bluuebunny/crossref_metadata_2025 huggingface dataset:
Transmural pressure in rat initial subpleural lymphatics during spontaneous or mechanical ventilation
Authors: Moriondo Andrea , Mukenge Sylvain , Negrini Daniela
Published: April 2005

The role played by the mechanical tissue stress in supporting lymph formation and propulsion in thoracic tissues was studied in deeply anesthetized rats ( n = 13) during spontaneous breathing or mechanical ventilation. After arterial and venous catheterization and insertion of an intratracheal cannula, fluorescent dextrans were injected intrapleurally to serve as lymphatic markers. After 2 h, the fluorescent intercostal lymphatics were identified, and the hydraulic pressure in lymphatic vessels (Plymph) and adjacent interstitial space (Pint) was measured using micropuncture. During spontaneous breathing, end-expiratory Plymph and corresponding Pint were −2.5 ± 1.1 (SE) and 3.1 ± 0.7 mmHg ( P < 0.01), which dropped to −21.1 ± 1.3 and −12.2 ± 1.3 mmHg, respectively, at end inspiration. During mechanical ventilation with air at zero end-expiratory alveolar pressure, Plymph and Pint were essentially unchanged at end expiration, but, at variance with spontaneous breathing, they increased at end inspiration to 28.1 ± 7.9 and 28.2 ± 6.3 mmHg, respectively. The hydraulic transmural pressure gradient (ΔPtm = Plymph − Pint) was in favor of lymph formation throughout the whole respiratory cycle (ΔPtm = −6.8 ± 1.2 mmHg) during spontaneous breathing but not during mechanical ventilation (ΔPtm = −1.1 ± 1.8 mmHg). Therefore, data suggest that local tissue stress associated with the active contraction of respiratory muscles is required to support an efficient lymphatic drainage from the thoracic tissues.
Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats
Authors: Igase Michiya , Strawn William B. , Gallagher Patricia E. , Geary Randolph L. , Ferrario Carlos M.
Published: April 2005

When increased in vascular tissues, angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase that hydrolyzes angiotensin II to angiotensin-(1–7), may augment the growth inhibitory and vasodilatory effects of the heptapeptide. We investigated the regulation of ACE2 and angiotensin-(1–7) expression in aortas and carotid arteries of 12-wk-old male spontaneously hypertensive rats (SHR) by determining the effect of sustained angiotensin type 1 (AT1) receptor blockade with olmesartan (10 mg·kg−1·day−1, n = 13) compared with those that received atenolol (30 mg·kg−1·day−1, n = 13), hydralazine (10 mg·kg−1·day−1, n = 13), or vehicle ( n = 21). Systolic blood pressures were ∼30% lower ( P < 0.05) in rats treated for 2 wk with olmesartan compared with vehicle-treated rats. Both atenolol and hydralazine produced similar decreases in systolic blood pressure. ACE2 mRNA in the thoracic aorta of olmesartan-treated rats ( n = 8) was fivefold greater ( P < 0.05) than that in vehicle-treated rats ( n = 16), whereas atenolol ( n = 8) or hydralazine ( n = 8) had no effect. Immunostaining intensities in rats treated with olmesartan ( n = 5) were also associated with increased ( P < 0.05) ACE2 and angiotensin-(1–7) in thoracic aorta media compared with vehicle-treated rats. In contrast, immunostaining intensities for both ACE2 and angiotensin-(1–7) were not different from vehicle ( n = 5) in carotid arteries of SHR medicated with either atenolol ( n = 5) or hydralazine ( n = 5). A comparison of vessel wall dimensions showed that olmesartan selectively reduced the thoracic aorta media-to-lumen ratio ( P < 0.05) and media thickness ( P < 0.05) without an effect on carotid artery morphometry. Compared with vehicle-treated SHR, vascular hypertrophy determined from media and lumen measurements was not changed in SHR given either atenolol or hydralazine. These data represent the first report of ACE2 and angiotensin-(1–7) expression in the aorta and carotid arteries of SHR. Increased ACE2 and angiotensin-(1–7) in association with altered dimensions of the thoracic aorta but not carotid arteries in response to olmesartan treatment provides evidence that this pathway is regulated by AT1 receptors and may be important in mediating the pressure-independent vascular remodeling effects of angiotensin peptides.
Increased aortic stiffness in the insulin-resistant Zuckerfa/farat
Authors: Sista Akhilesh K. , O'Connell Mary K. , Hinohara Tomoya , Oommen Santosh S. , Fenster Brett E. , Glassford Alexander J. , Schwartz Eric A. , Taylor Charles A. , Reaven Gerald M. , Tsao Philip S.
Published: April 2005

