bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of nitric oxide synthase inhibitors and their D‐enantiomers with rat neutrophil luminol dependent chemiluminescence response
Authors: Dikshit M. , Chari S.S. , Seth P. , Kumari R. 
Published: July 2012

Formyl‐methionyl‐leucyl‐phenylalanine (FMLP) or arachidonic acid (AA) induced luminol dependent chemiluminescence (LCL) response of rat polymorphonuclear leukocytes (PMNLs) was found to be inhibited by nitric oxide synthease inhibitors and their D‐enantiomers.
Rat PMNLs LCL response was inhibited by NG‐nitro‐L‐arginine methyl ester (L‐NAME), D‐NAME, NG‐monomethyl‐L‐arginine (L‐NMMA) or D‐NMMA, in a concentration‐ and time‐dependent manner.
It was observed that both L‐ and D‐enantiomers of the arginine analogues (1000 μm) did not inhibit AA induced lucigenin‐dependent chemiluminescence (LUCDCL) response and cytochrome c reduction, used for estimating the NADPH‐oxidase activity in the cells and in the cell free system, respectively.
None of the L‐ and D‐enantiomers had any effect on either rat basal PMNLs or AA‐induced oxygen consumption.
In addition, neither the L nor D‐enantiomers of NAME altered either AA‐induced release or the activity of myeloperoxidase from rat PMNLs azurophilic granules.
The results obtained indicate that the attenuation of the LCL response by L‐ and D‐enantiomers of arginine analogues, is a non‐specific effect as there was no inhibition of NADPH‐oxidase and MPO activity, MPO release or oxygen consumption. Therefore, the data obtained indicate that these agents should be used with caution to analyse the role of nitric oxide in rat PMNLs LCL response.
Ligand‐gated ion channels opened by 5‐HT in molluscan neurones
Authors: Green K.A. , Lambert J.J. , Cottrell G.A. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT) activated a fast (70 ms to half maximum) and desensitizing inward current through non‐selective channels conducting predominantly monovalent cations in neurones of Helix aspersa.
α‐Methyl‐5‐HT was equipotent with 5‐HT in activating this current, but the known selective agonists at vertebrate 5‐HT3 receptors, 2‐methyl‐5‐HT and arylbiguanides were ineffective (> 100 μm). 5‐Methoxytryptamine which is inactive on vertebrate 5‐HT3 receptors was a very weak agonist.
The responses were antagonized by the specific vertebrate 5‐HT3 receptor blocker MDL‐72222 (IC50 = 1 μm), but were only weakly affected by ondansetron (10 μm). The 5‐HT2‐type antagonist, ketanserin (> 5 μm), had no effect. The responses were also antagonized by the non‐specific antagonists (+)‐tubocurarine and strychnine.
Unitary currents through channels non‐selective for monovalent cations, and with a conductance of 2pS, could be activated repeatedly by 5‐HT or α‐methyl‐5‐HT in outside‐out patches from neurones exhibiting the fast 5‐HT‐activated current (I[5‐HT]fast), even in the presence of 500 μm GDP‐[βS] in the recording pipette. This strongly supports direct‐gating of these channels by 5‐HT. The properties of these unitary currents resembled those of I[5‐HT]fast.
The pharmacological properties of this molluscan 5‐HT‐operated, ligand‐gated channel differed sufficiently from known vertebrate 5‐HT3‐type receptors to suggest that it represents a new class of 5‐HT receptor.
Inhibition of Ca2+‐sensitive K+ currents in NG 108‐15 cells by substance P and related tachykinins
Authors: Phenna S. , Carpenter E. , Peers C. , Maudsley S. , Gent J.P. 
Published: July 2012

