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Maximal Response (maximal + response)
Selected AbstractsRandomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disordersDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 2 2008S M Reid MClinEpi BAppSc (physio) The primary aim of this randomized, controlled trial was to assess the effectiveness of botulinum toxin A (BoNT-A) injections into the submandibular and parotid glands on drooling in children with cerebral palsy (CP) and other neurological disorders. Secondary aims were to ascertain the duration of any such effect and the timing of maximal response. Of the 48 participants (27 males, 21 females; mean age 11y 4mo [SD 3y 3mo], range 6-18y), 31 had a diagnosis of CP and 15 had a primary intellectual disability; 27 children were non-ambulant. Twenty-four children randomized to the treatment group received 25 units of BoNT-A into each parotid and submandibular gland. Those randomized to the control group received no treatment. The degree and impact of drooling was assessed by carers using the Drooling Impact Scale questionnaire at baseline and at monthly intervals up to 6 months postinjection/baseline, and again at 1 year. Maximal response was at 1 month at which time there was a highly significant difference in the mean scores between the groups. This difference remained statistically significant at 6 months. Four children failed to respond to the injections, four had mediocre results, and 16 had good results. While the use of BoNT-A can help to manage drooling in many children with neurological disorders, further research is needed to fully understand the range of responses. [source] 2,3,4,7,8-pentachlorodibenzofuran is a more potent cytochrome P4501A inducer than 2,3,7,8-tetrachlorodibenzo- p -dioxin in herring gull hepatocyte culturesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2010Jessica C. Hervé Abstract Concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) on cytochrome P4501A (CYP1A) induction were determined in primary cultures of embryonic herring gull (Larus argentatus) hepatocytes exposed for 24,h. Based on the concentration that induced 50% of the maximal response (EC50), the relative potencies of TCDD and TCDF did not differ by more than 3.5-fold. However, also based on the EC50, PeCDF was 40-fold, 21-fold, and 9.8-fold more potent for inducing ethoxyresorufin- O -deethylase (EROD) activity, CYP1A4 mRNA expression, and CYP1A5 mRNA expression than TCDD, respectively. The relative CYP1A-inducing potencies of PeCDF and of other dioxin-like chemicals (DLCs) in herring gull hepatocytes (HEH RePs), along with data on concentrations of DLCs in Great Lakes herring gull eggs, were used to calculate World Health Organization toxic equivalent (WHO-TEQ) concentrations and herring gull embryonic hepatocyte toxic equivalent (HEH-TEQ) concentrations. The analysis indicated that, when using avian toxic equivalency factors (TEFs) recommended by the WHO, the relative contribution of TCDD (1.1,10.2%) to total WHO-TEQ concentration was higher than that of PeCDF (1.7,2.9%). These results differ from the relative contribution of TCDD and PeCDF when HEH RePs were used; PeCDF was a major contributor (36.5,52.9%) to total HEH-TEQ concentrations, whereas the contribution by TCDD (1.2,10.3%) was less than that of PeCDF. The WHO TEFs for avian species were largely derived from studies with the domestic chicken (Gallus gallus domesticus). The findings of the present study suggest that it is necessary to determine the relative potencies of DLCs in wild birds and to re-evaluate their relative contributions to the biochemical and toxic effects previously reported in herring gulls and other avian species. Environ. Toxicol. Chem. 2010;29:2088,2095. © 2010 SETAC [source] Dose,response and time course relationships for vitellogenin induction in male western fence lizards (Sceloporus occidentalis) exposed to ethinylestradiolENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2002Sandra M. Brasfield Abstract The long-term goal of this research is to develop and validate an in vivo reptile model for endocrine-mediated toxicity using fence lizards (Sceloporus spp.). One of the best defined estrogenic responses in oviparous vertebrates is induction of the yolk precursor protein, vitellogenin (Vtg). In this study, dose,response and time course relationships for Vtg induction were determined in male western fence lizards (Sceloporus occidentalis) given intraperitoneal injections of 17,-ethinylestradiol (EE2). Plasma Vtg was quantified directly with an antibody-capture enzyme-linked immunosorbent assay (ELISA) and indirectly using plasma alkalinelabile phosphate (ALP) in order to compare these two methods. Both ELISA and ALP predicted similar median effective dose (ED50 [dose causing a 50% maximal response]) values for plasma Vtg induction (0.167 mg/kg for ELISA and 0.095 mg/kg for ALP). In addition, both ELISA and ALP detected significant Vtg induction at a dose of 0.0003 mg/kg of EE2, which was the lowest dose used in our study. A decrease in body weight at the highest dose (10 mg/kg) and an increase in hepatosomatic index at the four highest doses were observed. Serial dilutions of plasma from an EE2 -exposed male revealed a high correlation between plasma Vtg and ALP determinations in this species. In conclusion, our data show that plasma ALP may be a suitable alternative for measuring plasma Vtg compared with developing a Vtg ELISA in fence lizards exposed to estrogenic compounds. [source] Glutamate-induced elevations in intracellular chloride concentration in hippocampal cell cultures derived from EYFP-expressing miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2004Jennifer E. Slemmer Abstract The homeostasis of intracellular Cl, concentration ([Cl,]i) is critical for neuronal function, including ,-aminobutyric acid (GABA)ergic synaptic transmission. Here, we investigated activity-dependent changes in [Cl,]i using a transgenetically expressed Cl, -sensitive enhanced yellow-fluorescent protein (EYFP) in cultures of mouse hippocampal neurons. Application of glutamate (100 µm for 3 min) in a bath perfusion to cell cultures of various days in vitro (DIV) revealed a decrease in EYFP fluorescence. The EYFP signal increased in amplitude with increasing DIV, reaching a maximal response after 7 DIV. Glutamate application resulted in a slight neuronal acidification. Although EYFP fluorescence