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Estrogen receptor-? mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract  

Microsoft Academic Search

It is generally believed that estrogen receptor-dependent and -independent pathways are involved in mediating the developmental effects of the synthetic estrogen, diethylstilbestrol (DES). However, the precise role and extent to which each pathway contributes to the resulting pathologies remains unknown. We have employed the estrogen receptor knockout (ERKO) mice, which lack either estrogen receptor-? (?ERKO or estrogen receptor-? (?ERKO), to

John F. Couse; Kenneth S. Korach



Prenatal exposure to diethylstilbestrol (DES): Childhood play behavior and adult gender-role behavior in women  

Microsoft Academic Search

Data from lower mammals suggest a masculinizing or defeminizing influence of pre- or perinatal diethylstilbestrol (DES) exposure on various aspects of the sex-dimorphic behavior (including juvenile rough-and-tumble play) of genetic females. However, three previous studies on childhood play and adult gender-role behavior in human females have led to ambiguous results. In a follow-up study of 60 women with prenatal exposure

Jennifer D. Lish; Heino F. L. Meyer-Bahlburg; Anke A. Ehrhardt; Bayla G. Travis; Norma P. Veridiano



Preterm Birth, Fetal Growth, and Age at Menarche among Women Exposed Prenatally to Diethylstilbestrol (DES)  

PubMed Central

Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR) = 2.97; 95%CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31,1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as <= 10 years (OR = 1.41 95%CI=0.97, 2.03) than defined as <= 11 years (OR=1.16; 95%CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.

Hatch, Elizabeth E.; Troisi, Rebecca; Wise, Lauren A.; Titus-Ernstoff, Linda; Hyer, Marianne; Palmer, Julie R.; Strohsnitter, William C; Robboy, Stanley J.; Anderson, Diane; Kaufman, Raymond; Adam, Ervin; Hoover, Robert N.



In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer  

Microsoft Academic Search

Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic\\u000a changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer\\u000a in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that\\u000a epigenetic alterations would precede the increased risk of

Leo F. Doherty; Jason G. Bromer; Yuping Zhou; Tamir S. Aldad; Hugh S. Taylor



Birth Defects in the Sons and Daughters of Women who were Exposed in utero to Diethylstilbestrol (DES)  

PubMed Central

Background Prenatal exposure to diethylstilbestrol (DES) is associated with adverse health outcomes, including anatomic anomalies of the reproductive tract in women and of the genitourinary tract in men. The mouse model, which replicates many DES-related effects seen in humans, suggests that prenatal DES exposure causes alterations that may affect the next generation of offspring. Methods Women participating in a large multi-center study of prenatal DES exposure were asked to report birth defects occurring among 4,029 sons and 3,808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters were also queried for birth defects. We used logistic regression models to generate odds ratios and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring. Results Based on the mothers’ reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34. Conclusions . Our data suggest a possible association between the mother’s prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters’ elevated risk of cardiac defects may be due to the underreporting of these conditions by unexposed mothers.

Titus-Ernstoff, Linda; Troisi, Rebecca; Hatch, Elizabeth E.; Palmer, Julie R.; Hyer, Marianne; Kaufman, Raymond; Noller, Kenneth; Hoover, Robert N.



Nuclear aberrations and loss of synaptonemal complexes in response to diethylstilbestrol (DES) in Caenorhabditis elegans hermaphrodites.  


In Caenorhabditis elegans, loss of viability and fertility is observed after treatment with DES. The decrease in life span is associated with senescent morphology of meiotic prophase nuclei, such that nuclei from young and old specimens cannot be differentiated. Aging in oocytes at the pachytene stage of meiotic prophase is manifested by nucleo-cytoplasmic aberrations, increased density of the nucleoplasm and cytoplasm and decrease in numbers of mitochondria. Increasing concentrations of DES are characterized by concomitant decrease in fertility and increased production of abnormal gametes. At DES concentrations higher than 1.25 micrograms/ml, synaptonemal complexes (SC) are absent from the nuclei, thus, effective pairing and segregation of homologous chromosomes is not possible. The absence of SCs may be the result of: a premeiotic colchicine-like effect that influences pairing of chromosomes; changes in the structure of the DNA due to DES binding that results in changes in expression of the DNA; and changes in temporal DNA synthesis in response to DES. Since the SC is essential for regulating pairing and subsequent separation of bivalents, the lack of an SC explains the loss of fertility, due to the production of unbalanced gametes, observed in DES-treated specimens. PMID:3713734

Goldstein, P



The improvement of in vivo model (Balb/c mice) for cervical carcinogenesis using diethylstilbestrol (DES).  


Cervical cancer is the most common gynecological cancer and one of the major causes of female cancer-related death worldwide particularly in developing countries. Thus far, there are a few in vivo models have been developed in investigating this type of cancer. In this study, we induced cervical cancer in Balb/c mice by exploiting the carcinogenic property of diestylstilbestrol (DES). The Balb/c pregnant mice were given subcutaneous (SC) injection of 67?g/kg body weight of DES on GD 13, and the mice gave birth approximately at gestation day 19-22. Female offspring were reared and the body weight was recorded once weekly. The female offspring were sacrificed at age of 5 months. Upon termination, blood was collected in a plain tube via cardiac puncture and the reproductive tracts were collected and weighed. The reproductive tract sections were stained using H&E for observation of pathological changes. The progression of disease state was monitored by measuring the level of serum interleukin (IL-6) using the Mouse IL-6 ELISA Assay Kit (BD OptEIA™, USA). All parameters were compared with Not-induced group. The outcome of this study demonstrated a significant difference in body weight gain, reproductive organ weight, diameter of cervix and the level of serum IL-6 in the Induced group as compared to the Not-induced group (P<0.05). Histopathological findings revealed the presence of adenosis only in the Induced group. It shows that DES could be employed as an agent to induce cervical carcinogenesis in animal model. In addition to that, new potential anti-cancer agents from various sources could be further evaluated using this technique. PMID:23726752

Zulfahmi, Said; Yazan, Latifah Saiful; Ithnin, Hairuszah; Armania, Nurdin



Effect of diethylstilbestrol on reproductive function  

Microsoft Academic Search

Objective: To review the effects of in utero exposure to diethylstilbestrol (DES) on müllerian development and subsequent reproductive function.Design: The literature on DES and reproductive function was reviewed and summary data are presented. The studies were identified through the computerized MEDLINE database and a manual search of relevent bibliographies.Result(s): In utero exposure to DES resulted in reduced fertility and increased

Jeffrey M Goldberg; Tommaso Falcone



Spectra of glutamate dehydrogenase with diethylstilbestrol.  


Glutamate dehydrogenase displays hyperchromicity at 256 nm and at 276 nm upon binding of diethylstilbestrol. Increase in absorbancy is linear at both regions up to 250 micrometer DES, and becomes parabolic at higher concentration of DES. ADP in the presence of DES causes decrease in absorbancy at 256 nm; absorbancy at 276 nm increased by DES is not affected by ADP. DES prevents spectral effects produced by GTP (decrease in absorbancy at 254 nm and at 276 nm). ADP still decreases absorbancy at 254 nm, leaving the 276 nm region unchanged. ADP enhances spectral effects produced by GTP. GTP, however, prevents changes produced by ADP. PMID:80167

Hillar, M



Prenatal Diethylstilbestrol Exposure and Risk of Breast Cancer  

Microsoft Academic Search

It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We

Julie R. Palmer; Lauren A. Wise; Elizabeth E. Hatch; Rebecca Troisi; Linda Titus-Ernstoff; William Strohsnitter; Raymond Kaufman; Arthur L. Herbst; Kenneth L. Noller; Marianne Hyer; Robert N. Hoover


Effects of Diethylstilbestrol on Mouse Hippocampal Evoked Potentials in Vitro  

Microsoft Academic Search

1.Several steroids and related compounds can bind to central opiate receptors in whole-brain mouse homogenates. Among these drugs, the synthetic estrogen, diethylstilbestrol (DES), exhibits one of the highest affinities in binding experiments labeling opiate receptors with the nonselective opiate antagonist, [3H]diprenorphine.

S. SanMartín; M. Gutiérrez; L. Menéndez; A. Hidalgo; A. Baamonde



Effects of Diethylstilbestrol in Fathead Minnows: Part 2. Concentrations in Water and Tissues  

EPA Science Inventory

Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was once widely prescribed to prevent miscarriages, and was used as a growth promoter in feed for beef and poultry production. After it was determined that DES caused significant adverse effects in the offspring of mot...


Rapid time-resolved fluoroimmunoassay for diethylstilbestrol in cow milk samples with a highly luminescent Tb 3+ chelate  

Microsoft Academic Search

Diethylstilbestrol (DES) is a non-steroidal synthetic molecule with estrogenic activity that provokes increased health risk in women whose mothers were given DES during pregnancy. In spite of this, it is sometimes illegally used as growth promoter in livestock breeding. Therefore methods that make it possible to monitor the presence of DES in food or in the environment might be of

Francesco Secundo; Maria A. Bacigalupo; Chiara Scalera; Silvio Quici


Localization of 3H-diethylstilbestrol in skeletal muscle  

SciTech Connect

The localization of diethylstilbestrol (DES) in skeletal muscle was studied in CF1 mice and perfused rat hindlimbs. There was a slow accumulation of 3H-DES in mouse muscle from 4 to 24 hours following i.p. injection even though plasma DES was decreasing. Twenty-four hours after injection of 50 microCi 3H-DES (714 pmole) mouse gastrocnemius contained 8.9 x 10(-17) mole unaltered 3H-DES per mg muscle. Extrapolating to the entire skeletal muscle mass of the animal, this represents 0.15% of the radioactivity injected. The radioactivity in muscle was completely extracted with 95% ethanol or ether: ethanol (3:1), and both unaltered DES and DES-metabolites were present in the extracts. The fraction of radioactivity due to unaltered DES 4 hours after injection was 0.51 +/- 0.09 in muscle and 0.30 +/- 0.11 in plasma. Significant extrahepatic metabolism of DES was demonstrated in perfused isolated rat hindlimbs by the presence of DES-metabolites in the perfusate. The radioactivity extracted from the perfused muscle itself was unaltered DES. These results indicate that skeletal muscle is an important site of DES localization in rodents.

Gruber, B.; Cohen, L.



Bioactivation of diethylstilbestrol by the Syrian hamster kidney  

SciTech Connect

Male Syrian golden hamsters chronically exposed to diethylstilbestrol (DES) develop renal adenocarcinomas with an incidence approaching 100%. The ability of the hamster kidney to bioactivate DES was assessed using hamster kidney slices. The male hamster renal cortex has a 2- to 5-fold greater capacity to irreversibly bind ({sup 3}H)DES as compared with female hamster renal cortex and with male hamster renal medulla. Incubation of the tissue under anaerobic conditions inhibited the metabolism and irreversible binding of ({sup 3}H)DES. Gel electrophoresis analysis of covalently modified proteins revealed several radioactive peaks indicating that specific adduct formation had occurred. The cytochrome P-450 inhibitors SKF 525-A, metyrapone, carbon monoxide, butylated hydroxytoluene, and dicumarol decreased the irreversible binding of ({sup 3}H)DES to renal cortical protein by 38 to 72%.

Adams, S.P.



Strain differences in the response of the mouse to diethylstilbestrol  

Microsoft Academic Search

BALB\\/c StCrlfC3Hf\\/Nctr, CS7BL\\/6J, C57BL\\/6 X BALB\\/c F1 hybrid (B6CF1), and monohybrid?cross offspring from the breeding of B6CF1 mice were examined with respect to uterine, vaginal, and thymus responses to diethylstilbestrol (DES). About 400 mice of each genetic population were used. Weanling mice were fed DES at dietary concentrations of 2.5 to 1,000 ppb (?g\\/kg feed) for 6 days and were

David L. Greenman; Kenneth Dooley; Cloyd R. Breeden; George H. Gass



Dietary Diethylstilbestrol but Not Genistein Adversely Affects Rat Testicular Development1,2  

Microsoft Academic Search

Isoflavones, including genistein, contribute to the health benefits of a soy diet. However, the estrogenic activity of genistein suggests that there may be adverse effects on reproductive tract development. We investigated the potential of exposure to genistein (250 and 1000 mg\\/kg diet) and the synthetic estrogen and known male reproductive toxicant, diethylstilbestrol (DES, 75 g\\/kg diet) from d 21 to

Wayne A. Fritz; Michelle S. Cotroneo; Jun Wang; Isam-Eldin Eltoum; Coral A. Lamartiniere


Sexual Dimorphism in Diethylstilbestrol-Induced Prolactin Pituitary Tumors in F344 Rats  

Microsoft Academic Search

Female F344 rats treated chronically with diethylstilbestrol (DES) develop prolactin (PRL)-producing pituitary tumors. These tumors are larger in female than in male rats. To investigate gender differences in DES-induced pituitary tumor formation, we employed female and male rats and neonatally androgenized females, which received 100 ?g of testosterone propionate (TP) after birth. At 3 months of age, all rats were

Gerardo G. Piroli; Alicia Torres; Luciana Pietranera; Claudia A. Grillo; Mónica G. Ferrini; Victoria Lux-Lantos; Agustin Aoki; Alejandro F. De Nicola



Long-Term Effects on the Female Mouse Genital Tract Associated with Prenatal Exposure to Diethylstilbestrol  

Microsoft Academic Search

The association between treatment of pregnant women with diethylstilbestrol (DES) and reproductive tract abnormalities in their female offspring is well known. Reports of comparable in utero exposure in animals are few. In this paper, pregnant outbred mice were treated s.c. with daily doses of DES ranging from 0.01 to 100 jug\\/kg on Days 9 to 16 of gestation. This period

John A. McLachlan; Retha R. Newbold; Bill C. Bullock


Response of Young Holstein-Friesian Heifers to Phenothiazine and Diethylstilbestrol1  

Microsoft Academic Search

A 2 × 2 factorial experiment with 48 Holstein heifers was conducted over a 2-yr pe~iod to study the effects of adding 10 mg diethylstilbestrol (DES) ; 1.5 g phenothiazine; or 10 mg DES and 1.5 g phenothiazine to the daily ration of young heifers on growth response and control of internal nematode parasites. When phenothiazine alone was added to

O. T. Fosgate; K. S. Hegde



Dependence on Exogenous Metabolic Activation for Induction of Unscheduled DMA Synthesis in Syrian Hamster Embryo Cells by Diethylstilbestrol and Related Compounds  

Microsoft Academic Search

Diethylstilbestrol (DES) induces morphological and neoplastia transformation of Syrian hamster embryo cells in vitro in the absence of any measurable induction of gene mutations, which is consistent with the lack of genotoxicity of DES in a number of other assays. However, a few reports of a genotoxic activity of DES in certain systems have been published. In order to under

Takeki Tsutsui; Gisela H. Degen; Dietmar Schiffmann; Annette Wong; Heiji Maizumi; John A. McLachlan; J. Carl Barrett


Diethylstilbestrol impairs the morphology and function of mouse gubernaculum testis in culture.  


Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen widely used in estrogen therapy. In animal models, exposure to DES disrupts the outgrowth of the gubernacula, leading to testis maldescent. However, it remains unclear whether the effects of DES on gubernaculum are direct or indirect, and the underlying mechanisms are largely obscure. In this study, mouse gubernaculum testis cells were isolated and treated by DES, and cell morphology and function were examined. The results showed that DES changed the morphology and inhibited the proliferation of gubernacular cells. Furthermore, DES increased intracellular [Ca(2+)] and induced F-actin rearrangement and stress fiber formation in gubernaculum testis cells in a dose-dependent manner. Taken together, these data suggest that DES impairs the morphology and inhibits the proliferation and contractility of gubernaculum testis cells. The experimental model we established and our observations based on this model help provide new insight into the role of DES in the etiology of cryptorchidism. PMID:22945456

Zhang, Xuan; Li, Jian-hong; Ma, Lian; Huang, Tian-hua; Jiang, Xue-wu



Quantitative proteomic determination of diethylstilbestrol action on prostate cancer  

PubMed Central

Diethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis (2D-DIGE) and isotope labelling tags for relative and absolute quantification (iTRAQ). Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins (P<0.01) were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins (>1.3 fold; P<0.05). The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure (i.e., 23 overexpressed and 42 underexpressed). Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT (P=0.006) and HSPB1 (P=0.046).

Bigot, Pierre; Mouzat, Kevin; Lebdai, Souhil; Bahut, Muriel; Benhabiles, Nora; Tassin, Geraldine Cancel; Azzouzi, Abdel-Rahmene; Cussenot, Olivier



Graphene oxide-modified electrodes for sensitive determination of diethylstilbestrol  

NASA Astrophysics Data System (ADS)

This paper reports an electrochemical sensor fabricated with graphene oxide (GO) modified on a chitosan-coated glassy carbon electrode (GO-CS/GCE) and its application for the detection of diethylstilbestrol (DES). It was observed that the effective electrochemical surface area of the GO modified electrode was nearly 10 times that of the bare GCE. This could be used to explain the results that the oxidation peak current of DES on the GO-CS/GCE was much larger than on the bare GCE. Under optimized conditions, the prepared electrode could be used to electrochemically detect DES according to the oxidation of the DES. Based on the technique of differential pulse voltammetry and the accumulation of DES on GO modified electrodes, the calibration curve for DES determination could be obtained with a linear range of 1.5 × 10-8-3.0 × 10-5 M and an estimated detection limit of 3.0 × 10-9 M (S/N = 3). The feasibility of the developed electrode for tablet sample analysis was investigated. Our investigation revealed that GO could significantly improve the analytical performance of electrochemical sensors.

Yu, Chunmei; Ji, Wanyu; Wang, Yidan; Bao, Ning; Gu, Haiying



Graphene oxide-modified electrodes for sensitive determination of diethylstilbestrol.  


This paper reports an electrochemical sensor fabricated with graphene oxide (GO) modified on a chitosan-coated glassy carbon electrode (GO-CS/GCE) and its application for the detection of diethylstilbestrol (DES). It was observed that the effective electrochemical surface area of the GO modified electrode was nearly 10 times that of the bare GCE. This could be used to explain the results that the oxidation peak current of DES on the GO-CS/GCE was much larger than on the bare GCE. Under optimized conditions, the prepared electrode could be used to electrochemically detect DES according to the oxidation of the DES. Based on the technique of differential pulse voltammetry and the accumulation of DES on GO modified electrodes, the calibration curve for DES determination could be obtained with a linear range of 1.5 × 10(-8)-3.0 × 10(-5) M and an estimated detection limit of 3.0 × 10(-9) M (S/N = 3). The feasibility of the developed electrode for tablet sample analysis was investigated. Our investigation revealed that GO could significantly improve the analytical performance of electrochemical sensors. PMID:23448852

Yu, Chunmei; Ji, Wanyu; Wang, Yidan; Bao, Ning; Gu, Haiying



Diethylstilbestrol increases the density of prolactin cells in male mouse pituitary by inducing proliferation of prolactin cells and transdifferentiation of gonadotropic cells  

Microsoft Academic Search

Diethylstilbestrol (DES) has been implicated in mammalian abnormalities. We examined the effects of DES on follicle-stimulating\\u000a hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) cells in the pituitaries of male mice treated with various doses\\u000a of DES for 20 days. DES reduced the density of FSH and LH cells in a dose-dependent manner, but increased that of PRL cells.\\u000a When the

Keiko Shukuwa; Shin-ichi Izumi; Yoshitaka Hishikawa; Kuniaki Ejima; Satoshi Inoue; Masami Muramatsu; Yasuyoshi Ouchi; Takashi Kitaoka; Takehiko Koji



Comparison of the Developmental and Reproductive Toxicity of Diethylstilbestrol Administered to Rats in Utero, Lactationally, Preweaning, or Postweaning  

Microsoft Academic Search

The objective of the study was to determine which period of exposure produces the most marked effects on the reproductive capacity and sexual development of the rat, with particular em- phasis on the relative sensitivity of in utero and postnatal expo- sures. The endocrine active chemical, diethylstilbestrol (DES) was used as an agent known to affect many of the endpoints

J. Odum; P. A. Lefevre; H. Tinwell; J. P. Van Miller; R. L. Joiner; R. E. Chapin; N. T. Wallis; J. Ashby



Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects.  


Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to the 1970s by pregnant women in hopes of preventing miscarriage. Decades later, DES is known to enhance breast cancer risk in exposed women and cause a variety of birth-related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a pinnacle compound that demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren. PMID:23897597

Reed, Casey E; Fenton, Suzanne E



Extracellular distribution of radiolabel obscures specific binding of diethylstilbestrol in mouse skeletal muscle  

SciTech Connect

The extracellular distribution of /sup 3/H-diethylstilbestrol (/sup 3/H-DES) in mouse skeletal muscle was assessed following intraperitoneal injection. Total muscle extracellular space was measured with /sup 14/C-inulin, and the vascular space with /sup 125/I-albumin. A significant difference in the distribution of native /sup 3/H-DES and its metabolites in muscle and blood was found. This could only be explained if these compounds distributed with the albumin space and not the inulin space.

Gruber, B.; Blix, P.M.; Cohen, L.



Effects of postnatal administration of diethylstilbestrol on puberty and thyroid function in male rats.  


To examine the effects of diethylstilbestrol (DES) on male pubertal development and thyroid function, juvenile male Sprague-Dawley rats were given DES daily by oral intubation at doses of 10, 20 and 40 microg/kg/day from postnatal day 33 for 20 days. Prepuce separation was significantly delayed at the dose of 20 microg/kg/day and above in the DES-treated rats. DES treatment induced a significant reduction in the weights of testes, epididymides, the ventral prostate, seminal vesicles plus coagulating glands and fluid, levator ani bulbocavernosus muscles, Cowper's glands and the glans penis. The weights of the liver and adrenals increased in the DES-treated animals. DES caused a dose-dependent reduction in germ cells; in particular the spermatids were mainly affected. The serum levels of testosterone and luteinizing hormone were significantly reduced in the DES-treated groups, but that of estradiol decreased. No differences were observed in the serum thyroxine levels of the control and DES-treated groups. In microscopic observation of the DES-treated animals, degeneration of germ cells and tubular atrophy in the testis were noted, but there were no microscopic changes in the thyroid. These results indicate that DES affected the pubertal development of juvenile male rats and that its mode of action may be related to alterations in hormone levels. PMID:19444002

Shin, Jae-Ho; Kim, Tae Sung; Kang, Il Hyun; Kang, Tae Seok; Moon, Hyun Ju; Han, Soon-Young



Abnormal Morphology of the Penis in Male Rats Exposed Neonatally to Diethylstilbestrol Is Associated with Altered Profile of Estrogen Receptor-a Protein, but Not of Androgen Receptor Protein: A Developmental and Immunocytochemical Study1  

Microsoft Academic Search

Objectives of the study were to determine developmental changes in morphology and expression of androgen receptor (AR) and estrogen receptor (ER)a in the body of the rat penis exposed neonatally to diethylstilbestrol (DES). Male pups re- ceived DES at a dose of 10 mg per rat on alternate days from Postnatal Day 2 to Postnatal Day 12. Controls received olive

H. O. Goyal; T. D. Braden; C. S. Williams; P. Dalvi; M. M. Mansour; J. W. Williams; F. F. Bartol; A. A. Wiley; L. Birch; G. S. Prins


Developmental effects of perinatal exposure to bisphenol-A and diethylstilbestrol on reproductive organs in female mice  

Microsoft Academic Search

Reproductive tract development is influenced by estrogen. The aim of this study was to determine the effects of an environmental estrogenic chemical bisphenol-A (BPA) on prenatal and postnatal development of female mouse reproductive organs. In the prenatal treatment group, BPA or the synthetic estrogen diethylstilbestrol (DES) were given by subcutaneous (s.c.) injections to pregnant mice during gestational days 10–18. Some

Atsuko Suzuki; Akika Sugihara; Kaoru Uchida; Tomomi Sato; Yasuhiko Ohta; Yoshinao Katsu; Hajime Watanabe; Taisen Iguchi



Mineral deposition in diethylstilbestrol- and Synovex-treated steers.  


The effects of diethylstilbestrol (DES) and Synovex-S hormonal growth promotants on composition of body ash deposited by feedlot beef steers were studied in two slaughter-balance trials. Trial 1 consisted of three groups of eight Hereford steers averaging 225 kg initial body weight. One group was initially slaughtered (IS) at the beginning of the trial and two groups, control (C) and DES-treated (20 mg/steer daily in diet), were fed for 177 d and then slaughtered. Trial 2 consisted of 28 Hereford steers averaging 310 kg initial body weight. Four steers were IS and 24 steers were assigned to a factorial arrangement of treatments (- or + Synovex-S ear implant and - or + dietary kiln dust), fed for 126 d and slaughtered. Each Synovex-S ear implant contained 200 mg progesterone and 20 mg estradiol benzoate. Kiln dust (KD) was fed as a digestive tract buffer, and the +KD diets contained 1.23% Ca and .37% P compared with .45% Ca and .36% P in -KD diets on an as-fed basis. Mineral concentration in body tissue was greater for IS than for fed steers reflecting deposition of soft tissue, particularly fat, during the feeding period. Mineral concentration in body tissue was similar between C and hormonally-treated steers. Mineral composition of tissue ash in IS, C and hormonally-treated steers and composition of ash deposited during the feeding period for C and treated steers were similar. The results suggest that both DES and Synovex treatments of beef steers do not cause an increased propensity for skeletal growth but that ash deposition is of similar composition in C and treated steers. PMID:4085903

Rumsey, T S; Kozak, A S; Tyrrell, H F



The Development of Cervical and Vaginal Adenosis as a Result of Diethylstilbestrol Exposure In Utero  

PubMed Central

Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed with DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses its molecular pathogenesis.

Laronda, Monica M.; Unno, Kenji; Butler, Lindsey M.; Kurita, Takeshi



Direct effects of diethylstilbestrol on the gene expression of the cholesterol side-chain cleavage enzyme (P450scc) in testicular Leydig cells  

Microsoft Academic Search

AimsTo investigate the precise mechanisms underlying the action of estrogenic endocrine disruptors, we evaluated the direct effects of synthetic estrogen diethylstilbestrol (DES) on steroidogenesis in Leydig cells, with particular emphasis on the expression of the cholesterol side-chain cleavage enzyme P450scc. Furthermore, the mechanism underlying the action of DES was compared with that of endogenous estrogen 17?-estradiol (E2), which has a

Katsuhiko Warita; Tomoko Mitsuhashi; Teruo Sugawara; Yoshiaki Tabuchi; Takashi Tanida; Zhi-Yu Wang; Yoshiki Matsumoto; Toshifumi Yokoyama; Hiroshi Kitagawa; Takanori Miki; Yoshiki Takeuchi; Nobuhiko Hoshi



Oxidative metabolites of diethylstilbestrol in the fetal Syrian golden hamster  

SciTech Connect

/sup 14/C-Diethylstilbestrol was administered orally, intraperitoneally, and intrafetally to 15-day pregnant hamsters at a dose of 20 mg/kg body weight, and the radioactivity was determined in the fetus, placenta, and maternal liver after 6 hours. Significant amounts of radioactivity were found in these tissues in every case, indicating maternal-fetal and fetal-maternal transfer of diethylstilbestrol. Part of the radioactivity found in the tissues could not be extracted even after excessive washing. This implied the presence of reactive metabolites. In the fetal and placental extracts, eight oxidative metabolites of diethylstilbestrol were identified by mass fragmentography as hydroxy- and methoxy-derivatives of diethylstilbestrol, pseudodiethylstilbestrol, and dienestrol. The presence of oxidative metabolites in the hamster fetus and the covalent binding to tissue macromolecules are possibly associated with the fetotoxic effects of diethylstilbestrol.

Maydl, R.; Metzler, M.



The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice.  


Epidemiology studies indicate that exposure to endocrine disruptors during developmental "window" contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) ? as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPAR? activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. PMID:22710028

Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei; Ma, Xu



The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice  

PubMed Central

Studies in rodents have shown that male sexual function can be disrupted by fetal or neonatal administration of compounds that alter endocrine homeostasis, such as the synthetic nonsteroidal estrogen diethylstilbestrol (DES). Although the molecular basis for this effect remains unknown, estrogen receptors likely play a critical role in mediating DES-induced infertility. Recently, we showed that the orphan nuclear receptor small heterodimer partner (Nr0b2), which is both a target gene and a transcriptional repressor of estrogen receptors, controls testicular function by regulating germ cell entry into meiosis and testosterone synthesis. We therefore hypothesized that some of the harmful effects of DES on testes could be mediated through Nr0b2. Here, we present data demonstrating that Nr0b2 deficiency protected mice against the negative effects of DES on testis development and function. During postnatal development, Nr0b2-null mice were resistant to DES-mediated inhibition of germ cell differentiation, which may be the result of interference by Nr0b2 with retinoid signals that control meiosis. Adult Nr0b2-null male mice were also protected against the effects of DES; however, we suggest that this phenomenon was due to the removal of the repressive effects of Nr0b2 on steroidogenesis. Together, these data demonstrate that Nr0b2 plays a critical role in the pathophysiological changes induced by DES in the mouse testis.

Volle, David H.; Decourteix, Melanie; Garo, Erwan; McNeilly, Judy; Fenichel, Patrick; Auwerx, Johan; McNeilly, Alan S.; Schoonjans, Kristina; Benahmed, Mohamed



Diethylstilbestrol inhibits tumor growth and prolactin production in rat pituitary tumors.  

PubMed Central

Treatment of rats bearing transplantable MtT/W15 tumors with 10 mg of diethylstilbestrol (DES) for 3 weeks led to inhibition of tumor growth. The inhibition of tumor growth was reversible after removal of the DES. Histologic examination revealed decreased mitotic activity; however, DES did not produce cell necrosis. Concomitantly, the anterior pituitary glands of animals treated with DES became hyperplastic, with an increased number of prolactin (PRL)-producing cells. DES resulted in a decreased number of PRL cells in the tumor and decreased serum PRL/tumor weight, compared with that of control rats. There was also an increase in the number of growth hormone (GH) tumor cells and an increased serum GH/tumor weight. 17 beta-Estradiol had an effect similar to that of DES, while progesterone did not inhibit tumor growth or cause pituitary cell hyperplasia. Ovariectomy resulted in a decrease in the tumor growth rate, compared with that of control animals, suggesting that the MtT/W 15 tumors are relatively dependent on estrogens for optimal growth. These results indicate that DES inhibition of MtT/W 15 tumor growth is an excellent model for study of the mechanism of the inhibition of tumor growth and the modification of GH and PRL expression by the tumor cells. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Lloyd, R. V.; Landefeld, T. D.; Maslar, I.; Frohman, L. A.



Physiological and biochemical perturbations in Daphnia magna following exposure to the model environmental estrogen diethylstilbestrol  

SciTech Connect

The estrogenic properties of many environmental contaminants, such as DDE and PCBs, have been associated with reproductive failure in a variety of vertebrate species. While estrogens have been measured in many invertebrate species, the function of this hormone in invertebrates is controversial. The objective of the present study was to identify possible physiological and biochemical target sites for the estrogenic effects of some xenobiotics on the freshwater crustacean Daphnia magna using the model environmental estrogen diethylstilbestrol (DES). Chronic exposure of daphnids to 0.50 mg/L DES reduced molting frequency among first-generation juveniles and decreased fecundity of second-generation daphnids. Adult first-generation daphnids chronically exposed to DES, as well as adult daphnids acutely exposed to DES for only 48 h, were examined for steroid hormone metabolic capabilities using testosterone as the model steroid. The rate of elimination of two major hydroxylated metabolites of testosterone was significantly reduced, and elimination of glucose conjugates of testosterone was significantly elevated from exposure to 0.50 mg/L DES. These results demonstrate that multigeneration exposure of daphnids to DES results in reduced fecundity and altered steroid metabolic capabilities. Thus, some arthropods, like vertebrates, are sensitive to the effects of endocrine-disrupting chemicals.

Baldwin, W.S.; Milam, D.L.; LeBlanc, G.A. [North Carolina State Univ., Raleigh, NC (United States). Dept. of Toxicology



Cloperastine rescues impairment of passive avoidance response in mice prenatally exposed to diethylstilbestrol.  


We previously reported that prenatal exposure to diethylstilbestrol (DES) impaired passive avoidance responses in mice. Apart from the above, we also found that cloperastine, a centrally acting antitussive, ameliorated depression-like and anxiety-like behaviors in rodents at antitussive-effective doses. In this study, we investigated whether or not cloperastine rescues impairment of passive avoidance responses in mice prenatally exposed to DES. Male DES-exposed mice were subcutaneously administered cloperastine at 10 or 30 mg/kg twice a day from 32 to 41 days after birth and subjected to behavioral testing 42 to 46 days after birth. Cloperastine at 10 and 30 mg/kg ameliorated DES-induced impairment of passive avoidance responses. In addition, cloperastine affected the levels of 5-HT(1A) receptors, GIRK and BDNF in the hippocampus of DES-exposed mice. However, the number of BrdU-positive cells in the hippocampus of DES-exposed mice was not changed by chronic administration of cloperastine. These findings suggest that the action of endocrine disruptors in the brain may not always be irreversible, and that the symptoms caused by endocrine disruptors might be curable with drugs such as cloperastine. © 2012 Wiley Periodicals, Inc. Environ Toxicol, 2012. PMID:22223406

Soeda, Fumio; Hirakawa, Emi; Inoue, Masako; Shirasaki, Tetsuya; Takahama, Kazuo



Urogenital teratogenicity of synthetic and natural estrogens in the rat: diethylstilbestrol and estradiol  

SciTech Connect

Diethylstilbestrol (DES), a synthetic estrogen and a carcinogen, is a potent urogenital teratogen in humans and rodents. The natural estrogen, estradiol (E/sub 2/), induces malformations in rats only at a maternal toxic dose. This difference in potency could result from differences in fetal sensitivity, or in the distribution and/or metabolism of the two compounds. The current studies tested the hypothesis that the teratogenicity of DES is mediated by its estrogenic activity (rather than its metabolic activation). The two estrogens were directly compared by injecting them into day 19 fetuses, bypassing any maternal modifying factors. Both DES (0.1, 1 or 10 and E/sub 2/ (10 or 100 caused dose-related incidences of urogenital malformations (diagnosed at 6-7 weeks), but DES was 10- to 100-fold more potent. Between 24 h and 9 days after DES or E/sub 2/ exposure, histologic evidence of estrogenic stimulation was observed, including premature myometrial growth and differentiation, and vaginal epithelial thickening. Thus, DES and E/sub 2/ act directly in the fetus, to produce similar teratogenic effects, without maternal mediation. Following both maternal and fetal administration of /sup 14/C-DES or /sup 3/H-E/sub 2/, the /sup 14/C (from DES) was concentrated in fetal tissues, whereas /sup 3/H (from E/sub 2/) was retained in fetal plasma (protein-bound). Fetal genital tract contained the largest proportion of unchanged E/sub 2/ (74%) or DES (86%). It was concluded that (1) the teratogenicity of DES reflects its estrogenic activity in the fetus; (2) the fetus is sensitive to a brief exposure to estrogens, including LY and (3) the synthetic estrogen is more potent that estradiol because of its greater availability to fetal genital tissues: protein binding and rapid metabolism reduce the teratogenicity of the natural estrogen.

Henry, E.C.



Model ecosystem evaluation of the environmental impacts of the veterinary drugs phenothiazine, sulfamethazine, clopidol, and diethylstilbestrol.  

PubMed Central

Four veterinary drugs of dissimilar chemical structures were evaluated for environmental stability and penchant for bioaccumulation. The techniques used were (1) a model aquatic ecosystem (3 days) and (2) a model feedlot ecosystem (33 days) in which the drugs were introduced via the excreta of chicks or mice. The model feedlot ecosystem was supported by metabolism cage studies to determine the amount and the form of the drug excreted by the chicks or mice. Considerable quantities of all the drugs were excreted intact or as environmentally short-lived conjugates. Diethylstilbestrol (DES) and Clopidol were the most persistent molecules, but only DES bioaccumulated to any appreciable degree. Phenothiazine was very biodegradable; sulfamethazine was relatively biodegradable and only accumulated in the organisms to very low levels. Data from the aquatic model ecosystem demonstrated a good correlation between the partition coefficients of the drugs and their accumulation in the fish. Images FIGURE 1.

Coats, J R; Metcalf, R L; Lu, P Y; Brown, D D; Williams, J F; Hansen, L G



Lack of Effects for Low Dose Levels of Bisphenol A and Diethylstilbestrol on the Prostate Gland of CF1 Mice Exposed in Utero  

Microsoft Academic Search

vom Saal et al. (Proc. Natl. Acad. Sci. 94, 2056–2061, 1997) have reported that low dose exposure (0.02–2 ?g\\/kg\\/day) of CF1 mice to diethylstilbestrol (DES) in utero led to increases in the prostate gland weight when the pups reached 8 months of age. Nagel et al. (Environ. Health Perspect. 105, 70–76, 1997) reported similar effects in CF1 mice at 6

John Ashby; H. Tinwell; J. Haseman



Towards functional glycomics by localization of binding sites for tissue lectins: lectin histochemical reactivity for galectins during diethylstilbestrol-induced kidney tumorigenesis in male Syrian hamster  

Microsoft Academic Search

Endogenous lectins act as effectors of cellular activities such as growth regulation, migration, and adhesion. Following their\\u000a immunohistochemical localization in our previous study (Saussez et al. in Histochem Cell Biol 123:29–41, 2005) we purified\\u000a several galectins and used them as tools for monitoring accessible binding sites. Herein, we report the use of galectin histochemistry\\u000a for the analysis of diethylstilbestrol (DES)-induced

Sven Saussez; Francois Lorfevre; Denis Nonclercq; Guy Laurent; Sabine André; Fabrice Journé; Robert Kiss; Gérard Toubeau; Hans-Joachim Gabius



Effects of Neonatal Exposure to 4-Tert-Octylphenol, Diethylstilbestrol, and Flutamide on Steroidogenesis in Infantile Rat Testis  

Microsoft Academic Search

Exposure of neonatal testis, populated by fetal-type Leydig cells, to endocrine-active compounds may have far-reaching consequences. Our aim was to resolve the sensitivity of testosterone synthesis of infant rat (Sprague-Dawley) testis to diethylstilbestrol (DES; 0.1-1.0 mg\\/kg), 4-tert-octylphenol (OP; 10-100 mg\\/kg), and Flutamide (FLU; 2.0-25 mg\\/kg) given by daily sc injections from birth to postnatal day 4. Testes and serum were

Tiina F. M. Mikkila; Jorma Toppari; Jorma Paranko



Modulation of murine liver macrophage clearance of liposomes by diethylstilbestrol. The effect of vesicle surface charge and a role for the complement receptor Mac1 (CD11b\\/CD18) of newly recruited macrophages in liposome recognition  

Microsoft Academic Search

We have studied the blood clearance and reticuloendothelial organ distribution of intravenously injected neutral (egg phosphatidylcholine, egg PC\\/cholesterol, mol ratio 7:2), anionic (egg PC\\/cholesterol\\/dicetylphosphate, mol ratio 7:2:1), and cationic (egg PC\\/cholesterol\\/stearylamine, mol ratio 7:2:1) liposomes of approximately the same size distribution in mice 3 days after treatment with the synthetic oestrogen diethylstilbestrol (DES). Male mice administered DES intraperitoneally at a

S. M Moghimi; H. M Patel



Effect of in utero exposure to diethylstilbestrol on lumbar and femoral bone, articular cartilage, and the intervertebral disc in male and female adult mice progeny with and without swimming exercise  

PubMed Central

Introduction Developmental exposure to estrogens has been shown to affect the musculoskeletal system. Furthermore, recent studies have shown that environmental exposure to estrogen-like compounds is much higher than originally anticipated. The aim of this study was to determine the effects of diethylstilbestrol (DES), a well-known estrogen agonist, on articular cartilage, intervertebral disc (IVD), and bone phenotype. Methods C57Bl/6 pregnant mice were dosed orally with vehicle (peanut oil) or 0.1, 1.0, and 10 ?g/kg/day of DES on gestational days 11 to 14. Male and female pups were allowed to mature without further treatment until 3 months of age, when swim and sedentary groups were formed. After euthanasia, bone mineral density (BMD), bone mineral content (BMC), bone area (BA), and trabecular bone area (TBA) of the lumbar vertebrae and femur were measured by using a PIXImus Bone Densitometer System. Intervertebral disc proteoglycan was measured with the DMMB assay. Histologic analysis of proteoglycan for IVD and articular cartilage was performed with safranin O staining, and degeneration parameters were scored. Results The lumbar BMC was significantly increased in female swimmers at both the highest and lowest dose of DES, whereas the femoral BMC was increased only at the highest. The males, conversely, showed a decreased BMC at the highest dose of DES for both lumbar and femoral bone. The female swim group had an increased BA at the highest dose of DES, whereas the male counterpart showed a decreased BA for femoral bone. The TBA showed a similar pattern. Proteoglycan analysis of lumbar IVDs showed a decrease at the lowest doses but a significant increase at the highest doses for both males and females. Histologic examination showed morphologic changes of the IVD and articular cartilage for all doses of DES. Conclusions DES significantly affected the musculoskeletal system of adult mice. Results suggest that environmental estrogen contaminants can have a detrimental effect on the developmental lumbar bone growth and mineralization in mice. Further studies measuring the impact of environmental estrogen mimics, such as bisphenol A, are then warranted.



An imprinted crystalline colloidal array chemical-sensing material for detection of trace diethylstilbestrol.  


Based on a combination of the molecular imprinting technique and polymerized crystalline colloidal array, we have developed an imprinted crystalline colloidal array (ICCA) chemical-sensing material for the real-time and label-free detection of diethylstilbestrol (DES) in aqueous solution. This novel sensing material was prepared by a noncovalent and self-assembly approach using liquid monodispersed DES-imprinted colloidal spheres and was characterized by a three-dimensional (3D) ordered opal structure in which numerous nanocavities were derived from DES imprinting. Thus, the inherent high affinity of the nanocavities allowed ICCA to recognize DES with high specificity, and changes of the ordered periodic structure enabled ICCA to transfer the recognition events into readable optical signals (label-free). Owing to the special opal structure and without interference from the bulk hydrogel film, the ICCA enabled the rapid and sensitive detection of the target analyte. The understanding of the recognizing response has also been advanced by using molecular modeling software to compute rational interaction between the template molecules and the function monomers. After careful optimization of the assay conditions, the ICCA could decrease its diffraction intensity within just 7 min according to the DES concentration from 2 ng mL(-1) to 8.192 ?g mL(-1), whereas there were no obvious diffraction intensity changes for the DES analogues. The adsorption results showed that the homogenous structure and large surface area of ICCA could improve its adsorption capacity. Therefore, such a sensing material with high selectivity, high sensitivity, high stability, and easy operation might offer an attractive alternative for establishing optical sensors for the rapid real-time monitoring of different residues in food and the environment. PMID:23482908

Sai, Na; Ning, Baoan; Huang, Guowei; Wu, Yuntang; Zhou, Zhijiang; Peng, Yuan; Bai, Jialei; Yu, Guanggui; Gao, Zhixian



Effect of diethylstilbestrol on feedlot associated bacteria  

Microsoft Academic Search

Oiethylstilbestr ol (DES) was used as an ingredient of cattle feed for many years because it increased the rate of weight gain. Unfortunately, this synthetic steroid hormone is not degraded significantly in manure and accumulates in cattle feed wastes and recently has been banned for use in feeds because it is a potential cause of cance~. Its use in implants~

D. W. Thayer; D. W. Unfred; R. K. Ando



Expression of Aquaporin 9 in Rat Liver and Efferent Ducts of the Male Reproductive System After Neonatal Diethylstilbestrol Exposure  

PubMed Central

Aquaporins (AQP) have important solute transport functions in many tissues including the epididymal efferent ducts (ED) and in the liver. We investigated the effect of neonatal exposure to diethylstilbestrol (DES) on AQP9 expressions in the ED and in the liver of rats. DES was administered from day 2 to day 20 postnatally at a dose of 4,8 ?g/day, and AQP9 protein and mRNA were measured by immunoblotting and real-time PCR, respectively, along with immunohistochemistry. DES caused hepatic downregulation of AQP9 at both the protein and mRNA level; however, decreased AQP9 labeling was only observed in the periportal zone. In the ED, AQP9 protein expression was increased in the DES-treated animals by 300% that could be ascribed to a widening of the ED lumen, whereas no difference was observed in AQP9 mRNA expression. Immunohistochemical findings revealed that AQP9 expression was confined to the epithelial cells of the ED. In conclusion, neonatal DES exposure appears to upregulate AQP9 channels in the ED in male rats, whereas a downregulation in the hepatic expression was observed, particularly in the periacinous area.(J Histochem Cytochem 56:425–432, 2008)

Wellejus, Anja; Jensen, Henrik E.; Loft, Steffen; Jonassen, Thomas E.



Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny.  


Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0?g/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3months, male progeny were left sedentary or were swim trained for 4weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. PMID:23142472

Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A; Chalifour, Lorraine E



[Histrelin acetate--the first once yearly LHRH agonist].  


Long-acting synthetic luteinising hormone-releasing hormone agonists have become the mainstay for androgen-deprivation therapy, because they avoid the physical and psychological discomfort associated with orchidectomy and lack the potential cardiotoxicity associated with estrogens such as diethylstilbestrol. Currently available luteinising hormone-releasing hormone agonist analogues include leuprolide, goserelin, triptorelin, degarelix and buserelin were administered as either intramuscular or subcutaneous depot injections on a 1, 2, 3 or 6 months basis. Histrelin acetate is the first long-acting luteinising hormone-releasing hormone agonist available as a once-yearly subcutaneous implant. PMID:22165080

Altarac, Silvio


Rapid time-resolved fluoroimmunoassay for diethylstilbestrol residues in chicken liver.  


A competitive time-resolved fluoroimmunoassay (TR-FIA) was developed for the determination of diethylstilbestrol (DES) residues in chicken liver. Prior to analysis, the residues were extracted from chicken liver with acetonitrile. The assay could be used in a quantitative or qualitative mode. The limit of detection (LOD) was determined to be 0.05 ngg(-1), and the limit of quantification (LOQ) was less than 0.18 ngg(-1). The intraassay variations were less than 10%, and the interassay variations were from 9.8 to 12.7%. The mean recoveries established at six concentration levels varied from 84.3 to 109.6%, and the coefficients of variation were from 8.3 to 12.4%. The results obtained by the TR-FIA and enzyme-linked immunosorbent assay (ELISA) showed a good correlation. The established TR-FIA was validated for the determination of incurred chicken liver and was confirmed by liquid chromatography and tandem mass spectrometry (LC-MS/MS). This proposed technique could be applied to routine residue analysis. PMID:16945319

Huo, Tieming; Wang, Liyin; Liu, Liqiang; Chu, Xiaogang; Xu, Chuanlai



Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium.  


Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ?Np63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5' sequence of ?Np63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ?Np63 in vaginal epithelium and developed adenosis. This SMAD-dependent ?Np63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ?Np63 expression in vaginal epithelium. Instead, the activity of the ?Np63 locus in vaginal epithelium was maintained by a ?Np63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate. PMID:23830984

Laronda, Monica M; Unno, Kenji; Ishi, Kazutomo; Serna, Vanida A; Butler, Lindsey M; Mills, Alea A; Orvis, Grant D; Behringer, Richard R; Deng, Chuxia; Sinha, Satrajit; Kurita, Takeshi



Effects of 4-tert-octylphenol, 4-tert-butylphenol, and diethylstilbestrol on prenatal testosterone surge in the rat.  


In the present study, we evaluated the effects that 4-tert-octylphenol (OP) and 4-tert-butylphenol (BP) had on the prenatal testicular testosterone surge at embryonic day (ED) 19.5 in the rat. In utero exposure to alkylphenols (0.1-100 mg/kg maternal weight) on EDs 13.5, 15.5, and 17.5 did not decrease testicular testosterone content, whereas exposure to diethylstilbestrol (DES) caused a significant depression in testosterone synthesis and secretion. The depression was maintained during ex vivo tissue culture. In order to elucidate the observed differences in the in vivo effects between alkylphenols and DES, the exposures were also carried out in tissue culture of intact ED 19.5 testes. Basal testosterone, progesterone, cAMP production and hCG-induced testosterone levels were determined during and after a 3-h culture period. DES (100 mg/l) did not alter testosterone production but caused a two-fold increase in progesterone. OP (10, 100, 500 mg/l) and BP (100 mg/l) significantly increased testosterone and progesterone levels by up to seven-fold. In the presence of BP 100 mg/l, however, the intratesticular testosterone content did not correlate with the significantly increased fraction of secreted, or leaked, testosterone. The latter was correlated with tissue damage observed at electron microscopic level. Consistent with this, BP 500 mg/l elevated testicular testosterone level slightly during the first hour in the culture but the level subsequently returned to the control value. At the electron microscopic level, alkylphenols caused most severe changes in Leydig cell membrane structures and lipid droplets. In the DES-treated testes, membrane vesicle formation around the lipid droplets and increased mitochondrial pleiomorphy were observed. Altogether, the present in vivo and in vitro analyses confirm different effects of alkylphenols and DES on fetal rat steroidogenesis and tissue structure. PMID:14555198

Haavisto, Tapio E; Adamsson, N Annika; Myllymäki, Sari A; Toppari, Jorma; Paranko, Jorma


Risks of prenatal exposure to diethylstilbestrol amongst males and females  

PubMed Central

The history of the drug diethystilbestrol (DES) is reviewed from its market entry in 1941 to its current status. In similarity to thalidomide, this drug was introduced without properly controlled clinical trials. However, in contrast to thalidomide, the effects of DES exposure are being recognized some 30 years later. DES was originally prescribed for pregnant women during high risk pregnancies to prevent miscarriage and premature birth. A review of the literature is presented and the long range effects in DES children are explained.

Dhami, MSI; Vernon, H; Kilgannon, R; Manolis, A



DES Education and Research Amendments of 1992. Report to accompany H.R. 4178. House of Representatives, 102D Congress, 2d Session.  

ERIC Educational Resources Information Center

|This document is a Congressional report about a proposed amendment to the Public Health Service Act to provide for a program to carry out research on the drug diethylstilbestrol (DES), to educate health professionals and the public on the drug, and to provide for certain longitudinal studies regarding DES. The amendment itself is presented in the…

Congress of the U.S., Washington, DC. House Committee on Energy and Commerce.


Diethylstilbestrol treatment increases the amount of choline kinase in rooster liver.  


Studies have been performed on the mechanism by which diethylstilbestrol stimulates the activity of choline kinase in livers from cockerels. The enzyme was purified 700-900-fold by affinity chromatography. The increased enzyme activity could not be accounted for by diethylstilbestrol alteration of the kinetic constants of the enzyme. Rabbit antibody was raised to the purified enzyme. Titration studies with antiserum demonstrated a 2-fold increase in the amount of choline kinase in diethylstilbestrol-treated cytosol, which correlated with a 2-fold elevation of the activity of the enzyme. We conclude that diethylstilbestrol stimulates the activities of choline kinase in cockerel liver by corresponding increase in the amount of enzyme. PMID:6275901

Paddon, H B; Vigo, C; Vance, D E



Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression through estrogen receptor element and nuclear factor-?B motifs.  


Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor ?B (NF-?B), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-?B, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-?B2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions. PMID:22888145

Singh, Narendra P; Singh, Udai P; Nagarkatti, Prakash S; Nagarkatti, Mitzi



An ERRbeta/gamma agonist modulates GRalpha expression, and glucocorticoid responsive gene expression in skeletal muscle cells.  


Estrogen-related receptors (ERRs) are constitutively active orphan nuclear receptors. Natural ligands have not been identified, however, recent reports have demonstrated the synthetic phenolic acyl hydrazone, GSK4716, functions as a selective ERRbeta/gamma agonist. We demonstrate that ERRbeta is transiently induced, and ERRgamma is dramatically induced (and accumulates) in a differentiation-dependent manner in skeletal muscle cells. Treatment of differentiated skeletal muscle cells with the ERRbeta/gamma agonist (GSK4716) produced a significant increase in the expression of GRalpha (isoform D) protein. Quantitative RT-PCR (Q-RT-PCR) analysis after treatment with GSK4716, revealed induction of the mRNAs encoding the glucocorticoid receptor (GR), 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), the enzyme that converts inactive cortisone to cortisol and hexose-6-phosphate dehydrogenase expression (H6PDH) that stimulates oxoreduction by 11beta-HSD1. Candidate based expression profiling also demonstrated the mRNAs encoding characterized GR target genes, including C/EBP, ApoD and Monoamine oxidase-A (MAO-A) are induced in GSK4716 treated cells. In concordance with these observations, siRNA-mediated suppression of the mRNA encoding ERRgamma (but not ERRalpha and beta) attenuated the expression of mRNAs encoding GR, 11betaHSD1 and GR target gene(s). Similarly, treatment with the ERRgamma (and ERalpha) antagonist diethylstilbestrol (DES) suppressed glucocorticoid responsive gene expression in skeletal muscle cells. Interestingly, we observed that GSK4716 trans-activated GRE-TK-LUC in a GR-dependent manner. This study highlights the regulatory crosstalk between ERRgamma and GR signaling in skeletal muscle cells, and suggests the ERRgamma agonist modulates the expression of critical genes that control GR signaling and glucocorticoid sensitive gene expression. PMID:19631715

Wang, Shu-Ching Mary; Myers, Stephen; Dooms, Cedric; Capon, Robert; Muscat, George E O



The avian egg as a test system for endocrine disrupters: effects of diethylstilbestrol and ethynylestradiol on sex organ development.  


Many environmental contaminants are known or suspected to interfere with hormonal function in animals. In vivo test methods to detect and characterize chemicals that disrupt the endocrine system are therefore urgently needed. In this study, we assessed the usefulness of abnormalities of the reproductive organs as test endpoints for estrogenic activity of xenobiotics in Japanese quail embryos. Two synthetic estrogens, diethylstilbestrol (DES) and ethynylestradiol (EE2), were injected into the yolks of embryonated eggs. At a dose as low as 2 ng EE2/g egg, all male embryos became feminized, containing ovary-like tissue in the left testis. The extent of feminization of the testes was determined by measuring the relative area of the ovary-like component. Persistent Müllerian ducts (oviducts) in male embryos, and malformations of the Müllerian ducts in females occurred at 2 ng EE2/g egg and higher doses. DES was approximately one-third to one-tenth as potent as EE2. The morphological changes studied were dose-dependent, indicating that they are useful as test endpoints for estrogenic activity. Feminization of the left testis in males proved to be the most sensitive endpoint. We propose the quail egg as a simple in vivo test system for estrogenic compounds. PMID:10492898

Berg, C; Halldin, K; Fridolfsson, A K; Brandt, I; Brunström, B



Structural basis for androgen receptor agonists and antagonists: interaction of SPEED 98-listed chemicals and related compounds with the androgen receptor based on an in vitro reporter gene assay and 3D-QSAR.  


The androgen receptor (AR) activity of listed chemicals, so called SPEED 98, by the Ministry of the Environment, Japan, and structurally related chemicals was characterized using MDA-kb2 human breast cancer cells stably expressing an androgen-responsive luciferase reporter gene, MMTV-luc. Since our results suggested that chemicals with diverse chemical structures were capable of disrupting the endocrine systems mediated by AR, a comparative molecular field analysis (CoMFA) model was developed to analyze the structural requirements necessary to disrupt AR function. A significant CoMFA model with r(2)=0.825 and q(2)=0.332 was developed for AR antagonist activity of 35 pure antagonists excluding procymidone. On the other hand, a good CoMFA model with r(2)=0.983 and q(2)=0.555 was obtained for antagonist activity of 13 chemicals with both agonist and antagonist activities. The steric and electrostatic properties were sufficient to describe the structural requirements for AR antagonist activity. In addition, the structural difference of AR agonists and antagonists was explained based on CoMFA results and the AR-LBD crystal structure. As several ERalpha agonists such as diethylstilbestrol (DES) acted as AR antagonists, the surface area of the AR ligand-binding domain (LBD) was compared with that of the ERalpha-LBD based on their reported crystal structures to analyze how those ligands interact with LBDs. The surface area of AR-LBD was shown to be smaller than that of ERalpha-LBD and therefore compounds with both estrogenic and antiandrogenic activities can fit well into the ERalpha-LBD but may protrude from the AR-LBD. It is likely that this subtle difference of the surface areas of the LBDs determines whether an ERalpha agonist acts as an AR antagonist or an agonist. PMID:16876421

Tamura, Hiroto; Ishimoto, Yoichi; Fujikawa, Tomoko; Aoyama, Hiroaki; Yoshikawa, Hiromichi; Akamatsu, Miki



Effects of non-steroidal estrogen diethylstilbestrol on pH and ion transport in the mantle epithelium of a bivalve Anodonta cygnea.  


Freshwater bivalves are used as sentinel organisms to detect pollutants effects in the aquatic environment due to their sedentary nature, filter-feeding behaviour. We aimed to determine the in vivo, ex vivo and in vitro influence of Diethylstilbestrol (DES), a widely used synthetic non-steroidal estrogen and endocrine disruptor, in Anodonta cygnea shell growth mechanisms. For that, in vivo exposure to DES (0.75?M) during 15 days, in vitro and ex vivo exposure of outer mantle epithelium (OME) cells to DES (0.75?M), were performed followed by study of short-circuit current (Isc), transepithelial potential (Vt) and transepithelial conductance (Gt) as well as identification of membrane transport systems and intracellular pH (pHi). Our results show that in vivo exposure to DES decreases in 30% the OME Isc and ex vivo addition of DES to the basolateral side of OME also induced Isc decrease. Several membrane transporters such as V-type ATPases, Na(+)/H(+) exchangers, Na(+)-K(+) pump, Na(+)-driven and Na(+)-independent HCO3(-)/Cl(-) transporters and Na(+)/HCO3(-) co-transporter were identified as responsible for pHi maintenance in OME and noteworthy, DES caused a pHi decrease in OME cells similar to the effect observed when OME cells were exposed to 4,4'-diisothiocyanostilbene disulfonic acid (DIDS), an inhibitor of several bicarbonate membrane transporters. The addition of DIDS after OME cells exposure to DES did not cause any alteration. We concluded that DES is able to modulate membrane ion transport and pHi in the OME of A. cygnea and that this effect seems to be due to inhibition of HCO3(-)/Cl(-) co-transporters present on the basolateral membrane. PMID:23953926

Alves, Marco G; Oliveira, Pedro F



Increased exocytosis of secretory granules in contrast to reduced serum hormone levels in pituitary adenomas of humans and rats treated with dopamine agonist  

Microsoft Academic Search

. The release of secretory granules outside the cells increased in frequency, in inverse proportion to the marked decrease in serum prolactin (PRL) levels in human prolactin-secreting adenomas (PRLomas) treated with bromocriptine (CB), a dopamine agonist. Rat pituitary adenomas induced by diethylstilbestrol also showed an increase in exocytosis of the granules despite a reduction in serum PRL levels after CB

Hiroshi Mori; Youichi Saitoh; Tamaki Maeda; Yoshikatsu Okada; Hiroshi Hirano; Motomu Tsuji



Analysis of the Effect of Estrogen/Androgen Perturbation on Penile Development in Transgenic and Diethylstilbestrol-Treated Mice  

PubMed Central

Because both androgens and estrogens have been implicated in penile morphogenesis, we evaluated penile morphology in transgenic mice with known imbalance of androgen and estrogen signaling using scanning electron microscopy (SEM), histology, and immunohistochemistry of androgen and estrogen receptors ?/?. Penises of adult wild-type, estrogen receptor-? knockout (?ERKO), estrogen receptor-? knockout (?ERKO), aromatase knockout (Arom-KO), and aromatase overexpression (Arom+) mice were evaluated, as well as adult mice treated with diethylstilbestrol (DES) from birth to day 10. Adult penises were examined because the adult pattern is the endpoint of development. The urethral orifice is formed by fusion of the MUMP (male urogenital mating protuberance) with the MUMP ridge, which consists of several processes fused to each other and to the MUMP. Similarly, the internal prepuce is completed ventrally by fusion of a ventral cleft. In adult murine penises the stromal processes that form the MUMP ridge are separated from their neighbors by clefts. ?ERKO, ?ERKO, and Arom-KO mice have penises with a MUMP ridge clefting pattern similar to that of wild-type mice. In contrast, Arom+ mice and neonatally DES-treated mice exhibit profound malformations of the MUMP, MUMP ridge clefting pattern, and internal prepuce. Abnormalities observed in Arom+ and neonatally DES-treated mice correlate with the expression of estrogen receptor-beta (ER?) in the affected structures. This study demonstrates that formation of the urethal orifice and internal prepuce is due to fusion of separate epithelial-surfaced mesenchymal elements, a process dependent upon both androgen and estrogen signaling, in which ER? signaling is strongly implicated.




Persistent Hypomethylation in the Promoter of Nucleosomal Binding Protein 1 (Nsbp1) Correlates with Overexpression of Nsbp1 in Mouse Uteri Neonatally Exposed to Diethylstilbestrol or Genistein  

PubMed Central

Neonatal exposure of CD-1 mice to diethylstilbestrol (DES) or genistein (GEN) induces uterine adenocarcinoma in aging animals. Uterine carcinogenesis in this model is ovarian dependent because its evolution is blocked by prepubertal ovariectomy. This study seeks to discover novel uterine genes whose expression is altered by such early endocrine disruption via an epigenetic mechanism. Neonatal mice were treated with 1 or 1000 ?g/kg DES, 50 mg/kg GEN, or oil (control) on d 1–5. One group of treated mice was killed before puberty on d 19. Others were ovariectomized or left intact, and killed at 6 and 18 months of age. Methylation-sensitive restriction fingerprinting was performed to identify differentially methylated sequences associated with neonatal exposure to DES/GEN. Among 14 candidates, nucleosomal binding protein 1 (Nsbp1), the gene for a nucleosome-core-particle binding protein, was selected for further study because of its central role in chromatin remodeling. In uteri of immature control mice, Nsbp1 promoter CpG island (CGI) was minimally methylated. Once control mice reached puberty, the Nsbp1 CGI became hypermethylated, and gene expression declined further. In contrast, in neonatal DES/GEN-treated mice, the Nsbp1 CGI stayed anomalously hypomethylated, and the gene exhibited persistent overexpression throughout life. However, if neonatal DES/GEN-treated mice were ovariectomized before puberty, the CGI remained minimally to moderately methylated, and gene expression was subdued except in the group treated with 1000 ?g/kg DES. Thus, the life reprogramming of uterine Nsbp1 expression by neonatal DES/GEN exposure appears to be mediated by an epigenetic mechanism that interacts with ovarian hormones in adulthood.

Tang, Wan-Yee; Newbold, Retha; Mardilovich, Katerina; Jefferson, Wendy; Cheng, Robert Y. S.; Medvedovic, Mario; Ho, Shuk-Mei



Metal ions-based immunosensor for simultaneous determination of estradiol and diethylstilbestrol.  


Environmental estrogens (EEs) can cause various endocrine diseases. Herein, we designed an ultrasensitive electrochemical immunosensor for simultaneous detection of two typical EEs, estradiol and diethylstilbestrol. These two analytes were immobilized on graphene sheet (GS) modified glassy carbon electrode (GCE). Amino-group functionalized mesoporous Fe3O4 (Fe3O4-NH2) was loaded with Pb(2+) or Cd(2+), and then incubated with estradiol and diethylstilbestrol antibodies, respectively. Using an electrochemical analysis technique, two well-separated peaks were generated by the redox reaction of Pb(2+) or Cd(2+), making the simultaneous detection of two analytes on the electrode possible. Subsequently, square wave anodic stripping voltammetry (SWASV) and electrochemical impedance spectroscopy (EIS) were used to investigate the electrochemical behaviors of the immunosensor. Under optimized conditions, the SWASV peak currents were proportional to the concentrations of estradiol and diethylstilbestrol in the range from 0.050pgmL(-1) to 100ngmL(-1) and 1.0pgmL(-1) to 100ngmL(-1), respectively. The immunosensor exhibited highly sensitive response to estradiol with a detection limit of 0.015pgmL(-1) and diethylstilbestrol with a detection limit of 0.38pgmL(-1). Furthermore, the immunosensor was satisfactorily employed to detect estradiol and diethylstilbestrol simultaneously in water samples. PMID:24055936

Zhang, Sen; Du, Bin; Li, He; Xin, Xiaodong; Ma, Hongmin; Wu, Dan; Yan, Liangguo; Wei, Qin



Neonatal Diethylstilbestrol Exposure Disrupts Female Reproductive Tract Structure/Function Via Both Direct And Indirect Mechanisms In The Hamster  

PubMed Central

We assessed neonatal diethylstilbestrol (DES)-induced disruption at various endocrine levels in the hamster. In particular, we used organ transplantation into the hamster cheek pouch to determine whether abnormalities observed in the post-pubertal ovary are due to: a) a direct (early) mechanism; or b) an indirect (late) mechanism that involves altered development and function of the hypothalamus and/or pituitary. Of the various disruption endpoints and attributes assessed: 1) some were consistent with the direct mechanism (altered uterine and cervical dimensions/organization, ovarian polyovular follicles, vaginal hypospadius, endometrial hyperplasia/dysplasia); 2) some were consistent with the indirect mechanism (ovarian/oviductal salpingitis, cystic ovarian follicles); 3) some were consistent with a combination of the direct and indirect mechanisms (altered endocrine status); and 4) the mechanism(s) for one (lack of corpora lutea) was uncertain. This study also generated some surprising observations regarding vaginal estrous assessments as a means to monitor periodicity of ovarian function in the hamster.

Alwis, Imala D.; Maroni, Dulce M.; Hendry, Isabel R.; Roy, Shyamal K.; May, Jeffrey V.; Leavitt, Wendell W.; Hendry, William J.



Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen  

SciTech Connect

Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.

Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States)]. E-mail:; Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States); Ward, Jerrold M. [National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892 (United States); Diwan, Bhalchandra A. [Basic Research Program, Science Applications International Corporation, National Cancer Institute at Frederick, Frederick, MD 21702-1201 (United States)



Determination of diethylstilbestrol in milk using carbon nanotube-reinforced hollow fiber solid-phase microextraction combined with high-performance liquid chromatography.  


Carbon nanotube-reinforced hollow fiber solid-phase microextraction (CNTs-HF-SPME) combined with high-performance liquid chromatography (HPLC) was used to extract and determine diethylstilbestrol (DES) in milk products. Wall pores of the hollow fiber were filled with multi-walled carbon nanotubes (MWCNTs) using sol-gel technology. In the proposed method, DES was selectively extracted by MWCNTs, desorbed to methanol, and analyzed by HPLC. The parameters affecting the efficiency of CNTs-HFSPME, such as the length of the hollow fiber, extraction and desorption times, extraction temperature, stirring rate, pH of the sample solution, and the amount of organic solvent and salt in the sample solution, were investigated and optimized. Under the optimized extraction conditions, the method showed good linearity (24-960 ?g L(-1)), a low method detection limit (MDL, 5.1 ?g L(-1)), and good recoveries at four different concentrations. It was proven to be simple, rapid, sensitive, and solvent free for the analysis of DES in dairy products. PMID:22841071

Yang, Yang; Chen, Juan; Shi, Yan-Ping



A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol  

PubMed Central

Background: The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS). Methods: From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1?:?1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan–Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance. Results: At study entry, the median age was 76 years (inter-quartile range: 70–80 years), the median PSA was 79?ng?ml?1, and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ?11?g?dl?1 decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25–0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno–thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001). Conclusion: Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

Shamash, J; Powles, T; Sarker, S J; Protheroe, A; Mithal, N; Mills, R; Beard, R; Wilson, P; Tranter, N; O'Brien, N; McFaul, S; Oliver, T



No Increased Risk for Most Cancers Yet Observed in Daughters of Women Exposed to DES in the 1940s and 1950s

The first systematic follow-up study of a large group of women, whose mothers were given the synthetic estrogen diethylstilbestrol (DES) during pregnancy in the 1940s and 1950s, found no increase in any type of cancer except for clear cell adenocarcinoma of the vagina and cervix in women under age 30.


The effect of neonatal exposure to diethylstilbestrol, coumestrol, and beta-sitosterol on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat.  


The neonatal hormone environment influences the sexually differentiated patterns of development. Estrogens, derived from intracerebral aromatization, promote male pattern development of the central nervous system. The purpose of this study was to determine the effects of neonatal exposure to environmental estrogens on luteinizing hormone (LH) secretion and development of the sexually dimorphic nucleus of the medial preoptic area (SDN-POA) in castrated adult rats. Neonatal rats of both sexes received injections of either corn oil, 0.1 microgram diethylstilbestrol (DES), 3 micrograms beta-sitosterol (B1), 30 micrograms beta-sitosterol (B2), 0.1 microgram coumestrol (C1), 1 microgram coumestrol (C2), or 10 micrograms coumestrol (C3) on Day 1-10 of life and were castrated on Day 21. Right heart catheters were placed on Day 42, and GnRH (50 ng/kg) was administered. Blood was sampled for LH at 0-, 5-, 10-, 15-, and 30-min intervals. All doses of beta-sitosterol and coumestrol elicited increased basal levels of LH in females. In males, B1, B2, C2, and C3 increased basal levels of LH. The GnRH-induced LH increase was prevented in females treated with diethylstilbestrol and 10 micrograms of coumestrol. Males in all treatment groups exhibited GnRH-induced LH surges. The animals were sacrificed by decapitation on Day 49. Volumes of the SDN-POA of the groups were compared. Treatment with the agents did not result in significantly increased SDN volume in females; nor was there a difference in SDN size among the male groups. These data show that exposure to environmental estrogens early in development alters both postpubertal pituitary response to GnRH and basal LH secretion in females and alters only basal LH secretion in males. No significant enlargement (i.e., masculinization) of the SDN-POA was exhibited. PMID:7892299

Register, B; Bethel, M A; Thompson, N; Walmer, D; Blohm, P; Ayyash, L; Hughes, C



Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca2+ Signals in Pancreatic ?-Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans  

PubMed Central

Glucagon, secreted from pancreatic ?-cells integrated within the islets of Langerhans, is involved in the regulation of glucose metabolism by enhancing the synthesis and mobilization of glucose in the liver. In addition, it has other extrahepatic effects ranging from lipolysis in adipose tissue to the control of satiety in the central nervous system. In this article, we show that the endocrine disruptors bisphenol A (BPA) and diethylstilbestrol (DES), at a concentration of 10?9 M, suppressed low-glucose–induced intracellular calcium ion ([Ca2+]i) oscillations in ?-cells, the signal that triggers glucagon secretion. This action has a rapid onset, and it is reproduced by the impermeable molecule estradiol (E2) conjugated to horseradish peroxidase (E-HRP). Competition studies using E-HRP binding in immunocytochemically identified ?-cells indicate that 17?-E2, BPA, and DES share a common membrane-binding site whose pharmacologic profile differs from the classical ER. The effects triggered by BPA, DES, and E2 are blocked by the G?i- and G?o-protein inhibitor pertussis toxin, by the guanylate cyclase–specific inhibitor 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one, and by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. The effects are reproduced by 8-bromo-guanosine 3?,5?-cyclic monophosphate and suppressed in the presence of the cGMP-dependent protein kinase inhibitor KT-5823. The action of E2, BPA, and DES in pancreatic ?-cells may explain some of the effects elicited by endocrine disruptors in the metabolism of glucose and lipid.

Alonso-Magdalena, Paloma; Laribi, Ouahiba; Ropero, Ana B.; Fuentes, Esther; Ripoll, Cristina; Soria, Bernat; Nadal, Angel



In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles.  


Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10(-6) M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals. PMID:15781295

Myllymäki, Sari; Haavisto, Tapio; Vainio, Minna; Toppari, Jorma; Paranko, Jorma



In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles  

SciTech Connect

Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.

Myllymaeki, Sari [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland) and Departments of Physiology and Pediatrics, University of Turku, Turku (Finland)]. E-mail:; Haavisto, Tapio [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Vainio, Minna [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Toppari, Jorma [Departments of Physiology and Pediatrics, University of Turku, Turku (Finland); Paranko, Jorma [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland)



Metabolism of diethylstilbestrol by horseradish peroxidase and prostaglandin-H synthase. Generation of a free radical intermediate and its interaction with glutathione  

SciTech Connect

Diethylstilbestrol is carcinogenic in rodents and in humans and its peroxidatic oxidation in utero has been associated with its carcinogenic activity. Horseradish peroxidase-catalyzed oxidation of (14C)diethylstilbestrol and (14C)diethylstilbestrol analogs induced binding of radiolabel to DNA only when the compound contained a free hydroxy group (Metzler, M., and Epe, B. (1984) Chem. Biol. Interact. 50, 351-360). We have found that horseradish peroxidase or prostaglandin-H synthase-catalyzed oxidation of diethylstilbestrol in the presence of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide caused the generation of an ESR signal indicative of a free radical intermediate (aN = 14.9 G, aH = 18.3 G). The identity of the trapped radical could not be identified on the basis of published hyperfine coupling constants, but the observation that horseradish peroxidase-catalyzed oxidation of 1-naphthol produced an identical ESR signal suggests that the radical was either a phenoxy or phenoxy-derived radical. During horseradish peroxidase-catalyzed oxidation of diethylstilbestrol in the presence of glutathione the thiol reduced the diethylstilbestrol radical to generate a thiyl radical. This was shown by a thiol-dependent oxygen uptake during horseradish peroxidase-catalyzed oxidation of diethylstilbestrol and the observation of an ESR signal consistent with 5,5-dimethylpyrroline-N-oxide-glutathionyl radical adduct formation. A diethylstilbestrol analog devoid of free hydroxy groups, namely diethylstilbestrol dipropionate, did not produce an ESR signal above control levels during horseradish peroxidase-catalyzed metabolism in the presence of 5,5-dimethylpyrroline-N-oxide. Thus, free radicals are formed during peroxidatic oxidation of diethylstilbestrol and must be considered as possible determinants of the genotoxic activity of this compound.

Ross, D.; Mehlhorn, R.J.; Moldeus, P.; Smith, M.T.



Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring  

PubMed Central

Maternal exposure to estrogenic xenobiotics or phthalates has been implicated in the distortion of early male reproductive development, referred to in humans as the testicular dysgenesis syndrome. It is not known, however, whether such early gestational and/or lactational exposure can influence the later adult-type Leydig cell phenotype. In this study, Sprague–Dawley rats were exposed to dibutyl phthalate (DBP; from gestational day (GD) 14.5 to postnatal day (PND) 6) or diethylstilbestrol (DES; from GD14.5 to GD16.5) during a short gestational/lactational window, and male offspring subsequently analysed for various postnatal testicular parameters. All offspring remained in good health throughout the study. Maternal xenobiotic treatment appeared to modify specific Leydig cell gene expression in male offspring, particularly during the dynamic phase of mid-puberty, with serum INSL3 concentrations showing that these compounds led to a faster attainment of peak values, and a modest acceleration of the pubertal trajectory. Part of this effect appeared to be due to a treatment-specific impact on Leydig cell proliferation during puberty for both xenobiotics. Taken together, these results support the notion that maternal exposure to certain xenobiotics can also influence the development of the adult-type Leydig cell population, possibly through an effect on the Leydig stem cell population.

Ivell, Richard; Heng, Kee; Nicholson, Helen; Anand-Ivell, Ravinder



Diethylstilbestrol treatment modulates the enzymatic activities of phosphatidylcholine biosynthesis in rooster liver.  


The effect of diethylstilbestrol injection on the activities of phosphatidylcholine biosynthetic enzymes in rooster liver has been determined. Choline kinase activity was stimulated within 4 h after the first hormone injection. By the third day enzyme activity reached 5.47 nmol . min-1 . mg-1 protein compared to control values (1.83 nmol . min-1 . mg-1 protein) which were unchanged during the the experiment. CTP : phosphocholine cytidylyltransferase activity was unaffected until Day 3 when its activity was 50% that of control values. When assayed in the presence of exogenous phospholipid, no significant change was noted in cytidylyltransferase activity. The activity of CDPcholine : 1,2-diacylglycerol phosphocholinetransferase was not altered by the hormone injections. The activity of phosphatidylethanolamine-N-methyltransferase gradually increased so that by Day 3, the enzyme activity was elevated 2-fold (0.12 to 0.24 nmol methyl group transferred per mg microsomal protein). These results are consistent with earlier in vivo studies (Vigo, C. and Vance, D.E. (1981) Eur. J. Biochem., in the press) that indicated a stimulation of phosphatidylcholine biosynthesis via CDPcholine during the first 2 days of diethylstilbestrol injection and inhibition on the third day. PMID:6271230

Vigo, C; Paddon, H B; Millard, F C; Pritchard, P H; Vance, D E



Ga-67 uptake in diethylstilbestrol-induced gynecomastia. Experience with six patients  

SciTech Connect

Six patients who had been treated with diethylstibestrol (DES) for prostatic cancer had symmetrical breast uptake of Ga-67. Of these patients, five proved to have DES-induced gynecomastia. The minimum dose and administration period of DES required for Ga-67 uptake in gynecomastia is discussed.

Kosuda, S.; Kawahara, S.; Tamura, K.; Saito, K.; Kubo, A.; Hashimoto, S. (Tokyo Metropolitan Komagome Hospital (Japan))



Women exposed to DES in the womb face increased cancer risk:

A large study of the daughters of women who had been given DES, the first synthetic form of estrogen, during pregnancy has found that exposure to the drug while in the womb (in utero) is associated with many reproductive problems and an increased risk of certain cancers and pre-cancerous conditions. Beginning in 1940, diethylstilbestrol, known as DES, was used clinically to prevent certain complications of pregnancy. In the 1950s, clinical studies showed DES was ineffective for this purpose. In the late 1960s, an unusual occurrence of a rare cancer of the vagina among young women, called clear cell adenocarcinoma (CCA), was observed and subsequently linked to their exposure to DES while in the womb.


Inhibition of Adenosine Triphosphatase Activity of the Plasma Membrane Fraction of Oat Roots by Diethylstilbestrol 1  

PubMed Central

Diethylstibestrol (DES) inhibited noncompetitively the ATPase in the plasma membrane fraction from Avena sativa L. cv. Goodfield roots when assayed in the presence of MgSO4 or MgSO4 plus KCl. In the presence of MgSO4, 7.1×10?5 molar DES inhibited the enzyme 50%; whereas in the presence of MgSO4 and KCl, 1.3×10?4 molar DES was required for the same inhibition. Dixon plots indicated that in the presence of MgSO4, one molecule of DES bound to one molecule of ATPase; however, in the presence of MgSO4 and KCl, two or more molecules bound to one ATPase molecule. These results suggested that KCl causes a conformational change in the enzyme which exposes additional binding sites for DES, but that these sites are not as inhibitory as the first binding site. In addition to KCl, other factors also affected the DES inhibition of the ATPase. Plasma membrane vesicles warmed to 38 C were inhibited more than vesicles kept on ice prior to assay. DES inhibited the Triton X-100-treated ATPase less than the ATPase which was not detergent-treated. Finally, studies with DES analogs showed that the hydroxyl groups of DES were essential for inhibition and that steric configurations of the molecule were important. DES inhibition of the ATPase suggests that DES inhibits K+ absorption in oat roots by inhibiting the ATPase. Inhibition of K+ absorption was greater than inhibition of the ATPase, and thus DES may also inhibit other aspects of metabolism that are involved with ion absorption.

Balke, Nelson E.; Hodges, Thomas K.



Emerging adenosine receptor agonists.  


Adenosine receptors (ARs) are a four-member subfamily of G protein-coupled receptors and are major targets of caffeine and theophylline. There are four subtypes of ARs, designated as A1, A2A, A2B and A3. Selective agonists are now available for all four subtypes. Over a dozen of these selective agonists are now in clinical trials for various conditions, although none has received regulatory approval except for the endogenous AR agonist adenosine itself. A1AR agonists are in clinical trials for cardiac arrhythmias and neuropathic pain. A2AAR agonists are now in trials for myocardial perfusion imaging and as anti-inflammatory agents. A2BAR agonists are under preclinical scrutiny for potential treatment of cardiac ischemia. A3AR agonists are in clinical trials for the treatment of rheumatoid arthritis and colorectal cancer. The present review will mainly cover the agonists that are presently in clinical trials for various conditions and only a brief introduction will be given to major chemical classes of AR agonists presently under investigation. PMID:17874974

Gao, Zhan-Guo; Jacobson, Kenneth A



Role of hormones including diethylstibestrol (DES) in the pathogenesis of cervical and vaginal intraepithelial neoplasia.  


Since 1971 several studies have reported the appearance of clear-cell carcinoma and clear-cell cervical carcinoma in young women exposed prenatally to diethylstilbestrol (DES). Several recent reports have been conflicting on this subject. The reported prevalence rate of dysplasia and carcinoma in situ (CIS) range from 0% to 18%, or from 0% to 6% for severe cases. Factors accounting for such discrepancies can be overdiagnosis or a biased selection of patients; as a study of 1424 patients conducted at the Massachusetts General Hospital has shown, the overall rate of severe dysplasia and CIS appeared relatively high only until patients were divided into 2 groups, those referred because of earlier diagnosis of dysplasia, and those screened because of known DES exposure; exclusion from the study of the 1st group reduced the frequency of all grades of dysplasia and CIS to 2.1%, and the rate of severe dysplasia to 0%. The National Collaborative Diethylstilbestrol Adenosis (DESAD) Project has also shown that rates of dysplasia were only 1.83% in DES-exposed daughters while subjects referred for screening exams had rates nearly 3/4 higher. Furthermore, 2 recent studies which compared rates of dysplasia in exposed and nonexposed cohorts showed that dysplasia was found more often in DES-exposed women, while in the DESAD project the prevalence rates were not statistically significant between exposed and nonexposed patients, but the ocurrence of dysplasia was more frequent in older women and in those who had intercourse with increased numbers of partners, a factor which was found to be important also when considering the association between oral contraceptives (OCs) and CIS. Microglandular hyperlasia can also arise in DES-exposed women, but it must not be interpreted as clear-cell adenocarcinoma, and it is associated with long-term use of OCs. PMID:7030882

Robboy, S J; Truslow, G Y; Anton, J; Richart, R M



Synergistic interactions of various doses of diethylstilbestrol and x irradiation on mammary neoplasia in female ACI rats  

SciTech Connect

It has been shown that DES will interact synergistically with either x-irradiation or neutron irradiation for the production of MAC in female ACI (AxC or Irish) rats. In both of these studies, the DES treatment was the same, a single compressed pellet of 5 mg DES mixed with 15 mg cholesterol implanted s.c. into each rat. The present study was undertaken to investigate the relationship between the dose of DES and the synergistic interaction with x-irradiation for MAC production. DES-induced increases in plasma prolactin were also studied since the MAC response to DES treatment (5-mg pellet) in the female ACI rat has been associated with the induction of mammotrophic pituitary tumors and very high levels of circulating prolactin.

Stone, J.P.; Holtzman, S.; Shellabarger, C.J.



Sulfonamide Cannabinoid Agonists and Antagonists.  

National Technical Information Service (NTIS)

Cannabinoid agonists an antagonists are provided for use in the treatment of disorders such as acute and chronic pain, inflammation , loss of appetite, convulsions, multiple sclerosis, nausea and vomiting. The cannabinoid agonists and antagonists contain ...

B. R. Martin R. G. Pertwee R. K. Razdan



Injection of diethylstilbestrol on the first day of incubation affects morphology of sex glands and reproductive behavior of Japanese quail.  


Japanese quail eggs were injected with DES (0.9-1,000 micrograms) dissolved in 50-microliter of corn oil on day 1 of incubation. Higher doses of DES (250-1,000 micrograms) reduced hatchability to 37-33% compared to 61% for corn oil-injected controls. Lower doses of DES (0.9-125 micrograms) had no effects on hatchability. In a second study, eggs were injected with 0.9 or 1.9 micrograms of DES and the survivors were assessed up to 12 weeks posthatch. DES did not affect hatchability, but did increase mortality during the first 4 weeks posthatch. Females were affected more than males. At 10 days of age, open-field activity of some birds was examined. The acquisition and reversal of a visual discrimination task was studied at 6 weeks of age. DES had no effect on these measurements. Ten females from each group were chosen randomly to determine egg production over a single 28-day period beginning at 6 weeks of age. Exposure to DES blocked egg production in these birds. The oviduct weights of 12-week-old females were decreased by 50%, but ovarian weights were not affected. Testicular weights were not affected. In a third study reproductive behaviors and social-dominance behaviors of males were markedly attenuated in birds exposed to 0.48 or 1.9 micrograms DES in ovo. PMID:3983852

Gildersleeve, R P; Tilson, H A; Mitchell, C L



Des Moines.  

ERIC Educational Resources Information Center

|This document, intended for elementary students, contains articles and activities designed to acquaint young people with the history of Des Moines, Iowa. The articles are short, and new or difficult words are highlighted and defined for young readers. "The Raccoon River Indian Agency" discusses the archeological exploration of the indian…

Gore, Deborah, Ed.



Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors  

PubMed Central

Measurements of affinity and efficacy are fundamental for work on agonists both in drug discovery and in basic studies on receptors. In this review I wish to consider methods for measuring affinity and efficacy at G protein coupled receptors (GPCRs). Agonist affinity may be estimated in terms of the dissociation constant for agonist binding to a receptor using ligand binding or functional assays. It has, however, been suggested that measurements of affinity are always contaminated by efficacy so that it is impossible to separate the two parameters. Here I show that for many GPCRs, if receptor/G protein coupling is suppressed, experimental measurements of agonist affinity using ligand binding (Kobs) provide quite accurate measures of the agonist microscopic dissociation constant (KA). Also in pharmacological functional studies, good estimates of agonist dissociation constants are possible. Efficacy can be quantitated in several ways based on functional data (maximal effect of the agonist (Emax), ratio of agonist dissociation constant to concentration of agonist giving half maximal effect in functional assay (Kobs/EC50), a combined parameter EmaxKobs/EC50). Here I show that EmaxKobs/EC50 provides the best assessment of efficacy for a range of agonists across the full range of efficacy for full to partial agonists. Considerable evidence now suggests that ligand efficacy may be dependent on the pathway used to assess it. The efficacy of a ligand may, therefore, be multidimensional. It is still, however, necessary to have accurate measures of efficacy in different pathways.

