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Sample records for normal gonadotropin responsiveness

  1. The aryl hydrocarbon receptor is required for normal gonadotropin responsiveness in the mouse ovary

    SciTech Connect

    Barnett, Kimberly R.; Tomic, Dragana; Gupta, Rupesh K.; Babus, Janice K.; Roby, Katherine F.; Terranova, Paul F.; Flaws, Jodi A.

    2007-08-15

    The aryl hydrocarbon receptor (AHR) mediates the toxicity of a variety of environmental chemicals. Although little is known about the physiological role of the AHR, studies suggest that it plays an important role in regulating ovulation because Ahr deficient (AhRKO) mice have a reduced number of ovulations compared to wild-type (WT) mice. The reasons for the reduced ability of AhRKO mice to ovulate are unknown. Normal ovulation, however, requires estrous cyclicity, appropriate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and LH and FSH responsiveness. Thus, the purpose of this study was to test the hypothesis that Ahr deletion regulates ovulation by altering cyclicity, FSH and LH levels, follicle-stimulating hormone receptor (Fshr) and luteinizing hormone receptor (Lhcgr) levels and/or gonadotropin responsiveness. The data indicate that AhRKO and WT mice have similar levels of FSH and LH, but AhRKO mice have reduced Fshr and Lhcgr mRNA levels compared to WT mice. Furthermore, AhRKO ovaries contain fewer corpora lutea compared to WT ovaries after 5 IU equine chorionic gonadotropin (eCG) treatment. Lastly, both AhRKO and WT mice ovulate a similar number of eggs in response to 5 IU human chorionic gonadotropin (hCG), but AhRKO mice ovulate fewer eggs than WT mice in response to 2.5 IU and 1.25 IU hCG. Collectively, these data indicate that AhRKO follicles have a reduced capacity to ovulate compared to WT follicles and that this is due to reduced responsiveness to gonadotropins. Thus, in addition to mediating toxicity of environmental chemicals, the Ahr is required for normal ovulation.

  2. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling.

    PubMed

    Abedini, Atefeh; Zamberlam, Gustavo; Lapointe, Evelyne; Tourigny, Catherine; Boyer, Alexandre; Paquet, Marilène; Hayashi, Kanako; Honda, Hiroaki; Kikuchi, Akira; Price, Christopher; Boerboom, Derek

    2016-04-01

    Whereas the roles of the canonical wingless-type MMTV (mouse mammary tumor virus) integration site family (WNT) signaling pathway in the regulation of ovarian follicle growth and steroidogenesis are now established, noncanonical WNT signaling in the ovary has been largely overlooked. Noncanonical WNTs, including WNT5a and WNT11, are expressed in granulosa cells (GCs) and are differentially regulated throughout follicle development, but their physiologic roles remain unknown. Using conditional gene targeting, we found that GC-specific inactivation ofWnt5a(but notWnt11) results in the female subfertility associated with increased follicular atresia and decreased rates of ovulation. Microarray analyses have revealed that WNT5a acts to down-regulate the expression of FSH-responsive genesin vitro, and corresponding increases in the expression of these genes have been found in the GCs of conditional knockout mice. Unexpectedly, we found that WNT5a regulates its target genes not by signalingviathe WNT/Ca(2+)or planar cell polarity pathways, but rather by inhibiting the canonical pathway, causing both β-catenin (CTNNB1) and cAMP responsive element binding (CREB) protein levels to decreaseviaa glycogen synthase kinase-3β-dependent mechanism. We further found that WNT5a prevents follicle-stimulating hormone and luteinizing protein from up-regulating the CTNNB1 and CREB proteins and their target genes, indicating that WNT5a functions as a physiologic inhibitor of gonadotropin signaling. Together, these findings identify WNT5a as a key regulator of follicle development and gonadotropin responsiveness.-Abedini, A., Zamberlam, G., Lapointe, E., Tourigny, C., Boyer, A., Paquet, M., Hayashi, K., Honda, H., Kikuchi, A., Price, C., Boerboom, D. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling. PMID:26667040

  3. A normal cumulative conception rate after human pituitary gonadotropin.

    PubMed

    Healy, D L; Kovacs, G T; Pepperell, R J; Burger, H G

    1980-10-01

    Forty consecutive women were treated with human pituitary gonadotropin to induce ovulation. Thirty-seven patients (93%) ovulated and thirty (75%) conceived on at least one occasion. The cumulative conception rate for the series equaled that of the general population. Women with a past history of anorexia nervosa had the shortest average time to pregnancy. Of patients who did not conceive, four represented failures of patient selection in that they withdrew from treatment for a variety of psychiatric and social reasons, and six represented failures of treatment, not becoming pregnant despite the induction of ovulation. It is concluded that realistic goals for a contemporary human gonadotropin program include induction of ovulation in all patients and a cumulative conception rate equal to that of the general community. PMID:6252067

  4. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone.

    PubMed

    Adams, J; Franks, S; Polson, D W; Mason, H D; Abdulwahid, N; Tucker, M; Morris, D V; Price, J; Jacobs, H S

    By means of pelvic ultrasonography, a multifollicular ovarian appearance was observed in women with weight-loss-related amenorrhoea. Multifollicular ovaries (MFO) are normal in size or slightly enlarged and filled by six or more cysts 4-10 mm in diameter; in contrast to women with polycystic ovaries (PCO), stroma is not increased. Unlike PCO patients, women with MFO were not hirsute and serum concentrations of luteinising hormone and follicle stimulating hormone were normal and decreased, respectively. The uterus was small indicating oestrogen deficiency. In MFO, treatment with gonadotropin releasing hormone (LHRH) induced ovulation in 83% of cycles and there were seven pregnancies in 8 women; in PCO, only 40% of cycles were ovulatory and there were eleven pregnancies (8 women) but six of these aborted. In MFO ovarian morphology reverted to normal in ovulatory cycles, whereas in PCO the polycystic pattern persisted despite the presence of a dominant follicle. MFO may represent a normal ovarian response to weight-related hypothalamic disturbance of gonadotropin control. PMID:2867389

  5. [Gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in patient with partial hydatidiform mole].

    PubMed

    Matos, Michelle; Ferraz, Leda; Lopes, Patrícia de Fátima; Lozoya, Consuelo; Amim Junior, Joffre; Rezende-Filho, Jorge; Braga, Antonio

    2015-07-01

    We report here a case of gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in a patient with a partial hydatidiform mole. This is the second occurrence of this event to be reported and the first one with proven immunohistochemical evidence. Besides showing the treatment for this pregnancy complication, this case report discusses the possibility of reducing the duration of post-molar follow-up, as well as strategies for early recognition of gestational trophoblastic neoplasia after spontaneous remission of molar pregnancy. PMID:26247255

  6. Normal gonadotropin production and fertility in gonadotrope-specific Bmpr1a knockout mice.

    PubMed

    Zhou, Xiang; Wang, Ying; Ongaro, Luisina; Boehm, Ulrich; Kaartinen, Vesa; Mishina, Yuji; Bernard, Daniel J

    2016-06-01

    Pituitary follicle-stimulating hormone (FSH) synthesis is regulated by transforming growth factorβsuperfamily ligands, most notably the activins and inhibins. Bone morphogenetic proteins (BMPs) also regulate FSHβ subunit (Fshb) expression in immortalized murine gonadotrope-like LβT2 cells and in primary murine or ovine primary pituitary cultures. BMP2 signals preferentially via the BMP type I receptor, BMPR1A, to stimulate murine Fshb transcription in vitro Here, we used a Cre-lox approach to assess BMPR1A's role in FSH synthesis in mice in vivo Gonadotrope-specific Bmpr1a knockout animals developed normally and had reproductive organ weights comparable with those of controls. Knockouts were fertile, with normal serum gonadotropins and pituitary gonadotropin subunit mRNA expression. Cre-mediated recombination of the floxed Bmpr1a allele was efficient and specific, as indicated by PCR analysis of diverse tissues and isolated gonadotrope cells. Furthermore, BMP2 stimulation of inhibitor of DNA binding 3 expression was impaired in gonadotropes isolated from Bmpr1a knockout mice, confirming the loss of functional receptor protein in these cells. Treatment of purified gonadotropes with small-molecule inhibitors of BMPR1A (and the related receptors BMPR1B and ACVR1) suppressed Fshb mRNA expression, suggesting that an autocrine BMP-like molecule might regulate FSH synthesis. However, deletion of Bmpr1a and Acvr1 in cultured pituitary cells did not alter Fshb expression, indicating that the inhibitors had off-target effects. In sum, BMPs or related ligands acting via BMPR1A or ACVR1 are unlikely to play direct physiological roles in FSH synthesis by murine gonadotrope cells. PMID:27029473

  7. Altered ovarian responsiveness to gonadotropins in neonatally irradiated immature rats

    SciTech Connect

    Freud, A.; Sod-Moriah, U.A.

    1988-01-01

    Female rats which were exposed to a single low dose of gamma irradiation (6R or 15R) at the age of 8 days produce smaller litters when mature than untreated controls. In order to study the possibility that such an impaired reproductive performance could result from a reduced ovulation rate, neonatally irradiated females were treated with PMSG (12 iu/rat) at the age of 26 days. Another group of rats, similarly treated, was further injected with hCG (5 iu/rat) 48 hours later. Animals were killed 48, 55, 60 and 72 hours after PMSG treatment or 72 and 120 after hCG injection. The results indicated that PMSG treatment increased the ovarian weight of non-irradiated controls as well as of irradiated rats and in all animals induced a proestrus like profile of LH. Only a combined treatment of PMSG and hCG resulted in ovulation and corpora lutea formation with significantly increased numbers of corpora lutea in the ovaries of the irradiated rats. The latter was associated with higher progesterone plasma levels not correlated to the number of corpora lutea. The gradual decrease in the number of ovarian binding sites for hCG with increased radiation dose and the increased association constant in the 15R group could not explain the increased sensitivity of the ovary to exogenous gonadotropins which results from neonatal exposure to low doses of gamma irradiation.

  8. Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: implications for male contraceptive development.

    PubMed

    Amory, J K; Anawalt, B D; Bremner, W J; Matsumoto, A M

    2001-01-01

    Weekly intramuscular administration of testosterone esters such as testosterone enanthate (TE) suppresses gonadotropins and spermatogenesis and has been studied as a male contraceptive. For unknown reasons, however, some men fail to achieve azoospermia with such regimens. We hypothesized that either 1) daily circulating serum fluoroimmunoreactive gonadotropins were higher or testosterone levels were lower during the weekly injection interval, or 2) monthly circulating bioactive gonadotropin levels were higher in nonazoospermic men. We therefore analyzed daily testosterone and fluoroimmunoreactive gonadotropin levels as well as pooled monthly bioactive and fluoroimmunoreactive gonadotropin levels in normal men receiving chronic TE injections and correlated these levels with sperm production. After a 3-month control period, 51 normal men were randomly assigned to receive intramuscular TE at 25 mg (n = 10), 50 mg (n = 9), 100 mg (n = 10), 300 mg (n = 10), or placebo (n = 12) weekly for 6 months. After 5 months of testosterone administration, morning testosterone and fluoroimmunoreactive follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured daily for a 1-week period between TE injections. In addition, fluoroimmunoreactive and bioactive FSH and LH levels were measured in pooled monthly blood samples drawn just before the next TE injection. In the 100-mg and 300-mg TE groups, mean monthly fluoroimmunoreactive FSH and LH levels were suppressed by 86%-97%, bioactive FSH and LH levels by 62%-80%, and roughly half the subjects became azoospermic. In the 1-week period of month 6, daily testosterone levels between TE injections were within the normal range in men receiving placebo, or 25 or 50 mg of weekly TE, but were significantly elevated in men receiving 100 or 300 mg of weekly TE. At no point during treatment, however, were there significant differences in daily testosterone or fluoroimmunoreactive gonadotropin levels, or monthly bioactive

  9. Secretion of Unconjugated Androgens and Estrogens by the Normal and Abnormal Human Testis before and after Human Chorionic Gonadotropin

    PubMed Central

    Weinstein, R. L.; Kelch, R. P.; Jenner, M. R.; Kaplan, S. L.; Grumbach, M. M.

    1974-01-01

    The secretion of androgens and estrogens by normal and abnormal testes was compared by determining the concentrations of dehydroepiandrosterone (DHEA), androstenedione (Δ4A), testosterone (T), estrone (E1), and 17β-estradiol (E2) in peripheral and spermatic venous plasma samples from 14 normal men and 5 men with unilateral testicular atrophy. Four normal men and one patient with unilateral atrophy of the testis were given human chorionic gonadotropin (HCG) before surgery. Plasma estrogens were determined by radioimmunoassay; plasma androgens were measured by the double-isotope dilution derivative technique. Peripheral concentrations of these steroids before and after HCG were similar in both the normal men and the patients with unilateral testicular atrophy. In normal men, the mean ±SE spermatic venous concentrations were DHEA, 73.1±11.7 ng/ml; Δ4A, 30.7±7.9 ng/ml; T, 751±114 ng/ml; E1, 306±55 pg/ml; and E2, 1298±216 pg/ml. Three of four subjects with unilateral testicular atrophy had greatly diminished spermatic venous levels of androgens and estrogens. HCG treatment increased the testicular secretion of DHEA and T fivefold, Δ4A threefold, E1 sixfold, and E2 eightfold in normal men. In the single subject with an atrophic testis who received HCG, the spermatic venous concentrations of androgens and estrogens were much less than in normal men similarly treated. We conclude that: (a) E1 is secreted by the human testis, but testicular secretion of E1 accounts for less than 5% of E1 production in normal men; (b) HCG stimulation produces increases in spermatic venous estrogens equal to or greater than the changes in androgens, including testosterone; and (c) strikingly decreased secretion of androgen and estrogen by unilateral atrophic human tests cannot be appreciated by analyses of peripheral steroid concentrations. PMID:4271572

  10. Characterization of Ovarian Responses to Equine Chorionic Gonadotropin of Aromatase-Deficient Mice With or Without 17β-Estradiol Supplementation.

    PubMed

    Toda, Katsumi; Hayashi, Yoshihiro; Ono, Masafumi; Saibara, Toshiji

    2016-05-01

    Aromatase is an enzyme catalyzing the final step of 17β-estradiol (E2) biosynthesis. Aromatase-deficient (ArKO) mice displayed vital roles of E2 at various tissue sites, including ovary. Here, we report attenuated responses of ArKO ovary to equine chorionic gonadotropin (eCG), an alternative to FSH. Ovarian contents of cAMP and anti-Müllerian hormone (AMH), putative factors reducing sensitivity to gonadotropins, were significantly elevated in ArKO mice compared with those in wild type (WT) mice in the basal state. Accordingly, eCG-induced ovarian alterations in cAMP contents, phosphorylation levels of signaling molecules, and mRNA expression of eCG-targeted genes were blunted in ArKO mice compared with those in WT mice. Treatment of ArKO mice with E2 decreased ovarian cAMP and AMH contents to the WT levels but did not restore the sensitivity. Microarray analysis coupled with quantitative RT-PCR analysis identified 7 genes of which the mRNA expression levels in ArKO ovaries were significantly different from those in the WT ovaries in the basal state and were not normalized by E2 supplementation, indicating possible involvement of these gene products in the determination of ovarian sensitivity to eCG. Thus, present analyses revealed that estrogen deficiency attenuates sensitivity of the ovary to gonadotropin, which might be associated with alterations in the ovarian contents of multiple molecules including cAMP and AMH. Given the importance of the ovarian responses to gonadotropins in reproductive function, detailed knowledge about the underlying mechanisms of abnormalities in the ArKO ovary might help to develop potential targets for infertility treatments. PMID:26919384

  11. Regulation of gonadotropin receptors, gonadotropin responsiveness, and cell multiplication by somatomedin-C and insulin in cultured pig Leydig cells

    SciTech Connect

    Bernier, M.; Chatelain, P.; Mather, J.P.; Saez, J.M.

    1986-11-01

    The author have investigated the effects of insulin and somatomedin-C/insulin like growth factor I(Sm-C) in purified porcine Leydig cells in vitro on gonadotrophins (hCG) receptor number, hCG responsiveness (cAMP and testosterone production), and thymidine incorporation into DNA. Leydig cells cultured in a serum-free medium containing transferrin, vitamin E, and insulin (5 ..mu..g/ml) maintained fairly constant both hCG receptors and hCG responsiveness. When they were cultured for 3 days in the same medium without insulin, there was a dramatic decline (more than 80%) in both hCG receptor number and hCG responsiveness. However the cAMP but not the testosterone response to forskolin was normal. Both insulin and Sm-C at nanomolar concentrations prevent the decline of both hCG receptors and hCG-induced cAMP production. At nanomolar concentrations, Sm-C and insulin enhanced hCG-induced testosterone production but the effect of Sm-C was significantly higher than that of insulin. However, the effect of insulin at higher concentrations (5 ..mu..g/ml) was significantly higher than that of Sm-C at 50 ng/ml. In contrast, at nanomolar concentrations only Sm-C stimulated (/sup 3/H)-thymidine incorporation into DNA and cell multiplication, the stimulatory effect of insulin on these parameters, was seen only at micromolar concentrations. These results indicate that both Sm-C and insulin acting through the receptors increase Leydig cell steroidogenic responsiveness to hCG by increasing hCG receptor number and improving some step beyond cAMP formation. In contrast, the mitogenic effects of insulin are mediated only through Sm-C receptors.

  12. Signaling Responses to Pulsatile Gonadotropin-releasing Hormone in LβT2 Gonadotrope Cells*

    PubMed Central

    Tsutsumi, Rie; Mistry, Devendra; Webster, Nicholas J. G.

    2010-01-01

    The hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) is secreted in a pulsatile fashion by hypothalamic neurons, and alterations in pulse frequency and amplitude differentially regulate gonadotropin synthesis and release. In this study, we investigated the kinetics of Gs and Gq signaling in response to continuous or pulsatile GnRH using fluorescence resonance energy transfer reporters in live mouse LβT2 gonadotrope cells. cAMP and protein kinase A-dependent reporters showed a rapid but transient increase in fluorescence resonance energy transfer signal with increasing doses of constant GnRH, and in contrast diacylglycerol (DAG) and calcium reporters showed a rapid and sustained signal. Multiple pulses of GnRH caused multiple pulses of cAMP and protein kinase A activation without desensitization, but the DAG and calcium reporters were rapidly desensitized resulting in inhibition of calcium and DAG responses. At the transcriptional level, both a cAMP-dependent cAMP-response element reporter and a DAG/calcium-dependent AP-1 reporter showed a pulse frequency-dependent increase in luciferase activity. However, constant GnRH stimulation gave very little cAMP-response element activation but very strong AP-1 activation. Based on these data, we propose that both the GnRH-R-Gs and Gq pathways are responsive to pulses of GnRH, but only the Gq pathway is responsive to constant GnRH. Furthermore, the Gq pathway is subject to desensitization with multiple GnRH pulses, but the Gs pathway is not. PMID:20406815

  13. Ovarian Hyper-Response to Administration of an GnRH-Agonist Without Gonadotropins

    PubMed Central

    Park, Hyun Tae; Bae, Hyo Sook; Kim, Tak

    2011-01-01

    Several case reports have indicated that a small subgroup of patients may develop ovarian hyperstimulation following the administration of gonadotropin-releasing hormone agonists (GnRHa) without gonadotropins. However, since only few such cases have been published, it is unclear what course to follow in subsequent cycles after ovarian hyperstimulation in the first cycle using only GnRHa. A 33-yr-old woman was referred to in vitro fertilization for oocyte donation. A depot preparation (3.75 mg) of tryptorelin without gonadotropins induced ovarian multifollicular enlargement with high estradiol level, and was followed by human chorionic gonadotropin administration and oocyte retrieval. In a subsequent cycle of the same patient, a low dose of tryptorelin (0.05 mg) did not induce ovarian hyperstimulation, and resulted in clinical pregnancy. This report shows potential management of ovarian hyperstimulation following the administration of GnRHa without gonadotropins. PMID:22022197

  14. Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults.

    PubMed

    Rohayem, J; Sinthofen, N; Nieschlag, E; Kliesch, S; Zitzmann, M

    2016-01-01

    Germ cell and Sertoli cell proliferation and maturation in human testes occur in three main waves, during the late fetal and early neonatal period and at early puberty. They are triggered by periods of increased activity of the hypothalamic-pituitary-gonadal (HPG) axis. In hypogonadotropic hypogonadism (HH), these processes are variably disturbed. The objective of this study was to explore whether success of gonadotropin replacement in HH men is predictable by the origin of HH, indicating time of onset and severity of GnRH/gonadotropin deficiency. The data of 51 adult HH patients who had undergone one cycle of hCG/FSH treatment were reviewed. Five groups were established, according to the underlying HH origin. Therapeutic success by final bi-testicular volumes (BTVs) final sperm concentrations (SC) and conception rates were compared and related to baseline parameters, indicative of the degree of HPG-axis disruption. Overall, BTVs rose from 13 ± 15 to 27 ± 15 mL, spermatogenesis was induced in 98%, with mean SCs of 15 ± 30 mill/mL, spontaneous pregnancies in 37% and additional 18% via intracytoplasmic sperm injection. Kallmann syndrome patients had the poorest responses (BTV: 16.9 ± 10 mL; SC: 3.5 ± 5.6 mill/mL), followed by patients with congenital/infancy-acquired multiple pituitary hormone deficiencies (MPHD) and patients with HH+absent puberty (BTV: 21 ± 14/24 ± 9 mL; SC: 5.5 ± 6.5/ 14.5 ± 23.8 mill/mL). HH men with pubertal arrest and with post-pubertally acquired MPHD had the best results (BTV: 36 ± 14/38 ± 16 mL; SC: 25.4 ± 34.2/29.9 ± 50.5 mill/mL). Earlier conception after 20.3 ± 11.5 months (vs. 43.1 ± 43.8; p = 0.047) of gonadotropin treatment with higher pregnancy rates (62% vs. 42%) was achieved in the two post-pubertally acquired HH subgroups, compared to the three pre-pubertally acquired. Therapeutic success was higher in patients without previously undescended testes, with higher baseline BTVs

  15. Ovarian response to repeated administration of alternating exogenous gonadotropin regimens in the ocelot (Leopardus pardalis) and tigrinus (Leopardus tigrinus).

    PubMed

    da Paz, Regina Celia Rodrigues; Dias, Eduardo Antunes; Adania, Cristina Harumi; Barnabe, Valquíria Hippólito; Barnabe, Renato Campanarut

    2006-10-01

    Exogenous gonadotropins are used to stimulate ovarian follicular growth and ovulation in mammalian species, including wild cats. However, successes in application of assisted reproduction techniques in nondomestic felids have been sparse. Our objectives were to assess the effectiveness of alternating gonadotropin regimens on ovarian responses. Five adult female ocelots and four adult female tigrinus were treated four to six times, using alternating eCG/hCG and pFSH/pLH at 4-month intervals. Laparoscopies were done to assess follicular development and to collect oocytes from matures follicles. The average number of follicles and corpus luteum (CL) per stimulation was higher in ocelots (7.0 +/- 0.8; mean +/- S.E.M.) than in tigrinus (2.5 +/- 0.4; P < 0.05), but the percentage of mature oocytes did not differ between the two species (mean range, 54-55%). Within species, both gonadotropin regimens were equally effective in inducing follicular growth and oocyte maturation. The total number of ovarian structures and oocyte maturation percentages did not decrease in either species with sequential stimulations. In summary, female ocelots and tigrinus continued to respond to repeated alternating ovarian stimulation protocols. In conclusion, the use of alternating gonadotropin regimens may permit more intensive reproductive management in these endangered cats. PMID:16472853

  16. Reproductive responses of dairy cows with ovarian cysts to simultaneous human chorionic gonadotropin or gonadotropin-releasing hormone and cloprostenol compared to gonadotropin-releasing hormone alone treatment

    PubMed Central

    Taktaz, T.; Kafi, M.; Mokhtari, Adel; Heidari, M.

