bluuebunny/crossref_metadata_2025 huggingface dataset:
Zone-specific cell proliferation during compensatory adrenal growth in rats
Authors: Engeland W. C. , Ennen W. B. , Elayaperumal A. , Durand D. A. , Levay-Young B. K.
Published: September 2004

Compensatory adrenal growth after unilateral adrenalectomy (ULA) leads to adrenocortical hyperplasia. Because zonal growth contributions are not clear, we characterized the phenotype of cortical cells that proliferate using immunofluorescence histochemistry and zone-specific cell counting. Rats underwent ULA, sham adrenalectomy (sham), or no surgery and were killed at 2 or 5 days. Adrenals were weighed and sections immunostained for Ki67 (proliferation), cytochrome P-450 aldosterone synthase (P450aldo, glomerulosa), and cytochrome P-450 11β-hydroxylase ( P45011 β, fasciculata). Unbiased stereology was used to count proliferating glomerulosa and fasciculata cells. Adrenal weight increased after ULA compared with sham and no surgery at both time points, and there was no difference between sham and no surgery. However, either ULA or sham increased Ki67-positive cells in the outer fasciculata at both time points compared with no surgery. Outer fasciculata-restricted proliferation is thus associated with adrenal weight gain in ULA but not sham. Experiment repetition using proliferating cell nuclear antigen and bromodeoxyuridine showed similar results. After ULA, adrenal DNA, RNA, and protein increased at both time points, whereas after sham, only adrenal DNA increased at 2 days. Compensatory growth thus results from hyperplasia and hypertrophy, whereas sham induces only a transient adrenal hyperplasia. Dexamethasone pretreatment prevented the increase in adrenal weight after ULA and blocked Ki67 labeling in the outer fasciculata but not zona glomerulosa in all groups. These results clearly show that the outer fasciculata is the primary adrenal zone responsible for compensatory growth, responding to steroid-suppressible stress signals that alone are ineffective in increasing adrenal mass.
Intramuscular gene transfer of CGRP inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta
Authors: Wang Wang , Sun Wei , Wang Xian
Published: September 2004

CGRP is a well-known neuropeptide that has various protective effects on cardiovascular system. Our previous studies have shown that CGRP inhibits vascular smooth muscle cell (VSMC) proliferation in vitro. The present study aimed to explore the role of the CGRP in neointimal formation after balloon injury in the rat aortic wall and the underlying mechanism. Gene transfer of CGRP was performed with the use of intramuscular electroporation in a balloon-injured rat aorta model. Apoptosis in VSMCs was determined by electrophoresis assessment of DNA fragmentation and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay. Overexpression of the CGRP gene significantly inhibited the neointimal formation after balloon injury compared with the mock transfer, as assessed by the intima-to-media ratio 14 days after balloon injury (29.2 ± 3.7% vs. 52.7 ± 5.4%; n = 9–12, P < 0.05). In addition, CGRP gene expression increased the number of apoptotic cells in the neointima in vivo 14 days after balloon injury. Similarly, the addition of bioactive CGRP and the nitric oxide donor induced similar apoptosis in cultured VSMCs. The antagonist of the CGRP1 receptor and inhibitors of cAMP-PKA and nitric oxide blocked CGRP-mediated apoptosis. Furthermore, CGRP gene transfer increased inducible nitric oxide synthase and p53 but decreased PCNA and Bcl-2 protein levels in balloon-injured rat aorta. Our data demonstrated that CGRP potently inhibited neointimal thickening in the rat aorta, at least in part through its distinct effects on apoptosis and proliferation of VSMCs both in vivo and in vitro. Therefore, delivery of the CGRP gene may have therapeutic implications in limiting vascular restenosis.
Biaxial incremental homeostatic elastic moduli of coronary artery: two-layer model
Authors: Lu Xiao , Pandit Aditya , Kassab Ghassan S.
Published: September 2004

The detailed mechanical properties of various layers of the coronary artery are important for understanding the function of the vessel. The present article is focused on the determination of the incremental modulus in different layers and directions in the neighborhood of the in vivo state. The incremental modulus can be defined for any material subjected to a large deformation if small perturbations in strain lead to small perturbations of stresses in a linear fashion. This analysis was applied to the porcine coronary artery, which was treated as a two-layered structure consisting of an inner intima-media layer and an outer adventitia layer. We adopted a theory based on small-perturbation experiments at homeostatic conditions for determination of incremental moduli in circumferential, axial, and cross directions in the two layers. The experiments were based on inflation and axial stretch. We demonstrate that under homeostatic conditions the incremental moduli are layer- and direction dependent. The incremental modulus is highest in the circumferential direction. Furthermore, in the circumferential direction, the media is stiffer than the whole wall, which is stiffer than the adventitia. In the axial direction, the adventitia is stiffer than the intact wall, which is stiffer than the media. Hence, the coronary artery must be treated as a composite, nonisotropic body. The data acquire physiological relevance in relation to coronary artery health and disease.
Dopamine in vivo inhibits VEGF-induced phosphorylation of VEGFR-2, MAPK, and focal adhesion kinase in endothelial cells
Authors: Sarkar Chandrani , Chakroborty Debanjan , Mitra Rita Basu , Banerjee Samir , Dasgupta Partha Sarathi , Basu Sujit
Published: September 2004