Strange, P G



Quantification of des-Arg 9-bradykinin using a chemiluminescence enzyme immunoassay: application to its kinetic profile during plasma activation  

Microsoft Academic Search

There is a renewed interest in the kininase I pathway of kinin metabolism, because des-Arg9-bradykinin (des-Arg9-BK) and des-Arg10-Lys-BK are selective and potent agonists of the B1 receptors, that are apparently upregulated by tissue injury. We have developed a polyclonal rabbit antiserum against des-Arg10-Lys-BK. In a radioimmunoassay for des-Arg10-Lys-BK, this antiserum exhibited high specificity. Notably, native kinins with the C-terminal Arg

Philippe Raymond; Guy Drapeau; Robert Raut; Ritchie Audet; François Marceau; Huy Ong; Albert Adam



Définition des priorités sanitaires et rationnement. L'opinion des Suisses, des Administrateurs hospitaliers et des Départements sanitaires des Cantons  

Microsoft Academic Search

Objectifs. Le but de cette analyse est,[i] de présenter l'opinion actuelle de la population suisse sur des thèmes liés à la limitation des ressources, à la définition des priorités et au rationnement dans le secteur sanitaire, [ii] de comparer cette opinion avec celle d'autres groupes professionnellement engagés dans le secteur (administrateurs des hôpitaux et directions des Départements sanitaires des cantons)




Tragic Freedom in Samson Agonistes  

Microsoft Academic Search

In his preface to Samson Agonistes, Milton cites “the ancients” and especially Aeschylus, Sophocles, and Euripides, as his models in a tragedy “after the Greek manner.” In this preface, Milton interprets Aristotelian catharsis in medical terms as a restoration of balance or “just measure.” The final lines of Samson Agonistes, beginning with the words “All is best,” are an attempt

Warren Chernaik



An optimised method for the accurate determination of zeranol and diethylstilbestrol in animal tissues using isotope dilution-liquid chromatography/mass spectrometry.  


Isotope dilution-liquid chromatography/mass spectrometry (ID-LC/MS) has been established as a candidate reference method for the accurate determination of growth promoters (zeranol, taleranol, and diethylstilbesterol) in raw meat samples. Sample preparation processes including an enzymatic hydrolysis, extraction, and SPE clean-up were optimised. The sensitivity difference of trans- and cis-diethylstilbestrol (isomerizing in sample preparation processes) by the LC/MS was measured by running a trans/cis mixture (ratio measured by a quantitative NMR) with and without sample matrices, and applied for the determination of total diethylstilbestrol. Validity, repeatability, and reproducibility of the analytical method were tested by measuring gravimetrically fortified samples (chicken breast, bovine muscles, and porcine muscle) in a number of different time periods. Measurement results agreed with the fortified values within their uncertainties. The method provided accurate results of the target analytes in the range of 0.05-15 ?g/kg with the relative expanded uncertainty of 2-15%. PMID:23578613

Han, Hyesun; Kim, Byungjoo; Lee, Sueg Geun; Kim, Jeongkwon



Effect of PCB and DES on rat monoamine oxidase, acetylcholinesterase, testosterone, and estradiol ontogeny  

SciTech Connect

Diethylstilbestrol (DES) and polychlorinated biphenyl (PCB) have been documented as potentially hazardous environmental agents. In utero exposure to DES produces human vaginal adenocarcinoma, male reproductive tract lesions in mice, and has been correlated with personality changes in human males. PCB (Kanechlor) was found to be the major toxin in the {open_quotes}Yusho{close_quotes} rice oil poisoning in Japan in 1968. Other investigators have shown in rats that PCB (Arochlor) causes liver adenofibrosis, thyroid dysfunction, atypical mitochondria, and dilation of both smooth and rough endoplasmic reticulum. Matthews et al. (1978) also reported that 4, 4{prime} chlorinated biphenyl was the most potent inducer of monooxygenases, irrespective of chlorination at other sites. Although these compounds have been studied extensively in mammals, there is a paucity of data examining their effects when non-fetotoxic amounts are administered chronically and orally during gestation. The present study is part of a larger effort designed to establish a protocol for testing the developmental effects of xenobiotics such as DES and PCB. Levels of acetylcholinesterase (AChE) were measured as an indicator of the integrity of nerve transmission in the central nervous system. Monoamine oxidase (MAO) is a marker for the outer mitochondrial membrane and is an important amine metabolizing enzyme. Testosterone and estradiol are important sex steroids in mammals, and effects upon levels of the two hormones may signal anomalies in development of sex characteristics. 35 refs., 3 figs., 1 tab.

Vincent, D.R.; Bradshaw, W.S.; Booth, G.M.; Seegmiller, R.E. [Brigham Young Univ., Provo, UT (United States); Allen, S.D. [Utah State Univ., Logan, UT (United States)



Dopamine agonists in Parkinson's disease.  


Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson's disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm. PMID:18416667

Yamamoto, Mitsutoshi; Schapira, Anthony H V



Agonist-activated ion channels  

PubMed Central

This paper looks at ion channels as an example of the pharmacologist's stock in trade, the action of an agonist on a receptor to produce a response. Looked at in this way, ion channels have been helpful because they are still the only system which is simple enough for quantitative investigation of transduction mechanisms. A short history is given of attempts to elucidate what happens between the time when agonist first binds, and the time when the channel opens.

Colquhoun, David



Dopamine receptor sensitivity after chronic dopamine agonists  

Microsoft Academic Search

Several previous reports have demonstrated that chronic administration of both directly and indirectly acting dopamine agonists produces a supersensitive behavioral response to challenge doses of dopamine agonists when compared to the responses induced by acute administration of these drugs. That is, a given dose of a dopamine agonist will produce a greater response after chronic dopamine agonist treatment than is

William H. Riffee; Richard E. Wilcox; Dana M. Vaughn; Robert V. Smith



Der Sauerstoffverbrauch des stillstehenden, des leerschlagenden und des flimmernden Herzens  

Microsoft Academic Search

An Hunden mit offenem Thorax wurden unter Verwendung eines extrakorporalen Kreislaufs vergleichende Messungen von O2-Verbrauch und Durchblutung des stillstehenden, leerschlagenden und flimmernden Herzens durchgeführt. Durch eine besondere Technik war es möglich, ohne Kanulierung beide Coronarien zu durchströmen und damit den O2-Verbrauch des ganzen Herzens zu messen.

Hans-Eberhard Hoffmeister; Heinrich Kreuzer; Wilhelm Schoeppe



Accumulation des profits et désendettement des entreprises  

Microsoft Academic Search

En modélisant un arbitrage intertemporel, le désendettement est un choix rationnel en présence d'un rendement marginal des nouveaux investissements inférieur au taux d'intérêt réel sur l'encours de la dette et supérieur au coût d'opportunité des placements des fonds internes. Dans ce cas, le désendettement évince l'investissement ; les profits n'ont pas d'effet sur l'investissement et un effet négatif sur le

Jean-Bernard Chatelain



Clinical concerns with inhaled ? 2 -agonists  

Microsoft Academic Search

Inhaled ?2-agonists, when used regulary, cause subtle but significant worsening of asthma control. Overuse of inhaled ?2-agonists is associated with increased risk of death from asthma in a dose-response fashion. ?2-Agonists enhance airway responses to allergens, including induced airway hyperresponsiveness and induced airway inflammation.\\u000a This is a plausible explanation for ?2-agonist-worsened asthma control. These direct effects of inhaled ?2-agonists, including

D. W. Cockcroft



The Structural Basis of Estrogen Receptor\\/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen  

Microsoft Academic Search

Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. Here we report the crystal structure of the human estrogen receptor ? (hER?) ligand-binding domain (LBD) bound to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator

Andrew K. Shiau; Danielle Barstad; Paula M. Loria; Lin Cheng; Peter J. Kushner; David A. Agard; Geoffrey L. Greene



Évaluation des produits combinés  

Center for Biologics Evaluation and Research (CBER)

Text Version... des Centres respectifs. Les cases du tableau présentent quelques- unes des principales étapes d'examen. Veuillez noter ... More results from


Agonist-receptor efficacy II: agonist trafficking of receptor signals  

Microsoft Academic Search

There is evidence to suggest that receptors with seven transmembrane domains can exist in G protein-activating conformations. It is not known how many activated receptor forms exist for each receptor. Furthermore, if there are multiple forms, does the chemical structure of the agonist determine which form dominates, and therefore, which response pathway is activated? This latter scheme is referred to

T. Kenakin



Chronique des tendances de la société française  

Microsoft Academic Search

[fre] Cette chronique porte sur quatre des tendances que Louis Dirn suit régulièrement : • L'effort pour assurer une meilleure égalité des chances sco- laires se heurte à des effets pervers qui résultent des politiques de gestion des établissements et des stratégies des familles. La diver- sification des établissements offre une nouvelle liberté de choix aux familles qui en jouent

Alain Beurdeley; Jean-Pierre Jaslin; Nicolas Herpin; Serge Paugam



Pharmacotherapy for tobacco cessation: Nicotine agonists, antagonists, and partial agonists  

Microsoft Academic Search

Nicotine replacement therapies (NRT) were the main pharmacologic option for treatment of nicotine dependence until the early\\u000a 1990s, when controlled clinical trials confirmed the efficacy of bupropion, the first treatment not based on nicotine. Varenicline,\\u000a a partial agonist at nicotine receptors, gained US regulatory approval in 2006 for smoking cessation. Although these agents\\u000a are all effective for nicotine dependence, their

Maher Karam-Hage; Paul M. Cinciripini



Effets secondaires des androgènes  

Microsoft Academic Search

Resume  Les androgènes utilisés à des doses 10 à 100 fois supérieures aux doses thérapeutiques provoquent des effets qui peuvent être\\u000a classés en 4 catégories: 1) Effets androgéniques: Chez l’homme, les androgènes provoquent atrophie testiculaire et azoospermie\\u000a avec stérilité, réversibles en 2 à 3 mois à l’arrêt du traitement. Il serait utile de surveiller à long terme la prostate\\u000a des sujets

I. Mowszowicz



Les vacances des Français  

Microsoft Academic Search

[fre] Depuis 1964, l'INSEE effectue chaque année une enquête sur les vacances. De 1964 à 1977, la proportion des Français qui sont partis en vacances a augmenté de 44 % à 53 %; pendant la période, la part des séjours d'hiver est passée de 15 à 29 %. Il faut remarquer toutefois la baisse du taux de départ entre 1976

Jean Anfré; Jean-Michel Rempp



La structure des verres étudiée par diffraction des neutrons  

NASA Astrophysics Data System (ADS)

La diffraction des neutrons est une méthode largement utilisée pour déterminer la structure des matériaux amorphes et en particulier des verres. L'utilisation de la méthode de substitution isotopique permet d'extraire les fonctions de distribution de paires partielles centrées autour d'un élément choisi. Nous présentons quelques exemples récents d'études par diffraction des neutrons sur des verres qui ont permis de mieux comprendre à la fois le réseau polymérique de la matrice vitreuse et l'environnement local et à moyenne distance autour des cations. Ces études ont révélées un ordre structural s'étendant au delà des premiers voisins, jusque vers de distances d'environ 10Å. Le couplage avec d'autres méthodes expérimentales (diffraction anormale des rayons X) et des techniques de simulations (dynamique moléculaire, Monte Carlo Inverse ou RMC) sont indispensables pour affiner nos connaissances de la structure des verres.

Cormier, L.



Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists  

PubMed Central

Drug effects can be classified into three major phenotypes: agonist, antagonist and inverse agonist. Agonist and inverse agonist effects are associated with receptor activation and inactivation, respectively, whereas antagonism implies that a drug produces no effect when administered alone but blocks the effects of agonists and inverse agonists. Attention has only recently begun to focus on the theoretical and clinical implications of inverse agonists, and studies of inverse agonism have also stimulated revisions in receptor theory. This commentary addresses two specific issues related to the application of receptor theory to studies of inverse agonists in vivo. First, principles of receptor theory suggest that increasing drug doses produce a graded pharmacological stimulus that is transduced by receptor-containing tissue into a biological response. However, assays vary in their ability to detect those responses, and any given assay provides only a narrow window on the full range of underlying drug effects. Consequently, in vivo assessment of inverse agonists will benefit from development of assays sensitive to graded inverse agonist effects. Second, detection of inverse agonist effects requires some preexisting level of receptor activity (or tone). This tone can result from at least two sources: (a) endogenous ligands for the receptor, or (b) constitutive receptor activity. Strategies for discriminating these two sources of tone will also contribute to the in vivo assessment of inverse agonist effects. Studies with intermediate efficacy ligands may be especially helpful in this regard, because their effects are differentially influenced by endogenous agonist tone versus constitutive receptor tone.

Negus, S. Stevens



La structure des solutions aqueuses  

NASA Astrophysics Data System (ADS)

En commençant par l'étude par diffraction neutronique de la structure des liquides moléculaires puis de l'hydratation des ions en solution, ce cours montrera comment les principes présentés lors des cours précédents peuvent être appliqués à des systèmes aqueux. Des exemples tirés de la littérature seront utilisés pour illustrer les considérations expérimentales propre à ce domaine et le genre d'informations que nous pouvons obtenir. Ce cours montrera également l'applicaton de la diffraction neutronique à des systèmes d'intérêt biologique et environnemental et se terminera par un examen de la complémentarité fournie par la diffraction des rayons X, l'EXAFS et la RMN.

Powell, D. H.



Tyrphostin analogs are GPR35 agonists.  


GPR35 is an orphan G protein-coupled receptor that is not well-characterized. Here we employ dynamic mass redistribution (DMR) assays to discover new GPR35 agonists. DMR assays identified tyrphostin analogs as GPR35 agonists, which were confirmed with receptor internalization, Tango ?-arrestin translocation, and extracellular-signal-regulated kinase phosphorylation assays. These agonists provide pharmacological tools to study the biology and function of GPR35. PMID:21601572

Deng, Huayun; Hu, Haibei; Fang, Ye



? 2 -Agonists at the olympic games  

Microsoft Academic Search

The different approaches that the International Olympic Committee (IOC) had adopted to ?2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the\\u000a Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled ?2-agonists on health, is concerned with the fact that oral ?2-agonists may be

Kenneth D. Fitch



The cannabinoid receptor inverse agonist AM251 regulates the expression of the EGF receptor and its ligands via destabilization of oestrogen-related receptor ? protein  

PubMed Central

BACKGROUND AND PURPOSE AM251 is an inverse agonist of the cannabinoid 1 receptor (CB1R) that can exert ‘off-target’ effects in vitro and in CB1R knock-out mice. AM251 is also potent at modulating tumour cell growth, suggesting that growth factor-mediated oncogenic signalling could be regulated by AM251. Since dysregulation of the EGF receptor has been associated with carcinogenesis, we examined AM251 regulation of EGF receptor (EGFR) expression and function. EXPERIMENTAL APPROACH The various biological functions of AM251 were measured in CB1R-negative human cancer cells. Pharmacological and genetic approaches were used to validate the data. KEY RESULTS The mRNA levels for EGFR and its associated ligands, including HB-EGF, were induced several fold in PANC-1 and HCT116 cells in response to AM251. This event was associated with enhanced expression of EGFR on the cell surface with concomitant increase in EGF-induced cellular responses in AM251-treated cells. Exposure to XCT790, a synthetic inverse agonist of the orphan nuclear oestrogen-related receptor ? (ERR?), also induced EGFR and HB-EGF expression to the same extent as AM251, whereas pretreatment with the ERR?-selective agonist, biochanin A, blunted AM251 actions. AM251 promoted the degradation of ERR? protein without loss of the corresponding mRNA. Knock-down of ERR? by siRNA-based approach led to constitutive induction of EGFR and HB-EGF levels, and eliminated the biological responses of AM251 and XCT790. Finally, AM251 displaced diethylstilbestrol prebound to the ligand-binding domain of ERR?. CONCLUSIONS AND IMPLICATIONS AM251 up-regulates EGFR expression and signalling via a novel non-CB1R-mediated pathway involving destabilization of ERR? protein in selected cancer cell lines.

Fiori, JL; Sanghvi, M; O'Connell, MP; Krzysik-Walker, SM; Moaddel, R; Bernier, M



Zur Physiologie des Liegens  

Microsoft Academic Search

Zusammenfassung  Durch Unterwasseraufnahmen wird die Winkelstellung in Hüfte und Knie bei maximaler Entspannung ermittelt sowie die Abhängigkeit des Kniewinkels vom Hüftwinkel bei Zwischenstellungen zwischen Sitzen und Liegen. Die gewonnenen Unterlagen können für die zweckmäßige Konstruktion von Liegestühlen verwendet werden.

Gunther Lehmann



Sulfonamides as selective oestrogen receptor ? agonists.  


A series of p-hydroxybenzenesulphonamides ER? receptor agonists were discovered and several compounds identified had excellent selectivity over the related ER? receptor. One of these, compound 11, had an interesting binding conformation determined by X-ray and represents an excellent starting point in the quest for further selective ER? agonists. PMID:21885279

Roberts, Lee R; Armor, Duncan; Barker, Carolyn; Bent, Andrew; Bess, Kirstin; Brown, Alan; Favor, David A; Ellis, David; Irving, Stephen L; MacKenny, Malcolm; Phillips, Chris; Pullen, Nick; Stennett, Adam; Strand, Linda; Styles, Michelle



Anatomophysiologie des algies pudendales  

Microsoft Academic Search

Résumé  Les algies pudendales sont périnéales de type tronculaire et somatique. Elles siègent dans le territoire du nerf atteint et\\u000a sont positionnelles, ce qui évoque un phénomène de compression lors de la position assise. L’anatomophysiologie de ces douleurs\\u000a met l’accent sur plusieurs items: a) définition et innervation du périnée; b) étude du parcours des voies de la douleur; étude\\u000a des structures

R. Robert; Y. Beaudic; O. Hamel; M. Khalfallah; J.-J. Labat; T. Riant



Development and validation of a screening method for DES, zeranol, and beta-zearalanol in bovine urine by HRGC-MS and evaluation of robustness for routine survey of the Brazilian herd.  


A method and evaluated for screening and confirmation of diethylstilbestrol (DES), alpha- and beta-zearalanol in bovine urine was developed. The residues were extracted from urine by C18 cartridges and purified on alumina columns. For screening and confirmation purposes, the anabolic derivatives were analyzed by gas chromatography-mass spectrometry after derivatization with BSTFA + 1% TMCS or a solution of PFPA/acetone (1:2, v/v), respectively. The recovery of most analytes for the whole procedure was higher than 96%, with a detection limit of 0.5 ppb. This procedure is being routinely applied to the Brazilian National Program for the Control of Residues in Meat (PNCRBC). PMID:9737331

Marques, M A; Lima, L A; Bizarri, C H; Neto, F R; Cardoso, J N



Agonist-specific Gating of NMDA Receptors  

PubMed Central

The mechanism by which ligand binding at extracellular receptor domains gates a transmembrane ion-conducting pore is insufficiently understood. Examining a channel’s activation reaction in the presence of agonists with distinct efficacies may inform this issue and may help identify agonist-dependent transitions. We have recently applied this approach to NMDA receptors composed of GluN1 and GluN2A subunits. Based on our results with several subunit-specific partial agonists we concluded that agonist effects were distributed over several of the multiple transitions that make up NMDA receptor gating and that these changes were subunit independent. Here we examine an additional GluN2A partial agonist, 4-fluoro-D, L-glutamic acid, and we summarize the observed kinetic changes of all nine partial agonists investigated. These results support the premise that regardless of the subunit-type to which they bind, agonists influence multiple equilibria within the NMDA receptor reaction and may stabilize a slightly different family of conformers.

Kussius, Cassandra L.; Popescu, Andrei M.; Popescu, Gabriela K.



Die pharmakologische Wirkung des Ephedrins  

Microsoft Academic Search

Zusammenfassung 1.Die pharmakologische Wirkung des Ephedrins wurde zu analysieren versucht durch Studium der Beeinflussung des Blutdrucks, der Herzaktion und der Gefäße, des Effekts am Atemzentrum und an den Bronchien, der Wirkung auf die Pupillenweite, auf den Darm und den Uterus, auf die Sekretion verschiedener Drüsen und den Blutzuckerspiegel.2.Es wurden folgende Wirkungen gefunden: Der Blutdruck wird erhöht durch kleine Dosen, erniedrigt

H. Kreitmair



Dopamine agonists and pathologic behaviors.  


The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson's disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics. PMID:22567537

Kelley, Brendan J; Duker, Andrew P; Chiu, Peter



Dopamine Agonists and Pathologic Behaviors  

PubMed Central

The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson's disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

Kelley, Brendan J.; Duker, Andrew P.; Chiu, Peter



Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-? receptor agonist GW7647  

Microsoft Academic Search

The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-? (PPAR-?) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts

Roberto Russo; Jesse LoVerme; Giovanna La Rana; Giuseppe D'Agostino; Oscar Sasso; Antonio Calignano; Daniele Piomelli



La diffraction des neutrons et des rayons X pour l'étude structurale des liquides et des verres  

NASA Astrophysics Data System (ADS)

La compréhension de mainte propriété physique d'un verre ou d'un liquide nécessite la connaissance des facteurs de structure partiels (PSFs) qui décrivent chacun la distribution d'une espèce atomique autour d'une autre. La technique de diffraction des neutrons avec substitution isotopique (NDIS) [1,2,3], ayant bien réussi a déterminer les PSFs de certains composés [4,5], est pourtant restreinte aux isotopes présentant un contraste suffisant en longueur de diffusion. D'un autre cote, la technique de diffusion anomale des rayons X (AXS ou AXD) [6] permet de faire varier la longueur de diffusion d'une espèce atomique pourvu que son énergie d'absorption soit à la fois accessible et suffisamment élevée pour donner un assez grand transfert du moment. La combinaison des techniques de diffraction des neutrons (avec ou sans substitution isotopique) et de diffraction des rayons X (avec ou sans diffusion anomale) peut donc permettre d'obtenir un meilleur contraste en longueurs de diffusion pour un système donné, mais exige une analyse de données plus soignée pour pouvoir bien tenir compte des erreurs systématiques qui sont différentes pour les 2 techniques [7]. Pour les atomes ayant des distributions électroniques quasi-sphériques, e.g. dans le cas d'un alliage liquide, la combinaison des techniques de NDIS et de diffraction des rayons X s'est déjà montrée très avantageuse pour la détermination des PSFs [8,9]. Dans le cas des verres ayant d'importantes liaisons covalentes, l'effective combinaison des 2 techniques peut être moins directe mais facilitée lorsqu'il s'agit des atomes de grand Z [10,11]. Nous présentons ici un sommaire du méthode et quelques exemples des résultats.

Fischer, H. E.; Salmon, P. S.; Barnes, A. C.



Gamma hydroxybutyrate is not a GABA agonist.  


Gamma hydroxybutyrate (GHB) is primarily known and used as a relatively specific inhibitor of central DA release. However, it is also widely assumed to be an agonist or prodrug of gamma-aminobutyric acid (GABA) and its central activity has been attributed to an action exerted at GABA receptors. Nevertheless, there is compelling evidence that: (1) GHB formation may occur independently of GABA; (2) GHB is behaviorally, biochemically and physiologically distinct from GABA in many ways, and does not consistently effect GABAA or GABAB agonist induced responses; (3) GHB has little effect on either GABAA or GABAB receptors at less than millimolar concentrations. Consequently, GHB does not appear to be either a GABA prodrug or a GABA agonist. However, the GHB metabolite gamma butyrolactone (GBL) may possess some limited GABA agonist activity. PMID:8931105

Feigenbaum, J J; Howard, S G



? 2 -Agonists and exercise-induced asthma  

Microsoft Academic Search

?2-Agonists taken immediately before exercise provide significant protection against exercise-induced asthma (EIA) in most patients.\\u000a However, when they are taken daily, there are some negative aspects regarding severity, control, and recovery from EIA. First,\\u000a there is a significant minority (15–20%) of asthmatics whose EIA is not prevented by ?2-agonists, even when inhaled corticosteroids are used concomitantly. Second, with daily use,

Sandra D. Anderson; Corinne Caillaud; John D. Brannan



Interactions between corticosteroids and ? 2 -agonists  

Microsoft Academic Search

In vitro studies have demonstrated numerous ways in which ?2-agonists and corticosteroids may interact. Together with evidence of improved control of airway diseases using a combination\\u000a therapy of inhaled corticosteroids and long-acting ?-agonists compared with treatment with either drug alone, this suggests\\u000a that there may be a beneficial synergy between these two classes of medication. However, a positive interaction has

Robert J. Hancox



La vitalité des spermatozoïdes  

Microsoft Academic Search

Résumé  Malgré l’existence de nombreux moyens d’étude de la vitalité des spermatozoïdes, la plupart restent dans le domaine de la\\u000a recherche biomédicale. Ce sont surtout les tests classiques, tels que le test à l’éosinenigrosine et le test de gonflement\\u000a flagellaire en milieu hypo-osmolaire (HOST) qui permettent d’apprécier le pourcentage de vitalité des spermatozoïdes en spermiologie\\u000a courante. Un résultat anormalement bas définit

T. Forges; P. Monnier-Barbarino; B. Foliguet



Prenatal Exposure to Low Doses of the Estrogenic Chemicals Diethylstilbestrol and o,p ?DDT Alters Aggressive Behavior of Male and Female House Mice  

Microsoft Academic Search

Exposure to estrogenic chemicals during critical periods in fetal life can alter the development of reproductive organs, the neuroendocrine system, and subsequent behavior. We examined the effects of prenatal exposure to the estrogenic chemicals, o,p?-DDT (the estrogenic contaminant in commercial DDT) and the drug diethystilbestrol (DES), as a positive control, on different forms of aggressive behavior in both male and

Paola Palanza; Stefano Parmigiani; Huifen Liu; Frederick S. Vom Saal



Dopaminergic agonists in Parkinson's disease.  


BACKGROUND: Non-ergot dopamine agonists (DA) are effective treatments for Parkinson's disease (PD). A review is presented of the pharmacology, evidence of efficacy and safety profile of pramipexole, ropinirole and rotigotine, and practical recommendations are given regarding their use in clinical practice. RESULTS: Extended release formulations of pramipexole and ropinirole and transdermal continuous delivery rotigotine patches are currently available; these may contribute to the stability of plasma levels and continuous dopaminergic stimulation. In early PD, the three of them significantly improved disability scales, delay time to dyskinesia and allow a later introduction of levodopa. In late PD they reduced total off-time, improved Unified Parkinson's Disease Rating Scale (UPDRS) in both on and off state and allowed a reduction in total levodopa dosage. Also, a significant improvement in quality of life scales has been demonstrated. Extended release formulations have proved to be non-inferior to the immediate release formulations, and even better tolerated (ropinirole). Despite a generally good safety profile, serious adverse events, such as impulse control disorder and sleep attacks need to be routinely monitored. Although combination therapy has not been addressed in scientific literature, certain combinations, such as apomorphine and another DA, may be helpful. Switching from a DA to another is feasible and safe, although in the first days an overlap of dopaminergic side effects may occur. When treatment with DA is stopped, dopamine withdrawal syndrome needs to be prevented. On suspension of a DA, especially pramipexole, the risk of producing apathy has to be considered. CONCLUSIONS: New non-ergot DA are a valuable option for the treatment of both early and late PD. Despite a good safety profile, serious adverse effects may appear and need to be monitored. A pathoplastic effect on the course of the disease cannot be ruled out. PMID:21724302

Alonso Cánovas, A; Luquin Piudo, R; García Ruiz-Espiga, P; Burguera, J A; Campos Arillo, V; Castro, A; Linazasoro, G; López Del Val, J; Vela, L; Martínez Castrillo, J C



Novel Human Interleukin-15 Agonists  

PubMed Central

IL-15 is an immunostimulatory cytokine trans-presented with the IL-15 receptor ? chain to the shared IL-2/IL-15R? and common ? chains displayed on the surface of T cells and NK cells. To further define the functionally important regions of this cytokine, activity and binding studies were conducted on human IL-15 muteins generated by site-directed mutagenesis. Amino acid substitutions of the asparagine residue at position 72, which is located at the end of helix C, were found to provide both partial agonist and superagonist activity, with various non-conservative substitutions providing enhanced activity. Particularly, the N72D substitution provided a 4–5 fold increased in biological activity of the IL-15 mutein compared to the native molecule based on proliferations assays with cells bearing human IL-15R? and common ? chains. The IL-15N72D mutein exhibited superagonist activity through improved binding ability to the human IL-15R? chain. However, the enhanced potency of IL-15N72D was not observed with cells expressing the mouse IL-15R?-IL-15R?-?c complex suggesting that this effect is specific to human IL-15 receptor. The enhanced biological activity of IL-15N72D was associated with more intense phosphorylation of Jak1 and Stat5 and better anti-apoptotic activity compared to the wild-type IL-15. IL-15N72D superagonist activity was also preserved when linked to a single-chain T cell receptor domain to generate a tumor-specific fusion protein. Thus, the human IL-15 superagonist muteins and fusions may create opportunities to construct more efficacious immunotherapeutic agents with clinical utility.

Zhu, Xiaoyun; Marcus, Warren D.; Xu, Wenxin; Lee, Hyung-Il; Han, Kaiping; Egan, Jack O.; Yovandich, Jason L.; Rhode, Peter R.; Wong, Hing C.



Des Vents et des Jets Astrophysiques  

NASA Astrophysics Data System (ADS)

Plasma outflows from a central gravitating object are a widespread phenomenon in astrophysics. They include the solar and stellar winds, jets from Young Stellar Objects, jets from compact stellar objects and extra-galactic jets associated with Active Galactic Nuclei and quasars. Beyond this huge zoology, a common theoretical ground exists. The aim of this review is to present qualitatively the various theories of winds (Part 1) and how different astrophysical domains interplay. A more or less complete catalog of the ideas proposed for explaining the acceleration and the morphologies of winds and jets is intended. All this part avoids getting into any mathematical formalism. Some macroscopic properties of such outflows may be described by solving the time-independent and axisymmetric magnetohydrodynamic equations. This formalism, underlying most of the theories, is presented in Part 2. It helps to introduce quantitatively the free integrals that such systems possess. Those integrals play an important role in the basic physics of acceleration and collimation, in particular the mass loss rate, the angular momentum loss rate and the energy of the magnetic rotator. Most of the difficulty in modelling flows lies in the necessity to cross critical points, characteristic of non linear equations. The physical nature and the location of such critical points is debated because they are the clue towards the resolution. We thus introduce the notions of topology and critical points (Parts 3 and 4) from the simplest hydrodynamic and spherically symmetric case to the most sophisticated, MHD and axisymmetric cases. Particular attention is given to self-similar models which allows to give some general and simple ideas on the problem due to their semi-analytical treatment. With the use of these notions, a more quantitative comparison of the various models is given (Parts 3 and 4), especially on the shape of the flows. It is thus shown that magnetic collimation of winds into jets is a well expected result from the theory. Although, collimation may be conical, paraboloidal or cylindrical (Part 4), cylindrical collimation is the more likely to occur. The shape of outflows may then be used as a tool to predict physical conditions on the flows or on their source. L'éjection continue de plasma autour d'objets massifs est un phénomène largement répandu en astrophysique, que ce soit sous la forme du vent solaire, de vents stellaires, de jets d'étoiles en formation, de jets stellaires autour d'objets compacts ou de jets extra-galactiques. Cette zoologie diversifiée fait pourtant l'objet d'un commun effort de modélisation. Le but de cette revue est d'abord de présenter qualitativement le développement, depuis leur origine, des diverses théories de vents (Partie 1) et l'inter disciplinarité dans ce domaine. Il s'agit d'une énumération, plus ou moins exhaustive, des idées proposées pour expliquer l'accélération et la morphologie des vents et des jets, accompagnée d'une présentation sommaire des aspects observationnels. Cette partie s'abstient de tout aspect faisant appel au formalisme mathématique. Ces écoulements peuvent être décrits, au moins partiellement, en résolvant les équations magnétohydrodynamiques, axisymétriques et stationnaires. Ce formalisme, à la base de la plupart des théories, est exposé dans la Partie 2. Il permet d'introduire quantitativement les intégrales premières qu'un tel système possède. Ces dernières sont amenées à jouer un rôle important dans la compréhension des phénomènes d'accélération ou de collimation, en particulier le taux de perte de masse, le taux de perte de moment angulaire ou l'énergie du rotateur magnétique. La difficulté de modélisation réside dans l'existence de points critiques, propres aux équations non linéaires, qu'il faut franchir. La nature physique et la localisation de ces points critiques fait l'objet d'un débat important car ils sont la clef de voute de la résolution. Nous introduisons donc la notion de topologie des points critiques (Parties 3 et 4

Sauty, C.


La rigidité des prix en France : quelques enseignements des relevés de prix à la consommation  

Microsoft Academic Search

[fre] La rigidité des prix en France: quelques enseignements des relevés de prix à la consommation . . Pour décrire À l’aide de l’échantillon des relevés de prix utilisés pour le calcul de l’indice des prix à la consommation (IPC), les la rigidité des prix à la consommation en France, divers indicateurs (durée de vie des prix, fréquence et amplitude

Laurent Baudry; Hervé Le Bihan; Patrick Sevestre; Sylvie Tarrieu



Betriebliche Determinanten des Überstundeneinsatzes  

Microsoft Academic Search

Auswertungen repräsentativer Daten des IAB-Betriebspanels für Westdeutschland von 1993 bis 1998 zeigen, dass nur zwischen 20 und 30 Prozent aller Betriebe bezahlte Überstunden einsetzten. In diesen Betrieben fielen im Durchschnitt 1,6 bezahlte Überstunden pro abhängig Beschäftigten und Woche an. Weniger als 7 Prozent der Betriebe griffen in jedem Jahr auf Überstunden zurück, wozu vor allem Großbetriebe zählten. Auch generell stieg

Thorsten Schank; Claus Schnabel



Le Chemin des Ecoliers  

Microsoft Academic Search

This article is developed from extracts from a report of a study undertaken by the authors on the availability and use of television in primary and nursery schools. It looks at ‘Le Chemin des Ecoliers’ developed by CNDP (the Centre National de Documentation Pedagogique), Paris and transmitted on the French TV Channel TF1. It estimates the audiences, sees how the

Josette Blanc



The structural basis for agonist and partial agonist action on a ?(1)-adrenergic receptor.  


?-adrenergic receptors (?ARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit ?ARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) ?(1)-adrenergic receptor (?(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1?Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies. PMID:21228877

Warne, Tony; Moukhametzianov, Rouslan; Baker, Jillian G; Nehmé, Rony; Edwards, Patricia C; Leslie, Andrew G W; Schertler, Gebhard F X; Tate, Christopher G



Gonadotropin releasing hormone agonists: Expanding vistas.  


Gonadotropin-releasing hormone (GnRH) agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a) work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women's healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential. PMID:22028996

Magon, Navneet



Effects of Prenatal Exposure to Low Doses of Diethylstilbestrol, o,p'DDT, and Methoxychlor on Postnatal Growth and Neurobehavioral Development in Male and Female Mice  

Microsoft Academic Search

We examined effects of a wide range of doses of three man-made estrogenic chemicals during fetal life on neurobehavioral changes during early postnatal life in mice. Pregnant mice were fed a 4-log range of o,p'DDT, methoxychlor (MXC), and the drug diethystilbestrol (DES) from gestation days 11 to 17. Offspring were examined for changes in postnatal growth and the development of

Paola Palanza; Stefano Parmigiani; Frederick S. vom Saal



Die bestimmung des diacetyls im sprit  

Microsoft Academic Search

Zusammenfassung Die für die Bestimmung des Diacetylgehaltes im Sprit entwickelte Methode beruht auf der photometrischen Messung der in einer Pyridin-Äthylendiaminhydrat-lösung des bis-2,4-Dinitrophenylhydrazons des Diacetyls entstandenen violetten Färbung. Bis-2,4-Dinitrophenylhydrazon des Diacetyls wird von anderen Hydrazonen, wenigstens von dem Hydrazon des Acetaldehydes and dem bei den Reaktionsumständen sich bildenden Monohydrazon des Acetylmethylearbinols Bowie von dem überschüssigen Reagens auf Grund seiner Schwerlöslichkeit in

Tapio Salo; Heikki Suomalainen



[Receptor agonists as perspective neuroprotective agents].  


Selective agonists of adenosine A1, GABAa, GABAb, and alpha 2-receptors (inhibitory neurotransmitter analogs) have a high neuroprotective effects (NPE) on two models of complete cerebral ischemia (CI). These NPEs are specific as they are inhibited by selective antagonists and, in addition, the selective alpha 1- and beta-receptor agonists have no NPE. The natural resistance to CI is also associated with A- and alpha 1-receptors. NPE does not result from improved cerebral blood flow. The receptor agonists protect the brain itself. They use a tolerance strategy and hypothermia is an important component, but not the only mechanism of NPE. Unlike most drugs, receptor neuroprotectors (RNP) guard not only a penumbra zone, but the core of ischemia as they are effective in complete global CI. Moreover, RNP-induced delay of irreversible lesions may increase a therapeutical window for using other drugs. RNPs are promising potential drugs in CI. PMID:11055199

Kulinski?, V I



[Radioprotective effect of alpha 2- adrenoreceptor agonists].  


It is confirmed in experiments with selective antagonists, that radioprotective effects (RPE) of phenylephrine is realised by means of alpha 1--and RPE of clonidine--by means of alpha 2-adrenoceptors (AR). Guanobenz, more selective alpha 2-agonist with another structure, has high RPE too. Chemical analogues of clonidine (alpha-antagonist phentolamine, L-DOPA, DOP-serine), which don't cause selective stimulation of alpha 2-AR, don't protect mice. alpha 2-Agonists are new effective group of radioprotectors. PMID:7904881

Kulinski?, V I; Kovtun, V Iu; Klimova, A D; Iashunski?, V G


Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure  

PubMed Central

Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor.

Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.



Les budgets des ménages  

Microsoft Academic Search

[fre] L'enquête sur les budgets des ménages effectuée en 1979 renoue avec la série interrompue en 1972. Au-delà du budget moyen, ses résultats mettent en lumière les comportements typiques de sous-groupes de la population : les jeunes, les familles, les vieux. Le niveau de vie reste la première variable selon laquelle s'agencent les comportements, mais il n'explique pas tout. Divers

Mireille Moutardier; Michel Glaude



Grundlagen des Tissue Engineering  

NASA Astrophysics Data System (ADS)

Die Organtransplantation stellt eine verbreitete Therapie dar, um bei krankheitsoder unfallbedingter Schädigung eines Organs die Gesamtheit seiner Funktionen wieder herzustellen, indem es durch ein Spenderorgan ersetzt wird. Organtransplantationen werden für die Leber, die Niere, die Lunge, das Herz oder bei schweren grossflächigen Verbrennungen der Haut vorgenommen. Der grosse apparative, personelle und logistische Aufwand und die Risiken der Transplantationschirurgie (Abstossungsreaktionen) sowie die mangelnde Verfügbarkeit von immunologisch kompatiblen Spenderorganen führen jedoch dazu, dass der Bedarf an Organtransplantaten nur zu einem sehr geringen Teil gedeckt werden kann. Sind Spenderorgane nicht verfügbar, können in einzelnen Fällen lebenswichtige Teilfunktionen, wie beispielsweise die Filtrationsfunktion der Niere durch die Blutreinigung mittels Dialyse ersetzt oder, bei mangelnder Funktion der Bauchspeicheldrüse (Diabetes), durch die Verabreichung von Insulin ein normaler Zustand des Gesamtorganismus auch über Jahre hinweg erhalten werden. Bei der notwendigen lebenslangen Anwendung apparativer oder medikamentöser Therapie können für den Patienten jedoch häufig schwerwiegende, möglicherweise lebensverkürzende Nebenwirkungen entstehen. Daher werden in der Forschung Alternativen gesucht, um die Funktionen des ausgefallenen Organs durch die Implantation von Zellen oder in vitro gezüchteten Geweben möglichst umfassend wieder herzustellen. Dies erfordert biologisch aktive Implantate, welche die für den Stoffwechsel des Organs wichtigen Zellen enthalten und einen organtypischen Stoffwechsel entfalten.

Mayer, Jörg; Blum, Janaki; Wintermantel, Erich


FXR agonist activity of conformationally constrained analogs of GW 4064  

SciTech Connect

Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)



Agonist induction, conformational selection, and mutant receptors  

Microsoft Academic Search

Current models of receptor activation are based on either of two basic mechanisms: agonist induction or conformational selection. The importance of one pathway relative to the other is controversial. In this article, the impossibility of distinguishing between the two mechanisms under a thermodynamic approach is shown. The effect of receptor mutation on the constants governing ligand–receptor equilibria is discussed. The

Jesús Giraldo



Biomarker Development for TLR4 Agonists.  

National Technical Information Service (NTIS)

In DARPA-supported studies, we have shown that a family of novel synthetic glycolipids known as the aminoalkyl glucosaminide phosphates (AGPs) act as potent agonists of Toll-like receptor 4 (TLR4), and that administration of AGPs to the airways results in...

D. H. Persing



Agonistic ethogram of the equid bachelor band  

Microsoft Academic Search

An ethogram of agonistic and related behaviors among equid bachelor band members was developed. Several key English-language studies on equids were reviewed to derive a preliminary inventory of specific behaviors to be included in the ethogram. A bachelor band of domestic pony stallions pastured together was observed for approximately 50 daylight hours to obtain detailed descriptions of each behavior, enable

S. M. McDonnell; J. C. S. Haviland



?2-adrenoceptor agonists: current and future direction  

PubMed Central

Despite the passionate debate over the use of ?2-adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of ?2-adrenoceptor agonists with long half-lives, also called ultra long-acting ?2-adrenoceptor agonists (ultra-LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF-610355) are currently under development with the hopes of achieving once-daily dosing. It is likely that the once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long-acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a ?2-adrenoceptor agonist, some novel once-daily combinations of LABAs and ICSs or LAMAs are under development. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit

Cazzola, Mario; Calzetta, Luigino; Matera, Maria Gabriella



Multiple tyrosine metabolites are GPR35 agonists  

PubMed Central

Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including ?-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3?,5?-triiodothyronine, 3,3?,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism.

Deng, Huayun; Hu, Haibei; Fang, Ye



The agonist paradox: agonists and antagonists of acetylcholine receptors and opioid receptors.  


In contrast to antagonists, agonists tend to induce considerable conformational changes in their receptors, resulting in opening of ion channels, either directly or via secondary messengers. These conformational transformations require great energy expenses. However, the experimentally determined free energies of complexation between agonists and receptors are often relatively smaller than those for the corresponding antagonists. To rationalize this so-called 'agonist paradox', which has not been clarified in the literature, we have developed an alternative model. Our model may help to discriminate between agonists and antagonists of the acetylcholine (ACh) and mu-opioid receptors. For this purpose, a series of ligands (1-18) have been analyzed both in structural terms and with respect to complexation geometry within the anionic binding sites of these two receptor types. PMID:17191984

Dukhovich, Felix S; Darkhovskii, Michael B; Gorbatova, Elena N; Polyakov, Victor S



Agonistic CD40 antibodies and cancer therapy  

PubMed Central

Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anti-cancer immunity by various mechanisms. CD40 is a tumor necrosis factor receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many non-immune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote anti-tumor T cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain regarding dose, schedule, route of administration, and formulation. Recent findings regarding the role played by the IgG isotype and the Fc gamma receptor (Fc?R) in mAb crosslinking, together with insights into mechanisms of action, particularly with regards to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field.