    2015-01-01

    Aim: Bovine ovarian cysts are a common cause of economic loss in modern dairy herds. The objective of the present study was to evaluate the reproductive responses to three protocols using hCG, GnRH and cloprostenol when the definite diagnosis of the type of ovarian cyst is/is not possible in dairy cows. Materials and Methods: A total of 144 lactating dairy cows with ovarian cysts were divided into three groups. At diagnosis (Day 0), cows in Group 1 (the conventional method, n=47) were injected with 0.02 mg of a GnRH analogue i.m. (Buserelin); cows in Group 2 (n=47) were intramuscularly treated with 0.02 mg Buserelin plus 500 µg cloprostenol; and cows in Group 3 (n=50) were intramuscularly treated with 1500 IU hCG plus 500 µg cloprostenol. All cows received 500 µg cloprostenol intramuscularly on Day 10. Results: No statistically significant differences were found in the recovery time, interval to conception, conception rate at first AI, and pregnancy rates by Days 70 and 100 after treatment among the three groups. Conclusions: Simultaneous treatment of ovarian cysts with hCG or GnRH and cloprostenol appeared to have no advantage over the conventional method, GnRH alone, in dairy cows. Furthermore, hCG and GnRH have an equal therapeutic effect in cows with ovarian cysts. PMID:27047149

  17. Developmental Programming: Exogenous Gonadotropin Treatment Rescues Ovulatory Function But Does Not Completely Normalize Ovarian Function in Sheep Treated Prenatally with Testosterone1

    PubMed Central

    Steckler, Teresa L.; Lee, James S.; Ye, Wen; Inskeep, E. Keith; Padmanabhan, Vasantha

    2008-01-01

    Prenatal testosterone treatment leads to LH excess as well as ovarian follicular and ovulatory defects in the adult. These disruptions may stem from LH excess, abnormal FSH input, compromised ovarian sensitivity to gonadotropins, or intrinsic ovarian defects. To determine if exogenous gonadotropins rescue ovarian and ovulatory function of testosterone-treated sheep, the release of endogenous LH and biopotent FSH in control and prenatal testosterone-treated sheep was blocked with a GnRH antagonist during the first two breeding seasons and with LH/FSH coadministered in a manner approximating natural follicular phase. An acidic mix of FSH was administered the first 36 h at 2-h intervals and a less acidic mix for the next 12 h at 1-h intervals (different FSH preparations were used each year), and ovulation was induced with hCG. Circulating FSH and estradiol responses to gonadotropins measured in 2-h samples differed between treatment groups in Year 1 but not in Year 2. Ovarian follicular distribution and number of corpora lutea (in ewes that ovulated) tracked by ultrasonography and luteal progesterone responses were similar between control and prenatal testosterone-treated females but differed between years. Furthermore, hCG administration induced large cystic and luteinized follicles in both groups of females in Year 2, although the growth rate differed between control and prenatal testosterone-treated females. Our findings provide evidence that 1) ovulatory response in prenatal testosterone-treated females can be rescued with exogenous gonadotropins, 2) resultant follicular response is dependent on the nature of gonadotropic input, and 3) an abnormal follicular milieu may underlie differences in developmental trajectory of cystic follicles in prenatal testosterone-treated females. PMID:18524978

  18. Neonatal exposure to xenoestrogens impairs the ovarian response to gonadotropin treatment in lambs.

    PubMed

    Rivera, Oscar E; Varayoud, Jorgelina; Rodríguez, Horacio A; Santamaría, Clarisa G; Bosquiazzo, Verónica L; Osti, Mario; Belmonte, Norberto M; Muñoz-de-Toro, Mónica; Luque, Enrique H

    2015-06-01

    Bisphenol A (BPA) and diethylstilbestrol (DES) are xenoestrogens, which have been associated with altered effects on reproduction. We hypothesized that neonatal xenoestrogen exposure affects the ovarian functionality in lambs. Thus, we evaluated the ovarian response to exogenous ovine FSH (oFSH) administered from postnatal day 30 (PND30) to PND32 in female lambs previously exposed to low doses of DES or BPA (BPA50: 50 μg/kg per day, BPA0.5: 0.5 μg/kg per day) from PND1 to PND14. We determined: i) follicular growth, ii) circulating levels of 17β-estradiol (E2), iii) steroid receptors (estrogen receptor alpha, estrogen receptor beta, and androgen receptor (AR)) and atresia, and iv) mRNA expression levels of the ovarian bone morphogenetic protein (BMPs) system (BMP6, BMP15, BMPR1B, and GDF9) and FSH receptor (FSHR). Lambs neonatally exposed to DES or BPA showed an impaired ovarian response to oFSH with a lower number of follicles ≥2 mm in diameter together with a lower number of atretic follicles and no increase in E2 serum levels in response to oFSH treatment. In addition, AR induction by oFSH was disrupted in granulosa and theca cells of lambs exposed to DES or BPA. An increase in GDF9 mRNA expression levels was observed in oFSH-primed lambs previously treated with DES or BPA50. In contrast, a decrease in BMPR1B was observed in BPA0.5-postnatally exposed lambs. The modifications in AR, GDF9, and BMPR1B may be associated with the altered ovarian function due to neonatal xenoestrogen exposure in response to an exogenous gonadotropin stimulus. These alterations may be the pathophysiological basis of subfertility syndrome in adulthood. PMID:25778539

  19. Comparison of Detection of Normal Puberty in Girls by a Hormonal Sleep Test and a Gonadotropin-Releasing Hormone Agonist Test

    PubMed Central

    Bordini, Brian; Yu, Christine

    2013-01-01

    Context: The magnitude of sleep-related gonadotropin rise required to activate pubertal feminization is not established. Objective: The objective of the study was to determine the normal relationship of pubertal hormone responses to sleep and to GnRH agonist (GnRHag) challenge across the female pubertal transition. Design/Setting: This was a prospective study in a General Clinical Research Center. Participants: Sixty-two healthy 6- to 13-year-old volunteer girls participated in the study. Interventions: Interventions included overnight blood sampling followed by GnRHag (leuprolide acetate) injection. Primary Outcome Variables: The primary outcome variables included LH, FSH, and estradiol. Results: LH levels rose steadily during sleep and after GnRHag throughout the prepubertal years. The LH response to sleep and GnRHag correlated well across groups (eg, r = 0.807, peak vs 4 h post-GnRHag value); however, this correlation was less robust than in boys (r = 0.964, P < .01). Sleep peak LH of 1.3 U/L or greater had 85% sensitivity and 2.1 U/L or greater 96% specificity for detecting puberty (thelarche). The LH 1-hour post-GnRHag value of 3.2 U/L or greater had 95% sensitivity and 5.5 U/L or greater 96% specificity for detecting puberty. Girls entered puberty at lower LH levels than boys. FSH levels rose day and night during the prepubertal years to reach 1.0 U/L or greater during puberty but discriminated puberty poorly. Estradiol of 34 pg/mL or greater at 20–24 hours after GnRHag was 95% sensitive and 60 pg/mL or greater was 95% specific for puberty. Thirty-six percent of overweight early pubertal girls had meager hormonal evidence of puberty. Conclusions: These data suggest that sleep-related pubertal hormone levels critical for puberty are normally reflected in the responses to GnRHag testing across the normal female pubertal transition. Inconsistencies between clinical and hormonal staging may arise from peripubertal cyclicity of neuroendocrine function and from

  20. Interactions between protein kinase C and arachidonic acid in the gonadotropin response to salmon and chicken gonadotropin-releasing hormone-II in goldfish.

    PubMed

    Chang, J P; Van Goor, F; Neumann, C M

    1994-03-01

    Previous studies have shown that, in goldfish, the gonadotropin (GTH) response to salmon GTH-releasing hormone (sGnRH) is partly mediated by arachidonic acid (AA) metabolism via the lipoxygenase enzyme system, whereas protein kinase C (PKC) participates in both sGnRH- and chicken (c)GnRH-II-induced GTH secretion. In this study, the interactions between AA- and PKC-dependent pathways in mediating the long-term GnRH stimulation of GTH release were further investigated using dispersed goldfish pituitary cell cultures in static incubation. Treatments with AA or the PKC activator tetradecanoylphorbol acetate (TPA) increased GTH release. The GTH responses to AA and TPA were additive. The lipoxygenase inhibitor nordihydroguairetic acid (NDGA) and the PKC inhibitor H7 selectively reduced AA- and TPA-stimulated GTH release, respectively. These findings suggest that the GTH responses to stimulation by AA- and PKC-dependent signaling pathways are independent of one another. In other experiments, the GTH response to cGnRH-II was unaffected by NDGA but was abolished by H7. In contrast, sGnRH-induced GTH release was attenuated by NDGA and H7. Furthermore, in the presence of both NDGA and H7, the GTH response to sGnRH was abolished. These data suggest that sGnRH stimulation of GTH secretion involves both AA- and PKC-dependent mechanisms; in contrast, cGnRH-II action is not dependent on AA metabolism. The pathway by which AA might be mobilized in response to a GnRH challenge was also investigated by pharmacological manipulations. The diacylglcerol (DG) lipase inhibitor, U-57908, did not decrease sGnRH- and cGnRH-II-induced GTH secretion. On the other hand, the phospholipase A2 (PLA2) inhibitors, bromophenacyl bromide (BPB), chloroquine, and quinacrine, reduced sGnRH-elicited, but not cGnRH-II-stimulated GTH release. The addition of AA reversed the inhibitory action of BPB on sGnRH-elicited GTH release. In addition, the GTH response to AA was additive to the cGnRH-II-induced, but

  1. Comparison of Detection of Normal Puberty in Boys by a Hormonal Sleep Test and a Gonadotropin-Releasing Hormone Agonist Test

    PubMed Central

    Bordini, Brian; Yu, Christine

    2012-01-01

    Context: The magnitude of sleep-related gonadotropin rise required to activate pubertal gonadal function is not established. Objective: Our objective was to determine the normal relationship between sleep-related pubertal hormone levels and pituitary-testicular responsiveness to a GnRH agonist (GnRHag) test across the pubertal transition. Design/Setting and Participants: We conducted a prospective study in a General Clinical Research Center with healthy 9- to 15-yr-old volunteer boys. Interventions: Interventions included overnight blood sampling followed by leuprolide acetate injection (10 μg/kg). Primary Outcome Variables: LH, FSH, and testosterone levels were evaluated. Results: LH levels during sleep and post-GnRHag rose steadily during the late prepubertal years. Sleep peak LH correlated highly with the LH response to GnRHag across groups (r = 0.913). A sleep peak LH level of at least 3.7 U/liter predicted pubertal testicular activation with 100% accuracy. LH of at least 14.8 and at least 19.0 U/liter 4 h after GnRHag, respectively, predicted puberty with 100% sensitivity/94% specificity and 100% specificity/94% sensitivity. Overweight pubertal boys had transiently prolonged responses to GnRHag. FSH rose during both waking and sleeping hours during the prepubertal years, and all pubertal boys had an FSH level of at least 0.9 U/liter awake and at least 1.2 U/liter asleep. Sleep LH was more closely related than FSH to testicular size. Conclusions: These data suggest that a critical LH level during sleep (≥3.7 U/liter) heralds the onset of pubertal virilization and that this level is predictable by LH of at least 14.8–19 U/liter 4 h after GnRHag. These data also suggest that LH stimulation of testicular androgen production plays a role in stimulating testicular tubule growth once a critical level of FSH is achieved. PMID:23043188

  2. Extracellular signal-regulated kinase mediates gonadotropin subunit gene expression and LH release responses to endogenous gonadotropin-releasing hormones in goldfish.

    PubMed

    Klausen, Christian; Booth, Morgan; Habibi, Hamid R; Chang, John P

    2008-08-01

    The possible involvement of extracellular signal-regulated kinase (ERK) in mediating the stimulatory actions of two endogenous goldfish gonadotropin-releasing hormones (salmon (s)GnRH and chicken (c)GnRH-II) on gonadotropin synthesis and secretion was examined. Western blot analysis revealed the presence of ERK and phosphorylated (p)ERK in goldfish brain, pituitary, liver, ovary, testis and muscle tissue extracts, as well as extracts of dispersed goldfish pituitary cells and HeLa cells. Interestingly, a third ERK-like immunoreactive band of higher molecular mass was detected in goldfish tissue and pituitary cell extracts in addition to the ERK1-p44- and ERK2-p42-like immunoreactive bands. Incubation of primary cultures of goldfish pituitary cells with either a PKC-activating 4beta-phorbol ester (TPA) or a synthetic diacylglycerol, but not a 4alpha-phorbol ester, elevated the ratio of pERK/total (t)ERK for all three ERK isoforms. The stimulatory effects of TPA were attenuated by the PKC inhibitor GF109203X and the MEK inhibitor PD98059. sGnRH and cGnRH-II also elevated the ratio of pERK/tERK for all three ERK isoforms, in a time-, dose- and PD98059-dependent manner. In addition, treatment with PD98059 reduced the sGnRH-, cGnRH-II- and TPA-induced increases in gonadotropin subunit mRNA levels in Northern blot studies and sGnRH- and cGnRH-II-elicited LH release in cell column perifusion studies with goldfish pituitary cells. These results indicate that GnRH and PKC can activate ERK through MEK in goldfish pituitary cells. More importantly, the present study suggests that GnRH-induced gonadotropin subunit gene expression and LH release involve MEK/ERK signaling in goldfish. PMID:18558406

  3. Normalizing Catastrophe: An Educational Response

    ERIC Educational Resources Information Center

    Jickling, Bob

    2013-01-01

    Processes of normalizing assumptions and values have been the subjects of theoretical framing and critique for several decades now. Critique has often been tied to issues of environmental sustainability and social justice. Now, in an era of global warming, there is a rising concern that the results of normalizing of present values could be…

  4. Physiologic responses following gonadotropin-releasing hormone immunization in intact male dogs.

    PubMed

    Donovan, C E; Greer, M; Kutzler, M A

    2012-12-01

    We investigated the use of a commercial gonadotropin-releasing hormone (GnRH) vaccine as a method of temporary and reversible immunocastration in intact male dogs. Four privately owned dogs were vaccinated twice at 4-week intervals. Blood samples were collected at 0, 4, 12 and 20 weeks following the initial vaccination. These samples were analysed for GnRH antibody titres, luteinizing hormone (LH) and testosterone concentrations. Scrotal measurements were made at the time of sample collection, and testicular volume was calculated using the formula of an ellipsoid. As a result of vaccination, dogs displayed an elevated GnRH antibody titre, decreased LH and testosterone concentrations and decreased testicular volume, which reversed by the end of the study period. Therefore, these results suggest that immunizing against GnRH may be a possible choice for temporary and reversible immunocastration. PMID:23279550

  5. Effects of estrogens, clomiphene and castration in a male transsexual with as compared to those without hypersecretion of gonadotropins.

    PubMed

    Goh, H H; Ratnam, S S

    1990-06-01

    A 24-year-old male-to-female transsexual with hypersecretion of gonadotropins was studied with regard to his recovery from sex steroid hormone treatment before his sex change operation and the effects of castration, clomiphene tests and estrogens on the hypersecretion of gonadotropins. Computer-assisted tomography and X-ray results indicated that the possibility that the hypersecretion of gonadotropins was not associated with a pituitary adenoma could not be ruled out. After a period of recovery from previous sex steroid hormone therapy, inappropriately high FSH and LH levels in the presence of normal male levels of testosterone and estradiol were found. The latter normal levels failed to suppress both the FSH and LH levels. From the clomiphene challenge tests carried out before and after the sex reassignment operation, the estradiol infusion studies and treatment with ethinyl estradiol after the sex reassignment operation, it appears that the hypersecretion of gonadotropins was responsive to the negative feedback effect of estrogens. However, the sensitivity, especially that of FSH, was very attenuated. Even after 23 weeks of ethinyl estradiol treatment FSH remained well above the upper limit for normal men. The results showed that before his sex change operation the hypersecretion of gonadotropins in the patient was probably under autonomous control. Testicular factors at normal male concentrations appear to have a minimal negative feedback effect on the hypersecretion of gonadotropins. However, hypersecretion of gonadotropins can be suppressed by prolonged exposure to estrogens. PMID:2118708

  6. Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization

    PubMed Central

    Bloom, Michael S.; Kim, Dongsul; vom Saal, Frederick S.; Taylor, Julia A.; Cheng, Gloria; Lamb, Julie D.; Fujimoto, Victor Y.

    2011-01-01

    Objective Investigate associations between serum BPA concentrations and follicular response to exogenous ovary stimulation. Design Fasting serum was prospectively collected on the day of oocyte retrieval and assessed for unconjugated BPA using high-performance liquid chromatography (HPLC) with Coularray detection. Multivariable linear regression and negative binomial regression were used to assess associations between concentrations of BPA and outcome measures. Models were adjusted for race/ethnicity, antral follicle count at baseline, and cigarette smoking. Setting A reproductive health center. Patients Forty-four women undergoing in vitro fertilization (IVF). Main outcome measures Peak-estradiol level (E2) and the number of oocytes retrieved during IVF. Results The median unconjugated serum BPA concentration is 2.53 ng/ml (range 0.3–67.36 ng/ml). Bisphenol A is inversely associated with E2 (β=−0.16; 95% confidence interval (CI) −0.32, 0.01), as well as with E2 normalized to the number of mature-sized follicles at the hCG trigger (β=−0.14; 95%CI −0.24, −0.03). No association is observed for BPA and the number of oocytes retrieved (adjusted risk ratio=0.95; 95%CI 0.82, 1.10). Conclusions Bisphenol A is associated with a reduced estradiol response during IVF. Although limited by the preliminary nature of this study, these results merit confirmation in a future comprehensive investigation. PMID:21813122

  7. Gonadotropin-releasing Hormone Agonist Overuse: Urologists’ Response to Reimbursement and Characteristics Associated with Persistent Overuse

    PubMed Central

    Ellis, Shellie D.; Nielsen, Matthew E.; Carpenter, William R.; Jackson, George L.; Wheeler, Stephanie B.; Liu, Huan; Weinberger, Morris

    2015-01-01

    BACKGROUND Medicare reimbursement cuts have been associated with declining Gonadotropin-releasing Hormone (GnRH) agonist overuse in localized prostate cancer. Medical school affiliation and foreign training have been associated with persistent overuse. However, physician-level prescribing changes and the practice type of persistent overusers have not been examined. We sought to describe physician-level changes in GnRH agonist overuse and test the association of time in practice and solo practice type with GnRH agonist overuse. METHODS We matched American Medical Association physician data for 2,138 urologists to SEER–Medicare data for 12,943 men diagnosed with early stage and lower grade adenocarcinoma of the prostate between 2000 and 2007. We conducted a population-based, retrospective study using multi-level modeling to control for patient and provider characteristics. RESULTS Three distinct patterns of GnRH agonist overuse were observed. Urologists’ time in practice was not associated with GnRH agonist overuse (OR 0.89; 95% CI 0.75–1.05).However, solo practice type (OR 1.65; 95% CI 1.34–2.02), medical school affiliation (OR 0.65; 95% CI 0.55–0.77), and patient race were. Compared to non-Hispanic whites, non-Hispanic blacks (OR 1.76; 95% CI 1.37–2.27), Hispanics (OR 1.41; 95% CI 1.12–1.79) and men of “other” race (OR 1.44; 95% CI 1.04–1.99) had greater odds of receiving unnecessary GnRH agonists. CONCLUSIONS GnRH agonist overuse remains high among some urologists who may be professionally isolated and difficult to reach. These urologists treat more vulnerable populations, which may contribute to health disparities in prostate cancer treatment quality. Nonetheless, these findings provide guidance to develop interventions to address overuse in prostate cancer. PMID:25849354

  8. Pulsatile intravenous gonadotropin-releasing hormone administration averts fasting-induced hypogonadotropism and hypoandrogenemia in healthy, normal weight men.

    PubMed

    Aloi, J A; Bergendahl, M; Iranmanesh, A; Veldhuis, J D

    1997-05-01

    Fasting or severe caloric restriction in the human or experimental animal suppresses serum LH and sex steroid concentrations. In healthy men undergoing prolonged (5-day) nutrient deprivation, the daily LH secretion rate, the mass of LH secreted per burst, and the serum testosterone concentration fall markedly, with no decrease in responsiveness to a single bolus of GnRH. Here we test the hypothesis that the hypogonadotropic hypoandrogenemia accompanying fasting reflects decreased endogenous GnRH release. To this end, six healthy young men were studied on a fed day and during two 83-h fasting sessions with concurrent saline or pulsatile GnRH administration (100 ng/kg, i.v., every 90 min for 24 h) followed by a single bolus of 10 microg GnRH, i.v., to evaluate pituitary responsiveness. We employed a highly sensitive LH immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay, and deconvolution analysis to calculate in vivo LH secretory burst frequency, amplitude, duration, mass, and LH half-life. Fasting resulted in 30-50% declines in serum total and free testosterone and LH concentrations, and a 3-fold decrease in the calculated 24-h LH secretion rate (fed, 42 +/- 12; fasting, 14 +/- 1.9 U/L distribution volume x day; mean +/- SEM; P < 0.05, by ANOVA). Reduced LH secretion was accounted for by dual mechanisms, viz. a fall in both the apparent number of computer-resolved LH secretory bursts per 24 h (fed, 16 +/- 1.1; fasting, 10 +/- 1.2; P < 0.01) and the mass of LH secreted per burst (fed, 2.5 +/- 0.5; fasting, 1.5 +/- 0.1 U/L; P < 0.05). Fasting also decreased the mean value of the 24-h (nyctohemeral) rhythm in serum LH concentrations and reduced the approximate entropy (disorderliness) of LH release. Exogenous pulsatile GnRH injections prevented both the reduction in the calculated daily LH secretion rate (fed, 42 +/- 12; fasting plus GnRH, 64 +/- 16 IU/L; P = NS) and the decline in serum testosterone concentrations (fed, 556 +/- 71 ng

  9. Concurrent Gonadotropin-Releasing Hormone Agonist Administration with Chemotherapy Improves Neoadjuvant Chemotherapy Responses in Young Premenopausal Breast Cancer Patients

    PubMed Central

    Kim, Hee Jeong; Yoon, Tae-In; Chae, Hee Dong; Kim, Jeong Eun; Chae, Eun Young; Yu, Jong Han; Sohn, Guiyun; Ko, Beom Seok; Lee, Jong Won; Son, Byung Ho

    2015-01-01

    Purpose This study aimed to determine the oncologic efficacy of gonadotropin-releasing hormone (GnRH) agonist treatment concurrent with chemotherapy in a neoadjuvant setting. Methods A retrospective analysis was performed on 332 cases of invasive breast cancer in patients who were <40 years old at diagnosis and received GnRH agonists concurrent with neoadjuvant chemotherapy (GnRH agonist group) or neoadjuvant chemotherapy alone (neochemotherapy-alone group) from December 2010 to September 2014. Pathologic complete response rates (pCR) and Ki-67 changes were evaluated between the two groups. Results Median age was 32±3.9 and 36±3.0 years in the GnRH agonist group and neochemotherapy-alone group, respectively (p<0.001). After adjustment for tumor size, grade, lymph node metastasis, hormone receptor (HR) status, and chemotherapy regimen, the GnRH agonist group exhibited a higher pCR rate with an odds ratio (OR) of 2.98 (95% confidence interval [CI], 1.37-6.34) and a greater decrease in Ki-67 expression after treatment (p=0.05) than the neochemotherapy-alone group. For HR-negative tumors, the GnRH agonist group showed a higher pCR rate (multivariate OR, 3.50; 95% CI, 1.37-8.95) and a greater decrease in Ki-67 expression (p=0.047). For HR-positive breast cancer, the pCR rate, change in Ki-67 index, and clinical response were higher, and preoperative endocrine prognostic index scores were lower, in the GnRH agonist group, but these did not reach statistical significance. Conclusion Concurrent administration of GnRH agonists during neoadjuvant chemotherapy improved pCR rates and suppressed Ki-67 expression, especially in HR-negative tumors. PMID:26770243

  10. Gonadotropin-releasing hormone receptor mRNA expression by human pituitary tumors in vitro.

    PubMed Central

    Alexander, J M; Klibanski, A

    1994-01-01

    An important question in the pathogenesis and regulation of human gonadotroph adenomas is whether heterogeneous gonadotropin responses to gonadotropin-releasing hormone (GnRH) are due to dysregulation of GnRH receptor biosynthesis and/or cell-signaling pathways. We investigated gonadotropin responsiveness to pulsatile GnRH in 13 gonadotroph adenomas. All tumors had evidence of follicle-stimulating hormone (FSH) beta and alpha subunit biosynthesis using reverse transcriptase/polymerase chain reaction (RTPCR) techniques. Four tumors significantly increased gonadotropin and/or free subunit secretion during pulsatile 10(-8) M GnRH administration. The GnRH antagonist Antide (10(-6) to 10(-8) M) blocked secretory increases in all GnRH-responsive tumors. Gonadotropin and/or free subunit secretion increased after 60 mM KCl, confirming that GnRH nonresponsiveness was not due to intracellular gonadotropin depletion. We hypothesized that GnRH nonresponsiveness in these tumors may be due to GnRH receptor (GnRH-Rc) biosynthetic defects. RTPCR analyses detected GnRH-Rc transcripts only in responsive tumors and normal human pituitary. This is the first demonstration of a cell-surface receptor biosynthetic defect in human pituitary tumors. We conclude (a) one third of gonadotroph tumors respond to pulsatile GnRH in vitro, (b) GnRH-Rc mRNA is detected in human gonadotroph adenomas and predicts GnRH responsiveness, and (c) GnRH-Rc biosynthetic defects may underlie GnRH nonresponsiveness in gonadotroph tumors. Images PMID:8200967

  11. Mach bands explained by response normalization.

    PubMed

    Kingdom, Frederick A A

    2014-01-01

    Mach bands are the illusory dark and bright bars seen at the foot and knee of a luminance trapezoid. First demonstrated by Ernst Mach in the latter part of the 19th century, Mach bands are a test bed not only for models of brightness illusions but of spatial vision in general. Up until 50 years ago the dominant explanation of Mach Bands was that they were caused by lateral inhibition among retinal neurons. More recently, the dominant idea has been that Mach bands are a consequence of a visual process that generates a sparse, binary description of the image in terms of "edges" and "bars". Another recent explanation is that Mach bands result from learned expectations about the pattern of light typically found on sharply curved surfaces. In keeping with recent multi-scale filtering accounts of brightness illusions as well as current physiology, I show however that Mach bands are most simply explained by response normalization, whereby the gains of early visual channels are adjusted on a local basis to make their responses more equal. I show that a simple one-dimensional model of response normalization explains the range of conditions under which Mach bands occur, and as importantly, the conditions under which they do not occur. PMID:25408643

  12. Mach bands explained by response normalization

    PubMed Central

    Kingdom, Frederick A. A.

    2014-01-01

    Mach bands are the illusory dark and bright bars seen at the foot and knee of a luminance trapezoid. First demonstrated by Ernst Mach in the latter part of the 19th century, Mach bands are a test bed not only for models of brightness illusions but of spatial vision in general. Up until 50 years ago the dominant explanation of Mach Bands was that they were caused by lateral inhibition among retinal neurons. More recently, the dominant idea has been that Mach bands are a consequence of a visual process that generates a sparse, binary description of the image in terms of “edges” and “bars”. Another recent explanation is that Mach bands result from learned expectations about the pattern of light typically found on sharply curved surfaces. In keeping with recent multi-scale filtering accounts of brightness illusions as well as current physiology, I show however that Mach bands are most simply explained by response normalization, whereby the gains of early visual channels are adjusted on a local basis to make their responses more equal. I show that a simple one-dimensional model of response normalization explains the range of conditions under which Mach bands occur, and as importantly, the conditions under which they do not occur. PMID:25408643

  13. Responses of luteinizing hormone, follicle-stimulating hormone, and prolactin to prolonged administration of the dopamine antagonist in normal women and women with low-weight amenorrhea.

    PubMed

    Larsen, S

    1981-06-01

    The responses of luteinizing hormone, follicle-stimulating hormone, and prolactin to prolonged administration of the dopamine receptor antagonist metoclopramide (5 mg twice daily) were investigated in six normal women and six women with low-weight amenorrhea (LWA). In contrast to the normal group, the LWA group showed no significant changes in the mean basal prolactin level or the mean prolactin response to stimulation with thyrotropin-releasing hormone, but there was an significant elevation of the mean net increase in luteinizing hormone after stimulation with gonadotropin-releasing hormone. On the basis of these data, the possibility of increased central dopaminergic activity in women with LWA is discussed. PMID:6788608

  14. Enhanced response of granulosa and theca cells from sheep carriers of the FecB mutation in vitro to gonadotropins and bone morphogenic protein-2, -4, and -6.