Vascular permeability factor (VPF)/VEGF is a potent multifunctional cytokine and growth factor that has critical roles in vasculogenesis and in both physiological and pathological angiogenesis. Because it has been recently shown that the neurotransmitter dopamine at pharmacological dose can inhibit VEGF/VPF-mediated microvascular permeability, proliferation, and migration of endothelial cells in vitro, we therefore hypothesized that endogenous dopamine may regulate the actions of VPF/VEGF in vivo. We report that VPF/VEGF-induced phosphorylation of VEGF receptor 2, focal adhesion kinase, and MAPK in the endothelial cells is strikingly increased in both dopamine-depleted and dopamine D2 receptor knockout mice compared with normal controls, thereby indicating that endogenous dopamine regulate these critical signaling cascades required for the in vivo endothelial functions of VPF/VEGF. Together, these observations provide new mechanistic insight into the dopamine-mediated inhibition of the activities of VPF/VEGF and suggest that endogenous neurotransmitter dopamine might be an important physiological regulator of VPF/VEGF activities in vivo.
Intracorporal injection ofhSlocDNA restores erectile capacity in STZ-diabetic F-344 rats in vivo
Authors: Christ George J. , Day Nancy , Santizo Cristian , Sato Yoshi , Zhao Weixin , Sclafani Theresa , Bakal Ron , Salman Masha , Davies Kelvin , Melman Arnold
Published: September 2004

The ability of gene transfer with the pore-forming subunit of the human maxi-K channel ( hSlo) to ameliorate the decline in erectile capacity commensurate with 12–24 wk of streptozotocin (STZ)-diabetes was examined in 181 Fischer-344 rats. A 2-mo period of STZ-diabetes was induced before gene transfer, and erectile capacity was evaluated by measuring the intracavernous pressure response (ICP) to cavernous nerve (CN) stimulation (ranging from 0.5 to 10 mA). In the first series of experiments, ANOVA revealed increased CN-stimulated ICP responses at 1 and 2 mo postinjection of 100 μg pcDNA- hSlo compared with control values. A second series of experiments further examined the dose dependence and duration of gene transfer. The ICP response to submaximal (0.5 mA) and maximal (10 mA) nerve stimulation was evaluated 3 or 4 mo postinjection of a single dose of pcDNA- hSlo ranging from 10 to 1,000 μg. ANOVA again revealed that hSlo overexpression was associated with increased CN-stimulated ICP responses compared with responses in corresponding control animals. Histological studies revealed no immune response to the presence of hSlo. PCR analysis documented that expression of both plasmid and transcript were largely confined to the corporal tissue. In the third series of pharmacological experiments, hSlo gene transfer in vivo was associated with iberiotoxin-sensitive relaxation responses to sodium nitroprusside in corporal tissue strips in vitro. The latter data indicate that gene transfer produces functional maxi-K channels that participate in the modulation of corporal smooth muscle cell tone. Taken together, these observations suggest a fundamental diabetes-related change in corporal myocyte maxi-K channel regulation, expression, or function that may be corrected by expression of recombinant hSlo.
Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta
Authors: Jin Liming , Ying Zhekang , Webb R. Clinton
Published: September 2004

Evidence indicates that both the Rho/Rho kinase signaling pathway and reactive oxygen species (ROS) such as superoxide and H2O2are involved in the pathogenesis of hypertension. This study aimed to determine whether ROS-induced vascular contraction is mediated through activation of Rho/Rho kinase. Rat aortic rings (endothelium denuded) were isolated and placed in organ chambers for measurement of isometric force development. ROS were generated by a xanthine (X)-xanthine oxidase (XO) mixture. The antioxidants tempol (3 mM) and catalase (1,200 U/ml) or the XO inhibitor allopurinol (400 μM) significantly reduced X/XO-induced contraction. A Rho kinase inhibitor, (+)-( R)- trans-4-(1-aminoethyl- N-4-pyridil)cyclohexanecarboxamide dihydrochloride (Y-27632), decreased the contraction in a concentration-dependent manner; however, the Ca2+-independent protein kinase C inhibitor rottlerin did not have an effect on X/XO-induced contraction. Phosphorylation of the myosin light chain phosphatase target subunit (MYPT1) was increased by ROS, and preincubation with Y-27632 blocked this increased phosphorylation. Western blotting for cytosolic and membrane-bound fractions of Rho showed that Rho was increased in the membrane fraction by ROS, suggesting activation of Rho. These observations demonstrate that ROS-induced Ca2+sensitization is through activation of Rho and a subsequent increase in Rho kinase activity but not Ca2+-independent PKC.
Excessive ATP hydrolysis in ischemic myocardium by mitochondrial F1F0-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity
Authors: Grover Gary J. , Atwal Karnail S. , Sleph Paul G. , Wang Feng-Li , Monshizadegan Hossain , Monticello Thomas , Green David W.
Published: September 2004