Vonderheide, Robert H.; Glennie, Martin J.



Le financement des agents non financiers en Europe : le rôle des intermédiaires financiers demeure prépondérant  

Microsoft Academic Search

[fre] Le financement des agents non financiers en Europe: le rôle des intermédiaires financiers demeure prépondérant . . Le degré d’intermédiation des financements de treize pays européens entre 1994 et 2001 est évalué à partir des comptes financiers nationaux (base Eurostat). Deux approches sont distinguées. L’approche par la demande adopte le point de vue des agents à besoin de financement

Jézabel Couppey-Soubeyran; Gunther Capelle-Blancard



Dual dopamine agonist treatment inParkinson’s disease  

Microsoft Academic Search

We studied the effectiveness of cabergoline as an adjunct in patients with early Parkinson’s disease receiving another dopamine agonist (pramipexole or ropinirole), at the maximal permitted dose. The study enrolled 47 patients: 35 had motor fluctuations and were receiving a dopamine agonist with levodopa; and 12, without motor fluctuations, were receiving a dopamine agonist without levodopa. These medications had in

Fabrizio Stocchi; Laura Vacca; Alfredo Berardelli; Marco Onofrj; Mario Manfredi; Stefano Ruggieri



Intervention in autoimmunity: The potential of vitamin D receptor agonists  

Microsoft Academic Search

Vitamin D receptor (VDR) agonists are well known for their capacity to control calcium metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess immunoregulatory properties and, in particular, pronounced pro-tolerogenic activities. VDR agonists can act directly on T cells, but DCs appear to be their primary targets. The

Luciano Adorini



Radiolabelled D2 agonists as prolactinoma imaging agents  

SciTech Connect

During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

Otto, C.A.



Effects of Continuously Feeding DES (Diethylstilbestrol) for Different Periods of Time to C3H MTV-Mice at Various Ages on Mammary Tumorigenesis of Uterine-Cervical Lesions.  

National Technical Information Service (NTIS)

The study described in the report was initiated after results from two earlier studies revealed discrepancies in the rate at which two C3H substrains (C3H/HeJ and C3H/HeN-MTV+) developed mammary tumors. In addition to the substrain difference, the age at ...

D. L. Greenman G. J. Schieferstein



Glucagon Receptor Agonists and Antagonists Affect the Growth of the Chick Eye: A Role for Glucagonergic Regulation of Emmetropization?  

PubMed Central

Purpose In chicks, plus defocus retards eye growth, thickens the choroid, and activates glucagonergic amacrine cells, probably releasing glucagon. Glucagon receptor antagonists (expected to inhibit compensation to plus defocus) and agonists (expected to block myopia induction by form deprivation) were administered to eyes of chicks, to test the hypothesis that glucagon mediates the induction of changes in eye growth by plus defocus. Methods Seven-day-old (P7) chick eyes were injected intravitreally with peptides at concentrations of ~10?9 to 10?5 M in 20 ?L (injection volume). The glucagon-receptor antagonists [des-His1,des- Phe6,Glu9]-glucagon-NH2 (des- Phe6-antagonist) and [des-His1,Glu9]-glucagon-NH2 (Phe6-antagonist) were administered daily for 4 to 5 days to plus-defocused eyes. Agonists (porcine glucagon-[1–29] and [Lys17,18,Glu21]-glucagon-NH2) were monocularly administered daily for 5 days to form-deprived eyes. The contralateral eye remained open and received saline. After treatment, eyes were refracted, measured, and examined for histologic changes. Results The Phe6-antagonist at 10?5 M (in the syringe) inhibited changes in both refractive error and axial length compensation induced by +7-D lens wear; however, des-Phe6-antagonist (10?5 M) had weak, inconsistent effects and did not antagonize the action of exogenous glucagon. Glucagon prevented ocular elongation and myopia and induced choroidal thickening in form-deprived eyes. [Lys17,18,Glu21]-glucagon-NH2 had little effect at 1037 M, but at 10?6 to 10?5 M altered rod structure and inhibited eye growth. Conclusions Exogenous glucagon inhibited the growth of form-deprived eyes, whereas Phe6-antagonist inhibited compensation to plus defocus, as might be expected if glucagon is an endogenous mediator of emmetropization. The reason for the failure of des-Phe6-antagonist to counteract the effects of exogenous glucagon requires further investigation.

Vessey, Kirstan A.; Lencses, Kathy A.; Rushforth, David A.; Hruby, Victor J.; Stell, William K.



Histrionicotoxin enhances agonist-induced desensitization of acetylcholine receptor.  


Dihydroisohistrionicotoxin inhibits acetylcholine receptor-dependent 22Na+ uptake of cultured chick muscle cells with a KI of 0.2 micrometer. The inhibition is noncompetitive with respect to agonists. The toxin enhances desensitization of the receptor by agonists which is accompanied by a 10-fold increase in receptor affinity for agonists. Dihydroisohistrionicotoxin increases the affinity of the desensitized form of the receptor for agonists but not antagonists. The results suggest that dihydroisohistrionicotoxin inhibits the acetylcholine receptor by causing an increase in the affinity of the desensitized form of the receptor for agonists and thereby stabilizing the desensitized state. PMID:272000

Burgermeister, W; Catterall, W A; Witkop, B



AMPK and PPAR? agonists are exercise mimetics  

PubMed Central

SUMMARY The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPAR?/? agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1?, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPAR? pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

Narkar, Vihang A.; Downes, Michael; Yu, Ruth T.; Embler, Emi; Wang, Yong-Xu; Banayo, Ester; Mihaylova, Maria M.; Nelson, Michael C.; Zou, Yuhua; Juguilon, Henry; Kang, Heonjoong; Shaw, Reuben; Evans, Ronald M.



AMPK and PPARdelta agonists are exercise mimetics.  


The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise. PMID:18674809

Narkar, Vihang A; Downes, Michael; Yu, Ruth T; Embler, Emi; Wang, Yong-Xu; Banayo, Ester; Mihaylova, Maria M; Nelson, Michael C; Zou, Yuhua; Juguilon, Henry; Kang, Heonjoong; Shaw, Reuben J; Evans, Ronald M



PPAR? Agonists: Blood Pressure and Edema  

PubMed Central

Peroxisome proliferator activated receptor ? (PPAR?) agonists are widely used in the treatment of type 2 diabetes. Side effects of drug treatment include both fluid retention and a lowering of blood pressure. Data from animal and human studies suggest that these effects arise, at least in part, from drug-induced changes in the kidney. In order to capitalize on the positive aspect (lowering of blood pressure) and exclude the negative one (fluid retention), it is necessary to understand the mechanisms of action underlying each of the effects. When interpreted with known physiological principles, current hypotheses regarding potential mechanisms produce enigmas that are difficult to resolve. This paper is a summary of the current understanding of PPAR? agonist effects on both blood pressure and fluid retention from a renal perspective and concludes with the newest studies that suggest alternative pathways within the kidney that could contribute to the observed drug-induced effects.

Blazer-Yost, Bonnie L.



Fonction diélectrique des milieux inhomogènes  

NASA Astrophysics Data System (ADS)

This review article is based on the thesis of Berthier — Laboratoire d'Optique des solides, Université P. et M. Curie— and on various contributions or ulterior works. Its aim is to present a critical and detailed review of the main theories of the optical dielectric function of inhomogeneous media. Together with a mathematical description of the theories, we give a physical interpretation of the results and the practical limits of validity. Each theory is compared to experimental results and other theoretical predictions as well. This study is introduced by theoretical reminders about the electric polarization and considerations about the physical meaning of some fundamental parameters when going from a microscopic to a macroscopic point of view. Cette revue est tirée de la thèse de Berthier préparée au Laboratoire d'Optique des Solides, Université P. et M. Curie, ainsi que des travaux qui lui font suite (thèse en préparation de Driss-Khodja) ou de ceux menés parallèlement (systèmes 2D) par d'autres membres de l'équipe. Son ambition est de présenter une étude approfondie et critique des différentes théories de la fonction diélectrique optique des milieux inhomogènes à trois dimensions. Après une description mathématique détaillée des principales théories, nous donnons une interprétation physique des résultats et les limites concrètes d'utilisation de chacune d'elles. Chaque grande théorie est confrontée à la fois à des résultats expérimentaux et aux prédictions des autres théories. Cette étude est précédée de rappels théoriques sur la polarisation électrique et de considérations sur la signification réelle de certains paramètres lors du passage d'un système microscopique isolé à un système macroscopique aléatoire.

Berthier, Serge


MCH receptor peptide agonists and antagonists.  


Melanin-concentrating hormone (MCH) is an important neuropeptide hormone involved in multiple physiological processes. Peptide derivatives of MCH have been developed as tools to aid research including potent radioligands, receptor selective agonists, and potent antagonists. These tools have been used to further understand the role of MCH in physiology, primarily in rodents. However, the tools could also help elucidate the role for MCHR1 and MCHR2 in mediating MCH signaling in higher species. PMID:19397944

MacNeil, Douglas J; Bednarek, Maria A



Design of a partial PPARdelta agonist.  


Structure based ligand design was used in order to design a partial agonist for the PPARdelta receptor. The maximum activation in the transactivation assay was reduced from 87% to 39%. The crystal structure of the ligand binding domain of the PPARdelta receptor in complex with compound 2 was determined in order to understand the structural changes which gave rise to the decrease in maximum activation. PMID:17560785

Pettersson, Ingrid; Ebdrup, Søren; Havranek, Miroslav; Pihera, Pavel; Korínek, Marek; Mogensen, John P; Jeppesen, Claus B; Johansson, Eva; Sauerberg, Per



Transdermal delivery of dopamine receptor agonists  

Microsoft Academic Search

Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). l-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the

Heinz Reichmann



Novel prostanoid thromboxane A2 agonists.  


The chemistry and biology of novel TXA2(TP)-receptor agonists based on the prostanoid skeleton is described and structure-activity-relationships are discussed. One compound,(5Z,13E), (9R,15R)-9-fluoro-15-hydroxy-16-phenoxy-17,18,19,20-tetranor- 5,13-prostadienoic acid (33), was identified which is 10 times more potent than the standard TP-receptor against U 46619. PMID:8588073

Joachim, K D; Klar, U; Pletsch, A; Rehwinkel, H; Skuballa, W



Über das Bandenspektrum des Wismuthydrids  

Microsoft Academic Search

Zusammenfassung Im Bandenspektrum des Wismuthydrids sind drei Bandensysteme gefunden, ein1S*-1S- und ein1S*-1II-System, die gemeinsamen Anfangszustand haben, und ein1Sx-1Sy- System, welches mit den anderen Systemen nicht kombiniert. In1S und in1II sind die drei ersten Kernschwingungsniveaus und in1S* die zwei ersten Kernschwingungsniveaus festgestellt worden. Im1Sx-1Sy-System sind das gefundene Kernschwingungsniveau des Anfangszustandes alsv=0 und die beiden Kernschwingungsniveaus des Endzustandes alsv=0 undv=1 bezeichnet. Die

Alf Heimer



Novel endogenous peptide agonists of cannabinoid receptors  

PubMed Central

Hemopressin (Hp), a 9-residue ?-hemoglobin-derived peptide, was previously reported to function as a CB1 cannabinoid receptor antagonist (1). In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hp?) or two (VD-Hp?) additional amino acids, as well as a ?-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hp?). Characterization of the ?-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB1 cannabinoid receptor antagonist, both RVD-Hp? and VD-Hp? function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca2+ indicate that these peptides activate a signal transduction pathway distinct from that activated by the endocannabinoid, 2-arachidonoylglycerol, or the classic CB1 agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB1 receptor is involved in the integration of signals from both lipid- and peptide-derived signaling molecules.—Gomes, I., Grushko, J. S., Golebiewska, U., Hoogendoorn, S., Gupta, A., Heimann, A. S., Ferro, E. S., Scarlata, S., Fricker, L. D., Devi, L. A. Novel endogenous peptide agonists of cannabinoid receptors.

Gomes, Ivone; Grushko, Julia S.; Golebiewska, Urszula; Hoogendoorn, Sascha; Gupta, Achla; Heimann, Andrea S.; Ferro, Emer S.; Scarlata, Suzanne; Fricker, Lloyd D.; Devi, Lakshmi A.



Transdermal delivery of dopamine receptor agonists.  


Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). L-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the prevention of dyskinesia; but this is also true for other dopamine receptor agonists such as ropinirole or pramipexole, which have a shorter half-life of about 6-8 hours. Due to the possible development of valvular fibrosis, cabergoline is, however, only approved as a second-line treatment in PD, and patch technology has therefore gained major interest. So far, rotigotine is the only dopamine receptor agonist available as a patch. There is good evidence that once-daily patch usage provides patients with constant dopaminergic stimulation, and that patches are of equal potency to other oral non-ergot derivatives such as ropinirole and pramipexole. The disadvantages of patches are skin irritation and crystallization of the drug if not kept in the refrigerator. PMID:20123566

Reichmann, Heinz



Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties  

PubMed Central

Chronic use of mu-opioid agonists has been shown to cause neurochemical adaptations resulting in tolerance and dependence. While the analgesic effects of these drugs are mediated by mu-opioid receptors (MOR), several studies have shown that antagonism or knockdown of delta-opioid receptors (DOR) can lessen or prevent development of tolerance and dependence. Based on computational modeling of putative active and inactive conformations of MOR and DOR, we have synthesized a series of pentapeptides with the goal of developing a MOR agonist/DOR antagonist peptide with similar affinity at both receptors as a tool to probe functional opioid receptor interaction(s). The eight resulting naphthylalanine-substituted cyclic pentapeptides displayed variable mixed-efficacy profiles. The most promising peptide (9; Tyr-c(S-CH2-S)[D-Cys-Phe-2-Nal-Cys]NH2) displayed a MOR agonist and DOR partial agonist/antagonist profile and bound with equipotent affinity (Ki ~ 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity.

Purington, Lauren C.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.



The effect of different LH-RH agonists on the levels of immunoreactive gonadotropins.  


The present study compared the effect of D-Ser(tBU)6-des-Gly-LHRH-ethylamide in the form of a nasal spray, D-Trp6-LHRH, which is applied in daily intramuscular injections, and the long-acting preparation, D-Trp6-LHRH, which is given as a monthly intramuscular injection, on the function of the pituitary-ovarian axis. Forty spontaneously menstruating women not belonging to the PCOD group participated in the study, the results of which indicate that the three LH-RH agonists used are similarly effective in their ability to down-regulate the pituitary-ovarian axis. The time required for the appearance of the suppressive effect, as measured by reduced levels of gonadotropins and estradiol as well as by the abolishment of the hypophyseal response to rising estrogens, usually does not exceed 14 days and is never more than 28 days. The immunoreactive LH-reducing effect of the LH-RH agonists was true only if the basic levels of the hormone were higher than 11 mIU/ml. This fact might be particularly significant in patients with polycystic ovarian disease or in perimenopausal women. PMID:2976572

Insler, V; Lunenfeld, E; Potashnik, G; Levy, J



Rapid nongenomic actions of inhaled corticosteroids on long-acting ?2-agonist transport in the airway  

PubMed Central

Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting ?2-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the noncharged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid sensitive disposition mechanism for cationic long-acting ?2-agonist bronchodilators in the airway. Potency rank order and other ‘classical’ features of anti-inflammatory effects do not apply to inhaled corticosteroids’ rapid drug transport actions.

Horvath, Gabor; Mendes, Eliana S.; Schmid, Nathalie; Schmid, Andreas; Conner, Gregory E.; Fregien, Nevis L.; Salathe, Matthias; Wanner, Adam



Rapid nongenomic actions of inhaled corticosteroids on long-acting ?(2)-agonist transport in the airway.  


Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting ?(2)-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting ?(2)-agonist bronchodilators in the airway. Potency rank order and other 'classical' features of anti-inflammatory effects do not apply to inhaled corticosteroids' rapid drug transport actions. PMID:21914487

Horvath, Gabor; Mendes, Eliana S; Schmid, Nathalie; Schmid, Andreas; Conner, Gregory E; Fregien, Nevis L; Salathe, Matthias; Wanner, Adam



Effet établissement et salaires des diplômés des universités françaises  

Microsoft Academic Search

A la suite notamment des travaux de Card et Krueger en 1992, une abondante littérature micro-économétrique, principalement développée aux Etats-Unis, a étudié les liens entre qualité de l'éducation, mesurée par différents inputs éducatifs et salaires des diplômés ou les rendements de l'éducation. À partir de données françaises provenant de l'enquête « Génération 98 » du Céreq enrichies pour les sortants

Jean-François Giret; Mathieu Goudard



Die fermentative Spaltung des Acetylcholins  

Microsoft Academic Search

Zusammenfassung Es wird eine neue Methode zum Nachweis des Fermentes, das Acetylcholin in Cholin und Essigsäure hydrolysiert, die Cholinesterase, beschrieben. Das Verfahren ist nach derWarburgschen Methode aufgebaut.

R. Ammon




Center for Food Safety and Applied Nutrition (CFSAN)

... avoisinants ne polluent pas les zone de culture de produits ... la conservation des ressources naturelles (National Resources Conservation Service ... More results from


Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-? receptor agonist GW7647  

PubMed Central

The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-? (PPAR-?) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-? systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid.

Russo, Roberto; LoVerme, Jesse; La Rana, Giovanna; D'Agostino, Giuseppe; Sasso, Oscar; Calignano, Antonio; Piomelli, Daniele



Vecteurs Singuliers des Theories des Champs Conformes Minimales  

NASA Astrophysics Data System (ADS)

En 1984 Belavin, Polyakov et Zamolodchikov revolutionnent la theorie des champs en explicitant une nouvelle gamme de theories, les theories quantiques des champs bidimensionnelles invariantes sous les transformations conformes. L'algebre des transformations conformes de l'espace-temps presente une caracteristique remarquable: en deux dimensions elle possede un nombre infini de generateurs. Cette propriete impose de telles conditions aux fonctions de correlations qu'il est possible de les evaluer sans aucune approximation. Les champs des theories conformes appartiennent a des representations de plus haut poids de l'algebre de Virasoro, une extension centrale de l'algebre conforme du plan. Ces representations sont etiquetees par h, le poids conforme de leur vecteur de plus haut poids, et par la charge centrale c, le facteur de l'extension centrale, commune a toutes les representations d'une meme theorie. Les theories conformes minimales sont constituees d'un nombre fini de representations. Parmi celles-ci se trouvent des theories unitaires dont les representation forment la serie discrete de l'algebre de Virasoro; leur poids h a la forme h_{p,q}(m)=[ (p(m+1) -qm)^2-1] (4m(m+1)), ou p,q et m sont des entiers positifs et p+q<= m+1. L'entier m parametrise la charge centrale: c(m)=1 -{6over m(m+1)} avec n>= 2. Ces representations possedent un sous-espace invariant engendre par deux sous-representations avec h_1=h_{p,q} + pq et h_2=h_{p,q} + (m-p)(m+1-q) dont chacun des vecteurs de plus haut poids portent le nom de vecteur singulier et sont notes respectivement |Psi _{p,q}> et |Psi_{m-p,m+1-q}>. . Les theories super-conformes sont une version super-symetrique des theories conformes. Leurs champs appartiennent a des representation de plus haut poids de l'algebre de Neveu-Schwarz, une des deux extensions super -symetriques de l'algebre de Virasoro. Les theories super -conformes minimales possedent la meme structure que les theories conformes minimales. Les representations sont elements de la serie h_{p,q}= [ (p(m+2)-qm)^2-4] /(8m(m+2)) ou p,q et m sont des entiers positifs, p et q etant de meme parite, et p+q<= m+2. La charge centrale est donnee par c(m)={3over 2}-{12over m(m+2)} avec m >= 2. Les vecteurs singuliers | Psi_{p,q}> et |Psi_{m-p,m+2-q} > sont respectivement de poids h _{p,q}+pq/2 et h_ {p,q}+(m-p)(m+2-q)/2.. Les vecteurs singuliers ont une norme nulle et on doit les eliminer des representations pour que celles -ci soient unitaires. Cette elimination engendrent des equations (super-)differentielles qui dependent directement de la forme explicite des vecteurs singuliers et auxquelles doivent obeir les fonctions de correlations de la theorie. Ainsi la connaissance de ces vecteurs singuliers est intimement reliee au calcul des fonctions de correlation. Les equations definissant les vecteurs singuliers forment un systeme lineaire surdetermine dont le nombre d'equations est de l'ordre de N(pq), le nombre de partitions de l'entier pq. Puisque les vecteurs singuliers jouent un role capital en theorie conforme, il est naturel de chercher des formes explicites pour les vecteurs (ou pour des familles infinies de ceux -ci). Nous donnons ici la forme explicite pour la famille infinie de vecteurs singuliers ayant un de ses indices egal a 1, pour les algebres de Virasoro et de Neveu-Schwarz. Depuis ces decouvertes, d'autres techniques de construction des vecteurs singuliers ont ete developpees, dont celle de Bauer, Di Francesco, Itzykson et Zuber pour l'algebre de Virasoro qui reproduit directement l'expression explicite des vecteurs singuliers |Psi _{1,q}> et |Psi_{p,1}>. Ils ont utilise l'algebre des produits d'operateurs et la fusion entre representations irreductibles pour engendrer des relations de recurence produisant les vecteurs singuliers. Dans le dernier chapitre de cette these nous adaptons cet algorithme a la construction des vecteurs singuliers de l'algebre de Neveu-Schwarz.

Benoit, Louis


Alloplastischer Ersatz des vorderen Kreuzbandes  

Microsoft Academic Search

Zusammenfassung  Es wurden 24 Polythylenterephtalatbnder (acht Dacron-, elf Trevira-und fnf Ligaprobnder), die als Ersatz des vorderen\\u000a Kreuzbandes wegen Ruptur oder Lockerung explantiert werden muten, histologisch untersucht. Die wnschenswerte Ausbildung\\u000a von longitudinal orientiertem Typ-I-Kollagen entlang des Kunstbandes fand sich als eine Art “Neoligament” nur in einem Treviraband.\\u000a Die Kollagenfaserbndel haben sich bei allen drei Bandarten in nur geringer Menge gebildet und sich

G. Sowa; D. Sowa; J. Koebke



Hemmstoffe des Folsäure-Stoffwechsels  

Microsoft Academic Search

Zusammenfassung Anders als die Antibiotika-Forschung steht die Erforschung des Folsäure-Stoffwechsels und der Folsäure-Antagonisten ganz in der klassischen aufPaul Ehrlich zurückgehenden Tradition der Chemotherapie. Mit der Aufklärung des Wirkungsmechanismus der Sulfonamide wurde eine wichtige Voraussetzung zum Verständnis der Biosynthese der Folsäure geschaffen. Die Synthese von Inhibitoren der Dihydrofolat-Reduktase orientierte sich einerseits an der Struktur der Dihydrofolsäure selbst, andererseits an der Tatsache,

J. Drews



Nouvelles régulations territoriales et l'évaluation des activités des entreprises et de leurs système de parties prenantes  

Microsoft Academic Search

Nous analysons dans ces travaux de recherche l'évolution des stratégies des entreprises et des territoires vers des logiques fonctionnelles comme conséquence de l'importance de plus en plus grande des enjeux environnementaux dans la création et l'évaluation de la valeur produite et partagée entre les acteurs. L'importance d'une cohérence des performances économiques, environnementales et sociales d'une part des activités des entreprises

Ingrid Vaileanu Paun



Altération des sulfures des granulats dans les chaussées  

NASA Astrophysics Data System (ADS)

Sulfides present in hornsfeld aggregates, used in light pavanent construction in contact with humid air alter rapidly. Crystallisation of sulfates at the interface of bitumastic material and sub-base creates serious problems (intumescence and crazing) that can lead to a total reconstruction of the project (roads, sidewalks, sports areas, etc). The sulfides in the aggregates and the sulfates produced due to alteration are studied by SEM and XRD. The results show that the intensity of this phenomenon is linked to the nature and the crystallinity of the sulfides. The evolution of the sulfates formed during this alteration process is slow and complex. In new pavements (3 years) the sulfates have a pulverised appearance and consist mostly of epsomite, associated with pickeringite and halotrichite. In older pavements (20 years) the sulfates form a fibrous concretion consisting of pickeringite and small quantities of halotrichite. Les sulfures présents dans les granulats élaborés à partir de cornéen nes s'altèrent rapidement dans les chaussées légères en présence d'air humide. La cristallisation des sulfates à l'interface enrobé-couche de fondation crée des désordres si importants (intumescences, faiençage) qu'il est bien souvent nécessaire d'assurer la réfection totale des ouvrages (routes, trottoirs, plateaux sportifs...). Les sulfures des granulats et les sulfates issus du processus d'altération ont été étudiés par diffractométrie X et examen su Microscope Electronique à Balayage équipé de microanalyse X. Les résultats montrent que !intensité des désordres est liée à la nature et à la cristallinité des sulfures. Les sulfates formés évoluent su cours du processus d'altération qui est long et complexe. Dans les chaussées récentes (3 ans) ils ont un aspect pulvérulent et sont constitués d'epsomite dominante associée à de la pickeringite et à de l'halotrichite. Dans les chaussées plus anciennes (20 ans) ils forment des concrétions fibreuses constituées de pickeringite et d'une faible quantité d'halotrichite.

Jigorel, A.; Jauberthie, R.



Sports doping: Emerging designer and therapeutic ?2-agonists.  


Beta2-adrenergic agonists, or ?2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ?2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel ?2-agonists molecules either by modifying the molecule of known ?2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging ?2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. PMID:23954776

Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F



Architecture gouvernementale ouverte:Évolution des normes, des standards de consortium et des logiciels libres  

Microsoft Academic Search

Cette étude, réalisée pour le Conseil du trésor du Québec, a pour objectifs de présenter, dans un contexte d’architecture d’entreprise, les récents développements dans l’évolution des normes et standards par les différents acteurs du milieu, les consortiums industriels et les comités de normalisation internationaux en s’arrimant avec les logiciels ouverts.Pour pouvoir atteindre ses objectifs de services auprès des citoyens et

François Coallier; Robert Gérin-Lajoie



Compound and compositions as TGR5 agonists: WO2012082947.  


The patent application WO2012082947 claims novel compounds as agonists of a plasma membrane-bound bile acid receptor TGR5. By activating TGR5, the agonists improve glycemic control and enhance energy expenditure. The basic generic claim of the patent covers pyrazole derivatives, different permutations on the core pyrazole ring are covered in the subsidiary claims. The claimed compounds are human TGR5 agonists having potency in the nM range. PMID:23409864

Raval, Saurin



Indacaterol, A Novel Once Daily Inhaled ?2-Adrenoreceptor Agonist  

PubMed Central

In this article we will review the role of long acting ?2-adrenoreceptor agonists and long-acting muscarinic agents in the management of airflow obstruction. We will then focus our attention on indacaterol, one of the new once daily inhaled ?2-adrenoreceptor agonists. Pharmacologically this drug is a nearly full ?2-agonist without loss of efficacy after prolonged administration. We will also discuss its dosing, safety and tolerability.

Roig, Jorge; Hernando, Rosana; Mora, Ramon



Cognitive enhancing effects of ghrelin receptor agonists  

Microsoft Academic Search

Rationale  Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been shown to play a role in multiple physiological\\u000a processes including appetite regulation, metabolism and, more recently, dendritic spine architecture, long-term potentiation\\u000a and cognition.\\u000a \\u000a \\u000a \\u000a Objective  The objective of this study was to determine the effects of two structurally non-peptide ghrelin receptor agonists (GSK894490A\\u000a and CP-464709-18) on rodent cognition.\\u000a \\u000a \\u000a \\u000a Methods  All experiments

Zeenat Atcha; Woei-Shin Chen; Agnes B. Ong; Fong-Kuan Wong; Aveline Neo; Edward R. Browne; Jason Witherington; Darrel J. Pemberton



Beta 2-adrenoceptor agonists and thyroid hormones.  

PubMed Central

The potential influence of the selective beta 2-adrenoceptor agonist terbutaline on the serum concentration of the thyroid hormones in humans was studied in 11 healthy euthyroid subjects. Five served as a control group without medication while six received 5 mg terbutaline three times daily for 2 weeks. No significant differences were found between the two groups by measuring the serum concentrations of thyroxine, triiodothyronine, reverse triiodothyronine and resin-triiodothyronine uptake. The use of a beta 2-adrenergic receptor stimulating drug is relatively contraindicated in untreated thyrotoxicosis. This recommendation is based upon a summation of clinical adverse reactions and not due to an effect on the serum concentrations of thyroid hormones.

Kampmann, J P; Svendsen, T L; Skovsted, L; M?lholm Hansen, J E



Compulsive eating and weight gain related to dopamine agonist use  

Microsoft Academic Search

Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobby- ism, and other repetitive, purposeless behaviors (\\

Melissa J. Nirenberg; Cheryl Waters



Adverse effects of opioid agonists and agonist-antagonists in anaesthesia.  


The traditional view of opioids held that the individual opioid agonists shared the same mechanism of action, differing only in their potency and pharmacokinetic properties. However, recent advances in opioid receptor pharmacology have made this view obsolete. Distinguishing features of the synthetic opioid agonists are related, at least in part, to variation in affinity and intrinsic efficacy at multiple opioid receptors. Respiratory depression is the opioid adverse effect most feared by anaesthesiologists. Specific kappa-receptor agonists produce analgesia with little or no respiratory depression. There are a number of commercially available kappa-receptor partial agonist drugs, the so-called agonist-antagonist or nalorphine-like opioids, which appear to have a limited effect on breathing. Within the series of fentanyl analogues there are differences in behaviour towards particular opioid receptors and there is evidence for subtle differences in respiratory depressant effects. Pethidine (meperidine) causes histamine release and myocardial depression, while the fentanyl analogues do not. Pethidine has atropine-like effects on heart rate, while fentanyl analogues reduce heart rate by a vagomimetic action. Severe bradycardia or even asystole is possible with fentanyl analogues, especially in conjunction with the vagal stimulating effects of laryngoscopy. Fentanyl analogues often produce minor reductions in blood pressure, and occasionally severe hypotension by centrally mediated reduction in systemic vascular resistance. Muscle rigidity and myoclonic movement occurs frequently during induction of anaesthesia with larger doses of opioids. Fentanyl and alfentanil have been reported to produce localised temporal lobe electrical seizure activity in patients with complex partial epilepsy. There are probably fewer biliary effects with agonist-antagonist opioids than the agonist opioids. The mechanism of adverse effects after spinal administration is distinctly different for morphine, which is very water soluble, compared with more lipid-soluble opioids. The systemic absorption of morphine after intrathecal or epidural administration is very slow, resulting in long duration of analgesia and low plasma concentrations, while lipid-soluble opioids are rapidly absorbed into the circulation and redistributed to the brain. The serotonin syndrome may result from coadministration of pethidine, dextromethorphan, pentazocine or tramadol with monoamine oxidase inhibitors (MAOIs) or selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). There are clinically important interactions between opioids and hypnosedatives, resulting in synergistic effects on sedation, breathing and blood pressure. PMID:9747665

Bowdle, T A



Sécurité virale des produits dérivés du plasma  

Center for Biologics Evaluation and Research (CBER)

Text Version... Par exemple, certaines étapes de précipitation et de séparation dans le processus de fabrication des produits dérivés du plasma et des produits ... More results from


Aktuelle Entwicklungen des Wettbewerbs der Gesellschaftsrechte  

Microsoft Academic Search

Die drei causes célèbres des EuGH zur Niederlassungsfreiheit der Gesellschaften, Centros, Überseering und Inspire Art , haben eine Flut von Anmerkungen, Besprechungsaufsätzen und Monographien hervorgebracht, die den Beginn des Wettbewerbs der Gesellschaftsrechtsordnungen\\

Eva-Maria Kieninger


Agonistic and antagonistic activities of chemokines.  


Since the discovery of interleukin-8, about 50 chemokines have been identified and characterized. Originally, they were considered as inducible mediators of inflammation, but in recent years, several chemokines were identified that are expressed constitutively and function in physiological traffic and homing of leukocyte-lymphocytes in particular. All chemokines act via seven-transmembrane domain, G protein-coupled receptors. Eighteen such receptors have been identified so far. Studies on structure-activity relationships indicate that chemokines have two main sites of interaction with their receptors, the flexible NH2-terminal region and the conformationally rigid loop that follows the second cysteine. Chemokines are thought to dock onto receptors by means of the loop region, and this contact is believed to facilitate the binding of the NH2-terminal region that results in receptor activation. These studies have also highlighted the importance of the NH2-terminal region for agonistic and antagonistic activity. Recently, we have shown that some naturally occurring chemokines can function as receptor antagonists. These observations suggest a new mechanism for the regulation of leukocyte recruitment during inflammatory and immune reactions, which are based on the combination of agonistic and antagonistic effects. PMID:11404371

Loetscher, P; Clark-Lewis, I



Novel endogenous peptide agonists of cannabinoid receptors.  


Hemopressin (Hp), a 9-residue alpha-hemoglobin-derived peptide, was previously reported to function as a CB(1) cannabinoid receptor antagonist (1) . In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hpalpha) or two (VD-Hpalpha) additional amino acids, as well as a beta-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hpbeta). Characterization of the alpha-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB(1) cannabinoid receptor antagonist, both RVD-Hpalpha and VD-Hpalpha function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca(2+) indicate that these peptides activate a signal transduction pathway distinct from that activated by the endocannabinoid, 2-arachidonoylglycerol, or the classic CB(1) agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB(1) receptor is involved in the integration of signals from both lipid- and peptide-derived signaling molecules. PMID:19380512

Gomes, Ivone; Grushko, Julia S; Golebiewska, Urszula; Hoogendoorn, Sascha; Gupta, Achla; Heimann, Andrea S; Ferro, Emer S; Scarlata, Suzanne; Fricker, Lloyd D; Devi, Lakshmi A



Chimpanzees extract social information from agonistic screams.  


Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see. PMID:20644722

Slocombe, Katie E; Kaller, Tanja; Call, Josep; Zuberbühler, Klaus



Les attitudes des ménages : leur signification  

Microsoft Academic Search

[fre] Les attitudes des ménages : leur signification - Instrument privilégié d'analyse conjoncturelle, l'enquête de l'INSEE sur les « attitudes et intentions d'achats des particuliers» cherche également à connaître l'opinion des ménages sur la situation économique française récente et future. A la lumière d'une expérience de plus de quinze années, l'auteur, rapprochant l'évolution observée des opinions émises, s'interroge sur la

Philippe lHardy



Ephémérides astronomiques 2011 : Connaissance des Temps  

NASA Astrophysics Data System (ADS)

Cet ouvrage d'éphémérides destiné aux astronomes, aux professeurs et aux étudiants est divisé en deux parties. Il donne les positions des astres pour l'année 2011. Le livre présente l'état actuel des connaissances sur les bases et les explications de calculs des éphémérides puis donne sous forme d'éphémérides tabulées les données permettant d'obtenir la position des astres à observer. En utilisant le CD-ROM, l'utilisateur peut préparer ses observations.

Bureau Des Longitudes (Bdl); Institut de Mécanique Céleste Et de Calcul Des Ephémérides (Imcce); Observatoire de Paris



La Dyssymétrie des Régimes Pluviaux au Nord et au sud des Alpes Suisses  

Microsoft Academic Search

Résumé L'indice de similitude calculé entre une station alpine, Sion en Valais, et quelques localités situées de part et d'autre des Alpes met en évidence la dissemblance des régimes pluviaux des deux versants. Au Nord, les indices quasi normaux reflètent la distribution homogène des pluies en plages de grandes dimensions; au Sud, les indices trop faibles trahissent l'irrégularité des zones

Max Bouët



L'astronomie des Anciens  

NASA Astrophysics Data System (ADS)

Quelle que soit la civilisation à laquelle il appartient, l'être humain cherche dans le ciel des réponses aux questions qu'il se pose sur son origine, son avenir et sa finalité. Le premier mérite de ce livre est de nous rappeler que l'astronomie a commencé ainsi à travers les mythes célestes imaginés par les Anciens pour expliquer l'ordre du monde et la place qu'ils y occupaient. Mais les savoirs astronomiques passés étaient loin d'être négligeables et certainement pas limités aux seuls travaux des Grecs : c'est ce que l'auteur montre à travers une passionnante enquête, de Stonehenge à Gizeh en passant par Pékin et Mexico, fondée sur l'étude des monuments anciens et des sources écrites encore accessibles. Les tablettes mésopotamiennes, les annales chinoises, les chroniques médiévales, etc. sont en outre d'une singulière utilité pour les astronomes modernes : comment sinon remonter aux variations de la durée du jour au cours des siècles, ou percer la nature de l'explosion qui a frappé tant d'observateurs en 1054 ? Ce livre offre un voyage magnifiquement illustré à travers les âges, entre astronomie et archéologie.

Nazé, Yaël



Une théorie des années quatre-vingt  

Microsoft Academic Search

[fre] Les années quatre-vingt présentent, pour les analyses macroéconomiques habituelles, des énigmes majeures, dont, aux premiers rangs, la persistance d'un chômage élevé en Europe et la désynchronisation des conjonctures américaine et européennes pendant la première moitié de la décennie. Des «faits» nouveaux, qui distinguent la période considérée sont mal pris en compte par les modèles usuels. Cet article propose une

Jacques Le Cacheux; Jean-Paul Fitoussi



Le contrôle des réseaux de franchise  

Microsoft Academic Search

La problématique du contrôle des réseaux de franchise doit prendre en compte la nature spécifique de ce type de réseau, les motivations et les comportements du franchiseur et des franchisés et les modalités techniques du contrôle mis en oeuvre. Une analyse du contrôle au sein des réseaux de franchise est développée mettant en évidence ses diverses modalités et leur évolution

Catherine Goullet; François Meyssonnier



Le contrôle des réseaux de franchise  

Microsoft Academic Search

La problématique du contrôle des réseaux de franchise est dégagée, prenant en compte la nature spécifique de ce type de réseau, les motivations et les comportements du franchiseur et des franchisés et les différentes dimensions du contrôle mis en oeuvre. Une analyse du contrôle au sein des réseaux de franchise est développée mettant en évidence ses diverses modalités et leur

Catherine Goullet; François Meyssonnier



Le piratage des biens d'information  

Microsoft Academic Search

Où se situe le juste milieu entre les propos alarmistes des uns (“le piratage tue la production musicale!”) et les appels libertaires des autres (“l'accès à toute information doit être libre!”) ? Une analyse économique simple nous permet de mieux comprendre les enjeux et de dégager des pistes de réflexion pour l'avenir.

Paul Belleflamme



Diffusion et usage des comptes de chèques  

Microsoft Academic Search

[fre] Actuellement, les dépôts à vue représentent en France les deux tiers des disponibilités monétaires alors qu'ils en constituaient seulement la moitié en 1950 et environ le tiers en 1938. . Ces dépôts à vue proviennent, pour une grande part, des ménages. Quelles sont les caractéristiques des titulaires de compte-chèque ? . Une enquête par sondage réalisée en 1967 (8

André Villeneuve



Chronique des tendances de la société française  

Microsoft Academic Search

[fre] Cette chronique couvre quatre domaines : • Le mouvement d'égalisation des revenus des ménages a marqué les années 1965- 1979 et a contribué à la prépondérance de la classe moyenne durant ces années. Depuis, différentes enquêtes permettent de constater que l'échelle des revenus se distend de nouveau, amenant de plus en plus de ménages à la lisière de la

Louis Dirn




Microsoft Academic Search

L'étude porte sur la gestion des résultats afin d'éviter les pertes et les baisses de résultats. L'analyse des distributions de résultats et de variation des résultats, et la mise en oeuvre de tests complémentaires, permettent de vérifier les hypothèses sur un échantillon de 294 entreprises françaises cotées.

Yves Mard




Microsoft Academic Search

Cet article a pour objectif d'étudier la structure des liens humains entre les conseils d'administration et son influence sur la rémunération incitative du premier dirigeant. Un échantillon de 181 dirigeants des sociétés du SBF 250 entre 2002 et 2005 est retenu. Nos résultats montrent que la position du conseil dans le réseau des liens, appréhendée par la centralité de proximité,

Ali Dardour



Synthesis and SAR of Tetrahydroisoquinolines as Rev-erb? agonists  

PubMed Central

The design and synthesis of a novel series of Rev-erb? agonists is described. The development and optimization of the tetrahydroisoquinoline series was carried out from an earlier acyclic series of Rev-erb? agonists. Through the optimization of the scaffold 1, several potent compounds with good in vivo profiles were discovered.

Noel, Romain; Song, Xinyi; Shin, Youseung; Banerjee, Subhashis; Kojetin, Douglas; Lin, Li; Ruiz, Claudia H.; Cameron, Michael D.; Burris, Thomas P.




Microsoft Academic Search

A tradition stretching back to early Greek philosophy has described the mind as a field of struggle or even battle. This comparison has been termed the agonistic metaphor, based on the Hellenistic notion of athletic contests. Today, it is not uncommon for psychotherapists and the general public to seek solutions to mental health problems agonistically. Examples of this are cited




CB 2 cannabinoid receptor agonists: pain relief without psychoactive effects?  

Microsoft Academic Search

Cannabinoid receptor agonists significantly diminish pain responses in animal models; however, they exhibit only modest analgesic effects in humans. The relative lack of efficacy in man may be because of the dose limitations imposed by psychoactive side effects. Cannabinoid agonists that selectively target CB2 (peripheral) cannabinoid receptors should be free of psychoactive effects, perhaps allowing for more effective dosing. CB2

T Philip Malan; Mohab M Ibrahim; Josephine Lai; Todd W Vanderah; Alexandros Makriyannis; Frank Porreca



Dopamine receptor agonists and sleep disturbances in Parkinson's disease.  


Non-ergot dopamine receptor agonists, such as ropinirole, pramipexole, rotigotine and apomorphine, may alleviate some non-motor symptoms in Parkinson's disease (PD) while others may be precipitated. In this review, we discuss how dopamine receptor agonists can both ameliorate and aggravate the sleep problems in PD, a key non-motor symptom of this disease. PMID:20123546

Chaudhuri, K Ray; Logishetty, Kartik




EPA Science Inventory

Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...


Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists  

ERIC Educational Resources Information Center

|Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like…

King, Angela G.



GnRH agonist triggering: recent developments.  


The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin(HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages, including virtually complete prevention of ovarian hyperstimulation syndrome(OHSS), the introduction of a surge of FSH in addition to the LH surge and finally the possibility to individualize luteal-phase supplementation based on ovarian response to stimulation. We maintain that the automatic HCG triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. PMID:23337420

Kol, Shahar; Humaidan, Peter



GLP-1 agonists in type 1 diabetes.  