Accumulating clinical evidence indicates increased aortic stiffness, an independent risk factor for cardiovascular and all-cause mortality, in type 2 diabetic and glucose-intolerant individuals. The present study sought to determine whether increased mechanical stiffness, an altered extracellular matrix, and a profibrotic gene expression profile could be observed in the aorta of the insulin-resistant Zucker fa/fa rat. Mechanical testing of Zucker fa/fa aortas showed increased vascular stiffness in longitudinal and circumferential directions compared with Zucker lean controls. Unequal elevations in developed strain favoring the longitudinal direction resulted in a loss of anisotropy. Real-time quantitative PCR and immunohistochemistry revealed increased expression of fibronectin and collagen IVα3in the Zucker fa/fa aorta. In addition, expression of transforming growth factor-β and several Smad proteins was increased in vessels from insulin-resistant animals. In rat vascular smooth muscle cells, 12–18 h of exposure to insulin (100 nmol/l) enhanced transforming growth factor-β1 mRNA expression, implicating a role for hyperinsulinemia in vascular stiffness. Thus there is mechanical, structural, and molecular evidence of arteriosclerosis in the Zucker fa/fa rat at the glucose-intolerant, hyperinsulinemic stage.
Pentoxifylline attenuates cardiac dysfunction and reduces TNF-α level in ischemic-reperfused heart
Authors: Zhang Ming , Xu Yan-Jun , Saini Harjot K. , Turan Belma , Liu Peter P. , Dhalla Naranjan S.
Published: April 2005

Although pentoxifylline (PTXF), a phosphodiesterase inhibitor, has been reported to exert beneficial effects in cardiac bypass surgery, its effect and mechanisms against ischemia-reperfusion (I/R) injury in heart are poorly understood. Because I/R is known to increase the level of tumor necrosis factor (TNF)-α in myocardium and PTXF has been shown to depress the production of TNF-α in failing heart, this study examined the hypothesis that PTXF may attenuate cardiac dysfunction and reduce TNF-α content in I/R heart. For this purpose, isolated rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 2–30 min. Although cardiac dysfunction due to ischemia was not affected, the recovery of heart function upon reperfusion was markedly improved by PTXF treatment. This cardioprotective effect of PTXF was dose dependent; maximal effect was seen at a concentration of 125 μM. TNF-α, nuclear factor-κB (NF-κB), and phosphorylated NF-κB contents were decreased in ischemic heart but were markedly increased within 2 min of starting reperfusion. The ratio of cytosolic-to-homogenate NF-κB was decreased, whereas the ratio of particulate-to-homogenate NF-κB was increased in I/R hearts. These changes in TNF-α and NF-κB protein contents as well as in NF-κB redistribution due to I/R were significantly attenuated by PTXF treatment. The results of this study indicate that the cardioprotective effects of PTXF against I/R injury may be due to reductions in the activation of NF-κB and the production of TNF-α content.
Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy
Authors: Hemmings D. G. , Williams S. J. , Davidge S. T.
Published: April 2005

Intrauterine growth restriction (IUGR) increases the risk of cardiovascular disease later in life. Vascular dysfunction occurs in adult offspring from animal models of IUGR including maternal undernutrition, but the influence of reduced fetal oxygen supply on adult vascular function is unclear. Myogenic responses, essential for vascular tone regulation, have not been evaluated in these offspring. We hypothesized that 7-mo-old offspring from hypoxic (12% O2; H) or nutrient-restricted (40% of control; NR) rat dams would show greater myogenic responses than their 4-mo-old littermates or control (C) offspring through impaired modulation by vasodilators. Growth restriction occurred in male H ( P < 0.01), male NR ( P < 0.01), and female NR ( P < 0.02), but not female H, offspring. Myogenic responses in mesenteric arteries from males but not females were increased at 7 mo in H ( P < 0.01) and NR ( P < 0.05) vs. C offspring. There was less modulation of myogenic responses after inhibition of nitric oxide synthase ( P < 0.05), prostaglandin H synthase ( P < 0.005), or both enzymes ( P < 0.001) in arteries from 7-mo male H vs. C offspring. Thus reduced vasodilator modulation may explain elevated myogenic responses in 7-mo male H offspring. In contrast, there was increased modulation of myogenic responses in arteries from 7-mo female H vs. C or NR offspring after inhibition of both enzymes ( P < 0.05). Thus increased vasodilator modulation may maintain myogenic responses in female H offspring at control levels. In summary, vascular responses in adult offspring from adverse intrauterine environments are impaired in a gender-specific, age-dependent, and maternal insult-dependent manner, with males more profoundly affected.
Mathematical modeling of the nitric oxide/cGMP pathway in the vascular smooth muscle cell
Authors: Yang Jin , Clark John W. , Bryan Robert M. , Robertson Claudia S.
Published: April 2005

The nitric oxide (NO)/cGMP pathway in the vascular smooth muscle cell (VSMC) is an important cellular signaling system for the regulation of VSMC relaxation. We present a mathematical model to investigate the underlying mechanisms of this pathway. The model describes the flow of NO-driven signal transduction: NO activation of soluble guanylate cyclase (sGC), sGC- and phosphodiesterase-catalyzed cGMP production and degradation, cGMP-mediated regulation of protein targets including the Ca2+-activated K+(KCa) channel, and the myosin contractile system. Model simulations reproduce major NO/cGMP-induced VSMC relaxation effects, including intracellular Ca2+concentration reduction and Ca2+desensitization of myosin phosphorylation and force generation. Using the model, we examine several testable principles. 1) Rapid sGC desensitization is caused by end-product cGMP feedback inhibition; a large fraction of the steady-state sGC population is in an inactivated intermediate state, and cGMP production is limited well below maximum. 2) NO activates the KCachannel with both cGMP-dependent and -independent mechanisms; moderate NO concentration affects the KCavia the cGMP-dependent pathway, whereas higher NO concentration is accommodated by a cGMP-independent mechanism. 3) Chronic NO synthase inhibition may cause underexpressions of K+channels including inward rectifier and KCachannels. 4) Ca2+desensitization of the contractile system is distinguished from Ca2+sensitivity of myosin phosphorylation. The model integrates these interactions among the heterogeneous components of the NO signaling system and can serve as a general modeling framework for studying NO-mediated VSMC relaxation under various physiological and pathological conditions. New data can be readily incorporated into this framework for interpretation and possible modification and improvement of the model.
Effects of pulsation frequency and endothelial integrity on enhanced arterial transmural filtration produced by pulsatile pressure
Authors: Alberding Jonathan P. , Baldwin Ann L. , Barton Jennifer K. , Wiley Elizabeth
Published: April 2005