Mitochondrial F1F0-ATPase normally synthesizes ATP in the heart, but under ischemic conditions this enzyme paradoxically causes ATP hydrolysis. Nonselective inhibitors of this enzyme (aurovertin, oligomycin) inhibit ATP synthesis in normal tissue but also inhibit ATP hydrolysis in ischemic myocardium. We characterized the profile of aurovertin and oligomycin in ischemic and nonischemic rat myocardium and compared this with the profile of BMS-199264, which only inhibits F1F0-ATP hydrolase activity. In isolated rat hearts, aurovertin (1–10 μM) and oligomycin (10 μM), at concentrations inhibiting ATPase activity, reduced ATP concentration and contractile function in the nonischemic heart but significantly reduced the rate of ATP depletion during ischemia. They also inhibited recovery of reperfusion ATP and contractile function, consistent with nonselective F1F0-ATPase inhibitory activity, which suggests that upon reperfusion, the hydrolase activity switches back to ATP synthesis. BMS-199264 inhibits F1F0hydrolase activity in submitochondrial particles with no effect on ATP synthase activity. BMS-199264 (1–10 μM) conserved ATP in rat hearts during ischemia while having no effect on preischemic contractile function or ATP concentration. Reperfusion ATP levels were replenished faster and necrosis was reduced by BMS-199264. ATP hydrolase activity ex vivo was selectively inhibited by BMS-199264. Therefore, excessive ATP hydrolysis by F1F0-ATPase contributes to the decline in cardiac energy reserve during ischemia and selective inhibition of ATP hydrolase activity can protect ischemic myocardium.
Influence of head position on carotid hemodynamics in young adults
Authors: Glor F. P. , Ariff B. , Hughes A. D. , Verdonck P. R. , Barratt D. C. , Augst A. D. , Thom S. A. M. , Xu X. Yun
Published: September 2004

Studies in adults have shown marked changes in geometry and relative positions of the carotid arteries when rotating the head. The aim of this study was to quantify the change in geometry and analyze its effect on carotid hemodynamics as a result of head rotation. The right carotid arteries of nine young adult subjects were investigated in supine position with straight and left turned head positions, respectively. The three-dimensional (3D) carotid geometry was reconstructed by using 3D ultrasound (3D US), and the carotid hemodynamics were calculated by combining 3D US with computational fluid dynamics. It was observed that cross-sectional areas and shapes did not change markedly with head rotation, but carotid vessel center lines altered with planarification of the common carotid artery as a main feature ( P < 0.05). Measured common carotid flow rates changed significantly at the individual level when the head was turned, but on the average, the change in mean common carotid flow rate was relatively small (0.37 ± 1.11 ml/s). The effect of the altered center lines and flow rates on the atherogenic nature of the carotid bifurcation was evaluated by using calculated hemodynamic wall parameters, such as wall shear stress (WSS) and oscillatory shear index (OSI). It was found that WSS and OSI patterns changed significantly with head rotation, but the variations were very subject dependent and could not have been predicted without assessing the altered geometry and flow of the carotid bifurcation for individual cases. This study suggests that there is a need for standardization of the choice of head position in the 3D US scan protocol, and that carotid stents and emboli diverters should be studied in different head positions.
AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure
Authors: Zhu Guo-Qing , Gao Lie , Li Yifan , Patel Kaushik P. , Zucker Irving H. , Wang Wei
Published: September 2004

Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT1R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT1R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT1R mRNA. AT1R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT1R mRNA antisense reduces expression of AT1R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.
Interaction between NO and COX pathways in retinal cells exposed to elevated glucose and retina of diabetic rats
Authors: Du Yunpeng , Sarthy V. P. , Kern T. S.
Published: September 2004

A nonselective inhibitor of cyclooxygenase (COX; high-dose aspirin) and a relatively selective inhibitor of inducible nitric oxide synthase (iNOS; aminoguanidine) have been found to inhibit development of diabetic retinopathy in animals, raising a possibility that NOS and COX play important roles in the development of retinopathy. In this study, the effects of hyperglycemia on retinal nitric oxide (NO) production and the COX-2 pathway, and the interrelationship of the NOS and COX-2 pathways in retina and retinal cells, were investigated using a general inhibitor of NOS [ NG-nitro-l-arginine methyl ester (l-NAME)], specific inhibitors of iNOS [l- N6-(1-iminoethyl)lysine (l-NIL)] and COX-2 (NS-398), and aspirin and aminoguanidine. In vitro studies used a transformed retinal Müller (glial) cell line (rMC-1) and primary bovine retinal endothelial cells (BREC) incubated in 5 and 25 mM glucose with and without these inhibitors, and in vivo studies utilized retinas from experimentally diabetic rats (2 mo) treated or without aminoguanidine or aspirin. Retinal rMC-1 cells cultured in high glucose increased production of NO and prostaglandin E2(PGE2) and expression of iNOS and COX-2. Inhibition of NO production with l-NAME or l-NIL inhibited all of these abnormalities, as did aminoguanidine and aspirin. In contrast, inhibition of COX-2 with NS-398 blocked PGE2production but had no effect on NO or iNOS. In BREC, elevated glucose increased NO and PGE2significantly, whereas expression of iNOS and COX-2 was unchanged. Viability of rMC-1 cells or BREC in 25 mM glucose was significantly less than at 5 mM glucose, and this cell death was inhibited by l-NAME or NS-398 in both cell types and also by l-NIL in rMC-1 cells. Retinal homogenates from diabetic animals produced significantly greater than normal amounts of NO and PGE2and of iNOS and COX-2. Oral aminoguanidine and aspirin significantly inhibited all of these increases. The in vitro results suggest that the hyperglycemia-induced increase in NO in retinal Müller cells and endothelial cells increases production of cytotoxic prostaglandins via COX-2. iNOS seems to account for the increased production of NO in Müller cells but not in endothelial cells. We postulate that NOS and COX-2 act together to contribute to retinal cell death in diabetes and to the development of diabetic retinopathy and that inhibition of retinopathy by aminoguanidine or aspirin is due at least in part to inhibition of this NO/COX-2 axis.
Depressor and bradycardic responses to microinjections of endomorphin-2 into the NTS are mediated via ionotropic glutamate receptors
Authors: Kasamatsu Ken , Chitravanshi Vineet C. , Sapru Hreday N.
Published: September 2004

