bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of MX-68 on airway inflammation and hyperresponsiveness in mice and guinea-pigs
Authors: Nagao Koichi , Akabane Hirotomo , Masuda Taisei , Komal Masato , Tanaka Hiroyuki , Nagai Hiroichi
Published: February 2004

MX-68 is a newly synthesized antifolate, which is a derivative of methotrexate (MTX). In this paper, the effect of MX-68 on allergic airway responses in mice and guinea-pigs was studied. In the first experiment, antigen-induced airway inflammation and airway hyperresponsiveness (AHR) to acetylcholine in mice were examined and compared with the effects of classical antifolate methotrexate and prednisolone. Mice were sensitized with ovalbumin as an antigen and challenged with ovalbumin inhalation three times. After the last inhalation, AHR and airway inflammation were observed. An increase in Th2 cytokines (IL-4 and IL-5) and a decrease in a Th1 cytokine (IFN-γ) in the bronchoalveolar lavage fluid (BALF), as well as an elevation of the immunoglobulin level in serum, were observed in sensitized mice. Oral administration of MX-68 had no effect on changes of body weight, but prednisolone reduced body weight during the experiment. The antigen-induced AHR and increases in the number of eosinophils and lymphocytes in BALF were significantly inhibited by MX-68. MX-68 interfered with the elevation of IL-4 and IL-5 levels in BALF, but had no effect on the decrease in IFN-γ. Moreover, MX-68 significantly inhibited the elevation of serum IgE and IgG levels. In the guinea-pig model for bronchial asthma, biphasic increases in airway resistance (immediate asthmatic response, IAR, and late asthmatic response, LAR), as well as accumulated inflammatory cells in BALF, were observed after repeated antigen challenge. These asthmatic responses and inflammatory signs were significantly decreased by administration of MX-68. These results suggest that MX-68 obviously has an anti-inflammatory effect in an animal model of asthma and would be useful clinically for the treatment of bronchial asthma.
Pharmacological characterization and identification of EP3 prostanoid receptor binding sites in hamster uterus homogenates
Authors: Sharif N A , Xu S X
Published: February 2004

The pharmacological properties of [3H]-prostaglandin E2 ([3H]-PGE2) binding to washed homogenates of hamster uterus were determined. Scatchard analysis of competition data yielded dissociation constants (Kds) of 30.9 + 5.6 nm (n = 3) and apparent receptor density (Bmax) of 25.25 + 1.89 pmol g−1 wet weight tissue (74 + 8% specific binding). Competition studies yielded the following affinity parameters (Ki) for various prostanoids: GR63799X = 13 + 4 nm; PGE2 = 17 + 3 nm; sulprostone = 64 + 5 nm; enprostil = 67 + 3 nm; misoprostol = 124 + 15 nm; cloprostenol = 187 + 33 nm; carba-prostacyclin = 260 + 167 nm; iloprost = 555 + 162 nm; PGF2α = 767 + 73 nm; PGD2 > 3560 nm; fluprostenol = 11790 + 2776 nm; RS93520 = 21 558 + 14228 nm. These data closely matched the pharmacological profile of previously described EP3 receptors such as in bovine corpus luteum (BCLM) and the cloned mammalian EP3 receptors. The high correlation between the current hamster uterus pharmacology data vs the EP3 receptor binding in BCLM (r = 0.94; P < 0.0001), vs cloned human EP3 receptor (r = 0.94, P < 0.0001), vs the cloned mouse EP3 receptor binding (r = 0.78; P < 0.002), vs cloned rat EP3 receptor (r = 0.9, P < 0.0004), and vs EP3 receptor-mediated functional responses (r = 0.72, P < 0.02) substantiated the conclusion that the hamster uterus contains EP3 receptor binding sites.
The effect of repeat dosing with cimetidine on the pharmacokinetics of intravenous granisetron in healthy volunteers
Authors: Youlten Lawrence
Published: February 2004

The primary route of elimination of granisetron is by oxidative hepatic metabolism, thus its pharmacokinetic profile may be altered by co-administration of other drugs that inhibit or induce hepatic drug metabolizing enzymes. This open-label study investigated the effect of inhibition of cimetidine, a potent inhibitor of CYP1A2, CYP2D6 and CYP3A4, on the pharmacokinetic profile of intravenous granisetron in healthy male volunteers. Subjects (n = 12; 18–60 years) received granisetron (40 μg kg−1) infused over 3 min, six days before and on the eighth day of dosing with cimetidine (200 mg, four times a day). Blood samples were taken for pharmacokinetic analysis at intervals over 48 h following the administration of each dose of granisetron. Clinical chemistry, haematology and urinalysis were performed before, and 24 h after, each infusion. Electrocardiogram (ECG), resting blood pressure (BP) and pulse were monitored. There were no significant changes in the ECG, lead II trace or ECG time intervals, pulse or blood pressure on each study day. Minor falls in pulse rate and BP (likely to be related to recumbent posture) were seen during both granisetron dosing days, lasting 2 h after each infusion. No significant changes were apparent in the clinical chemistry, haematology or urinalysis measurements following granisetron dosing. No pharmacokinetic parameters measured after cimetidine administration were significantly different from those taken before. Adverse events were mild-to-moderate in severity and were similar to those reported in other studies with granisetron. The pharmacokinetics of granisetron, when administered as a single dose, appeared to be unaltered by cimetidine, an inhibitor of multiple hepatic enzymes (CYP1A2, CYP2D6 and CYP3A4). Granisetron was equally well tolerated before and after repeated dosing with cimetidine.
Studies on 1-arylpiperazine derivatives with affinity for rat 5-HT7 and 5-HT1A receptors
Authors: Leopoldo Marcello , Berardi Francesco , Colabufo Nicola A , Contino Marialessandra , Lacivita Enza , Perrone Roberto , Tortorella Vincenzo
Published: February 2004