    PubMed

    Campbell, B K; Souza, C J H; Skinner, A J; Webb, R; Baird, D T

    2006-04-01

    The FecB (Booroola) mutation, which leads to increased ovulation rates and multiple births in sheep, is now known to occur in the signaling domain of the bone morphogenic protein (BMP)-1B receptor. We examined the effect of the mutation on the responsiveness of granulosa (GC) and theca cells (TC) to BMPs and other local regulators using tissue from animals with (Fec(B/B)) and without (Fec(+/+)) the FecB mutation. Experiments examined the effect of BMP-2, -4, and -6 (0.005-50 ng/ml), and their interaction with IGF-I (0.1-10 ng/ml LR3 analog) and gonadotropins, on the proliferation and differentiation of GCs and TCs isolated from small (<2 mm) antral follicles and maintained in serum-free culture for up to 8 d. Dose-finding studies using ovaries from wild-type sheep obtained from the abbattoir showed no difference among the different BMPs in stimulating (P < 0.001) estradiol (E2) production by GCs cultured with FSH (10 ng/ml), but there was a clear interaction (P < 0.001) with IGF-I. BMPs had no effect on GC proliferation or the sensitivity of GCs to FSH. In contrast, higher doses of BMPs (5-50 ng/ml) inhibited LH-stimulated androstenedione production by TCs, whereas lower doses (0.005-0.05 ng/ml) stimulated TC proliferation (P < 0.01). Regardless of dose of IGF-I, at the end of culture (96-192 h) hormone production by GCs (E2, inhibin A) and TCs (androstenedione) was 4- to 5-fold greater (P < 0.001) by cells from Fec(B/B), compared with Fec(+/+) ewes exposed to the same dose of gonadotropin. In the presence of low concentrations of IGF-I (0.1 ng/ml), the maximum increase in the production of E2 and inhibin A by GCs from FF ewes in response to BMPs was observed at doses that were 3- to 10-fold lower (3-10 ng/ml) than ++ (30 ng/ml; P < 0.001). Low doses of BMPs stimulated proliferation of TCs from ++ (P < 0.01) but not FF ewes. Immunohistochemistry confirmed BMP-6 protein expression in the oocyte, granulosa, and thecal layers of antral follicles from both genotypes

  15. Torsional optokinetic nystagmus: normal response characteristics

    PubMed Central

    Farooq, S J; Proudlock, F A; Gottlob, I

    2004-01-01

    Background/aims: Few studies have investigated normal response characteristics of torsional optokinetic nystagmus (tOKN). The authors have investigated the effect of stimulus velocity and central/peripheral stimulation on tOKN. Methods: Torsional OKN was elicited using a sinusoidal grating rotating at velocities of 3°/s to 1000°/s in clockwise and anticlockwise directions. To investigate the effect of central stimulation, stimulus size was varied from 2.86° to 50.8°. An artificial scotoma placed over a 50.8° stimulus was varied from 2.86° to 43.2° to investigate peripheral stimulation. Eight subjects participated in each experiment and torsional eye movements were recorded using video-oculography. The mean slow phase velocity (MSPV) and gain were calculated. Results: The maximum gain occurred in response to 8°/s stimulation. The MSPV increased up to a stimulus velocity of 200°/s achieving a maximum of 3°/s in both directions. MSPV was linearly correlated with the log of stimulus velocity. The smallest field size, rotating at 40°/s, evoked 10% of the gain elicited by the largest display. When the most peripheral stimulus was used, the gain was maintained at 50% of the gain evoked when the full display was used. Conclusions: A wide range of stimulus velocities can elicit tOKN and peripheral field stimulation contributes significantly to its response. PMID:15148215

  16. Differential responsiveness of luteinized human granulosa cells to gonadotropins and insulin-like growth factor I for induction of aromatase activity

    SciTech Connect

    Christman, G.M.; Randolph, J.F. Jr.; Peegel, H.; Menon, K.M. )

    1991-06-01

    The objective of this study was to examine the in vitro responsiveness of cultured luteinized human granulosa cells over time to insulin-like growth factor 1 (IGF-1), human follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) for the induction of aromatase activity. Granulosa cells were retrieved from preovulatory follicles in patients undergoing in vitro fertilization. Cells were cultured for a period of 72 hours or 10 days. The ability of hCG, human FSH, and/or IGF-I to induce aromatase activity was assayed by the stereospecific release of tritium from (1B-3H)androstenedione. Short-term cultures (72 hours) demonstrated a marked rise in aromatase activity in response to human FSH and IGF-I, whereas a smaller response to hCG was observed. In contrast, 10-day cultures demonstrated responsiveness predominantly to hCG rather than human FSH for the induction of aromatase activity with no remarkable effect of IGF-I. Luteinized human granulosa cells undergo a transformation from an initial human FSH and IGF-I responsive state to an hCG responsive state in long-term cultures.

  17. Evidence that obesity and androgens have independent and opposing effects on gonadotropin production from puberty to maturity.

    PubMed

    Rosenfield, Robert L; Bordini, Brian

    2010-12-10

    Optimal fat mass is necessary for normal gonadotropin levels in adults, and both undernutrition and overnutrition suppress gonadotropins: thus, the gonadotropin response to relative adipose mass is biphasic. Adult obesity is associated with blunted luteinizing hormone (LH) pulse amplitude that is partially attributable to increased LH clearance rate. Testosterone appears to have a biphasic effect on gonadotropin production in females. Moderate elevations of testosterone appear to stimulate LH production at both the hypothalamic and pituitary level, while very high levels of testosterone suppress LH. Thus, obesity per se appears to suppress gonadotropin production, and moderate hyperandrogenemia in women appears to stimulate LH. The ordinary hypergonadotropic hyperandrogenism of obese women appears to be an exception to this model because it is usually due to polycystic ovary syndrome (PCOS), a condition in which intrinsic functional ovarian hyperandrogenism and excess adiposity share a common origin that involves insulin-resistant hyperinsulinemia. LH elevation seems to be secondary to hyperandrogenemia and is absent in the most obese cases. Overweight early pubertal girls have significant blunting of sleep-related LH production, which is the first hormonal change of puberty. The data are compatible with the possibility that excess adiposity may paradoxically subtly suppress hypothalamic-pituitary-gonadal function in early puberty although it is known to contribute to the early onset of puberty. PMID:20816944

  18. Plasma prorenin response to human chorionic gonadotropin in ovarian-hyperstimulated women: correlation with the number of ovarian follicles and steroid hormone concentrations.

    PubMed Central

    Itskovitz, J; Sealey, J E; Glorioso, N; Rosenwaks, Z

    1987-01-01

    Plasma prorenin and active renin were measured before and after human chorionic gonadotropin (hCG) administration in two groups of patients undergoing ovarian stimulation for 4-6 days with follicle-stimulating hormone alone or in combination with luteinizing hormone, for in vitro fertilization. Baseline total plasma renin (prorenin plus active renin; n = 12) averaged 25 +/- 8 ng/ml per hr (mean +/- SD). Total renin did not change during ovarian stimulation but it increased to 46 +/- 16 ng/ml per hr (P less than 0.05) 1 or 2 days later, just before hCG administration. Thirty-six hours after hCG administration, just before laparoscopy and egg retrieval, total renin was 123 +/- 97 ng/ml per hr; a peak of 182 +/- 143 ng/ml per hr occurred 2-6 days later--i.e., during the luteal phase of the menstrual cycle. In eight of the patients who did not conceive, total renin returned to baseline 14 days after hCG administration. In four who conceived, a nadir was reached (57 +/- 13 ng/ml per hr) 8-12 days after hCG administration and then total renin increased again as the plasma beta hCG measurement began to rise. By day 16 it averaged 225 +/- 157 ng/ml per hr. In a second group of five patients active renin and prorenin were measured separately. Active renin comprised less than 20% of the total renin at all times. It was unchanged until day 4 after hCG administration and then increased significantly only when plasma progesterone was high. Thus, the initial response to hCG was entirely due to an increase in prorenin. A highly significant correlation was observed between the number of follicles and the total renin increases on the day of aspiration (r = 0.93, P less than 0.001) and at the peak (r = 0.89, P less than 0.001). After hCG administration, a temporal relationship was observed between the rise in total renin and plasma estradiol and progesterone levels. These results demonstrate that plasma prorenin increases markedly after administration of hCG and that the rise is

  19. Parents' Responses to Normal and Premature Infants.

    ERIC Educational Resources Information Center

    Frodi, Ann; Willie, Diana

    This paper discusses a series of three studies investigating the influence of infants' characteristics and signaling behavior on parents. Videotapes of either smiling/cooing/gurgling or crying infants were used to elicit parents' physiological and affective responses. Measured physiological responses included skin conductance, heart rate, and…

  20. Multivariate Models for Normal and Binary Responses in Intervention Studies

    ERIC Educational Resources Information Center

    Pituch, Keenan A.; Whittaker, Tiffany A.; Chang, Wanchen

    2016-01-01

    Use of multivariate analysis (e.g., multivariate analysis of variance) is common when normally distributed outcomes are collected in intervention research. However, when mixed responses--a set of normal and binary outcomes--are collected, standard multivariate analyses are no longer suitable. While mixed responses are often obtained in…

  1. 21 CFR 522.1079 - Serum gonadotropin and chorionic gonadotropin.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Serum gonadotropin and chorionic gonadotropin. 522.1079 Section 522.1079 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN.... (i) Gilts. For induction of fertile estrus (heat) in healthy prepuberal (noncycling) gilts. (ii)...

  2. 21 CFR 522.1079 - Serum gonadotropin and chorionic gonadotropin.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Serum gonadotropin and chorionic gonadotropin. 522.1079 Section 522.1079 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN.... (i) Gilts. For induction of fertile estrus (heat) in healthy prepuberal (noncycling) gilts. (ii)...

  3. 21 CFR 522.1079 - Serum gonadotropin and chorionic gonadotropin.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Serum gonadotropin and chorionic gonadotropin. 522.1079 Section 522.1079 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN.... (i) Gilts. For induction of fertile estrus (heat) in healthy prepuberal (noncycling) gilts. (ii)...

  4. The Higher Response of Vascular Endothelial Growth Factor and Angiotensin-II to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome

    PubMed Central

    Qu, Junwei; Che, Yena; Xu, Pei; Xia, Yanjie; Wu, Xiaoke; Wang, Yong

    2015-01-01

    Background This research investigated the response of vascular active factors, vascular endothelial growth factor (VEGF) and angiotensin-II (AT-II) to ovarian stimulation during 24 hours in patients with polycystic ovary syndrome (PCOS). Materials and Methods In this clinical trial study, 52 patients with PCOS and 8 control cases were stimulated with human chorionic gonadotropin (HCG) on the 4th to 7th day of the patients’ natural or induced menstrual cycles. We measured VEGF and AT-II by radioimmunoassay before the injection (0 hour) and 3, 8, 12, 18 and 24 hours after the stimulation. Results After ovarian stimulation, there was substantially higher level of VEGF in typical PCOS patients than the other three groups at the 3 hour time point (p<0.05), while there were no significant differences in VEGF at all the other time points among the four groups. As for AT-II, before and at all time points after the ovarian stimulation, it seemed that the AT-II levels in patients’ sera with different phenotypes of PCOS by the Rotterdam criteria were all higher than in the control group although the differences were not statistically significant. The level of AT-II in typical PCOS patients was also significantly higher than the other three groups at the 3 hour time point (p<0.05), while no significant differences at all the other time points among the four groups were observed. Conclusion The response to the stimulation varied among patients with different phenotypes of PCOS according to the Rotterdam criteria. Serum VEGF and AT-II were possible contributors to an increased risk of developing ovarian hyperstimulation syndrome (OHSS) in patients with typical PCOS during the early follicular phase (3 hours) after ovarian stimulation (Registration Number: NCT02265861). PMID:25780518

  5. Oral Progestin Priming Increases Ovarian Sensitivity to Gonadotropin Stimulation and Improves Luteal Function in the Cat1

    PubMed Central

    Stewart, Rosemary A.; Pelican, Katharine M.; Crosier, Adrienne E.; Pukazhenthi, Budhan S.; Wildt, David E.; Ottinger, Mary Ann; Howard, JoGayle

    2012-01-01

    ABSTRACT As the only domesticated species known to exhibit both induced and spontaneous ovulation, the cat is a model for understanding the nuances of ovarian control. To explore ovarian sensitivity to exogenous gonadotropins and the influence of progestin priming, we conducted a study of queens that were down-regulated with oral progestin or allowed to cycle normally, followed by low or high doses of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG). Our metrics included 1) fecal steroid metabolite profiles before and after ovulation induction, 2) laparoscopic examination of ovarian follicles and corpora lutea (CL) on Days 2 and 17 (Day 0 = hCG administration), and 3) ovariohysterectomy (Day 17) to assess CL progesterone concentrations, morphometrics, and histology. Reproductive tracts from time-matched, naturally mated queens (n = 6) served as controls. Every progestin-primed cat (n = 12) produced the desired response of morphologically similar, fresh CL (regardless of eCG/hCG dose) by Day 2, whereas 41.7% of unprimed counterparts (n = 12) failed to ovulate or had variable-aged CL suggestive of prior spontaneous ovulation (P < 0.05). The ovarian response to low, but not high, eCG/hCG was improved (P < 0.05) in primed compared to unprimed cats, indicating increased sensitivity to gonadotropin in the progestin-primed ovary. Progestin priming prevented hyperelevated fecal steroid metabolites and normalized CL progesterone capacity, but only when combined with low eCG/hCG. However, priming failed to prevent ancillary CL formation, smaller CL mass, or abnormal luteal cell density, which were common to all eCG/hCG-treated cats. Thus, the domestic cat exposed to eCG/hCG produces CL with structural and functional aberrations. These anomalies can be partially mitigated by progestin priming, possibly due to a protective effect of progestin associated with enhanced ovarian sensitivity to gonadotropins. PMID:23100619

  6. Ephrin-A5 Is Required for Optimal Fertility and a Complete Ovulatory Response to Gonadotropins in the Female Mouse.

    PubMed

    Buensuceso, Adrian V; Son, Alexander I; Zhou, Renping; Paquet, Marilène; Withers, Benjamin M; Deroo, Bonnie J

    2016-02-01

    Follicle growth and ovulation involve the coordinated expression of many genes, driven by FSH and LH. Reports indicate that Eph receptors and ephrins are expressed in the ovary, suggesting roles in follicle growth and/or ovulation. We previously reported FSH-induced expression of ephrin-A5 (EFNA5) and 4 of its cognate Eph receptors in mouse granulosa cells. We now report that female mice lacking EFNA5 are subfertile, exhibit a compromised response to LH, and display abnormal ovarian histology after superovulation. Efna5(-/-) females litters were 40% smaller than controls, although no difference in litter frequency was detected. The ovarian response to superovulation was also compromised in Efna5(-/-) females, with 37% fewer oocytes ovulated than controls. These results corresponded with a reduction in ovarian mRNA levels of several LH-responsive genes, including Pgr, Ptgs2, Tnfaip6, Ereg, Btc, and Adamts4, suggesting that Efna5(-/-) ovaries exhibit a partially attenuated response to LH. Histopathological analysis indicated that superovulated Efna5(-/-) females exhibited numerous ovarian defects, including intraovarian release of cumulus oocyte complexes, increased incidence of oocytes trapped within luteinized follicles, granulosa cell and follicular fluid emboli, fibrin thrombi, and interstitial hemorrhage. In addition, adult Efna5(-/-) ovaries exhibited a 4-fold increase in multioocyte follicles compared with controls, although no difference was detected in 3-week-old mice, suggesting the possibility of follicle merging. Our observations indicate that loss of EFNA5 in female mice results in subfertility and imply that Eph-ephrin signaling may also play a previously unidentified role in the regulation of fertility in women. PMID:26672804

  7. Effects of inhibition of gonadotropin releasing hormone secretion on the response to novel objects in young male and female sheep.

    PubMed

    Robinson, Jane E; Evans, Neil P; Dumbell, Rebecca; Solbakk, Anne-Kristin; Ropstad, Erik; Haraldsen, Ira Ronit Hebold

    2014-02-01

    This study investigated the actions of blocking the GnRH receptor using a specific agonist on the response of male and female sheep to a novel object placed in their pen. The study is part of a series performed on 46 same sex twin animals. One of the pair received a subcutaneous implant of the GnRH agonist Goserelin acetate every four weeks while the other remained untreated. Implantation began immediately prior to puberty; at 8 weeks in the males and 28 weeks in the females (as timing of puberty is sex specific). To determine the effects of agonist treatment on the reproductive axis blood samples were collected for measurement of testosterone in the males and progesterone in the females. In addition the volume of the scrotum was determined. The present study aimed to determine whether there are sexually differentiated behavioural responses to a novel object at different stages of brain development (8, 28 and 48 weeks of age) and whether these responses are altered by GnRHa treatment. Approach behaviour towards and interactions with the novel object were monitored as was the number of vocalisations per unit time during the test period. GnRHa treatment suppressed testosterone concentrations and testicular growth in the males and progesterone release in the females. Sheep vocalised significantly more prior to weaning (8 weeks of age) than post weaning (28 and 48 weeks of age) suggesting stress on separation from their dams. Our current study shows that males are more likely to leave their conspecifics to approach a novel object than females. As this behaviour was not altered by suppression of the reproductive axis we suggest that, although sex differences are more obviously expressed in the phenotype after puberty, these may be developed during adolescence but not primarily altered during puberty by sex hormones. PMID:24485485

  8. Discrete Latent Markov Models for Normally Distributed Response Data

    ERIC Educational Resources Information Center

    Schmittmann, Verena D.; Dolan, Conor V.; van der Maas, Han L. J.; Neale, Michael C.

    2005-01-01

    Van de Pol and Langeheine (1990) presented a general framework for Markov modeling of repeatedly measured discrete data. We discuss analogical single indicator models for normally distributed responses. In contrast to discrete models, which have been studied extensively, analogical continuous response models have hardly been considered. These…

  9. Oocyte and cumulus cell transcripts from cultured mouse follicles are induced to deviate from normal in vivo conditions by combinations of insulin, follicle-stimulating hormone, and human chorionic gonadotropin.

    PubMed

    Sánchez, Flor; Romero, Sergio; Smitz, Johan

    2011-09-01

    Gonadotropins and insulin are major regulators of cell proliferation, differentiation, and survival in cultured mouse ovarian follicles. Applications of variable doses of insulin in combination with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were studied at the gene expression level in oocytes and cumulus cells. Early preantral follicles grown over 9 days were sequentially exposed to combinations of doses of insulin, FSH, and human chorionic gonadotropin (hCG). From culture Day 1 to 6 (preantral stage), two insulin concentrations (5 ng/ml and 5 μg/ml) were combined with 10 mIU/ml FSH. From Days 6 to 9 (antral stage), the three variable gonadotropin treatments set under each insulin condition were 10 mIU/ml FSH, 25 mIU/ml FSH, and 25 mIU/ml FSH plus 3 mIU/ml hCG. The Gdf9, Bmp15, Fgf8, Dazl, Pou5f1, and Pik3ca mRNA transcripts were quantified in oocytes, and the Amh, Lhcgr, Hsd3b1, Vegfa, and Insig1 mRNA transcripts were quantified in cumulus cells. In vivo controls were unprimed and eCG (equine chorionic gonadotropin)-primed prepubertal female mice. During the preantral stage, none except the Amh transcripts was regulated by insulin. Oocyte transcripts were not affected by the variable gonadotropin treatments on the last culture day but were upregulated in the combination of high insulin plus 25 mIU/ml FSH. Under low insulin conditions, high FSH levels increased levels of Lhcgr and Vegfa expression, and hCG abated this effect. However, under high insulin conditions, hCG upregulated levels of Lhcgr, Vegfa, and Insig1 mRNA. High insulin concentrations upregulated Hsd3b1 transcripts. These results demonstrate that in an in vitro follicle culture, a near physiological insulin background yields oocyte and cumulus cell transcript levels that are more similar to those in vivo. PMID:21565993

  10. Potential Diagnostic Utility of Intermittent Short-Acting GnRH Agonist Administration in Gonadotropin Deficiency

    PubMed Central

    Zimmer, Carrie A.; Ehrmann, David A; Rosenfield, Robert L.

    2010-01-01

    Objective The objective was to determine if intermittent, low-dose, short-acting GnRH agonist (GnRHag) administration up-regulates pituitary-gonadal function in gonadotropin deficiency (GnD) sufficiently to be of diagnostic or therapeutic value. Design/Intervention Low-dose leuprolide acetate was administered SC at 4–5 d intervals up to one year. Patients Adult volunteers and GnD patients were studied. Setting The studies were performed in a General Clinical Research Center. Main Outcome Measures LH, FSH, and sex steroid responses were determined. Results In normal men and women, low-dose GnRHag repetitively transiently stimulated gonadotropins in a gender-dimorphic manner. In congenitally GnD deficient men (n=6) and women (n=1), none of whom had a normal LH response to an initial GnRHag test dose, this regimen consistently stimulated LH to the normal baseline range within two weeks. Long-term GnRHag administration to a partially GnD man did not alleviate hypogonadism, however. Women with hypothalamic amenorrhea (n=2) responded normally to a single GnRHag injection; however, repeated dosing did not seem to induce the normal priming effect. Conclusions The subnormal LH response to GnRHag of congenital GnD normalized in response to repetitive intermittent GnRHag, but not sufficiently to improve hypogonadism. Hypothalamic amenorrhea patients lacked the priming response to repeated GnRHag, but otherwise had normal hormonal responses to GnRHag. We conclude that intermittent administration of a short-acting GnRHag is of potential diagnostic value in distinguishing hypothalamic from pituitary causes of GnD. PMID:20553679

  11. Normal Caloric Responses during Acute Phase of Vestibular Neuritis

    PubMed Central

    Lee, Sun-Uk; Park, Seong-Ho; Kim, Hyo-Jung; Koo, Ja-Won

    2016-01-01

    Background and Purpose We report a novel finding of caloric conversion from normal responses into unilateral paresis during the acute phase of vestibular neuritis (VN). Methods We recruited 893 patients with a diagnosis of VN at Dizziness Clinic of Seoul National University Bundang Hospital from 2003 to 2014 after excluding 28 patients with isolated inferior divisional VN (n=14) and those without follow-up tests despite normal caloric responses initially (n=14). We retrospectively analyzed the neurotological findings in four (0.5%) of the patients who showed a conversion from initially normal caloric responses into unilateral paresis during the acute phase. Results In those four patients, the initial caloric tests were performed within 2 days of symptom onset, and conversion into unilateral caloric paresis was documented 1–4 days later. The clinical and laboratory findings during the initial evaluation were consistent with VN in all four patients except for normal findings in bedside head impulse tests in one of them. Conclusions Normal findings in caloric tests should be interpreted with caution during the acute phase of suspected VN. Follow-up evaluation should be considered when the findings of the initial caloric test are normal, but VN remains the most plausible diagnosis. PMID:26932259

  12. Effect of timing of oestradiol benzoate injection relative to gonadotropin treatment on superovulatory response, and on embryo yield and quality in beef heifers.

    PubMed

    Yaakub, H; Duffy, P; O'Callaghan, D; Boland, M P

    1998-09-11

    Variation in superovulatory responses in cattle may be related to the stage of follicular growth at the time of gonadotropin treatment. Waves of follicle growth are regulated by both follicle-stimulating hormone (FSH) and oestradiol. The objective of experiment 1 was to determine the dynamics of follicle wave emergence and the relationship with FSH and oestradiol concentrations, after treatment of heifers with oestradiol benzoate (ODB) in the presence of an intravaginal progesterone-releasing device (CIDR-B). Experiment 2 examined the superovulatory response, embryo yield and quality following treatment with porcine follicle-stimulating hormone (pFSH) at different times relative to ODB injection. In experiment 1, 28 beef heifers were treated with a CIDR for 9 days and allocated at random to one of four groups to receive either: (I) CIDR only, or 5 mg ODB given as a single intramuscular injection at (II) day 0 (d0); (III) day 1.5 (d1.5); or (IV) day 3 (d3) post CIDR insertion. Ovaries were examined using daily ultrasound and blood samples were collected twice daily for 11 days. In experiment 2, 96 heifers were treated with a CIDR and 5 mg ODB as in experiment 1, and were allocated using a 4 x 3 factorial design plan to a superovulation programme using three doses (400 IU; 600 IU; 800 IU) of pFSH. FSH was given for 4 days at 12-h intervals beginning 6.5 days after CIDR insertion. Heifers received prostaglandin analogue 12 h before CIDR removal and were inseminated (AI) at 48 and 60 h post CIDR withdrawal and embryos were recovered 7 days after AI. In experiment 1, the interval from CIDR insertion to follicle wave emergence (FWE) was longer (P < 0.05) in heifers treated with ODB at d1.5 (5.4 +/- 0.4 days) and d3 (5.1 +/- 0.6 days) compared to heifers treated with CIDR only (2.4 +/- 0.4 days). On the basis of time to proposed injection of pFSH heifers would have had follicle emergence 4.4, 2.3, 1.5 and 1.4 days prior to pFSH for groups I, II, III and IV, respectively

  13. Effects of prolonging administration gonadotropin on unexpectedly poor ovarian responders undergoing in vitro fertilization

    PubMed Central

    2010-01-01

    Background There are still some patients who show poor response to ovarian stimulation prior to evidence of normal ovarian reserve in vitro fertilization. However, there are few studies about how to treat the unexpectedly ovarian poor responder in vitro fertilization. The main aim of this study evaluate the effect of prolonging administration follicle-stimulating hormone in woman with the unexpectedly ovarian poor responder in vitro fertilization on implantation rate, clinical pregnancy rate and live birth rate. Methods 922 patients subjected to IVF were divided into two groups according to the predicted criterion of ovarian poor response. 116 patients predicted poor response received the short protocol (group C). The others received the long protocol, among the latter, there were 149 patients undergoing unexpectedly ovarian poor response (group B) and 657 patients exhibited normal ovarian response (group A). The doses of gonadotropin, duration of administration, implantation rate, clinical pregnancy rate and live birth rate were recorded among three groups. Results The implantation rate of embryo, clinic pregnancy rate and delivery rate are similar between the group A and group B, while there are significant differences between the doses of gonadotropins (35.1 +/- 8.9 ampules vs.53.0 +/- 15.9 ampules) and the duration of administration (15.3 +/- 3.6D vs. 9.8 +/- 2.6D) of these two groups. There are no significant differences about clinical pregnancy rate and live birth rate between group B and group C. Conclusion Prolonging administration gonadotropin on the unexpectedly poor ovarian responders does not lower live birth rate in vitro fertilization. PMID:20236519

  14. Granulosa cell apoptosis, aromatase activity, cyclic adenosine 3',5'-monophosphate response to gonadotropins, and follicular fluid steroid levels during spontaneous and induced follicular atresia in ewes.

    PubMed

    Jolly, P D; Tisdall, D J; De'ath, G; Heath, D A; Lun, S; Hudson, N L; McNatty, K P

    1997-04-01

    the number of follicles per ewe with aromatase activity (p < 0.05) and with follicular fluid E2 > 20 ng/ml (p < 0.05). By 24 h after bFF treatment, apoptosis was evident in all follicles (> or = 3 mm diameter), fewer follicles contained FSH-responsive granulosa cells in terms of cAMP production (p < 0.05), and none were LH-responsive. A significant negative relationship was found between the degree of granulosa cell death as measured by L1 and follicular fluid E2 concentrations. In summary, the presence of apoptotic granulosa cells in an appreciable number of follicles considered to be healthy by morphometric criteria and before their commitment to preovulatory enlargement and ovulation suggests that apoptosis may be a physiological process in developing follicles and/or a very early event in atresia. Collectively, these data provide strong evidence that granulosa cells may die by apoptosis before there is an appreciable decrease in the capacity of the granulosa cell layer as a whole to respond to gonadotropins or to produce E2. PMID:9096862

  15. Side Effects of Injectable Fertility Drugs (Gonadotropins)

    MedlinePlus

    ... usually are used during fertility treatments such as intrauterine insemination (IUI) or in vitro fertilization (IVF). Injections of gonadotropins ... Gestation. When using injectable gonadotropins alone or with IUI, up to 30% of pregnancies are associated with ...