The presence of endomorphin-like immunoreactivity has been reported in the nucleus tractus solitarius (NTS). It was hypothesized that endomorphins may play a role in cardiovascular regulation in the medial subnucleus of the NTS (mNTS). Endomorphin-2 (E-2, 0.1–4 mmol/l) was microinjected (100 nl) into the mNTS of urethane-anesthetized, artificially ventilated, adult male Wistar rats. E-2 (0.2 mmol/l) elicited decreases in mean arterial pressure (40 ± 3.5 mmHg) and heart rate (50 ± 7.0 beats/min). These responses were blocked by prior microinjections of naloxonazine (1 mmol/l) into the mNTS. Responses to microinjections of E-2 into the mNTS were abolished by prior combined microinjections of d-2-amino-7-phosphonoheptanoic acid (an NMDA receptor antagonist, 5 mmol/l) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[ f]quinoxaline-7-sulfonamide disodium (a non-NMDA receptor antagonist, 2 mmol/l) into the mNTS. These results were confirmed by extracellular neuronal recordings. Blockade of GABA receptors in the mNTS by prior combined microinjections of gabazine (a GABAA receptor antagonist, 2 mmol/l) and 2-hydroxysaclofen (a GABAB receptor antagonist, 100 mmol/l) also blocked the responses to E-2. It was concluded that 1) the depressor and bradycardic responses to microinjections of E-2 into the mNTS are mediated via μ1-opioid receptors as well as ionotropic glutamate receptors, 2) GABAergic neurons in the mNTS, which may inhibit the release of glutamate from nerve terminals, are inhibited by E-2 via μ1-opioid receptors, and 3) disinhibition caused by the inhibition of GABAergic neurons by E-2 may result in an increase in the glutamate release from nerve terminals, which, in turn, may elicit depressor and bradycardic responses.
Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats
Authors: Ling Pei-Ra , Smith Robert J. , Kie Susanne , Boyce Patricia , Bistrian Bruce R.
Published: September 2004

This study examines the effects of malnutrition on IL-6 signaling pathways of rats fed 2% vs. 20% casein diets for 14 days. Effects of malnutrition on the abundance and IL-6-stimulated phosphorylation of signaling proteins in the JAK-STAT and MAP kinase pathways were examined in the liver. Changes of the acute-phase response as reflected by serum α1-acid glycoprotein (AG), TNF-α (TNF), and IL-1β (IL-1) were compared in the two dietary groups at 0, 4, 8, 16, and 24 h after IL-6 administration. Under basal conditions, the abundance of the IL-6 receptor, gp130, JAK1, STAT1, and STAT3 proteins and levels of phosphorylation of ERK1/2 and p38 were significantly increased in the liver in the 2% casein group compared with the 20% casein group. With IL-6 stimulation, the increased phosphorylation per unit of protein of these signaling proteins was not different in the liver between the two groups. Before IL-6 stimulation, serum levels of TNF, IL-1, IL-6, and AG were significantly higher in the 2% casein group than in the 20% casein group. After bolus injection of IL-6, changes in IL-1 and AG were similar in the two dietary groups, although a slight decline in AG level was noted after 8 h of IL-6 administration in the 2% protein group. These data demonstrate that protein malnutrition produces changes in inflammation-related proteins characteristic of a low-grade systemic inflammatory response and, thus, can serve as an inflammatory stimulus. The capacity for response to IL-6 is preserved, suggesting adaptive preservation of acute-phase responsiveness during malnutrition.
Angiotensin II-dependent induction of AT2receptor expression after renal ablation
Authors: Vázquez Erika , Coronel Israel , Bautista Rocio , Romo Eunice , Villalón Carlos M. , Avila-Casado M. Carmen , Soto Virgilia , Escalante Bruno
Published: September 2004