is sensitive to pH, EYFP signals were virtually abolished in Cl, -free solution, demonstrating that the EYFP signal represented an increase in [Cl,]i. Similar to glutamate, a rise in [Cl,]i was also induced by specific ionotropic glutamate receptor agonists and by increasing extracellular [K+], indicating that an increase in driving force for Cl, suffices to increase [Cl,]i. To elucidate the membrane mechanisms mediating the Cl, influx, a series of blockers of ion channels and transporters were tested. The glutamate-induced increase in [Cl,]i was resistant to furosemide, bumetanide and 4,4,-diisothiocyanato-stilbene-2,2,-disulphonic acid (DIDS), was reduced by bicuculline to about 80% of control responses, and was antagonized by niflumic acid (NFA) and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We conclude that membrane depolarization increases [Cl,]i via several pathways involving NFA- and NPPB-sensitive anion channels and GABAA receptors, but not through furosemide-, bumetanide- or DIDS-sensitive Cl, transporters. The present study highlights the vulnerability of [Cl,]i homeostasis after membrane depolarization in neurons. [source] Transgenerational plasticity for sexual reproduction and diapause in the life cycle of monogonont rotifers: intraclonal, intraspecific and interspecific variation in the response to crowdingFUNCTIONAL ECOLOGY, Issue 3 2004T. SCHRÖDER Summary 1In monogonont rotifers parthenogenetic reproduction allows population growth, and mictic (sexual) reproduction leads to the production of diapausing eggs. When amictic females are exposed to a mixis stimulus, they produce mictic daughters, whose eggs develop into males or, if fertilized, into diapausing eggs. Experiments showed that mictic offspring production is initiated by crowding in females of Brachionus angularis Gosse 1851, Epiphanes senta (O.F. Müller 1773) and Rhinoglena frontalis Ehrenberg 1853, just as it is in Brachionus calyciflorus Pallas 1766 and B. plicatilis Müller 1786. 2In B. calyciflorus, B. angularis, E. senta and R. frontalis, the propensity of amictic females to respond to crowding by producing mictic female offspring is low in the stem female hatching from a diapausing egg, but then increases after some generations. In many cases, only few mictic offspring are produced by crowded females of the second to the fifth generation, but the maximal response occurs only in later generations. Delayed sexual reproduction in early generations from the resting egg may be advantageous, because it first favours rapid population growth and later on maximizes resting egg production. However, it may be disadvantageous, if unpredictable environmental variation causes a population decline when sexual reproduction is still suppressed. 3The extent to which sexual reproduction is delayed varies among and within species. When strains from populations in temporary and permanent habitats were compared, sexual reproduction was significantly delayed in strains from temporary habitats in all species, whereas in B. calyciflorus and R. frontalis mixis was not significantly delayed in strains from permanent habitats. In E. senta mixis was significantly delayed in clones from both habitat types. 4Within all strains there was significant variation among clones in the propensity to produce mictic offspring, the extent to which sexual reproduction was delayed in the first generations after the stem female hatched, or both. [source] Infancy is not a quiescent period of testicular developmentINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2001Héctor E. Chemes Postnatal evolution of the testis in most laboratory animals is characterized by the close continuity between neonatal activation and pubertal development. In higher primates, infancy, a long period of variable duration, separates birth from the beginning of puberty. This period has been classically considered as a quiescent phase of testicular development, but is actually characterized by intense, yet inapparent activity. Testicular volume increases vigorously shortly after birth and in early infancy due to the growth in length of seminiferous cords. This longitudinal growth results from active proliferation of infantile Sertoli cells which otherwise display a unique array of functional capabilities (oestrogen and anti-müllerian hormone secretion, increase of FSH receptors and maximal response to FSH). Leydig cells also show recrudescence after birth, possibly determined by an active gonadotrophic-testicular axis which results in increased testosterone secretion of uncertain functional role. This postnatal activation slowly subsides during late infancy when periodic phases of activation of the hypothalamo-pituitary-testicular axis are paralleled by incomplete spermatogenic spurts. The beginning of puberty is marked by the simultaneous reawakening of Leydig cell function and succeeding phases of germ cell differentiation/degeneration which ultimately lead to final spermatogenic maturation. The marked testicular growth in this stage is due to progressive increase at seminiferous tubule diameter. Sertoli cells, which have reached mitotic arrest, develop and differentiate, establishing the seminiferous tubule barrier, fluid secretion and lumen formation, and acquiring cyclic morphological and metabolic variations characteristic of the mature stage. All of these modifications indicate that, far from being quiescent, the testis in primates experiences numerous changes during infancy, and that the potential for pubertal development and normal adult fertility depends on the successful completion of these changes. [source] Influence of cosolvents and in situ forming hydroxyapatite on the mechanical characteristics of collagen filmsJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 1 2002Hsiu-O Ho Abstract Collagen was processed into films in mixtures containing various ratios of water, propylene glycol, and ethanol. An experimental mixture design was applied to characterize the effects of individual solvents and their interactions on the mechanical properties of collagen films. Scanning electron microscopy (SEM) was used to examine the surface properties of collagen films. The ultimate tensile strength (UTS) and related characteristics of collagen films were also evaluated with dynamic mechanical analysis. The effect of in situ forming hydroxyapatite (HAP) within collagen films at a concentration of 10 mM on the physical characteristics of these films was evaluated by the same methods. With X-ray and SEM examinations, it was confirmed that HAP was formed inside the collagen film. However, the UTS of collagen films without HAP was 4,5 times higher than that with HAP. This was probably due to the discontinuity of the film structure caused by HAP in the collagen films. The results of a statistical analysis of the experimental design revealed the influence of the solvent mixtures on the mechanical properties of the collagen films with and without HAP, showing similar responses for the UTS and modulus of elasticity. Both parameters showed a maximal response in the solvent range containing a lower percentage of ethanol with the desired percentage of propylene glycol to plasticize the collagen films. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 62: 22,29, 2002 [source] Phosphodiesterase inhibition by naloxone augments the inotropic actions of ,-adrenergic stimulationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2009W. K. PARK Background: In a shock state, naloxone generates the cardiovascular pressor effect by displacing the endogenous opiate-like peptide ,-endorphin, resulting in restoration of the normal response to catecholamines. In addition to this opioid antagonistic effect, the non-opiate receptor-mediated effect has also been proposed. The aim of this study was to define the mechanism of non-opiate receptor-mediated action of naloxone. Methods: In guinea-pig ventricular tissues, cumulative concentration,response curves for isoproterenol as well as for forskolin and 3-isobutylmethylxanthine (IBMX) were obtained by increasing the concentration stepwise. To assess the effect on the phosphodiesterase (PDE), the effects of naloxone on contractile forces induced by isoproterenol (0.05 ,M) in the presence of IBMX, cilostamide (a PDE III inhibitor), or rolipram (a PDE IV inhibitor) were observed. Naloxone-induced changes in cAMP production by isoproterenol both in the absence and in the presence of IBMX were measured. Naloxone-induced changes in cAMP production by forskolin in the presence of IBMX were also measured. Results: Naloxone (30 ,M) produced a leftward shift of the isoproterenol concentration,response curve (0.01,2 ,M) without changing the maximal response. Forskolin (0.5,10 ,M) produced a concentration-dependent increase in contractile forces. Naloxone increased the maximal inotropic response of forskolin. Naloxone showed no effect on the IBMX concentration,response curve. In the presence of IBMX (200 ,M), naloxone did not alter the contractions evoked by isoproterenol or forskolin. Whereas naloxone increased contractile forces significantly (approximately 25%) more than that of isoproterenol in the presence of rolipram, no alteration of contractile forces in the cilostamide-incubated muscles was observed. Naloxone caused a concentration-related increase of cAMP in the absence of IBMX, but caused no change in its presence. Conclusions: The enhancement of myocardial contractility by naloxone in the presence of stimulation of adenylyl cyclase activity appears to be mediated by inhibition of PDE, specifically PDE III. [source] ACUTE APOPTOTIC RESPONSE INDUCED BY THE COLON CARCINOGEN AOM IS DEPENDENT ON P53 GENE and NOT THE APC GENEJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2001Background/objective, Apoptosis is disordered in tumourigensis, however, the importance of apoptosis in relation to DNA damage created at the time of initiation by genotoxic carcinogens, i.e. the acute apoptotic response to genotoxic carcinogens (AARGC), has hardly been explored. p53 and APC are tumor suppressor genes known to be altered frequently in colon cancer, however, it remains unclear whether AARGC is dependent on the function of p53 or APC. p53 ,/,, p53 ± and APCMin/+ mice provide an excellent model to test the biological significance of AARGC in colon in terms of its ability to delete genetically damaged cells that might progress to cancer. Thus, we have tested the hypothesis that p53 and APC play a critical role in AARGC, by studying AARGC in p53+/, , p53 ,/, mice and APCMin/+0. Methods, p53 knockout mice were produced by breeding male p53+/, with female C57BL/J mice or interbreeding p53+/, mice. APCMin/+ mice were produced by breeding male APCMin/+ mice with female C57BL/J mice. Mice geno-typing were confirmed by PCR. At 10,12 weeks age, 44 mice were given a single subcutaneous azoxymethane (AOM 10 mg/kg) injection to induce AARGC, and killed 6 h later (the time of the maximal response). There were eight p53,/, mice, 11 p53+/, mice, nine p53+/+mice, 12 APCMin/+ mice, and six APC+/+ mice. Three p53,/, mice, four p53+/, mice, seven p53+/+ mice, two APCMin/+, and six APC+/+ mice without AOM injection were used as controls. Apoptosis in colon was measured by classic morphological H & E criteria. Results, In p53+/+ mice, AOM induced a significant increase in apoptosis (4.70 ± 0.35, SEM, apoptotic cells per crypt column) in the distal colon, located almost exclusively in the proliferative compartment. In comparison to the pattern of apoptosis observed in the p53+/+ mice, the apoptotic response of p53,/, mice was almost nonexistent (0.12 ± 0.06) while in p53+/, mice it was significantly suppressed by approximately 50% (2.26 ± 0.28); P < 0.01. In contrast to the importance of p53 gene on AARGC, absence of the APC gene had no obvious effect on AARGC: APCMin/+ mice (5.07 ± 0.30) and APC+/+ (5.50 ± 0.33); P > 0.05. Conclusion, p53 function appears to be critically important for carcinogen-induced apoptosis in colon, while APC homeostasis appears not to be involved in this type of apoptosis. The loss of just one allele of p53, interferes with its function. Further studies are required to determine whether defective AARGC in p53 knockout mice puts them at increased risk of subsequent events in tumorigensis, and whether AARGC can be regulated by known protective agents. [source] A comparison of HIV-1 drug susceptibility as provided by conventional phenotyping and by a phenotype prediction tool based on viral genotypeJOURNAL OF MEDICAL VIROLOGY, Issue 10 2009Margriet Van Houtte Abstract Concordance between the conventional HIV-1 phenotypic drug resistance assay, PhenoSenseŌ (PS), and virco®TYPE HIV-1 (vT), a drug resistance assay based on prediction of the phenotype, was investigated in a data set from the Stanford HIV Resistance database (hivdb). Depending on the drug, between 287 and 902 genotype,phenotype data pairs were available for comparisons. Test results (fold-change values) in the two assays were highly correlated, with an overall mean correlation coefficient of 0.90 using single PS measurements. This coefficient rose to 0.94 when the vT results were compared to the mean of repeat PS measurements. These results are comparable with the corresponding correlation coefficients of 0.87 and 0.95, calculated using single measurements, and the mean of repeat measurements, respectively, as obtained in the Antivirogram® assay, the conventional HIV-1 phenotypic drug resistance test on which vT is based. The proportion of resistance calls resulting in a "major" discordance (fully susceptible or maximal response by one assay but fully resistant or minimal response by the other) ranged from 0% to 8.1% for drugs for which two clinical test cut-offs were available in both assays (didanosine, abacavir, tenofovir, saquinavir/r, fosamprenavir/r, and lopinavir/r), from 2.4% to 8.1% for the drugs for which two clinical test cut-offs were available in the vT assay and one clinical test cut-off in the PS assay (lamivudine, stavudine, indinavir/r, and atazanavir/r) and from 3.1% to 10.3% for drugs for which biological test cut-offs were used (zidovudine, nevirapine, delavirdine, efavirenz, indinavir, ritonavir, nelfinavir, saquinavir, and fosamprenavir). Our analyses suggest that these assays provide comparable resistance information, which will be of value to physicians who may be presented with either or both types of test report in their practice. J. Med. Virol. 81:1702,1709, 2009. © 2009 Wiley-Liss, Inc. [source] Potentiation of PGE2 -mediated cAMP production during neuronal differentiation of human neuroblastoma SK-N-BE(2)C cellsJOURNAL OF NEUROCHEMISTRY, Issue 2 2001Se-Young Choi The prostaglandin-evoked cAMP production was studied in human neuroblastoma SK-N-BE(2)C cells during neuronal differentiation induced by all- trans retinoic acid. The incubation with 5 µm all- trans retinoic acid for 4,6 days promoted neurite outgrowth of cells. After differentiation, prostaglandin E2 (PGE2)-induced cAMP production was dramatically increased, whereas forskolin- and AlF -induced cAMP productions were not changed. The increase reached maximum after 4-days of incubation with all- trans retinoic acid. The differentiation caused an increase in the maximal response and a decrease in the half-maximal effective concentration of the PGE2 -induced cAMP production. In addition, the binding of [3H]PGE2 to membrane receptors was enhanced in differentiated cells. However, the order of potency of the various prostaglandins (PGE1 = PGE2 > PGD2 = PGF2, = PGI2) in cAMP production did not change during the differentiation, suggesting that mainly E-prostanoid (EP) receptors were involved. Butaprost, an EP2 receptor specific agonist, increased the cAMP level in a concentration dependent manner and had a similar potentiating effect on cAMP production as PGE2 upon differentiation. Northern blot analysis using the human cDNA probes shows that the EP2 mRNA level was about seven times higher in differentiated cells, while the dopamine ,-hydroxylase (DBH) mRNA completely disappeared. Our results, thus, suggest that elevated gene expression of the prostanoid EP2 receptor results in an increase in the PGE2 -evoked cAMP production in SK-N-BE(2)C cells during neuronal differentiation. [source] 1,8-Cineole induces relaxation in rat and guinea-pig airway smooth muscleJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2009Nilberto Robson Falcćo Nascimento Abstract Objectives 1,8-Cineole is a monoterpene with anti-inflammatory, vascular and intestinal smooth muscle relaxant activity. We have evaluated the potential bronchodilatatory activity of this compound. Methods 1,8-Cineole was tested against carbachol, histamine, K+ 80 mM and ovalbumin-induced bronchial contractions in Wistar rat or guinea-pig tissues. Some of the guinea-pigs had been previously sensitized with an intramuscular injection of 5% (w/v) ovalbumin/saline solution. Control animals received 0.3 ml saline. In separate experimental groups the response to 1,8-cineole (1,30 mg/kg), phenoterol (0.05,5 mg/kg) or vehicle (0.3% Tween in saline) was studied. Key findings 1,8-Cineole decreased, in vivo, rat bronchial resistance with similar efficacy as phenoterol (66.7 ± 3.2% vs 72.1 ± 5.3%). On the other hand, the maximal relaxant response to 1,8-cineole in carbachol-precontracted rat tracheas was 85.5 ± 5.7% (IC50 = 408.9 (328,5196) ,g/ml) compared with 80.2 ± 4.8% (IC50 = 5.1 (4.3,6.1) ,g/ml) with phenoterol. The addition of 1,8-cineole to guinea-pig tracheal rings tonically contracted with K+ 80 mM induced a concentration-related relaxation. The maximal relaxation elicited by 1,8-cineole was 113.6 ± 11.7% (IC50 127.0 (115.9,139.2) ,g/ml) compared with 129.7 ± 14.6% (IC50 0.13 (0.12,0.14) ,g/ml) achieved after phenoterol administration. In addition, the incubation of tracheal rings with 1,8-cineole (100, 300 or 1000 ,g/ml), 15 min before inducing phasic contractions with K+ 80 mM, decreased the maximal amplitude of the contraction by 31.6 ± 4.6, 75.7 ± 2.7 and 92.2 ± 1.5%, respectively. In another set of experiments, neither the maximal response nor the IC50 for the 1,8-cineole-induced relaxation were different between normal and ovalbumin-sensitized tissues. Moreover, the relaxation of bronchial rings contracted after exposure to 1 ,g/ml ovalbumin occurred at a faster rate in rings pre-incubated with 1,8-cineole when compared with rings pre-incubated with vehicle only (Tween 0.3%). Therefore, in the first minute after the antigen challenge, the tracheal tissue relaxed after the peak contraction by 6.5, 21.4 (P < 0.05 vs control) and 66.9% (P < 0.05 vs control) in the presence of 100, 300 or 1000 ,g/ml 1,8-cineole, respectively. Conclusions 1,8-Cineole relaxed rat and guinea-pig (nonsensitized and ovalbumin-sensitized) airway smooth muscle by a nonspecific mechanism. [source] Synthesis and pharmacological evaluation of 5-dialkylaminomethyl-2-amino-2-oxazolines as H1 -antagonistsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001J. J. Bosc New 5-dialkylaminomethyl-2-amino-2-oxazolines have been synthezised in two steps from the corresponding dialkylamines. They were evaluated in-vitro as H1 -antagonists. Compounds 1c, 1d and 1j significantly antagonized histamine-induced