Despite years of research in the field of type 1 diabetes, patients with the disease remain without a therapeutic agent that can alter the underlying immune response in a clinically beneficial way. Glucagon-like peptide 1 agonist therapies have shown some promising effects in terms of positively affecting overall beta cell health and increasing beta cell mass, primarily in mouse models. The three agents of this class currently available for patients with type 2 diabetes have shown beneficial clinical effects on glucose control in this patient population. The purpose of this article is to review the preclinical and clinical data of these agents to date with a focus on the potential immunological and clinical benefits these drugs may have on patients with type 1 diabetes. PMID:23643354

Pettus, Jeremy; Hirsch, Irl; Edelman, Steven



LPA receptor agonists and antagonists (WO2010051053)  

PubMed Central

Summary Lysophosphatidic acid (LPA) is a bioactive lipid involved in signaling pathways that result in cell survival, proliferation, migration, and invasion. These cellular responses are a critical element of both normal development as well as pathophysiology. In particular, disregulated LPA production and function have been linked with cancer and cardiovascular disease. RxBio, Inc., have generated several series of LPA analogs with varied agonist/antagonist function at the LPA1–3 G protein-coupled receptor targets of LPA signaling. These analogs are simplified relative to LPA, through deletion of the glycerol moiety linking the LPA phosphate and fatty acid groups. One of the example compounds was shown to protect intestinal crypt cells from radiation-induced apoptosis in mice when whole-body irradiation occurred two hours after oral dosing.

Parrill, Abby L.



Enhanced gastrointestinal motility with orally active ghrelin receptor agonists.  


The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders. PMID:19252061

Charoenthongtrakul, Soratree; Giuliana, Derek; Longo, Kenneth A; Govek, Elizabeth K; Nolan, Anna; Gagne, Samantha; Morgan, Kristen; Hixon, Jeffrey; Flynn, Neil; Murphy, Brian J; Hernández, Andres S; Li, Jun; Tino, Joseph A; Gordon, David A; DiStefano, Peter S; Geddes, Brad J



Dopamine agonists in dihydropteridine reductase deficiency.  


The traditional treatment of severe disorders of tetrahydrobiopterin (BH4) metabolism is based on the replacement therapy with BH4, 5-hydroxytryptophan, and L-dopa. Major problems are encountered with L-dopa therapy, especially with increasing age when higher doses are necessary, because of its short half-life and adverse effects. Consequently, different L-dopa-sparing strategies have been successively introduced, with partial reduction of L-dopa dosage and amelioration of the clinical outcome. Recently, we demonstrated that the dopamine agonist pramipexole improves the therapeutic effect of L-dopa in 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency, the most common disorder of BH4 metabolism. Here we report its effectiveness in two patients (males, 7 and 22 years) with dihydropteridine reductase (DHPR) deficiency, the second most frequent cause of BH4 deficiency. Both patients experienced residual symptoms of dopamine deficiency, movement and behavioral disability, and complications of L-dopa therapy, associated with fluctuating hyperprolactinemia. They had full clinical and biochemical assessment, by an adapted Unified Parkinson's Disease Rating Scale (UPDRS) and measurement of diurnal plasma prolactin (PRL) profile before and after a trial with pramipexole. Besides allowing the reduction of L-dopa daily dosage (-58%) and administrations (from three to two) in one patient and to stop L-dopa therapy in the other, the introduction of pramipexole markedly improved and stabilized clinical and biochemical picture in both patients, as revealed by reduction of UPDRS scores and normalization of diurnal plasma prolactin profiles. Dopamine agonists can improve or even replace L-dopa therapy in disorders of synthesis and regeneration of BH4. PMID:22325981

Porta, Francesco; Mussa, Alessandro; Concolino, Daniela; Spada, Marco; Ponzone, Alberto



Transport quantique dans des nanostructures  

NASA Astrophysics Data System (ADS)

Quantum transport in nanostructures This work is devoted to the design, fabrication and magnetotransport investigations of mesoscopic devices. The sample are obtain by e-beam lithography and the measurements are performed at low temperature in a dilution refrigerator in the presence of a magnetic field. We have used MBE grown AlGaAs/GaAs heterojonctions as starting material to fabricate a bipartite tiling of rhombus called mathcal{T}3 lattice. We observe for the first time large amplitude h/e oscillations in this network as compared to the one measured in square lattices of similar size. These oscillations are the signature of a recently predited localization phenomenon induced by Aharonov-Bohm interferences on this peculiar topology. For particular values of the magnetic field the propagation of the electron wave function is bounded in a small number of cells, called Aharonov-Bohm cages. More strikingly, at high magnetic field, h/2e oscillations appear whose amplitude can be much higher than the fundamental period. Their temperature dependence is similar to that of the h/e signal. These observations withdraw a simple interpretation in terms of harmonics generation. The origin of this phenomenon is still unclear and needs more investigations. The influence electrical width of the wire defining the network and so the rule of the number of channels can be studied using a gate deposited over the lattice. In particular we have measured the amplitude dependence of the h/e and h/2e signal versus the gate voltage. Ce travail est consacré à la réalisation d'échantillons mésoscopiques à partir de la lithographie électronique ainsi qu'à leur caractérisation à très basse température en magnétotransport. Nous avons pour cela exploité le gaz bidimensionnel d'électrons situé à l'interface d'une hétérojonction AlGaAs/GaAs pour réaliser un réseau de boucle d'une géométrie particulière baptisée la géométrie mathcal{T}3. Nous avons observé sur cette structure des oscillations de conductance en fonction du flux du champ magnétique de période h/e dont l'amplitude est beaucoup plus importante que celle mesurée sur un réseau carré de même dimension. Cette différence constitue une signature d'un effet de localisation induit par le champ magnétique sur la topologie mathcal{T}3. Pour des valeurs spécifiques du champ magnétique, du fait des interférences destructives Aharonov-Bohm, la propagation des fonctions d'ondes est limitée à un ensemble fini de cellule du réseau appelé cage. De la dépendance en température des oscillations de période h/e mesurées sur le réseau mathcal{T}3 nous avons tiré une longueur caractéristique qui peut être rattachée au périmètre des cages. Un phénomène inattendu fut l'observation, pour des champs magnétiques plus importants, d'un doublement de fréquence des oscillations. Ces oscillations de période h/2e pouvant avoir une amplitude supérieure aux oscillations de période h/e, une interprétation en terme d'harmonique n'est pas possible. Enfin, l'influence de la largeur électrique des fils constituant le réseau et donc celle du nombre de canaux par brin a été étudiée en réalisant des grilles électrostatique. Les variations de l'amplitude des signaux en h/e et h/2e en fonction de la tension de grille ont été mesurés.

Naud, C.



The Shift from Agonistic to Non-Agonistic Debate in Early Ny?ya  

Microsoft Academic Search

This article examines the emergence of the Ny?ya distinction between v?da and jalpa as didactic-scientific and agonistic-sophistical\\u000a forms of debate, respectively. Looking at the relevant sutras in Gautama’s Ny?ya-s?tra (NS 1.2.1-3) in light of the earlier discussion of the types of debate in Caraka Sa?hit? 8, the article argues that certain ambiguities and obscurities in the former text can be

Hugh Nicholson



Annuaire du Bureau des longitudes - 2006  

NASA Astrophysics Data System (ADS)

This annual publication provides ephemerides and data to the use of professionnal and amateur astronomers. Divided in 11 chapters it covers concordance of various calendars, explanation of fondamental astronomy and various time scales, explanation for the use of ephemerides; tables provide ephemerides (positions, rise/set/passage) of the Sun and the Moon, planets, planetary satellites, asteroids, comets, bright stars; data and explanation for the physical observation of the surface of the Sun, the Moon, and planets; chart of the sky and a list of constellations and galaxies; prediction and ephemerides for astronomical phenomenon: occultation by the moon, stellar occultations by asteroids and appulses, solar eclipses and lunar eclipses; and an additional review about a hot scientific topic, this year: "Legendre et le méridien terrestre, 200 ans après". Cette publication annuelle fournit des éphémérides et des données à l'usage des astronomes professionnels et des astronomes amateurs. Composée de 11 chapitres elle comprend les rubriques sur les différents calendriers et leurs concordance, les fêtes légales en France, les dates et décrets sur les heures légales en France métropolitaine ; une introduction à l'astronomie fondamentale et aux différentes échelles de temps, des explications sur l'utilisation des éphémérides ; des tables fournissent les éphémérides (positions, heures de lever/coucher/passage) du Soleil et de la Lune, de planètes, de satellites naturels, d'astéroïdes, de comètes, d'étoiles brillantes ; des données pour l'observation de la surface du Soleil, de la Lune, et des planètes ; des cartes du ciel ainsi qu'une liste de constellations et de galaxies ; des prédictions des phénomènes astronomiques : occultation par la Lune, occultation stellaires par des astéroïdes et appulses, éclipses de Soleil et de la Lune; la liste et les coordonnées des observatoires astronomiques les plus connus ; et enfin un cahier thématique sur un sujet d'actulaité, pour cette année : "Legendre et le méridien terrestre, 200 ans après".

Imcce; Bureau Des Longitudes



Proprietes optiques et mecanismes de relaxation de l'energie des porteurs dans des boites quantiques  

NASA Astrophysics Data System (ADS)

L'objet de ce doctorat est l'etude des proprietes optiques, et en particulier de la relaxation de l'energie des porteurs dans des structures a boites quantiques d'InAs/GaAs. Le travail experimental a ete realise grace aux techniques de photoluminescence (PL) continue et de photoluminescence resolue dans le temps, sur des echantillons comprenant un tres grand nombre de boites. A l'aide des mesures experimentales effectuees sur une serie d'echantillons de boites quantiques interdiffusees a divers degres, et des calculs variationnels de leurs etats electroniques, nous avons demontre clairement que la largeur des raies d'emission de la PL, qui est due aux inhomogeneites dans l'ensemble de boites etudie, peut etre attribuee principalement a des fluctuations de la hauteur des boites. D'autre part, la determination des temps de montee et de decroissance des intensites de photoluminescence a montre l'importance de certains mecanismes de transport et de relaxation, en fonction des conditions experimentales. En effet, les temps caracteristiques de la capture, de la relaxation interniveaux et de la recombinaison des porteurs varient significativement, selon le mecanisme predominant, en fonction de la temperature, de la densite d'excitation et de la separation interniveaux quantiques. Ainsi, les principaux mecanismes mis en evidence sont: la localisation des porteurs dans les barrieres a basse temperature dans le cas des echantillons interdiffuses, les collisions de type Auger sous forte excitation, les processus multiphononiques et la re-emission thermique a haute temperature. Un modele de relaxation, base sur les equations d'evolution de la population de porteurs de chaque niveau quantique, a aussi ete developpe pour mieux identifier l'effet de chacun des principaux mecanismes de relaxation des porteurs considere separement. Ces simulations ont permis une analyse plus approfondie du role de ces mecanismes. Ainsi, nous avons mis en evidence l'importance de la localisation des porteurs dans la couche de mouillage, ainsi que l'importance des mecanismes de collisions Auger lors de la capture, la capture et la relaxation interniveaux des porteurs vers tous les niveaux d'energie inferieure simultanement. Finalement, les resultats experimentaux montrent que la relaxation de l'energie des porteurs est beaucoup plus rapide que cela avait ete predit initialement par la theorie du "phonon bottleneck". Nos resultats indiquent que l'intensite lumineuse emise par les boites est regie principalement par le taux de capture/relaxation interniveaux des porteurs dans les boites. Mais elle est limitee par la re-emission thermique des porteurs hors des boites, a haute temperature. (Abstract shortened by UMI.)

Perret, Nathalie Emmanuelle


Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice  

PubMed Central

Summary Affiliative and agonistic social interactions are mediated by gonadal hormones. Research with estrogen receptor alpha (ER?) or beta (ER?) knockout (KO) mice show that long-term inactivation of ER? decreases, while inactivation of ER? increases, male aggression. Opposite effects were found in female ?ERKO and ?ERKO mice. The role of acute activation of ER? or ER? in the agonistic responses of adult non-KO mice is unknown. We report here the effects of the ER? selective agonist WAY-200070 on agonistic and social behavior in gonadally intact and gonadectomized (gonadex) male and female CD-1 mice towards a gonadex, same-sex intruder. All 15 min resident-intruder tests were videotaped for comprehensive behavioral analysis. Separate analyses assessed: 1) effects of WAY-200070 on each sex and gonadal condition; 2) differences between sexes, and between gonadally intact and gonadex mice, in untreated animals. Results show that in gonadally intact male and female mice WAY-200070 increased agonistic behaviors such as pushing down and aggressive grooming, while leaving attacks unaffected. In untreated mice, males attacked more than females, and gonadex animals showed less agonistic behavior than same-sex, gonadally intact mice. Overall, our detailed behavioral analysis suggested that in gonadally intact male and female mice, ER? mediates patterns of agonistic behavior that are not directly involved in attacks. This suggests that specific aspects of aggressive behavior are acutely mediated by ER? in adult mice. Our results also showed that, in resident-intruder tests, female mice spend as much time in intrasexual agonistic interactions as males, but use agonistic behaviors that involve extremely low levels of direct attacks. This non-attack aggression in females is increased by acute activation of ER?. Thus, acute activation of ER? similarly mediates agonistic behavior in adult male and female CD-1 mice.

Allen, Amy E. Clipperton; Cragg, Cheryl L.; Wood, Alexis J.; Pfaff, Donald W.; Choleris, Elena



Souvenirs du monde des montagnes  

Microsoft Academic Search

This paper describes a particular book called Souvenirs du monde des montagnes, which draws its iconography from the history of a Swiss mountain family from 1910 to 1930. By simply dipping into the first few pages, the reader will be lost between real and virtual universes, wonder about the evolution of the images’ meanings, and question an object’s true content.

Camille Scherrer



Souvenirs du monde des montagnes  

Microsoft Academic Search

This paper describes a particular book called Souvenirs du monde des montagnes, which draws its iconography from the history of a Swiss mountain family from 1910 to 1930. By simply dipping into the first few pages, the reader will be lost between real and virtual universes, wonder about the evolution of the images' meanings, and question an object's true content.

Camille Scherrer; Julien Pilet; Vincent Lepetit; Pascal Fua



Le maintien du tourbillon des ondes planétaires stationnaires  

Microsoft Academic Search

La dynamique des ondes planétaires stationnaires est étudiée à l'aide des données de la PEMG de janvier 1979. On a calculé et comparé les moyennes temporelles des divers termes de l'équation du tourbillon. La variance zonale des termes principaux atteint des maxima en trois régions : le flanc nord du courant jet stratosphérique, le centre et le flanc nord du

Bernard Dugas; Jacques Derome



Agonists of luteinizing hormone-releasing hormone in prostate cancer.  


Introduction: Androgen deprivation therapy (ADT) has been the first-line standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for many decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT. Areas covered: This article reviews the available data and most recent information concerning the use of LHRH agonists in advanced PCa. This article also reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PCa. Expert opinion: The introduction and application of agonists of LHRH has modernized and improved the treatment of advanced PCa. The life-saving benefits of LHRH agonists are well established, yet underestimated. Despite their efficacy, agonists of LHRH have several disadvantages or drawbacks including disease flare. The approach to ADT has been recently further refined with the development of the LHRH antagonist degarelix. Degarelix, a highly clinically effective third-generation LHRH antagonist, is currently available in most countries for therapy of advanced PCa. This new drug offers attractive alternatives to LHRH agonists for treatment of advanced PCa. A therapy for castration-resistant PCa based on a targeted cytotoxic analog of LHRH, AEZS-108, is also emerging. PMID:23984804

Rick, Ferenc G; Block, Norman L; Schally, Andrew V



Radiolabelled D/sub 2/ agonists as prolactinoma imaging agents: Progress report for period February 1, 1987-January 31, 1988  

SciTech Connect

Three D/sub 2/ agonists, /sup 3/H-DHEC, /sup 3/H-BrCr and /sup 3/H-ADTN, were evaluated with /sup 3/H-DHEC showing the most promise as a potential prolactinoma imaging agent. Concentration vs time plots for all three compounds in normal and in DES-treated pituitary tissue are reported. The exceptional D/sub 2/ receptor affinity of N-0437 has prompted synthetic efforts towards preparation of iodo-N-0437 in spite of a lack of preliminary tissue distribution data. An evaluation of /sup 18/F-FDG uptake in the prolactinoma model and as a muscarinic ligand in control animals were evaluated. 2 refs., 3 figs.

Otto, C.A.



Dopamine agonist withdrawal syndrome: implications for patient care.  


Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

Nirenberg, Melissa J



Toll-like receptor agonists in cancer therapy.  


Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. PMID:20563267

Adams, Sylvia



The agonistic metaphor in psychotherapy: should clients battle their blues?  


A tradition stretching back to early Greek philosophy has described the mind as a field of struggle or even battle. This comparison has been termed the agonistic metaphor, based on the Hellenistic notion of athletic contests. Today, it is not uncommon for psychotherapists and the general public to seek solutions to mental health problems agonistically. Examples of this are cited from major psychodynamic, cognitive, behavioral, family, and humanistic theorists, and advantages and disadvantages of the metaphor are explored. Although agonistic thinking can energize clients and ennoble the therapeutic journey, it runs the risk of ignoring educative aspects of problematic situations and ironically perpetuating the resistance it predicts. PMID:22402002

Heide, Frederick J



Diagnostic et prise en charge des néoplasies intraépithéliales vulvaires et des cancers invasifs de la vulve  

Microsoft Academic Search

RésuméObjectif: Mise au point à propos du diagnostic et de la prise en charge des néoplasies intraépithéliales vulvaires (VIN) et des cancers de la vulve. Méthode: Revue de la littérature. Résultats: La classification des VIN évolue vers deux modèles anatomo-cliniques distincts: les VIN classiques et les VIN différenciées. De nouveaux traitements, moins traumatisants et tout aussi efficaces, des lésions pré-invasives

Philippe Sauthier; Patrick Petignat



Dossier Engagement public des chercheurs Cultures épistémiques et engagement public des chercheurs dans la controverse OGM  

Microsoft Academic Search

Résumé - De l'appel Berg en 1974 aux appels « Défendons la recherche » et « Ouvrons la recherche » en 2003, les biologistes n'ont cessé d'interpeller et de se faire interpeller dans l'espace public autour des enjeux et des risques potentiels liés au génie génétique. Les engagements éphémères, mais proactifs, des années 1970 s'opposent aux engagements plus réactifs des

Christophe Bonneuil



[Choosing a dopamine agonist in Parkinson's disease].  


The number of dopamine agonists (DA) used in Parkinson's disease (PD) is gradually increasing. They have different affinity to the dopamine receptor subtypes. When choosing one of these drugs one should consider its efficacy in monotherapy in early phase and in combined therapy with levodopa in advanced PD, side effects profile, effectiveness in non-motor symptoms of PD, dosing and route of administration. The efficacy of new DA (pramipexol, ropinirol, cabergoline) is probably higher than bromocriptine and comparable to pergolide with similar profile of the most common side effects (headache, vertigo, nausea, somnolence, oedema). However, fibrosis of the pleura, peritoneum and pericardium as well as valvular heart disease (caused by noninflammatory fibrotic degeneration) are significantly more common after ergoline DA (pergolide, cabergoline). Pramipexol shows antidepressant activity. Ropinirol is metabolised by the liver and can be safely administered in renal insufficiency. Pramipexol is excreted in urine and the risk of interaction with other drugs metabolised in the liver is reduced. Rotigotine is the only DA available as skin patches. Whenever necessary, one DA agent can be changed safely overnight to another one. PMID:17941454

Bogucki, Andrzej; Gajos, Agata


[GnRH agonists and breast pathology].  


The discovery of hormone receptors and tamoxifen has revolutionized the management of breast cancer in women as the existence of oestrogen receptors has improved the response rate to hormone treatment from 30 to 50-70% with a further increase in this efficacy if there are also progesterone-positive receptors. LH-RH analogs induce medical castration. Their efficacy in combination with tamoxifen was demonstrated in terms of survival in pre-menopausal women with metastatic cancer. In the adjuvant situation, a meta-analysis of the 1980s demonstrated a benefit in terms of survival without relapse confirmed by more recent studies showing a reduction in the relative risk of relapse. On radiotherapy or ovariectomy, which are radical treatments, medical castration with LH-RH agonist analogs in combination with tamoxifen is therefore an alternative, reversible therapy for outpatients in particular now that a possible direct anti-tumor effect has been suggested by in vitro studies. Nevertheless, at present in France, Marketing Authorisation has not yet been granted for metastatic cancer. PMID:16302713

Espié, Marc



Caractérisation des convertisseurs matriciels : II. Synthèse des fonctions de connexion  

NASA Astrophysics Data System (ADS)

Knowing the wished conversion levels (-1,0,1) of a power converter, this paper describes a particular method for setting the corresponding states of switches into the matrix converter. In a first step, a mathematical analysis establishes the relations linking the states of switches with the conversion functions. Afterwards, the presented method gives the inverse relations which constitute the sequential part of the converter control. The turn-on and the turn-off sequences are designed by considering the on-line wished level conversions. This general method enhances the idea that a converter functionnality must be defined by its structure and its control. Cet article propose une méthode originale pour définir la séquence de commande d'un convertisseur à partir de la fonction de conversion globalement souhaitée. Les auteurs procèdent d'abord à une analyse mathématique précise des relations qui existent entre les états des interrupteurs et les fonctions de conversion obtenues. À partir de cette analyse, la méthode developpée permet d'établir systématiquement les relations inverses qui constituent alors le module séquentiel de la commande rapprochée du convertisseur. Les ordres d'ouverture et de fermeture des interrupteurs sont élaborés en considérant à tout instant les niveaux de conversion souhaités pour les grandeurs électriques. Cette méthode générale renforce l'idée que la fonction remplie par un convertisseur moderne doit être définie à la fois par sa structure et sa commande.

François, B.; Cambronne, J. P.; Hautier, J. P.



Sensibilité des résultats bancaires au taux d'intérêt  

Microsoft Academic Search

[fre] La concurrence accrue, la restructuration mais aussi l'harmonisation prudentielle à l'échelle internationale des conditions d'activités dans l'industrie bancaire oblige à s'interroger sur d'éventuelles spécificités de la réaction des systèmes bancaires à l'évolution des taux d'intérêt. Cet article propose ainsi une évaluation empirique de la sensibilité des résultats des banques des pays du G5 au niveau et à la volatilité

Daniel Goyeau; Alain Sauviat; Amine Tarazi



Agonist Replacement for Stimulant Dependence: A Review of Clinical Research.  


Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that agonist replacement therapy may be effective for managing stimulant use disorders, however, the clinical selection of an agonist replacement medication likely needs to be based on the pharmacological mechanism of the medication and the stimulant abused by patients. Specifically, dopamine releasers appear most effective for reducing cocaine use whereas dopamine reuptake inhibitors appear most effective for reducing amphetamine use. PMID:23574440

Stoops, William W; Rush, Craig R



Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity.  

National Technical Information Service (NTIS)

We hypothesized that dehydroepiandrosterone (DHEA) metabolites or their synthetic derivatives are able to bind to the androgen receptor with low, if any, agonist activity and thus function as better antiandrogens than currently available ones. We previous...

H. Miyamoto



Gonadotropin-Releasing Hormone (GnRH) Agonists ...  

Center for Drug Evaluation (CDER)

... of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases 10/20 ... More results from


Agonist replacement therapy for cocaine dependence: a translational review  

PubMed Central

Cocaine use disorders are prevalent throughout the world. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. This paper reviews the translational literature, including preclinical experiments, human laboratory studies and clinical trials, to determine whether agonist-replacement therapy is a viable strategy for managing cocaine dependence. Discussion is limited to transporter blockers (i.e., methylphenidate) and releasers (i.e., amphetamine analogs) that are available for use in humans in the hope of impacting clinical research and practice more quickly. The translational review suggests that agonist-replacement therapy, especially monoamine releasers, may be effective for managing cocaine dependence. Future directions for medications development are also discussed because the viability of agonist-replacement therapy for cocaine dependence may hinge on identifying novel compounds or formulations that have less abuse and diversion potential.

Rush, Craig R; Stoops, William W



[Comparative characteristics of A1-receptor agonists as neuroprotective agents].  


Comparative characteristics of a series of selective A1 agonists influencing the complex global cerebral ischemia (CGCI) are presented and the optimum conditions for realization of the neuroprotective effect are selected. The degree of the neuroprotective action blocking by theophylline and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) decreases in the following order: CPA CHA ADAC. The A1-receptor agonists exhibit both direct action upon brain (maximum for ADAC) and a peripheral mechanism (especially pronounced for CPA). There is a close correlation between the neuroprotective activity of the A1-receptor agonists and their hypothermal effect. It is suggested that the hypothermal action plays an important part in the neuroprotective activity of the A1-receptor agonists. PMID:11764492

Kulinski?, V I; Minakina, L N; Usov, L A


Determination Des ‘Épaisseurs Équivalentes’ Des Couches D'un Empilement Multidielectrique  

Microsoft Academic Search

Nous proposons de calculer les ‘épaisseurs équivalentes’ théoriques d'un filtre qui éclairé suivant une incidence normale ou oblique aurait les mêmes propriétés optiques (j u) et T (u) qu'un filtre obtenu expérimentalement dont les épaisseurs des couches seraient réalisées avec des erreurs quelconques supposées connues. Les calculs ont été faits par une méthode générale analytique approchée et vérifiée par des

J. M. Saurel



Habitude, cognition et actions des dirigeants  

Microsoft Academic Search

(VF)Nous montrons, à travers l’exemple des habitudes de deux dirigeants, comment le patrimoine des habitudes du dirigeant peut influencer ou bloquer son action, voire celle de l’organisation. Le patrimoine des habitudes est à la base d’intuitions et de la perspicacité du dirigeant et celui-ci est un agent à la fois créateur et transmetteur de routines organisa-tionnelles qu’il a incorporées au

Martine Séville



Iatrogénie Sexuelle des Médicaments: conduite à tenir  

Microsoft Academic Search

Résumé  Une des étapes primordiale de la prise en charge des troubles sexuelles est l’identification d’une éventuelle cause médicamenteuse.\\u000a De nombreux médicaments sont en fait probablement moins impliqués eux-mêmes dans la survenue de troubles sexuels que la maladie\\u000a pour laquelle ils ont été prescrits. Ainsi, l’analyse critique de la littérature, la standardisation des paramètres mesurables\\u000a de la sexualité utilisés en études

Stéphane Droupy



Dopamine receptor agonistic and antagonistic effects of 3PPP enantiomers  

Microsoft Academic Search

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (-)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of

J. Arnt; K. P. Bøgesø; A. V. Christensen; J. Hyttel; J.-J. Larsen; O. Svendsen



Toll-like receptor 2 agonists inhibit human fibrocyte differentiation  

Microsoft Academic Search

BACKGROUND: In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and\\/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. RESULTS: When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8

Anu S Maharjan; Darrell Pilling; Richard H Gomer



5-HT4 receptor agonists: similar but not the same.  


5-Hydroxytryptamine(4) (5-HT(4)) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT(4) receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT(4) receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K(+) channel and tegaserod: 5-HT(1) and 5-HT(2) receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT(4) receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT(4) receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT(4) receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT(4) receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT(4) receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders. PMID:18199093

De Maeyer, J H; Lefebvre, R A; Schuurkes, J A J



PPAR? agonists suppress angiogenesis in a VEGFR2-dependent manner  

Microsoft Academic Search

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that have a pleiotropic impact\\u000a on the regulation of differentiation, cell growth, and the metabolism of lipids and glucose. PPAR? agonists display a variety\\u000a of effects on pro- and anti-tumor processes, and seem to have pro-angiogenic activity at very low concentrations. We analyzed\\u000a the influence of higher concentrations of PPAR? agonists on

Markus Meissner; Igor Hrgovic; Monika Doll; Roland Kaufmann



Comparative behavioral sensitization to stereotypy by direct and indirect dopamine agonists in CF1 mice  

Microsoft Academic Search

The present experiments were designed to compare the properties of behavioral sensitization induced by the indirect agonists, amphetamine and cocaine, to that induced by the direct dopamine agonists, apomorphine and PPHT. Both classes of agonist produced sensitization when administered either in relatively low daily doses or in a single high dose. Mice sensitized to the indirect agonists were cross-sensitized to

J. B. BedingfieldL; L. D. Calder; R. Karler




Microsoft Academic Search

One type of social behavior-agonistic behavior-is commonly observed among food animals. Agonistic behaviors are those behaviors which cause, threaten to cause or seek to reduce physical damage. Agonistic behavior is comprised of threats, aggression and submission. While any one of these divisions of agonistic behavior may be observed alone, they usually are found, in sequence, from the start to the

John J. McGlone



Plan directeur d'exploitation des carrieres  

Microsoft Academic Search

Résumé  Le Plan Directeur d'Exploitation des Carrières (PDM) fut élaboré pour répondre au besoin d'intégrer et d'adapter l'activité\\u000a d'extraction des minéraux aux directives de l'aménagement métropolitain. Ce projet réunit des contributions du Bureau des\\u000a Affaires Métropolitaines de l'Etat de Sao Paulo (SNM), du Département national de Production Minérale (DNPM), de l'EMPLASA—Entreprise\\u000a Métropolitaine de Planification de la Région de Sao Paulo S.A.,

Ivan Carlos Maglio; Nivaldo José Chiossi; Décio S. Casadei; Décio J. A. M. Freire; Ubirajara Fontes; Cleide Poletto; Marisa Frischembruder; Anelise Bassoli



Therapeutic significance of estrogen receptor ? agonists in gliomas  

PubMed Central

Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two ER subtypes: ER?, that functions as tumor promoter and ER? that function as tumor suppressor. We examined the potential use of ER? agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ER? with little or no ER?. Treatment of glioma cells with ER? agonists resulted in significant decrease in proliferation. IHC analysis of tumor tissues revealed that ER? expression is down regulated in high-grade gliomas. We found that ER? agonists promote both expression and tumor suppressive functions of ER? in glioma cells. Liquiritigenin, a plant-derived ER? agonist significantly reduced in vivo tumor growth in a xenograft model. Compared to control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. IHC analysis of tumors revealed a significant increase in the nuclear ER? expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ER? signaling has a tumor suppressive function in gliomas. Since ER? agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ER? agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients.

Sareddy, Gangadhara R; Nair, Binoj C.; Gonugunta, Vijay K.; Zhang, Quan-guang; Brenner, Andrew; Brann, Darrell W.; Tekmal, Rajeshwar Rao; Vadlamudi, Ratna K.



Inhaled beta 2-adrenoceptor agonists in asthma: help or hindrance?  

PubMed Central

Conventional low doses of inhaled beta 2-adrenoceptor agonists produce effective bronchodilation without systemic effects. Higher doses of inhaled beta 2-adrenoceptor agonists may produce substantial improvements in bronchodilator response, which may be helpful to patients with more severe airway obstruction. At higher than recommended doses, in asthmatic patients, fenoterol appears to cause greater dose-related systemic beta 2-responses compared with salbutamol or terbutaline, although there is no evidence to suggest that fenoterol is any less beta 2-selective in vivo. Furthermore, tolerance develops to systemic but not to bronchodilator effects during chronic treatment with inhaled beta 2-adrenoceptor agonists. The link between asthma mortality and systemic adverse effects of inhaled beta 2-adrenoceptor agonists at present remains unproven. A critical reappraisal of the regular use of inhaled beta 2-adrenoceptor agonists including long-acting drugs is now indicated in the light of their possible adverse effects on disease control. Patients requiring regular use of inhaled beta 2-adrenoceptor agonists should be given additional anti-inflammatory therapy with inhaled corticosteroids.

Lipworth, B J; McDevitt, D G



Syndrome des jambes sans repos  

Microsoft Academic Search

Résumé  Le syndrome des jambes sans repos (SJSR) est caractérisé par un besoin urgent de mouvoir les jambes, ou d’autres parties du\\u000a corps parfois, typiquement induit et\\/ou aggravé par le repos avec une recrudescence vespérale et nocturne. Ce syndrome pourrait\\u000a affecter 7 à 10 % de la population dans le monde et 8,5 % de la population francçise. Une histoire familiale

L. Guilloton; A. Drouet; D. Felten



Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor {gamma} agonists in colon cancer cells.  


Glycyrrhizin, a pentacyclic triterpene glycoside, is the major phytochemical in licorice. This compound and its hydrolysis product glycyrrhetinic acid have been associated with the multiple therapeutic properties of licorice extracts. We have investigated the effects of 2-cyano substituted analogues of glycyrrhetinic acid on their cytotoxicities and activity as selective peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate (beta-CDODA-Me) and methyl 2-cyano-3,11-dioxo-18alpha-olean-1,12-dien-30-oate (alpha-CDODA-Me) were more cytotoxic to colon cancer cells than their des-cyano analogues and introduction of the 2-cyano group into the pentacyclic ring system was necessary for the PPARgamma agonist activity of alpha-CDODA-Me and beta-CDODA-Me isomers. However, in mammalian two-hybrid assays, both compounds differentially induced interactions of PPARgamma with coactivators, suggesting that these isomers, which differ only in the stereochemistry at C18 which affects conformation of the E-ring, are selective receptor modulators. This selectivity in colon cancer cells was shown for the induction of two proapoptotic proteins, namely caveolin-1 and the tumor-suppressor gene Krüppel-like factor-4 (KLF-4). beta-CDODA-Me but not alpha-CDODA-Me induced caveolin-1 in SW480 colon cancer cells, whereas caveolin-1 was induced by both compounds in HT-29 and HCT-15 colon cancer cells. The CDODA-Me isomers induced KLF-4 mRNA levels in HT-29 and SW480 cells but had minimal effects on KLF-4 expression in HCT-15 cells. These induced responses were inhibited by cotreatment with a PPARgamma antagonist. This shows for the first time that PPARgamma agonists derived from glycyrrhetinic acid induced cell-dependent caveolin-1 and KLF-4 expression through receptor-dependent pathways. PMID:17513608

Chintharlapalli, Sudhakar; Papineni, Sabitha; Jutooru, Indira; McAlees, Alan; Safe, Stephen



Perception of specific trigeminal chemosensory agonists.  


The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects' ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system's chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory systems. PMID:21575683

Frasnelli, J; Albrecht, J; Bryant, B; Lundström, J N



Dihydrocodeine/Agonists for Alcohol Dependents  

PubMed Central

Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14?years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6?weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4?years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2?years. The demand for medically assisted detoxifications in the 2?years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6?U/l at baseline to 66.8?U/l after 2?years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further optimizations are possible.

Ulmer, Albrecht; Muller, Markus; Frietsch, Bernhard



Evidence for postsynaptic dopamine agonist effects of BHT 920 in the presence of the dopamine D-1 agonist SKF 38393  

Microsoft Academic Search

The ability of B-HT 920, a selective dopamine (DA) D-2 agonist, to stimulate postsynaptic DA receptors in brain was evaluated by assessing its ability to induce stereotypy and to increase locomotor activity in rats. When administered alone, B-HT 920 (0.03–3.0 mg\\/kg) did not induce stereotypy and produced only inhibition of locomotor activity, suggesting a lack of postsynaptic DA agonist actions.

Leonard T. Meltzer; James N. Wiley; Ann E. Williams; Thomas G. Heffner



Combinational effect of PPAR? agonist and RXR agonist on the growth of SGC7901 gastric carcinoma cells in vitro.  


In order to investigate the inhibitory effects and mechanisms of troglitazone (TGZ), a peroxisome proliferator-activated receptor ? (PPAR?) agonist, and retinoid X receptor (RXR) agonist (9-cis-retinoic acid (RA)) on gastric carcinoma cells SGC7901, SGC7901 cells were treated with TGZ and 9-cis-RA, respectively, or in combination. Then, the cell growth, apoptosis, morphological changes, and the expression of PPAR?, RXR?, Bcl-2, and Bax were detected by MTT assay, flow cytometry, HE staining, immunocytochemistry staining, and Western blot assay, respectively. Our results showed that the growth of SGC7901 cells was inhibited and the cells got sparser at the concentrations of 50 ?mol/L TGZ, 20 ?mol/L 9-cis-RA, or combination of TGZ (25 ?mol/L) and 9-cis-RA (10 ?mol/L). Immunocytochemistry and Western blot showed that after 72 h, the expression of PPAR?, RXR?, and Bax were upregulated; Bcl-2 was downregulated compared with the negative control group. These data indicated that PPAR? agonist and RXR agonist could inhibit the proliferation of SGC7901 cells via inducing the apoptosis, which involved the increase in the level of Bax/Bcl-2. The combination of RXR agonist and PPAR? agonist could induce the maximal inhibitory effects on tumor growth and apoptosis via promoting the formation of RXR/PPAR? heterodimer. PMID:23605322

Liu, Ying; Zhu, Zu-an; Zhang, Shang-Nuan; Mou, Jie; Liu, Lei; Cui, Tao; Pei, Dong-Sheng



Truncated (N)-Methanocarba Nucleosides as A1 Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a Recognition Element  

PubMed Central

A1 adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A1AR were truncated to eliminate 5?-CH2OH. This modification previously converted A3AR agonists into antagonists, but the comparable effect at A1AR is unknown. In comparison to ribosides, affinity at the A1AR was less well preserved than at the A3AR, although a few derivatives were moderately A1AR selective, notably full agonist 21 (N6-dicyclopropylmethyl, Ki 47.9 nM). Thus, at the A1AR recognition elements for nucleoside binding depend more on 5?region interactions, and in their absence A3AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A1 but not A3AR. The derivatives ranged from partial to full agonists in A1AR-mediated adenylate cyclase inhibition. Truncated derivatives have more drug-like physical properties than other A1AR agonists; this approach is appealing for preclinical development.

Tosh, Dilip K.; Phan, Khai; Deflorian, Francesca; Wei, Qiang; Gao, Zhan-Guo; Jacobson, Kenneth A.



Truncated (N)-Methanocarba Nucleosides as A(1) Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a Recognition Element.  


A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5'-CH(2)OH. This modification previously converted A(3)AR agonists into antagonists, but the comparable effect at A(1)AR is unknown. In comparison to ribosides, affinity at the A(1)AR was less well preserved than at the A(3)AR, although a few derivatives were moderately A(1)AR selective, notably full agonist 21 (N(6)-dicyclopropylmethyl, K(i) 47.9 nM). Thus, at the A(1)AR recognition elements for nucleoside binding depend more on 5'region interactions, and in their absence A(3)AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A(1) but not A(3)AR. The derivatives ranged from partial to full agonists in A(1)AR-mediated adenylate cyclase inhibition. Truncated derivatives have more drug-like physical properties than other A(1)AR agonists; this approach is appealing for preclinical development. PMID:21858244

Tosh, Dilip K; Phan, Khai; Deflorian, Francesca; Wei, Qiang; Gao, Zhan-Guo; Jacobson, Kenneth A



Differential effects of selective adenosine A 1 and A 2A receptor agonists on dopamine receptor agonist-induced behavioural responses in rats  

Microsoft Academic Search

The effects of the systemic (i.p.) administration of the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the selective adenosine A2A receptor agonist sodium 2-p-carboxyethyl)phenylamino-5?-N-carboxamidoadenosine (CGS 21680) on different dopamine receptor agonist-induced behaviours were studied in the male rat. CGS 21680 (1 ?mol\\/kg), but not CPA, was found to counteract the stereotypies induced by the non-selective dopamine receptor agonist apomorphine

Roberto Rimondini; Sergi Ferré; Lydia Giménez-Llort; Sven Ove Ögren; Kjell Fuxe



Retraite choisie et réduction des déficits  

Microsoft Academic Search

[fre] Jean-Olivier Hairault François Langot Thepthida Sopraseuth Retraite choisie et réduction des déficits. Nous proposons un modèle de cycle de vie où les décisions de départ à la retraite sont endogènes, ainsi que les choix de consommation et d'épargne, dans un environnement marqué par des risques de chômage en fin de vie active et une incertitude sur la date de

Jean-Olivier Hairault; François Langot; Thepthida Sopraseuth



Analyse des possibilités de fonctionnement en régime des désexcitation des moteurs à aimants permanents  

NASA Astrophysics Data System (ADS)

In this paper, we study the extending of speed range of motors (or generators) with permanent magnet inductor and supplied by electronic converter. The amplitude of phase voltage and current waveforms are limited by electronics supply. The aim of this study is to achieve a maximum power near of the base speed one on an extended speed range. This require an airgap flux weakening so called “flux weakening” above base speed. A parametric analysis of motor electromagnetic characteristics is made to show the influence of armature reaction and magnetic saliency on speed range. We show that exists an ideal condition to obtain a constant power speed range theoretically unlimited. Magnetic saliency permits to enhance the power factor especially when L_d> L_q. As main hypotheses, we consider no saturation, e.m.f. and current sine waveforms and a sinusoidal airgap flux density. Finally, we recapitulate the permanent magnet rotor structures able to obtain a flux-weakening operation. Cet article traite de l'extension de la plage de vitesse des moteurs (ou alternateurs) à excitation par aimants permanents et alimentés par convertisseur électronique. La tension et le courant sont limités en amplitude par l'alimentation électronique.L'objectif est d'obtenir une puissance proche de celle correspondant au régime de base sur une plage de vitesse étendue. Ceci nécessite une réduction de flux d'entrefer ou “désexition” au delà de la vitesse de base. Une analyse paramétrique des caractéristiques du moteur est effectuée pour mettre en évidence l'influence de la réaction d'induit et de la saillance magnétique. Nous montrons qu'il existe une condition idéale pour obtenir une plage de fonctionnement à puissance constante théoriquement illimitée. La saillance magnétique permet d'accroître le facteur de puissance surtout lorsque L_d> L_q. Les principales hypothèses de cette étude sont l'absence de saturation, des f.e.m. et des courants sinusoïdaux et une induction spatiale sinusoïdale dans l'entrefer. Enfin, nous effectuons un bilan des structures de rotors permettant un fonctionnement en régime de désexcitation.

Multon, Bernard; Lucidarme, Jean; Prévond, Laurent



La réfrigération des grandes machines supraconductrices  

NASA Astrophysics Data System (ADS)

The large scale superconducting devices which are now in operation for deviation of heavy particles, acceleration of light particles or plasma confinement need very large powers of refrigeration. After a short survewing of the different functions of refrigerators and the special requirements for large units, the paper describes some existing or envisaged cooling systems which have an equivalent cooling power in the range of 5 kW at 4.5 K. Les grands appareils de physique utilisant les supraconducteurs demandent des puissances cryogéniques de plus en plus importantes. Après un examen des fonctions élémentaires assurées par un réfrigérateur liées au cahier des charges spécifique à chaque utilisation, les spécificités des grosses unités de réfrigération (fiabilité, efficacité, flexibilité, automatisme) sont mises en évidence. Les solutions proposées dans plusieurs grands projets nécessitant des puissances froides supérieures à 5 kW à 4,5 K sont discutées.

Gistau, Guy



Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists  

PubMed Central

BACKGROUND AND PURPOSE Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1–300 nM and the selective motilin agonist GSK962040 0.1–30 µM acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (Emax? 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation. LINKED ARTICLE This article is commented on by Depoortere, pp. 760–762 of this issue. To view this commentary visit

Broad, J; Mukherjee, S; Samadi, M; Martin, JE; Dukes, GE; Sanger, GJ



Cannabinoid receptor agonist 13, a novel cannabinoid agonist: first in human pharmacokinetics and safety.  


Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB(1) and CB(2) receptors. This phase I study aimed to evaluate the pharmacokinetics, safety, and tolerability of single oral doses of CRA13. Sixty-three of 69 healthy adult males were randomized in seven cohorts (n = 9) to receive 1 to 80 mg of CRA13 or placebo orally in fasted condition. To investigate the diet effect, an independent group (n = 6) was randomized to receive 40 mg of CRA13 after high-fat and high-calorie breakfast in crossover design with a 2-week washout period. Peak plasma concentration (C(max)) ranged from 7.8 to 467.6 ng/ml (1-80 mg). CRA13 was rapidly absorbed and demonstrated linear pharmacokinetics (1-80 mg). Time to reach C(max) (t(max)) was 1.5 to 2 h for all doses in both fasted and fed groups. Administration of 40 mg of CRA13 with food induced approximately 2-fold increase in the C(max) and the area under the concentration-time curve, AUC(0 - tz). The apparent elimination half-life (t(1/2)) was 21 to 36 h and 30 to 41 h for fasted and fed groups, respectively. Dizziness, headache, and nausea were the most frequently reported adverse events (AEs), predominantly at the 40- and 80-mg doses. The incidence of AEs was dose-dependent and mild to moderate. No deaths and serious adverse events were reported. In conclusion, CRA13 was reasonably well tolerated and demonstrated a linear pharmacokinetics over the studied dose range (1-80 mg). Food intake increased CRA13 C(max) and AUC(0 - tz) by approximately 2-fold, whereas t(max) was unaffected. PMID:19144772

Gardin, Anne; Kucher, Klaus; Kiese, Beate; Appel-Dingemanse, Silke



Modification of peptide interaction with MHC creates TCR partial agonists.  


We report the creation of TCR partial agonists by the novel approach of manipulating the interaction between immunogenic peptide and MHC. Amino acids at MHC anchor positions of the I-E(k)-restricted hemoglobin (64-76) and moth cytochrome c (88-103) peptides were exchanged with MHC anchor residues from the low affinity class II invariant chain peptide (CLIP), resulting in antigenic peptides with altered affinity for MHC class II. Several low affinity peptides were identified as TCR partial agonists, as defined by the ability to stimulate cytolytic function but not proliferation. For example, a peptide containing methionine substitutions at positions one and nine of the I-E(k) binding motif acted as a partial agonist for two hemoglobin-reactive T cell clones (PL.17 and 3.L2). The identical MHC anchor substitutions in moth cytochrome c (88-103) also created a partial agonist for a mCC-reactive T cell (A.E7). Thus, peptides containing MHC anchor modifications mediated similar T cell responses regardless of TCR fine specificity or antigen reactivity. This data contrasts with the unique specificity among individual clones demonstrated using traditional altered peptide ligands containing substitutions at TCR contact residues. In conclusion, we demonstrate that altering the MHC anchor residues of the immunogenic peptide can be a powerful method to create TCR partial agonists. PMID:15051516

Ryan, Kelli R; McNeil, Lisa K; Dao, Chinh; Jensen, Peter E; Evavold, Brian D



Honokiol: A non-adipogenic PPAR? agonist from nature?  

PubMed Central

Background Peroxisome proliferator-activated receptor gamma (PPAR?) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPAR? activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPAR? agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPAR? ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPAR? ligand-binding domain (LBD) and acted as partial agonist in a PPAR?-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPAR? agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine.

Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.



A Simple Method for Quantifying Functional Selectivity and Agonist Bias  

PubMed Central

Activation of seven-transmembrane (7TM) receptors by agonists does not always lead to uniform activation of all signaling pathways mediated by a given receptor. Relative to other ligands, many agonists are “biased” toward producing subsets of receptor behaviors. A hallmark of such “functional selectivity” is cell type dependence; this poses a particular problem for the profiling of agonists in whole cell test systems removed from the therapeutic one(s). Such response-specific cell-based variability makes it difficult to guide medicinal chemistry efforts aimed at identifying and optimizing therapeutically meaningful agonist bias. For this reason, we present a scale, based on the Black and Leff operational model, that contains the key elements required to describe 7TM agonism, namely, affinity (KA–1) for the receptor and efficacy (?) in activating a particular signaling pathway. Utilizing a “transduction coefficient” term, log(?/KA), this scale can statistically evaluate selective agonist effects in a manner that can theoretically inform structure–activity studies and/or drug candidate selection matrices. The bias of four chemokines for CCR5-mediated inositol phosphate production versus internalization is quantified to illustrate the practical application of this method. The independence of this method with respect to receptor density and the calculation of statistical estimates of confidence of differences are specifically discussed.



Sound production during agonistic behavior of male Drosophila melanogaster.  


Male Drosophila fruit flies acquire and defend territories in order to attract females for reproduction. Both, male-directed agonistic behavior and female-directed courtship consist of series of recurrent stereotypical components. Various studies demonstrated the importance of species-specific sound patterns generated by wing vibration as being critical for male courtship success. In this study we analyzed the patterns and importance of sound signals generated during agonistic interactions of male Drosophila melanogaster. In contrast to acoustic courtship signals that consist of sine and pulse patterns and are generated by one extended wing, agonistic signals lack sine-like components and are generally produced by simultaneous movements of both wings. Though intra-pulse oscillation frequencies (carrier frequency) are identical, inter-pulse intervals are twice as long and more variable in aggression signals than in courtship songs, where their precise temporal pattern serves species recognition. Acoustic signals accompany male agonistic interactions over their entire course but occur particularly often after tapping behavior which is a major way to identify the gender of the interaction partner. Since similar wing movements may either be silent or generate sound and wing movements with sound have a greater impact on the subsequent behavior of a receiver, sound producing wing movements seem to be generated intentionally to serve as a specific signal during fruit fly agonistic encounters. PMID:20953152

Jonsson, Thorin; Kravitz, Edward A; Heinrich, Ralf



Role of dopamine agonists in Parkinson's disease: an update.  


At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained. PMID:17939774

Bonuccelli, Ubaldo; Pavese, Nicola



Etude des effets du martelage repetitif sur les contraintes residuelles  

NASA Astrophysics Data System (ADS)

L'assemblage par soudage peut engendrer des contraintes residuelles. Ces contraintes provoquent des fissurations prematurees et un raccourcissement de la duree de vie des composants. Dans ce contexte, le martelage robotise est utilise pour relaxer ces contraintes residuelles. Trois volets sont presentes: le premier est l'evaluation des effets des impacts unitaires repetes sur le champ de contraintes developpe dans des plaques d'acier inoxydable austenitique 304L vierges ou contenant des contraintes residuelles initiales. Dans la deuxieme partie de ce projet, le martelage est applique grace au robot SCOMPI. Les contraintes residuelles induites et relaxees par martelage sont ensuite mesurees par la methode des contours, qui a ete adaptee a cet effet. Dans la troisieme partie, le martelage est modelise par la methode des elements finis. Un modele axisymetrique developpe grace au logiciel ANSYS permet de simuler des impacts repetes d'un marteau elastique sur une plaque ayant un comportement elastoplastique.

Hacini, Lyes


Novel potent and efficacious nonpeptidic urotensin II receptor agonists.  


Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)-propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC(50) 7.49). PMID:16570919

Lehmann, Fredrik; Pettersen, Anna; Currier, Erika A; Sherbukhin, Vladimir; Olsson, Roger; Hacksell, Uli; Luthman, Kristina



Anti-CD40 agonist antibodies: preclinical and clinical experience  

PubMed Central

The cell-surface molecule CD40, a member of the tumor necrosis factor receptor superfamily, broadly regulates immune activation and mediates tumor apoptosis. CD40 is expressed by antigen-presenting cells (APC) and engagement of its natural ligand on T cells activates APC including dendritic cells and B cells. Agonistic CD40 antibodies have been shown to substitute for T cell help provided by CD4+ lymphocytes in murine models of T cell-mediated immunity. In tumor-bearing hosts, CD40 agonists trigger effective immune responses against tumor-associated antigens. In contrast, CD40 is also expressed on many tumor cells and its ligation in this setting mediates a direct cytotoxic effect. Engagement of CD40 on tumor cells results in apoptosis in vitro and impaired tumor growth in vivo. These observations have prompted efforts to use agonistic CD40 antibodies for the treatment of cancer patients and initial clinical results have been promising.

Khalil, Magi; Vonderheide, Robert H.



Therapeutic significance of estrogen receptor ? agonists in gliomas.  


Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two estrogen receptor (ER) subtypes: ER?, which functions as tumor promoter, and ER?, which functions as tumor suppressor. We examined the potential use of ER? agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ER? with little or no ER?. Treatment of glioma cells with ER? agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ER? expression is downregulated in high-grade gliomas. We found that ER? agonists promote both expression and tumor-suppressive functions of ER? in glioma cells. Liquiritigenin, a plant-derived ER? agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ER? expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ER? signaling has a tumor-suppressive function in gliomas. Because ER? agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ER? agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients. PMID:22442308

Sareddy, Gangadhara R; Nair, Binoj C; Gonugunta, Vijay K; Zhang, Quan-guang; Brenner, Andrew; Brann, Darrell W; Tekmal, Rajeshwar Rao; Vadlamudi, Ratna K



La technique des incidents critiques pour cerner l'efficacité des feed-back de correction en danse moderne  

Microsoft Academic Search

Résumé — Les études descriptives en classe de danse ont démontré qu'une des principales habiletés d'intervention des professeurs consiste à corriger les erreurs d'exécutions motrices des étudiants. Les professeurs utilisent à cette fin un vaste éventail de stratégies. Y a-t- il des stratégies plus efficaces que d'autres? Pour répondre à cette question, la méthodologie qualitative des incidents critiques a été

Sylvie Fortin




Microsoft Academic Search

Cette recherche examine la gestion des résultats comptables par les dirigeants d'entreprises sujettes à des offres publiques d'achat (OPA) dans le contexte Suisse. La recherche comptable suggère que les transactions de fusions et acquisitions offrent un cadre propice à la gestion des résultats tant pour les dirigeants de l'entreprise cible que pour ceux de l'acquéreur (Easterwood, 1998 ; Erickson et

Franck Missonier-Piera; Walid Ben-Amar



Modélisation et simulation à topologie variable des convertisseurs statiques et des entraînements électromécaniques  

NASA Astrophysics Data System (ADS)

This paper deals with the automatic modeling with changeable topology of static converters (ideal discret-time modeling of switches), mainly for their own simulation and specifically the one of electric drives. Nous proposons une approche pour synthétiser automatiquement le modèle à topologie variable des convertisseurs statiques (modèle discret idéal des semi-conducteurs), principalement en vue de leur propre simulation et notamment celle des entraînements électromécaniques.

Gerbaud, L.; Lechevalier, C.; Bolopion, A.; Bigeon, J.



Gesundheitsökonomische Aspekte des telematischen Glaukom-Monitorings  

Microsoft Academic Search

Zusammenfassung\\u000a Hintergrund  Ein ambulantes telematisch gestütztes Glaukom-Monitoring gehört gegenwärtig nicht zum Leistungsumfang der gesetzlichen Krankenkassen.\\u000a Verschiedene klinische Studien geben Hinweise, dass es mittels des 24-h-Augeninnendruck- und Blutdruck-Monitorings besser\\u000a gelingt, die individuelle Erkrankungssituation des Glaukompatienten zu erfassen. Wenn die hierfür erforderlichen Parameter\\u000a durch Anwendung des telematisch gestützten Glaukom-Monitorings erhoben werden, ließe sich der Umfang heute noch ausschließlich\\u000a stationär zu erbringender 24-h-Augeninnendruck-Profile zu

T. Swierk; C. Jürgens; R. Großjohann; S. Fleßa; F. Tost



Estradiol and ER? agonists enhance recognition memory, and DPN, an ER? agonist, alters brain monoamines  

PubMed Central

Effects of estradiol benzoate (EB), ER?-selective agonist, propyl pyrazole triol (PPT) and ER?-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) on memory were investigated in OVX rats using object recognition (OR) and placement (OP) memory tasks. Treatments were acute (behavior 4 h later) or sub chronic (daily injections for 2 days with behavior 48 h later). Objects were explored in sample trials (T1), and discrimination between sample (old) and new object/location in recognition trials (T2) was examined after 2–4 h inter-trial delays. Subjects treated sub chronically with EB, DPN, and C-19, but not PPT, discriminated between old and new objects and objects in old and new locations, suggesting that, at these doses and duration of treatments, estrogenic interactions with ER? contributes to enhancements in recognition memory. Acute injections of DPN, but not PPT, immediately after T1, also enhanced discrimination for both tasks (C19 was not investigated). Effects of EB, DPN and PPT on anxiety and locomotion, measured on elevated plus maze and open field, did not appear to account for the mnemonic enhancements. Monoamines and metabolites were measured following DPN treatment in subjects that did not receive behavioral testing. DPN was associated with alterations in monoamines in several brain areas: indexed by the metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the MHPG/norepinephrine (NE) ratio, NE activity was increased by 60–130% in the prefrontal cortex (PFC) and ventral hippocampus, and NE activity was decreased by 40–80% in the v. diagonal bands and CA1. Levels of the dopamine (DA) metabolite, homovanillic acid (HVA), increased 100% in the PFC and decreased by 50% in the dentate gyrus following DPN treatment. The metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), was increased in the PFC and CA3, by approximately 20%. No monoaminergic changes were noted in striatum or medial septum. Results suggest that ER? mediates sub chronic and acute effects of estrogens on recognition memory and that memory enhancements by DPN may occur, in part, through alterations in monoaminergic containing systems primarily in PFC and hippocampus.

Jacome, Luis F.; Gautreaux, Claris; Inagaki, Tomoko; Mohan, Govini; Alves, Stephen; Lubbers, Laura S.; Luine, Victoria



Agonist-antagonist muscle activation during drop jumps.  


Abstract Pre-programmed and stretch-induced muscle activities of agonist muscles can play important roles during stretch-shortening cycle exercises. It is still not clear how the antagonist muscles function when the drop and rebound intensities are varied during drop jump (DJ) exercises. The purpose of the present study was to examine the regulation of agonist-antagonist muscle activation during DJ with different drop and rebound heights. The subjects performed DJs with two drop heights (0.2 and 0.4 m) and three different efforts (maximal rebound height, 50% effort of maximal rebound height and landing without rebound). Ankle and knee joint angles, and vertical ground reaction force together with an electromyogram of the lower leg muscles (medial gastrocnemius [MG], soleus [SOL] and tibialis anterior [TA]) were measured simultaneously during DJ. Our results clearly showed that the pre-activation of the antagonist TA was increased with increasing rebound height. Our results further showed that the coactivations of agonist and antagonist muscles during the post-impact 30-ms phase were increased with increasing rebound height. These results suggested that not only the pre-programmed agonist MG muscle activation, but also the pre-programmed antagonist TA activation and the coactivation of the post-impact 30-ms phase may play important roles in the control of rebound height. PMID:24050466

Arai, Aya; Ishikawa, Masaki; Ito, Akira



Agonistic behavior in a schooling fish: form, function and ontogeny  

Microsoft Academic Search

Synopsis Although juvenile chum salmon,Oncorhynchus keta, are generally regarded as a schooling fish, when presented with a defensible point-source of food, some individuals abandon schooling, aggressively subordinate competitors, and monopolize food. When food is removed, fish gradually abandon solitary agonistic behaviors and return to schooling behavior. Agonism increases in frequency and intensity as juveniles age. The ability to alternate facultatively

Clifford H. Ryer; Bori L. Olla



Effects of three dopamine agonists on cage climbing behavior  

Microsoft Academic Search

The effects of three structurally related dopamine (DA) agonists (pergolide, lergotrile, bromocriptine) on motor activity and induction of cage climbing behavior were compared in mice. Pergolide stimulated activity and induced cage climbing that persisted for at least 5h. Lergotrile depressed activity and failed to induce climbing over a wide range of doses. Bromocriptine produced stimulation and climbing, but only after

Gerald Gianutsos; Joseph L. Palmeri



Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism  

SciTech Connect

Binding to helix 12 of the ligand-binding domain of PPAR{gamma} is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPAR{gamma} with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPAR{gamma} transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Bushby, S.A.; Kamenecka, T.A.; He, Y.; Nettles, K.W.; Griffin, P.R.



Discovery of a novel class of PPARdelta partial agonists.  


Anthranilic acid GW9371 was identified as a novel class of PPARdelta partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARdelta target genes CPT1a and PDK4 in skeletal muscle cells. PMID:18722772

Shearer, Barry G; Patel, Hari S; Billin, Andrew N; Way, James M; Winegar, Deborah A; Lambert, Millard H; Xu, Robert X; Leesnitzer, Lisa M; Merrihew, Raymond V; Huet, Stephane; Willson, Timothy M



2,5-Disubstituted pyridines as potent GPR119 agonists.  


A series of 2-piperazinyl-5-alkoxypyridines were synthesized and screened against human GPR119 receptor. Through SAR analysis, compounds containing 2-alkylsulfonylpiperazinyl-5-alkoxypyridines were discovered and found to be potent agonists of the human GPR119 receptor. PMID:20227877

Wu, Yulin; Kuntz, Judith D; Carpenter, Andrew J; Fang, Jing; Sauls, Howard R; Gomez, Daniel J; Ammala, Carina; Xu, Yun; Hart, Shane; Tadepalli, Sarva



Suppression of methamphetamine-seeking behavior by nicotinic agonists  

Microsoft Academic Search

To understand the mechanism of methamphetamine (MAP) craving from the viewpoint of nicotinic acetylcholinergic transmission, we examined the responsible site of the brain for anticraving effects produced by nicotinic agonists by using a MAP self-administration paradigm in rats. Systemic nicotine and an acetylcholinesterase inhibitor, donepezil, attenuated the reinstatement of MAP-seeking behavior by means of the activation of nicotinic acetylcholinergic receptors,

Takato Hiranita; Yoko Nawata; Katsuya Sakimura; Kusnandar Anggadiredja; Tsuneyuki Yamamoto



Electrochemical behavior of ? 2-agonists at graphite nanosheet modified electrodes  

Microsoft Academic Search

In this paper, the voltammetric characteristics of several ?2-agonists including salbutamol, ractopamine, bamethane, isoxsuprine, ritodrine, fenoterol, terbutaline, metaproterenol, clenbuterol, clenproperol, mabuterol, cimaterol, cimbuterol and brombuterol were comparatively evaluated using graphite nanosheet (GN) modified glassy carbon (GC) electrodes. All the compounds can be oxidized at GN modified electrodes with enhanced peak current and reduced peak potential compared with naked GC electrodes.

Li Shen; Zhen Li; Pingli He



Elastic, Agonistic Publics: John Dewey's Call for a Third Party.  

ERIC Educational Resources Information Center

Notes that John Dewey committed to the construction of an "elastic" social imaginary responsive to the rhetorical needs of a public in crisis. Explains that Dewey argued that a new third party must adopt an agonistic style of communication. Suggests that Dewey described the role of a third party in ways that might prove productive for scholars…

Finnegan, Cara A.



PPAR agonists modulate human osteoclast formation and activity in vitro  

Microsoft Academic Search

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear steroid hormone superfamily and exist in three isoforms: PPAR?, ? and ?, each with specific functions. In this study, we have investigated the expression of PPARs by human osteoclast precursors and osteoclasts generated in vitro. In addition, the effects of fibrates and isoform-specific PPAR agonists on osteoclast formation and resorption in

B. Y. Chan; A. Gartland; P. J. M. Wilson; K. A. Buckley; J. P. Dillon; W. D. Fraser; J. A. Gallagher



Anthranilic acid replacements in a niacin receptor agonist  

Microsoft Academic Search

Niacin is an effective drug for raising HDL cholesterol. However, niacin must be taken in large doses and significant side effects are often observed, including facial flushing, loss of glucose tolerance, and liver toxicity. An anthranilic acid was identified as an agonist of the niacin receptor. In order to improve efficacy and provide structural diversity, replacements for the anthranilic acid

Darby Schmidt; Abigail Smenton; Subharekha Raghavan; Hong Shen; Fa-Xiang Ding; Ester Carballo-Jane; Silvi Luell; Tanya Ciecko; Tom G. Holt; Michael Wolff; Andrew Taggart; Larissa Wilsie; Mihajlo Krsmanovic; Ning Ren; Daniel Blom; Kang Cheng; Peggy E. McCann; M. Gerard Waters; James Tata; Steven Colletti



Qualitative and quantitative assessment of relative agonist efficacy  

Microsoft Academic Search

Historically, the ability of a ligand to bind to its receptor and the ability to subsequently activate that receptor have been described as the properties of affinity and intrinsic efficacy, respectively. These properties were originally believed to be independent of one another; both are possessed by ligands classed as “agonists,” and they have served as the quantitative foundation of the

Arthur Christopoulos; Esam E. El-Fakahany



Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease.  


The dopamine agonist medications, pramipexole and ropinirole, are commonly used to treat Parkinson's disease. These two drugs have a highly specific affinity for cerebral D3 receptors, known to be localized to the mesolimbic system. Herein is described a common side effect of these drugs, encountered in our routine clinical practice: pathological behaviors. This includes excessive gambling, hypersexuality, shopping, hyperphagia or obsessive hobbying, which may develop in up to 30% of people taking higher agonist doses. In contrast, treatment with the dopamine precursor, levodopa, in the absence of D3 agonist therapy very rarely provokes such behavioral syndromes. Although these agonist-induced behaviors have been called "impulse control disorders", the problem is not simply loss of impulse control, but rather a novel obsessive-compulsion directed at one or a few behaviors, often taking on pathological proportions. This experience points to the dopamine D3 receptor as a potential therapeutic target for gambling, sex or other addictions occurring spontaneously in the general population. PMID:21557955

Ahlskog, J Eric



[The antihypoxic and radioprotective properties of selective adenosine receptor agonists].  


The selective A1- and A2-receptor agonists L-PIA (ED50 = 0.55-0.78 mmole/kg) and NEGA (D50 = 0.05-0.1 mmole/kg) possess high antihypoxic and radioprotective effects. A2-subtype receptors may be involved in the antihypoxic and radioprotective effects of adenosine analogs. PMID:1458173

Ol'khovski?, I A; Kulinski?, V I; Klimova, A D; Lidak, M Iu; Tsalmane, L V


Die Vereinbarkeit des Handels mit LMOs gemäß den Vorgaben des Biosafety-Protokolls mit den Vorschriften des WTO\\/GATT-Regimes  

Microsoft Academic Search

\\u000a Die gegenwärtige Weltwirtschaftsordnung zielt auf eine Liberalisierung des grenzüberschreitenden Wirtschaftsverkehrs.677 Sie tut dies nicht als Selbstzweck, sondern, wie die Präambel des Übereinkommens zur Errichtung der WTO ausweist, als Mittel\\u000a zur Erhöhung des Lebensstandards, zur Sicherung der Vollbeschäftigung, für ein beständiges steigendes Realeinkommen, eine\\u000a wirksame Nachfrage sowie eine Ausweitung der Produktion und des Handels.678 Die zu erwartenden Vorteile einer fortlaufenden Handelsliberalisierung

Markus Böckenförde


Melatonin receptor agonists: new options for insomnia and depression treatment.  


The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT? or MT? subtype-selective compounds are available up to now. Administration of the MT?-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT? receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT? or MT? receptors are expected in coming years. PMID:21554566

Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco



Dopamine agonists and risk: impulse control disorders in Parkinson's; disease  

PubMed Central

Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at ?$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J.; Hallett, Mark



Characterization of AhR agonist compounds in roadside snow.  


Aryl hydrocarbon receptor (AhR) agonistic contaminants were identified in roadside snow samples. Snow was collected in Oslo, Norway, and compared to a background sample collected from a mountain area. The water and particulate fractions were analysed for AhR agonists using a dioxin-responsive, chemically activated luciferase expression (CALUX) cell assay and by gas chromatography coupled to high-resolution time-of-flight mass spectrometry with targeted analysis for polycyclic aromatic hydrocarbons (PAHs) and broad-spectrum non-target analysis. The AhR agonist levels in the dissolved fractions in the roadside samples were between 15 and 387 pg/L CALUX toxic equivalents (TEQ(CALUX)). An elevated AhR activity of 221 pg TEQ(CALUX) per litre was detected in the mountain sample. In the particle-bound fractions, the TEQ(CALUX) was between 1,350 and 7,390 pg/L. One possible explanation for the elevated levels in the dissolved fraction of the mountain sample could be the presence of black carbon in the roadside samples, potentially adsorbing dioxin-like compounds and rendering them unavailable for AhR interaction. No polychlorinated dibenzodioxins and dibenzofurans or polychlorinated biphenyls were detected in the samples; the occurrence of PAHs, however, explained up to 9 % of the AhR agonist activity in the samples, whilst comprehensive two-dimensional gas chromatography coupled to mass spectrometry GCxGC-ToF-Ms identified PAH derivatives such as polycyclic aromatic ketones and alkylated, nitrogen sulphur and oxygen PAHs in the particle fractions. The (large) discrepancy between the total and explained activity highlights the fact that there are other as yet unidentified AhR agonists present in the environment. PMID:22538776

Muusse, Martine; Langford, Katherine; Tollefsen, Knut Erik; Cornelissen, Gerard; Haglund, Peter; Hylland, Ketil; Thomas, Kevin V



The ?2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.  


Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the ?-adrenoceptor (?-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple ?-AR agonists: isoproterenol (nonselective ?-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective ?(3)-AR agonist), and formoterol (selective ?(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the ?-AR antagonist propranolol and the ?(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor ? coactivator 1?, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1? subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of ?(2)-AR ligands for therapeutic MB. PMID:22490378

Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G



Caracterisation des proprietes acoustiques des materiaux poreux a cellules ouvertes et a matrice rigide ou souple  

NASA Astrophysics Data System (ADS)

L'objectif global vise par les travaux de cette these est d'ameliorer la caracterisation des proprietes macroscopiques des materiaux poreux a structure rigide ou souple par des approches inverses et indirectes basees sur des mesures acoustiques faites en tube d'impedance. La precision des approches inverses et indirectes utilisees aujourd'hui est principalement limitee par la qualite des mesures acoustiques obtenues en tube d'impedance. En consequence, cette these se penche sur quatre problemes qui aideront a l'atteinte de l'objectif global precite. Le premier probleme porte sur une caracterisation precise de la porosite ouverte des materiaux poreux. Cette propriete en est une de passage permettant de lier la mesure des proprietes dynamiques acoustiques d'un materiau poreux aux proprietes effectives de sa phase fluide decrite par les modeles semi-phenomenologiques. Le deuxieme probleme traite de l'hypothese de symetrie des materiaux poreux selon leur epaisseur ou un index et un critere sont proposes pour quantifier l'asymetrie d'un materiau. Cette hypothese est souvent source d'imprecision des methodes de caracterisation inverses et indirectes en tube d'impedance. Le critere d'asymetrie propose permet ainsi de s'assurer de l'applicabilite et de la precision de ces methodes pour un materiau donne. Le troisieme probleme vise a mieux comprendre le probleme de transmission sonore en tube d'impedance en presentant pour la premiere fois un developpement exact du probleme par decomposition d'ondes. Ce developpement permet d'etablir clairement les limites des nombreuses methodes existantes basees sur des tubes de transmission a 2, 3 ou 4 microphones. La meilleure comprehension de ce probleme de transmission est importante puisque c'est par ce type de mesures que des methodes permettent d'extraire successivement la matrice de transfert d'un materiau poreux et ses proprietes dynamiques intrinseques comme son impedance caracteristique et son nombre d'onde complexe. Enfin, le quatrieme probleme porte sur le developpement d'une nouvelle methode de transmission exacte a 3 microphones applicable a des materiaux ou systemes symetriques ou non. Dans le cas symetrique, on montre que cette approche permet une nette amelioration de la caracterisation des proprietes dynamiques intrinseques d'un materiau. Mots cles. materiaux poreux, tube d'impedance, transmission sonore, absorption sonore, impedance acoustique, symetrie, porosite, matrice de transfert.

Salissou, Yacoubou


Hémoparasites des oiseaux sauvages à Madagascar  

Microsoft Academic Search

RESUME : Cette étude évalue la prévalence et la densité des hémoparasites chez 387 oiseaux appartenant à 43 espèces,et collectés sur 6 sites répartis dans différents milieux bio-climatiques de Madagascar. 139 (35,9%) se sont révélés porteurs d'au moins un hémoparasite avec par ordre de fréquence Plasmodium et\\/ou Haemoproteus (19,9% des 387 oiseaux), microfilaires (13,7%), Leucocytozoon (11,1%) et Trypanosoma (1,0%). Pour

Raharimanga V; Soula F; Raherilalao MJ; Goodman SM; Tall A; Randrianarivelojosia M; Raharimalala L; Duchemin JB; Ariey F; Robert V


Aspects macroscopiques des lymphomes digestifs primitifs  

Microsoft Academic Search

Résumé  Les lymphomes primitifs du tube digestif ont, en général, une présentation macroscopiqe proche du celles des adénocarcinomes,\\u000a tumeurs malignes les plus fréquentes du tube digestif. Le diagnostic macroscopique différentiel de ces deux affections est\\u000a aléatoire; parmi les rares critères de différenciation, on peut citer la multifocalité des lésions dans les lymphomes et la\\u000a présence d’un relief muqueux cérébriforme.\\u000a \\u000a La classification

Anne Jouret; J. Haot



Sedimentologie des Lias der Berchtesgadener Kalkalpen  

Microsoft Academic Search

Zusammenfassung  Ausgehend von der herrschenden Vorstellung einer Transgression roter Liaskalke zur Zeit des oberen Unterlias über ein subaerisch verkarstetes Dachsteinkallerelief, untersuchte ich die Liassedimente in den Berchtesgadener Alpen eingehender und unternahm vergleichende Begehungen im östlichen Hagengebirge, im Steinernen Meer und in den Steinbrüchen von Adnet.Die Sedimente des Lias liegen in einer Graukalk- und einer abwechslungsreicheren Rotkalk-Fazies (F.Fabricius 1962) vor. Ammoniten zeigten,

Hermann Jurgan



Les instruments des politiques d'environnement  

Microsoft Academic Search

[fre] Les instruments des politiques d'environnement . Les problèmes d'environnement peuvent être ramenés à l'analyse du marché de chaque bien concerné : eau, air, espaces naturels... L'inexistence ou l'imperfection des marchés de ces ressources mène souvent à leur sur-exploitation, car le prix auquel elles sont disponibles est en général inférieur à leur coût pour la collectivité. Le dysfonctionnement d'autres marchés

Xavier Delache; Sylviane Gastaldo



Receptor reserve and affinity of mu opioid agonists in mouse antinociception: correlation with receptor binding  

Microsoft Academic Search

In order to quantitate the extent to which opioid agonist potencies obtained in behavioral assays are determined by the apparent in vivo affinity and efficacy of the agonist, the antinociceptive effects of the mu opioid agonists morphine, fentanyl, etonitazene, and NIH 10741 were assessed before and after administration of the insurmountable mu opioid antagonist clocinnamox (CCAM) in a 55 °C

Gerald Zernig; Tom Issaevitch; Jillian H. Broadbear; Timothy F. Burke; John W. Lewis; George A. Brine; James H. Woods



Synthesis and SAR of potent LXR agonists containing an indole pharmacophore  

SciTech Connect

A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.; (GSKNC); (GSKPA)



Age–Sex Differences in the Expression of Agonistic Behavior in Rhesus Monkey (Macaca mulatta) Groups  

Microsoft Academic Search

Both age and sex influence rhesus monkey agonistic behavior. In intragroup episodes, submission was most frequent in juveniles, but aggression increased steadily with age, albeit much more sharply in females. As infants, males were more often involved in agonistic behavior than were females, but this sex difference reversed with age. A notable change in the frequency and forms of agonistic

Irwin S. Bernstein; Carolyn L. Ehardt



The Risk of Myocardial Infarction Associated with Inhaled b Adrenoceptor Agonists  

Microsoft Academic Search

Beta-adrenoceptor agonists ( b -agonists), in widespread clinical use for obstructive lung disease, have been associated with an increased risk of cardiovascular mortality. The objective of this study was to assess the association between incident myocardial infarction and the use of inhaled b -agonists. We performed a case-control study within the Group Health Cooperative of Puget Sound (GHC). Be- tween



Acute Effect on Power Output of Alternating an Agonist and Antagonist Muscle Exercise During Complex Training  

Microsoft Academic Search

The efficient coordination of agonist and antagonist muscles is one of the important early adaptations in resistance training responsible for large increases in strength. Weak antagonist muscles may limit speed of movement; consequently, strengthening them leads to an increase in agonist muscle movement speed. However, the effect of combining agonist and antagonist muscle exercises into a power training session has

Daniel Baker; Robert U. Newton



Activity patterns, behavioural repertoires, and agonistic interactions of crayfish: A non-manipulative field study  

Microsoft Academic Search

Summary Agonistic behaviour of crayfish has been studied extensively in laboratory settings where pairs or groups of individuals are allowed to interact within an experimental arena. Crayfish agonistic behaviour within its natural context, however, has received little attention to date. The present, non-manipulative field study explored activity patterns, behavioural repertoires, and agonistic encounters of rusty crayfish (Orconectes rusticus) during the

Karen M. Davis; Robert Huber



?4?2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain.  


?4?2* neuronal nicotinic acetylcholine receptor are ligand-gated ion channels and widely expressed throughout the central and peripheral nervous system. ?4?2* neuronal nicotinic acetylcholine receptor play crucial role in pain signaling via modulation of multiple neurotransmitters like acetylcholine, dopamine, ?-amino butyric acid (GABA) and norepinephrine. Both spinal and supraspinal pathways are involved in the mechanisms by which ?4?2* neuronal nicotinic acetylcholine receptor ligands modulate the neuropathic and inflammatory pain. Selective ?4?2* neuronal nicotinic acetylcholine receptor ligands are being developed for the treatment of neuropathic and inflammatory pain as they show considerable efficacy in a wide range of preclinical pain models. Agonists/partial agonists of ?4?2* neuronal nicotinic acetylcholine receptor show efficacy in animal models of pain and their anti-nociceptive properties are blocked by nicotinic antagonists. Positive allosteric modulators are being developed with the aim to increase the potency or therapeutic window of agonists/partial agonists. Accumulating evidences suggest that anti-nociceptive effects of nicotinic acetylcholine receptor ligands may not be mediated solely by ?4?2* neuronal nicotinic acetylcholine receptor. We have also reviewed the stage of clinical development of various ?4?2* neuronal nicotinic acetylcholine receptor ligands. PMID:23660369

Nirogi, Ramakrishna; Goura, Venkatesh; Abraham, Renny; Jayarajan, Pradeep



Effects of ionizing radiation and pretreatment with (D-Leu6,des-Gly10) luteinizing hormone-releasing hormone ethylamide on developing rat ovarian follicles  

SciTech Connect

To assess the effects of a gonadotropin-releasing hormone agonist, (D-Leu6,des-Gly10) luteinizing hormone-releasing hormone ethylamide, in ameliorating the damage caused by ionizing radiation, gonadotropin-releasing hormone agonist was administered to rats from day 22 to 37 of age in doses of 0.1, 0.4, and 1.0 microgram/day or vehicle and the rats were sacrificed on day 44 of age. There were no effects on estradiol, progesterone, luteinizing, or follicle-stimulating hormone, nor an effect on ovarian follicle numbers or development. In separate experiments, rats treated with gonadotropin-releasing hormone agonist in doses of 0.04, 0.1, 0.4, or 1.0 microgram/day were either irradiated or sham irradiated on day 30 and all groups sacrificed on day 44 of age. Irradiation produced a reduction in ovarian weight and an increase in ovarian follicular atresia. Pretreatment with the agonist prevented the reduction in ovarian weight and numbers of primordial and preantral follicles but not healthy or atretic antral follicles. Such putative radioprotection should be tested on actual reproductive performance.

Jarrell, J.; YoungLai, E.V.; McMahon, A.; Barr, R.; O'Connell, G.; Belbeck, L.



Analyse évaluative des unités conventionnées et des unités autonomes de services  

Microsoft Academic Search

Analyse évaluative des unités conventionnées et des unités autonomes de services analyzes the contribution of financial easing and power delegations granted to units which have committed themselves by signing Accountability and Performance Agreements (APAs) and to autonomous service units (ASUs) as far as performance improvement is concerned. The results clearly show that the financial easing as well as easing of

Benoit A. Aubert; Simon Bourdeau; Frédéric Gagné; Nicolas Perreault



Des orphelins de la JAC aux enfants perdus des parcours individuels  

Microsoft Academic Search

[fre] En France, en 1966, la politique de la formation professionnelle a été organisée en fonction d'un public bien précis : les jeunes exploitants familiaux. Elle a été ensuite étendue aux femmes, aux salariés, aux jeunes chômeurs. A l'heure actuelle, la décentralisation des décisions pose des problèmes de cohérence au niveau national et de priorité en fonction de la CEE.

Jean-François Chosson



Equations de transport relatives à des champs de vecteurs non-lipschitziens et mécanique des fluides  

Microsoft Academic Search

Le but de cet article est l'étude des équations de transport relatives à des champs de vecteurs non-lipschitziens, mais seulement logarithmiquement lipschitziens. Ces champs possèdent un flot dont la régularité hölderienne est exponentiellement décroissante. On exhibe une solution de l'équation d'Euler bidimensionnelle présentant effectivement ce phénomène.

H. Bahouri; J.-Y. Chemin




Microsoft Academic Search

En se basant sur le modèle de Fama et French (1993), nous avons essayé de mesurer l'impact de la qualité du résultat comptable sur le coût des fonds propres des entreprises tunisiennes. La revue de la littérature nous renseigne que plus la qualité de l'information – véhiculée par le résultat comptable – est meilleure, moins sera le risque informationnel, ce

Fatma Triki; Rym Hachana



Inhibition of dopamine neuron firing by pramipexole, a dopamine D 3 receptor-preferring agonist: comparison to other dopamine receptor agonists  

Microsoft Academic Search

Pramipexole, an amino-benzathiazole [(S)-4,5,6,7-tetrahydro-N-6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate] direct-acting dopamine receptor agonist effective in treating Parkinson's disease, bound selectively and with high affinity to dopamine D2-like receptors, with highest affinity at dopamine D3 receptors. Ergot dopamine receptor agonists (bromocriptine, lisuride, pergolide) bound to both dopamine and non-dopamine receptors. Although all agonists depressed dopamine neuron firing, only pramipexole and quinpirole completely silenced firing

Montford F. Piercey; William E. Hoffmann; Martin W. Smith; Deborah K. Hyslop



Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes.  


Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression. PMID:10319995

Thacher, S M; Nagpal, S; Klein, E S; Arefieg, T; Krasinski, G; DiSepio, D; Agarwal, C; Johnson, A; Eckert, R L; Chandraratna, R A



Developpement des betons semi autoplacants a rheologie adaptee pour des infrastructures  

NASA Astrophysics Data System (ADS)

Au cours des dernières décennies, les infrastructures canadiennes et québécoises comportent plusieurs structures en béton armé présentant des problèmes de durabilité dus aux conditions climatiques sévères, à la mauvaise conception des structures, à la qualité des matériaux, aux types des bétons choisis, aux systèmes de construction ou à l'existence d'événements incontrôlables. En ce qui concerne le choix du béton pour la construction des infrastructures, une vaste gamme de béton divisée en deux principaux types peut être utilisée: le béton conventionnel vibré (BCV) et le béton autoplaçant (BAP). Dans le cas d'un BCV, la consolidation inadéquate par vibration a été un problème récurrent, occasionnant des dommages structuraux. Ceci a conduit à une réduction de la durabilité et à une augmentation du coût d'entretien et de réparation des infrastructures. Rien que l'utilisation d'un BAP a des avantages tels que l'élimination de la vibration, la réduction des coûts de main d'oeuvre et l'amélioration de la qualité des structures, néanmoins, le coût initial d'un BAP par rapport à un BCV ne permet pas encore de généraliser son utilisation dans l'industrie de la construction. Ce mémoire présente la conception d'une nouvelle gamme de béton semi-autoplaçant pour la construction des infrastructures (BSAP-I) exigeant une vibration minimale. Il s'agit de trouver un équilibre optimal entre la rhéologie et le coût initial du nouveau béton pour conférer une bonne performance structurale et économique aux structures. Le programme expérimental établi a premièrement permis d'évaluer la faisabilité d'utilisation des BSAP-I pour la mise en place des piliers d'une infrastructure de pont à Sherbrooke. En plus, l'utilisation d'un plan d'expériences a permis l'évaluation de trois paramètres de formulation sur les propriétés des mélanges de BSAP-I à l'état frais et durci. Finalement, l'évaluation de la performance des BSAP-I optimisés à travers une caractérisation complète des propriétés mécaniques et de la durabilité a été réalisée. A la suite de cette étude, les résultats obtenus nous permettent de conclure que : (1) L'utilisation d'un BSAP-I avec un gros granulat de 5 – 14 mm, des rapports E/L = 0,37 et S/G = 0,52 et une teneur en air de 6 à 9% a été possible en conférant un équilibre optimal fluidité / stabilité à l'état frais, ainsi qu'un niveau de thixotropie adéquate au chantier permettant d'optimiser la conception du coffrage des piliers de pont et de conférer des qualités de surfaces très acceptables de ces infrastructures. (2) La méthode adaptée pour l'essai L-Box contenant 2 barres et une vibration de 5 secondes a permis de bien caractériser la capacité de remplissage d'un BSAP-I. (3) L'utilisation d'un plan factoriel 23 a permis d'obtenir des modèles statistiques fiables, capables de prédire les propriétés rhéologiques à l'état frais et les résistances en compression des BSAP-I avec des dosages en liant entre 370 et 420 kg/m3, des rapports E/L entre 0,34 et 0,40 et S/G entre 0,47 et 0,53. (4) Des mesures de vitesse d'écoulement T40 d'un BSAP-I sont très semblables à celles d'un BAP. En plus, des valeurs T40 montrent une bonne corrélation linéaire avec celles de T400 mesurés dans la boîte L-Box. (5) À la frontière du BAP et du BCV, une bande rhéologique possédant un ?0 entre 30 et 320 Pa et un ? entre 10 et 140 Pa.s a été trouvée pour la conception optimale des BSAP-I. (6) Les BSAP-I optimisés ont également conféré une très bonne performance à l'état frais, en permettant maintenir un bon équilibre entre la rhéologie et la stabilité dans le temps, lorsqu'on utilise une énergie de vibration minimale pour amorcer son écoulement. (7) À l'état durci Les BSAP-I ont conféré une bonne performance présentant des résistances mécaniques élevées et des niveaux négligeables de pénétration aux ions chlores, de perte de masse par écaillage et des attaques par le gel/dégel. (8) L'utilisation des c

Sotomayor Cruz, Cristian Daniel


Agonist-Selective Signaling of G Protein-Coupled Receptor: Mechanisms and Implications  

PubMed Central

Agonist-selective signaling or ligand-biased signaling of G protein-coupled receptor (GPCR) has become the focus of an increasing number of laboratories. The principle of this concept is that agonist possesses different abilities to activate different signaling pathways. Current review summarizes the observations of agonist-selective signaling of various GPCRs, indicating the significance of agonist-selective signaling in biological processes. In addition, current review also provides an overview on how agonist-selective signaling is initiated. Especially, the relationship between GPCR-G protein interaction and GPCR-?-arrestin interaction is discussed in depth.

Zheng, Hui; Loh, Horace H.; Law, Ping-Yee



Cardiac and noncardiac fibrotic reactions caused by ergot-and nonergot-derived dopamine agonists.  