Several 1-aryl-4-(2-arylethyl)piperazine derivatives were synthesized and tested in-vitro for their binding affinity for 5-HT7 and 5-HT1A receptors. These compounds displayed 5-HT7 receptor affinity ranging between Ki = 474 nm and Ki = 8.2 nm, besides high affinity for the 5-HT1A receptor. Intrinsic activity of the most potent compounds was assessed. 4-[2-(3-Methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine (16) and 1-(1,2-benzisoxazol-3-yl)-4-[2-(3-methoxyphenyl)ethyl]piperazine (20) (Ki = 24.5 and 8.2 nm, respectively) behaved as partial agonist and full agonist, respectively, when tested for 5-HT7 receptor-mediated relaxation of substance P-induced guinea-pig ileum contraction.
Biodistribution and safety studies of hDel-1 plasmid-based gene therapy in mouse and rabbit models
Authors: Quezada A , French M , Perrard J , Durland R , Coleman M , Larson J , Ponce R
Published: February 2004

A plasmid encoding the human developmentally regulated endothelial locus-1 (hDel-1) protein formulated with poloxamer 188 is a potential gene therapy for peripheral arterial disease in man. As a prelude to clinical trials, the biodistribution and safety of this therapy were evaluated after intramuscular and intravenous administration in mice and rabbits. In mice, plasmid DNA persisted at the intramuscular injection site for at least 28 days, but was barely detectable in distal tissues by 24 h and essentially cleared by 28 days. By 24 h after intravenous administration, plasmid DNA was readily detected in blood, muscle, and lungs but sporadically and at low levels in other tissues. At 28 days, plasmid DNA was readily detectable only at the intravenous injection site (tail) after low- and high-dose administration, and sporadically in blood and muscle after high-dose administration. In rabbits, the highest intramuscular (4.2 mg kg−1) or intravenous (3.7 mg kg−1) dose caused no deaths; no treatment-related clinical signs; no changes in body weight, clinical pathology parameters, ophthalmology, ECG, or histopathology; and no detectable increase in antinuclear antibodies by 28 days. The results supported testing of hDel-1 plasmid-based gene therapy in phase I clinical trials.
The effects of imidazoline agents on the aggregation of human platelets
Authors: Pinthong Darawan , Songsermsakul Piyada , Rattanachamnong Piyanee , Kendall David A
Published: February 2004

Clonidine (2-[(2, 6-dichlorophenyl)amino]-2-imidazoline), an imidazoline α2-adrenoceptor agonist, is known to exert complex effects on human platelet aggregation distinct from those of the catecholamines, which are non-imidazoline α-adrenoceptor agonists. This study has investigated the aggregatory/anti-aggregatory effects of various imidazolines on human platelets. Blood samples were taken from normal volunteers and platelet aggregation was assessed by a turbidimetric method using a Chronolog aggregometer. Noradrenaline (2 μm) and adenosine diphosphate (1 μm) were used as aggregating agents. The results showed that, with the exception of moxonidine, all of the imidazoline agents used (with or without α2-adrenoceptor activity) were able to inhibit noradrenaline-induced platelet aggregation. Compared with the non-imidazoline α2-adrenergic antagonist, yohimbine, the rank order of potency was: efaroxan (IC50 = 3.07 times 10−8  m) > idazoxan (IC50 = 1.74 times 10−7  m) > tolazoline (IC50 = 3.90 times 10−7  m) > clonidine (IC50 = 1.49 times 10−6  m) ≅ antazoline (IC50 = 1.77 times 10−6  m) > yohimbine (IC50 = 3.19 times 10−6  m) > rilmenidine (IC50 = 1.27 times 10−5  m) > moxonidine (IC50 > 10−4  m). Clonidine-displacing substance (CDS), a putative endogenous ligand at imidazoline receptors, was found to inhibit noradrenaline-induced platelet aggregation. Harmane, norharmane and agmatine, putative candidates for the active principle of CDS, had no effect on noradrenaline-induced platelet aggregation. In contrast to noradrenaline-induced aggregation, ADP-induced platelet aggregation was neither potentiated nor inhibited by the imidazoline agents, with the exceptions of clonidine and moxonidine. In conclusion, most imidazoline agents effectively inhibit noradrenaline-induced human platelet aggregation. The lack of effect of moxonidine and the proposed endogenous ligands suggested this effect was mediated by an ‘atypical’ non-adrenoceptor imidazoline-binding site. The results indicated an anti-aggregatory role of imidazoline compounds on noradrenaline-induced human platelet aggregation. In addition, CDS might be an endogenous modulator that prevented platelet hyper-reactivity to catecholamine stimulation.
(–)-Epicatechin 3-O-gallate ameliorates the damages related to peroxynitrite production by mechanisms distinct from those of other free radical inhibitors
Authors: Yokozawa Takako , Rhyu Dong Young , Cho Eun Ju
Published: February 2004