The whole‐cell patch‐clamp technique was used to investigate the actions of substance P and other agonists at neurokinin (NK) receptors on voltage‐gated K+ and Ca+ channel currents in undifferentiated mouse neuroblastoma x rat glioma NG 108‐15 cells.
Both substance P (0.3–30 μm) and the NK1 receptor selective agonist GR73632 (10 nM‐10 μm) caused concentration‐dependent inhibition of K+ currents. GR64349 and senktide (agonists at NK2 and NK3 receptors respectively) also inhibited K+ currents, but only at concentrations which were several orders of magnitude greater than GR73632, suggesting that current inhibition was mediated via NK1 receptors.
Substance P and GR73632 were without effect on residual K+ currents recorded in the presence of extracellular Co2+ (4 mM) to abolish the Ca2+‐sensitive component (IKCa) of the K+ current. Ca2+ channel currents, recorded with either Ba2+ or Ca2+ as charge carrier, were unaffected by NK1, NK2 and NK3 receptor ligands.
Iontophoretic application of GR73632 produced a current‐dependent reduction of K+ currents. In the presence of the non‐peptide NK1 antagonists, CP‐99,994 and RP67580, and the peptide antagonist, GR82334, the current‐response relationship was reversibly shifted to the right. This indicates that the response is mediated by NK1 receptors.
Our results indicate that activation of NK1 receptors leads to the selective inhibition of IKCa in undifferentiated NG 108‐15 cells.
The functional investigation of a human adenocarcinoma cell line, stably transfected with the neuropeptide Y Y1 receptor
Authors: Holliday Nicholas D. , Cox Helen M. 
Published: July 2012

The human adenocarcinoma cell line, HT‐29, has been stably transfected with the cDNA sequence for the rat neuropeptide Y (NPY) Y1 receptor, and three Y1 clones (Y1‐4, Y1‐7 and Y1‐16) have been isolated which express high levels of specific [125I]‐PYY binding. We have studied the functional responses or lack of responses to peptide YY (PYY) and its analogues in the three transfected clones and HT‐29 wild type (wt) cells.
Vasoactive intestinal polypeptide (VIP) produced long‐lasting increases in short‐circuit current (SCC) in both HT‐29 wt cells and the Y1 clones. VIP EC50 values were 8.4–11.7 nM in all four cases. The elevation in SCC after a maximal concentration of VIP (30 nM) was significantly greater in Y1‐7 cells than in either HT‐29 wt epithelia or the other Y1 cell lines.
PYY (100 nM) and human pancreatic polypeptide (hPP; 1 μm) were ineffective in HT‐29 wt cells under either basal or stimulated conditions. In contrast, basolateral additions of PYY reduced both basal and VIP‐stimulated SCC in all three Y1 clones. After VIP, the PYY EC50 values (in nM) were 18.6 in Y1‐4, 8.0 in Y1‐7 and 52.5 in Y1‐16. hPP (1 μm) produced only small and transient responses in each transfected cell type.
The Y1 receptor agonist, [Leu31, Pro34] NPY (1 μm) was also effective in the three Y1 cell lines. In the Y1‐7 clone the EC50 value for the effect of this peptide was 149 nM, 18.6 fold less potent than PYY.
PYY and the Y1‐selective non‐peptide antagonist, BIBP 3226 displaced [125I]‐PYY binding from Y1‐7 cell membranes with Ki values of 2.0 and 3.1 nM respectively. In the Y1‐7 clone, BIBP 3226 fully inhibited the reductions in VIP‐stimulated SCC induced by 30 nM PYY, with an IC50 of 27.2 nM and 30 nM BIBP 3226 caused a parallel rightward shift on the PYY concentration‐response curve, with an approximate pKB of 8.0.
HT‐29 clones stably expressing the Y1 receptor therefore show responses to PYY and its analogues that are characteristic of that subtype, and the Y1‐7 clone in particular will be useful in the assessment of novel Y1‐specific drugs. This approach will also allow the functional study of NPY Y1 receptors with selected mutations.
Antioxidant protection of NO‐induced relaxations of the mouse anococcygeus against inhibition by superoxide anions, hydroquinone and carboxy‐PTIO
Authors: Lilley Elliot , Gibson Alan 
Published: July 2012