There is growing evidence that the ergot-derived dopamine agonists cabergoline and pergolide can cause fibrotic cardiac valvulopathy. Data on other fibrotic reactions and nonergot-derived dopamine agonists are sparse. Aim of this study was to investigate whether there are signals that dopamine agonists are related to cardiac and other fibrotic reactions. We identified all reports of fibrotic reactions at the heart, lung, and retroperitoneal space associated with dopamine agonists within the US Adverse Event Reporting System database. Disproportionality analyses were used to calculate adjusted reporting odds ratios (RORs). For ergot-derived dopamine agonists (bromocriptine, cabergoline, pergolide), the RORs of all reactions under study were increased, whereas no such increases were observed for nonergot-derived drugs (apomorphine, pramipexole, ropinirole, rotigotine). Fibrotic reactions due to ergot-derived dopamine agonists may not be limited to heart valves. For nonergot-derived dopamine agonists, no drug safety signals were evident. PMID:19170199

Andersohn, Frank; Garbe, Edeltraut



Point de vue réglementaire sur le développement des vaccins ...  

Center for Biologics Evaluation and Research (CBER)

Text Version... et des centres universitaires sur le développement clinique et l'homologation des produits, notamment les vaccins contre le paludisme, le VIH et la ... More results from


La variabilité des canaux semi-circulaires osseux  

Microsoft Academic Search

Résumé Depuis le début du siècle les observations anatomiques ont révélé la variabilité de la disposition des canaux semi-circulaires osseux (canales semi-circulares ossei) et celle des appareils vestibulaires droit et gauche pris dans leur ensemble.

M. Caix; G. Outrequin



Induction of TRPV1 desensitization by a biased receptor agonist.  


Selective suppression of hyperactive sensory neurons is an attractive strategy for managing pathological pain. Blocking Na(+) channels to eliminate action potentials and desensitizing transduction channels can both reduce sensory neuron excitability. The novel synthetic vanilloid ligand cap-ET preserves agonist activation of intracellular Ca(2+) signals and large organic cation transport but loses effective electric current induction. Cap-ET can therefore be used to deliver the membrane impermeable Na(+) channel blocker QX-314 to substantially inhibit voltage-activated Na(+) currents. We explored, besides facilitating entry of organic cationic therapeutics, whether cap-ET can also produce receptor desensitization similar to the natural agonist capsaicin. Using the YO-PRO-1 based fluorescent dye uptake assay, we found that cap-ET effectively triggered Ca(2+) dependent desensitization of TRPV1 when the receptor was pre-sensitized with the surrogate oxidative chemical phenylarsine oxide (PAO), suggesting an alternative use of permanently charged cationic capsaicinoids in differential neuronal silencing. PMID:21829089

Wang, Elaine E; Li, Hui; Wang, Shu; Chuang, Alexander Y; Chuang, Huai-hu



RH 5849, a Nonsteroidal Ecdysone Agonist: Effects on Larval Lepidoptera.  


The ecdysone agonist RH 5849 (1,2-dibenzoyl-1-tert-butylhydrazine) causes the premature initiation of molting at all stages of larval development of the tobacco hornworm, Manduca sexta. This phenomenon occurs without an increase in the endogenous ecdysone (20-hydroxyecdysone) titers. RH 5849 likewise provokes the initiation of molting in larval abdomens in the absence of a source of endogenous hormone. Although substantially less active than 20-hydroxyecdysone in vitro, RH 5849 was 30 to >670 times as active as the authentic molting hormone in bioassays with isolated larval abdomens or intact hornworms. This reversal in potency can be attributed to the superior transport properties and metabolic stability of RH 5849 relative to 20-hydroxyecdysone. Thus RH 5849 and its analogs are relatively persistent ecdysone agonists that halt feeding in larval lepidoptera by forcing an ultimately lethal, developmentally premature molt. PMID:17792610

Wing, K D; Slawecki, R A; Carlson, G R



Agonist-antagonist combinations in opioid dependence: a translational approach.  


The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

Mannelli, P



Italy's electronic health record system for opioid agonist treatment.  


Electronic health record systems (EHRs) play an increasingly important role in opioid agonist treatment. In Italy, an EHR called the Multi Functional Platform (MFP) is in use in 150 opioid-agonist treatment facilities in 8 of Italy's 23 regions. This report describes MFP and presents 2010 data from 65 sites that treated 8145 patients, of whom 72.3% were treated with methadone and 27.7% with buprenorphine. Patients treated with buprenorphine compared to methadone were more likely to be male (p < .01) and younger (p < .001). Methadone compared to buprenorphine patients had a higher percentage of opioid-positive urine tests (p < .001) and longer mean length of stay (p = .004). MFP has been implemented widely in Italy and has been able to track patient outcomes across treatment facilities. In the future, this EHR system can be used for performance improvement initiatives. PMID:23518287

Serpelloni, Giovanni; Gomma, Maurizio; Genetti, Bruno; Zermiani, Monica; Rimondo, Claudia; Mollica, Roberto; Gryczynski, Jan; O'Grady, Kevin E; Schwartz, Robert P



New class of glutamate agonist structurally related to ibotenic acid  

Microsoft Academic Search

L-Glutamic acid (Glu) and L-aspartic acid (Asp) are putative excitatory transmitters in the mammalian central nervous system (CNS)1-3. Receptors at Glu- and Asp-mediated synapses are presumably different4,5, and a prerequisite for the identification and characterisation of such sites is the availability of specific antagonists and agonists. Among various potential Glu and Asp antagonists3-6 Glu diethyl ester (GDEE)7-9 and (D)-alpha-aminoadipic acid

P. Krogsgaard-Larsen; T. Honoré; J. J. Hansen; D. R. Curtis; D. Lodge



Antidepressant effects of pramipexole, a novel dopamine receptor agonist  

Microsoft Academic Search

Summary Pramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride), a new dopamine receptor agonist with preference for D3 compared to D2 and D4 receptors, was tested in rats in respect of its potential antidepressant activity. In the forced swimming test the drug under study, given three times in rats, reduced the immobility time. In the forced swimming test, joint treatment with antidepressants (imipramine, amitriptyline) and pramipexole

J. Maj; Z. Rogó?; G. Skuza; K. Ko?odziejczyk



Behavioural profile of partial D2 dopamine receptor agonists  

Microsoft Academic Search

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg\\/kgd-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blockedd-amphetamine (1.5 mg\\/kg)-induced increases in photocell

David Clark; Lesley J. Furmidge; Nancy Petry; Zhang-Yan Tong; Mia Ericsson; Diane Johnson



The behavioural effects of pramipexole, a novel dopamine receptor agonist  

Microsoft Academic Search

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride) is a novel dopamine D2 family receptor agonist with a predominant action on D2 autoreceptors and with some D3 vs. D2 receptor preference. The central behavioural effects of pramipexole given subcutaneously to rats (male Wistar) and mice (Albino Swiss) are presented in this paper. Used in low doses (0.001–0.1 mg\\/kg), pramipexole induced locomotor hypoactivity which was

Jerzy Maj; Zofia Rogó?; Gra?yna Skuza; Krzysztof Ko?odziejczyk



Continuous dopaminergic stimulation and novel formulations of dopamine agonists  

Microsoft Academic Search

There is now accumulating evidence that the combination of progressive pathology of Parkinson’s disease, the change in drug\\u000a pharmacodynamics, and the pulsatile manner in which short-acting dopaminergic agents stimulate striatal dopamine receptors\\u000a are the key contributing factors to the priming of the basal ganglia for induction of motor complications. Long-acting drugs\\u000a provide a more physiological dopaminergic stimulation. Dopamine agonists have

Fabrizio Stocchi



Kaempferol is an estrogen-related receptor ? and ? inverse agonist  

Microsoft Academic Search

Kaempferol is a dietary flavonoid that is thought to function as a selective estrogen receptor modulator. In this study, we established that kaempferol also functions as an inverse agonist for estrogen-related receptors alpha and gamma (ERR? and ERR?). We demonstrated that kaempferol binds to ERR? and ERR? and blocks their interaction with coactivator peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?). Kaempferol

Junjian Wang; Fang Fang; Zhiyan Huang; Yanfei Wang; Chiwai Wong



Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine  

Microsoft Academic Search

Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization.

Daphne Simeon; Eric Hollander; Dan J. Stein; Concetta DeCaria; Lisa J. Cohen; Jihad B. Saoud; Nazrul Islam; Michael Hwang



Excretion study of the ? 2-agonist reproterol in human urine  

Microsoft Academic Search

An excretion study of the ?2-agonist 7-[3-[(?-3,5-trihydroxyphenethyl)amino]-propyl]theophylline (reproterol) in human urine, which is reportedly misused by athletes and horses as a doping agent, is presented. The study was performed after an oral administration of 20 mg of reproterol hydrochloride. The collected urine samples were prepared using the standard anabolic steroid extraction procedure and analyzed by gas chromatography coupled with quadrupole

C. G Georgakopoulos; C Tsitsimpikou; M.-H. E Spyridaki



ACP-103, a 5-HT2A receptor inverse agonist.  


ACADIA Pharmaceuticals is developing ACP-103, lead compound in a series of 5-HT2A inverse agonists, as a potential antipsychotic agent and for the potential treatment of insomnia. Phase II clinical trials in treatment-induced psychosis in Parkinson's disease (PD) patients and in schizophrenic patients are ongoing, as are phase II trials evaluating the effects of the drug on PD symptoms and dyskinesias. PMID:16869120

Roberts, Claire



Treatment of cerebellar ataxia with 5HT1A agonist  

Microsoft Academic Search

Effective, pharmacologic approaches to the treatment of cerebellar ataxia are lacking or inadequate. We recently reported\\u000a preliminary evidence that tandospirone citrate (tandospirone), a 5-HT1A agonist, improved cerebellar ataxia in patients with\\u000a Machado-Joseph disease (MJD). In the course of that study, we found that such treatment also alleviated the pain associated\\u000a with cold sensations in the legs, insomnia, anorexia, and depression,

Asako Takei; Takeshi Hamada; Ichiro Yabe; Hidenao Sasaki



Development of High Affinity Selective VIP 1 Receptor Agonists  

Microsoft Academic Search

Gourlet, P., A. Vandermeers, P. Vertongen, J. Rathe, P. De Neef, J. Cnudde, M. Waelbroeck and P. Robberecht. Development of high affinity selective VIP1 receptor agonists. Peptides 18(10) 1539–1545, 1997.—The biological effects of VIP are mediated by at least two VIP receptors: the VIP1 and the VIP2 receptors that were cloned in rat, human and mice. As the mRNA coding

Philippe Gourlet; Andre Vandermeers; Pascale Vertongen; Jean Rathe; Philippe de Neef; Johnny Cnudde; Magali Waelbroeck; Patrick Robberecht



Octopaminergic agonists for the cockroach neuronal octopamine receptor  

PubMed Central

The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(?-phenylethylamino)-2-thiazoline BPAT 2-(?-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(?-aminoethyl ether)-N,N,N?,N?-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane

Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa



Pharmacophore-driven identification of PPAR? agonists from natural sources  

Microsoft Academic Search

In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists\\u000a of PPAR?. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived\\u000a natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found,\\u000a among others,

Rasmus K. Petersen; Kathrine B. Christensen; Andreana N. Assimopoulou; Xavier Fretté; Vassilios P. Papageorgiou; Karsten Kristiansen; Irene Kouskoumvekaki




Microsoft Academic Search

One hundred twenty-four prepuberal crossbred pigs were used in a series of behavioral bioassays to determine the minimum dose of androstenone (5c~-androst-16-en-3-one) that would reduce the level of agonistic behavior among dyads of newly regrouped pigs. Randomly selected females and castrated males were used in 21-h videotaped observation periods. In Exp. 1, isopropyl alcohol was tested against no aerosol to

John J. McGlone; Julie L. Morrow



Cannabinoid Receptor Agonists Protect Cultured Rat Hippocampal Neurons from Excitotoxicity  

Microsoft Academic Search

Cannabinoid receptor agonists act presynaptically to inhibit the release of glutamate. Because other drugs with this action are known to reduce excitotoxicity, we tested several cannabimi- metics in a model of synaptically mediated neuronal death. Reduction of the extracellular Mg21 concentration to 0.1 mM evoked a repetitive pattern of intracellular Ca21 concentration ((Ca21)i) spiking that, when maintained for 24 hr,



Inverse agonist binding of peripheral benzodiazepine receptors in anxiety disorder  

Microsoft Academic Search

The binding characteristics of the pBR (peripheral benzodiazepine receptor) inverse agonist, [3H]-Ro 5-4864, were examined in patients diagnosed as generalized anxiety disorder. As compared to normal healthy controls,\\u000a the anxious subjects demonstrated a statistically significant (p < 0.001) increase in the density of pBR in platelets. The\\u000a enhanced pBR binding correlated significantly with the severity of global anxiety symptom of

Simon Chiu; Amarendra N. Singh; Pauline Chiu; Ram K. Mishra



Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation  

Microsoft Academic Search

Background Case reports and echocardiographic studies suggest that the ergot-derived dopa- mine agonists pergolide and cabergoline, used in the treatment of Parkinson's dis- ease and the restless legs syndrome, may increase the risk of cardiac-valve regur- gitation. Methods We used data from the United Kingdom General Practice Research Database to identify a population-based cohort comprising 11,417 subjects 40 to 80

René Schade; Frank Andersohn; Samy Suissa; Wilhelm Haverkamp; Edeltraut Garbe



Évolution des prix alimentaires : les enquêtes confirment l'indice  

Microsoft Academic Search

[fre] L'indice des prix à la consommation fournit, mois par mois, une estimation de l'évolution des prix. Pour les prix alimentaires, une autre estimation annuelle est possible, à partir de données recueillies auprès des ménages. Ces deux estimations, complètement indépendantes, ne s'écartent que de 0,2% pour la période 1970-1982. . Pour certains postes, les deux sources conduisent à des écarts

Tanneguy de Jouvencel



Politique des déchets : l'approche du Royaume-Uni  

Microsoft Academic Search

[fre] Politique des déchets : l'approche du Royaume-Uni . L'évolution récente de la réglementation européenne en dématière de déchets risque d'entraîner des coûts importants pour les États membres. L'exemple britannique est d'autant plus intéressant pour la France que les deux pays présentent des similitudes : quantité presque identique de déchets ménagers (environ 20 millions de tonnes), faible capacité des incinérateurs

David Litvan



L'Internet des objets. Quels enjeux pour les Européens ?  

Microsoft Academic Search

L'Internet accueille aujourd'hui des milliards de connexions et d'échanges qui en font l'outil le plus puissant jamais inventé pour le partage de l'information. En quelques décennies, il est devenu le moteur de profondes transformations dans la vie des entreprises, des individus et des institutions. Cet élan n'est pas près de cesser et dans tous les pays ingénieurs et techniciens, industriels

Pierre-Jean Benghozi; Sylvain Bureau; Françoise Massit-Folea



Recouvrement des coûts et demande de soins dans les PED  

Microsoft Academic Search

[fre] Boubou Cissé Stéphane Luchini Jean-Paul Moatti Recouvrement des coûts et demande de soins dans les PED Suite à la crise financière qui a durement frappé les pays en développe- ment dès le début des années 1980, l'instauration du recouvrement des coûts d'accès aux soins (politique de tarification des prestations de services de santé) a été proposée à ces pays

Boubou Cissé; Stéphane Luchini; Jean-Paul Moatti



Évolution des salaires : normes collectives et facteurs individuels  

Microsoft Academic Search

[fre] L'évolution individuelle des salaires est influencée par des facteurs collectifs comme les taux uniformes résultant des négociations salariales ou l'existence de l'avancement à l'ancienneté. Mais des facteurs individuels jouent aussi, promotions au choix, événements divers de la vie professionnelle de chacun. L'article propose un indicateur original pour séparer ces deux ensembles de facteurs. Les salariés sont répartis en groupes

Christian Baudelot



Structure of the agonist-bound neurotensin receptor.  


Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8?Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity. PMID:23051748

White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard



Isochromanone-based urotensin-II receptor agonists.  


A series of analogues of the selective non-peptide urotensin II (UII) receptor agonist 3-(4-chlorophenyl)-3-(2-dimethylaminoethyl)-isochroman-1-one (AC-7954, 1) was synthesized and evaluated for UII agonist activity using a functional cell-based assay. The introduction of a methyl group in the 4-position resulted in a complete loss of activity, whereas substituents in the aromatic rings were beneficial. Sterically demanding amino groups were also detrimental to the activity. Several potent agonists were identified, six compounds being equally or more potent than 1. The most potent compound in the series was the 6,7-dimethyl analogue of 1 (16, pEC50 6.87). The racemate of 16 was resolved into the pure enantiomers using preparative straight phase HPLC. It was shown that the potency resides in the (+)-enantiomer (pEC50 7.11). The synthesized compounds seem to be selective for the UII receptor as no activities were observed at the closely related SSTR3 and 5 receptors. PMID:15781415

Lehmann, Fredrik; Currier, Erika A; Olsson, Roger; Hacksell, Uli; Luthman, Kristina



?7 Nicotinic receptor agonist reactivates neurogenesis in adult brain.  


Reactivation of neurogenesis by endogenous Neural Stem/Progenitor Cells (NS/PC) in the adult brain or spinal cord holds the key for treatment of CNS injuries as well as neurodegenerative disorders, which are major healthcare issues for the world's aging population. Recent studies show that targeting the ?7 nicotinic acetylcholine receptors (?7nAChR) with a specific TC-7020 agonist inhibits proliferation and stimulates neuronal differentiation of NS/PC in subventricular zone (SVZ) in the adult mouse brain. TC-7020-induced neuronogenesis is observed in different brain regions, including: (1) ?III Tubulin-expressing cortical neurons, (2) calretinin expressing hippocampal neurons and (3) cells in substantia nigra (SN) expressing predopaminergic Nurr1+phenotype. Reactivation of developmental integrative nuclear FGFR1 signaling (INFS), via gene transfection reinstates neurogenesis in the adult brain by promoting neuronal differentiation of brain NS/PC. TC-7020 neuronogenic effect is associated with a robust accumulation of endogenous FGFR1 in the nuclei of differentiating cells. Furthermore, direct in vitro stimulation of neural stem/progenitor cells with ?7nAChR agonist activates INFS and neuronal-like differentiation and activation of neuronal genes. The ?7nAChR upregulation of early neuronal ?III-Tubulin gene involves neurogenic FGFR1-Nur signaling and direct FGFR1 interaction with the gene promoter. The reactivation of developmental INFS and neurogenesis in adult brain by the ?7nAChR agonist may offer new strategy to treat brain injuries, neurodegenerative and neurodevelopmental diseases. PMID:23933384

Narla, Sridhar; Klejbor, Ilona; Birkaya, Barbara; Lee, Yu-Wei; Morys, Janusz; Stachowiak, Ewa K; Terranova, Christopher; Bencherif, Merouane; Stachowiak, Michal K



Emerging strategies for exploiting cannabinoid receptor agonists as medicines.  


Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

Pertwee, Roger G



Pregnane X receptor agonists impair postprandial glucose tolerance.  


We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600?mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16?-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance. PMID:23588309

Rysä, J; Buler, M; Savolainen, M J; Ruskoaho, H; Hakkola, J; Hukkanen, J



Development of specific dopamine D-1 agonists and antagonists  

SciTech Connect

To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo(a,d)cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5d,e)isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC{sub 50} of compound 11 for displacement of {sup 3}H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of {sup 3}H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor.

Sakolchai, S.



Treatment of cerebellar ataxia with 5-HT1A agonist.  


Effective, pharmacologic approaches to the treatment of cerebellar ataxia are lacking or inadequate. We recently reported preliminary evidence that tandospirone citrate (tandospirone), a 5-HT1A agonist, improved cerebellar ataxia in patients with Machado-Joseph disease (MJD). In the course of that study, we found that such treatment also alleviated the pain associated with cold sensations in the legs, insomnia, anorexia, and depression, all of which are thought to be mediated through activation of the 5-HT1A receptor. In this paper, we reviewed the few published clinical trials that involved the use of 5-HT1A receptor agonists for the treatment of cerebellar ataxia, and discussed the current theories regarding their mechanism of action. Cortical cerebellar atrophy (CCA) was reported, in a double-blind study, to be amenable to treatment with tandospirone. Other types of spinocerebellar degeneration (SCD) i.e., olivopontocerebellar atrophy (OPCA) and Machado-Joseph disease (MJD) have also been reported to respond to the drug, but these have been small studies. Responsive patients exhibited only mild ataxia. The doses of 5-HT1A agonists that have been used successfully ranged from 12.5 mg/day to 60 mg/day (or 1 mg/kg), and were well tolerated by most patients. PMID:16147954

Takei, Asako; Hamada, Takeshi; Yabe, Ichiro; Sasaki, Hidenao



Potent adjuvanticity of a pure TLR7-agonistic imidazoquinoline dendrimer.  


Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-? induction in human PBMCs, with preservation of TLR7-driven IFN-? induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine ?-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen. PMID:22952720

Shukla, Nikunj M; Salunke, Deepak B; Balakrishna, Rajalakshmi; Mutz, Cole A; Malladi, Subbalakshmi S; David, Sunil A



Pharmacophore-driven identification of PPAR? agonists from natural sources.  


In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPAR?. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPAR? agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPAR?. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPAR? agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery. PMID:21069556

Petersen, Rasmus K; Christensen, Kathrine B; Assimopoulou, Andreana N; Fretté, Xavier; Papageorgiou, Vassilios P; Kristiansen, Karsten; Kouskoumvekaki, Irene



Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer  

PubMed Central

Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-? induction in human PBMCs, with preservation of TLR7-driven IFN-? induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine ?-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen.

Shukla, Nikunj M.; Salunke, Deepak B.; Balakrishna, Rajalakshmi; Mutz, Cole A.; Malladi, Subbalakshmi S.; David, Sunil A.



Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human ? 3 adrenergic receptor agonists  

Microsoft Academic Search

A novel class of human ?3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed ?3-AR agonists. As observed, many of the ?3-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human ?3 functional

Gregori J. Morriello; Harvey R. Wendt; Alka Bansal; Jerry Di Salvo; Scott Feighner; Jiafang He; Amanda L. Hurley; Donna L. Hreniuk; Gino M. Salituro; Marat Vijay Reddy; Sheila M. Galloway; Katherine K. McGettigan; George Laws; Crystal McKnight; George A. Doss; Nancy N. Tsou; Regina M. Black; Judy Morris; Richard G. Ball; Anthony T. Sanfiz; Eric Streckfuss; Mary Struthers; Scott D. Edmondson



Über die Verweildauer des Blutersatzmittels Subsidon im Kreislauf  

Microsoft Academic Search

Zusammenfassung Das Plasmavolumen von Hunden wurde mit Hilfe von mit J131 markiertem Plasmaalbumin bei Hunden vor und nach Ersatz einer größeren Blutmenge durch Subsidon überprüft. Gleichzeitig wurde das Verhalten des Plasmaprotein verfolgt. Auch nach 9–18 Std läßt sich ein Abwandern von Flüssigkeit nicht nachweisen. Der Gehalt des Plasma an Eiweiß nimmt rasch wieder zu. Subsidon hemmt die physiologische Regeneration des

K. Lang; H. Lang



Formen des politischen Terrorismus: ein Plädoyer für eine Differentialdiagnose  

Microsoft Academic Search

Ziel dieses Beitrag ist die Herausarbeitung einer präziseren Definition des Terrorismus anhand eines Minimalsatzes an Kriterien (Teil 1). Sodann werden verschiedene Typologien des Terrorismus diskutiert, mit Schwerpunkt auf substaatlichem politischem Terrorismus (Teil 2). Anschließend wird ein Kausalmodell des Terrorismus auf vier Erklärungsebenen entwickelt, von der individuellen über die Gruppen- und Organisationsebene bis zur staatlichen und globalen Ebene. Kausale Zusammenhänge zwischen

Ekkart Zimmermann



Le rôle des banques dans le gouvernement des entreprises allemandes. Etude à travers trois cas d'OPA hostiles  

Microsoft Academic Search

Le gouvernement d'entreprises (désormais GE) allemand a connu ces dernières années une évolution importante. S'inclinant devant les directives européennes, le Parlement a adopté des nouvelles lois visant, principalement, à améliorer le fonctionnement du marché des capitaux et à réduire l'influence des banques. Notre article consiste à étudier le rôle important des banques dans le GE allemand afin de comprendre la

Mehdi Nekhili



DCG-IV, a potent metabotropic glutamate receptor agonist, as an NMDA receptor agonist in the rat cortical slice  

Microsoft Academic Search

The depolarization induced by DCG-IV, a potent agonist for Group II metabotropic glutamate receptors (Group II mGluRs), was depressed by selective antagonists for NMDA receptors in the rat cortical slice, but was not affected even by a high concentration of a selective antagonist for Group II mGluRs. DCG-IV caused depolarization more effective than NMDA in a dose-dependence manner with a

Yoshiaki Uyama; Michiko Ishida; Haruhiko Shinozaki



Opposite effects of agonist and inverse agonist ligands of benzodiazepine receptor on self-defensive and submissive postures in the rat  

Microsoft Academic Search

The effects of benzodiazepine receptor ligands on different types of defensive behaviours were examined in intruder male rats confronted with offensive residents. Chronic administration, via a subcutaneous silastic pellet, of a full agonist (diazepam) for 15 days increased self-defensive postures as well as social and non-social behaviour whereas submissive postures and flight were reduced. Acute administration of a partial agonist

Bertrand Piret; Antoine Depaulis; Marguerite Vergnes



Virtual screening of CB(2) receptor agonists from bayesian network and high-throughput docking: structural insights into agonist-modulated GPCR features.  


The relevance of CB(2)-mediated therapeutics is well established in the treatment of pain, neurodegenerative and gastrointestinal tract disorders. Recent works such as the crystallization of class-A G-protein-coupled receptors in a range of active states and the identification of specific anchoring sites for CB(2) agonists challenged us to design a reliable agonist-bound homology model of CB(2) receptor. Docking-scoring enrichment tests of a high-throughput virtual screening of 140 compounds led to 13 hits within the micromolar affinity range. Most of these hits behaved as CB(2) agonists, among which two novel full agonists emerged. Although the main challenge was a high-throughput docking run targeting an agonist-bound state of a CB(2) model, a prior 2D ligand-based Bayesian network was computed to enrich the input commercial library for 3D screening. The exclusive discovery of agonists illustrates the reliability of this agonist-bound state model for the identification of polar and aromatic amino acids as new agonist-modulated CB(2) features to be integrated in the wide activation pathway of G-protein-coupled receptors. PMID:23217060

Renault, Nicolas; Laurent, Xavier; Farce, Amaury; El Bakali, Jamal; Mansouri, Roxane; Gervois, Philippe; Millet, Régis; Desreumaux, Pierre; Furman, Christophe; Chavatte, Philippe



NOD2 Agonist Promotes the Production of Inflammatory Cytokines in VSMC in Synergy with TLR2 and TLR4 Agonists  

PubMed Central

Objective. To investigate the expression of NOD2 in human VSMCs, its role in the production of inflammatory cytokines in VSMC and the possible interaction of NOD2-mediated signaling pathway with those mediated by TLR2 and TLR4. Methods. Human coronary artery smooth muscle cells were stimulated with NOD2 agonist MDP alone or in combination with either TLR2 agonist PAM3 or TLR4 agonist LPSs. The mRNA expression of NOD2 and FGF-2 were measured by RT-PCR. The concentration of IL-8 and TNF-? in the culture supernatants was determined by ELISA. VSMC proliferation ability was analyzed by MTT assay. Results. MDP up regulated the expression of NOD2 mRNA in VSMC in a time-dependent manner, up regulated the expression of FGF-2 mRNA in VSMC, induced the production of IL-8 and TNF-?, and promoted the proliferation of VSMC. Additionally, MDP synergied with LPS and PAM3 to promote the proliferation of VSMC and induce the production of IL-8 and TNF-?. Conclusion. The activation of NOD2-mediated innate immune signaling pathway can increase the proliferation ability of VSMC and induce the production of inflammatory cytokines in VSMC. It is also shown a synergistic effect with TLR2- and TLR4-mediated signaling pathways in this process.

Sun, Jinghua; Ding, Yanchun



Developpement d'une methode calorimetrique de mesure des pertes ac pour des rubans supraconducteurs a haute temperature critique  

Microsoft Academic Search

Le travail de recherche effectue dans le cadre de ce projet de doctorat a permis la mise au point d'une methode de mesure des pertes ac destinee a l'etude des supraconducteurs a haute temperature critique. Pour le choix des principes de cette methode, nous nous sommes inspires de travaux anterieurs realises sur les supraconducteurs conventionnels, afin de proposer une alternative

Patricia Dolez



La structure des systèmes désordonnés et sa mesure par diffraction  

NASA Astrophysics Data System (ADS)

La compréhension de mainte propriété physique d'un verre ou d'un liquide nécessite la connaissance des facteurs de structure partiels (PSFs) qui décrivent chacun la distribution d'une espèce atomique autour d'une autre. La technique de diffraction des neutrons avec substitution isotopique (NDIS) [1,2,3], ayant bien réussi a déterminer les PSFs de certains composés [4,5], est pourtant restreinte aux isotopes présentant un contraste suffisant en longueur de diffusion. D'un autre cote, la technique de diffusion anomale des rayons X (AXS ou AXD) [6] permet de faire varier la longueur de diffusion d'une espèce atomique pourvu que son énergie d'absorption soit à la fois accessible et suffisamment élevée pour donner un assez grand transfert de moment. La combinaison des techniques de diffraction des neutrons (avec ou sans substitution isotopique) et de diffraction des rayons X (avec ou sans diffusion anomale) peut donc permettre d'obtenir un meilleur contraste en longueurs de diffusion pour un système donné, mais exige une analyse de données plus soignée pour pouvoir bien tenir compte des erreurs systématiques qui sont différentes pour les 2 techniques [7]. Pour les atomes ayant des distributions électroniques quasi-sphériques, e.g. dans le cas d'un alliage liquide, la combinaison des techniques de NDIS et de diffraction des rayons X s'est déjà montrée très avantageuse pour la détermination des PSFs [8,9]. Dans le cas des verres ayant d'importantes liaisons covalentes, l'effective combinaison des 2 techniques peut être moins directe mais facilitée lorsqu'il s'agit des atomes de grand Z [10,11]. Nous présentons ici un sommaire du méthode et quelques exemples des résultats.

Barnes, A. C.; Fischer, H. E.; Salmon, P. S.



Computational structure-activity relationship analysis of small-molecule agonists for human formyl peptide receptors.  


N-formyl peptide receptors (FPRs) are important in host defense. Because of the potential for FPRs as therapeutic targets, recent efforts have focused on identification of non-peptide agonists for two FPR subtypes, FPR1 and FPR2. Given that a number of specific small-molecule agonists have recently been identified, we hypothesized that computational structure-activity relationship (SAR) analysis of these molecules could provide new information regarding molecular features required for activity. We used a training set of 71 compounds, including 10 FPR1-specific agonists, 36 FPR2-specific agonists, and 25 non-active analogs. A sequence of (1) one-way analysis of variance selection, (2) cluster analysis, (3) linear discriminant analysis, and (4) classification tree analysis led to the derivation of SAR rules with high (95.8%) accuracy for correct classification of compounds. These SAR rules revealed key features distinguishing FPR1 versus FPR2 agonists. To verify predictive ability, we evaluated a test set of 17 additional FPR agonists, and found that the majority of these agonists (>94%) were classified correctly as agonists. This study represents the first successful application of classification tree methodology based on atom pairs to SAR analysis of FPR agonists. Importantly, these SAR rules represent a relatively simple classification approach for virtual screening of FPR1/FPR2 agonists. PMID:20870313

Khlebnikov, Andrei I; Schepetkin, Igor A; Quinn, Mark T



Computational Structure-activity Relationship Analysis of Small-Molecule Agonists for Human Formyl Peptide Receptors  

PubMed Central

N-formyl peptide receptors (FPR) are important in host defense. Because of the potential for FPRs as therapeutic targets, recent efforts have focused on identification of non-peptide agonists for two FPR subtypes, FPR1 and FPR2. Given that a number of specific small molecule agonists have recently been identified, we hypothesized that computational structure-activity relationship (SAR) analysis of these molecules could provide new information regarding molecular features required for activity. We used a training set of 71 compounds, including 10 FPR1-specific agonists, 36 FPR2-specific agonists, and 25 non-active analogs. A sequence of (1) one-way analysis of variance selection, (2) cluster analysis, (3) linear discriminant analysis, and (4) classification tree analysis led to the derivation of SAR rules with high (95.8%) accuracy for correct classification of compounds. These SAR rules revealed key features distinguishing FPR1 versus FPR2 agonists. To verify predictive ability, we evaluated a test set of 17 additional FPR agonists, and found that the majority of these agonists (>94%) were classified correctly as agonists. This study represents the first successful application of classification tree methodology based on atom pairs to SAR analysis of FPR agonists. Importantly, these SAR rules represent a relatively simple classification approach for virtual screening of FPR1/FPR2 agonists.

Khlebnikov, Andrei I.; Schepetkin, Igor A; Quinn, Mark T.



Direct detection of ?-agonists by use of gold nanoparticle-based colorimetric assays.  


?-Agonists fed to animals for human consumption pose a serious threat to human health. Fast, broad-spectrum detection methods are needed for on-site screening of various types of ?-agonists from animal feeds, meats, and animal body fluids. We developed a colorimetric assay that uses gold nanoparticle (AuNP) plasmon absorption to realize quick detection of ?-agonists from liquid samples. ?-Agonists showed the capability of directly reducing HAuCl(4) into atomic gold, which involved oxidation of the amine or phenol group on the benzene ring of the ?-agonists. The resulting atomic gold formed AuNPs spontaneously, which had strong plasmon absorption at 528 nm. The linear relationship between the concentrations of ?-agonists and the AuNPs plasmon absorbance granted quantitative determination of ?-agonists in solution. The AuNPs colorimetric assay showed different sensitivities toward ?-agonists with different substituent groups on the aromatic ring. ?-Agonists with phenol groups had a lower limit of quantitation (LOQ) than those with amine groups. High-resolution transmission electron microscopy (TEM) images revealed the sizes of the AuNPs were in the range 15-25 nm, while X-ray energy-dispersive spectroscopic data suggested the smaller particles observed in TEM with lower contrast may be salt particles from the buffer solution. The developed colorimetric assay can potentially be used for the detection of ?-agonists and their analogues from serum, urine, and other liquid samples in the presence of interference from common antibiotics and glucose. PMID:21846151

He, Pingli; Shen, Li; Liu, Rongyuan; Luo, Zhiping; Li, Zhen



Inverse Agonists: Tools to Reveal Ligand-Specific Conformations of G Protein-Coupled Receptors  

NSDL National Science Digital Library

G protein–coupled receptors (GPCRs) traverse the plasma membrane seven times and produce intracellular effects through interaction with G proteins. Three classes of ligands bind and regulate the activity of GPCRs: agonists, antagonists, and inverse agonists. To describe the activity of these ligands at GPCRs, a two-state receptor model has been proposed in which receptors exist in an equilibrium between inactive (R) and active (R*) states. Agonists preferentially bind and stabilize the active (R*) state. This results in an enrichment of the proportion of active receptors, producing an increase in receptor activity. In contrast, inverse agonists preferentially bind and stabilize receptors in the inactive (R) state. This results in an enrichment of the proportion of inactive receptors, producing a reduction in spontaneous receptor activity. Neutral antagonists have equal preferences for both R and R* states, lack any intrinsic activity, and are able to block actions produced by either agonists or inverse agonists. Exciting observations reported in two recent manuscripts by Gbahou et al. and Azzi et al. indicate that some inverse agonists act not only in opposition to agonists by suppressing constitutive receptor activity, but may also initiate unique signal transduction cascades as well. Specifically, it is proposed that these unique ligands are able to enrich several distinct active receptor conformations, each demonstrating a preference for regulation of a discrete intracellular effector. This suggests that inverse agonists are not merely "the opposite of agonists," but instead may serve as useful tools to investigate ligand-specific conformations of GPCRs.

Paul L. Prather (University of Arkansas for Medical Sciences;Department of Pharmacology and Toxicology REV)



Pharmacological characterization of the effects of dopamine D(1) agonists on eye blinking in rats.  


Dopamine D(1)-like partial agonists antagonize some abuse-related effects of cocaine and have been proposed as candidate medications for psychostimulant abuse. Earlier studies have showed that D(1)-like agonists increase eye blinking in monkeys and that the magnitude of this effect may be related to agonist efficacy. These studies characterized the effects of D(1)-like agonists on eye blinking in female Sprague-Dawley rats placed in customized restraint tubes. After vehicle injections, eye blink rates averaged 2.1+/-0.25 blinks/min, or 31+/-4 blinks/15 min. The D(1)-like agonists SKF 82958 and R(+)-6Br-APB dose-dependently increased eye blinking to 136 and 124/15 min, respectively. The selective D(1)-like antagonist SCH 23390 decreased eye blinking and the peripherally selective D(1)-like agonist fenoldopam, the D(2)-like agonist (+)PHNO, and the indirect dopamine agonist methamphetamine all failed to alter eye blink rates relative to vehicle levels. Additional studies with unique congeners and isomers of the D(1)-like partial agonist SKF 83959, MCL 202, MCL 204, MCL 206, MCL 207 and MCL 209, resulted in only moderate increases in eye blink rates (27-84 blinks/15 min). These effects were dose-related for one compound, MCL 209 (max 84+/-19 blinks/15 min) and plateaued at the highest doses, suggestive of partial agonist effects. Additionally, the agonist MCL 206, like the D(1)antagonist SCH 23390, antagonized the effects of SKF 82958 on eye blinking. The findings suggest that D(1)-like agonists increase eye blinking in rats and that these effects may provide a simple measure that can be used to distinguish partial D(1)-like ligands. Further studies with novel D(1)-like partial agonists may be useful in the development of pharmacotherapies for cocaine abuse. PMID:17989512

Desai, Rajeev I; Neumeyer, John L; Bergman, Jack; Paronis, Carol A



Krankheitskosten des akuten Koronarsyndroms in Deutschland  

Microsoft Academic Search

Zusammenfassung\\u000a Einleitung  Das akute Koronarsyndrom (AKS) ist eine akute Form der Erkrankung bei Patienten mit koronarer Herzkrankheit (KHK). Ziel dieses\\u000a Beitrages ist es, die Krankheitskosten des AKS zu erfassen und die Ressourcenverbräuche den unterschiedlichen Behandlungsstationen\\u000a zuzuordnen.\\u000a \\u000a \\u000a \\u000a \\u000a Methodik  Die Krankheitskosten wurden mittels einer systematischen Literaturrecherche erhoben.\\u000a \\u000a \\u000a \\u000a Ergebnisse  Die Behandlung des AKS verursacht mit 3,3 Mrd. EUR pro Jahr etwa die Hälfte der direkten Kosten der

K. Damm; C. Runge; U. Zeymer; J.-M. Graf von der Schulenburg



Effet antihypertenseur des feuilles d’ Inula viscosa  

Microsoft Academic Search

Résumé  L’effet antihypertenseur de l’extrait aqueux (EA) des feuilles d’Inula viscosa a été évalué sur des rats rendus hypertendus par un traitement au L-NAME (NG-nitro-L-arginine méthyle ester). L’évolution\\u000a de la pression artérielle est évaluée en mesurant la pression artérielle systolique (PAS) à l’aide d’un plétysmographe. Nos\\u000a investigations ont porté sur trois groupes de rats: un groupe témoin, un groupe traité au

J. Kattouf; M. Belmoukhtar; H. Harnafi; H. Mekhfi; A. Ziyyat; M. Aziz; M. Bnouham; A. Legssyer



Der Einfluß des Wetters auf den Scharlach  

Microsoft Academic Search

1.Bei 1090 Aufnahmen mit Scharlach in der Bremer Kinderklinik währen 4 Jahren wurde der Beginn genau festgelegt.2.Die Krankheit begann—nach Eliminierung des Jahresganges—überzufällig oft bei den warmen Wetterphasen (Wph 3A warm-trocken und Wph 4 warm-feucht) mit einem Meteorotropie-Index von 1,31 (Beobachtungswert 1,31 zu Erwartungswert 1,00).3.Das Auftreten des Exanthems zeigte eine besonders ausgeprägte Biotropie, da bei warmen Wetterphasen (Wph 3A+4) der Abstand

Ingrid Nicolai; Helmuth Brezowsky; Wolfgang Menger



Annual Program Management Report, 1991, Des Moines Recreational River and Greenbelt, Des Moines River, Iowa.  

National Technical Information Service (NTIS)

The General Design Memorandum (GDM) and Programmatic Environmental Impact Statement for the Des Moines Recreational River and Greenbelt were approved on August 1, 1988. The GDM included a recommendation to increase the Federal construction cost estimate, ...



Influence des défauts de la structure du verre sur la résistance mécanique des fibres optiques  

NASA Astrophysics Data System (ADS)

For silica (pure and doped) optical fibers prepared from preforms irradiated by thermal neutrons and Ar^+ ions, the measurements of lifetime under transverse stress were carried out. It is found that the neutron bombardment leads to decrease of the lifetime and the strength of fiber while the ion implantation results in increasing of these parameters. The influence of particle irradiation on the glass strength is explained by the generation of structural defects which were observed by the infrared an Raman spectroscopy methods. The direction of the change of mechanical properties of fibers is determined by the type of defects and their distribution in the cross-section of fiber. Des préformes de fibres optiques de silice ont été exposées à un bombardement par des faisceaux de neutrons thermiques et d'ions Ar^+ à énergie de 40 keV afin d'engendrer des défauts de la structure respectivement dans le volume ou dans la couche superficielle des échantillons. Les fibres obtenues des préformes irradiées et non irradiées ont été mises en charge de flexion. On a déterminé leur temps de rupture sous diverses contraintes de traction sur la surface extérieure de la fibre en flexion. On a observé une diminution du temps de rupture des fibres après le bombardement neutronique et une augmentation après l'implantation ionique. L'analyse de la nature des défauts en faisant appel à la spectroscopie infrarouge et Raman a fait ressortir que l'irradiation aux ions entraînait essentiellement des liaisons chimiques dans une fine couche superficielle de l'échantillon alors que l'irradiation aux neutrons occasionnait une déformation des zones du réseau silicique dans toute la section de la préforme et de la fibre. L'amélioration de la résistance mécanique s'explique par une augmentation de la mobilité des éléments structuraux de la matrice de verre par suite d'une rupture partielle des liaisons chimiques et sa diminution par l'apparition de concentrateurs supplémentaires de contraintes à l'échelle moléculaire.

Chmel, A.; Baptizmanski, V. V.; Kharshak, A. A.