The role of the endothelium in regulating transmural fluid filtration into the artery wall under pulsatile pressure and the effects of changes in pulsatile frequency on filtration have received little attention. Previous experiments (Alberding JP, Baldwin AL, Barton JK, and Wiley E. Am J Physiol Heart Circ Physiol 286: H1827–H1835, 2004) demonstrated significantly increased filtration after initial onset of pulsatile pressure compared with that predicted by using parameters measured under steady pressure. To determine the role of the endothelium in this phenomenon, the following experiments were performed on five New Zealand White rabbits (anesthetized with 30 mg/kg pentobarbital sodium). One of each pair of carotid arteries was deendothelialized, and filtration measurements under steady and pulsatile pressure were compared with those made in intact vessels (Alberding JP, Baldwin AL, Barton JK, and Wiley E. Am J Physiol Heart Circ Physiol 286: H1827–H1835, 2004). To determine the effect of increasing pulsatile frequency on arterial filtration, transmural filtration was measured by using pulsatile pressure frequencies of 1 Hz, followed by 2 Hz, in another set of intact arteries (6 arteries and 3 animals). For deendothelialized vessels, the initial increase in filtration after onset of pulsatility was similar to that observed in intact vessels, but the subsequent reduction in filtration was less abrupt. When pulsatile frequency was increased from 1 to 2 Hz in intact arteries, an initial increase in filtration was observed, similar to that obtained after onset of pulsatile pressure subsequent to a steady pressure. The observed responses of arteries to pulsatile pressure, with and without endothelium, or undergoing a frequency change, suggest a dynamic role for the endothelium in regulating transvascular transport in vivo.
Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia
Authors: Chalothorn Dan , Zhang Hua , Clayton Jason A. , Thomas Steven A. , Faber James E.
Published: April 2005

Catecholamine stimulation of α1-adrenoceptors exerts growth factor-like activity, mediated by generation of reactive oxygen species, on arterial smooth muscle cells and adventitial fibroblasts and contributes to hypertrophy and hyperplasia in models of vascular injury and disease. Adrenergic trophic activity also contributes to flow-mediated positive arterial remodeling by augmenting proliferation and leukocyte accumulation. To further examine this concept, we studied whether catecholamines contribute to collateral growth and angiogenesis in hindlimb insufficiency. Support for this hypothesis includes the above-mentioned studies, evidence that ischemia augments norepinephrine release from sympathetic nerves, and proposed involvement of reactive oxygen species in angiogenesis and collateral growth. Mice deficient in catecholamine synthesis [by gene deletion of dopamine β-hydroxylase (DBH−/−)] were studied. At 3 wk after femoral artery ligation, increases in adductor muscle perfusion were similar in DBH−/−and wild-type mice, whereas recovery of plantar perfusion and calf microsphere flow were attenuated, although not significantly. Preexisting collaterals in adductor of wild-type mice showed increases in lumen diameter (60%) and medial and adventitial thickness (57 and 119%, P < 0.05 here and below). Lumen diameter increased similarly in DBH−/−mice (52%); however, increases in medial and adventitial thicknesses were reduced (30 and 65%). Leukocyte accumulation in the adventitia/periadventitia of collaterals was 39% less in DBH−/−mice. Increased density of α-smooth muscle actin-positive vessels in wild-type adductor (45%) was inhibited in DBH−/−mice (2%). Although both groups experienced similar atrophy in the gastrocnemius (∼22%), the increase in capillary-to-muscle fiber ratio in wild-type mice (21%) was inhibited in DBH−/−mice (7%). These data suggest that catecholamines may contribute to collateral growth and angiogenesis in tissue ischemia.
Thrombin, TNF-α, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells
Authors: Wu Sheng-Qian , Aird William C.
Published: April 2005

Thrombin, TNF-α, and LPS have each been implicated in endothelial cell and vascular smooth muscle cell (VSMC) activation. We wanted to test the hypothesis that these three agonists display mediator and/or cell type-specific properties. The addition of thrombin to human pulmonary artery endothelial cells resulted in an upregulation of PDGF-A, tissue factor (TF), ICAM-1, and urokinase-type plasminogen activator (u-PA), whereas TNF-α and LPS failed to induce PDGF-A. These effects were mimicked by protease-activated receptor-1 activation. In VSMC, thrombin induced expression of TF and PDGF-A but failed to consistently induce ICAM-1 or u-PA expression. In contrast, TNF-α and LPS increased expression of all four genes in this cell type. Inhibitor studies in endothelial cells demonstrated a critical role for PKC in mediating thrombin, TNF-α, and LPS induction of ICAM-1, TF, and u-PA and for p38 MAPK in mediating thrombin, TNF-α, and LPS induction of TF. Taken together, these results suggest that inflammatory mediators engage distinct signaling pathways and expression profiles in endothelial cells and VSMC. The data support the notion that endothelial cell activation is not an all-or-nothing phenomenon but rather is dependent on the nature of the extracellular mediator.
Delayed adenosine A1 receptor preconditioning in rat myocardium is MAPK dependent but iNOS independent
Authors: Lasley Robert D. , Keith Byron J. , Kristo Gentian , Yoshimura Yukihiro , Mentzer Robert M.
Published: April 2005