The potential protective effect of several antioxidants [Cu/Zn superoxide dismutase (Cu/Zn SOD), ascorbate, reduced glutathione (GSH), and α‐tocopherol (α‐TOC)] on relaxations of the mouse anococcygeus muscle to nitric oxide (NO; 15 μm) and, where appropriate, nitrergic field stimulation (10 Hz; 10 s trains) was investigated.
The superoxide anion generating drug duroquinone (100 μm) reduced relaxations to exogenous NO by 54 ± 6%; this inhibition was partially reversed by Cu/Zn SOD (250 u ml−1), and by ascorbate (500 μm). Following inhibition of endogenous Cu/Zn SOD activity with diethyldithiocarbamate (DETCA), duroquinone (50 μm) also reduced relaxations to nitrergic field stimulation (by 53 ± 6%) and this effect was again reversed by Cu/Zn SOD and by ascorbate. Neither GSH (500 μm) nor α‐TOC (400 μm) afforded any protection against duroquinone.
Xanthine (20 mu ml−1):xanthine oxidase (100 μm) inhibited NO‐induced relaxations by 73 ± 14%, but had no effect on those to nitrergic field stimulation, even after DETCA treatment. The inhibition of exogenous NO was reduced by Cu/Zn SOD (250 u ml−1) and ascorbate (400 μm), but was unaffected by GSH or α‐TOC (both 400 μm).
Hydroquinone (100 μm) also inhibited relaxations to NO (by 52 ± 10%), but not nitrergic stimulation. In this case, however, the inhibition was reversed by GSH (5–100 μm) and ascorbate (100–400 μm), although Cu/Zn SOD and α‐TOC were ineffective.
2‐(4‐Carboxyphenyl)‐4,4,5,5,‐tetramethylimidazoline‐1‐oxyl‐3‐oxide (carboxy‐PTIO, 50 μm) inhibited NO‐induced relaxations by 50 ± 4%, but had no effect on nitrergic responses; the inhibition was reduced by ascorbate (2–200 μm) and α‐TOC (10–200 μm), but not by Cu/Zn SOD or GSH.
Hydroxocobalamin (5–1000 μm) inhibited, equally, relaxations to both NO (‐logIC40 3.14 ± 0.33) and nitrergic stimulation (‐logIC40 3.17 ± 0.22).
Thus, a number of physiological antioxidants protected NO from superoxide anions, and from direct NO‐scavengers. The possibility that the presence of these antioxidants within nitrergically‐innervated tissues might explain the lack of effect of the NO inhibitors on nerve‐induced relaxation, without the need to invoke a transmitter other than free radical NO, is discussed.
Inward transport of [3H]‐1‐methyl‐4‐phenylpyridinium in rat isolated hepatocytes: putative involvement of a P‐glycoprotein transporter
Authors: Martel F. , Martins M.J. , Hipólito‐Reis C. , Azevedo I. 
Published: July 2012