Angiotensin (ANG) II can be associated with gene expression regulation. Thus we studied the possible role of ANG II in the regulation of AT2mRNA and protein expression. We utilized sham-operated renal ablation rats as well as renal ablation rats pretreated during the first 7 days of the development of renal damage with either the angiotensin-converting inhibitor ramipril, the AT1receptor antagonist losartan, or the AT2receptor antagonist PD-123319. Renal tissue was analyzed for histological changes and expression of AT2receptor mRNA (by RT-PCR) and protein (by immunohistochemistry). To explore the physiological role of AT2receptor overexpression in the development of renal damage, blood pressure, urinary protein excretion, and renal damage were evaluated. A time-dependent increase in the expression of AT2receptor mRNA and protein was observed at 7, 15, and 30 days after renal ablation. Because these effects were already evident at day 7, the effects of ramipril, losartan, or PD-123319 were tested at this time. The ramipril group and the PD-123319-pretreated group showed inhibition of AT2receptor expression, whereas the losartan-pretreated group showed a further increase in AT2receptor expression. Inhibition of the AT2receptor during renal ablation was associated with increased renal damage and a further increase in the blood pressure. This suggests that overexpression of AT2receptors after renal ablation is modulated by ANG II through its own AT2receptor and that functional expression of this effect may represent a counterregulatory mechanism to modulate the renal damage induced by renal ablation.
Transepithelial pressure pulses induce nucleotide release in polarized MDCK cells
Authors: Praetorius H. A. , Frøkiær J. , Leipziger J.
Published: September 2004

The release of nucleotides is involved in mechanosensation in various epithelial cells. Intriguingly, kidney epithelial cells are absolutely dependent on the primary cilium to sense changes in apical laminar flow. During fluid passage, the renal epithelial cells are subjected to various mechanical stimuli in addition to changes in the laminar flow rate. In the distal part of the collecting duct, the epithelial cells are exposed to pressure changes and possibly distension during papillary contractions. The aim of the present study was to determine whether nucleotide release contributes to mechanosensation in kidney epithelial cells, thereby establishing whether pressure changes are sufficient to produce nucleotide-mediated responses. Madin-Darby canine kidney (MDCK) cells grown on permeable supports were mounted in a closed double perfusion chamber on an inverted microscope. The intracellular Ca2+ concentration ([Ca2+]i) was monitored with the Ca2+-sensitive fluorescence probe fluo 4. Transepithelial pressure pulses of 30–80 mmHg produced a transient increase in [Ca2+]i of MDCK cells. This response is independent of the primary cilium, since it is readily observed in immature cells that do not yet express primary cilia. The amplitudes of the pressure-induced Ca2+ transients varied with the applied chamber pressure in a quantity-dependent manner. The ATPase apyrase and the P2Y antagonist suramin significantly reduced the pressure-induced Ca2+ transients. Applying apyrase or suramin to both sides of the preparation simultaneously nearly abolished the pressure-induced Ca2+ response. In conclusion, these observations suggest that rapid pressure changes induce both apical and basolateral nucleotide release that contribute to mechanosensation in kidney epithelial cells.
Enhancer-dependent inhibition of mouse renin transcription by inflammatory cytokines
Authors: Pan Li , Wang Yanping , Jones Craig A. , Glenn Sean T. , Baumann Heinz , Gross Kenneth W.
Published: September 2004

Inflammatory cytokines have been shown to inhibit renin gene expression in the kidney in vivo and the kidney tumor-derived As4.1 cell line. In this report, we show that cytokines oncostatin M (OSM), IL-6, and IL-1β inhibit transcriptional activity associated with 4.1 kb of the mouse renin 5′-flanking sequence in As4.1 cells. The 242-bp enhancer (−2866 to −2625 bp) is sufficient to mediate the observed inhibitory effects. Sequences within the enhancer required for inhibition by each of these cytokines have been determined by deletional and mutational analysis. Results indicate that a 39-bp region (CEC) containing a cAMP-responsive element, an E-box, and a steroid receptor-binding site, previously identified as the most critical elements for enhancer activity, is sufficient for the inhibition induced by IL-1β. However, mutation of each of the three component sites does not abolish the inhibition by IL-1β, suggesting that the target(s) of cytokine action may not be the transcription factors binding directly to these sites. This CEC region is also critical, but not sufficient, for the inhibition mediated by OSM and IL-6. These data suggest that the direct target of the associated cytokines may be coactivators interacting with transcription factors binding at the enhancer. Finally, we show that OSM treatment caused a 17-fold increase in promoter activity when only 2,625 bp of the Ren-1cflanking sequence were tested, in which the enhancer is not present. Three regions including −2625 to −1217 bp, the HOX·PBX binding site at −60 bp, and −59 to +6 bp have been found to contribute to this induction.
Spatial Overlap of on and off Subregions and Its Relation to Response Modulation Ratio in Macaque Primary Visual Cortex
Authors: Mata Mario L. , Ringach Dario L.
Published: September 2004

We studied the spatial overlap of on and off subregions in macaque primary visual cortex and its relation to the response modulation ratio (the F1/ F0 ratio). Spatial maps of on and off subregions were obtained by reverse correlation with a dynamic noise pattern of bright and dark spots. Two spatial maps, on and off, were produced by cross-correlating the spike train with the location of bright and dark spots in the stimulus respectively. Several measures were used to assess the degree of overlap between subregions. In a subset of neurons, we also computed the F1/ F0 ratio in response to drifting sinusoidal gratings. Significant correlations were found among all the overlap measures and the F1/ F0 ratio. Most overlap indices considered, and the F1/ F0 measure, had bimodal distributions. In contrast, the distance between on and off subregions normalized by their size was unimodal. Surprisingly, a simple model that additively combines on and off subregions with spatial separations drawn from a unimodal distribution, can readily explain the data. These analyses clarify the relationship between subregion overlap and the F1/ F0 ratio in macaque primary visual cortex, and a simple model provides a parsimonious explanation for the co-existence of bimodal distributions of overlap indices and a unimodal distribution of the normalized distance.
Sympathetic Modulation of Activity in Aδ- and C-Primary Nociceptive Afferents After Intradermal Injection of Capsaicin in Rats
Authors: Ren Yong , Zou Xiaoju , Fang Li , Lin Qing
Published: September 2004