Adenosine A1 receptor delayed preconditioning (PC) against myocardial infarction has been well described; however, there have been limited investigations of the signaling mechanisms that mediate this phenomenon. In addition, there are multiple conflicting reports on the role of inducible nitric oxide synthase (iNOS) in mediating A1 late-phase PC. The purpose of this study was to determine the roles of the p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs) in in vivo delayed A1 receptor PC and whether this protection at the myocyte level is due to upregulation of iNOS. Myocardial infarct size was measured in open-chest anesthetized rats 24 h after treatment with vehicle or the adenosine A1 agonist 2-chloro- N6-cyclopentyladenosine (CCPA; 100 μg/kg ip). Additional rats receiving CCPA were pretreated with the p38 inhibitor SB-203580 (1 mg/kg ip) or the MAPK/ERK kinase (MEK) inhibitor PD-098059 (0.5 mg/kg ip). At 24 h after CCPA administration, a group of animals was given the iNOS inhibitor 1400W 10 min before ischemia. Treatment with CCPA reduced infarct size from 48 ± 2 to 28 ± 2% of the area at risk, an effect that was blocked by both SB-203580 and PD-098059 but not 1400W. Ventricular myocytes isolated 24 h after CCPA injection exhibited significantly reduced oxidative stress during H2O2 exposure compared with myocytes from vehicle-injected animals, and this effect was not blocked by the iNOS inhibitor 1400W. Western blot analysis of whole heart and cardiac myocyte protein samples revealed no expression of iNOS 6 or 24 h after CCPA treatment. These results indicate that adenosine A1 receptor delayed PC in rats is mediated by MAPK-dependent mechanisms, but this phenomenon is not associated with the early or late expression of iNOS.
Tempol therapy attenuates medial smooth muscle cell apoptosis and neointima formation after balloon catheter injury in carotid artery of diabetic rats
Authors: Jagadeesha D. K. , Lindley Timothy E. , DeLeon Jason , Sharma Ram V. , Miller Francis , Bhalla Ramesh C.
Published: April 2005

Accumulating data support the hypothesis that reactive oxygen species (ROS) play a critical role in the vascular complications observed in diabetes. However, the mechanisms of ROS-mediated vascular complications in diabetes are not clear. We tested the hypothesis that ROS-mediated increase in proapoptotic factor Bax expression leads to medial smooth muscle cell (SMC) apoptosis that is associated with neointima formation. We used a fructose-rich diet for 4 wk to model Type 2 diabetes in rats. SOD mimetic membrane-permeable 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (Tempol, 1 mM) was administered in drinking water to scavenge superoxide starting 1 day before surgery and continued during the duration of the experiment. Vascular injury resulted in a significant increase in medial SMC apoptosis that was associated with neointima formation. The number of medial SMC positive for Bax immunostaining significantly increased in injured arteries compared with uninjured arteries. Superoxide scavenging by Tempol treatment inhibited both the Bax-positive index as well as the apoptotic index of medial SMC in response to vascular injury. Tempol treatment inhibited apoptotic loss of medial SMC, thus increasing their density in the injured arteries. These alterations in the media were associated with a marked decrease in neointima formation in injured arteries. We conclude that Bax expression may play an important role in vascular SMC apoptosis and, finally, that this regulatory mechanism is redox sensitive.
Microdialysis separately monitors myocardial interstitial myoglobin during ischemia and reperfusion
Authors: Kitagawa Hirotoshi , Yamazaki Toji , Akiyama Tsuyoshi , Sugimachi Masaru , Sunagawa Kenji , Mori Hidezo
Published: April 2005

Direct monitoring of myoglobin efflux during ischemia and reperfusion has been limited because of inherent sample collection problems in the ischemic region. Recently, the cardiac dialysis technique has offered a powerful method for monitoring myocardial interstitial levels of low-molecular-weight compounds in the cardiac ischemic region. In the present study, we extended the molecular target to high-molecular-weight compounds by use of microdialysis probes with a high-molecular-mass cutoff and monitored myocardial interstitial myoglobin levels. A dialysis probe was implanted in the left ventricular free wall in anesthetized rabbits. The main coronary artery was occluded for 60 or 120 min. We examined the effects of myocardial ischemia and reperfusion on myocardial interstitial myoglobin levels. Interstitial myoglobin increased within 15 min of ischemia and continued to increase during 120 min of ischemia, whereas blood myoglobin increased at 45 min of ischemia. Lactate and myoglobin in the interstitial space increased during the same period. At 60 min of ischemia, reperfusion markedly accelerated interstitial myoglobin release. The interstitial myoglobin level was fivefold higher at 0–15 min of reperfusion than at 60–75 min of coronary occlusion. The dialysis technique permits earlier detection of myoglobin release and separately monitors myoglobin release during ischemia and reperfusion. Myocardial interstitial myoglobin levels can serve as an index of myocardial injury evoked by ischemia or reperfusion.
Primary type II alveolar epithelial cells present microbial antigens to antigen-specific CD4+T cells
Authors: Debbabi Hajer , Ghosh Shamik , Kamath Arati B. , Alt Jennifer , deMello Daphne E. , Dunsmore Sarah , Behar Samuel M.
Published: April 2005