The liver has an important role in the detoxification of organic cations from the circulation. [3H]‐1‐methyl‐4‐phenylpyridinium ([3H]‐MPP+), a low molecular weight organic cation, is efficiently taken up and accumulated by rat hepatocytes through mechanisms partially unknown.
The aim of the present work was to characterize further the uptake of MPP+ by rat isolated hepatocytes. The putative interactions of a wide range of drugs, including inhibitors/substrates of P‐glycoprotein, were studied.
The uptake of MPP+ was investigated in rat freshly isolated hepatocytes (incubated in Krebs‐Henseleit medium with 200 nM [3H]‐MPP+ for 5 min) and in the rat liver in situ (perfused with Krebs‐Henseleit/BSA medium with 200 nM [3H]‐MPP+ for 30 min). [3H]‐MPP+ accumulation in the cells and in tissue was determined by liquid scintillation counting.
Verapamil (100 μm), quinidine (100 μm), amiloride (1 mM), (+)‐tubocurarine (100 μm), vecuronium (45 μm), bilirubin (200 μm), progesterone (200 μm), daunomycin (100 μm), vinblastine (100 μm), cyclosporin A (100 μm) and cimetidine (100 μm) had a significant inhibitory effect on the accumulation of [3H]‐MPP+ in isolated hepatocytes. Tetraethylammonium (100 μm) had no effect.
In the rat perfused liver, both cyclosporin A (100 μm) and verapamil (100 μm) had much less marked inhibitory effects as compared to their effects on isolated hepatocytes (0% against 35% and 45% against 96% of inhibition, respectively).
Inhibition of alkaline phosphatase activity by increasing or decreasing the pH of the incubation medium or by the presence of vanadate (1 mM) or homoarginine (500 μm) led to a significant increase in the accumulation of [3H]‐MPP+ in isolated hepatocytes.
It was concluded that, in addition to the type I organic cation hepatic transporter, [3H]‐MPP+ is taken up by rat isolated hepatocytes through P‐glycoprotein, a canalicular transport system that usually excretes endobiotics and xenobiotics. We proposed that the reversal of transport through P‐glycoprotein may be related to the loss of efficiency of alkaline phosphatase in isolated hepatocytes.
Alterations of cyclo‐oxygenase products and NO in responses to angiotensin II of resistance arteries from the spontaneously hypertensive rat
Authors: Côrtes Steyner de F. , Andriantsitohaina Ramaroson , Stoclet Jean Claude 
Published: July 2012

The involvement of cyclo‐oxygenase (COX) products and nitric oxide (NO) in contractile responses of resistance arteries to angiotensin II (AII) were investigated in small mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats.
In endothelium intact vessels, AII induced concentration‐dependent responses without any significant difference between the two strains. However, removal of functional endothelium resulted in enhanced sensitivity to AII, the pD2 value increasing from 8.4 ± 0.2 to 8.9 ± 0.2 (P < 0.05) in WKY and from 8.2 ± 0.1 to 8.6 ± 0.1 (P < 0.05) in SHR (not significantly different between strains, n = 9–12). In addition, endothelium removal enhanced maximal contractions elicited by AII in SHR (1.4 ± 0.1 to 2.1 ± 0.2 mN mm−1, n = 5; P < 0.01) but not in WKY (1.0 ± 0.1 to 1.2 ± 0.1 mN mm−1, n = 5) vessels.
In the absence of functional endothelium, the COX inhibitor indomethacin (10−5 m) reduced contractile responses elicited by AII in SHR arteries, resulting in 33 ± 5% (n = 5) decrease in maximal contraction. However, it produced minimal if any, effect on responses of WKY vessels. In both strains, the TP receptor antagonist GR32191 B (3 × 10−6 m) did not modify contractions elicited by AII in these conditions.
In the presence of functional endothelium, indomethacin (10−5 m) almost abolished the responses to AII in both strains. GR32191 B (3 × 10−6 m) reduced the sensitivity of WKY arteries to AII (pD2 = 8.1 ± 0.1, P < 0.01) without any effect on maximal contraction. In SHR arteries, it markedly reduced maximal contraction (47 ± 3.5%).
In both strains, the NO synthase inhibitor NG‐nitro‐L‐arginine methy lester (L‐NAME; 10−4 m) had no effect in the absence of functional endothelium but it markedly reduced the inhibitory influence of endothelium on contractile responses to AII Furthermore, in arteries with endothelium, it reduced the effect of both indomethacin and GR32191 B to the same level as observed in vessels without functional endothelium.
The results suggest that enhanced contraction caused by COX products was counteracted by enhanced relaxation caused by endothelium‐derived NO in resistance mesenteric arteries of the SHR exposed to AII, compared to WKY arteries. The COX products involved in alterations of SHR responses comprised an endothelium‐derived prostaglandin activating TP receptors and another non‐endothelial unidentified vasoconstrictor compound which did not activate these receptors.
Glucose transporter type I deficiency syndrome: Epilepsy phenotypes and outcomes
Authors: Pong Amanda W. , Geary Brianna R. , Engelstad Kris M. , Natarajan Ashwini , Yang Hong , De Vivo Darryl C. 
Published: July 2012