contraction of guinea-pig trachea with a rightward shift of the concentration-response curve to histamine. Compound 1f, 5-[(4-benzyl-1-piperidinyl)methyl]-2-amino-2-oxazoline, induced an increase in acetylcholine Emax (the maximal response to acetylcholine 10,3 M) and a shift to the left of the concentration-response curve. The lack of effect of this compound on histamine-induced contraction rules out a non-selective potentiation of the contraction mechanisms. Preliminary structure-activity results were reported partly based on physicochemical results. [source] Effects of coil characteristics for femoral nerve magnetic stimulationMUSCLE AND NERVE, Issue 3 2010Katja Tomazin PhD Abstract The aim of this study was to compare the efficiency of two coils used for femoral nerve magnetic stimulation and to compare them with electrical stimulation in inducing maximal response of the quadriceps. The mechanical and electromyographic (EMG) responses were dependent on the coil used. The 45-mm double coil showed greater efficiency to elicit a maximal quadriceps response, which was similar to electrical stimulation. Muscle Nerve, 2010 [source] Lower oesophageal sphincter relaxation evoked by stimulation of the dorsal motor nucleus of the vagus in ferretsNEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2002T. P. Abrahams Abstract, An understanding of the neural control of lower oesophageal sphincter (LOS) relaxation is clinically relevant because transient LOS relaxations (TLOSRs) are a mechanism of acid reflux into the oesophagus. Preganglionic motor neurones innervating the LOS are localized in the dorsal motor nucleus of the vagus (DMV). Based on a single study in cats, it is now widely accepted that these neurones are functionally organized into two separate populations, such that stimulation of the caudal and rostral DMV evokes LOS relaxation and contraction, respectively. Our goal was to map the functional LOS responses to chemical stimulation in the DMV and nucleus tractus solitarius (NTS) of ferrets, an animal model commonly used for conscious studies on TLOSRs, and to test whether DMV-evoked LOS relaxation is mediated through hexamethonium-sensitive vagal-inhibitory pathways to the LOS. We used miniaturized manometry with Dentsleeve to monitor LOS and oesophageal pressures in decerebrate unanaesthetized ferrets. LOS relaxation was evoked readily in response to gastric insufflation, which shows that the vago,vagal reflex was intact in this preparation. Microinjections of l -glutamate (12.5 nmol L,1in 25 nL) were made into the DMV from approximately ,,1.5 to +,2.0 mm relative to the obex. Microinjections into the caudal (, 1.5 to +,0.0 mm behind obex) and intermediate (+ 0.1 to +,1.0 mm rostral to obex) DMV both significantly decreased LOS pressure, and complete LOS relaxation was noted in 28/32 and 11/18 cases, respectively. LOS relaxation responses to DMV microinjection were highly reproducible and abolished by bilateral vagotomy or hexamethonium (15 mg kg,1intravenously). A nitric oxide synthase inhibitor (l -NAME 100 mg kg,1intramuscularly) significantly increased the time taken to reach the maximal response. Increases in LOS pressure (24 ± 4 mmHg; n = 3) were obtained only when stimulation sites were located equal to greater than 1.5 mm rostral to the obex. LOS relaxation (, 78 ± 10%; n = 6) was evoked by stimulation of the NTS but not immediately outside of the NTS (11 ± 27%; n = 5). We conclude that there is a very extensive population of ,inhibitory' motor neurones in the DMV that may account for the predominant vagal-inhibitory tone in ferrets. As NTS stimulation evokes LOS relaxation and the predominant response to DMV stimulation is also LOS relaxation, this vago,vagal reflex may involve an excitatory interneurone between the NTS and DMV vagal inhibitory output. [source] Oligocarrageenans and tissue-dependant oxidative burst in Solieria chordalis (Rhodophyceae, Gigartinales)PHYCOLOGICAL RESEARCH, Issue 1 2008Erwan Ar Gall SUMMARY The release of hydrogen peroxide by thallus fragments of the rhodophycean Solieria chordalis (C. Agardh) J. Agardh has been documented both in the presence and in the absence of oligosaccharides. Within 1 h, ramuli were able to release large amounts of peroxide in the absence of any chemical stress. Among potential elicitors tested, only degree of polymerization 1 (DP1) and DP7-8 oligo-iota-carrageenans stimulated defense mechanisms in both axes and ramuli as shown by the occurrence of an oxidative burst. Chopping of the tissues had no effect on the intensity of the burst, therefore suggesting that mainly cortical cell layers were involved in the process. After 5 min incubation, a dose of 125 ,g mL,1 of an oligomeric mixture containing a large proportion of DP1 units proved to be sufficient to obtain a maximal response. The intensity of the burst was significantly higher with isolated ramuli than with pieces of the axis, with outer peroxide accumulations reaching 200 nmol g,1 fresh weight of treated tissue. Altogether, our results show that S. chordalis is able to react to a simulated pathogen attack by an oxidative burst and that the capacity to carry out an oxidative burst is stronger in ramuli than in axes. [source] Specific GABAA agonists and partial agonistsTHE CHEMICAL RECORD, Issue 6 2002Povl Krogsgaard-Larsen Abstract The GABAA receptor system is implicated in a number of neurological and psychiatric diseases, making GABAA receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABAA receptor complex, reflecting the very strict structural requirements for GABAA receptor recognition and activation. Within the series of compounds showing agonist activity at the GABAA receptor site that have been developed, most of the ligands are structurally derived from the GABAA agonists muscimol, THIP, or isoguvacine, which we developed in the initial stages of the project. Using recombinant GABAA receptors, functional selectivity was demonstrated for a number of compounds, including THIP, showing highly subunit-dependent potency and maximal response. In light of the interest in partial GABAA receptor agonists as potential therapeutics, structure,activity studies of a number of analogs of 4-PIOL, a low-efficacy partial GABAA agonist derived from THIP, have been performed. In this connection, a series of GABAA ligands has been developed that exhibit pharmacological profiles from moderately potent low-efficacy partial GABAA agonist activity to potent and selective antagonist effects. Very little information is available on direct-acting GABAA receptor agonists in clinical studies. However, the results of clinical studies on the effect of the partial GABAA agonist THIP on human sleep patterns show that the functional consequences of a direct-acting agonist are different from those seen after the administration of GABAA receptor modulators, such as benzodiazepines and barbiturates. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc., Chem Rec 2: 419,430; 2002: Published online in Wiley Interscience (www.interscience.wiley.com) DOI 10.1002/tcr.10040 [source] Cholinergic responses of ileal longitudinal muscle under short-lasting exposure to cupric ionsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2008Ch. Nachev Summary 1 The effect of short-term exposure to cupric ions (Cu2+) on electric field-stimulated (EFS) or agonist-induced contractions of guinea-pig isolated ileum was studied. 2 EFS elicited tetrodotoxin- and atropine-sensitive contractions that were concentration dependently inhibited by Cu2+ (IC50 = 14.7 ± 4.2 ,m). Maximal inhibition (90.4 ± 3.1% of baseline contractions) was attained with 30 ,m Cu2+. 3 Carbachol induced concentration-dependent contractions (EC50 = 0.021 ± 0.004 ,m) that were inhibited by 0.3 ,m atropine to a non-competitive manner (decreased maximal response, EC50 value = 0.26 ± 0.04 ,m, Ke = 0.026 ,m). Cu2+ (15 ,m) potentiated contractions induced by carbachol, such that the maximum response was increased by 30.3 ± 10.4%. 4 Histamine induced concentration-dependent contractions of the longitudinal muscle (EC50 = 0.11 ± 0.03 ,m). Dyphenhydramine (0.1 ,m) decreased the maximum response to histamine and shifted the curve to the right (EC50 value = 4.71 ± 0.35 ,m, Ke = 0.0024 ,m). Cu2+ (15 ,m) caused a rightward shift of the histamine concentration,response curve (EC50 = 0.61 ± 0.1 ,m) without changing the maximum response. Serotonin induced concentration-dependent contractions at concentrations higher than 10 nM (EC50 value of 0.34 ± 0.12 ,m) were not significantly affected by 15 ,m Cu2+. 5 Our results suggest that in ileal longitudinal muscle, Cu2+ inhibits cholinergic neurotransmission but also facilitates postsynaptic muscarinic receptor responses. [source] Effects of lipopolysaccharide on vascular reactivity and mortality in ratsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 5-6 2002J. P. L. Nunes Summary 1 The effects of intraperitoneal (i.p.) lipopolysaccharide on vascular reactivity to noradrenaline in rat aorta under different conditions of passive tension, as well as on mortality in normotensive and hypertensive rats, were studied. 2 Concentration,response curves to noradrenaline were obtained in aorta rings, at two levels of passive tension: 3 and 0.5 g, from control and lipopolysaccharide-treated Wistar rats. Contractile responses were expressed as percentage of the maximal response to noradrenaline obtained in the beginning of the experiment at a resting tension of 2 g. The maxima were significantly larger (P < 0.05) at 3 g than at 0.5 g in both groups of rats: 117.8 vs. 62.3%, respectively, for control animals; 85.8 vs. 32.5%, respectively, for lipopolysaccharide-treated rats. 3 The 24-h mortality after the i.p. administration of lipopolysaccharide was lower in spontaneously hypertensive rats (1/12; 8%), when compared with control Wistar,Kyoto rats (5/11; 45%). However, mortality was higher in Wistar,Kyoto made hypertensive by 8-day administration of corticosterone (6/6; 100%). 4 We conclude that a differential sensitivity to noradrenaline of aortic smooth muscle at two different levels of passive tension is still present in lipopolysaccharide-treated animals. Chronic hypertension in SHR rats is associated with resistance to the lethal effects of lipopolysaccharide, whereas abrupt-onset hypertension induced by corticosterone leads to an increased mortality. 5 These results are compatible with the myofibrillary hypothesis, which explains vascular hyper-reactivity in chronic arterial hypertension, by postulating that a more favourable relative position (and/or proportion) for actin and myosin occurs, whereas in states of vascular hypo-reactivity, such as vasodilatory shock, the opposite phenomenon may exist. [source] Functional importance of the actin cytoskeleton in contraction of bovine iris sphincter muscleAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2002J. A. C. Filipe Summary 1 The contractile capacity of smooth muscle cells depends on the cytoskeletal framework of the cell. The aim of this study was to determine the functional importance of both the actin and the tubulin components of the cytoskeleton in contractile responses of the bovine isolated iris sphincter muscle. 2 In each preparation, two contractions to the muscarinic agonist carbachol were obtained. The maximum responses of the first contractions were taken as 100%. The second contractions to carbachol were elicited in the presence of either cytochalasin B (50 and 5 ,m), an inhibitor of the actin cytoskeleton, or colchicine (100 ,m), an inhibitor of the tubulin cytoskeleton (30 min incubation). 3 Cytochalasin B, at a concentration of 50 ,m, significantly decreased the contractions induced by carbachol, with the maximum response reduced to 21.8 ± 6.6% (n = 12) of the initial maximum. The maximal contractions to carbachol in the presence of colchicine reached 96.2 ± 7.9% (n = 9) of the initial contraction, which was not significantly different from control second responses to carbachol with neither drug present, which reached 113.3 ± 7.6% (n = 7). 4 The effect of cytochalasin B was dose-dependent, since at a lower concentration of 5 ,m, the drug decreased the maximum contraction to carbachol to 60.3 ± 8.8% (n = 6). The effect of cytochalasin B was at least partially reversible, since after the use of the higher concentration of 50 ,m, contractions to carbachol increased to 62.3 ± 15.5% (n = 4) of the maximal response, after 1 h repeated washing of the preparations. 5 Cytochalasin D, at a concentration of 50 ,m, completely abolished the contractions induced by carbachol (n = 4). 