M, 20 s) evoked a transient increase in intracellular Ca2+concentration ([Ca2+]i) in 175 of the 522 neurons tested (Δ[Ca2+]i= 142.2 ± 12.3 nM); the response was reproducible, with a small reduction in peak amplitude in the same neurons when the challenge was repeated 20 min later. 2) A majority (59.7%) of these nicotine-sensitive neurons were also activated by capsaicin (10−7M). 3) 1,1-Dimethyl-4-phenylpiperazinium iodide (DMPP; 10−4M, 20 s), a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a pattern of response similar to that of nicotine. 4) The responses to nicotine and DMPP were either totally abrogated or markedly attenuated by hexamethonium (10−4M). 5) In anesthetized rats, right atrial bolus injection of nicotine (75–200 μg/kg) evoked an immediate (latency <1–2 s) and intense burst of discharge in 47.8% of the pulmonary C-fiber endings and 28.6% of the RARs tested. In conclusion, nicotine exerts a direct stimulatory effect on vagal pulmonary sensory nerves, and the effect is probably mediated through an activation of the NnAChRs expressed on the membrane of these neurons.
CFTR inhibition mimics the cystic fibrosis inflammatory profile
Authors: Perez Aura , Issler Amanda C. , Cotton Calvin U. , Kelley Thomas J. , Verkman Alan S. , Davis Pamela B.
Published: August 2006

Primary airway epithelial cells grown in air-liquid interface differentiate into cultures that resemble native epithelium morphologically, express ion transport similar to those in vivo, and secrete cytokines in response to stimuli. Comparisons of cultures derived from normal and cystic fibrosis (CF) individuals are difficult to interpret due to genetic differences besides CFTR. The recently discovered CFTR inhibitor, CFTRinh-172, was used to create a CF model with its own control to test if loss of CFTR-Cl− conductance alone was sufficient to initiate the CF inflammatory response. Continuous inhibition of CFTR-Cl− conductance for 3–5 days resulted in significant increase in IL-8 secretion at basal ( P = 0.006) and in response to 109 Pseudomonas ( P = 0.0001), a fourfold decrease in Smad3 expression ( P = 0.02), a threefold increase in RhoA expression, and increased NF-κB nuclear translocation upon TNF-α/IL-1β stimulation ( P < 0.000001). CFTR inhibition by CFTRinh-172 over this period does not increase epithelial sodium channel activity, so lack of Cl− conductance alone can mimic the inflammatory CF phenotype. CFTRinh-172 does not affect IL-8, IL-6, or granulocyte/macrophage colony-stimulating factor secretion in two CF phenotype immortalized cell lines: 9/HTEo− pCEP-R and 16HBE14o− AS, or IL-8 secretion in primary CF cells, and inhibitor withdrawal abolishes the increased response, so CFTRinh-172 effects on cytokines are not direct. Five-day treatment with CFTRinh-172 does not affect cells deleteriously as evidenced by lactate dehydrogenase, trypan blue, ciliary activity, electron micrograph histology, and inhibition reversibility. Our results support the hypothesis that lack of CFTR activity is responsible for the onset of the inflammatory cascade in the CF lung.
Contract Law Harmonization and Regional Integration: Can the CIS Learn From the EU?
Authors: Ferrari Elena Ioriatti , Dragneva Rilka
Published: August 2006

In this article, the authors discuss the experience of the EU in pursuing contract law harmonization in relation to similar developments in the Commonwealth of Independent States (hereinafter, "the CIS") and consider its potential learning effects for the processes in the CIS. They start by noting several key general features of the EU and the CIS (also making reference to some of the more advanced regional sub-groupings within the CIS) which bear on the comparability of the two formations; namely, the degree of diversity of member states, the level of economic integration achieved, and the strength of (common) institutions, insofar as they affect the issue of contract law harmonization in the respective regional formation.The authors continue by discussing the specific experience of the EU, followed by that of the CIS. In doing so, they distinguish between two main mechanisms: conflicts of laws unification and substantive unification. The main focus is on the instruments developed regionally (i.e., agreements and legislative acts as well as "soft" model laws), yet, the authors also note the membership in key instruments of international unification. Drs Dragneva and Ioriatti conclude by identifying a number of possible learning points for the CIS in relation to the substance or scope of the harmonization process, the instruments used for it, and the process of pursuing harmonization itself.
Bulgarian Criminal Procedure: The New Philosophy and Issues of Approximation
Authors: Marinova Gergana
Published: August 2006