This study was carried out to elucidate whether the protective activity of (–)-epicatechin 3-O-gallate (ECg) against excessive peroxynitrite (ONOO−) production, is distinct from the activity of several well-known free radical inhibitors, the ONOO− inhibitors ebselen and uric acid, the superoxide anion (O2−) scavenger copper zinc superoxide dismutase (CuZnSOD) and the selective inducible nitric oxide synthase inhibitor l-N6-(1-iminoethyl)lysine hydrochloride (l-NIL). To generate ONOO−, male Wistar rats (n = 6/group) were subjected to ischaemia–reperfusion process together with lipopolysaccharide (LPS) injection. Although ECg did not scavenge the ONOO− precursors nitric oxide (NO) and O2−, it reduced the 3-nitrotyrosine level, a property similar to that of uric acid, but distinct from l-NIL. In addition, the elevation in myeloperoxidase activity was reversed by the administration of ECg, uric acid and SOD, but not by that of l-NIL. Furthermore, ECg was the more potent scavenger of the ONOO− decomposition product, the hydroxyl radical (·OH), than any other free radical inhibitor tested. The LPS plus ischaemia–reperfusion process resulted in renal dysfunction, estimated by measuring the parameters of renal function – serum urea nitrogen and creatinine levels. However, administration of ECg ameliorated renal dysfunction more than that of the other free radical inhibitors. Moreover, ECg reduced the excessive uric acid level, while the others did not, suggesting a property of ECg distinct from the others. Furthermore, proteinuria, which was demonstrated by the low- and high-molecular weight (LMW and HMW) protein bands of the sodium dodecyl sulfate-polyacrylamide gel electrophoresis pattern, caused by LPS plus ischaemia–reperfusion, was attenuated by administration of ECg and l-NIL, after which the HMW band intensities decreased and LMW protein bands were absent. This study indicates that, in an in-vivo model of ONOO− generation, ECg, l-NIL and uric acid exert stronger protective activity against ONOO−-induced oxidative damage than SOD and ebselen, and that the mechanism whereby ECg protects against ONOO− is distinct from that of l-NIL or uric acid.
In-vitro anti-inflammatory effect of Eucalyptus globulus and Thymus vulgaris: nitric oxide inhibition in J774A.1 murine macrophages
Authors: Vigo E , Cepeda A , Perez-Fernandez R , Gualillo O
Published: February 2004

It is well known that nitric oxide (NO) plays an important role in the pathogenesis of inflammatory diseases. Eucalyptus globulus Labill. and Thymus vulgaris L. have been used in traditional medicine in the treatment of bronchitis, asthma and other respiratory diseases. The present study focuses on the effects of these two extracts on NO production induced by lipopolysaccharide (LPS) and interferon-γ (IFN-γ) in the murine macrophage cell line J774A.1. In addition, cell viability, scavenging activity and inducible nitric oxide synthase (iNOS) mRNA expression were evaluated. E. globulus and T. vulgaris extracts significantly inhibited the enhanced production of NO induced by LPS and IFN-γ in a dose-dependent manner. Treatment with these two extracts did not reduce cell viability at any dose used. Both plant extracts showed significant scavenging of NO radicals released by an NO donor, PAPANONOate. Results also show that pre-treatment with E. globulus and T. vulgaris extracts significantly inhibits iNOS mRNA expression. This study thus suggests that the inhibition of net NO production by these two extracts may be due to their NO scavenging activity and/or their inhibitory effects on iNOS gene expression.
Anti-tussive activity of benproperine enantiomers on citric-acid-induced cough in conscious guinea-pigs
Authors: Chen Siwei , Min Li , Li Weijing , Kong Weixi , Li Yan , Zhong Dafang
Published: February 2004

The anti-tussive effect of the R-(+)- and S-(-)-enantiomers of benproperine was evaluated and compared with that of the racemate on cough induced by 7.5% citric acid in conscious guineapigs. All the three compounds, intraperitoneally administered 1.5 h before the test, significantly inhibited citric-acid-induced cough. The ID50 values (effective doses for 50% inhibition) (with 95% confidence intervals) were 16.1 (9.1–28.4), 23.3 (11.2–48.6), 25.4 (11.7–55.1) mg kg−1 for the number of coughs in the 3 min of challenge, and 11.9 (5.3–26.6), 13.5 (5.6–32.4), 19.2 (12.8–28.9) mg kg−1 for the number of coughs in the 5 min immediately after the challenge, for (+)-benproperine, R-(+)-benproperine and S-(-)-benproperine, respectively. These findings suggest that the use of either enantiomer does not show any advantage over the racemate with regard to their anti-tussive effect.
The importance of gel properties for mucoadhesion measurements: a multivariate data analysis approach
Authors: Hägerström Helene , Bergström Christel A S , Edsman Katarina
Published: February 2004