Etude de la validité d’une classification a priori des compétences des elèves requises par les apprentissages scolaires  

Microsoft Academic Search

Résumé  A l’occasion de la publication par le Ministère français de l’Education Nationale des résultats d’une enquête ayant pour objet\\u000a l’évaluation des acquisitions des élèves à la fin de la scolarité élementaire (âge: 11 ans), des experts en pédagogie ont\\u000a élaboré une classification des differents exercices de Français, de Mathématiques, et relatifs aux disciplines d’Eveil, soumis\\u000a aux élèves lors de l’enquête,

Jacques Aubret



Aspects cliniques spécifiques des douleurs dans les méningites carcinomateuses des enfants porteurs de tumeurs solides  

Microsoft Academic Search

Résumé  Lesméningites carcinomateuses de l’enfant sont en progression. Un diagnostic précoce et précis des différents types de douleurs permet une prise en charge antalgique\\u000a précoce et adaptée dans le but d’améliorer la qualité de vie. Le but était de définir les types et les spécificités des différentes\\u000a douleurs rencontrées au cours de cette affection. Tous les enfants suspects de présenter un

E. Pichard-Léandri; V. Schmitz



Structures conceptuelles, représentation des objets et des relations entre les objets  

Microsoft Academic Search

Cet article présente un panorama général de l'étude psychologique des concepts liés aux objets, l'insistance étant mise sur les conceptualisations les plus récentes et les derniers développements de la recherche dans ce domaine. Ces derniers développements portent essentiellement d'une part sur la notion de contexte et son rôle dans l'organisation des concepts, et d'autre part sur la notion de relations

Soulaimane Chemlal; Françoise Cordier



Le modèle triadique des aspects neurobiologiques des comportements motivés à l’adolescence  

Microsoft Academic Search

Résumé\\u000a Prérequis  Le comportement de prise de risque est une cause majeure de morbidité et de mortalité à l’adolescence. Dans le contexte d’une\\u000a théorie de la décision et des comportements motivés (c’est-à-dire dirigé vers un but), la prise de risque reflète un motif\\u000a de prise de décision qui favorise la sélection du déroulement de l’action avec des conséquences incertaines et potentiellement

M. Ernst; D.-S. Pine; M. Hardin



Le déclassement à l'embauche des jeunes: vers un changement de la valeur des diplômes?  

Microsoft Academic Search

De nombreuses recherches ont mis en évidence l’existence en France d’un déclassement massif des jeunes diplômés sur le marché du travail. La comparaison de deux enquêtes du Céreq sur les sortants du système éducatif en 1992 et 1998 met en évidence un résultat apparemment contradictoire si l’on prend en compte deux mesures du déclassement :des jeunes sortis en 1998, qui

Jean-François Giret; Philippe Lemistre



Communication environnementale et coût des fonds propres : Le cas des entreprises du SBF120  

Microsoft Academic Search

Quel est l'impact sur le coût des fonds propres des divulgations volontaires d'informations environnementales ? C'est à cette question de recherche que nous tentons ici de répondre. L'étude empirique porte sur un échantillon de 119 entreprises cotées du SBF120. La majorité de ces entreprises consacre en 2006 un chapitre ou une partie au domaine environnemental dans leur rapport annuel tandis

Frédérique Dejean; Isabelle Martinez



Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface  

NASA Astrophysics Data System (ADS)

G-PROTEIN-COUPLED receptors for catecholamines and some other small ligands are activated when agonists bind to the transmem-brane region of the receptor1. The docking interactions through which peptide agonists activate their receptors are less well characterized2-7. The thrombin receptor is a specialized peptide receptor. It is activated by binding its tethered ligand domain, which is unmasked upon receptor cleavage by thrombin8,9. Human and Xenopus thrombin receptor homologues are each selectively activated by the agonist peptide representing their respective tethered ligand domains. Here we identify receptor domains that confer this agonist specificity by replacing the Xenopus receptor's amino-terminal exodomain and three extracellular loops with the corresponding human structures. This switches receptor specificity from Xenopus to human. The specificity of these thrombin receptors for their respective peptide agonists is thus determined by their extracellular surfaces. Our results indicate that agonist interaction with extracellular domains is important for thrombin receptor activation.

Gerszten, Robert E.; Chen, Ji; Ishli, Maki; Ishil, Kenji; Wang, Ling; Nanevicz, Tania; Turck, Christoph W.; Vu, Thien-Khai H.; Coughlin, Shaun R.



A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency  

PubMed Central

Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9?Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general.

Chodorge, M; Zuger, S; Stirnimann, C; Briand, C; Jermutus, L; Grutter, M G; Minter, R R



Antidepressant-like Effects of ? Opioid Receptor Agonists in Animal Models  

PubMed Central

Recently, ? opioid receptor agonists have been proposed to be attractive targets for the development of novel antidepressants. Several studies revealed that single treatment of ? opioid receptor agonists produce antidepressant-like effects in the forced swimming test, which is one of the most popular animal models for screening antidepressants. In addition, subchronic treatment with ? opioid receptor agonists has been shown to completely attenuate the hyperemotional responses found in olfactory bulbectomized rats. This animal model exhibits hyperemotional behavior that may mimic the anxiety, aggression, and irritability found in depressed patients, suggesting that ? opioid receptor agonists could be effective in the treatment of these symptoms in depression. On the other hand, prototype ? opioid receptor agonists produce convulsive effects, which limit their therapeutic potential and clinical development. In this review, we presented the current knowledge regarding the antidepressant-like effects of ? opioid receptor agonists, which include some recently developed drugs lacking convulsive effects.

Saitoh, Akiyoshi; Yamada, Mitsuhiko



La planification pr?alable des soins pour les patients en p?diatrie  

PubMed Central

RÉSUMÉ Les progrès médicaux et technologiques ont permis d’ac-croître les taux de survie et d’améliorer la qualité de vie des nourrissons, des enfants et des adolescents ayant des maladies chroniques mettant la vie en danger. La planifi-cation préalable des soins inclut le processus relié aux discussions sur les traitements essentiels au maintien de la survie et la détermination des objectifs des soins de longue durée. Les dispensateurs de soins pédiatriques ont l’obligation éthique d’assimiler cet aspect des soins médicaux. Le présent document de principes vise à aider les dispensateurs de soins à discuter de la planification préalable des soins des patients pédiatriques dans diverses situations. La planification préalable des soins exige des communications efficaces afin de clarifier les objectifs des soins et de s’entendre sur les traitements pertinents ou non pour réaliser ces objectifs, y compris les mesures de réanimation et les mesures palliatives.



Room air entrainment during beta-agonist delivery with heliox.  


Studies of the efficacy of heliox in patients with severe asthma have shown mixed results. Among the factors that are responsible for variable outcomes, the failure of heliox delivery systems to prevent room air entrainment (RAE) during beta-agonist delivery is probably the most critical. While keeping the rotameter flow rate (FR) of heliox mixed 70:30 to a nebulizer at 10 L/min, the FR of heliox from a second gas source to a T-connector (TC) was increased during the delivery of the beta-agonist with a conventional T-nebulizer delivery system (TNDS). A negative peak inspiratory flow (pneumotachometer reading) or a helium concentration of < 70% (quadralizer reading) were indicators of RAE. RAE was tested during spontaneous tidal breathing and acute asthma. A rotameter FR of 10 L/m to the nebulizer with no flow from a second gas source to a TC (conventional TNDS) resulted in a significant drop in helium concentration during tidal breathing (46.2%) and acute asthma (27.5%) due to RAE. This degree of helium dilution can negate the beneficial effects of heliox to lung mechanics almost completely. A rotameter FR of 10 L/m each to a nebulizer and a TC resulted in a helium concentration 69.8% during tidal breathing (no RAE), but 49% (significant RAE) during asthma events. A rotameter FR of 15 L/m (pressure regulator setting, 100 lbs per square inch) to a TC, while maintaining a rotameter FR of 10 L/m to a nebulizer prevented RAE during asthma (helium concentration, 69.9%). Conventional TNDS may be used to deliver the beta-agonist with heliox during asthma without RAE. PMID:17035439

Dhuper, Sunil; Choksi, Sonia; Selvaraj, Simdararajan; Jha, Gautam; Ahmed, Aziz; Babbar, Harsh; Walia, Baljit; Chandra, Alpana; Chung, Virginia; Shim, Chang



Spinal cord pharmacology of adrenergic agonist-mediated antinociception.  


Intrathecal administration of norepinephrine (NE) and alpha adrenergic agonists in rats with chronic spinal catheters produced a significant elevation of the nociceptive threshold as measured by hot plate and tail flick. The intrathecal NE effect was dose-dependent and antagonized in a competitive fashion by pretreatment with phentolamine (alpha antagonist) but not by propranolol (beta antagonist). Intrathecal administration of isoproterenol (beta agonist) did not alter the nociceptive threshold. Effective doses of intrathecal NE did not produce demonstrable motor effects. Doses 20 times greater than the maximum analgesic dose produced marked weakness of the hindlimbs and tails. The intrathecal NE effect was not antagonized by intrathecal papaverine of bradykinin (vasodilators) or mimicked by angiotensin-II (vasoconstrictor). The intrathecal NE effect was not altered by intrathecal administration of subconvulsant doses of either picrotoxin (gamma-aminobutyric acid antagonist) or strychnine (glycine antagonist) or by i.p. administration of either naloxone (opiate antagonist) or methysergide (serotinin antagonist). The nociceptive threshold was significantly decreased 1 week after intrathecal administration of 6-hydroxydopamine, which depleted spinal cord NE by 85%. Intrathecal administration of tyramine (indirectly acting sympathomimetic amine) produced an elevation of the nociceptive threshold in a control group of animals but was less effective in animals pretreated with intrathecal 6-hydroxydopamine. The tyramine effect was antagonized by intrathecal phentolamine. Intravenous administration of aminophylline (phosphodiesterase inhibitor) did not potentiate the intrathecal NE effect. The relative antinociceptive potencies of alpha adrenergic agonists after intrathecal administration were: l-norepinephrine = dl-epinephrine greater than dl-alpha-methyl norepinephrine greater than clonidine greater than or equal to l-phenylephrine greater than or equal to 3,4-dihydroxytolazoline greater than or equal to oxymetazoline. The relative potencies of intrathecally administered alpha antagonists in antagonizing the intrathecal NE effect were: phentolamine greater than phenoxybenzamine greater than tolazoline greater than or equal to yohimbine. PMID:6110767

Reddy, S V; Maderdrut, J L; Yaksh, T L



Effect of pindolol on hormone secretion and body temperature: Partial agonist effects  

Microsoft Academic Search

Summary Pindolol has been shown to be a partial agonist at 5-HT1a receptors in preclinical studies. It has also been reported to inhibit the effects of other 5-HT1a partial agonists such as ipsapirone and buspirone on hormone secretion and body temperature in man, indicating its antagonist action at 5-HT1a receptors in man. To determine if pindolol has 5-HT1a agonist as

H. Y. Meltzer; M. Maes



Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.  


Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a. PMID:19410460

Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Parks, Derek J; Todd, Dan; Williams, Shawn P; Wisely, G Bruce



Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy  

Microsoft Academic Search

The effect of CB-1 and CB-2 receptor agonists, as well as an influence of a non-selective inhibitor of nitric oxide synthase (NOS), L-NOArg, and an inhibitor acting preferentially on cyclooxygenase-1 (COX-1), indomethacin, on the action of cannabinoid receptor agonists in a streptozotocin (STZ)-induced neuropathic model was investigated. When administered alone, a non-selective cannabinoid receptor agonist, WIN 55,212-2, a potentially selective

Magdalena Bujalska



Dissociation of Hippocampus and Caudate Nucleus Memory Systems by Posttraining Intracerebral Injection of Dopamine Agonists  

Microsoft Academic Search

The effect of posttraining intracerebral injections of the indirect dopamine (DA) agonist d-amphetamine, the direct D2 agonist LY 171555, and the direct D1 agonist SKF-38393 on the acquisition of two 8-arm radial maze tasks were examined. On a win–stay task, a light cue signaled the location of food in 4 randomly selected maze arms on each trial, and animals were

Mark G. Packard; Norman M. White



Neurochemical analysis of rat strain differences in the startle gating-disruptive effects of dopamine agonists  

Microsoft Academic Search

The disruption of prepulse inhibition (PPI) in rats by dopamine (DA) agonists is used to study the neural basis of strain differences in dopaminergic function. We reported that, compared to Long–Evans (LEH) rats, Sprague–Dawley (SDH) rats are more sensitive to the PPI-disruptive effects of the direct D1\\/D2 agonist apomorphine (APO) and the indirect DA agonist d-amphetamine (AMPH). This strain difference

Neal R. Swerdlow; Ronald Kuczenski; Jana C. Goins; Sarah K. Crain; Lillian T. Ma; Michele J. Bongiovanni; Jody M. Shoemaker



Synthesis and biological evaluation of novel 2,4-disubstituted quinazoline analogues as GPR119 agonists.  


GPR119 agonist has emerged as a promising target for the treatment of type 2 diabetes. A series of novel 2,4-disubstituted quinazoline analogues was prepared and evaluated their agonistic activity against human GPR119. The analogues bearing azabicyclic amine substituents (12a, 12c and 12g) exhibited better EC(50) values than that of OEA though they appeared to be partial agonists. PMID:23357035

Pham, Tuan-Anh N; Yang, Zunhua; Fang, Yuanying; Luo, Jun; Lee, Jongkook; Park, Haeil



Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064  

SciTech Connect

Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)



Protective effects of a peroxisome proliferator-activated receptor-?\\/? agonist in experimental autoimmune encephalomyelitis  

Microsoft Academic Search

Agonists of the peroxisome proliferator-activated receptor gamma (PPAR?) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In contrast, the effect of PPARdelta (PPAR?) agonists in EAE is not yet known. We show that oral administration of the selective PPAR? agonist GW0742 reduced clinical symptoms in C57BL\\/6

Paul E. Polak; Sergey Kalinin; Cinzia Dello Russo; Vitaliy Gavrilyuk; Anthony Sharp; Jeffrey M. Peters; Jill Richardson; Tim M. Willson; Guy Weinberg; Douglas L. Feinstein



Magnesium Ions and Opioid Agonist Activity in Streptozotocin-Induced Hyperalgesia  

Microsoft Academic Search

Streptozotocin-induced hyperglycemia accompanied by a chronic decrease in the nociceptive threshold is considered a useful model of experimental hyperalgesia. We examined (1) the effect of the opioid receptor agonists and (2) the effect of the magnesium ions (Mg2+) on the antinociceptive action of opioid agonists in a diabetic neuropathic pain model. When administered alone, opioid agonists like morphine (5 mg\\/kg

Magdalena Bujalska; Ewelina Malinowska; Helena Makulska-Nowak



PPAR-a and -g agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse  

Microsoft Academic Search

Backgound. Peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g agonists are widely used in diabetes. In addition to their effects on lipid and glucose homeostasis, these agents have been postulated to have independent renoprotective actions. In the current study, we assess the efficacy of the PPAR-a agonist, gemfibrozil, the PPAR-g agonist rosiglitazone and the non-thiazolidinedione PPAR-a\\/g coagonist, compound 3q, on kidney structure

Anna C. Calkin; Sara Giunti; Karin A. Jandeleit-Dahm; Terri J. Allen; Mark E. Cooper; Merlin C. Thomas



Opioid agonist and antagonist treatment differentially regulates immunoreactive ?-opioid receptors and dynamin-2 in vivo  

Microsoft Academic Search

Opioid agonists and antagonists can regulate the density of ?-opioid receptors in whole animal and in cell culture. High intrinsic efficacy agonists (e.g., etorphine), but not lower intrinsic efficacy agonists (e.g., morphine), produce ?-opioid receptor down-regulation and can alter the abundance of ?-opioid receptor mRNA. Conversely, opioid antagonists substantially increase the density of ?-opioid receptors without changing its mRNA. ?-Opioid

Byron C. Yoburn; Vishal Purohit; Kaushal Patel; Qiuyu Zhang



[New innate immunity receptor agonists from sea hydrobionts].  


Scientific data and data obtained by us regarding new innate immunity receptor agonists from sea hydrobionts are presented. Highly efficient and low toxic biologically active substances isolated from sea organisms are inductors of dendritic cells maturation, activate neutrophils, monocytes/macrophages and NK-cells, have an anticomplementary (fucoidans) and pro- and anti-inflammatory effects. Protective properties of biologically active substances are exhibited when various pathogens entering the organism--bacteria, viruses, protozoa, fungi. These substances may become a basis for the creation of new pharmaceutical preparations. PMID:22145361

Besednova, N N; Zaporozhets, T S


Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment  

Microsoft Academic Search

Rationale  Using biological markers to objectively measure addiction severity or to identify individuals who might benefit most from\\u000a pro-cognitive treatment could potentially revolutionize neuropsychopharmacology. We investigated the use of dopamine receptor\\u000a mRNA levels in circulating blood cells as predictors of cognitive response following dopamine agonist treatment, and as biomarkers\\u000a of the severity of stimulant drug dependence.\\u000a \\u000a \\u000a \\u000a \\u000a Methodology  We employed a double-blind, placebo-controlled

Karen D. Ersche; Jonathan P. Roiser; Mark Lucas; Enrico Domenici; Trevor W. Robbins; Edward T. Bullmore



Discriminative stimulus properties of the serotonin agonist MK 212  

Microsoft Academic Search

In an attempt to clarify the role of 5-hydroxytryptamine (5-HT) in the discriminative stimulus properties of MK 212 (6-chloro-2[1-piperazinyl]pyrazine), male Sprague-Dawley rats were trained to discriminate 0.5 mg\\/kg of this compound from saline. While the putative 5-HT agonists fenfluramine and m-chlorophenylpiperazine (MCPP) mimicked MK 212 in a dose-related manner, d-lysergic acid diethylamide (LSD), 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, Ru 24969,

K. A. Cunninghaln; P. M. Callahan; J. B. Appel



Esquisses de répartition des revenus pour 1985  

Microsoft Academic Search

[fre] Esquisses de répartition des revenus pour 1985 par Edgard Andréani . Cet article fait suite à un autre, les « Esquisses de croissance pour 1985 », paru dans cette même revue en septembre 1970 (n° 15). Ces esquisses décrivaient cinq évolutions possibles de l'économie française d'ici 1985 mais elles ne chiffraient que les conditions physiques de l'équilibre. Le chiffrement

Edgard Andréani



Analyse des mécanismes de détermination du chômage  

Microsoft Academic Search

[fre] Depuis 1965, la France, comme les pays membres de l'OCDE, est confrontée à une progression du chômage. Cette montée plus ou moins lente et régulière comporte des accélérations conjoncturelles suivies de pauses, voire de replis. Parallèlement les créations d'emplois semblent moins à même que par le passé de résorber le chômage. Comprendre ce mouvement implique de prendre en considération

Robert Salais



Maximalintensität und Breite der Hauptserienlinien des Natriums  

Microsoft Academic Search

Zusammenfassung Die Intensität und Breite der Hauptserienlinien des Natriums wurden in Absorption untersucht. Innerhalb der Serie nimmt der maximale Absorptionskoeffizient und die Halbwertsbreite der Linien mit wachsender Gliednummer rasch ab, die Halbwertsbreite ein wenig rascher als der Absorptionskoeffizient. Die Breite der Linien wird wesentlich durch die Natriumdampfkonzentration, in geringerem Maße durch den totalen Gasdruck, bestimmt, was durch die Lorentzsche Stoßdämpfung

B. Trumpy



Abdeckung und Aktualität des Suchdienstes Google Scholar  

Microsoft Academic Search

Der Beitrag widmet sich dem neuen Google-Suchdienst Google Scholar. Die Suchmaschine, die ausschließlich wissenschaftliche Dokumente durchsuchen soll, wird mit ihren wichtigsten Funktionen beschrieben und anschließend einem empirischen Test unterzogen. Die durchgeführte Studie basiert auf drei Zeitschriftenlisten: Zeitschriften von Thomson Scientific, Open Access-Zeitschriften des Verzeichnisses DOAJ und in der Fachdatenbank SOLIS ausgewertete sozialwissenschaftliche Zeitschriften. Die Abdeckung dieser Zeitschriften durch Google Scholar

Philipp Mayr; Anne-Kathrin Walter


Rekonstruktion des vorderen Kreuzbandes bei Kindern  

Microsoft Academic Search

Zusammenfassung Operationsziel Rekonstruktion des vorderen Kreuzbandes bei Kindern ohne dauerhafte Schädigung der Wachstumsfugen an Tibia und Femur. Die distal gestielte Semitendinosussehne wird durch einen Bohrkanal in der medialen tibialen Epiphyse eingezogen, dann durch das Gelenk hinter den lateralen Femurkondylus geführt und an seiner Außenseite mit einer Krampe fixiert. Indikationen Symptomatische oder chronische Knieinstabilität als Folge einer vorderen Kreuzbandruptur. Eingeschränkte Kniegelenkfunktion.

R. Merv Letts; Darin Davidson; Ari Pressman



Bestimmung des Methanolgehaltes im Sprit mit Chromotropsäure  

Microsoft Academic Search

Zusammenfassung Die Eignung der Bremanis-Methode für die Bestimmung des Methanolgehaltes im Sprit wurde geklärt. Besondere Beachtung wurde geschenkt der Äthanolkonzentration, der Erhitzungstemperatur und -dauer, der Schwefelsäure- und Chromotropsäure-Konzentration, dem Alter der Chromotropsäurelösung sowie der Oxydationszeit und der Stabilität der Farbe der Reaktionslösung zwecks Erreichung optimaler Bedingungen.

Lauri Uino; Tapio Salo



Zur Behandlung der Glomustumoren des Mittelohres  

Microsoft Academic Search

Zusammenfassung Die Glomustumoren des Mittelohres werden in ihrer klinischen Erscheinungsform geschildert, wobei besonders die Frühsymptome Berücksichtigung finden; denn diese müssen Veranlassung geben, eine alsbaldige operative Behandlung vorzunehmen, damit der Eintritt von Nachbarschaftsbeteiligung wie Labyrintheinbruch und Hirnnervenbeteiligung verhütet wird. Die chirurgische Beseitigung der Glomustumoren auf transmeatalem Wege oder durch Radikaloperation ist deshalb erfolgversprechend, weil es sich um histologisch gutartige Wucherungen glomerulär

K. Handl; K. W. Hommerich



Differential Cryptanalysis of DES-like Cryptosystems  

Microsoft Academic Search

The Data Encryption Standard (DES) is the best known and most widely used cryptosystem for civilian applications. It was developed at IBM and adopted by the National Bureau of Standards in the mid 1970s, and has successfully withstood all the attacks published so far in the open literature. In this paper we develop a new type of cryptanalytic attack which

Eli Biham; Adi Shamir



Chronique des tendances de la société française  

Microsoft Academic Search

[fre] Cette chronique porte sur des transformations au sein de la population active, sur la scolarisation régionale en France et la religion en Europe occidentale : • Naguère les pères de famille étaient « protégés » du chômage. Depuis cinq ans, ils ne le sont plus et il s'en suit une inquiétude qui pourrait avoir une influence sur le taux

Louis Chauvel; Jean-Pierre Jaslin; Laurent Mucchielli; Carole Rivière; Irène Fournier



Stratégies de localisation résidentielle des ménages et mobilité domicile-travail  

Microsoft Academic Search

PROBLEMATIQUE - Ces dernières décennies ont été fortement marquées en France par le mouvement bien identifié de la périurbanisation. Cette expansion urbaine s'accompagne d'une reconfiguration des localisations des fonctions urbaines, entraînant une modification des déplacements qui leur sont liés. Largement confortée par le spectaculaire développement de la motorisation, elle pose des problèmes de maîtrise des flux dans la mesure où

Odile Andan; Pascal Pochet; Jean-Louis Routhier; Scheou Bernard



Modelisations des effets de surface sur les jets horizontaux subsoniques d'hydrogene et de methane  

Microsoft Academic Search

Le developpement des codes et de normes bases sur une methodologie scientifique requiert la capacite de predire l'etendue inflammable de deversements gazeux d'hydrogene sous differentes conditions. Des etudes anterieures ont deja etabli des modeles bases sur les lois de conservation de la mecanique des fluides basees sur des correlations experimentales qui permettent de predire la decroissance de la concentration et

Luis Fernando Gomez



Methodes iteratives paralleles: Applications en neutronique et en mecanique des fluides  

Microsoft Academic Search

Dans cette these, le calcul parallele est applique successivement a la neutronique et a la mecanique des fluides. Dans chacune de ces deux applications, des methodes iteratives sont utilisees pour resoudre le systeme d'equations algebriques resultant de la discretisation des equations du probleme physique. Dans le probleme de neutronique, le calcul des matrices des probabilites de collision (PC) ainsi qu'un

Abdessamad Qaddouri



Calcul Matriciel Appliqué Aux Couches Minces élaboration des dérivées Partielles du Coefficient de Réflexion  

Microsoft Academic Search

Faute de pouvoir déterminer des tolérances de fabrication convenables, la réalisation de filtres optiques se heurte au problème de leur reproductibilité. Il ne peut être résolu que par la connaissance, a priori, des fluctuations sur les caractéristiques des revêtements qui sont provoquées par des variations d'épaisseur ou d'indice dans les différentes couches déposées. La détermination des dérivées partielles par rapport

Jacques Mouchart



Behemoth als Partner und Feind des Leviathan: zur politischen Ikonologie eines Monstrums  

Microsoft Academic Search

Zu den mächtigsten Bildern des Alten Testamentes gehören die beiden Monstra des Leviathan und des Behemoth, die Gott vor dem aufbegehrenden Hiob erscheinen läßt, um seine Macht zu demonstrieren. Während das Symbol des Leviathan als hobbesches Urbild des modernen Staates immer wieder erforscht worden ist, trifft dies auf den Behemoth weniger zu. Ausgehend von William Blakes Darstellungen der beiden Monstra

Horst Bredekamp



Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria  

SciTech Connect

In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-(/sup 125/I)iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants.

Molenaar, P.; Malta, E.



[Protective effect of adrenergic alpha 2-receptor agonists in hypoxic hypoxia].  


The antihypoxic effect of alpha 2-adrenoceptor agonists was studied by two different approaches: reproduction of the effect by a number of alpha 2-agonists and its blockade with selective antagonists. The data obtained suggest that alpha 2-adrenoceptor agonists increase the survival and the lifespan of mice in all the models of acute hypoxic hypoxia under study. A close correlation between antihypoxic action of alpha 2-adrenoceptor agonists and their anticalorigenic effect was established (r = +0.87; P less than 0.01). PMID:2873847

Kulinski?, V I; Ol'khovski?, I A; Kovalevski?, A N



Nouvelle approche ? la prise en charge des condylomes  

PubMed Central

Résumé Objectif Faire le résumé des anciens et des nouveaux moyens de traitement des verrues génitales ou condylomes et déterminer comment les utiliser de manière appropriée. Sources des données Une recherche documentaire a été effectuée dans les bases de données suivantes: MEDLINE, PubMed, EMBASE, base de données des synthèses systématiques et registre central des études contrôlées de la Collaboration Cochrane (en anglais), ACP Journal Club et Trip. Les bibliographies des articles extraits ont aussi été examinées. Les études cliniques, les articles de révision qualitative, les rapports consensuels et les guides de pratique clinique ont été retenus. Message principal Les verrues symptomatiques sont présentes chez au moins 1 % des personnes âgées entre 15 et 49 ans et on estime que jusqu’à 50 % des gens sont infectés par le virus du papillome humain à un moment donné de leur vie. L’imiquimod et la podophyllotoxine sont 2 nouveaux traitements pour les verrues génitales externes qui sont moins douloureux et peuvent être appliqués par les patients à la maison. De plus, il a été démontré que le vaccin quadrivalent contre le virus du papillome humain est efficace pour prévenir les condylomes et le cancer du col. Les plus anciennes méthodes thérapeutiques ont aussi leur place dans certaines situations, comme les verrues intravaginales, urétrales, anales ou récalcitrantes ou encore pour les patientes enceintes. Conclusion Les nouveaux traitements des verrues génitales externes peuvent réduire la douleur causée par la thérapie et le nombre de visites au cabinet. Les autres méthodes thérapeutiques demeurent utiles dans certaines situations.

Lopaschuk, Catharine C.



Impact of muscarinic agonists for successful therapy of Alzheimer's disease.  


The M1 muscarinic agonists AF102B, AF150(S) & AF267B--i) restored cognitive impairments in several animal models for AD with an excellent safety margin; ii) elevated alpha-APPs levels; iii) attenuated vicious cycles induced by A beta, and inhibited A beta- and oxidative stress-induced apoptosis; and iv) decreased tau hyperphosphorylation. AF150(S) and AF267B were more effectve than rivastigmine and nicotine in restoring memory impairments in mice with small hippocampi. In apolipoprotein E-knockout mice, AF150(S) restored cognitive impairments and cholinergic hypofunction and decreased tau hyperphosphorylation. In aged microcebes, AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, paired helical filaments and astrogliosis. In rabbits, AF267B & AF150(S) decreased CSF A beta(1-42 & 1-40), while AF102B reduced A beta(1-40). Finally AF102B decreased CSF A beta(total) in AD patients. Taken together, M1 agonists may represent a unique therapy in AD due to their beneficial effects on three major hallmarks of AD--cholinergic hypofunction, A beta and tau protein hyperphosphorylation. PMID:12456063

Fisher, A; Brandeis, R; Haring, R; Bar-Ner, N; Kliger-Spatz, M; Natan, N; Sonego, H; Marcovitch, I; Pittel, Z



Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.  


For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo



2-Bromomelatonin: synthesis and characterization of a potent melatonin agonist.  


A practical synthesis of N-[2-(2-bromo-5-methoxy-1H-indol-3-yl)ethyl]- acetamide (2-bromomelatonin) was achieved by direct bromination of melatonin with N-bromosuccinimide (NBS) in anhydrous acetic acid at room temperature under nitrogen, followed by flash-chromatography. 1H-NMR and mass spectra showed the bromine to be incorporated at the C-2 position of the indole moiety. Tests performed in vitro with isolated melatonin receptors from rabbit parietal cortex demonstrated that the relative binding affinity of 2-bromomelatonin was about ten times higher than that of melatonin and close to that of 2-iodomelatonin. 2-Bromomelatonin behaved as a potent agonist in the physiological studies. It showed enhanced activity in inhibiting the spontaneous firing activity of cortical neurons and similarly to melatonin and 2-iodomelatonin potentiated significantly the inhibitory effect of GABA. 2-Bromomelatonin was also an extremely effective agonist in the tests performed in vivo in the Syrian hamster gonadal regression model. PMID:1322481

Duranti, E; Stankov, B; Spadoni, G; Duranti, A; Lucini, V; Capsoni, S; Biella, G; Fraschini, F




PubMed Central

Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-? (PPAR-?), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-? in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-? agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-? expression and activation of NF-?B in small intestine. Pretreatment with PPAR-? agonist, 15d-PGJ2, attenuated intestinal NF-?B response and I/R-induced gut injury. Activation of PPAR-? demonstrated a protective effect on small bowel during I/R-induced gut injury.

Baregamian, Naira; Mourot, Joshua M.; Ballard, Amie R.; Evers, B. Mark; Chung, Dai H.



The biology of thrombopoietin and thrombopoietin receptor agonists.  


Thrombopoietin (TPO) is the major physiological regulator of platelet production. TPO binds the TPO receptor, activates JAK and STAT pathways, thus stimulating megakaryocyte growth and platelet production. There is no "sensor" of the platelet count; rather TPO is produced in the liver at a constant rate and cleared by TPO receptors on platelets. TPO levels are inversely proportional to the rate of platelet production. Early recombinant TPO molecules were potent stimulators of platelet production and increased platelets in patients with immune thrombocytopenia, chemotherapy-induced thrombocytopenia, myelodysplastic syndromes and platelet apheresis donors. Neutralizing antibodies formed against one recombinant protein and ended their development. A second generation of TPO receptor agonists, romiplostim and eltrombopag, has been developed. Romiplostim is an IgG heavy chain into which four TPO agonist peptides have been inserted. Eltrombopag is an oral small molecule. These activate the TPO receptor by different mechanisms to increase megakaryocyte growth and platelet production. After administration of either to healthy volunteers, there is a delay of 5 days before the platelet count rises and subsequently reaches a peak after 12-14 days. Both have been highly effective in treating ITP and hepatitis C thrombocytopenia. Studies in a wide variety of other thrombocytopenic conditions are underway. PMID:23821332

Kuter, David J



Cold suppresses agonist-induced activation of TRPV1.  


Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

Chung, M-K; Wang, S



A rationally designed agonist antibody fragment that functionally mimics thrombopoietin  

PubMed Central

By using rational design, antibody fragments (Fabs) that mimic thrombopoietin (TPO) were created. A peptide with cMpl receptor-binding capability was grafted into different complementarity-determining regions of a fully human Fab scaffold. Functional presentation of the peptide was optimized by using phage display and cell-based panning. Select antibodies and fragments containing two grafted peptides were assayed for their ability to stimulate the cMpl receptor in vitro. Several candidates demonstrated agonist activity in an in vitro cMpl receptor signaling reporter assay, including Fab59, which was estimated to be equipotent to TPO. Fab59 additionally was able to effectively stimulate platelet production in normal mice. These rationally designed mimetic Fabs may provide a therapeutic intervention for thrombocytopenia while avoiding the potential generation of neutralizing antibodies to endogenous TPO. Furthermore, this study demonstrates a method by which short-lived linear peptides with binding activity may be converted to more stable and potent agonists capable of activating cell surface receptors.

Frederickson, Shana; Renshaw, Mark W.; Lin, Bing; Smith, Lynette M.; Calveley, Peter; Springhorn, Jeremy P.; Johnson, Krista; Wang, Yi; Su, Xiao; Shen, Yamin; Bowdish, Katherine S.



Role of steroids in croup and beta agonists in bronchiolitis.  


The administration of corticosteroids by various routes in the treatment of croup remains controversial as studies with varying designs and outcome measures have reported conflicting results. However, meta-analysis supports the use of steroids in croup. A dose equivalent to or greater than 100 mg/kg body weight of hydrocortisone, administered orally or parenterally appears to be effective. Nebulized budesonide in a dose of 1,000 micrograms, when dosages are given 30 minutes apart is also effective. The L-epinephrine is as effective as racemic epinephrine and should be used to relieve symptoms with or without steroids. Summarizing the value of beta agonists, for treatment of bronchiolitis is rather challenging. Beta agonists offer significant relief to only a subgroup of infants, with bronchiolitis, albeit, it remains a challenge to identify these infants prospectively. Availability of RSV immune globulin for prevention of RSV disease in high-risk infants and better defining the role of ribavirin for selected patients may offer additional avenues to the treating physician. PMID:10830025

Veerappan, A; Kumar, A


Abondance et stratification verticale des elements dans l'atmosphere des etoiles mercure-manganese  

NASA Astrophysics Data System (ADS)

Les étoiles mercure-manganèse appartiennent à la famille des étoiles chimiquement particulières. Elles présentent d'importants excès de mercure et de manganèse par rapport au soleil. Ces anomalies d'abondance sont généralement expliquées par la théorie de la diffusion atomique, jouant possiblementun rôle important au sein de leurs atmosphères. Cette thèse a pour but, dans un premier temps, de déterminer les abondances d'un grand nombre d'éléments (C, O, Mg, Si, P, S, Ca, Sc, Ti, Cr, Mn, Fe, Sr, Hg) peuplant l'atmosphère de quatre étoiles mercure-manganèse (HD 71066, HD 175640, HD 178065 et HD 221507). La seconde étape consiste à vérifier la présence d'une quelconque dépendance de l'abondance de ces éléments par rapport à la profondeur de formation des raies. Une variation de l'abondance par rapport à la profondeur, c'est-à-dire stratification, apporterait la preuve observationnelle de la présence de la diffusion atomique au sein de l'atmosphère de ces étoiles, ainsi que des contraintes servant à l'amélioration des modèles théoriques. Les spectres des étoiles étudiées sont obtenus à partir de l'archive de l'ESO- UVES. Les raies investiguées se situent à des longueurs d'onde plus grandes que celle du saut de Balmer oû le signal sur bruit, après normalisation, est supérieur à 300. Parmi les quatre étoiles investiguées, uniquement de la stratification du manganèse a été découverte dans l'atmosphère de l'étoile HD 178065. L'abondance du manganèse augmente significativement (environ 0.7 dex) sur l'intervalle t 5000 sondé entre -3.8 et -2.5. Ceci est la première détection de stratification du manganèse dans une étoile de type HgMn. Pour HD 175640, des indices de stratification du manganèse existent, mais l'étude d'autres spectres aiderait à confirmer ou non, la stratification de cet élément.

Thiam, Mouhamadou


Impact of Secondary Structure of Toll-Like Receptor 9 Agonists on Interferon Alpha Induction ?  

PubMed Central

Oligodeoxynucleotides containing a CpG motif and double- or multistranded structure-forming sequences act as agonists of Toll-like receptor 9 (TLR9) and induce high levels of interferon alpha (IFN-?) in addition to other Th1-type cytokines. In the present study, we evaluated three highly effective IFN-?-inducing agonists of TLR9 to determine the type of duplex structures formed and the agonist's ability to induce immune responses, including IFN-? induction, in human cell-based assays and in vivo in mice and nonhuman primates. Thermal melting studies showed that two of the agonists evaluated had a single melting transition with similar hyperchromicity in both heating and cooling cycles, suggesting the formation of intermolecular duplexes. A third agonist showed a biphasic melting transition in the heating cycle and a monophasic melting transition with lower hyperchromicity during the cooling cycle, suggesting the formation of both intra- and intermolecular duplexes. All three agonists induced the production of Th1-type cytokines and chemokines, including high levels of IFN-?, in human peripheral blood mononuclear cell and plasmacytoid dendritic cell cultures. Subcutaneous administration of the two intermolecular duplex-forming agonists, but not the intramolecular duplex-forming agonist, induced cytokine secretion in mice. In nonhuman primates, the two agonists that formed intermolecular duplexes induced IFN-? and IP-10 secretion. On the contrary, the agonist that formed an intramolecular duplex induced only low levels of cytokines in nonhuman primates, suggesting that this type of structure formation is less immunostimulatory in vivo than the other structure. Taken together, the present results suggest that oligonucleotide-based agonists of TLR9 that form intermolecular duplexes induce potent immune responses in vivo.

Yu, Dong; Putta, Mallikarjuna R.; Bhagat, Lakshmi; Dai, Meiru; Wang, Daqing; Trombino, Anthony F.; Sullivan, Tim; Kandimalla, Ekambar R.; Agrawal, Sudhir



Les effets des interfaces sur les proprietes magnetiques et de transport des multicouches nickel/iron et cobalt/silver  

NASA Astrophysics Data System (ADS)

Cette these est consacree a l'etude de l'evolution structurale des proprietes magnetiques et de transport des multicouches Ni/Fe et nanostructures a base de Co et de l'Ag. Dans une premiere partie, essentiellement bibliographique, nous introduisons quelques concepts de base relies aux proprietes magnetiques et de transport des multicouches metalliques. Ensuite, nous presentons une breve description des methodes d'analyse des resultats. La deuxieme partie est consacree a l'etude des proprietes magnetiques et de transport des multicouches ferromagnetiques/ferromagnetiques Ni/Fe. Nous montrerons qu'une interpretation coherente de ces proprietes necessite la prise en consideration des effets des interfaces. Nous nous attacherons a mettre en evidence, a evaluer et a etudier les effets de ces interfaces ainsi que leur evolution, et ce, suite a des traitements thermiques tel que le depot a temperature elevee et l'irradiation ionique. Les analyses correlees de la structure et de la magnetoresistance nous permettront d'emettre des conclusions sur l'influence des couches tampons entre l'interface et le substrat ainsi qu'entre les couches elles-memes sur le comportement magnetique des couches F/F. La troisieme partie est consacree aux systemes a Magneto-Resistance Geante (MRG) a base de Co et Ag. Nous allons etudier l'evolution de la microstructure suite a l'irradiation avec des ions Si+ ayant une energie de 1 MeV, ainsi que les effets de ces changements sur le comportement magnetique. Cette partie debutera par l'analyse des proprietes d'une multicouche hybride, intermediaire entre les multicouches et les materiaux granulaires. Nous analyserons a l'aide des mesures de diffraction, de relaxation superparamagnetique et de magnetoresistance, les evolutions structurales produites par l'irradiation ionique. Nous etablirons des modeles qui nous aideront a interpreter les resultats pour une serie des multicouches qui couvrent un large eventail de differents comportements magnetiques et ceci en fonction de l'epaisseur de la couche magnetique de Co. Nous verrons que dans ces systemes les effets de l'irradiation ionique sont fortement influences par l'energie de surface ainsi que par l'enthalpie de formation, largement positive pour le systeme Co/Ag.

Veres, Teodor


Verhalten von Metaboliten des Fettstoffwechsels im Serum adipöser und nichtadipöser Personen unter Grundumsatzbedingungen  

Microsoft Academic Search

Zusammenfassung Bei 60 nichtadipösen und 48 adipösen Personen ohne wesentliche Begleitkrankheiten wurden die Blutkonzentrationen der freien Fettsäuren, des freien Glycerins, des Acetacetats, der veresterten Fettsäuren und des Blutzuckers unter Grundumsatzbedingungen bestimmt.

K. Jahnke; F. A. Gries; H. Wallenfels; H. Schulte



Enhanced BRET Technology for the Monitoring of Agonist-Induced and Agonist-Independent Interactions between GPCRs and ?-Arrestins.  


The bioluminescence resonance energy transfer (BRET) technique has become extremely valuable for the real-time monitoring of protein-protein interactions in live cells. This method is highly amenable to the detection of G protein-coupled receptor (GPCR) interactions with proteins critical for regulating their function, such as ?-arrestins. Of particular interest to endocrinologists is the ability to monitor interactions involving endocrine receptors, such as orexin receptor 2 or vasopressin type II receptor. The BRET method utilizes heterologous co-expression of fusion proteins linking one protein of interest (GPCR) to a bioluminescent donor enzyme, a variant of Renilla luciferase, and a second protein of interest (?-arrestin) to an acceptor fluorophore. If in close proximity, energy resulting from oxidation of the coelenterazine substrate by the donor will transfer to the acceptor, which in turn fluoresces. Using novel luciferase constructs, we were able to monitor interactions not detectable using less sensitive BRET combinations in the same configuration. In particular, we were able to show receptor/?-arrestin interactions in an agonist-independent manner using Rluc8-tagged mutant receptors, in contrast to when using Rluc. Therefore, the enhanced BRET methodology has not only enabled live cell compound screening as we have recently published, it now provides a new level of sensitivity for monitoring specific transient, weak or hardly detectable protein-protein complexes, including agonist-independent GPCR/?-arrestin interactions. This has important implications for the use of BRET technologies in endocrine drug discovery programs as well as academic research. PMID:22654789

Kocan, Martina; Dalrymple, Matthew B; Seeber, Ruth M; Feldman, Brian J; Pfleger, Kevin D G



Le traitement familial des enfants et des adolescents anorexiques : Des lignes directrices pour le m?decin communautaire  

PubMed Central

L’anorexie mentale (AM) est une maladie grave qui met la vie en danger et qui fait généralement son apparition pendant l’adolescence. Les données probantes au sujet du traitement optimal de l’AM chez les enfants et les adolescents sont en croissance, mais il reste beaucoup à apprendre. Même si les démarches thérapeutiques actuelles varient au Canada et ailleurs, les données jusqu’à présent indiquent que le traitement familial (TF) est le plus efficace pour les enfants et les adolescents anorexiques. Un élément essentiel du modèle de TF, c’est que les parents sont investis de la responsabilité de rétablir la santé physique de leur enfant et de s’assurer de la reprise complète de son poids. Le médecin qui comprend les principes fondamentaux et la philosophie du TF peut mettre en place les éléments de cette intervention fondée sur des faits probants auprès des jeunes patients anorexiques et de leur famille.

Findlay, S; Pinzon, J; Taddeo, D; Katzman, DK



Investigation of D1 Receptor-Agonist Interactions and D1/D2 Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling  

PubMed Central

The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.

Malo, Marcus; Brive, Lars; Luthman, Kristina; Svenss