The Bulgarian legal system forms part of the continental legal family and shares the main features of continental law. One of them is the codification of the main branches of law, among which is Criminal Procedure. In Bulgaria—as in all European countries—the Code of Criminal Procedure (CCP) is the main source of procedural rules of law. It was adopted in 1974 and entered into force in 1975; it was notable in its similarity to the CCP of the Soviet Union.Since 1975, it has been subjected to a vast number of amendments, most of which were introduced after 1990 as a consequence of radical changes in the Bulgarian political, economic, and legal system. Some of the amendments to CCP have brought the criminal justice system in line with the new 1991 Bulgarian Constitution and with the European Convention for the Protection of Human Rights and Fundamental Freedoms (ECHR)—ratified by the Republic of Bulgaria in 1992—as well as with other international acts and obligations, signed or undertaken by Bulgaria. Other amendments have provided for conceptually new institutions, unknown prior to this period in the development of Bulgarian procedural theory and practice.In short, Bulgarian criminal procedure has—since 1990—been undergoing a period of major reform, the most significant expression of which is to be seen in amendments to CCP, adopted in 1999. They represent what is called a "new philosophy" of criminal procedure. The basic elements thereof are:— instituting judicial control over investigative acts and coercive measures affecting fundamental human rights (detention, house arrest, committing a person to a psychiatric hospital for examination, prohibition against leaving the country, searches, seizures, etc.);— speeding up and simplifying the criminal process;— introducing more adversarial elements into judicial proceedings;— introducing police investigation as an alternative to preliminary investigations under which most criminal offenses would be investigated by police officers through more informal police investigative procedures than those of the more formal preliminary investigation.
1939-1945: Environmental Aspects of the War in Europe
Authors: Tikhomirov Sergey
Published: August 2006

World War II made it clear that the realization of the potential of existing military technology and methods for using it—along with the extraction of natural resources during the prosecution of the war—constitute a man-made burden for the environment threatening the sustainability of the ecosystems of the combatant countries. The discovery of this danger to the environment was made possible by the implementation of the doctrine of "total destruction" that was conducted under Hitler's direction.The subsequent sixty years have shown, however, that progress in society has been too slow with respect to the subordination of military expediency to environmental sensibility and the adoption of measures toward the ecologization of armed combat. An important strategic resource for resolving the environmental problem of armed conflicts—time—is being lost much more quickly than states are taking steps aimed at the elimination of the threat that was revealed by World War II and that has increased multifold in the six intervening decades.Using historical hindsight, the author proposes his own view of the problem from the perspective of international law.
Horizontal Transmission in the Hippocratic Tradition
Authors: Craik Elizabeth
Published: August 2006

The problem of intertextuality in the Hippocratic Corpus is addressed, with particular reference to Prorrhetic 1 and Coan Prognoses, which have blocks of prognostic material in common and which replicate passages of Epidemics. The relation between medical prognosis and religious divination is discussed. It is discovered that identical aphoristic wording is accompanied and probably safeguarded by metrical patterns, and argued that the compilers were amalgamating early sources of traditional wisdom, possibly from shrines in Thessaly, with later 'scientific' material. The term horizontal transmission, borrowed from textual criticism, describes the complex process of interpenetration seen in the Hippocratic tradition.
Persuasive Γελωζ: Public Speaking and the Use of Laughter
Authors: Spatharas Dimos
Published: August 2006

This paper aims to interpret the function of laughter in Greek oratory. Investigation of relevant passages in the preserved speeches of the Attic orators and rhetorical meta-texts shows how laughter propels the establishment of each one of the three kinds of εντεχνoι πíστειζ ('artistic' proofs), namely argument, êthos and pathos.
The Opening of On Interpretation: Toward a More Literal Reading
Authors: Walz Matthew
Published: August 2006