In this study we used tensile strength measurements and a recently developed interpretation procedure to evaluate the mucoadhesive properties of a large set of gel preparations with diverse rheological properties. Multivariate data analysis in the form of principal component analysis (PCA) and partial least square projection to latent structures (PLS) was applied to extract useful information from the rather large quantities of data obtained. PCA showed that the selected series of gels was heterogeneous. Some groupings could be detected but none of the gels was identified as an outlier. By using PLS we investigated the relations between the rheological properties of a gel and the parameters defining the cohesiveness, as measured with the texture analyser used for the mucoadhesion measurements. The rheological properties proved to be important for the results of both the mucoadhesion and the cohesiveness measurements. Furthermore, by using PLS two different measurement configurations were evaluated and it was concluded that the combination of a relatively small volume of gel and two pieces of mucosa seems to be more appropriate than a large volume of gel in combination with one piece of mucosa.
Effects of gemfibrozil treatment on vascular reactivity of streptozotocin-diabetic rat aorta
Authors: Ozansoy G , Akin F B
Published: February 2004

The effects of gemfibrozil treatment on plasma lipids, lipid peroxides and vascular reactivity of aorta were investigated in diabetic rats. Rats were divided randomly into two groups: control and diabetic. Diabetes was induced by a single intraperitoneal injection of streptozotocin (45 mg kg−1). Twelve weeks after the induction of diabetes, some of the control and diabetic rats were started treatment with gemfibrozil (100 mg kg−1 daily; gavage) for 2 weeks. Blood glucose, plasma triglyceride, cholesterol, low-density lipoprotein (LDL) cholesterol and thiobarbituric acid reactive substances (TBARS) levels were markedly increased and gemfibrozil treatment restored these parameters in diabetic rats. However high-density lipoprotein (HDL) cholesterol levels did not differ in all experimental groups. In diabetic rats, the endothelium-dependent relaxations to acetylcholine were decreased when compared with control rats. Gemfibrozil treatment restored the endothelium-dependent responses to acetylcholine in diabetic rats. The endothelium-independent relaxation responses to sodium nitroprusside were not altered in all groups. These findings suggest that gemfibrozil treatment has beneficial effects against cardiovascular and metabolic complications of diabetes via its hypolipidaemic and antioxidant properties.
Inhibiting cytokines of the interleukin-12 family: recent advances and novel challenges
Authors: Vandenbroeck Koen , Alloza Iraide , Gadina Massimo , Matthys Patrick
Published: February 2004

Interleukin-12 (IL-12) and the more recently discovered IL-23 and IL-27 constitute a unique family of structurally related, heterodimeric cytokines that regulate cell-mediated immune responses and T helper 1 (Th1)-type inflammatory reactions. Not surprisingly, the potentiality of treating conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA) through pharmacological interference with IL-12 pathways has received widespread attention. In this review we have examined over 50 substances with reported IL-12 inhibitory effects. We demonstrate that a majority of these belong to a limited number of major functional classes, each of which targets discrete events in the IL-12 biological pathway. Thus, most IL-12 inhibitory substances appear to work either through inhibition of transcription factor NF-κB activation, up-regulation of intracellular cAMP, blockage of posttranslational processing or interference with signal transduction pathways. In addition, cyclophilin-binding drugs, and generic inhibitors of nuclear histone deacetylases, and of ion channels, pumps and antiporters are emerging as potential leads to novel targets for interference with IL-12 production. Many inhibitors of NF-κB and of IL-12 signal transduction have been proven effective in limiting or preventing disease in experimental autoimmune encephalomyelitis (EAE) models of MS. The sharing of the p40 subunit, the IL-12Rβ1 and components of the signal transduction pathways between IL-12 and IL-23 raises the question as to whether the beneficial effects of various drugs previously ascribed to inhibition of IL-12 may, in fact, have been due to concurrent blockage of both cytokines, or of IL-23, rather than IL-12. Moreover, the homodimeric β2-form of IL-12, though originally considered to display only antagonistic effects, is now emerging as a pronounced agonist in a variety of inflammatory processes. Reassessment of IL-12 inhibitory compounds is therefore needed to scrutinize their effects on IL-12 αβ, β2 and IL-23 formation. This is likely to open exciting perspectives to the identification of drugs that target these cytokines either indiscriminately or selectively. The functional diversity of presently available inhibitors should facilitate an unprecedented flexibility in designing future trials for the treatment of IL-12- and IL-23-mediated disorders.
Acute nephrotoxicity of aristolochic acids in mice
Authors: Sato Noriko , Takahashi Daisuke , Tsuchiya Reiko , Mukoyama Takuya , Yamagata Shin-ichi , Satoh Nobunori , Ueda Shiro , Chen Shih-Ming , Ogawa Makoto , Yoshida Masaaki , Kondo Seizo
Published: February 2004

Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg−1 of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BL/6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice.
Characterization of enzymes responsible for biotransformation of the new antileukotrienic drug quinlukast in rat liver microsomes and in primary cultures of rat hepatocytes
Authors: Szotáková Barbora , Skálová Lenka , Baliharová Vendula , Dvorščaková Martina , Štorkánová Lenka , Šišpera Luděk , Wsól Vladimír
Published: February 2004