6 These findings suggest that in bovine iris sphincter muscle, contractions to carbachol are highly dependent, from a functional point of view, on actin polymerization, and not, to any important degree, on the polymerization of tubulin. [source] A comparison of agonist-specific coupling of cloned human ,2 -adrenoceptor subtypesBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2000Jane E Rudling The agonist-specific coupling properties of the three cloned human ,2 -adrenoceptor subtypes have been compared, when expressed at similar levels in Chinese hamster ovary (CHO) cell lines, using noradrenaline and (±)- meta -octopamine as agonists. Noradrenaline can couple the receptor to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production in all three receptor subtypes, with the relative strength of the coupling to the pathways varying for each of the receptor subtypes. meta -Octopamine selectively couples the ,2A -adrenoceptor only to the inhibition of forskolin-stimulated cyclic AMP production. However, meta -octopamine couples the ,2B - and ,2C -adrenoceptors to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production. The relative potency of meta -octopamine to noradrenaline varies between the different ,2 -adrenoceptor subtypes. The effects of meta -octopamine are around two orders of magnitude less potent than those of noradrenaline on both the ,2A - and ,2B -adrenoceptor subtypes. In contrast, in the case of the ,2C -adrenoceptor, meta -octopamine is only one order of magnitude less potent than noradrenaline in the stimulation of forskolin-stimulated cyclic AMP production and, in addition, is equipotent with noradrenaline in the inhibition of forskolin-stimulated cyclic AMP production and has an increased maximal response. This raises the possibility that meta -octopamine may have physiologically important actions via ,2C -adrenoceptors in vivo. The results show that the modulation of cyclic AMP production occurs in both a subtype- and agonist-specific manner for ,2A -adrenoceptors and in a subtype specific manner for ,2B - and ,2C -adrenoceptors. British Journal of Pharmacology (2000) 131, 933,941; doi:10.1038/sj.bjp.0703644 [source] Phase 2 trial of docetaxel and gefitinib in the first-line treatment of patients with advanced nonsmall-cell lung cancer (NSCLC) who are 70 years of age or older,CANCER, Issue 9 2008George R. Simon MD Abstract BACKGROUND This is a phase 2 study of chemotherapy-naive patients, 70 years of age or older, with nonsmall-cell lung cancer (NSCLC) who were treated with docetaxel and gefitinib. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS) and progression-free survival (PFS). METHODS Eligible patients were treated with docetaxel 75 mg/m2 every 3 weeks and gefitinib 250 mg orally, daily. Docetaxel and gefitinib were given for 2 cycles beyond maximal response. Gefitinib was continued until disease progression. Comorbidities and activities of daily living were assessed (IADL). RESULTS Forty-four patients initiated therapy between March 2003 and May 2005. Seventeen patients (40%; 95% confidence interval [CI], 26%,57%) had a partial response and 48% had stable disease. The median PFS was 6.9 months (95% CI, 3.95,7.8 months). Median survival time was 9.6 months (95% CI, 4.6,16.3 months). On univariate analyses, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and Charlson comorbidities index (CCI) score were predictors of improved survival. On multivariate analyses female sex was a statistically significant predictor of survival. The median survivals were 22.8 months in women and 4.8 months in men. This regimen was well tolerated, with the most common adverse events being hyperglycemia, fatigue, and lymphopenia. CONCLUSIONS Docetaxel combined with gefitinib is active and well tolerated in patients with advanced NSCLC who are 70 years of age and older. This paradigm of treatment merits further investigation as a first-line treatment strategy. Female sex-specific confirmatory clinical trials with this regimen may be warranted. Cancer 2008. © 2008 American Cancer Society. [source] Role of the nitric oxide on diazoxide-induced relaxation of the calf cardiac vein and coronary artery during coolingFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2009K. E. Atalik Abstract The effects of cooling (to 28 °C) on the vasodilation induced by diazoxide (10,9,3 × 10,4 m) on carbachol-pre-contracted calf cardiac vein and coronary artery and the role of nitric oxide in these effects were analyzed. Diazoxide produced concentration-dependent relaxation of calf cardiac vein and coronary artery rings pre-contracted with carbachol (10,6 m). During cooling, the pIC50 values, but not the maximal responses, to diazoxide were significantly lower than at 37 °C in both preparations. Cooling to 28 °C in the presence of NG -nitro-L-arginine methyl ester (10,4 m) did not modify the effect of temperature both in cardiac vein and coronary artery. These results suggest that cooling-induced changes of diazoxide in calf cardiac vein and coronary artery are independent of nitric oxide. [source] Nitric Oxide-Sensitive Guanylyl Cyclase Activity Inhibition Through Cyclic GMP-Dependent DephosphorylationJOURNAL OF NEUROCHEMISTRY, Issue 5 2000Rut Ferrero Abstract: The soluble form of guanylyl cyclase (sGC) plays a pivotal role in the transduction of inter- and intracellular signals conveyed by nitric oxide. Here, a feedback inhibitory mechanism triggered by cyclic guanosine-3,,5,-monophosphate (cGMP)-dependent protein kinase (PKG) activation is described. Preincubation of chromaffin cells with C-type natriuretic peptide, which increased cGMP levels and activated PKG, or with cGMP-permeant analogue (which also activates PKG), in the presence of a broad-spectrum phosphodiesterase inhibitor, resulted in a decrease in subsequent sodium nitroprusside (SNP)-dependent cGMP elevations. This inhibitory effect was mimicked by activating a protein phosphatase and counteracted by the selective PKG inhibitor KT-5823 and by different protein phosphatase inhibitors. Immunoprecipitation of sGC from cells submitted to different treatments followed by immunodetection with antiphosphoserine antibodies (clone 4A9) showed changes in phosphorylation levels of the , subunit of sGC, and these changes correlated well with differences in SNP-elicited cGMP accumulations. Pretreatment of cells with several PKG inhibitors or protein phosphatase inhibitors produced an enhancement of SNP-stimulated cGMP rises without changing the SNP concentration required to produce half-maximal or maximal responses. Taken together, these results indicate that the catalytic activity of sGC is closely coupled to