Type II alveolar epithelial cells (AEC) can produce various antimicrobial and proinflammatory effector molecules. This, together with their abundance and strategic location, suggests a role in host defense against pulmonary pathogens. We report that murine type II AEC, like their human counterparts, express class II major histocompatibility complex (MHC). Using a murine model of pulmonary tuberculosis, we find that type II AEC become activated and have increased cell surface expression of class II MHC, CD54, and CD95 following infection. Type II AEC use the class II MHC pathway to process and present mycobacterial antigens to immune CD4+T cells isolated from mice infected with Mycobacterium tuberculosis. Therefore, not only can type II AEC contribute to the pulmonary immunity by secreting chemokines that recruit inflammatory cells to the lung, but they can also serve as antigen-presenting cells. Although type II AEC are unlikely to prime naïve T cells, their ability to present antigens to T cells demonstrates that they can participate in the effector phase of the immune response. This represents a novel role for type II AEC in the immunological response to pulmonary pathogens.
Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide
Authors: Savov Jordan D. , Brass David M. , Lawson Barbara L. , McElvania-Tekippe Erin , Walker Julia K. L. , Schwartz David A.
Published: April 2005

Although chronic inhalation of endotoxin or lipopolysaccharide (LPS) causes all of the classic features of asthma, including airway hyperreactivity, airway inflammation, and airway remodeling, the mechanisms involved in this process are not clearly understood. The objective of this study was to determine whether intratracheal treatment with LPS antagonist (E5564, a lipid A analog) prevented the development of chronic endotoxin-induced airway disease in a mouse model of environmental airway disease. Pretreatment with 10 and 100 μg of E5564 was found to inhibit the airway response (hyperreactivity and inflammation) for up to 48 h after the administration of the compound. Repeated dosing with 50 μg of E5564 intratracheally did not cause any measurable toxicity. Therefore, in a chronic experiment, mice were treated with either E5564 (50 μg) or vehicle three times weekly for 5 wk and simultaneously daily exposed to either LPS (4.65 ± 0.30 μg/m3) or saline aerosol. E5564 was effective in decreasing the airway hyperreactivity to methacholine, the air space neutrophilia, the interleukin-6 in the lung lavage fluid, and the neutrophil infiltration of the airways 36 h after 5 wk of LPS inhalation. Less collagen deposition was observed in the airways of E5564-treated mice compared with vehicle-treated mice after a 4-wk recovery period. Our results indicate that E5564, a Toll-like receptor 4 antagonist, minimizes the physiological and biological effects of chronic LPS inhalation, suggesting a therapeutic role for competitive LPS antagonists in preventing or reducing endotoxin-induced environmental airway disease.
Role of CXCR2 in cigarette smoke-induced lung inflammation
Authors: Thatcher T. H. , McHugh N. A. , Egan R. W. , Chapman R. W. , Hey J. A. , Turner C. K. , Redonnet M. R. , Seweryniak K. E. , Sime P. J. , Phipps R. P.
Published: April 2005

It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 h, twice per day for 3 days, induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and the neutrophil chemotactic CXC chemokines macrophage inflammatory protein (MIP)-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histological changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. β-Glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, whereas MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils that either are not present to bind these chemokines or fail to provide a feedback signal to other cells producing these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.
Effects of Short-Term Training on Sensory and Motor Function in Severed Nerves of Long-Term Human Amputees
Authors: Dhillon G. S. , Krüger T. B. , Sandhu J. S. , Horch K. W.
Published: April 2005

Much has been studied and written about plastic changes in the CNS of humans triggered by events such as limb amputation. However, little is known about the extent to which the original pathways retain residual function after peripheral amputation. Our earlier, acute study on long-term amputees indicated that central pathways associated with amputated peripheral nerves retain at least some sensory and motor function. The purpose of the present study was to determine if these functional connections would be strengthened or improved with experience and training over several days time. To do this, electrodes were implanted within fascicles of severed nerves of long-term human amputees to evaluate the changes in electrically evoked sensations and volitional motor neuron activity associated with attempted phantom limb movements. Nerve stimulation consistently resulted in discrete, unitary, graded sensations of touch/pressure and joint-position sense. There was no significant change in the values of stimulation parameters required to produce these sensations over time. Similarly, while the amputees were able to improve volitional control of motor neuron activity, the rate and pattern of change was similar to that seen with practice in normal individuals on motor tasks. We conclude that the central plasticity seen after amputation is most likely primarily due to unmasking, rather than replacement, of existing synaptic connections. These results also have implications for neural control of prosthetic limbs.
Selective Serotonin Reuptake Inhibitors Induce Spontaneous Interneuronal Activity in the Leech Nervous System
Authors: Calviño María A. , Iscla Irene R. , Szczupak Lidia
Published: April 2005