  16. Spin response of a normal Fermi liquid with noncentral interactions

    SciTech Connect

    Pethick, C. J.; Schwenk, A.

    2009-11-15

    We consider the spin response of a normal Fermi liquid with noncentral interactions under conditions intermediate between the collisionless and hydrodynamic regimes. This problem is of importance for calculations of neutrino properties in dense matter. By expressing the deviation of the quasiparticle distribution function from equilibrium in terms of eigenfunctions of the transport equation under the combined influence of collisions and an external field, we derive a closed expression for the spin-density-spin-density response function and compare its predictions with that of a relaxation-time approximation. Our results indicate that the relaxation-time approximation is reliable for neutrino properties under astrophysically relevant conditions.

  17. Biologically Active Chorionic Gonadotropin: Synthesis by the Human Fetus

    NASA Astrophysics Data System (ADS)

    McGregor, W. G.; Kuhn, R. W.; Jaffe, R. B.

    1983-04-01

    The kidney, and to a slight extent the liver, of human fetuses were found to synthesize and secrete the α subunit common to glycoprotein hormones. Fetal lung and muscle did not synthesize this protein. Since fetal kidney and liver were previously found to synthesize β chorionic gonadotropin, their ability to synthesize bioactive chorionic gonadotropin was also determined. The newly synthesized hormone bound to mouse Leydig cells and elicited a biological response: namely, the synthesis of testosterone. These results suggest that the human fetus may participate in metabolic homeostasis during its development.

  18. Suppression of normal speech disfluencies through response cost1

    PubMed Central

    Siegel, Gerald M.; Lenske, Joanne; Broen, Patricia

    1969-01-01

    The speech disfluencies of five normal-speaking college students were modified in a series of 10 to 17 sessions by means of response cost. During Point-loss, each disfluency (repetition or interjection of a sound, syllable, word, etc.) resulted in the loss of a penny, as indicated on a screen in front of the subject. Disfluencies were suppressed and kept at very low levels for four of the subjects during the punishment procedures, and there was general resistance to extinction. Even though points were subtracted only during speech, there was a tendency for disfluencies to decrease, though not as markedly, during reading probes as well. PMID:16795231

  19. Heightened airway responsiveness in normal female children compared with adults.

    PubMed

    Tepper, R S; Stevens, J; Eigen, H

    1994-03-01

    Studies have suggested that airway responsiveness declines with maturation; however, studies comparing infants, children, and adults are confounded by differences in size as well as maturation. Therefore, to determine whether maturation has a significant affect on airway responsiveness, we compared normal female children (n = 9; mean age = 13.6 yr) and adults (n = 7; mean age = 42.4 yr) who were matched for body size. Bronchial challenge tests were performed with increasing methacholine concentrations to a maximum of 30 mg/ml. At baseline, there were no significant differences between the two groups in lung volumes (TGV, RV, TLC) or flow-volume curves (FEV1, average forced expiratory flow rate between 25% and 75% of the vital capacity [FEF25-75], FVC). All subjects but one adolescent completed the challenge (30 mg/ml). The children had a greater percentage decline from baseline in FEV1 than the adults (17 versus 7%, p < 0.03). The percentage decline in FEF25-75 was greater for the children than for the adults, but the difference was not statistically significant (35 versus 20%, p < 0.10). Compared with the children, the adults more often demonstrated a plateau in their dose-response curves for FEV1 (22 versus 86%) and for FEF25-75 (33 versus 100%). We conclude that normal female children have a greater airway responsiveness to inhaled methacholine than do adults, and that this difference is not related to baseline lung size, airway caliber, or delivered methacholine dose. PMID:8118636

  20. Cephalic phase metabolic responses in normal weight adults.

    PubMed

    Bruce, D G; Storlien, L H; Furler, S M; Chisholm, D J

    1987-08-01

    The presence and physiologic importance of cephalic phase insulin release in humans remains controversial. The aim of these studies was to determine whether cephalic phase insulin release could be demonstrated in normal weight subjects and whether it would be associated with changes in blood glucose, free fatty acid, and pancreatic polypeptide levels. The studies were followed by a hyperglycemic clamp to determine whether cephalic responses would alter overall glucose disposal or glucose-stimulated insulin secretion. In all, 17 subjects were studied on two occasions with and without (control study) presentation of food stimuli. Tease-feeding alone (n = 6), or the administration of a sweet taste alone (aspartame, n = 5) failed to stimulate cephalic responses. However, the presentation of the combined stimuli (tease meals plus sweet taste, n = 7) resulted in a significant fall (P less than .005) in blood glucose levels and a variable rise in serum insulin (% insulin rise 38 +/- 15%, P less than .05) and C-peptide levels (7 +/- 6%, NS) within five minutes of the food presentation when compared with control studies, with no change seen in free fatty acid or pancreatic polypeptide levels. The blood glucose fall correlated strongly (r = .90, P less than .01) with a score of the subjective response to the food and taste.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3298939

  1. Universal temperature-dependent normalized optoacoustic response of blood

    NASA Astrophysics Data System (ADS)

    Petrova, Elena V.; Liopo, Anton; Oraevsky, Alexander A.; Ermilov, Sergey A.

    2015-03-01

    We found and interpreted the universal temperature-dependent optoacoustic (photoacoustic) response (ThOR) in blood; the normalized ThOR is invariant with respect to hematocrit at the hemoglobin's isosbestic point. The unique compartmentalization of hemoglobin, the primary optical absorber at 805 nm, inside red blood cells (RBCs) explains the effect. We studied the temperature dependence of Gruneisen parameter in blood and aqueous solutions of hemoglobin and for the first time experimentally observed transition through the zero optoacoustic response at temperature T0, which was proved to be consistent for various blood samples. On the other hand, the hemoglobin solutions demonstrated linear concentration function of the temperature T0. When this function was extrapolated to the average hemoglobin concentration inside erythrocytes, the temperature T0 was found equivalent to that measured in whole and diluted blood. The obtained universal curve of blood ThOR was validated in both transparent and light scattering media. The discovered universal optoacoustic temperature dependent blood response provides foundation for future development of non-invasive in vivo temperature monitoring in vascularized tissues and blood vessels.

  2. The normal response to prolonged passive head up tilt testing

    PubMed Central

    Petersen, M; Williams, T; Gordon, C; Chamberlain-Webbe..., R; Sutton, R

    2000-01-01

    OBJECTIVE—To define the responses to head up tilt in a large group of normal adult subjects using the most widely employed protocol for tilt testing.
METHODS—127 normal subjects aged 19-88 years (mean (SD), 49 (20) years) without a previous history of syncope underwent tilt testing at 60° for 45 minutes or until syncope intervened. Blood pressure monitoring was performed with digital photoplethysmography, providing continuous, non-invasive, beat to beat heart rate and pressure measurements.
RESULTS—13% of subjects developed vasovagal syncope after a mean (SD) tilt time of 31.7 (12.4) minutes (range 8.5-44.9 minutes). Severe cardioinhibition during syncope was observed less often than is reported in patients investigated for syncope. There were no differences in the age or sex distributions of subjects with positive or negative outcomes, or in the proportions with cardioinhibitory and vasodepressor vasovagal syncope compared with previously reported patient populations. Subjects with negative outcomes showed age related differences in heart rate and blood pressure behaviour throughout tilt.
CONCLUSIONS—False positive results with tilting appear to be common. This has important implications for the use of diagnostic tilt testing. The magnitude of the heart rate and blood pressure changes observed during negative tilts largely invalidates previously suggested criteria for abnormal non-syncopal outcomes.


Keywords: syncope; head up tilt; postural hypotension PMID:11040011

  3. Regulation of tonic gonadotropin release in prepubertal female hamsters

    SciTech Connect

    Smith, S.G.; Matt, K.S.; Prestowitz, W.F.; Stetson, M.H.

    1982-04-01

    Basal serum gonadotropin levels were monitored weekly in female hamsters from birth to 10 weeks of age. Hamsters raised on three different photoperiods presented uniform pre- and postpubertal patterns of serum LH and FSH, suggesting that gonadotropin release in the young hamster occurs independently of ambient photoperiod. In all groups, serum LH levels increased gradually in animals up to 4 weeks of age, after which levels plateaued at 50--100 ng/ml. Serum FSH was markedly elevated in 2- and 3-week-old hamsters (800--1200 ng/ml), but remained at 200--400 ng/ml in all other groups. We next examined the change in the responsiveness of the pituitary to exogenous gonadotropin-releasing hormone (GnRH) challenge. Female hamsters 2 days of age failed to respond to any dose (0.025--1000 ng) of GnRH, while 10-day old females responded in typical dose-dependent fashion. GnRH-stimulated LH release first occurred in 6-day-old hamsters and was maximal by day 9, whereas FSH release first occurred on day 8 and was maximal by day 9. The prepubertal pattern of gonadotropin release can, in part, be explained on the basis of the development of pituitary GnRH sensitivity, which occurs independently of photoperiod.

  4. The postural response of normal dogs to sinusoidal displacement

    PubMed Central

    Brookhart, John M.; Talbott, Richard E.

    1974-01-01

    1. Normal dogs were trained to adopt a laterally symmetric stance on a horizontal platform. Sinusoidal oscillation of the platform in the cephalocaudal direction caused the dogs to adopt a strategy of response which would keep them from falling down during the period of imposed motion or perturbation. 2. A Fourier analysis of the response variables provided a quantitative measure of the distortion in the induced movement at the various hind leg joints and in the motion of the body. Certain aspects of the distortion could be accounted for by recognized random events such as drift and panting. The remainder of the distortion was task related and therefore provided evidence that the dog's postural control system behaved essentially as a non-linear system. 3. The motion of the body was less distorted than the motion at the joints. The frequency response of the body motion resembled that of a second order linear system, but the amplitude of the body motion did not vary in constant proportion with changes in the amplitude of the input. Further, the phase relation between body motion and platform motion was not constant when the amplitude of the input was changed. Therefore, it was concluded that the control of the body position was probably non-linearly related to the input disturbance but that the low pass filter characteristics tended to minimize the appearance of distortion in that system output. 4. Control of the position of the hind limb is related to the control of the torque generated at the hind limb joints. To the extent that joint angle and change in joint angle are related to the torque at a joint, the distortion of the motion at the joints clearly demonstrates that control of the hind limb during this postural task was non-linearly related to the sinusoidal input. 5. The uniformity of the response parameters, as assessed from the Fourier coefficients, indicated that all of the tested dogs adopted the same or nearly the same strategy for solving the problem of

  5. Photoacoustic monitoring of tumor and normal tissue response to radiation

    PubMed Central

    Rich, Laurie J.; Seshadri, Mukund

    2016-01-01

    Hypoxia is a recognized characteristic of tumors that influences efficacy of radiotherapy (RT). Photoacoustic imaging (PAI) is a relatively new imaging technique that exploits the optical characteristics of hemoglobin to provide information on tissue oxygenation. In the present study, PAI based measures of tumor oxygen saturation (%sO2) were compared to oxygen-enhanced magnetic resonance imaging (MRI) measurements of longitudinal relaxation rate (R1 = 1/T1) and ex-vivo histology in patient derived xenograft (PDX) models of head and neck cancer. PAI was utilized to assess early changes (24 h) in %sO2 following RT and chemoRT (CRT) and to assess changes in salivary gland hemodynamics following radiation. A significant increase in tumor %sO2 and R1 was observed following oxygen inhalation. Good spatial correlation was observed between PAI, MRI and histology. An early increase in %sO2 after RT and CRT detected by PAI was associated with significant tumor growth inhibition. Twenty four hours after RT, PAI also detected loss of hemodynamic response to gustatory stimulation in murine salivary gland tissue suggestive of radiation-induced vascular damage. Our observations illustrate the utility of PAI in detecting tumor and normal tissue hemodynamic response to radiation in head and neck cancers. PMID:26883660

  6. A high response to controlled ovarian stimulation induces premature luteinization with a negative impact on pregnancy outcomes in a gonadotropin-releasing hormone antagonist cycle

    PubMed Central

    Koo, Hwa Seon; Cha, Sun Hwa; Kim, Hye Ok; Song, In Ok; Min, Eung Gi; Yang, Kwang Moon

    2015-01-01

    Objective The goal of this study was to investigate the relationship between serum progesterone (P4) levels on the day of human chorionic gonadotropin (hCG) administration and the pregnancy rate among women undergoing controlled ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET) using a flexible antagonist protocol. Methods This prospective study included 200 IVF and ICSI-ET cycles in which a flexible antagonist protocol was used. The patients were divided into five distinct groups according to their serum P4 levels at the time of hCG administration (0.80, 0.85, 0.90, 0.95, and 1.00 ng/mL). The clinical pregnancy rate (CPR) was calculated for each P4 interval. Statistically significant differences were observed at a serum P4 level of 0.9 ng/mL. These data suggest that a serum P4 concentration of 0.9 ng/mL may represent the optimal threshold level for defining premature luteinization (PL) based on the presence of a significant negative impact on the CPR. Results The CPR for each round of ET was significantly lower in the PL group defined using this threshold (25.8% vs. 41.8%; p=0.019), and the number of oocytes retrieved was significantly higher than in the non-PL group (17.3±7.2 vs. 11.0±7.2; p=0.001). Elevated serum P4 levels on the day of hCG administration were associated with a reduced CPR, despite the retrieval of many oocytes. Conclusion Measuring serum P4 values at the time of hCG administration is necessary in order to determine the optimal strategy for embryo transfer. PMID:26816874

  7. The effect of dietary monensin on th luteinizing hormone response of prepuberal heifers given a multiple gonadotropin-releasing hormone challenge.

    PubMed

    Randel, R D; Rhodes, R C

    1980-10-01

    Ten prepuberal Simmental X Brahman-Hereford heifers (average weight 208 +/- 4 kg) were randomly assigned to receive either 2.7 kg/head/day of ground milo containing 0 mg monensin sodium (C) or 2.7 kg/head/day of ground milo containing 200 mg monensin sodium (M). Both groups of animals (n = 5) received Coastal bermudagrass hay ad libitum throughout the trial. On day 21 of the feeding period all heifers were fitted with jugular cannulas. Immediately after cannulation, the heifers were injected IM with 100 microgram of gonadotropin-releasing hormone (GnRH) and blood was collected every 10 min for 4 hours. Four hours after the first GnRH challenge, a second 100-microgram GnRH injection was administered, and blood samples were collected at 10-min intervals for an additional 5 hours. Serum was stored at -20 C until radioimmunoassayed for luteinizing hormone (LH). The amount of LH released after each GnRH injection was greater in the heifers fed M than in the controls (P less than .05). Peak LH after the first GnRH challenge was greater (P less than .05) in heifers fed M than in controls. The area under th first GnRH induced LH curve tended (P less than .20) to be greater for the M group than for the controls. Peak LH concentration was greater in heifers fed M than in control heifers, as the duration (P less than .05) and area under the second GnRH-induced LH curve. In prepuberal heifers, dietary monensin appears to increase hypophyseal capability of releasing LH after a first and second GnRH challenge. PMID:7007307

  8. Variable X-linked recessive hypopituitarism with evidence of gonadotropin deficiency in two pre-pubertal males.

    PubMed

    Zipf, W B; Kelch, R P; Bacon, G E

    1977-04-01

    Two half-brothers with short stature secondary to growth hormone deficiency and a family history implicating X-linked transmission were studied extensively for other endocrine abnormalities. The proband had a normal physical examination, except for small stature and small external genitalia. ACTH and TSH release were normal. LH and FSH responses during an i.v. GnRH test were severely blunted. His half-brother also had a normal physical examination, except for severe short stature and very small external genitalia. Deficiencies of ACTH, and TSH as well as GH were documented. An i.v. GnRH test showed no LH or FSH response. These studies support the existence of an X-linked recessive form of hypopituitarism and portend the clinical usefulness of the i.v. GnRH test in evaluating gonadotropin reserve. PMID:192503

  9. Pharmacological control of the hormonally modulated immune response. II. Blockade of antibody production by a combination of drugs acting on neuroendocrine functions. Its prevention by gonadotropins and corticotrophin.

    PubMed Central

    Pierpaoli, W; Maestroni, G J

    1978-01-01

    Injection of a combination of three drugs, 5-hydroxytryptophan, the alpha-blocker phentolamine and the neuroleptic drug haloperidol into mice before or together with sheep red blood cells (SRBC) induces a complete and long-lasting inhibition of antibody production to SRBC and leads to specific unresponsiveness. The mice unresponsive to SRBC respond normally to another antigen. Treatment with a combination of luteotropic (LH), follicle stimulating (FSH) and corticotropic hormone (ACTH) before administration of drugs and antigen prevents the immune blockade. Injection of SRBC induces an early elevation of LH in blood. This effect is prevented by previous administration of the three drugs in combination. The hormonal response to a second injection of the same antigen of mice previously made 'unresponsive' is different from that of immunized animals. The suppression of these hormonal changes which follow antigen injection by drugs acting on neuroendocrine regulation and cell membrane adrenergic receptors represents a step forward in efforts aimed at a pharmacological control of acquired immunity. PMID:205502

  10. Activation of the chicken gonadotropin-inhibitory hormone receptor reduces gonadotropin releasing hormone receptor signaling.

    PubMed

    Shimizu, Mamiko; Bédécarrats, Grégoy Y

    2010-06-01

    Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic peptide from the RFamide peptide family that has been identified in multiple avian species. Although GnIH has clearly been shown to reduce LH release from the anterior pituitary gland, its mechanism of action remains to be determined. The overall objectives of this study were (1) to characterize the GnIH receptor (GnIH-R) signaling pathway, (2) to evaluate potential interactions with gonadotropin releasing hormone type III receptor (GnRH-R-III) signaling, and (3) to determine the molecular mechanisms by which GnIH and GnRH regulate pituitary gonadotrope function during a reproductive cycle in the chicken. Using real-time PCR, we showed that in the chicken pituitary gland, GnIH-R mRNA levels fluctuate in an opposite manner to GnRH-R-III, with higher and lower levels observed during inactive and active reproductive stages, respectively. We demonstrated that the chicken GnIH-R signals by inhibiting adenylyl cyclase cAMP production, most likely by coupling to G(alphai). We also showed that this inhibition is sufficient to significantly reduce GnRH-induced cAMP responsive element (CRE) activation in a dose-dependent manner, and that the ratio of GnRH/GnIH receptors is a significant factor. We propose that in avian species, sexual maturation is characterized by a change in GnIH/GnRH receptor ratio, resulting in a switch in pituitary sensitivity from inhibitory (involving GnIH) to stimulatory (involving GnRH). In turn, decreasing GnIH-R signaling, combined with increasing GnRH-R-III signaling, results in significant increases in CRE activation, possibly initiating gonadotropin synthesis. PMID:20350548

  11. Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph

    SciTech Connect

    Winterer, J.; Barnes, K.M.; Lichter, A.S.; Deluca, A.M.; Loriaux, D.L.; Cutler, G.B. Jr.

    1988-03-01

    To test the hypothesis that the functional state of hypothalamic LHRH neurons and pituitary gonadotrophs might alter their radiosensitivity, we determined the experimental conditions under which the gonadotropin response to castration could be impaired by a single dose of cranial irradiation. Single doses of cranial irradiation greater than 2000 rads were lethal to unshielded rats. Shielding of the oropharynx and esophagus allowed the animals to survive doses up to 5000 rads. Doses between 2000 and 5000 rads had no effect on basal gonadotropin levels for as long as 3 months after irradiation. Irradiation caused a dose- and time-dependent impairment, however, in the gonadotropin response to castration. Impairment of the gonadotropin levels of castrate animals occurred in animals that were irradiated either before or after castration. However, rats irradiated in the castrate state showed a decreased susceptibility to irradiation damage. Additionally, stimulation of the pituitary by LHRH agonist (LHRHa) 3 h before irradiation significantly reduced the impairment of gonadotropin secretion 12-20 weeks after irradiation (P less than 0.05). Thus, increased functional activity of the rat hypothalamus or pituitary at the time of irradiation, induced by either castration or acute LHRHa administration, was associated with some protection against the gonadotropin-lowering effect of irradiation. Based upon these data, we hypothesize that stimulation of gonadotropin secretion at the time of therapeutic cranial irradiation in humans might protect against subsequent impairment of gonadotropin secretion.

  12. Clinical iron deficiency disturbs normal human responses to hypoxia

    PubMed Central

    Frise, Matthew C.; Cheng, Hung-Yuan; Nickol, Annabel H.; Curtis, M. Kate; Pollard, Karen A.; Roberts, David J.; Ratcliffe, Peter J.; Dorrington, Keith L.; Robbins, Peter A.

    2016-01-01

    BACKGROUND. Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia. METHODS. We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography. RESULTS. Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7–9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, –8.3 to –0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups. CONCLUSION. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01847352). FUNDING. M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was

  13. Monoclonal antibodies to gonadotropin subunits

    SciTech Connect

    Ehrlich, P.H.; Moyle, W.R.; Canfield, R.E.

    1985-01-01

    The production of monoclonal antibodies to peptide hormones, with their unifocal binding sites, can provide tools for understanding hormone structure and function. The paper focuses on techniques that are important for the study of monoclonal antibodies to chorionic gonadotropin (hCG), including hybridoma production, methods of screening for desired clones, properties of the monoclonal antibodies, effect of antibodies on hormone-receptor interaction, inhibition of binding of radiolabeled hCG, inhibition of hCG induced steroidogenesis, determination of relative orientation of epitopes, and synergistic actions of monoclonal antibodies to hCG.

  14. Gonadotropin therapy: a 20th century relic.

    PubMed

    Reindollar, Richard H; Goldman, Marlene B

    2012-04-01

    Gonadotropin therapy has been a cornerstone of infertility therapy for half a century. From the very beginning, its use has been associated with a high rate of multiple births, particularly high order multiples, and ovarian hyperstimulation syndrome. Initially, success rates seemed acceptable when used for superovulation (SO)/IUI therapy. However, as data from RCTs have emerged, reported outcomes suggest that we question the use of injectible gonadotropins. This manuscript examines the studies that have challenged gonadotropin use for SO/IUI and other research that supports reduced doses of gonadotropins for IVF. We examine the challenges for its continued use for SO/IUI and for moving to lower doses worldwide for IVF. We propose a future that views gonadotropins as a relic of the twentieth century. PMID:22463775

  15. Magnetic response measurements of mesoscopic superconducting and normal metal rings

    NASA Astrophysics Data System (ADS)

    Bluhm, Hendrik

    The main part of this thesis reports three experiments on the magnetic response of mesoscopic superconducting and normal metal rings using a scanning SQUID microscope. The first experiment explores the magnetic response and fluxoid transitions of superconducting, mesoscopic bilayer aluminum rings in the presence of two coupled order parameters arising from the layered structure. For intermediate couplings, metastable states that have different phase winding numbers around the ring in each of the two order parameters were observed. Larger coupling locks the relative phase, so that the two order parameters are only manifest in the temperature dependence of the response. With increasing proximitization, this signature gradually disappears. The data can be described with a two-order-parameter Ginzburg-Landau theory. The second experiment concentrates on fluxoid transitions in similar, but single-layer rings. Near the critical temperature, the transitions, which are induced by applying a flux to the ring, only admit a single fluxoid at a time. At lower temperatures, several fluxoids enter or leave at once, and the final state approaches the ground state. Currently available theoretical frameworks cannot quantitatively explain the data. Heating and quasiparticle diffusion are likely important for a quantitative understanding of this experiment, which could provide a model system for studying the nonlinear dynamics of superconductors far from equilibrium. The third and most important scanning SQUID study concerns 33 individual mesoscopic gold rings. All measured rings show a paramagnetic linear susceptibility and a poorly understood anomaly around zero field, both of which are likely due to unpaired defect spins. The response of sufficiently small rings also has a component that is periodic in the flux through the ring, with a period close to h/e. Its amplitude varies in sign and magnitude from ring to ring, and its typical value and temperature dependence agree with

  16. Pattern of human chorionic gonadotropin binding in the polycystic ovary

    SciTech Connect

    Brawer, J.; Richard, M.; Farookhi, R. )

    1989-08-01

    The histologic evolution of polycystic ovaries in the estradiol valerate-treated rat coincides with the development of a unique plasma pattern of luteinizing hormone. To assess the role of luteinizing hormone in polycystic ovaries, it is necessary to evaluate the luteinizing hormone sensitivity of the specific tissues in the polycystic ovary. Therefore, we examined the pattern of luteinizing hormone binding sites in polycystic ovaries. Rats at 4 or 8 weeks after estradiol valerate treatment each received an intrajugular injection of iodine 125-labeled human chorionic gonadotropin. Some rats also received a 1000-fold excess of unlabeled human chorionic gonadotropin in the same injection. Ovaries were prepared for autoradiography. Dense accumulations of grains occurred over the theca of normal and atretic secondary follicles in all ovaries and over clusters of secondary interstitial cells. The iodine label was variable over the typically hypertrophied theca of precystic follicles. The theca of definitive cysts showed little or no label. These results indicate that cyst formation coincides with the loss of luteinizing hormone/human chorionic gonadotropin binding to the affected follicles.

  17. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility

    PubMed Central

    Diamond, M.P.; Legro, R.S.; Coutifaris, C.; Alvero, R.; Robinson, R.D.; Casson, P.; Christman, G.M.; Ager, J.; Huang, H.; Hansen, K.R.; Baker, V.; Usadi, R.; Seungdamrong, A.; Bates, G.W.; Rosen, R.M.; Haisenleder, D.; Krawetz, S.A.; Barnhart, K.; Trussell, J.C.; Ohl, D.; Jin, Y.; Santoro, N.; Eisenberg, E.; Zhang, H.