the phosphorylation state of its , subunit and that the tonic activity of PKG or its stimulation regulates sGC activity through dephosphorylation of the , subunit. [source] Thermal Facilitation of Lymphocyte Trafficking Involves Temporal Induction of Intravascular ICAM-1MICROCIRCULATION, Issue 2 2009QING CHEN ABSTRACT Objective: Fever is associated with improved survival, although its beneficial mechanisms are poorly understood. Previous studies indicate that the thermal element of fever augments lymphocyte migration across high endothelial venules (HEVs) of lymphoid organs by increasing the intravascular display of a gatekeeper trafficking molecule, intercellular adhesion molecule-1 (ICAM-1). Here, we evaluated the spatio-temporal relationship between the thermal induction of intravascular ICAM-1 and lymphocyte trafficking. Methods: Intravascular ICAM-1 density was quantified by immunofluorescence staining in mice exposed to fever-range whole-body hyperthermia (39.5±0.5°C). ICAM-1,dependent lymphocyte trafficking was measured in short-term homing assays. Results: A linear relationship was observed between the duration of heat treatment and intravascular ICAM-1 density in HEVs with maximal responses requiring sustained (i.e., five hours) thermal stress. Circulating lymphocytes were found to sense incremental changes in ICAM-1 on HEVs, such that trafficking is proportional to the intravascular density of ICAM-1. We further identified a hydroxamate-sensitive shedding mechanism that restores ICAM-1 expression to homeostatic levels following the cessation of thermal stress. Conclusions: The time-dependent response to thermal stress indicates that ICAM-1 density governs the efficiency of lymphocyte interactions with HEVs in vivo. These studies highlight the dynamic role of the microcirculation in promoting immune surveillance during febrile inflammatory responses. [source] Long-lasting changes in small intestinal transport following the recovery from Trichinella spiralis infectionNEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2006K. Venkova Abstract, Changes in intestinal motility and visceral sensitivity are found after resolution of acute enteric inflammation. The study investigates whether a transient nematode-induced intestinal inflammation may result in long-lasting remodelling of epithelial transport. Ferrets infected with Trichinella spiralis or sham-infected animals were euthanized on day 10, 30 or 60 postinfection (PI) and the jejunum was isolated. The net transport of electrolytes was measured electrophysiologically as transmucosal short-circuit current (Isc) and responses to electrical field stimulation (EFS: 1,32 Hz) or secretagogues were investigated. Myeloperoxidase (MPO) activity, a marker of mucosal inflammation, was maximal during the enteric stage of T. spiralis infection (day 10 PI) and returned to normal on days 30 and 60 PI. Mucosal inflammation caused a reduction in basal Isc, increased electrical conductance (G) and decreased the maximal responses to EFS, carbachol or histamine. On days 30 and 60 PI the inflammation resolved and basal electrogenic transport appeared normal; however, the secretion induced by EFS, carbachol or histamine remained suppressed. Moreover, EFS-induced responses were shifted from predominantly cholinergic in controls to non-cholinergic in the infected animals. The results suggest that a transient small intestinal inflammation causes a long-term remodelling of epithelial function. [source] Cation-induced superoxide generation in tobacco cell suspension culture is dependent on ion valencePLANT CELL & ENVIRONMENT, Issue 11 2001T. Kawano Abstract There have been many reports suggesting the involvement of reactive oxygen species (ROS), including superoxide anion (O2.,), in salt stress. Herein, direct evidence that treatments of cell suspension culture of tobacco (Nicotiana tabacum L.; cell line, BY-2) with various salts of trivalent, divalent and monovalent metals stimulate the immediate production of O2., is reported. Among the salts tested, LaCl3 and GdCl3 induced the greatest responses in O2., production, whereas CaCl2 and MgCl2 showed only moderate effects; salts of monovalent metals such as KCl and NaCl induced much lower responses, indicating that there is a strong relationship between the valence of metals and the level of O2., production. As the valence of the added metals increased from monovalent to divalent and trivalent, the concentrations required for maximal responses were lowered. Although O2., production by NaCl and KCl required high concentrations associated with hyperosmolarity, the O2., generation induced by NaCl and KCl was significantly greater than that induced simply by hyperosmolarity. Since an NADPH oxidase inhibitor, diphenyleneiodonium chloride, showed a strong inhibitory effect on the trivalent and divalent cation-induced generation of O2.,, it is likely that cation treatments activate the O2., -generating activity of NADPH oxidase. [source] Vascular ,1 -adrenoceptors in isolated perfused rat kidney: influence of ageingAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2007S. O. Awe Summary 1 The present study identifies ,1 -adrenoceptor subtype(s) involved in constrictor responses of the kidney and how ageing influences it. 2 The study was conducted on kidneys from F344BNF1 rats, which unlike F344 or Wistar rats used by many previous investigators do not exhibit glomerulonephritis at advanced age. 3 Noradrenaline (NA) and phenylephrine (PHE) (non-selective ,1) and A61063 (selective ,1A) adrenoceptor agonists elicited constriction of perfused kidneys of young and old rats. The pD2 values (index of renovascular reactivity) were significantly higher for A61603 than for either PHE or NA, and significantly decrease across age groups. 4 BMY 7378 or RS 100329, ,1D - or ,1A -adrenoceptor antagonists, respectively antagonized the constrictor responses and suppressed the maximal responses to all agonists in young adult rat kidneys. However, antagonism of PHE or A61063 by BMY 7378 in old rat kidneys was surmountable. 5 This study suggests that: (i) ,1A and ,1D -adrenoceptor subtypes mediate vasoconstriction of perfused rat kidney; (ii) ,1A -adrenoceptor subtype appears to predominate in renal vasculature based on agonist relative potencies. (iii) Ageing significantly decreases ,1 -adrenoceptor-mediated vasoconstriction of rat kidney. [source] | ||||||||||||||||||||||||||||