Serotonin [5-hydroxytryptamine (5-HT)] is a conspicuous neuromodulator of sensory–motor networks that affects a variety of neurons at different levels of the network hierarchy. Because of its many possible targets, it has been difficult to obtain a comprehensive picture of how 5-HT achieves its final modulatory output on any given network. Our hypothesis is that the profile of 5-HT actions is dictated by its pattern of release from endogenous sites. We tested this hypothesis in the leech nervous system by means of a selective serotonin reuptake blocker (SSRI), fluoxetine. Fluoxetine evoked barrages of synaptic potentials in identified sensory, motor, and interneurons. This effect was mimicked by the tricyclic antidepressants imipramine and clomipramine, and by the SSRI citalopram, with relative efficacies that matched their known relative selectivities for the 5-HT transporter. The synaptic responses evoked by fluoxetine in different neurons were temporally correlated, suggesting that they had a common origin. The profile of the synaptic responses matched that expected from the activation of the mechanosensory pressure cells, known to act by polysynaptic pathways. The results suggest that endogenous 5-HT acted on cord spanning interneurons. On the other hand, bath-applied 5-HT evoked an effect different from that of the SSRI. Taken together, the results evidenced that the pattern of action of the monoamine is dictated by the spatial distribution of the 5-HT release sites.
Political Structure, Status Mobility, and Economic Growth in Imperial and Modern China
Authors: Brown Richard Harvey
Published: April 2005

Virtually all theorists agree that one indispensable antecedent of economic development is the existence of innovators who discover and implement better ways of organizing the resources of production and exchange. Such an emphasis on entrepreneurial innovation and investment has characterized economic thought since Adam Smith, and it was voiced again in a modified form by Joseph Schumpeter:The slow and continuous increase in time of the national supply of productive means and savings is obviously an important factor in explaining the course of economic history through the centuries, but it is overshadowed by the fact that development consists primarily in employing existing resources in a different way, in doing new things with them (1949:68).
Age structure in two populations of Triturus vittatus ophryticus at different altitudes
Authors: Kutrup Bilal , Yilmaz Nurhayat , Bulbul Ufuk
Published: April 2005

We investigated age structure by skeletochronology in two breeding populations of Triturus vittatus ophryticus inhabiting altitudes ranging from 300 m (in Gurbulak) to 1300 m (in Hidirnebi) in northeastern Turkey. The mean age was 4 years (maximum 10) in Gurbulak population and 8 (maximum 16) in Hidirnebi population. In the lowland population, minimum age at maturation was two to three years while it was four years in the highland population. The mean snout-vent length of the populations was significantly different and we found no correlation between age and snout-vent length except for females of Gurbulak. Sexual dimorphism in body size and weight was detected in both populations.
Microarray karyotyping of commercial wine yeast strains reveals shared, as well as unique, genomic signatures
Authors: Dunn Barbara , Levine R Paul , Sherlock Gavin
Published: April 2005

Background

Genetic differences between yeast strains used in wine-making may account for some of the variation seen in their fermentation properties and may also produce differing sensory characteristics in the final wine product itself. To investigate this, we have determined genomic differences among several Saccharomyces cerevisiae wine strains by using a "microarray karyotyping" (also known as "array-CGH" or "aCGH") technique.

Results

We have studied four commonly used commercial wine yeast strains, assaying three independent isolates from each strain. All four wine strains showed common differences with respect to the laboratory S. cerevisiae strain S288C, some of which may be specific to commercial wine yeasts. We observed very little intra-strain variation; i.e., the genomic karyotypes of different commercial isolates of the same strain looked very similar, although an exception to this was seen among the Montrachet isolates. A moderate amount of inter-strain genomic variation between the four wine strains was observed, mostly in the form of depletions or amplifications of single genes; these differences allowed unique identification of each strain. Many of the inter-strain differences appear to be in transporter genes, especially hexose transporters (HXT genes), metal ion sensors/transporters (CUP1, ZRT1, ENA genes), members of the major facilitator superfamily, and in genes involved in drug response (PDR3, SNQ1, QDR1, RDS1, AYT1, YAR068W). We therefore used halo assays to investigate the response of these strains to three different fungicidal drugs (cycloheximide, clotrimazole, sulfomethuron methyl). Strains with fewer copies of the CUP1 loci showed hypersensitivity to sulfomethuron methyl.

Conclusion

Microarray karyotyping is a useful tool for analyzing the genome structures of wine yeasts. Despite only small to moderate variations in gene copy numbers between different wine yeast strains and within different isolates of a given strain, there was enough variation to allow unique identification of strains; additionally, some of the variation correlated with drug sensitivity. The relatively small number of differences seen by microarray karyotyping between the strains suggests that the differences in fermentative and organoleptic properties ascribed to these different strains may arise from a small number of genetic changes, making it possible to test whether the observed differences do indeed confer different sensory properties in the finished wine.
Modulation of MAA-induced apoptosis in male germ cells: role of Sertoli cell P/Q-type calcium channels
Authors: Barone Fortunata , Aguanno Salvatore , D'Agostino Angela
Published: April 2005

Spontaneous germ cell death by apoptosis occurs during normal spermatogenesis in mammals and is thought to play a role in the physiological mechanism limiting the clonal expansion of such cell population in the male gonad. In the prepubertal rat testis, the most conspicuous dying cells are pachytene spermatocytes, which are also the primary target of the apoptosis experimentally induced by the methoxyacetic acid (MAA). Since we have recently reported that Sertoli cells, the somatic component of the seminiferous epithelium, regulate not only germ cell viability and differentiation but also their death, we have further investigated the mechanism involved in such a control.