Neuropathic and inflammatory pain can be modulated by the sympathetic nervous system. In some pain models, sympathetic postganglionic efferents are involved in the modulation of nociceptive transmission in the periphery. The purpose of this study is to examine the sensitization of Aδ- and C-primary afferent nociceptors induced by intradermal injection of capsaicin (CAP) to see whether the presence of sympathetic efferents is essential for the sensitization. Single primary afferent discharges were recorded from the tibial nerve after the fiber types were identified by conduction velocity in anesthetized rats. An enhanced response of some Aδ- and most C-primary afferent fibers to mechanical stimuli was seen in sham-sympathectomized rats after CAP (1%, 15 μl) injection, but the enhanced responses of both Aδ- and C-fibers were reduced after sympathetic postganglionic efferents were removed. Peripheral pretreatment with norepinephrine by intraarterial injection could restore and prolong the CAP-induced enhancement of responses under sympathectomized conditions. In sympathetically intact rats, pretreatment with an α1-adrenergic receptor antagonist (terazosin) blocked completely the enhanced responses of C-fibers after CAP injection in sympathetically intact rats without significantly affecting the enhanced responses of Aδ-fibers. In contrast, a blockade of α2-adrenergic receptors by yohimbine only slightly reduced the CAP-evoked enhancement of responses. We conclude that the presence of sympathetic efferents is essential for the CAP-induced sensitization of Aδ- and C-primary afferent fibers to mechanical stimuli and that α1-adrenergic receptors play a major role in the sympathetic modulation of C-nociceptor sensitivity in the periphery.
Properties of Cerebellar Fastigial Neurons During Translation, Rotation, and Eye Movements
Authors: Shaikh Aasef G. , Ghasia Fatema F. , Dickman J. David , Angelaki Dora E.
Published: September 2004

The most medial of the deep cerebellar nuclei, the fastigial nucleus (FN), receives sensory vestibular information and direct inhibition from the cerebellar vermis. We investigated the signal processing in the primate FN by recording single-unit activities during translational motion, rotational motion, and eye movements. Firing rate modulation during horizontal plane translation in the absence of eye movements was observed in all non-eye-movement-sensitive cells and 26% of the pursuit eye-movement-sensitive neurons in the caudal FN. Many non-eye-movement-sensitive cells recorded in the rostral FN of three fascicularis monkeys exhibited convergence of signals from both the otolith organs and the semicircular canals. At low frequencies of translation, the majority of these rostral FN cells changed their firing rates in phase with head velocity rather than linear acceleration. As frequency increased, FN vestibular neurons exhibited a wide range of response dynamics with most cells being characterized by increasing phase leads as a function of frequency. Unlike cells in the vestibular nuclei, none of the rostral FN cells responded to rotational motion alone, without simultaneously exhibiting sensitivity to translational motion. Modulation during earth-horizontal axis rotation was observed in more than half (77%) of the neurons, although with smaller gains than during translation. In contrast, only 47% of the cells changed their firing rates during earth-vertical axis rotations in the absence of a dynamic linear acceleration stimulus. These response properties suggest that the rostral FN represents a main processing center of otolith-driven information for inertial motion detection and spatial orientation.
The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades
Authors: Björkbacka Harry , Fitzgerald Katherine A. , Huet François , Li Xiaoman , Gregory James A. , Lee Melinda A. , Ordija Christine M. , Dowley Nicole E. , Golenbock Douglas T. , Freeman Mason W.
Published: September 2004

Myeloid differentiation protein-88 (MyD88) is a signal adaptor protein required for cytokine production following engagement of Toll-like receptors (TLRs) by their cognate ligands. Activation of both TLR-3 and TLR-4, however, can engage signaling events independent of MyD88 expression. The relative importance of these MyD88-dependent and -independent signaling pathways in the macrophage response to lipopolysaccharide (LPS) is unknown. Here we define these events using microarray expression profiling of LPS-stimulated macrophages taken from MyD88-null and wild-type mice. Of the 1,055 genes found to be LPS responsive, only 21.5% were dependent on MyD88 expression, with MyD88-independent genes constituting 74.7% of the genetic response. This MyD88-independent gene expression was predominantly transcriptionally regulated, as it was unaffected by cycloheximide blockade of new protein synthesis. A previously undescribed group of LPS-regulated genes (3.8%), whose induction or repression was significantly greater in the absence of MyD88, was also identified by these studies. The regulation of these genes suggested that MyD88 could serve as a molecular brake, constraining gene activity in a subset of LPS-responsive genes. The findings generated with LPS stimulation were recapitulated by exposure of macrophages to live Escherichia coli. These expression-profiling studies redefine the current dogma of TLR-4 signaling and establish that MyD88, although essential for some of the best-characterized macrophage responses to LPS, is not required for the regulation of the majority of genes engaged by macrophage exposure to endotoxin or live bacteria.
Functional allelic heterogeneity and pleiotropy of a repeat polymorphism in tyrosine hydroxylase: prediction of catecholamines and response to stress in twins
Authors: Zhang Lian , Rao Fangwen , Wessel Jennifer , Kennedy Brian P. , Rana Brinda K. , Taupenot Laurent , Lillie Elizabeth O. , Cockburn Myles , Schork Nicholas J. , Ziegler Michael G. , O’Connor Daniel T.
Published: September 2004