The promising new drug quinlukast, 4-(4-(quinoline-2′-yl-methoxy)phenylsulphanyl)benzoic acid (VÚFB 19363), is under investigation for its anti-inflammatory and anti-asthmatic effects. The main metabolite of quinlukast identified in incubations of rat microsomal fraction, and in primary culture of rat hepatocytes, is quinlukast sulfoxide (M2). Also, several other metabolites of quinlukast were found: two dihydrodiol derivatives (M3, M5) and quinlukast sulfone (M4). This study was conducted to characterize the enzymes involved in quinlukast biotransformation in rat in-vitro. Primary cultures of rat hepatocytes were treated with inducers of different cytochrome P450s (CYPs) for 48 h. Quinlukast (100 μm) was incubated for 24 h in a primary culture of induced or control hepatocytes. The effects of CYP inhibitors, ketoconazole, methylpyrazole, metyrapone and α-naphthoflavone (2, 10, 50 μm), on quinlukast metabolism were tested in induced and control hepatocytes. Significant induction of M2 (6 times), M5 (twice) and M3 (by 50%) formation by dexamethasone and strong concentration-dependent inhibition by ketoconazole indicated that CYP3A participates in formation of these metabolites. CYP1A catalyses formation of metabolite M3 mainly, as β-naphthoflavone induced (10 times) production of M3 and a strong inhibitory effect of α-naphthoflavone on its formation was observed. A significant inhibitory effect of quinlukast (2, 10, 50 μm) on ethoxyresorufin, methoxyresorufin and benzyloxyresorufin O-dealkylase activity was observed as well.
Anti-ulcerogenic effect of chitin and chitosan on mucosal antioxidant defence system in HCl-ethanol-induced ulcer in rats
Authors: Anandan R , Nair P G Viswanathan , Mathew Suseela
Published: February 2004

The anti-ulcerogenic effect of chitin and chitosan against ulcer induced by HCl-ethanol in male Wistar rats was studied. Levels of acid output, pepsin, protein, lipid peroxides and reduced glutathione and the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) were determined in the gastric mucosa of normal and experimental groups of rats. A significant increase in volume and acidity of the gastric juice was observed in the ulcer-induced group of rats. Peptic activity was significantly decreased as compared with that of normal controls. In the rats pre-treated with chitin and chitosan 2% along with feed, the volume and acid output and peptic activity of gastric mucosa were maintained at near normal levels. The level of lipid peroxidation was significantly higher in the ulcerated mucosa when compared with that of normal controls. This was paralleled by a decline in the level of reduced glutathione and in the activity of antioxidant enzymes like GPx, GST, CAT and SOD in the gastric mucosa of ulcer-induced rats. Also, the levels of mucosal proteins and glycoprotein components were significantly depleted in ulcerated mucosa. The pre-treatment with chitin and chitosan was found to exert a significant anti-ulcer effect by preventing all the HCl-ethanol-induced ulcerogenic effects in experimental rats.
Endothelin ETA receptor antagonist did not affect development of tolerance to glyceryl trinitrate in rat
Authors: Rai Aarati , Bhalla Shaifali , Gulati Anil , Gulati Anil
Published: February 2004

Glyceryl trinitrate (GTN), extensively used for the treatment of cardiovascular disorders, is associated with rapid development of tolerance. The exact mechanism responsible for tolerance development to GTN is still not known. Recently, it has been demonstrated that GTN tolerance is associated with increased expression of endothelin (ET). This study was carried out to determine the effect of ETA receptor antagonist, BMS182874, on the development of tolerance to GTN in urethane-anaesthetized rats. Diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR) were continuously recorded in vehicle- and BMS182874 (3 mg kg−1, i.v.)-treated rats. GTN was infused at the rate of 10 μg min−1, intravenously for 4 h. Tolerance to GTN was determined using challenge doses of GTN (10, 30 and 90 μg, i.v.). GTN produced a fall in DBP, SBP and an increase in HR. In vehicle-treated rats, the fall in SBP before induction of GTN tolerance was 28+2, 43+4 and 52+4 mmHg with 10, 30 and 90 μg GTN, respectively. However, following GTN infusion (10 μg min−1, i.v. for 4 h) a rapid development of tolerance was observed and the fall in SBP was 1+1, 9+4 and 15+4 mmHg with 10, 30 and 90 μg GTN, respectively. Similarly, in BMS182874-treated rats the fall in SBP in non-tolerant rats was 28+4, 42+4 and 48+5 mmHg with 10, 30 and 90 μg GTN, respectively. In BMS182874-treated rats following GTN infusion (10 μg min−1, i.v. for 4 h) a rapid development of tolerance was observed and the fall in SBP was 4+3, 10+2 and 13+4 mmHg with 10, 30 and 90 μg GTN, respectively. The decrease in DBP and SBP in vehicle- and BMS182874-treated GTN-tolerant rats was statistically similar. These results suggest that ETA receptor antagonist BMS182874 did not affect development of tolerance to GTN in rats.
On the coverage of space by random sets
Authors: Athreya Siva , Roy Rahul , Sarkar Anish
Published: February 2004

Let ξ1, ξ2,… be a Poisson point process of density λ on (0,∞)d, d ≥ 1, and let ρ, ρ1, ρ2,… be i.i.d. positive random variables independent of the point process. Let C := ⋃i≥1 {ξi + [0,ρi]d}. If, for some t > 0, (0,∞)d ⊆ C, then we say that (0,∞)d is eventually covered by C. We show that the eventual coverage of (0,∞)d depends on the behaviour of xP(ρ > x) as x → ∞ as well as on whether d = 1 or d ≥ 2. These results may be compared to those known for complete coverage of ℝd by such Poisson Boolean models. In addition, we consider the set ⋃{i≥1:Xi=1}
[i,i+ρi], where X1, X2,… is a {0,1}-valued Markov chain and ρ1, ρ2,… are i.i.d. positive-integer-valued random variables independent of the Markov chain. We study the eventual coverage properties of this random set.
On a random directed spanning tree
Authors: Bhatt Abhay G. , Roy Rahul
Published: February 2004