In this paper we have used the protein clusterin, produced by Sertoli cells and associated with tissue damage or injury, as indicator of germ cell apoptosis in rat seminiferous tubules treated with MAA in the presence or in the absence of omega-agatoxin, a specific inhibitor of P/Q type voltage-operated calcium channels (VOCC's). We performed both a qualitative analysis of clusterin content and germ cell apoptosis by immunofluorescence experiments and a quantitative analysis by in situ end labelling of apoptotic germ cells followed by flow cytometry. The results obtained demonstrate that Sertoli cells modulate germ cell apoptosis induced by methoxyacetic acid also throughout the P/Q-type VOCC's.
Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose
Authors: Dennison James E , Bigelow Philip L , Andersen Melvin E
Published: April 2005

Individuals are exposed to mixtures, and never to single chemicals. Depending on the composition of the elements of mixtures, significant toxicological interactions between the components may occur. These interactions are complex and often difficult to predict, ranging from synergistic to additive and subadditive interactions. The nature of the interactions needs to be evaluated as the target tissue dose of the active form of each chemical. PBPK modeling is an effective tool for determining the target tissue dose and evaluating these interactions when data are available for model development. Some of the interactions are pharmacokinetic in nature, affecting the disposition of other chemicals in the body. Other interactions can be pharmacodynamic in nature, altering the effects that other chemicals have on the organism. For many organic solvents, these interactions occur principally at the level of the metabolizing enzyme, cytochrome P-450 2E1 (CYP2E1). Many solvents are known to induce or inhibit CYP2E1, or both. Mixtures may be comprised of concomitant exposures to chemicals or from components encountered separately on-the-job, off-the-job, through the diet, and otherwise. Examples of mixtures where the exposure to separate components occurs off the job will be discussed, with special emphasis on ethanol consumption as a modifier of solvent pharmacokinetics. The present practice of the linear extrapolation of the toxicity of individual mixture components in the interpretation of occupational exposure limits will also be critiqued.
Inflammatory markers in bronchoalveolar lavage fluid from human volunteers 2 hours after hydrogen fluoride exposure
Authors: Lund K , Dunster C , Ramis I , Sandstrom T , Kelly F J , SøStrand P , Schwarze P , Skovlund E , Boe J , Kongerud J , Refsnes M
Published: April 2005

Fluoride has been in focus as a possible causal agent for respiratory symptoms amongst aluminium potroom workers for several decades. Previously, using bronchoalveolar lavage (BAL), we demonstrated airway inflammation in healthy volunteers 24 hours after exposure to hydrogen fluoride (HF). The objective of the present study was to examine early lung responses to HF exposure. Bronchoscopy with BAL was performed 2 hours after the end of 1-hour exposure to HF. Significant reductions in the total cell number and the number of neutrophils and lymphocytes were observed in bronchoalveolar portion (BAP), whereas there were no significant changes in the bronchial portion (BP). Significantly decreased concentrations of b2-MG, IL-6 and total protein were found in both BAP and BP. Additionally, IL-8 was significantly reduced in BP, and ICAM-1 and albumin were present in lower concentrations in BAP. Lung function measurements were not affected by HF exposure. These reported effects are presumably transitory, as many were not present in the airways 24 hours after a similar HF exposure.
Protective effects of metformin treatment on the liver injury of streptozotocin-diabetic rats
Authors: Yanardag R , Ozsoy-Sacan O , Bolkent S , Orak H , Karabulut-Bulan O
Published: April 2005

Metformin is a biguanide derivate used as an oral hypoglycaemic drug in diabetics. The aim of this study was to examine the histological and biochemical effects of metformin in streptozotocin (STZ)-treated rats. The animals were rendered diabetic by intraperitoneal injection of 65 mg/kg STZ. Fourteen days later, metformin was given at 25 mg/kg by gavage, daily for 28 days, to STZdiabetic rats and a control group. In the STZ-diabetic group, some degenerative changes were observed by light microscopic examination. But the degenerative changes were decreased in the STZ-diabetic group given metformin. In the STZ-diabetic group, blood glucose levels, serum alanine and aspartate transaminase (ALT and AST) activities, total lipid levels, and sodium and potassium levels increased, while body weight, serum magnesium levels and liver glutathione (GSH) levels decreased. In the STZ-diabetic group given metformin, blood glucose levels, serum ALT and AST activities, total lipid, and sodium and potassium levels decreased, and liver GSH and serum magnesium levels increased. As a result of all the morphological and biochemical findings obtained, it was concluded that metformin has a protective effect against the hepatotoxicity produced by STZ diabetes.
Antigenotoxic effects of ascorbic acid against megestrol acetate-induced genotoxicity in mice
Authors: Siddique Yasir Hasan , Beg Tanveer , Afzal Mohammad
Published: April 2005