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, has a common tetranucleotide repeat polymorphism, (TCAT)n. We asked whether variation at (TCAT)nmay influence the autonomic nervous system and its response to environmental stress. To understand the role of heredity in such traits, we turned to a human twin study design. Both biochemical and physiological autonomic traits displayed substantial heritability (h2), up to h2= 56.8 ± 7.5% ( P < 0.0001) for norepinephrine secretion, and h2= 61 ± 6% ( P < 0.001) for heart rate. Common (TCAT)nalleles, particularly (TCAT)6and (TCAT)10i, predicted such traits (including catecholamine secretion, as well as basal and poststress heart rate) in allele copy number dose-dependent fashion, although in directionally opposite ways, indicating functional allelic heterogeneity. (TCAT)ndiploid genotypes (e.g., [TCAT]6/[TCAT]10i) predicted the same physiological traits but with increased explanatory power for trait variation (in contrast to allele copy number). Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)10iallele on both biochemical (norepinephrine) and physiological (heart rate) traits. (TCAT)6allele frequencies were lower in normotensive twins at genetic risk of hypertension, consistent with an effect to protect against later development of hypertension, and suggesting that the traits predicted by these variants in still-normotensive subjects are early, heritable, “intermediate phenotypes” in the pathogenetic scheme for later development of sustained hypertension. We conclude that common allelic variation within the tyrosine hydroxylase locus exerts a powerful, heritable effect on autonomic control of the circulation and that such variation may have implications in later development of cardiovascular disease traits such as hypertension.
Vector dissipativity theory for large‐scale impulsive dynamical systems
Authors: Haddad Wassim M. , Chellaboina VijaySekhar , Hui Qing , Nersesov Sergey
Published: September 2004

Modern complex large‐scale impulsive systems involve multiple
modes of operation placing stringent demands on controller
analysis of increasing complexity. In analyzing these large‐scale
systems, it is often desirable to treat the overall impulsive
system as a collection of interconnected impulsive subsystems.
Solution properties of the large‐scale impulsive system are then
deduced from the solution properties of the individual impulsive
subsystems and the nature of the impulsive system
interconnections. In this paper, we develop vector dissipativity
theory for large‐scale impulsive dynamical systems. Specifically,
using vector storage functions and vector hybrid supply rates,
dissipativity properties of the composite large‐scale impulsive
systems are shown to be determined from the dissipativity
properties of the impulsive subsystems and their
interconnections. Furthermore, extended Kalman‐Yakubovich‐Popov
conditions, in terms of the impulsive subsystem dynamics and
interconnection constraints, characterizing vector
dissipativeness via vector system storage functions, are derived.
Finally, these results are used to develop feedback
interconnection stability results for large‐scale impulsive
dynamical systems using vector Lyapunov functions.
Localization of periodic orbits of autonomous systems based on high‐order extremum conditions
Authors: Starkov Konstantin E.
Published: September 2004

This paper gives localization and nonexistence conditions of
periodic orbits in some subsets of the state space. Mainly, our
approach is based on high‐order extremum conditions, on
high‐order tangency conditions of a nonsingular solution of a
polynomial system with an algebraic surface, and on some ideas
related to algebraically‐dependent polynomials. Examples of the
localization analysis of periodic orbits are presented including
the Blasius equations, the generalized mass action (GMA) system,
and the mathematical model of the chemical reaction with
autocatalytic step.
A hybrid neural network model for the dynamics of the Kuramoto‐Sivashinsky equation
Authors: Smaoui Nejib
Published: September 2004

A hybrid approach consisting of two neural networks is used to
model the oscillatory dynamical behavior of the
Kuramoto‐Sivashinsky (KS) equation at a bifurcation parameter
α = 84.25. This oscillatory behavior results from a fixed
point that occurs at α = 72
having a shape of two‐humped
curve that becomes unstable and undergoes a Hopf bifurcation at
α = 83.75. First, Karhunen‐Loève (KL) decomposition was
used to extract five coherent structures of the oscillatory
behavior capturing almost 100% of the energy. Based on the five
coherent structures, a system offive ordinary differential
equations (ODEs) whose dynamics is similar to the original
dynamics of the KS equation was derived via KL Galerkin
projection. Then, an autoassociative neural network was utilized
on the amplitudes of the ODEs system with the task of reducing
the dimension of the dynamical behavior to its intrinsic
dimension, and a feedforward neural network was usedto model
the dynamics at a future time. We show that by combining KL
decomposition and neural networks, a reduced dynamical model of
the KS equation is obtained.
A dynamic programming algorithm for the bufferallocation problem in homogeneous asymptotically reliable serial production lines
Authors: Diamantidis A. C. , Papadopoulos C. T.
Published: September 2004