We study the asymptotic properties of a minimal spanning tree formed by n points uniformly distributed in the unit square, where the minimality is amongst all rooted spanning trees with a direction of growth. We show that the number of branches from the root of this tree, the total length of these branches, and the length of the longest branch each converges weakly. This model is related to the study of record values in the theory of extreme-value statistics and this relation is used to obtain our results. The results also hold when the tree is formed from a Poisson point process of intensity n in the unit square.
Bayesian and geometric subspace tracking
Authors: Srivastava Anuj , Klassen Eric
Published: February 2004

We address the problem of tracking the time-varying linear subspaces (of a larger system) under a Bayesian framework. Variations in subspaces are treated as a piecewise-geodesic process on a complex Grassmann manifold and a Markov prior is imposed on it. This prior model, together with an observation model, gives rise to a hidden Markov model on a Grassmann manifold, and admits Bayesian inferences. A sequential Monte Carlo method is used for sampling from the time-varying posterior and the samples are used to estimate the underlying process. Simulation results are presented for principal subspace tracking in array signal processing.
Quasi-stationary distributions of a pair of Markov chains related to time evolution of a DNA locus
Authors: Bobrowski A.
Published: February 2004

We consider a pair of Markov chains representing statistics of the Fisher-Wright-Moran model with mutations and drift. The chains have absorbing state at 0 and are related by the fact that some random time τ ago they were identical, evolving as a single Markov chain with values in {0,1,…}; from that time on they began to evolve independently, conditional on a state at the time of split, according to the same transition probabilities. The distribution of τ is a function of deterministic effective population size 2N(·). We study the impact of demographic history on the shape of the quasi-stationary distribution, conditional on nonabsorption at the margin (where one of the chains is at 0), and on the speed with which the probability mass escapes to the margin.
The time back to the most recent common ancestor in exchangeable population models
Authors: Möhle M.
Published: February 2004

A class of haploid population models with population sizeN, nonoverlapping generations and exchangeable offspring distribution is considered. Based on an analysis of the discrete ancestral process, we present solutions, algorithms and strong upper bounds for the expected time back to the most recent common ancestor which hold for arbitrary sample sizen∈ {1,…,N}. New insights into the asymptotic behaviour of the expected time back to the most recent common ancestor for large population size are presented relating the results to coalescent theory.
On the distribution of the breaking strain of a bundle of brittle elastic fibers
Authors: Gleaton James U. , Lynch James D.
Published: February 2004

The maximum-entropy formalism developed by E. T. Jaynes is applied to the breaking strain of a bundle of fibers of various cross-sectional areas. When the bundle is subjected to a tensile load, and it is assumed that Hooke's law applies up to the breaking strain of the fibers, it is proved that the survival strain distribution for a fiber in the bundle is restricted to a certain class consisting of generalizations of the log-logistic distribution. Since Jaynes's formalism is a generalization of statistical thermodynamics, parallels are drawn between concepts in thermodynamics and in the theory of inhomogeneous bundles of fibers. In particular, heat transfer corresponds to damage to the bundle in the form of broken fibers, and the negative reciprocal of the parameter corresponding to thermodynamic temperature is the resistance of the bundle to damage.
Analysis of R-out-of-N repairable systems: the case of phase-type distributions
Authors: Barron Yonit , Frostig Esther , Levikson Benny
Published: February 2004

An R-out-of-N repairable system, consisting of N independent components, is operating if at least R
components are functioning. The system fails whenever the number of good components decreases from R to R-1. A failed component is sent to a repair facility. After a failed component has been repaired it is as good as new. Formulae for the availability of the system using Markov renewal and semi-regenerative processes are derived. We assume that either the repair times of the components are generally distributed and the components' lifetimes are phase-type distributed or vice versa. Some duality results between the two systems are obtained. Numerical examples are given for several distributions of lifetimes and of repair times.
Optimal control of a flexible server
Authors: Ahn Hyun-Soo , Duenyas Izak , Zhang Rachel Q.
Published: February 2004

We consider the dynamic scheduling of a multiclass queueing system with two servers, one dedicated (server 1) and one flexible (server 2), with no arrivals. Server 1 is dedicated to processing type-1 jobs while server 2 is primarily responsible for processing type-2 jobs but can also aid server 1 with its work. We address when it is optimal for server 2 to aid server 1 with type-1 jobs rather than process type-2 jobs. The objective is to minimize the total holding costs incurred until all jobs in the system are processed and leave the system. We show that the optimal policy can exhibit one of three possible structures: (i) an exhaustive policy for type-2 jobs, (ii) a nonincreasing switching curve in the number of type-1 jobs and (iii) a nondecreasing switching curve in the number of type-1 jobs. We characterize the necessary and sufficient conditions under which each policy will be optimal. We also explore the use of the optimal policy for the problem with no arrivals as a heuristic for the problem with dynamic arrivals.
Series representation and simulation of multifractional Lévy motions
Authors: Lacaux Céline
Published: February 2004