    2015-01-01

    BACKGROUND The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P = 0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P = 0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P = 0.15) or clomiphene alone (8 of 85, 9%; P = 0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P = 0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; Clinical

  18. RESPONSES OF BRIGHT, NORMAL, AND RETARDED CHILDREN TO LEARNING TASKS.

    ERIC Educational Resources Information Center

    CARRIER, NEIL A.; AND OTHERS

    THE RELATIONSHIPS AMONG THE VARIABLES OF INTELLIGENCE, LEARNING TASK PERFORMANCE, EMOTIONAL TENSION, AND TASK MOTIVATION WERE STUDIED. ABOUT 120 BRIGHT, NORMAL, AND RETARDED CHILDREN PERFORMED SIX TRIALS OF NUMBER LEARNING, CONCEPT FORMATION, PROBLEM SOLVING, PERCEPTUAL-MOTOR COORDINATION, AND VERBAL LEARNING TASKS. DURING THE LEARNING SESSIONS,…

  19. Is the assumption of normality or log-normality for continuous response data critical for benchmark dose estimation?

    SciTech Connect

    Shao, Kan; Gift, Jeffrey S.; Setzer, R. Woodrow

    2013-11-01

    Continuous responses (e.g. body weight) are widely used in risk assessment for determining the benchmark dose (BMD) which is used to derive a U.S. EPA reference dose. One critical question that is not often addressed in dose–response assessments is whether to model the continuous data as normally or log-normally distributed. Additionally, if lognormality is assumed, and only summarized response data (i.e., mean ± standard deviation) are available as is usual in the peer-reviewed literature, the BMD can only be approximated. In this study, using the “hybrid” method and relative deviation approach, we first evaluate six representative continuous dose–response datasets reporting individual animal responses to investigate the impact on BMD/BMDL estimates of (1) the distribution assumption and (2) the use of summarized versus individual animal data when a log-normal distribution is assumed. We also conduct simulation studies evaluating model fits to various known distributions to investigate whether the distribution assumption has influence on BMD/BMDL estimates. Our results indicate that BMDs estimated using the hybrid method are more sensitive to the distribution assumption than counterpart BMDs estimated using the relative deviation approach. The choice of distribution assumption has limited impact on the BMD/BMDL estimates when the within dose-group variance is small, while the lognormality assumption is a better choice for relative deviation method when data are more skewed because of its appropriateness in describing the relationship between mean and standard deviation. Additionally, the results suggest that the use of summarized data versus individual response data to characterize log-normal distributions has minimal impact on BMD estimates. - Highlights: • We investigate to what extent the distribution assumption can affect BMD estimates. • Both real data analysis and simulation study are conducted. • BMDs estimated using hybrid method are more

  20. Ovarian and endocrine responses associated with the treatment of cystic ovarian follicles in dairy cows with gonadotropin releasing hormone and prostaglandin F2α, with or without exogenous progesterone

    PubMed Central

    2004-01-01

    Abstract The objectives of this observational study were to document ovarian and endocrine responses associated with the treatment of cystic ovarian follicles (COFs) in dairy cows, using gonadotropin releasing hormone (GnRH) and prostaglandin F2α(PGF) with or without exogenous progesterone. A secondary objective was to determine pregnancy establishment following synchronization of ovulation and timed insemination in cows diagnosed with COFs. In trial I, 18 Holstein cows diagnosed with COFs received 2 injections of 100 μg GnRH, 9 d apart, with 25 mg PGF given 7 d after the 1st GnRH. A new follicle developed in all 18 cows after the 1st GnRH, and 83% of cows ovulated following the 2nd GnRH. Cows were inseminated 16 h after the 2nd GnRH. Of the 17 cows available for pregnancy diagnosis, 7 were confirmed pregnant. In trial II, 8 cows with COFs received GnRH and an intravaginal progesterone device (CIDR) concurrently, then PGF 7 d later. The CIDR was removed 2 d after PGF administration. Plasma estradiol concentrations declined following CIDR insertion. In all cows, a new follicle developed following GnRH treatment; estradiol-surge and estrus occurred spontaneously after CIDR-removal. Seven of 8 cows ovulated the new follicle. In dairy cows diagnosed with COFs, treatment with GnRH followed by PGF 7 d later, with or without exogenous progesterone, resulted in the recruitment of a healthy new follicle; synchronization of ovulation and timed insemination resulted in a 41% pregnancy rate. PMID:15600159

  1. Coupling of metabolism and cardiovascular response represents normal physiology.

    PubMed

    Steinberg, Helmut O

    2003-12-01

    In this issue of Clinical Science, Fugmann and co-workers demonstrate a highly integrated cardiovascular response to changes in plasma concentrations of glucose, triacylglycerols (triglycerides), fatty acids and insulin. Since the different substrates, alone and combined, evoked these changes, this response is likely to be a physiological one and directed towards minimizing the extent and duration of substrate elevations that could cause vascular dysfunction. PMID:12917009

  2. Gonadotropin-regulated Testicular RNA Helicase (GRTH/DDX25), a Negative Regulator of Luteinizing/Chorionic Gonadotropin Hormone-induced Steroidogenesis in Leydig Cells

    PubMed Central

    Fukushima, Masato; Villar, Joaquin; Tsai-Morris, Chon-Hwa; Dufau, Maria L.

    2011-01-01

    Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is a testis-specific gonadotropin-regulated RNA helicase that is present in Leydig cells (LCs) and germ cells and is essential for spermatid development and completion of spermatogenesis. Normal basal levels of testosterone in serum and LCs were observed in GRTH null (GRTH−/−) mice. However, testosterone production was enhanced in LCs of GRTH−/− mice compared with WT mice by both in vivo and in vitro human chorionic gonadotropin stimulation. LCs of GRTH−/− mice had swollen mitochondria with a significantly increased cholesterol content in the inner mitochondrial membrane. Basal protein levels of SREBP2, HMG-CoA reductase, and steroidogenic acute regulatory protein (StAR; a protein that transports cholesterol to the inner mitochondrial membrane) were markedly increased in LCs of GRTH−/− mice compared with WT mice. Gonadotropin stimulation caused an increase in StAR mRNA levels and protein expression in GRTH−/− mice versus WT mice, with no further increase in SREBP2 and down-regulation of HMG-CoA reductase protein. The half-life of StAR mRNA was significantly increased in GRTH−/− mice. Moreover, association of StAR mRNA with GRTH protein was observed in WT mice. Human chorionic gonadotropin increased GRTH gene expression and its associated StAR protein at cytoplasmic sites. Taken together, these findings indicate that, through its negative role in StAR message stability, GRTH regulates cholesterol availability at the mitochondrial level. The finding of an inhibitory action of GRTH associated with gonadotropin-mediated steroidogenesis has provided insights into a novel negative autocrine molecular control mechanism of this helicase in the regulation of steroid production in the male. PMID:21719703

  3. Abnormal gonadotropin release and carbohydrate metabolism in morbid obese women.

    PubMed

    Sheu, W H; Lee, W J

    1997-12-31

    Obese women are associated with clinical symptoms suggestive of abnormal reproductive functions including irregular menses and infertility. Previous studies of gonadotropin release in obese women, basal or after luteal hormone releasing hormone (LHRH) stimulation, are controversial. Obese women are also often characterized by glucose intolerance and hyperinsulinemia which might relate to their excessive body fat. To understand the link between abnormal gonadotropin release, carbohydrate metabolism and percent body fat, we examined 17 premenopausal morbid obese women with body mass index (BMI) 38.7 +/- 1.6 Kg/m2 (mean +/- SEM) and 16 age-matched lean controls with BMI 19.7 +/- 0.6 Kg/m2. Plasma glucose, insulin and C-peptide values were measured before and 30, 60, 90 and 120 min after a 75 gm oral glucose tolerant test (OGTT). Each individual also received LHRH test which involved determinations of serum LH and FSH values at basal, 15, 30 and 60 min after injection of LHRH for 0.1 mg intravenously. Women with morbid obesity had significantly greater responses of glucose, insulin and C-peptide values as compared with lean women (all p < 0.001, two-way ANOVA). Despite that basal concentrations were not different, serum LH, FSH and ratio of LH to FSH values in response to LHRH test showed significantly lesser increase in obese women than lean controls. Percent body fat, determined by bioelectrical impedance analysis, correlated positively with plasma glucose, insulin and C-peptide responses to OGTT while negatively with ratio of LH to FSH responses (r = -0.418, p < 0.01) to LHRH test. Body mass index also correlated inversely with ratio of LH to FSH responses (r = -0.472, p < 0.01). In conclusion, morbid obese women had glucose intolerance, hyperinsulinemia and lower responses of serum LH and FSH values as compared with lean women. Excessive body fat play an important role in mediating these carbohydrate and gonadotropin abnormalities. PMID:9551249

  4. Characterization of renal response to prolonged immersion in normal man

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Denunzio, A. G.; Ramachandran, M.

    1980-01-01

    ?jDuring the initial phase of space flight, there is a translocation of fluid from the lower parts of the body to the central vascular compartment with a resultant natriuresis, diuresis, and weight loss. Because water immersion is regarded as an appropriate model for studying the redistribution of fluid that occurs in weightlessness, an immersion study of relatively prolonged duration was carried out in order to characterize the temporal profile of the renal adaptation to central hypervolemia. Twelve normal male subjects underwent an immersion study of 8-h duration in the sodium-replete state. Immersion resulted in marked natriuresis and diuresis which were sustained throughout the immersion period. The failure of that natriuresis and diuresis of immersion to abate or cease despite marked extracellular fluid volume contraction as evidenced by a mean weight loss of -2.2 + or - 0.3 kg suggests that central blood volume was not restored to normal and that some degree of central hypervolemia probably persisted.

  5. Imaging radiation response in tumor and normal tissue

    PubMed Central

    Rafat, Marjan; Ali, Rehan; Graves, Edward E

    2015-01-01

    Although X-ray computed tomography (CT) and magnetic resonance imaging (MRI) are the primary imaging modalities used in the clinic to monitor tumor response to radiation therapy, multi-modal molecular imaging may facilitate improved early and specific evaluation of this process. Fast and accurate imaging that can provide both quantitative and biological information is necessary to monitor treatment and ultimately to develop individualized treatment options for patients. A combination of molecular and anatomic information will allow for deeper insight into the mechanisms of tumor response, which will lead to more effective radiation treatments as well as improved anti-cancer drugs. Much progress has been made in nuclear medicine imaging probes and MRI techniques to achieve increased accuracy and the evaluation of relevant biomarkers of radiation response. This review will emphasize promising molecular imaging techniques that monitor various biological processes following radiotherapy, including metabolism, hypoxia, cell proliferation, and angiogenesis. PMID:26269771

  6. Mouse genetic approaches applied to the normal tissue radiation response

    PubMed Central

    Haston, Christina K.

    2012-01-01

    The varying responses of inbred mouse models to radiation exposure present a unique opportunity to dissect the genetic basis of radiation sensitivity and tissue injury. Such studies are complementary to human association studies as they permit both the analysis of clinical features of disease, and of specific variants associated with its presentation, in a controlled environment. Herein I review how animal models are studied to identify specific genetic variants influencing predisposition to radiation-induced traits. Among these radiation-induced responses are documented strain differences in repair of DNA damage and in extent of tissue injury (in the lung, skin, and intestine) which form the base for genetic investigations. For example, radiation-induced DNA damage is consistently greater in tissues from BALB/cJ mice, than the levels in C57BL/6J mice, suggesting there may be an inherent DNA damage level per strain. Regarding tissue injury, strain specific inflammatory and fibrotic phenotypes have been documented for principally, C57BL/6 C3H and A/J mice but a correlation among responses such that knowledge of the radiation injury in one tissue informs of the response in another is not evident. Strategies to identify genetic differences contributing to a trait based on inbred strain differences, which include linkage analysis and the evaluation of recombinant congenic (RC) strains, are presented, with a focus on the lung response to irradiation which is the only radiation-induced tissue injury mapped to date. Such approaches are needed to reveal genetic differences in susceptibility to radiation injury, and also to provide a context for the effects of specific genetic variation uncovered in anticipated clinical association studies. In summary, mouse models can be studied to uncover heritable variation predisposing to specific radiation responses, and such variations may point to pathways of importance to phenotype development in the clinic. PMID:22891164

  7. Effect of prenatal and neonatal exposure to lead on gonadotropin receptors and steroidogenesis in rat ovaries

    SciTech Connect

    Wiebe, J.P.; Barr, K.J.; Buckingham, K.D.

    1988-01-01

    Sprague-Dawley rats were treated with lead chloride (20 or 200 ppm) or sodium chloride (controls) in their drinking water, either prior to pregnancy or during pregnancy and lactation, and female offspring were examined at weaning (21 d) or at 150 d. Other female rats were treated from d 21 to 35. Tissue (blood, kidney, bone) lead levels, body, ovary, and uterus weights, ovarian steroidogenesis, and gonadotropin (luteinizing hormone and follicle-stimulating hormone) levels, and gonadotropin-receptor binding were determined. Prenatal and/or postnatal exposure to lead at these levels (20 and 200 ppm) did not affect tissue weights but did cause a significant decrease in gonadotropin-receptor binding in the prepubertal, pubertal and adult females. Conversion of progesterone to androstenedione and dihydrotestosterone was significantly decreased in 21-d-old rats; in 150-d-old females, the prenatal and/or postnatal exposure to lead resulted in significantly increased conversion to the 5-alpha-reduced steroid, normally high during puberty. The results demonstrate that lead exposure prior to mating may affect gonadotropin-receptor binding in the offspring and that lead exposure (in utero, via mother's milk, or post weaning) may significantly alter steroid production and gonadotropin binding in ovaries of the prepubertal, pubertal, and adult female.

  8. Human chorionic gonadotropin measurements in parathyroid carcinoma

    PubMed Central

    Rubin, Mishaela R; Bilezikian, John P; Birken, Steven; Silverberg, Shonni J

    2010-01-01

    Objective Preoperatively, it is difficult to differentiate between parathyroid cancer (PtCa) and severe primary hyperparathyroidism (PHPT) due to a benign tumor. Human chorionic gonadotropin (hCG) is a tumor marker in trophoblastic and nontrophoblastic cancers and hyperglycosylated hCG is increased in hCG-secreting malignancies. We investigated whether hCG can distinguish PtCa cancer from benign disease and add prognostic information. Design Observational study. Methods Measurement of urinary hCG (total and malignant isoforms) and serum malignant hCG in 8 subjects with PtCa and in 18 subjects with PHPT (measurement of urine in ten and serum in eight). Results Total urinary hCG was normal in the benign PHPT control subjects (range: 0–17 fmol/mg Cr; nl < 50). In the PtCa subjects, three had normal total urinary hCG levels and survived complication free for at least 2 years; three had persistently elevated total urinary hCG levels (range: 217–1986 fmol/mg Cr) and sustained hip fracture (n = 3) and died (n = 2) within 3 and 6 months respectively; two had a rise in total urinary hCG and had hip fracture (n = 1) and died (n = 2) within 4 and 10 months respectively. Elevated urinary hCG was of the malignant hyperglycosylated isoform. Serum malignant hyperglycosylated hCG values in all of the cancer patients exceeded the maximal serum malignant hCG level of the PHPT subjects with benign disease (3.77 pmol/l). Conclusion hCG, especially itshyperglycosylated isoform, might add diagnostic and prognostic information in PtCa. Further studies would help to elucidate the role of hCG as a potential tumor marker in this disease. PMID:18625691

  9. Induction of spermatogenesis and fertility in hypogonadotropic azoospermic men by intravenous pulsatile gonadotropin-releasing hormone (GnRH).

    PubMed

    Blumenfeld, Z; Makler, A; Frisch, L; Brandes, J M

    1988-06-01

    Gonadotropin-releasing hormone (GnRH) has only recently become a helpful tool in the medication of hypogonadotropic hypogonadism (HH). Two azoospermic patients with HH who had previously been treated with hCG/hMG because of delayed puberty and each of whom had fathered a child after previous gonadotropin therapy were referred due to secondary failure of hCG/hMG treatment to induce spermatogenesis and fertility. A pulse study where blood was drawn every 15 minutes for LH, FSH and PRL RIAs was performed in each patient, and afterwards a bolus of i.v. GnRH was injected to assess gonadotropin responsiveness. A portable GnRH pump was connected to each patient so that it administered 5-20 micrograms of GnRH i.v. every 89 minutes. Spermatogenesis was first detected after 42 and 78 days respectively in the 2 treated HH men and 4 1/2 months from the start of treatment their wives became pregnant. No thrombophlebitis or other complications of the i.v. therapy occurred. In the case of the first patient, the semen was washed and concentrated and intra-uterine inseminations were carried out in an attempt to shorten the time needed to achieve fertility. The first pregnancy was successfully terminated at 38 weeks with the delivery of 2 heterozygotic normal male babies. The second pregnancy ended in spontaneous delivery of a healthy female. We conclude that i.v. pulsatile, intermittent GnRH administration is a safe, efficient and highly successful means of treating azoospermic men with HH. PMID:3055820

  10. Psychological response to growth hormone treatment in short normal children.

    PubMed Central

    Downie, A B; Mulligan, J; McCaughey, E S; Stratford, R J; Betts, P R; Voss, L D

    1996-01-01

    This study provides a controlled assessment of the psychological (and physical) effects of growth hormone treatment. Fifteen short 'normal' children (height SD score < -2) have been treated with growth hormone since the age of 7/8 years. They, together with untreated short controls and average controls (10th-90th centiles), were assessed at recruitment, after three years, and after five years. Only the treated group showed a significant height increase (SD score -2.44 to -1.21 over five years). No significant differences were found at recruitment, three years, or five years in IQ, attainment, behaviour, or self esteem. Also at five years, there were no significant differences in locus of control, self perception, or parental perceptions of competence. Both short groups displayed less satisfaction with their height than the controls (p < 0.01), though all groups were optimistic of being tall adults. The treated children were no more unrealistic over final height than the untreated children. To date, no psychological benefits of treatment have been demonstrated; but nor have there been any discernible ill effects for either the treated or the untreated children. PMID:8813867

  11. A normal tissue dose response model of dynamic repair processes

    NASA Astrophysics Data System (ADS)

    Alber, Markus; Belka, Claus

    2006-01-01

    A model is presented for serial, critical element complication mechanisms for irradiated volumes from length scales of a few millimetres up to the entire organ. The central element of the model is the description of radiation complication as the failure of a dynamic repair process. The nature of the repair process is seen as reestablishing the structural organization of the tissue, rather than mere replenishment of lost cells. The interactions between the cells, such as migration, involved in the repair process are assumed to have finite ranges, which limits the repair capacity and is the defining property of a finite-sized reconstruction unit. Since the details of the repair processes are largely unknown, the development aims to make the most general assumptions about them. The model employs analogies and methods from thermodynamics and statistical physics. An explicit analytical form of the dose response of the reconstruction unit for total, partial and inhomogeneous irradiation is derived. The use of the model is demonstrated with data from animal spinal cord experiments and clinical data about heart, lung and rectum. The three-parameter model lends a new perspective to the equivalent uniform dose formalism and the established serial and parallel complication models. Its implications for dose optimization are discussed.

  12. The general and comparative biology of gonadotropin-inhibitory hormone (GnIH).

    PubMed

    Tsutsui, Kazuyoshi; Bentley, George E; Ubuka, Takayoshi; Saigoh, Etsuko; Yin, Hong; Osugi, Tomohiro; Inoue, Kazuhiko; Chowdhury, Vishwajit S; Ukena, Kazuyoshi; Ciccone, Nick; Sharp, Peter J; Wingfield, John C

    2007-01-01

    The decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion. Gonadal sex steroids and inhibin inhibit gonadotropin secretion via feedback from the gonads, but a neuropeptide inhibitor of gonadotropin secretion was, until recently, unknown in vertebrates. In 2000, we identified a novel hypothalamic dodecapeptide that inhibits gonadotropin release in cultured quail pituitaries and termed it gonadotropin-inhibitory hormone (GnIH). To elucidate the mode of action of GnIH, we then identified a novel G protein-coupled receptor for GnIH in quail. The GnIH receptor possesses seven transmembrane domains and specifically binds to GnIH. The GnIH receptor is expressed in the pituitary and several brain regions including the hypothalamus. These results indicate that GnIH acts directly on the pituitary via GnIH receptor to inhibit gonadotropin release. GnIH may also act on the hypothalamus to inhibit GnRH release. To demonstrate the functional significance of GnIH and its potential role as a key regulatory neuropeptide in avian reproduction, we investigated GnIH actions on gonadal development and maintenance in quail. Chronic treatment with GnIH inhibited gonadal development and maintenance by decreasing gonadotropin synthesis and release. GnIH was also found in the hypothalamus of other avian species including sparrows and chickens and also inhibited gonadotropin synthesis and release. The pineal hormone melatonin may be a key factor controlling GnIH neural function, since quail GnIH neurons express melatonin receptor and melatonin treatment stimulates the expression of GnIH mRNA and mature GnIH peptide. Thus, GnIH is capable of transducing photoperiodic information via changes in the melatonin signal, thereby influencing the reproductive axis. It is concluded that GnIH, a newly discovered hypothalamic neuropeptide, is a key factor controlling avian reproduction. The discovery of avian GnIH opens

  13. Effect of certain toxicants on gonadotropin-induced ovarian non-esterified cholesterol depletion and steroidogenic enzyme stimulation of the common carp Cyprinus carpio in vitro

    SciTech Connect

    Mukherjee, D.; Guha, D.; Kumar, V. )

    1992-06-01

    Isolated ovarian tissues from the common carp, Cyprinus carpio were incubated in vitro to obtain a discrete effect of four common toxicants of industrial origin, namely phenol, sulfide, mercuric chloride and cadmium chloride, on gonadotropin-induced alteration of nonesterified and esterified cholesterol and steroidogenic enzymes, delta 5-3 beta-HSD and 17 beta-HSD activity. Stage II ovarian tissue containing 30-40% mature oocytes were shown to be most responsive to gonadotropins in depleting only nonesterified cholesterol moiety and stimulating the activity of both. Safe doses of above mentioned toxicants when added separately to stage II ovarian tissue with oLH (1 microgram/incubation) gonadotropin-induced depletion of nonesterified cholesterol and gonadotropin-induced stimulation of the activity of both enzymes was significantly inhibited. Esterified cholesterol remained almost unaltered. Findings clearly indicate the impairment of gonadotropin induced fish ovarian steroidogenesis by the four toxicants separately.

  14. Differential gene expression in normal and transformed human mammary epithelial cells in response to oxidative stress

    PubMed Central

    Cortes, Diego F; Sha, Wei; Hower, Valerie; Blekherman, Greg; Laubenbacher, Reinhard; Akman, Steven; Torti, Suzy V; Shulaev, Vladimir

    2011-01-01

    Oxidative stress plays a key role in breast carcinogenesis. To investigate whether normal and malignant breast epithelial cells differ in their responses to oxidative stress, we examined the global gene expression profiles of three cell types, representing cancer progression from a normal to a malignant stage, under oxidative stress. Normal human mammary epithelial cells (HMEC), an immortalized cell line (HMLER-1), and a tumorigenic cell line (HMLER-5), were exposed to increased levels of reactive oxygen species (ROS) by treatment with glucose oxidase. Functional analysis of the metabolic pathways enriched with differentially expressed genes demonstrates that normal and malignant breast epithelial cells diverge substantially in their response to oxidative stress. While normal cells exhibit the up-regulation of antioxidant mechanisms, cancer cells are unresponsive to the ROS insult. However, the gene expression response of normal HMEC cells under oxidative stress is comparable to that of the malignant cells under normal conditions, indicating that altered redox status is persistent in breast cancer cells, which makes them resistant to increased generation of ROS. This study discusses some of the possible adaptation mechanisms of breast cancer cells under persistent oxidative stress that differentiate them from the response to acute oxidative stress in normal mammary epithelial cells. PMID:21397008

  15. Experimental and computational study of inter- and intra- species specificity of gonadotropins for various gonadotropin receptors.

    PubMed

    Aizen, Joseph; Kowalsman, Noga; Kobayashi, Makito; Hollander, Lian; Sohn, Young Chang; Yoshizaki, Goro; Niv, Masha Y; Levavi-Sivan, Berta

    2012-11-25

    The gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and their receptors play critical roles in vertebrate reproduction. In order to study intra- and interspecies ligand promiscuity of gonadotropins, COS-7 cells were transiently transfected with one of the gonadotropin receptor genes, FSHR or LHR, and tested for activation by gonadotropins from representative fish orders: Aquilliformes (eel; e), Salmoniformes (trout; tr), and Perciformes (tilapia; ta), and of mammalian origin: porcine (p), bovine (b) and human (h). The study reveals complex relations between the gonadotropin hormones and their receptors. Each gonadotropin activated its own cognate receptor. However, taLHR was also activated by hCG and eLHR was activated by hFSH, hCG, and trFSH. For FSHR, the only cross-reactivity detected was for hFSHR, which was activated by pFSH and bFSH. These findings are of great interest and applicability in the context of activation of various GTHRs by their ligands and by ligands from other vertebrates. Analysis of the three-dimensional models of the structures highlights the importance of residues outside of the currently established hormone-receptor interface region. In addition, the interface residues in taFSHR and the effect of exon duplication, which causes an insert in the LRR domain, are suggested to affect the interaction and binding of taFSH. PMID:22954681

  16. 21 CFR 556.304 - Gonadotropin.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Gonadotropin. 556.304 Section 556.304 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS TOLERANCES FOR RESIDUES OF NEW ANIMAL DRUGS IN FOOD Specific Tolerances for Residues of New Animal Drugs §...

  17. 21 CFR 556.304 - Gonadotropin.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Gonadotropin. 556.304 Section 556.304 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....25 I.U. per kilogram of body weight per day. (b) Tolerances. A tolerance for residues of...

  18. 21 CFR 556.304 - Gonadotropin.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Gonadotropin. 556.304 Section 556.304 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....25 I.U. per kilogram of body weight per day. (b) Tolerances. A tolerance for residues of...

  19. 21 CFR 556.304 - Gonadotropin.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Gonadotropin. 556.304 Section 556.304 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....25 I.U. per kilogram of body weight per day. (b) Tolerances. A tolerance for residues of...

  20. 21 CFR 556.304 - Gonadotropin.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Gonadotropin. 556.304 Section 556.304 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....25 I.U. per kilogram of body weight per day. (b) Tolerances. A tolerance for residues of...