In this study, the buffer allocation problem (BAP) in
homogeneous, asymptotically reliable serial production lines is
considered. A known aggregation method, given by Lim, Meerkov, and
Top (1990), for the performance evaluation (i.e., estimation of
throughput) of this type of production lines when the buffer
allocation is known, is used as an evaluative method in
conjunction with a newly developed dynamic programming (DP)
algorithm for the BAP. The proposed algorithm is applied to
production lines where the number of machines is varying
from four
up to a hundred machines. The proposed algorithm is fast because
it reduces the volume of computations by rejecting allocations
that do not lead to maximization of the line′s throughput.
Numerical results are also given for large production lines.
Access control for MPEG video applications using neural network and simulated annealing
Authors: Ahmed N. U. , Yan Hong
Published: September 2004

We present a dynamic modelfor access control mechanism used in
computer communication network applied to MPEG video transmission
over Internet. This modelis different fromthosedeveloped
inthe previous works related to this topic. In our
model, token buckets supported by data buffersare used to shape
incoming traffic and one multiplexor, serving all the token
pools, multiplexes all theconforming
traffic. The model is governed by a system of discrete nonlinear
difference equations. Weuse neural network as the feedback
controller which receives at its input (measurable) available
information and provides at its output the optimal control. The
simulated annealing algorithm isusedto optimize the system
performance by adjusting the weights. For illustration, we
presentnumerical results which show that the system performance
of MPEG video server can be improved by using neural network and
simulated annealing approach.
An analytical solution of the generalized equation of energy transport in one‐dimensional semi‐infinite domains
Authors: Kulish Vladimir V.
Published: September 2004

This paper presents an integral solution of the
generalized one‐dimensional equation of energy transport
with the convective term.The solution of the problem has been
achieved by the use of a novel technique that involves
generalized derivatives (in particular, derivatives of noninteger
orders). Confluent hypergeometric functions, known as Whittaker′s
functions, appear in the course of the solution procedure upon
applying the Laplace transform to the original transport
equation.The analytical solution of the problem is written in
the integral form and provides a relationship between the
local values of the transported property (e.g.,
temperature, mass, momentum, etc.) and its flux.The solution is
valid everywhere within the domain, including the domain boundary.
Optimum feedback strategy for access control mechanism modelled as stochastic differential equation in computer network
Authors: Ahmed N. U. , Li Cheng
Published: September 2004

We consider optimum feedback control strategy for computer
communication network, in particular, the access control
mechanism. The dynamic model
representing the source and the access control system is
described by a system of stochastic differential equations
developed in our previous works. Simulated annealing (SA) was used
to optimize the parameters of the control law based on neural
network. This technique was found to be computationally
intensive. In this paper, we have proposed to use a more powerful
algorithm known as recursive random search (RRS). By using this
technique, we have been able to reduce the computation time by a
factor of five without compromising the optimality. This is very
important for optimization of high‐dimensional systems serving a
large number of aggregate users. The results show that the
proposed control law can improve the network performance by
improving throughput, reducing multiplexor and TB losses, and
relaxing, not avoiding, congestion.
Robust control of discrete‐time hybrid systems with uncertain modal dynamics
Authors: Runolfsson Thordur
Published: September 2004

We study systems that are subject to sudden structural changes
due to either changes in the operational mode of the system or
failure. We consider linear dynamicalsystems that depend on a
modal variable which is either modeled as a finite‐state Markov
chain or generated by an automaton that is subject to an external
disturbance. In the Markov chain case, the objective of the
control is to minimize a risk‐sensitive cost functional. The
risk‐sensitive cost functional measures the risk sensitivity of
the system to transitions caused by the random modal variable. In
the case when a disturbed automaton describes the modal variable,
the objective of the control is to make the system as robust to
changes in the external disturbance as possible. Optimality
conditions for both problems are derived and it is shown that the
disturbance rejection problem is closely related to a certain
risk‐sensitive control problem for the hybrid system.
Cocaine Use in Europe – A Multi-Centre Study
Authors: Haasen Christian , Prinzleve Michael , Zurhold Heike , Rehm Juergen , Güttinger Franziska , Fischer Gabriele , Jagsch Reinhold , Olsson Börje , Ekendahl Mats , Verster Annette , Camposeragna Antonella , Pezous Anne-Marie , Gossop Michael , Manning Victoria , Cox Gemma , Ryder Niamh , Gerevich Jozsef , Bacskai Erika , Casas Miguel , Matali Josep Lluis , Krausz Michael
Published: September 2004

An increase in the use of cocaine and crack in several parts of Europe has raised the question whether this trend is similar to that of the USA in the 1980s. However, research in the field of cocaine use in Europe has been only sporadic. Therefore, a European multi-centre and multi-modal project was designed to study specific aspects of cocaine and crack use in Europe, in order to develop guidelines for public health strategies. Data on prevalence rates were analysed for the general population and for specific subgroups. Despite large differences between countries in the prevalence of cocaine use in the general population, most countries show an increase in the last few years. The highest rate with a lifetime prevalence of 5.2% was found for the United Kingdom, although with a plateau effect around the year 2000. With regard to specific subgroups, three groups seem to show a higher prevalence than the general population: (1) youth, especially in the party scene; (2) socially marginalized groups, such as homeless and prostitutes or those found in open drug scenes; (3) opiate-dependent patients in maintenance treatment who additionally use cocaine. Specific strategies need to be developed to address problematic cocaine use in these subgroups.