SummaryPurpose:  Glut 1 deficiency syndrome (DS) is defined by hypoglycorrhachia with normoglycemia, acquired microcephaly, episodic movements, and epilepsy refractory to standard antiepileptic drugs (AEDs). Gold standard treatment is the ketogenic diet (KD), which provides ketones to treat neuroglycopenia. Our purpose is (1) to describe epilepsy phenotypes in a large Glut 1 DS cohort, to facilitate diagnosis; and (2) to describe cases in which non‐KD agents achieved seizure freedom (SF), highlighting potential adjunctive treatments.Methods:  Retrospective review of 87 patients with Glut 1 DS (45% female, age range 3 months–35 years, average diagnosis 6.5 years) at Columbia University, from 1989 to 2010.Key Findings:  Seventy‐eight (90%) of 87 patients had epilepsy, with average onset at 8 months. Seizures were mixed in 68% (53/78): generalized tonic–clonic (53%), absence (49%), complex partial (37%), myoclonic (27%), drop (26%), tonic (12%), simple partial (3%), and spasms (3%). We describe the first two cases of spasms in Glut 1 DS. Electrophysiologic abnormalities were highly variable over time; only 13 (17%) of 75 had exclusively normal findings. KD was used in 82% (64/78); 67% (41/61) were seizure‐free and 68% of seizure‐free patients (28/41) resolved in <1 week and 76% (31/41) in <1 month. Seven patients achieved SF with broad agents only.Significance:  Glut 1 DS is a genetic metabolic encephalopathy with variable focal and multifocal seizure types and electroencephalographic findings. Infants with seizures, spasms, or paroxysmal events should be tested for Glut 1 DS. Evidence is insufficient to recommend specific AEDs as alternatives to KD. Early diagnosis and initiation of KD and prevention of unnecessary AED trials in Glut 1 DS are important goals for the treatment of children with epilepsy.
Primary afterdischarge in organotypic hippocampal slice cultures: Effects of standard antiepileptic drugs
Authors: Albus Klaus , Wahab Abdul , Heinemann Uwe 
Published: July 2012