  1. Pituitary and ovarian response to acute stimulation with LH-RH in normal and anovulatory women.

    PubMed

    Aparicio, N J; Casas, P R; Galimberti, D M; de Laborde, N P; Badano, A; García, E P; Meichi, H R; Mirkin, A; Szejner, M; Jaitt, A; Margulies, M; Rosner, J M

    1977-01-01

    The LH FSH estradiol and progesterone responses to acute stimulation with LH-RH were studied in 12 normal women with ovulatory cycles (4 in the initial follicular phase, 4 in the mid-follicular phase and 4 in the late follicular phase) and in two castrated women, two under hormonal contraception, two with ovarian amenorrhea, twelve with central amenorrhea of no detectable origin (6 with normal and 6 with low basal gonadotrophins), eleven anovulatory patients with pseudomenstruation, two with anorexia nervosa, and two with pituitary amenorrhea. Each woman received a rapid i.v. injection of 100 microgram synthetic LH-RH at 9:00 a.m. Serum levels of LH, FSH, estradiol and progesterone were determined by radioimmunoassay in samples collected before and 60, 120, 240 and 480 minutes after injection. The findings were : 1) A significant rise in estradiol and progesterone levels, in addition to LH and FSH elevation, in normal women; 2) A lack of ovarian steroid response in the castrated women and in ovarian amenorrheas, which suggests that the source of steroid response to stimulation is not extragonadal; 3) Significant differences in the responses of the four hormones to LH-RH in the women with central amenorrhea in comparison with the normal group with great variability of results; the steroid response in the presence of a positive LH response might correlate with the severity and/or prognosis of the disorder, a point deserving further study; 4) In anovulatory women with pseudomenstruation, LH responses for the most part normal, and particularly, progesterone responses. PMID:18416

  2. A virilizing Leydig cell tumor of the ovary associated with stromal hyperplasia under gonadotropin control.

    PubMed

    Marcondes, J A; Nery, M; Mendonça, B B; Hayashida, S A; Halbe, H W; Carvalho, F M; Wajchenberg, B L

    1997-12-01

    A 34-yr-old nulliparous black woman presented with hair loss, facial hirsutism, irregular menses and infertility associated with greatly increased serum total testosterone levels. The adrenal glands and the ovaries were normal on radiological and ultrasonographic investigation. Catheterization of the veins draining from the adrenal glands and the ovaries yielded testosterone levels of 20.3 nmol/L and 20.0 nmol/L in the right and the left adrenal veins, respectively, and 17.9 nmol/L and 27.4 nmol/L in the right and left ovaries venous plexus, respectively. Sequencial dexamethasone and ethynyl estradiol suppression test showed a decrease in cortisol level with no change in total testosterone level on dexamethasone while an increase in testosterone from 10.5 nmol/L to 20.1 nmol/L was observed ten days after ethynil estradiol had been associated to dexamethasone. When a gonadotropin-releasing hormone agonist (gonadorelin 3.5 mg i.m.) was administered for 2 months, serum gonadotropins levels decreased to less than 2 IU/L, total testosterone to 3.8 nmol/L and estradiol to less than 36 pmol/L. The patient was submitted to a pelvic exploratory laparotomy and a left salpingo-oophorectomy was performed. A solid and circumscribed ovarian tumor of 1.0 cm in diameter was found. The pathological diagnosis was a Leydig cell tumor with surrounding stromal hyperplasia. These findings may suggest that this tumor was gonadotropin-dependent being indirectly stimulated by ethynil estradiol, through a sensitization of the pituitary gonadotropes and increase in gonadotropin levels and suppressed by a gonadotropin-releasing hormone agonist. PMID:9492110

  3. In Vivo Evaluation of the Genotoxic Effects of Gonadotropins on Rat Reticulocytes

    PubMed Central

    Duran, Bulent; Koc, Onder; Ozdemirci, Safak; Topcuoglu, Ata; Ozdemir, Ozturk

    2011-01-01

    Background Gonadotropins, as ovulation-inducing drugs, have been used widely to treat infertility. An epidemiologic correlation between infertility therapy and ovarian cancer development has been reported. However, the effect of gonadotropins in the formation of reproductive tract cancers is controversial. Objective The aim of the study was to determine the in vivo genotoxic effects of gonadotropins on rat reticulocytes. Methods In this prospective, randomized, controlled study, rats were randomly assigned to 1 of 5 groups. The calculated rat doses of 0.65 human menopausal gonadotropin (hMG), 0.95 hMG, 0.65 follitropin beta (FB), 0.95 FB, or normal saline (control group) were injected, respectively. These calculated rat doses (U/g) are based on average human gonadotropin doses of 150 and 225 IU/d for a 70-kg woman given in 2-mL saline (the control group received 2 mL of saline). Injections were administered once per day for 5 days, followed by 5 days of rest. Each treatment was repeated for 6 estrus cycles in the rats for a total of 12 estrus cycles. Six months after the last day of the 12th cycle, the rats were euthanized. Bone marrow tissues were removed, and pluripotent reticulocyte cells with micronuclei, nuclear buds, and binuclear abnormalities were analyzed using an in situ micronuclei assay under light microscopy. The proportion of micronucleated cells, cells with anaphase bridge, nuclear buds, and other nuclear abnormalities were measured. Results The number of cells with nuclear buds and binuclear abnormalities in the hMG 225 and FB 225 groups was significantly higher (P < 0.05) than that from the hMG 150, FB 150, and control groups in the cytogenetic analysis of bone marrow stem cells. An increased rate of genotoxicity in all gonadotropin groups versus that of placebo was found. Conclusion In rats, the micronucleus genotoxicity assay suggests a dose-dependent gonadotropin effect on genomic instability in bone marrow stem cells in vivo. PMID:24648576

  4. Frequency-Dependent Regulation of Follicle-Stimulating Hormone β by Pulsatile Gonadotropin-Releasing Hormone Is Mediated by Functional Antagonism of bZIP Transcription Factors ▿

    PubMed Central

    Ciccone, Nick A.; Xu, Shuyun; Lacza, Charlemagne T.; Carroll, Rona S.; Kaiser, Ursula B.

    2010-01-01

    Oscillatory synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), under the control of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH), is essential for normal reproductive development and fertility. The molecular mechanisms by which various patterns of pulsatile GnRH regulate gonadotrope responsiveness remain poorly understood. In contrast to the α and LHβ subunit genes, FSHβ subunit transcription is preferentially stimulated at low rather than high frequencies of pulsatile GnRH. In this study, mutation of a cyclic AMP response element (CRE) within the FSHβ promoter resulted in the loss of preferential GnRH stimulation at low pulse frequencies. We hypothesized that high GnRH pulse frequencies might stimulate a transcriptional repressor(s) to attenuate the action of CRE binding protein (CREB) and show that inducible cAMP early repressor (ICER) fulfills such a role. ICER was not detected under basal conditions, but pulsatile GnRH stimulated ICER to a greater extent at high than at low pulse frequencies. ICER binds to the FSHβ CRE site to reduce CREB occupation and abrogates both maximal GnRH stimulation and GnRH pulse frequency-dependent effects on FSHβ transcription. These data suggest that ICER production antagonizes the stimulatory action of CREB to attenuate FSHβ transcription at high GnRH pulse frequencies, thereby playing a critical role in regulating cyclic reproductive function. PMID:20008557

  5. Seasonal changes in plasma concentrations of gonadotropins and in the responsiveness of the pituitary and testis to GnRH in a desert rodent, the sand rat (Psammomys obesus).

    PubMed

    Khammar, F; Brudieux, R

    1991-01-01

    The male sand rat (Psammomys obesus), captured alive in the Sahara desert in the area of Béni-Abbès (Algeria), exhibited seasonal changes in plasma concentrations of LH, characterized by an increase in early summer. Administration of a standard dose of GnRH (200 ng/100 g body weight) failed to elicit significant season-dependent changes in LH release, whereas the increase in plasma testosterone was maximum in June-July and quite small between November and March-April. The present results suggest that the summer seasonal onset of the testicular endocrine activity of the sand rat is due to increases both in LH release and in testis sensitivity to gonadotropin. PMID:1777059

  6. Equine Chorionic Gonadotropin and Human Chorionic Gonadotropin Stimulation Increase the Number of Luteinized Follicles and the Progesterone Level Compared with Cabergoline Stimulation in Anoestrus Bitches.

    PubMed

    Jurczak, A; Domosławska, A; Bukowska, B; Janowski, T

    2016-08-01

    In this study, ovarian morphologies and blood progesterone concentrations following oestrous induction in bitches were examined. Fifty-three clinically healthy anoestrus bitches received cabergoline at a daily dose of 5 μg/kg of body weight per os for 21 days (group I) or subcutaneous equine chorionic gonadotropin at a dose of 20 IU/kg of body weight for five consecutive days with an additional 500 IU s.c. per bitch of human chorionic gonadotropin on the last day of treatment (group II). Twenty bitches that spontaneously displayed oestrous signs were left untreated and served as controls (group III). The induced oestrous rates and ovulation rates in groups I and II were 60.0% vs 64.3% and 86.7% vs 83.3%, respectively. Morphological assessments of the ovarian structures after ovariohysterectomy revealed an increase in the number of luteinized follicles and cysts in group II compared with the two other groups (p < 0.001). In contrast, the numbers of corpora lutea and follicles were similar in all groups. In accordance with the above-mentioned alteration, the progesterone concentration in the gonadotropin group (II) was increased (p < 0.001) in the periovulatory period compared with the other two groups. During the entire sampling period, the progesterone profiles in the cabergoline (I) and control (III) groups were similar and typical of normally cycling bitches. In conclusion, gonadotropin treatment is associated with an increased progesterone level during the periovulatory period that probably originates from luteinized follicles, whereas cabergoline treatment induces cycles with both physiological progesterone concentrations and ovarian morphologies. PMID:27321641

  7. Pitch-induced responses in the right auditory cortex correlate with musical ability in normal listeners.

    PubMed

    Puschmann, Sebastian; Özyurt, Jale; Uppenkamp, Stefan; Thiel, Christiane M

    2013-10-23

    Previous work compellingly shows the existence of functional and structural differences in human auditory cortex related to superior musical abilities observed in professional musicians. In this study, we investigated the relationship between musical abilities and auditory cortex activity in normal listeners who had not received a professional musical education. We used functional MRI to measure auditory cortex responses related to auditory stimulation per se and the processing of pitch and pitch changes, which represents a prerequisite for the perception of musical sequences. Pitch-evoked responses in the right lateral portion of Heschl's gyrus were correlated positively with the listeners' musical abilities, which were assessed using a musical aptitude test. In contrast, no significant relationship was found for noise stimuli, lacking any musical information, and for responses induced by pitch changes. Our results suggest that superior musical abilities in normal listeners are reflected by enhanced neural encoding of pitch information in the auditory system. PMID:23995293

  8. ST1571 (imatinib mesylate) reduces bone marrow cellularity and normalizes morphologic features irrespective of cytogenetic response.

    PubMed

    Hasserjian, Robert P; Boecklin, Federica; Parker, Sally; Chase, Andy; Dhar, Sunanda; Zaiac, Michael; Olavarria, Eduardo; Lampert, Irvin; Henry, Kristin; Apperley, Jane F; Goldman, John M

    2002-03-01

    The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML). We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571. Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome-positive hematopoiesis to exhibitfeatures resembling normal hematopoiesis. PMID:11888075

  9. Tumor Cell Response to Synchrotron Microbeam Radiation Therapy Differs Markedly From Cells in Normal Tissues

    SciTech Connect

    Crosbie, Jeffrey C.; Anderson, Robin L.; Rothkamm, Kai; Restall, Christina M.; Cann, Leonie; Ruwanpura, Saleela; Meachem, Sarah; Yagi, Naoto; Svalbe, Imants; Lewis, Robert A.; Williams, Bryan R.G.; Rogers, Peter A.W.

    2010-07-01

    Purpose: High-dose synchrotron microbeam radiation therapy (MRT) can be effective at destroying tumors in animal models while causing very little damage to normal tissues. The aim of this study was to investigate the cellular processes behind this observation of potential clinical importance. Methods and Materials: MRT was performed using a lattice of 25 {mu}m-wide, planar, polychromatic, kilovoltage X-ray microbeams, with 200-{mu}m peak separation. Inoculated EMT-6.5 tumor and normal mouse skin tissues were harvested at defined intervals post-MRT. Immunohistochemical detection of {gamma}-H2AX allowed precise localization of irradiated cells, which were also assessed for proliferation and apoptosis. Results: MRT significantly reduced tumor cell proliferation by 24 h post-irradiation (p = 0.002). An unexpected finding was that within 24 h of MRT, peak and valley irradiated zones were indistinguishable in tumors because of extensive cell migration between the zones. This was not seen in MRT-treated normal skin, which appeared to undergo a coordinated repair response. MRT elicited an increase in median survival times of EMT-6.5 and 67NR tumor-inoculated mice similar to that achieved with conventional radiotherapy, while causing markedly less normal tissue damage. Conclusions: This study provides evidence of a differential response at a cellular level between normal and tumor tissues after synchrotron MRT.

  10. Laboratory observations of fault strength in response to changes in normal stress

    USGS Publications Warehouse

    Kilgore, Brian D.; Lozos, Julian; Beeler, Nicholas M.; Oglesby, David

    2012-01-01

    Changes in fault normal stress can either inhibit or promote rupture propagation, depending on the fault geometry and on how fault shear strength varies in response to the normal stress change. A better understanding of this dependence will lead to improved earthquake simulation techniques, and ultimately, improved earthquake hazard mitigation efforts. We present the results of new laboratory experiments investigating the effects of step changes in fault normal stress on the fault shear strength during sliding, using bare Westerly granite samples, with roughened sliding surfaces, in a double direct shear apparatus. Previous experimental studies examining the shear strength following a step change in the normal stress produce contradictory results: a set of double direct shear experiments indicates that the shear strength of a fault responds immediately, and then is followed by a prolonged slip-dependent response, while a set of shock loading experiments indicates that there is no immediate component, and the response is purely gradual and slip-dependent. In our new, high-resolution experiments, we observe that the acoustic transmissivity and dilatancy of simulated faults in our tests respond immediately to changes in the normal stress, consistent with the interpretations of previous investigations, and verify an immediate increase in the area of contact between the roughened sliding surfaces as normal stress increases. However, the shear strength of the fault does not immediately increase, indicating that the new area of contact between the rough fault surfaces does not appear preloaded with any shear resistance or strength. Additional slip is required for the fault to achieve a new shear strength appropriate for its new loading conditions, consistent with previous observations made during shock loading.

  11. Skew-normal/independent linear mixed models for censored responses with applications to HIV viral loads

    PubMed Central

    Bandyopadhyay, Dipankar; Lachos, Victor H.; Castro, Luis M.; Dey, Dipak K.

    2012-01-01

    Often in biomedical studies, the routine use of linear mixed-effects models (based on Gaussian assumptions) can be questionable when the longitudinal responses are skewed in nature. Skew-normal/elliptical models are widely used in those situations. Often, those skewed responses might also be subjected to some upper and lower quantification limits (viz. longitudinal viral load measures in HIV studies), beyond which they are not measurable. In this paper, we develop a Bayesian analysis of censored linear mixed models replacing the Gaussian assumptions with skew-normal/independent (SNI) distributions. The SNI is an attractive class of asymmetric heavy-tailed distributions that includes the skew-normal, the skew-t, skew-slash and the skew-contaminated normal distributions as special cases. The proposed model provides flexibility in capturing the effects of skewness and heavy tail for responses which are either left- or right-censored. For our analysis, we adopt a Bayesian framework and develop a MCMC algorithm to carry out the posterior analyses. The marginal likelihood is tractable, and utilized to compute not only some Bayesian model selection measures but also case-deletion influence diagnostics based on the Kullback-Leibler divergence. The newly developed procedures are illustrated with a simulation study as well as a HIV case study involving analysis of longitudinal viral loads. PMID:22685005

  12. Absence of diurnal variation in visceromotor response to colorectal distention in normal Long Evans rats

    PubMed Central

    Welting, Olaf; Cailotto, Cathy; Kalsbeek, Andries; van den Wijngaard, Rene

    2016-01-01

    Background: Enhanced colorectal sensitivity (i.e. visceral hypersensitivity) is thought to be a pathophysiological mechanism in irritable bowel syndrome (IBS). In healthy men a circadian variation in rectal perception to colonic distention was described. Disturbed day and night rhythms, which occur in shift work and trans meridian flights, are associated with the prevalence of IBS. This raises the question whether disruptions of circadian control are responsible for the observed pathology in IBS. Prior to investigating altered rhythmicity in relation to visceral hypersensitivity in a rat model for IBS, it is relevant to establish whether normal rats display circadian variation similar to healthy men.  Methodology and findings: In rodents colorectal distension leads to reproducible contractions of abdominal musculature. We used quantification of this so called visceromotor response (VMR) by electromyography (EMG) to assess visceral sensitivity in rats. We assessed the VMR in normal male Long Evans rats at different time points of the light/dark cycle. Although a control experiment with male maternal separated rats confirmed that intentionally inflicted (i.e. stress induced) changes in VMR can be detected, normal male Long Evans rats showed no variation in VMR along the light/dark cycle in response to colorectal distension. Conclusions: In the absence of a daily rhythm of colorectal sensitivity in normal control rats it is not possible to investigate possible aberrancies in our rat model for IBS. PMID:26925229

  13. Normalizing and scaling of data to derive human response corridors from impact tests.

    PubMed

    Yoganandan, Narayan; Arun, Mike W J; Pintar, Frank A

    2014-06-01

    It is well known that variability is inherent in any biological experiment. Human cadavers (Post-Mortem Human Subjects, PMHS) are routinely used to determine responses to impact loading for crashworthiness applications including civilian (motor vehicle) and military environments. It is important to transform measured variables from PMHS tests (accelerations, forces and deflections) to a standard or reference population, termed normalization. The transformation process should account for inter-specimen variations with some underlying assumptions used during normalization. Scaling is a process by which normalized responses are converted from one standard to another (example, mid-size adult male to large-male and small-size female adults, and to pediatric populations). These responses are used to derive corridors to assess the biofidelity of anthropomorphic test devices (crash dummies) used to predict injury in impact environments and design injury mitigating devices. This survey examines the pros and cons of different approaches for obtaining normalized and scaled responses and corridors used in biomechanical studies for over four decades. Specifically, the equal-stress equal-velocity and impulse-momentum methods along with their variations are discussed in this review. Methods ranging from subjective to quasi-static loading to different approaches are discussed for deriving temporal mean and plus minus one standard deviation human corridors of time-varying fundamental responses and cross variables (e.g., force-deflection). The survey offers some insights into the potential efficacy of these approaches with examples from recent impact tests and concludes with recommendations for future studies. The importance of considering various parameters during the experimental design of human impact tests is stressed. PMID:24726322

  14. Accident and Off Normal Response and Recovery from Multi Canister Overpack (MCO) Processing Events

    SciTech Connect

    ALDERMAN, C.A.

    2000-09-19

    In the process of removing spent nuclear fuel (SNF) from the K Basins through its subsequent packaging, drymg, transportation and storage steps, the SNF Project must be able to respond to all anticipated or foreseeable off-normal and accident events that may occur. Response procedures and recovery plans need to be in place, personnel training established and implemented to ensure the project will be capable of appropriate actions. To establish suitable project planning, these events must first be identified and analyzed for their expected impact to the project. This document assesses all off-normal and accident events for their potential cross-facility or Multi-Canister Overpack (MCO) process reversal impact. Table 1 provides the methodology for establishing the event planning level and these events are provided in Table 2 along with the general response and recovery planning. Accidents and off-normal events of the SNF Project have been evaluated and are identified in the appropriate facility Safety Analysis Report (SAR) or in the transportation Safety Analysis Report for Packaging (SARP). Hazards and accidents are summarized from these safety analyses and listed in separate tables for each facility and the transportation system in Appendix A, along with identified off-normal events. The tables identify the general response time required to ensure a stable state after the event, governing response documents, and the events with potential cross-facility or SNF process reversal impacts. The event closure is predicated on stable state response time, impact to operations and the mitigated annual occurrence frequency of the event as developed in the hazard analysis process.

  15. Ejection fraction response to exercise in patients with chest pain and normal coronary arteriograms

    SciTech Connect

    Gibbons, R.L.; Lee, K.L.; Cobb, F.; Jones, R.H.

    1981-11-01

    In this study we describe the ejection fraction response to upright exercise using first-pass radionuclide angiocardiography in a group of 60 patients with chest pain, normal coronary ateriograms and normal resting ventricular function. A wide range of resting function (heart rate and ejection fraction) and exercise function (heart rate, ejection fraction, peak work load and estimated peak oxygen uptake) were measured. The ejection fraction response to exercise demonstrated wide variation, ranging from a decrease of 23% to an increase of 24%. Six of 22 clinical and radionuclide angiocardiographic variables (resting ejection fraction, peak work load, age, sex, body surface area and the change in end-diastolic volume index with exercise) were significant univariate predictors of the ejection fraction response to exercise. Multivariable analysis identified resting ejection fraction, the change in end-diastolic volume index with exercise and either sex or peak work load as variables that provided significant independent predictive information. These observations indicate that the ejection fraction response to exercise is a complex response that is influenced by multiple physiologic variables. The wide variation in this population suggests that the ejection fraction response to exercise is not a reliable test for the diagnosis of coronary artery disease because of its low specificity.

  16. Gonadotropin-Dependent Precocious Puberty: Neoplastic Causes and Endocrine Considerations

    PubMed Central

    2011-01-01

    Premature activation of the hypothalamic-pituitary-gonadal (HPG) axis manifests as gonadotropin-dependent precocious puberty. The mechanisms behind HPG activation are complex and a clear etiology for early activation is often not elucidated. Though collectively uncommon, the neoplastic and developmental causes of gonadotropin-dependent precocious puberty are very important to consider, as a delay in diagnosis may lead to adverse patient outcomes. The intent of the current paper is to review the neoplastic and developmental causes of gonadotropin-dependent precocious puberty. We discuss the common CNS lesions and human chorionic gonadotropin-secreting tumors that cause sexual precocity, review the relationship between therapeutic radiation and gonadotropin-dependent precocious puberty, and finally, provide an overview of the therapies available for height preservation in this unique patient population. PMID:21603196

  17. Effect of 2 different anesthesia methods on stress response in neurosurgical patients with hypertension or normal

    PubMed Central

    Chen, Ying; Jiang, Shan; Wu, Yong

    2016-01-01

    Abstract Hypertensive patients in neurosurgery are becoming more common, which increased the risk of surgical stress response. Meanwhile, the relationship between hypertension and anesthesia methods is unclear on the stress response. The purpose of this study is to compare the effect of different anesthesia methods on high-sensitivity C-reactive protein (Hs-CRP), blood glucose, and leucocyte levels in neurosurgical patients with hypertension or normal. Eighty neurosurgical patients were randomly divided into 4 groups (n = 20): balanced anesthesia group (A), balanced anesthesia with hypertension group (B), total intravenous anesthesia group (C), total intravenous anesthesia with hypertension group (D). The levels of Hs-CRP, blood glucose, leucocyte count, and neutrophil percentage and were detected at before anesthesia (T0), during anesthesia (T1), 2 hours post anesthesia (T2), 24 hours post anesthesia (T3). Patients with hypertension had higher Hs-CRP expression, blood glucose, and neutrophil percentage at time T0 than those of normal, but not leucocyte count. At time T3, patients with hypertension in D group had lower Hs-CRP expression than those in B group (P < 0.01). Patients with normal in C group had lower Hs-CRP expression (P < 0.01), blood glucose (P < 0.05), and leukocyte count (P < 0.05) than those in A group. Both hypertension history and anesthesia method had significant effects on the Hs-CRP expression, blood glucose, and leukocyte count. Total intravenous anesthesia decreases Hs-CRP expressions more efficiently than balanced anesthesia in neurosurgical patients with hypertension or normal. Moreover, total intravenous anesthesia can availably reduce the perioperative stress response by attenuating the increase of blood glucose and leukocyte count in normal tensive patients. PMID:27583931

  18. The gonadotropin-releasing hormone antagonist protocol--the protocol of choice for the polycystic ovary syndrome patient undergoing controlled ovarian stimulation.

    PubMed

    Kol, Shahar; Homburg, Roy; Alsbjerg, Birgit; Humaidan, Peter

    2012-06-01

    Polycystic ovary syndrome (PCOS) patients are prone to develop ovarian hyperstimulation syndrome (OHSS), a condition which can be minimized or completely eliminated by the use of a gonadotropin-releasing hormone agonist (GnRHa) trigger. In this commentary paper, we maintain that the gonadotropin-releasing hormone antagonist protocol should be the protocol of choice for the PCOS patient undergoing ovarian stimulation with gonadotropins for in vitro fertilization. If an excessive ovarian response is encountered, the clinician will always have two options: either to trigger final oocyte maturation with a bolus of GnRHa and supplement the luteal phase with a small bolus of human chorionic gonadotropin in addition to the standard luteal phase support and transfer in the fresh cycle or, alternatively, to trigger with GnRHa and perform a total freeze, resulting in a complete elimination of OHSS and high ongoing pregnancy rates in the subsequent frozen-thawed transfer cycles. PMID:22428986

  19. Chromosomal translocations deregulating c-myc are associated with normal immune responses.

    PubMed

    Roschke, V; Kopantzev, E; Dertzbaugh, M; Rudikoff, S

    1997-06-26

    Plasmacytomas induced in BALB/c mice by pristane consistently evidence chromosomal translocations involving the c-myc gene and one of the Ig loci. This observation has lead to the suggestion that c-myc deregulation is a critical event in the generation of such tumors. However, it is not clear whether c-myc translocation is related to pristane treatment or occurs in normal lymphocyte populations nor whether such translocations occur normally, and at similar frequencies, in strains genetically resistant to plasmacytoma development, such as DBA/2. In order to address these questions, a Long Distance PCR assay with single copy sensitivity was employed to assess the frequency of c-myc/IgA translocations in normal and immunized mice of both plasmacytoma resistant and susceptible lineages in the absence of pristane treatment. Our data demonstrate that spontaneous translocations occur in normal DBA/2 and BALB/c mice with no significant differences in frequency. A 3-5-fold increase in translocation frequency was observed in mice immunized with cholera toxin, a strong stimulator of IgA responses. We conclude that c-myc deregulation by chromosomal translocation is associated with normal physiological processes of B-cell differentiation and, as such, can not be the determining factor leading to malignancy. PMID:9223664

  20. Nystagmus responses in a group of normal humans during earth-horizontal axis rotation

    NASA Technical Reports Server (NTRS)

    Wall, Conrad, III; Furman, Joseph M. R.

    1989-01-01

    Horizontal eye movement responses to earth-horizontal yaw axis rotation were evaluated in 50 normal human subjects who were uniformly distributed in age (20-69 years) and each age group was then divided by gender. Subjects were rotated with eyes open in the dark, using clockwise and counter-clockwise 60 deg velocity trapezoids. The nystagmus slow component velocity is analyzed. It is shown that, despite large intersubject variability, parameters which describe earth-horizontal yaw axis responses are loosely interrelated, and some of them vary significantly with gender and age.