This paper introduces a method of generating real harmonizable multifractional Lévy motions (RHMLMs). The simulation of these fields is closely related to that of infinitely divisible laws or Lévy processes. In the case where the control measure of the RHMLM is finite, generalized shot-noise series are used. An estimation of the error is also given. Otherwise, the RHMLMXhis split into two independent RHMLMs,Xε,1andXε,2. More precisely,Xε,2is an RHMLM whose control measure is finite. It can then be rewritten as a generalized shot-noise series. The asymptotic behaviour ofXε,1as ε → 0+is further elaborated. Sufficient conditions to approximateXε,1by a multifractional Brownian motion are given. The error rate in terms of Berry-Esseen bounds is then discussed. Finally, some examples of simulation are given.
Estimating tail decay for stationary sequences via extreme values
Authors: Zeevi Assaf , Glynn Peter W.
Published: February 2004

We study estimation of the tail-decay parameter of the marginal distribution corresponding to a discrete-time, real-valued stationary stochastic process. Assuming that the underlying process is short-range dependent, we investigate properties of estimators of the tail-decay parameter which are based on the maximal extreme value of the process observed over a sampled time interval. These estimators only assume that the tail of the marginal distribution is roughly exponential, plus some modest ‘mixing’ conditions. Consistency properties of these estimators are established, as well as minimax convergence rates. We also provide some discussion on estimating the pre-exponent, when a more refined tail asymptotic is assumed. Properties of a certain moving-average variant of the extremal-based estimator are investigated as well. In passing, we also characterize the precise dependence (mixing) assumptions that support almost-sure limit theory for normalized extreme values and related first-passage times in stationary sequences.
Characterization and sufficient conditions for normed ergodicity of Markov chains
Authors: Borovkov A. A. , Hordijk A.
Published: February 2004

Normed ergodicity is a type of strong ergodicity for which convergence of the nth step transition operator to the stationary operator holds in the operator norm. We derive a new characterization of normed ergodicity and we clarify its relation with exponential ergodicity. The existence of a Lyapunov function together with two conditions on the uniform integrability of the increments of the Markov chain is shown to be a sufficient condition for normed ergodicity. Conversely, the sufficient conditions are also almost necessary.
Conductance bounds on theL2convergence rate of Metropolis algorithms on unbounded state spaces
Authors: Jarner Søren F. , Yuen Wai Kong
Published: February 2004

In this paper we derive bounds on the conductance and hence on the spectral gap of a Metropolis algorithm with a monotone, log-concave target density on an interval of ℝ. We show that the minimal conductance set has measure ½ and we use this characterization to bound the conductance in terms of the conductance of the algorithm restricted to a smaller domain. Whereas previous work on conductance has resulted in good bounds for Markov chains on bounded domains, this is the first conductance bound applicable to unbounded domains. We then show how this result can be combined with the state-decomposition theorem of Madras and Randall (2002) to bound the spectral gap of Metropolis algorithms with target distributions with monotone, log-concave tails on ℝ.
Birth-death processes with disaster and instantaneous resurrection
Authors: Chen Anyue , Zhang Hanjun , Liu Kai , Rennolls Keith
Published: February 2004

A new structure with the special property that instantaneous resurrection and mass disaster are imposed on an ordinary birth-death process is considered. Under the condition that the underlying birth-death process is exit or bilateral, we are able to give easily checked existence criteria for such Markov processes. A very simple uniqueness criterion is also established. All honest processes are explicitly constructed. Ergodicity properties for these processes are investigated. Surprisingly, it can be proved that all the honest processes are not only recurrent but also ergodic without imposing any extra conditions. Equilibrium distributions are then established. Symmetry and reversibility of such processes are also investigated. Several examples are provided to illustrate our results.
Queueing and scheduling in random environments
Authors: Bambos Nicholas , Michailidis George
Published: February 2004

We consider a processing system, composed of several parallel queues and a processor, which operates in a time-varying environment that fluctuates between various states or modes. The service rate at each queue depends on the processor bandwidth allocated to it, as well as the environment mode. Each queue is driven by a job traffic flow, which may also depend on the environment mode. Dynamic processor scheduling policies are investigated for maximizing the system throughput, by adapting to queue backlogs and the environment mode. We show that allocating the processor bandwidth to the queues, so as to maximize the projection of the service rate vector onto a linear function of the workload vector, can keep the system stable under the maximum possible traffic load. The analysis of the system dynamics is first done under very general assumptions, addressing rate stability and flow conservation on individual traffic and environment evolution traces. The connection with stochastic stability is later discussed for stationary and ergodic traffic and environment processes. Various extensions to feed-forward networks of such nodes, the multi-processor case, etc., are also discussed. The approach advances the methodology of trace-based modelling of queueing structures. Applications of the model include bandwidth allocation in wireless channels with fluctuating interference and allocation of switching bandwidth to traffic flows in communication networks with fluctuating congestion levels.
Addendum to ‘A stochastic algorithm to compute optimal probabilities in the chaos game’: a new convergence criterion
Authors: Morato Laura M. , Siri Paola
Published: February 2004

We propose a new convergence criterion for the stochastic algorithm for the optimization of probabilities (SAOP) described in an earlier paper. The criterion is based on the dissection principle for irreducible finite Markov chains.
Overlapping and non-redundant functions of theArabidopsisauxin response factorsMONOPTEROSandNONPHOTOTROPIC HYPOCOTYL 4
Authors: Hardtke Christian S. , Ckurshumova Wenzislava , Vidaurre Danielle P. , Singh Sasha A. , Stamatiou George , Tiwari Shiv B. , Hagen Gretchen , Guilfoyle Tom J. , Berleth Thomas
Published: February 2004