SummaryPurpose:  In the hippocampus intense high frequency electrical stimulation induces a long‐lasting rhythmic synchronization (primary afterdischarge). In order to examine the suitability of primary afterdischarges (PADs) in organotypic hippocampal slice cultures (OHSCs) as an in vitro model of evoked seizures, we have worked out in detail the sensitivity of PADs to standard antiepileptic drugs (AEDs) and compared the necessary concentrations to those that were effective in animal models of partial and generalized tonic–clonic seizures.Methods:  OHSCs were prepared according to the interface culture method from 8 to 11‐day‐old Wistar rats. A PAD in CA1 was elicited by stimulating the stratum radiatum with an intensity of two times that required to elicit a maximal population spike. The effects of carbamazepine, phenytoin, valproic acid, phenobarbital, diazepam, and ethosuximide on the duration and on frequency properties of PADs and the tonic‐like and clonic‐like subdivisions of PADs were determined, and as a measure of the AEDs potency half maximal effective concentration (EC50) values were calculated from concentration–response curves.Key Finding:  Carbamazepine, phenytoin, valproic acid, phenobarbital, and diazepam reduced the durations of PADs and tonic‐like and clonic‐like subdivisions of PADs. The effects were concentration dependent and reversible. Ethosuximide was ineffective. The effects on subdivisions of PADs differed between AEDs. Carbamazepine and phenytoin shortened the tonic‐like and clonic‐like subdivisions at similar proportions, whereas phenobarbital, diazepam, and valproic acid preferentially shortened the clonic‐like subdivision. Diazepam at low concentrations increased the duration of tonic‐like subdivisions, an effect not seen with the other AEDs. The suppressive effects of AEDs on frequency properties of tonic‐like and clonic‐like subdivisions were variable and observed only at higher concentrations.Significance:  Carbamazepine and phenytoin were more effective in the PAD test in OHSCs than in the maximal electroshock and kindled seizures tests. The effectiveness of phenobarbital, diazepam, and valproic acid in the PAD test matched their effectiveness in the MES test and—with the exception of valproic acid and diazepam—in kindled seizures tests. Valproic acid was less effective in OHSCs than in the kindled seizure tests, and diazepam was more (generalized seizures) or less (focal seizures and afterdischarge durations) effective in this animal model than in OHSCs. We conclude that the PAD test in OHSCs is a suitable in vitro model of evoked seizures. The model could serve as an initial screen to identify the most promising leads for further evaluation and characterization in in vivo models of efficacy and toxicity.
Predicting Multivariate Insurance Loss Payments Under the Bayesian Copula Framework
Authors: Zhang Yanwei , Dukic Vanja 
Published: July 2012

ABSTRACTThe literature of predicting the outstanding liability for insurance companies has undergone rapid and profound changes in the past three decades, most recently focusing on Bayesian stochastic modeling and multivariate insurance loss payments. In this article, we introduce a novel Bayesian multivariate model based on the use of parametric copula to account for dependencies between various lines of insurance claims. We derive a full Bayesian stochastic simulation algorithm that can estimate parameters in this class of models. We provide an extensive discussion of this modeling framework and give examples that deal with a wide range of topics encountered in the multivariate loss prediction settings.
Did Subjectivity Play a Role in CDO Credit Ratings?
Authors: GRIFFIN JOHN M. , TANG DRAGON YONGJUN 
Published: July 2012

ABSTRACTAnalyzing 916 collateralized debt obligations (CDOs), we find that a top credit rating agency frequently made positive adjustments beyond its main model that amounted to increasingly larger AAA tranche sizes. These adjustments are difficult to explain by likely determinants, but exhibit a clear pattern: CDOs with smaller model‐implied AAA sizes receive larger adjustments. CDOs with larger adjustments experience more severe subsequent downgrading. Additionally, prior to April 2007, 91.2% of AAA‐rated CDOs only comply with the credit rating agency's own AA default rate standard. Accounting for adjustments and the criterion deviation indicates that on average AAA tranches were structured to BBB support levels.
Modified anthropometry in prepubertal Israeli children while excluding the head’s weight and height
Authors: Makhoul IR , Abulhija H , Smolkin T , Shehadeh N , Hochberg Z 
Published: July 2012

AbstractAim:  A methodological inadequacy in anthropometric measurements of children exists because of an age‐dependent decelerating contribution of the head to body weight (Wt) and height (Ht). Hence, we aimed to assess the contribution of head measurements to anthropometry (Ht, Wt and BMI) in healthy prepubertal children.Methods:  This prospective study was conducted in 300 2‐ to 9‐year‐old typically growing children. Head‐excluded (HE) Ht was determined by a stadiometer that measured the distance from the foot plate to the lower margin of protuberance occipitalis externa. Head’s weight was calculated from the head volume using three different measurements of the head circumference.Results:  In the typically growing children, the HE/standard (STD) ratios for Wt and Ht increased significantly with age (p < 0.001 for both), but the HE/STD ratio for BMI did not increase with age.Conclusion:  Measurement of body Wt and Ht while excluding the head’s Wt and Ht provides a new dimension to standard anthropometry by eliminating the age‐dependent head bias with its unique pattern of growth and minimal adipose tissue.