The genotoxicity of megestrol acetate was studied in mouse bone marrow cells using sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) as parameters. Megestrol acetate (8.12, 16.25 and 32.50 mg/ kg of body weight) was injected intraperitoneally separately in different groups of animals. Both CAs and SCEs were statistically increased at 16.25 and 32.50 mg/kg of body weight. Our earlier in vitro studies show the generation of free oxygen radicals, by synthetic progestins responsible for the genotoxic damage. As the genotoxic effects of steroids can be reduced by natural products having antioxidant properties, and ascorbic acid possesses antioxidant activity, ascorbic acid (20, 40 or 60 mg/kg of body weight) administered together with megestrol acetate (32.50 mg/kg of body weight) significantly decreased CAs and SCEs, suggesting an antigenotoxic role of ascorbic acid against megestrol acetate induced genotoxic damage in mice bone marrow cells. The antigenotoxic effect was clearly dose dependent. The highest protective effect was observed at 60 mg/kg body weight of ascorbic acid treated with 32.50 mg/kg body weight of megestrol acetate.
Soy isoflavones inhibits the genotoxicity of benzo(a)pyrene in Swiss albino mice
Authors: Khan Tajdar Husain , Prasad Lakshmi , Sultana Anuradha , Sultana Sarwat
Published: April 2005

Dietary factors are considered important environmental risk determinants for various diseases. Isoflavones are one of the biologically active polyphenolic plant constituents that possess potential chemopreventive properties against a wide variety of chronic diseases. In the present study we have evaluated the antimutagenic potential of soy isoflavones against benzo(a)pyrene (B[a]P) (125 mg/ kg) induced genotoxicity in Swiss albino mice. The effect of soy isoflavones was studied by in vivo bone marrow chromosomal aberration and micronuclei induction test. Using an alkaline unwinding assay we monitored the DNA strand breaks. Two doses of soy isoflavones (20 and 40 mg/kg b.wt) were given orally for seven days prior to the administration of B[a]P. Soy isoflavone inhibited the genotoxicity of B[a]P in terms of chromosomal aberration and micronucleus formation. DNA strand break levels in only B[a]P treated group remained significantly high f the control values (P <0.001). The pretreatment of soy isoflavone showed gradual reduction in strand breaks significantly (P <0.001) and dose dependently. Soy isoflavone pretreatment also decreased cytochrome P450 (CYP) content. The activity of CYP was also decreased dose dependently by pretreatment with soy isoflavone. The chemopreventive effect of soy isoflavone on the inhibition of CYP activity and DNA integrity mediate the possible mechanism of inhibition of genotoxicity.
Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats
Authors: Ahmad Muzamil , Saleem Sofiyan , Ahmad Abdullah Shafique , Ansari Mubeen Ahmad , Yousuf Seema , Hoda Md Nasrul , Islam Fakhrul
Published: April 2005

6-Hydroxydopamine (6-OHDA) is one of the most widely used rat models for Parkinson's disease. There is ample evidence in the literature that 6-OHDA elicits its toxic manifestations through oxidant stress. In the present study, we evaluated the anti-parkinsonian effects of Withania somnifera extract, which has been reported to have potent anti-oxidant, anti-peroxidative and free radical quenching properties in various diseased conditions. Rats were pretreated with 100, 200 and 300 mg/kg b.w. of the W. somnifera extract orally for 3 weeks. On day 21, 2 mL of 6-OHDA (10 mg in 0.1% in ascorbic acidsaline) was infused into the right striatum while sham operated group received 2 mL of the vehicle. Three weeks after 6-OHDA injections, rats were tested for neurobehavioral activity and were killed 5 weeks after lesioning for the estimation of lipidperoxidation, reduced glutathione content, activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, catecholamine content, dopaminergic D2 receptor binding and tyrosine hydroxylase expression. W. somnifera extract was found to reverse all the parameters significantly in a dose-dependent manner. Thus, the study demonstrates that the extract of W. somnifera may be helpful in protecting the neuronal injury in Parkinson's disease.
Safety pharmacology of sibutramine mesylate, an anti-obesity drug
Authors: Kim Eun-Joo , Park Eun-Kyung , Suh Kwee-Hyun
Published: April 2005

Sibutramine mesylate is a new anti-obesity drug. It is a crystalline salt of sibutramine developed to improve the solubility of sibutramine hydrochloride. Methanesulfonic acid was used as a salt-forming acid instead of hydrochloric acid, resulting in a greatly improved solubility of 1000 mg/mL in water. Sibutramine mesylate was administered orally to ICR mice, Sprague / respiratory system and the other organ systems. Following administration of sibutramine mesylate, spontaneous locomotor activity was significantly increased from 120 min to 24 hours at 3.45 mg/kg and from 30 min to 24 hours at 11.50 mg/kg. Furthermore, there were a decrease in hexobarbitalinduced sleep time, an increase in respiratory rate at 120 min, increases in intestinal transport capacity and gastric pH at 11.50 mg/kg, and decreases in gastric / Dawley rats, and beagle dogs at dose levels of 1.15, 3.45, and 11.50 mg/kg to measure its effects on the central nervous system (CNS), general behaviour, cardiovascular volume and total acidity at 3.45 and 11.50 mg/kg. However sibutramine mesylate caused no effects on general behaviour, motor coordination, body temperature, analgesia, convulsion, blood pressure, heart rate, electrocardiogram, cardiac functions of the isolated rat heart, isolated smooth muscles and renal function. Based on the above results, it was concluded that sibutramine mesylate caused effects on the spontaneous locomotor activity, hexobarbital-induced sleep time, respiration, gastrointestinal transport, and gastric secretion at a dose level of 3.45 mg/kg or greater but caused no effects on other general pharmacological reactions.