  1. Neurological damage disrupts normal sex differences in psychophysiological responsiveness to music.

    PubMed

    Belfi, Amy M; Chen, Kuan-Hua; Schneider, Brett; Tranel, Daniel

    2016-01-01

    Men and women often display different physiological responses to emotional stimuli, and these responses can be affected by brain damage. Here, we investigated how brain damage differentially affects electrodermal responses based on sex. We studied neurologically normal, healthy adults and a sample of neurological patients. Participants listened to music, an emotional stimulus that reliably elicits skin conductance responses (SCRs). Electrodermal activity was recorded while participants listened to musical clips. When analyzing the data without regard to sex, there were no differences between healthy and brain-damaged participants in their SCRs. However, we found a significant interaction between brain injury status and sex. For men, brain damage significantly reduced SCRs. For women, there were no differences between brain-damaged participants and neurologically healthy participants. These findings illustrate the importance of including demographic variables, such as sex, when investigating brain-behavior relationships with a psychophysiological dependent variable. PMID:26681613

  2. Optimization of correlated multi-response quality engineering by the upside-down normal loss function

    NASA Astrophysics Data System (ADS)

    Zeybek, Melis; Köksoy, Onur

    2016-08-01

    Most of the published literature on robust design is basically concerned with a single response. However, the reality is that common industrial problems usually involve several quality characteristics, which are often correlated. Traditional approaches to multidimensional quality do not offer much information on how much better or worse a process is when finding optimal settings. Köksoy and Fan [Engineering Optimization 44 (8): 935-945] pointed out that the upside-down normal loss function provides a more reasonable risk assessment to the losses of being off-target in product engineering research. However, they only consider the single-response case. This article generalizes their idea to more than one response under possible correlations and co-movement effects of responses on the process loss. The response surface methodology has been adapted, estimating the expected multivariate upside-down normal loss function of a multidimensional system to find the optimal control factor settings of a given problem. The procedure and its merits are illustrated through an example.

  3. Gene Expression Profile Analysis as a Prognostic Indicator of Normal Tissue Response to Simulated Space Radiations

    NASA Technical Reports Server (NTRS)

    Story, Michael; Stivers, David N.

    2004-01-01

    This project was funded as a pilot project to determine the feasibility of using gene expression profiles to characterize the response of human cells to exposure to particulate radiations such as those encountered in the spaceflight environment. We proposed to use microarray technology to examine the gene expression patterns of a bank of well-characterized human fibroblast cell cultures. These fibroblast cultures were derived from breast or head and neck cancer patients who exhibited normal, minimal, or severe normal tissue reactions following low LET radiation exposure via radiotherapy. Furthermore, determination of SF2 values from fibroblasts cultured from these individuals were predictive of risk for severe late reactions. We hypothesized that by determining the expression of thousands of genes we could identify gene expression patterns that reflect how normal tissues respond to high Z and energy (HZE) particles, that is, that there are molecular signatures for HZE exposures. We also hypothesized that individuals who are intrinsically radiosensitive may elicit a unique response. Because this was funded as a pilot project we focused our initial studies on logistics and appropriate experimental design, and then to test our hypothesis that there is a unique molecular response to specific particles, in this case C and Fe, for primary human skin fibroblasts.

  4. Actions of pregnant mare serum gonadotropin in the immature female rat: correlative changes in blood steroids, gonadotropins, and cytoplasmic estradiol receptors of the anterior pituitary and hypothalamus.

    PubMed

    Parker, C R; Costoff, A; Muldoon, T G; Mahesh, V B

    1976-01-01

    resulting from PMSG administration to immature female rats. In addition, changes in blood steroids and gonadotropins after PMSG treatment are similar to those reported for proestrus-estrus-diestrus I of the normal adult estrous cycle. These findings further demonstrate the validity of the PMSG-primed immature female rat preparation as a model for the estrous cycle of the adult rat. PMID:174887

  5. Gonadotropin-releasing hormone in the ovary.

    PubMed

    Metallinou, Chryssa; Asimakopoulos, Byron; Schröer, Andreas; Nikolettos, Nikos

    2007-12-01

    Gonadotropin-releasing hormone (GnRH) plays a pivotal role in the physiology of reproduction in mammals. GnRH acts by binding to the GnRH receptor (GnRHR). In humans, only 1 conventional GnRH receptor subtype (type I GnRH receptor) has been found. In the human genome, 2 forms of GnRH have been identified, GnRH-I (mammal GnRH) and GnRH-II (chicken GnRH II). Both forms and their common receptor are expressed, apart from the hypothalamus, in various compartments of the human ovary. Gonadal steroids, gonadotropins, and GnRH itself controls the regulation of the GnRH/GnRHR system gene expression in the human ovary. The 2 types of GnRH acting paracrinally/autocrinally influence ovarian steroidogenesis, decrease the proliferation, and induce apoptosis of ovarian cells. In this review, the biology of GnRH/GnRHR system in humans, the potential roles of GnRH, and the direct effects of GnRH analogues in ovarian cells are discussed. PMID:18089592

  6. Disparity vergence responses before versus after repetitive vergence therapy in binocularly normal controls

    PubMed Central

    Talasan, Henry; Scheiman, Mitchell; Li, Xiaobo; Alvarez, Tara L.

    2016-01-01

    This study sought to determine whether significant changes would be observed between vergence eye movements before and after 12 hr of repetitive vergence therapy (1 hr per day on different days) in subjects with normal binocular vision compared to controls. Disparity vergence responses from 23 subjects were studied. An assessment protocol that minimized the influence of the near dissociated phoria on the disparity vergence system was designed. The following parameters were quantified for the responses: latency, time to peak velocity, settling time, peak velocity, and accuracy (difference between the response and stimulus amplitudes). The following outcomes were observed when comparing the results after vergence therapy to the baseline measurements: (a) near point of convergence and near dissociated phoria did not significantly change (p > 0.15); (b) latency, time to peak velocity, and settling time significantly decreased (p ≤ 0.01); and (c) accuracy significantly improved (p < 0.01). Results support that vergence peak velocity is dependent on the subject's near dissociated phoria. The accuracy and temporal properties of vergence eye movement responses from subjects with normal binocular vision can be improved after vergence therapy. These methods can be utilized within future studies to quantitatively assess vergence therapy techniques for patients with binocular dysfunction. PMID:26762276

  7. Regional and splenic lymphocyte proliferative responses of mice exposed to normal or irradiated Schistosoma mansoni cercariae

    SciTech Connect

    Lewis, F.A.; Wilson, E.M.

    1982-05-01

    Developing larvae of Schistosoma mansoni migrate through various tissues en route to the liver and mesenteric veins of their definitive host. Regional (lymph node) and systemic (spleen) blastogenic responses to cercarial, adult and egg antigens were measured in CBA/J mice at various times after exposure to normal or irradiated S. mansoni cercariae. Among the separate lymph node groups studied were those draining the tail, thoracic region, intestines, head and neck, and the pelvis. Blastogenic responses were assayed by a micromethod requiring 10(5) cells in 20 microliter volumes per culture. Up to 5 weeks post-cercarial exposure the pattern of responses in lymphoid tissues of infected mice coincided with the migratory route of the parasites. Following oviposition, cellular reactivity was pronounced in all lymph node groups. The reactivity of mice exposed to irradiated cercariae followed a pattern suggestive of a sustained antigenic stimulus only in the nodes draining the tail and lungs. Splenic (systemic) reactivity was roughly comparable between the two exposure groups. These data show the independence and vast differences in the host regional responses following normal or irradiated cercarial exposure.

  8. Disparity vergence responses before versus after repetitive vergence therapy in binocularly normal controls.

    PubMed

    Talasan, Henry; Scheiman, Mitchell; Li, Xiaobo; Alvarez, Tara L

    2016-01-01

    This study sought to determine whether significant changes would be observed between vergence eye movements before and after 12 hr of repetitive vergence therapy (1 hr per day on different days) in subjects with normal binocular vision compared to controls. Disparity vergence responses from 23 subjects were studied. An assessment protocol that minimized the influence of the near dissociated phoria on the disparity vergence system was designed. The following parameters were quantified for the responses: latency, time to peak velocity, settling time, peak velocity, and accuracy (difference between the response and stimulus amplitudes). The following outcomes were observed when comparing the results after vergence therapy to the baseline measurements: (a) near point of convergence and near dissociated phoria did not significantly change (p > 0.15); (b) latency, time to peak velocity, and settling time significantly decreased (p ≤ 0.01); and (c) accuracy significantly improved (p < 0.01). Results support that vergence peak velocity is dependent on the subject's near dissociated phoria. The accuracy and temporal properties of vergence eye movement responses from subjects with normal binocular vision can be improved after vergence therapy. These methods can be utilized within future studies to quantitatively assess vergence therapy techniques for patients with binocular dysfunction. PMID:26762276

  9. Estimating Non-Normal Latent Trait Distributions within Item Response Theory Using True and Estimated Item Parameters

    ERIC Educational Resources Information Center

    Sass, D. A.; Schmitt, T. A.; Walker, C. M.

    2008-01-01

    Item response theory (IRT) procedures have been used extensively to study normal latent trait distributions and have been shown to perform well; however, less is known concerning the performance of IRT with non-normal latent trait distributions. This study investigated the degree of latent trait estimation error under normal and non-normal…

  10. Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors.

    PubMed

    Wang, W-T; Catto, J W F; Meuth, M

    2015-05-28

    While DNA damage response pathways are well characterized in cancer cells, much less is known about their status in normal cells. These pathways protect tumour cells from DNA damage and replication stress and consequently present potential therapeutic targets. Here we characterize the response of human telomerase reverse transcriptase (hTERT)-immortalized normal human urothelial (NHU) and bladder cancer cell lines to agents that disrupt the DNA damage response. Effects of replication and DNA damage response inhibitors on cell cycle progression, checkpoint induction and apoptosis were analysed in hTERT-NHU and bladder cancer cell lines. The primary signalling cascade responding to replication stress in malignant cells (ataxia telangiectasia-mutated (ATM) and Rad3-related-checkpoint kinase 1 (ATR-CHK1)) is not activated in hTERT-NHU cells after treatment with a replication inhibitor and these cells do not depend upon CHK1 for protection from apoptosis during replication stress. Instead, ATM signalling is rapidly activated under these conditions. Intriguingly, an ATM inhibitor suppressed S-phase checkpoint activation after exposure to replication inhibitors and stopped entry of cells into S-phase indicating G1 checkpoint activation. Consistent with this, hTERT-NHU cells treated with the ATM inhibitor showed increased levels of cyclin-dependent kinase inhibitor p19(INK4D), reduced levels of cyclin D1 and CDK4, and reduced phosphorylation of the retinoblastoma protein. In contrast, a bladder cancer cell line cotreated with ATM and replication inhibitors progressed more slowly through S phase and showed a marked increase in apoptosis. Taken together, our findings suggest that ATM and CHK1 signalling cascades have different roles in tumour and normal epithelial cells, confirming these as promising therapeutic targets. PMID:25043304

  11. Effect of short-term fasting on lipolytic responsiveness in normal and obese human subjects

    SciTech Connect

    Wolfe, R.R.; Peters, E.J.; Klein, S.; Holland, O.B.; Rosenblatt, J.; Gary, H. Jr.

    1987-02-01

    In this study the rate of lipolysis (fatty acid and glycerol release into blood) has been quantified in both normal weight and obese volunteers after both 15 and 87 h of fasting. In each study, the basal rate and subsequent response to epinephrine infusion were determined. The rate of appearance (R/sub a/) of free fatty acids (FFA) and glycerol were quantified by infusion of (1- TC)palmitate and D-5-glycerol, respectively. Substrate flux rates per unit of body fat mass and lean body mass were calculated from total body water measurements using H2 YO dilution. In normal volunteers, the basal R/sub a/ FFA and R/sub a/ glycerol rose markedly with 87 h of fasting, whereas the increases were more modest in the obese subjects. However, the rate of mobilization of fat, in relation to the lean body mass, was higher in the obese subjects than in the normal subjects after 15 h of fasting, and the values were similar in both groups after 87 h of fasting. There was an increased lipolytic response to epinephrine after fasting in both groups. This increased sensitivity may have resulted from the enhancement of fatty acid-triglyceride substrate cycling that occurred after fasting.

  12. Brainstem auditory-evoked response (BAER) in client-owned pet ferrets with normal hearing.

    PubMed

    Piazza, S; Huynh, M; Cauzinille, L

    2014-06-01

    The objective of this study was to evaluate the feasibility of brainstem auditory-evoked response (BAER) testing in pet ferrets in a clinical setting, and to describe a routine method and baseline data for normal hearing ferrets for future investigation of deafness in this species. Twenty-eight clinically normal client-owned ferrets were included. BAER measurements were recorded under general anaesthesia (isoflurane delivered by mask), from subcutaneously placed needle electrodes. A 'click' stimulus applied by insert earphone with an intensity of 90 dB sound pressure level (SPL) was used. The final BAER waveform represents an average of 500 successive responses. Morphology of the waveform was studied; amplitude and latency measures were determined and means were calculated. The BAER waveform of the normal ferret included 4 reproducible waves named I, II, III and V, as previously described in dogs and cats. Measurements of latencies are consistent with previous laboratory research using experimental ferrets. In the present study, a reliable routine protocol for clinical evaluation of the hearing function in the pet ferret was established. This procedure can be easily and safely performed in a clinical setting in ferrets as young as eight weeks of age. The prevalence of congenital deafness in ferrets is currently unknown but may be an important consideration, especially in ferrets with a white coat. BAER test is a useful screening for congenital deafness in this species. PMID:24714054

  13. Use of the Hayling Task to Measure Inhibition of Prepotent Responses in Normal Aging and Alzheimer's Disease

    ERIC Educational Resources Information Center

    Belleville, Sylvie; Rouleau, Nancie; Van der Linden, Martial

    2006-01-01

    This study measures the effect of Alzheimer's disease (AD) and normal aging on the inhibition of prepotent responses. AD patients, normal aged controls, and young subjects were tested with the Hayling task, which measures the ability to inhibit a semantically constrained response, and with the Stroop procedure. AD patients showed a severe deficit…

  14. Neuroendocrine regulation of gonadotropin secretion in seasonally breeding birds

    PubMed Central

    Ubuka, Takayoshi; Bentley, George E.; Tsutsui, Kazuyoshi

    2013-01-01

    Seasonally breeding birds detect environmental signals, such as light, temperature, food availability, and presence of mates to time reproduction. Hypothalamic neurons integrate external and internal signals, and regulate reproduction by releasing neurohormones to the pituitary gland. The pituitary gland synthesizes and releases gonadotropins which in turn act on the gonads to stimulate gametogenesis and sex steroid secretion. Accordingly, how gonadotropin secretion is controlled by the hypothalamus is key to our understanding of the mechanisms of seasonal reproduction. A hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH), activates reproduction by stimulating gonadotropin synthesis and release. Another hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH), inhibits gonadotropin synthesis and release directly by acting on the pituitary gland or indirectly by decreasing the activity of GnRH neurons. Therefore, the next step to understand seasonal reproduction is to investigate how the activities of GnRH and GnIH neurons in the hypothalamus and their receptors in the pituitary gland are regulated by external and internal signals. It is possible that locally-produced triiodothyronine resulting from the action of type 2 iodothyronine deiodinase on thyroxine stimulates the release of gonadotropins, perhaps by action on GnRH neurons. The function of GnRH neurons is also regulated by transcription of the GnRH gene. Melatonin, a nocturnal hormone, stimulates the synthesis and release of GnIH and GnIH may therefore regulate a daily rhythm of gonadotropin secretion. GnIH may also temporally suppress gonadotropin secretion when environmental conditions are unfavorable. Environmental and social milieus fluctuate seasonally in the wild. Accordingly, complex interactions of various neuronal and hormonal systems need to be considered if we are to understand the mechanisms underlying seasonal reproduction. PMID:23531789

  15. Surface modification of microparticles causes differential uptake responses in normal and tumoral human breast epithelial cells

    NASA Astrophysics Data System (ADS)

    Patiño, Tania; Soriano, Jorge; Barrios, Lleonard; Ibáñez, Elena; Nogués, Carme

    2015-06-01

    The use of micro- and nanodevices as multifunctional systems for biomedical applications has experienced an exponential growth during the past decades. Although a large number of studies have focused on the design and fabrication of new micro- and nanosystems capable of developing multiple functions, a deeper understanding of their interaction with cells is required. In the present study, we evaluated the effect of different microparticle surfaces on their interaction with normal and tumoral human breast epithelial cell lines. For this, AlexaFluor488 IgG functionalized polystyrene microparticles (3 μm) were coated with Polyethyleneimine (PEI) at two different molecular weights, 25 and 750 kDa. The effect of microparticle surface properties on cytotoxicity, cellular uptake and endocytic pathways were assessed for both normal and tumoral cell lines. Results showed a differential response between the two cell lines regarding uptake efficiency and mechanisms of endocytosis, highlighting the potential role of microparticle surface tunning for specific cell targeting.

  16. Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients

    PubMed Central

    Dispenza, Melanie C.; Wolpert, Ellen B.; Gilliland, Kathryn L.; Dai, Pingqi; Cong, Zhaoyuan; Nelson, Amanda M.; Thiboutot, Diane M.

    2012-01-01

    Retinoids are used in the treatment of inflammatory skin diseases and malignancies, but studies characterizing the in vivo actions of these drugs in humans are lacking. Isotretinoin is a pro-drug for all-trans retinoic acid that can induce long-term remissions of acne; however, its complete mechanism of action is unknown. We hypothesized that isotretinoin induces remission of acne by normalizing the innate immune response to the commensal bacterium P. acnes. Compared to normal subjects, peripheral blood monocytes from acne patients expressed significantly higher levels of TLR-2 and exhibited significantly greater induction of TLR-2 expression following P. acnes stimulation. Treatment of patients with isotretinoin significantly decreased monocyte TLR-2 expression and subsequent inflammatory cytokine response to P. acnes by one week of therapy. This effect was sustained six months following cessation of therapy, indicating that TLR-2 modulation may be involved in the durable therapeutic response to isotretinoin. This study demonstrates that isotretinoin exerts immunomodulatory effects in patients and sheds light on a potential mechanism for its long-term effects in acne. The modulation of TLR-2 expression on monocytes has important implications in other inflammatory disorders characterized by TLR-2 dysregulation. PMID:22513780

  17. Landscape response to normal fault growth and linkage in the Southern Apennines, Italy.

    NASA Astrophysics Data System (ADS)

    Roda-Boluda, Duna; Whittaker, Alex

    2016-04-01

    It is now well-established that landscape can record spatial and temporal variations in tectonic rates. However, decoding this information to extract detailed histories of fault growth is often a complex problem that requires careful integration of tectonic and geomorphic data sets. Here, we present new data addressing both normal fault evolution and coupled landscape response for two normal faults in the Southern Apennines: the Vallo di Diano and East Agri faults. By integrating published constraints with new data, we show that these faults have total throws of up to 2100 m, and Holocene throw rates of up to 1 mm/yr at their maximum. We demonstrate that geomorphology is effectively recording tectonics, with relief, channel and catchment slopes varying along fault strike as normal fault activity does. Therefore, valuable information about fault growth and interaction can be extracted from their geomorphic expression. We use the spatial distribution of knickpoints on the footwall channels to infer two episodes of base level change, which can be associated with distinct fault interaction events. From our detailed fault throw profiles, we reconstruct the amount of throw accumulated after each of these events, and the segments involved in each, and we use slip rate enhancement factors derived from fault interaction theory to estimate the magnitude of the tectonic perturbation in each case. From this approach, we are able to reconstruct pre-linkage throw rates, and we estimate that fault linkage events likely took place 0.7 ± 0.2 Ma and 1.9 ± 0.6 Ma in the Vallo di Diano fault, and 1.1 ± 0.1 and 2.3 ± 0.9 Ma in the East Agri fault. Our study suggests that both faults started their activity at 3.6 ± 0.5 Ma. These fault linkage scenarios are consistent with the knickpoint heights, and may relate to soft-linkage interaction with the Southern Apennines normal fault array, the existence of which has been the subject of considerable debate. Our combined geomorphic and

  18. Early and late healing responses of normal canine artery to excimer laser irradiation.

    PubMed

    Prevosti, L G; Leon, M B; Smith, P D; Dodd, J T; Bonner, R F; Robinowitz, M; Clark, R E; Virmani, R

    1988-07-01

    Acute in vitro histologic studies have shown that the pulsed xenon chloride excimer laser causes precise microablation without the surrounding thermal tissue injury associated with frequently used continuous-wave lasers such as the argon, carbon dioxide, and neodymium:yttrium aluminum garnet lasers. However, the in vivo healing response of artery wall to excimer laser injury is not known. Accordingly, a xenon chloride excimer laser (308 nm, 40 nsec pulse width, 39 mJ/mm2/pulse) was transmitted via a 600 micron fused silica fiber to create 420 craters of varying depths (30 to 270 micron) in 21 normal canine femoral and carotid arteries. At 2 hours, 2 days, 10 days, and 42 days after excimer laser ablation, the artery segments were perfusion fixed in situ and analyzed by light, scanning, and transmission electron microscopy. At 2 hours, craters were covered by a carpet of platelets and entrapped red blood cells. Fibrin and exposed collagen fibers were seen at the crater base. There was a sharp demarcation of the crater-artery wall interface without lateral laser tissue injury. At 2 days, adherent platelets persisted with thrombus covering the base of the craters. Early healing responses were present, consisting of polymorphonucleated leukocytes and new endothelial cells, which extended over the crater rims. At 10 days, no thrombi were seen, and healing continued with almost complete reendothelialization. Macrophages, fibroblasts, fibrin, and entrapped red blood cells were present below the reendothelialized surface. At 42 days, healing was complete with obliteration of the craters by fibrointimal ingrowth. The surface was completely covered by a smooth monolayer of axially aligned endothelial cells. There were no aneurysms or surface hyperplastic responses. These favorable healing responses in normal canine arteries suggest that pulsed lasers with high tissue absorption coefficients, such as the xenon chloride excimer laser, may be suitable energy sources for

  19. Sex-related differences in the normal cardiac response to upright exercise

    SciTech Connect

    Higginbotham, M.B.; Morris, K.G.; Coleman, R.E.; Cobb, F.R.

    1984-09-01

    In previous studies from this laboratory, it was found that approximately 30% of women with chest pain and normal coronary arteries demonstrated either a decrease in or a failure to increase radionuclide ejection fraction during exercise. To examine the hypothesis that this apparent abnormality in left ventricular function represents a physiologic difference between men and women, a prospective study was made of central and peripheral cardiovascular responses to exercise in 31 age-matched healthy volunteers (16 women and 15 men). A combination of quantitative radionuclide (technetium) angiography and expired-gas analysis was used to measure ejection fraction and relative changes in end-diastolic counts, stroke counts, count output, and arteriovenous oxygen difference during symptom-limited upright bicycle exercise. Normal male and female volunteers demonstrated comparable baseline left ventricular function and similar aerobic capacity, as determined by weight-adjusted peak oxygen consumption. However, their cardiac responses to exercise were significantly different. The ejection fraction increased by 5 points or more in 14 of 15 men, but in only seven of the 16 women. End-diastolic counts increased by 30% in women, but was unchanged in men. Because decreases in ejection fraction were matched by increases in end-diastolic counts, relative increases in stroke counts and count output were the same for men and women. These data demonstrate a basic difference between men and women with respect to the mechanism by which they achieve a normal response of stroke volume to exercise; these differences must be taken into account when measurements of cardiac function during exercise stress are used for diagnostic purposes.

  20. Inhibition of the neutrophil oxidative response induced by the oral administration of nimesulide in normal volunteers.

    PubMed

    Ottonello, L; Dapino, P; Pastorino, G; Dallegri, F

    1992-01-01

    The superoxide (O2) production by phagocytes (neutrophils plus monocytes) and the lactoferrin release by neutrophils were measured in normal volunteers before and after the oral administration of the anti-inflammatory drug nimesulide. The chemotactic factor N-formylmethionyl-leucyl-phenylalanine (FMLP) and opsonized zymosan particles (OPZ) were used as activating stimuli. The oral administration of nimesulide lowered the phagocyte ability to generate O2- in response to both FMLP (percent inhibition = 67.62) and OPZ (percent inhibition = 36.75). The lactoferrin release by neutrophils was unaffected, proving that the drug does not affect the exocytosis of specific granules. The results provide direct evidence that the oral administration of nimesulide efficiently reduces the oxidative potential of phagocytes, particularly neutrophils, without interfering with mechanisms related to exocytosis of specific granules and involved in the amplification of the cell responses to inflammatory mediators. PMID:1340506

  1. Response to hypogravity of normal in vitro cultured follicular cells from thyroid

    NASA Astrophysics Data System (ADS)

    Meli, Antonella; Perrella, Giuseppina; Curcio, Francesco; Saverio, F.; Impiombato, Ambesi

    Aim of this investigation is the study of molecular modifications occurring in differentiated mammalian cells exposed to gravitational changes. The test system chosen is a well characterized clone of differentiated, normal thyroid follicular cells (FRTL5) in long-term culture. As a follow-up to our recent experiment performed during the MASER-7 sounding rocket mission, flown for European Space Agency by Swedish Space Corporation in May 1996, we evaluated FRTL5 cells responses to Thyroid Stimulating Hormone dependent cAMP production under acute hypogravity conditions obtained in a fast rotating clinostat. Following this approach, we evaluated the FRTL5 cells response to TSH under microgravity conditions in order to optimize experimental tools and strategies in preparation to, and in between real flight missions.

  2. Effects of gonadotropin and testosterone treatments on plasma leptin levels in male patients with idiopathic hypogonadotropic hypogonadism and Klinefelter's syndrome.