Aristotle begins On Interpretation with an analysis of the existence of linguistic entities as both physical and meaningful. Two things have been lacking for a full appreciation of this analysis: a more literal translation of the passage and an ample understanding of the distinction between symbols and signs. In this article, therefore, I first offer a translation of this opening passage (16a1-9) that allows the import of Aristotle's thinking to strike the reader. Then I articulate the distinction between symbol and sign so crucial to understanding this passage. Aristotle employs this distinction, I argue, in order to show how the linguistic entities he defines later in On Interpretation (that is, name, verb, denial, affirmation, declaration, and articulation) are both conventional and natural, owing to their being both symbols and signs, respectively. Finally, I suggest why Aristotle's analysis of how linguistic entities exist as both physical and meaningful is fitting, since man himself, "the animal that has speech," lives at the boundary between nature and intelligence.
Akrasia in the Protagoras and the Republic
Authors: Morris Michael
Published: August 2006

Although it is a commonplace that the Protagoras and the Republic present diffent views of akrasia, the nature of the difference is not well understood. I argue that the logic of the famous argument in the Protagoras turns just on two crucial assumptions: that desiring is having evaluative beliefs (or that valuing is desiring), and that no one can have contradictory preferences at the same time; hedonism is not essential to the logic of the argument. And the logic of the argument for the division of the soul in the Republic requires the rejection of just the second of these assumptions, but not the evaluative conception of desire. I also maintain that Plato was aware, at the time of composition, of these features of the argumentation of his dialogues. Finally, I argue that there is reason to think that, even at the time of the Protagoras, Plato held the conception of the soul expressed in the Republic, and not anything like that expressed in the famous argument of the Protagoras. The Protagoras view, even without hedonism, is a poor expression of the thesis that virtue is knowledge.
Food-deprivation affects tongue extrusions as well as attractivity and proceptivity components of sexual behavior in the lizard, Sceloporus jarrovii
Authors: Parker  , Punzo
Published: August 2006

Experiments were conducted to assess the effect of various levels of food deprivation (1, 2, 3, or 4-day periods) on tongue extrusions as well as attractivity and proceptivity components of sexual behavior in the sceloperine lizard Sceloporus jarrovii. Results showed sex differences with respect to effects of food deprivation on the attractiveness of male and female lizard odors toward conspecifics (attractivity). Males spent more time extruding their tongue to touch blocks containing odors of ad libitum-fed females as compared to odors from females deprived of food for 4 days, while spending a similar amount of time investigating blocks containing odors of ad libitum-fed females and females deprived of food for less than 4 days. In contrast, females spent similar amounts of time investigating odors associated with ad libitum-fed as well as food-deprived conspecifics. Results also showed that one day of food deprivation was sufficient to inhibit the desire to initiate or maintain contact with opposite-sex conspecifics (receptivity).
Niccolò da Reggio's Translations of Galen and their Reception in France
Authors: McVaugh Michael
Published: August 2006

In the first half of the fourteenth century, Niccolò da Reggio translated more than fifty works by Galen from Greek into Latin, and by mid-century most if not all of them had reached the papal court at Avignon, where Guy de Chauliac praised their accuracy and cited them regularly in his Great Surgery of 1363. Yet contemporary physicians at nearby Montpellier almost never referred to them, ordinarily preferring to quote from the older Arabic-Latin translations. Examining a particular context, the ways in which urological conditions were described in the old and new versions of Galen, suggests that medical teachers and commentators may have found it difficult to give up the familiarity of the traditional language in favor of Niccolò's new terminology.
Medicine and Moral Virtue in the Expositio Problematum Aristotelis of Peter of Abano
Authors: Klemm Matthew
Published: August 2006

This paper examines a set of questions concerning moralia in Peter of Abano's Expositio Problematum (1310) and shows that its author takes a naturalistic approach, heavily reliant on medical doctrine, to propose that not only the lower virtues, but also those dependent on the rational soul, are closely tied to physiological states. For the irrational soul, this close connection with the body is not surprising. However, in the case of the rational virtues, the dependence on the body is more unusual and offers a significant example of Peter's application of medical doctrine beyond the established bounds of the discipline. His is a very different approach to human virtue than that of his contemporaries, and it blurs the distinction between moral virtue and natural virtue throughout his exposition. At the same time, this commentary offers insight into Peter's broader position on the soul.