Transcription factors of the auxin response factor (ARF) family have been implicated in auxin-dependent gene regulation, but little is known about the functions of individual ARFs in plants. Here, interaction assays, expression studies and combinations of multiple loss- and gain-of-function mutants were used to assess the roles of two ARFs, NONPHOTOTROPIC HYPOCOTYL 4 (NPH4/ARF7)and MONOPTEROS (MP/ARF5), in Arabidopsis development. Both MP and NPH4 interact strongly and selectively with themselves and with each other,and are expressed in vastly overlapping domains. We show that the regulatory properties of both genes are far more related than suggested by their single mutant phenotypes. NPH4 and MP are capable of controlling both axis formation in the embryo and auxin-dependent cell expansion. Interaction of MP and NPH4 in Arabidopsis plants is indicated by their joint requirement in a number of auxin responses and by synergistic effects associated with the co-overexpression of both genes. Finally, we demonstrate antagonistic interaction between ARF and Aux/IAAgene functions in Arabidopsis development. Overexpression of MP suppresses numerous defects associated with a gain-of-function mutation in BODENLOS (BDL)/IAA12. Together these results provide evidence for the biological relevance of ARF-ARF and ARF-Aux/IAA interaction in Arabidopsis plants and demonstrate that an individual ARF can act in both invariantly programmed pattern formation as well as in conditional responses to external signals.
The role ofJAGGEDin shaping lateral organs
Authors: Dinneny José R. , Yadegari Ramin , Fischer Robert L. , Yanofsky Martin F. , Weigel Detlef
Published: February 2004

Position-dependent regulation of growth is important for shaping organs in multicellular organisms. We have characterized the role of JAGGED, a gene that encodes a protein with a single C2H2zinc-finger domain, in controlling the morphogenesis of lateral organs in Arabidopsis thaliana. Loss of JAGGED function causes organs to have serrated margins. In leaves, the blade region is most severely affected. In sepals, petals and stamens, the strongest defects are seen in the distal regions. By monitoring cell-cycle activity in developing petals with the expression of HISTONE 4, we show that JAGGED suppresses the premature differentiation of tissues, which is necessary for the formation of the distal region. The localization of defects overlaps with the expression domain of JAGGED, which is restricted to the growing regions of lateral organs. JAGGED expression is notably absent from the cryptic bract, the remnant of a leaf-like organ that subtends the flower in many species but does not normally develop in wild-type Arabidopsis. If misexpressed, JAGGED can induce the formation of bracts, suggesting that the exclusion of JAGGED from the cryptic bract is a cause of bractless flowers in Arabidopsis.
robo2androbo3interact witheagleto regulate serotonergic neuron differentiation
Authors: Couch Jessica A. , Chen John , Rieff Heather I. , Uri Ellen M. , Condron Barry G.
Published: February 2004

The function of the central nervous system (CNS) depends crucially upon the correct differentiation of neurons and formation of axonal connections. Some aspects of neuronal differentiation are known to occur as axonal connections are forming. Although serotonin is a highly conserved neurotransmitter that is important for many CNS functions, little is known about the process of serotonergic neuron differentiation. We show that in Drosophila,expression of the serotonin transporter (SerT) is both temporally and physically related to midline crossing. Additionally, we show that the axon guidance molecules roundabout2 and roundabout3(robo2/3) are necessary for serotonergic neuron differentiation and function independently of their ligand, slit. Loss of robo2or robo3 causes a loss of SerT expression in about half of neurons,and resembles the phenotype seen in mutants for the transcription factor eagle (eg). Finally, we show a direct relationship between robo2/3 and eg: robo2/3 mutants lose Eg expression in serotonergic neurons, and robo2 and eg interact genetically to regulate SerT expression. We propose that post-midline expression of Robo2/3 is part of a signal that regulates serotonergic neuron differentiation and is transduced by the transcription factor Eg.
Three putative murine Teashirt orthologues specify trunk structures inDrosophilain the same way as theDrosophila teashirtgene
Authors: Manfroid Isabelle , Caubit Xavier , Kerridge Stephen , Fasano Laurent
Published: February 2004

Drosophila teashirt (tsh) functions as a region-specific homeotic gene that specifies trunk identity during embryogenesis. Based on sequence homology, three tsh-like (Tsh) genes have been identified in the mouse. Their expression patterns in specific regions of the trunk, limbs and gut raise the possibility that they may play similar roles to tshin flies. By expressing the putative mouse Tsh genes in flies, we provide evidence that they behave in a very similar way to the fly tsh gene. First, ectopic expression of any of the three mouse Tsh genes, like that of tsh, induces head to trunk homeotic transformation. Second, mouse Tsh proteins can rescue both the homeotic and the segment polarity phenotypes of a tsh null mutant. Third, following ectopic expression, the three mouse Tsh genes affect the expression of the same target genes as tsh in the Drosophila embryo. Fourth, mouse Tsh genes, like tsh,are able to induce ectopic eyes in adult flies. Finally, all Tsh proteins contain a motif that recruits the C-terminal binding protein and contributes to their repression function. As no other vertebrate or fly protein has been shown to induce such effects upon ectopic expression, these results are consistent with the idea that the three mouse Tsh genes are functionally equivalent to the Drosophila tsh gene when expressed in developing Drosophila embryos.