    PubMed

    Ozata, M; Ozisik, G; Caglayan, S; Yesilova, Z; Bingöl, N; Saglam, M; Turan, M; Beyhan, Z

    1998-05-01

    Since little is known about the effects of gonadotropin and testosterone treatment on leptin levels in male hypogonadism, we determined fasting plasma leptin levels before and 3 months after treatment in 21 patients with idiopathic hypogonadotropic hypogonadism (IHH), 16 patients with Klinefelter's syndrome and 20 male controls. Patients with IHH were treated with hCG/human menopausal gonadotropin, whereas patients with Klinefelter's syndrome received T treatment. Plasma leptin levels were measured by an RIA with a sensitivity of 0.5 microg/L. Mean leptin levels in patients with IHH before treatment (9.23+/-4.09 microg/L) were not significantly different from those in patients with Klinefelter's syndrome (7.29+/-5.05 microg/L; z=-1.41; P=0.15). Leptin levels in both IHH and Klinefelter's syndrome groups were, however, significantly higher than in the normal men (3.91+/-1.67 microg/L) (P<0.001 and P<0.01, respectively). Mean leptin levels did not change significantly 3 months after the initiation of gonadotropin (11.6+/-6.44 microg/L) or T (8.32+/-5.17 microg/L) treatment in either IHH or Klinefelter's syndrome. Our study demonstrated that mean plasma leptin levels are not influenced by short-term gonadotropin or T treatment in male hypogonadism. PMID:9660087

  3. Sleep restriction increases the neuronal response to unhealthy food in normal-weight individuals

    PubMed Central

    St-Onge, M-P; Wolfe, S; Sy, M; Shechter, A; Hirsch, J

    2013-01-01

    Context Sleep restriction alters responses to food. However, the underlying neural mechanisms for this effect are not well understood. Objective The purpose of this study was to determine whether there is a neural system that is preferentially activated in response to unhealthy compared with healthy foods. Participants Twenty-five normal-weight individuals, who normally slept 7–9 h per night, completed both phases of this randomized controlled study. Intervention Each participant was tested after a period of five nights of either 4 or 9 h in bed. Functional magnetic resonance imaging (fMRI) was performed in the fasted state, presenting healthy and unhealthy food stimuli and objects in a block design. Neuronal responses to unhealthy, relative to healthy food stimuli after each sleep period were assessed and compared. Results After a period of restricted sleep, viewing unhealthy foods led to greater activation in the superior and middle temporal gyri, middle and superior frontal gyri, left inferior parietal lobule, orbitofrontal cortex, and right insula compared with healthy foods. These same stimuli presented after a period of habitual sleep did not produce marked activity patterns specific to unhealthy foods. Further, food intake during restricted sleep increased in association with a relative decrease in brain oxygenation level-dependent (BOLD) activity observed in the right insula. Conclusion This inverse relationship between insula activity and food intake and enhanced activation in brain reward and food-sensitive centers in response to unhealthy foods provides a model of neuronal mechanisms relating short sleep duration to obesity. PMID:23779051

  4. Cidofovir selectivity is based on the different response of normal and cancer cells to DNA damage

    PubMed Central

    2013-01-01

    Background Cidofovir (CDV) proved efficacious in treatment of human papillomaviruses (HPVs) hyperplasias. Antiproliferative effects of CDV have been associated with apoptosis induction, S-phase accumulation, and increased levels of tumor suppressor proteins. However, the molecular mechanisms for the selectivity and antitumor activity of CDV against HPV-transformed cells remain unexplained. Methods We evaluated CDV drug metabolism and incorporation into cellular DNA, in addition to whole genome gene expression profiling by means of microarrays in two HPV+ cervical carcinoma cells, HPV- immortalized keratinocytes, and normal keratinocytes. Results Determination of the metabolism and drug incorporation of CDV into genomic DNA demonstrated a higher rate of drug incorporation in HPV+ tumor cells and immortalized keratinocytes compared to normal keratinocytes. Gene expression profiling clearly showed distinct and specific drug effects in the cell types investigated. Although an effect on inflammatory response was seen in all cell types, different pathways were identified in normal keratinocytes compared to immortalized keratinocytes and HPV+ tumor cells. Notably, Rho GTPase pathways, LXR/RXR pathways, and acute phase response signaling were exclusively activated in immortalized cells. CDV exposed normal keratinocytes displayed activated cell cycle regulation upon DNA damage signaling to allow DNA repair via homologous recombination, resulting in genomic stability and survival. Although CDV induced cell cycle arrest in HPV- immortalized cells, DNA repair was not activated in these cells. In contrast, HPV+ cells lacked cell cycle regulation, leading to genomic instability and eventually apoptosis. Conclusions Taken together, our data provide novel insights into the mechanism of action of CDV and its selectivity for HPV-transformed cells. The proposed mechanism suggests that this selectivity is based on the inability of HPV+ cells to respond to DNA damage, rather than on a

  5. Neuroendocrine response to L-5-hydroxytryptophan challenge in prepubertal major depression. Depressed vs normal children.

    PubMed

    Ryan, N D; Birmaher, B; Perel, J M; Dahl, R E; Meyer, V; al-Shabbout, M; Iyengar, S; Puig-Antich, J

    1992-11-01

    The neuroendocrine response to L-5-hydroxytryptophan was compared in 37 prepubertal children who met the Research Diagnostic Criteria for major depressive disorder with that in 23 normal children with no lifetime history of any psychiatric disorder and very low rates of depression in both first- and second-degree relatives. Intravenous L-5-hydroxytryptophan (0.8 mg/kg) was given over a 1-hour interval after preloading with oral carbidopa, an inhibitor of peripheral but not central L-5-hydroxytryptophan metabolism. L-5-Hydroxytryptophan, a precursor of serotonin, increases serotonin turnover in the central nervous system when given after carbidopa. Seven (19%) of the 37 children with major depressive disorder and two (9%) of the 23 normal children had nausea or vomiting and therefore did not complete the full infusion. They were subsequently excluded from data analysis. After this stimulation, prolactin, cortisol, and growth hormone secretion were compared between diagnostic groups. The depressed children secreted significantly less cortisol (effect size, 0.70) and significantly more prolactin (effect size, 0.83). There was a sex-by-diagnosis interaction in prolactin response to L-5-hydroxytryptophan and, on examination, the prolactin hypersecretion was seen in depressed girls but not in depressed boys compared with same-sex controls. There was no significant stimulation of growth hormone in either group. These findings are consistent with dysregulation of central serotonergic systems in childhood major depression. PMID:1444721

  6. Attenuated insulin response and normal insulin sensitivity in lean patients with ankylosing spondylitis.

    PubMed

    Penesova, A; Rovensky, J; Zlnay, M; Dedik, L; Radikova, Z; Koska, J; Vigas, M; Imrich, R

    2005-01-01

    Chronic low-grade inflammation is associated with insulin resistance. The aim of this study was to determine insulin response to intravenous glucose load and insulin sensitivity in patients with ankylosing spondylitis (AS). Fourteen nonobese male patients with AS and 14 matched healthy controls underwent frequent-sampling intravenous glucose tolerance test (FSIVGTT). Insulin secretion and insulin sensitivity were calculated using the computer-minimal and homeostasis-model assessment 2 (HOMA2) models. Fasting glucose, insulin, cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglyceride levels, HOMA2, glucose effectiveness, insulin sensitivity and insulin response to FSIVGTT did not differ between patients and controls. Tumor necrosis factor-alpha and interleukin (IL)-6 concentrations tended to be higher in AS patients than in controls. Second-phase beta-cell responsiveness was 37% lower (p = 0.05) in AS patients than in controls. A negative correlation was found between the percentage of beta-cell secretion and IL-6 in all subjects (r = -0.54, p = 0.006). We found normal insulin sensitivity but attenuated glucose utilization in the second phase of FSIVGTT in AS patients. Our results indicate that elevated IL-6 levels may play a pathophysiological role in attenuating beta-cell responsiveness, which may explain the association between elevated IL-6 levels and increased risk for type 2 diabetes. PMID:16366418

  7. Patients with MS under daclizumab therapy mount normal immune responses to influenza vaccination

    PubMed Central

    Lin, Yen Chih; Winokur, Paige; Blake, Andrew; Wu, Tianxia; Manischewitz, Jody; King, Lisa R.; Romm, Elena; Golding, Hana

    2016-01-01

    Objective: The purpose of this study was to assess the potential immunosuppressive role of daclizumab, a humanized monoclonal antibody against the α chain of the interleukin 2 receptor, in vivo, by comparing immune responses to the 2013 seasonal influenza vaccination between patients with multiple sclerosis (MS) on long-term daclizumab therapy and controls. Methods: Previously defined subpopulations of adaptive immune cells known to correlate with the immune response to the influenza vaccination were evaluated by 12-color flow cytometry in 23 daclizumab-treated patients with MS and 14 MS or healthy controls before (D0) and 1 day (D1) and 7 days (D7) after administration of the 2013 Afluria vaccine. Neutralizing antibody titers and CD4+, CD8+ T cell, B cell, and natural killer cell proliferation to 3 strains of virus contained in the Afluria vaccine were assessed at D0, D7, and 180 days postvaccination. Results: Daclizumab-treated patients and controls demonstrated comparable, statistically significant expansions of previously defined subpopulations of activated CD8+ T cells and B cells that characterize the development of effective immune responses to the influenza vaccine, while proliferation of T cells to influenza and control antigens was diminished in the daclizumab cohort. All participants fulfilled FDA criteria for seroconversion or seroprotection in antibody assays. Conclusion: Despite the mild immunosuppressive effects of daclizumab in vivo demonstrated by an increased incidence of infectious complications in clinical trials, patients with MS under daclizumab therapy mount normal antibody responses to influenza vaccinations. PMID:26848487

  8. Luteinizing hormone/human chorionic gonadotropin receptors in breast cancer.

    PubMed

    Meduri, G; Charnaux, N; Loosfelt, H; Jolivet, A; Spyratos, F; Brailly, S; Milgrom, E

    1997-03-01

    Recent studies have suggested that human choriogonadotropin (hCG), in addition to its function in regulating steroidogenesis, may also play a role as a growth factor. Immunocytochemistry using two different monoclonal antibodies (LHR29 and LHR1055) raised against the human luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor allowed us to detect this receptor in breast cancer cell lines (T47D, MCF7, and ZR75) in individual cancer biopsies and in benign breast lesions. The receptor was also present in epithelial cells of normal human and sow breast. In the latter, its concentration increased after ovulation. The presence of LH/hCG receptor mRNA was confirmed by reverse transcription-PCR using primers extending over exons 2-4, 5-11, and 9-11. The proportion of LH/hCG-receptor positive cells and the intensity of the immunolabeling varied in individual biopsies, but there was no obvious correlation with the histological type of the cancer. These results are compatible with previous studies suggesting that during pregnancy, hCG is involved in the differentiation of breast glandular epithelium and that this hormone may play an inhibitory role in mammary carcinogenesis and in the growth of breast tumors. PMID:9041186

  9. Gonadotropins in European sea bass: Endocrine roles and biotechnological applications.

    PubMed

    Mazón, María José; Molés, Gregorio; Rocha, Ana; Crespo, Berta; Lan-Chow-Wing, Olivier; Espigares, Felipe; Muñoz, Iciar; Felip, Alicia; Carrillo, Manuel; Zanuy, Silvia; Gómez, Ana

    2015-09-15

    Follicle stimulating hormone (Fsh) and luteinizing hormone (Lh) are central endocrine regulators of the gonadal function in vertebrates. They act through specific receptors located in certain cell types found in the gonads. In fish, the differential roles of these hormones are being progressively elucidated due to the development of suitable tools for their study. In European sea bass (Dicentrarchus labrax), isolation of the genes coding for the gonadotropin subunits and receptors allowed in first instance to conduct expression studies. Later, to overcome the limitation of using native hormones, recombinant dimeric gonadotropins, which show different functional characteristics depending on the cell system and DNA construct, were generated. In addition, single gonadotropin beta-subunits have been produced and used as antigens for antibody production. This approach has allowed the development of detection methods for native gonadotropins, with European sea bass being one of the few species where both gonadotropins can be detected in their native form. By administering recombinant gonadotropins to gonad tissues in vitro, we were able to study their effects on steroidogenesis and intracellular pathways. Their administration in vivo has also been tested for use in basic studies and as a biotechnological approach for hormone therapy and assisted reproduction strategies. In addition to the production of recombinant hormones, gene-based therapies using somatic gene transfer have been offered as an alternative. This approach has been tested in sea bass for gonadotropin delivery in vivo. The hormones produced by the genes injected were functional and have allowed studies on the action of gonadotropins in spermatogenesis. PMID:26002037

  10. Sensitive subgroups and normal variation in pulmonary function response to air pollution episodes.

    PubMed Central

    Brunekreef, B; Kinney, P L; Ware, J H; Dockery, D; Speizer, F E; Spengler, J D; Ferris, B G

    1991-01-01

    The Clean Air Act requires that sensitive subgroups of exposed populations be protected from adverse health effects of air pollution exposure. Hence, data suggesting the existence of sensitive subgroups can have an important impact on regulatory decisions. Some investigators have interpreted differences among individuals in observed pulmonary function response to air pollution episodes as evidence that individuals differ in their sensitivity. An alternative explanation is that the differences are due entirely to normal variation in repeated pulmonary function measurements. This paper investigates this question by reanalyzing data from three studies of children exposed to air pollution episodes to determine whether the observed variability in pulmonary function response indicates differences in sensitivity or natural interoccasion variability. One study investigated exposures to total suspended particulates (TSP), the other two investigated exposure to ozone. In all studies, each child's response to air pollution exposures was summarized by regressing that child's set of pulmonary function measurements on the air pollution concentrations on the day or days before measurement. The within-child and between-child variances of these slopes were used to test the hypothesis of variable sensitivity. Regression slopes did not vary significantly among children exposed to episodes of high TSP concentration, but there was evidence of heterogeneity in both studies of ozone exposures. The finding of heterogeneous response to ozone exposure is consistent with the epidemiologic and chamber studies of ozone exposures, but the lack of evidence for heterogeneous response to TSP exposures implies that observed variation in response can be explained by sampling variability rather than the presence of sensitive subgroup. PMID:2050060

  11. Pituitary gonadotropin and testicular gonadotropin receptor expression in Atlantic cod (Gadusmorhua L.) during the first reproductive season: Effects of photoperiod modulation.

    PubMed

    de Almeida, Fernanda Ferreira Loureiro; Andersson, Eva; Mittelholzer, Christian; Karlsen, Orjan; Taranger, Geir Lasse; Schulz, Rüdiger W

    2011-08-01

    Pituitary mRNA levels of gonadotropin β-subunits and of their cognate receptors in the testis were studied during puberty in Atlantic cod under normal and experimental photoperiod conditions that suppressed, delayed or accelerated testis maturation. Results are discussed in context with changes in testicular histology and plasma androgen levels, considered as end points of gonadotropic regulation. Up-regulation of fshb was closely associated with the onset of puberty, decreased when spermatogenesis was completed and reached minimum levels after spawning. These results demonstrate, for the first time using an experimental approach, that activation of Fsh-dependent signaling is associated with spermatogonial proliferation and formation of spermatogenic cysts. Changes in fshr expression were less prominent and could be explained by changes in the cellular composition and RNA content of cod testis tissue. At more advanced stages of development (spermiogenesis, spermiation and spawning), lhb and, one month later, lhcgr transcript levels increased and reached peak values in spawning fish, in a positive feedback loop involving plasma androgens and Lh/Lhcgr-dependent signaling. This loop was broken by a loss of lhb expression at the end of the spawning season. Continuous light (LL) from summer solstice, ~8 months prior to spawning, suppressed the start of testis maturation and the changes in gonadotropin and receptor mRNA levels, while LL from winter solstice initially up-regulated lhb and lhcgr expression, before resulting in a precocious termination of the spawning season and low expression of all four genes. Our studies provide experimental evidence for a clear functional discrimination of cod gonadotropins. PMID:21605561

  12. Final heights of boys with normal growth hormone responses to provocative tests following priming.

    PubMed

    Gonc, E Nazli; Kandemir, Nurgun; Ozon, Alev; Alikasifoglu, Ayfer

    2008-10-01

    Priming with sex steroids prior to growth hormone (GH) stimulation tests for the diagnosis of GH deficiency is still debatable. We analyzed the auxological data of boys with growth retardation who had normal GH responses to stimulation tests only after priming to establish the validity of priming in the diagnosis of GH deficiency. We also analyzed the effect of different protocols for priming and their efficiency in the diagnosis of GH deficiency. Fifty boys with growth retardation who failed to respond to unprimed GH stimulation tests but responded normally to primed tests were included in the study. Thirty-one of 50 boys responded to GH stimulation tests after single low dose testosterone, 11/50 boys after single conventional dose, and 8/50 boys with multiple-dose testosterone. The study group was followed till final height; height velocity, final height and height SDS were compared to parental and mid-parental heights to determine whether or not the children achieved their height potential. Mean final height SDS of the study group (-1.27 +/- 0.72 SDS) was similar to mid-parental (-1.38 +/- 0.72 SDS) (p = 0.249) and maternal height SDS (-1.26 +/- 1.05 SDS) (p = 0.941), whereas it was greater than the paternal height SDS (-1.7 +/- 0.86) (p = 0.001). The final height SDS of the study group was correlated to maternal, paternal and mid-parental height SDS. Height velocity after the test was greater than the previous height velocity. Final height SDS of the boys who responded to the GH stimulation tests with different priming protocols were compared and found to be similar. Normal responders in primed GH tests grow normally to their target height, suggesting that priming might be a valuable method in the assessment of GH status. Use of priming in the GH stimulation tests of peripubertal boys with decreased growth rate may help avoid unnecessary GH therapy. Multiple-dose testing might exclude GHD in a patient population who failed to respond to a single dose of

  13. Heme oxygenase-1 determines the differential response of breast cancer and normal cells to piperlongumine.

    PubMed

    Lee, Ha-Na; Jin, Hyeon-Ok; Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, BoRa; Kim, Wonki; Hong, Sung-Eun; Lee, Yun-Han; Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun; Park, In-Chul; Surh, Young-Joon; Lee, Jin Kyung

    2015-04-01

    Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic α,β-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine. PMID:25813625

  14. Heme Oxygenase-1 Determines the Differential Response of Breast Cancer and Normal Cells to Piperlongumine

    PubMed Central

    Lee, Ha-Na; Jin, Hyeon-Ok; Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, BoRa; Kim, Wonki; Hong, Sung-Eun; Lee, Yun-Han; Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun; Park, In-Chul; Surh, Young-Joon; Lee, Jin Kyung

    2015-01-01

    Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic α,β-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine. PMID:25813625

  15. Gonadotropin-releasing hormone-regulated prohibitin mediates apoptosis of the gonadotrope cells.

    PubMed

    Savulescu, Dana; Feng, Jiajun; Ping, Yueh Shyang; Mai, Oliver; Boehm, Ulrich; He, Bin; O'Malley, Bert W; Melamed, Philippa

    2013-11-01

    GnRH regulates circulating levels of the gonadotropins but has also been implicated in establishing the gonadotrope cell population. Consistent with this, GnRH induces proliferation of partially differentiated gonadotropes, while reducing the numbers of fully differentiated cells. We have previously reported that the proapoptotic protein, prohibitin (PHB) is expressed more abundantly in gonadotrope-derived LβT2 cells than in partially differentiated αT3-1 gonadotrope precursor cells, suggesting a possible role for PHB in GnRH-induced apoptosis. We show here that PHB is required for GnRH-induced apoptosis in mature gonadotropes. PHB expression and activity are regulated by GnRH: its transcription is via c-Jun NH2-terminal kinase, whereas its nuclear export follows activation of ERK. Moreover, PHB levels are down-regulated by microRNA27, which is expressed at lower levels in mature gonadotropes, possibly explaining the switch to an apoptotic response with development. PHB is required for mitochondrial import of the proapoptotic BAX, whose expression is also induced by GnRH-activated c-Jun NH2-terminal kinase, as is expression of the BH3-only protein, HRK, and this too plays a role in GnRH-induced apoptosis. Finally, we show that gonadotrope-specific PHB-knockout mice display reproductive abnormalities, including a larger gonadotrope population, increased LH levels, reduced fertility, and altered gonad development. We thus demonstrate a role for PHB in GnRH-induced cell death in mature gonadotropes, which is crucial for the normal development and function of the reproductive axis. PMID:24085822

  16. Prolonged Postocclusive Hyperemia Response in Patients with Normal-Tension Glaucoma

    PubMed Central

    Wierzbowska, Joanna; Wojtkiewicz, Stanisław; Zbieć, Anna; Wierzbowski, Robert; Liebert, Adam; Maniewski, Roman

    2014-01-01

    Background It is believed that endothelial dysfunction may be a link between systemic and ocular dysregulation in glaucoma. The aim of this study was to evaluate peripheral vascular reactive hyperemia in response to occlusion test and to correlate peripheral vascular findings with retrobulbar hemodynamics parameters in patients with normal-tension glaucoma. Material/Methods Forty-eight patients with normal-tension glaucoma (mean age 58.1 years, 38 women) and 40 control subjects (mean age 54.1 years, 36 women) were subjected to a brachial arterial occlusion test and color Doppler imaging (LOGIQ 9, GE Medical Systems) of the retrobulbar arteries. Finger hyperemia was assessed by using a 2-channel laser Doppler flowmeter (MBF-3D, Moor Instruments, Ltd.). Time parameters (time to peak flow, half-time of hyperemia, time of recovery) and amplitude parameters (maximum hyperemia response, biological zero) of the post-occlusive reactive hyperemia signal pattern as well as velocities and resistance index of the ophthalmic, central retinal, and short posterior ciliary arteries were evaluated and compared between study groups. Results In glaucoma patients, time to peak flow and half-time of hyperemia were significantly longer (21.4 vs. 12.0 s, p=0.02 and 74.1 vs. 44.2 s, p=0.03, respectively) and biological zero was significantly lower (2.4 vs. 3.2, p=0.01) comparing with healthy subjects. In glaucoma patients, peak-systolic and end-diastolic velocities of central retinal artery were significantly lower (12.8 vs.14.1, p=0.03 and 3.9 vs. 4.7, p=0.01, respectively) and resistance index of this artery was significantly higher (0.69 vs. 0.67, p=0.03) compared to controls. In the glaucoma group, maximum hyperemic response was negatively correlated with the resistance index of temporal short posterior ciliary arteries (r=−0.4, p=0.01), whereas in the control group half-time of hyperemia was negatively correlated with end-diastolic velocity of the central retinal artery (r=−0

  17. The immune response to disialoganglioside GD3 vaccination in normal dogs: a melanoma surface antigen vaccine.

    PubMed

    Milner, R J; Salute, M; Crawford, C; Abbot, J R; Farese, J

    2006-12-15

    As a result of its metastatic potential, canine malignant melanoma like its human counterpart like its human counter part, has a poor response to conventional treatment protocols. This prompted us to investigate the possibility of enhancing the immune response against the melanoma cell surface antigen, disialoganglioside GD3. Initially a flow cytometric study was designed in which the incidence of GD3 on the cell surface, recognized by the monoclonal antibody Mel-1 (R24), was established in canine melanoma cell lines. Results from the flow cytometry found GD3 to be highly expressed (94.2%) in six out of seven canine melanoma cell lines. Since it was thus potentially a good target, a study in which normal dogs were vaccinated intradermally with a vaccine containing GD3 plus adjuvants was designed. The adjuvant included CpG oligodeoxynucleotide (CpG-ODN) sequences and RIBI-adjuvant, which are known to target toll-like receptors (TLR) of the innate immune system. From a cohort of 10 dogs, 4 were vaccinated 3 times, at 4 weekly intervals with GD3 plus adjuvant, and 4 received only RIBI-adjuvant, and 2 phosphate buffered saline. Caliper measurements were collected to assess skin reaction at the vaccination site and sera assayed for IgM and IgG antibodies against GD3 and cell-mediated cytotoxicity against a melanoma cell line. Results from the study found significant differences (P<0.05) in the vaccine site reactions, IgM/IgG levels and cell-mediated cytotoxicity in the vaccinated versus unvaccinated dogs. The addition of CpG-ODN sequences and increasing GD3 concentration in the vaccine increased the inflammation response at the injection site. GD3 IgG and IgM antibodies in vaccinated dogs showed increasing titers over time and achieved significance at weeks 9 and 12, respectively. Cell-mediated cytotoxicity was only detected in peripheral blood mononuclear cells from vaccinated dogs. In conclusion, by combining the tumor antigen GD3 (a known weak self-antigen) and an

  18. Assessment of cardiovascular response to treadmill exercise in normal healthy Indian adolescents.

    PubMed

    Pande, Sushma S; Pande, Santosh R; Dhore, Rajendra B; Daphale, Ajay V; Parate, Vrushali R; Patel, Shishir S; Agrekar, Sushil H

    2012-01-01

    The study aims to assess the cardiovascular response to treadmill exercise test in healthy Indian adolescents. A group of 50 healthy adolescents took part in the study. Cardiovascular response was assessed by using treadmill exercise test as per Bruce protocol. Pulse rate, blood pressure and ECG were recorded before, during and after undertaking the treadmill test. Mean age and body mass index (BMI) were 18.7 +/- 0.51 yrs. and 21.4 +/- 3.44 kg/m2 respectively. Karl Pearson Correlation analysis showed highly significant negative correlation between BMI and exercise time (r = -0.598, P<0.001) and between resting DBP and Exercise Time (r = -0.424, P<0.002). While BMI and DBP showed highly significant positive correlation (r = 0.463, P<0.001). During exercise pulse and SBP rose and DBP fell. SBP rose from mean 122 to 175 (rise by 53 mm of Hg) and DBP fell from mean 78 to 65 (fall by 13 mm of Hg). One min recovery pulse was 156 indicating 22% fall from target heart rate. All the parameters returned to near resting value at 6 min recovery. In 30% students DBP showed exaggerated response i.e. rise during exercise. These students had more BMI and higher resting DBP as compared to other students, which could be the reason for exaggerated response in these participants. In ECG there were no significant ST/T changes during exercise or recovery period. This study provides normal data for small sample of healthy Indian adolescents when subjected to treadmill exercise test. PMID:23029962

  19. Establishment of a human nonluteinized granulosa cell line that transitions from the gonadotropin-independent to the gonadotropin-dependent status.

    PubMed

    Bayasula; Iwase, Akira; Kiyono, Tohru; Takikawa, Sachiko; Goto, Maki; Nakamura, Tomoko; Nagatomo, Yoshinari; Nakahara, Tatsuo; Kotani, Tomomi; Kobayashi, Hiroharu; Kondo, Mika; Manabe, Shuichi; Kikkawa, Fumitaka

    2012-06-01

    The ovary is a complex endocrine organ responsible for steroidogenesis and folliculogenesis. Follicles consist of oocytes and two primary steroidogenic cell types, the granulosa cells, and the theca cells. Immortalized human granulosa cells are essential for researching the mechanism of steroidogenesis and folliculogenesis. We obtained granulosa cells from a 35-yr-old female and immortalized them by lentivirus-mediated transfer of several genes so as to establish a human nonluteinized granulosa cell line (HGrC1). We subsequently characterized HGrC1 and investigated its steroidogenic performance. HGrC1 expressed enzymes related to steroidogenesis, such as steroidogenic acute regulatory protein, CYP11A, aromatase, and gonadotropin receptors. Stimulation with FSH increased the mRNA levels of aromatase, which consequently induced the aromatization of androstenedione to estradiol. Activin A increased the mRNA levels of the FSH receptor, which were synergistically up-regulated with FSH stimulation. HGrC1 also expressed a series of ligands and receptors belonging to the TGF-β superfamily. A Western blot analysis showed that bone morphogenetic protein (BMP)-4, BMP-6, and BMP-7 phosphorylated small mother against decapentaplegic (Smad)1/5/8, whereas growth differentiation factor-9 phosphorylated Smad2/3. BMP-15 and anti-Müllerian hormone phosphorylated Smad1/5/8 while also weakly phosphorylating Smad2/3. These results indicate that HGrC1 may possess the characteristics of granulosa cells belonging to follicles in the early stage. HGrC1 might also be capable of displaying the growth transition from a gonadotropin-independent status to gonadotropin-dependent one. PMID:22467494

  20. Regulation of gonadotropin-releasing hormone gene expression.

    PubMed

    Kim, Helen H

    2007-09-01

    Reproductive function is influenced by several internal and external cues, which ultimately exert their effects on the gonadotropin-releasing hormone (GnRH) neuron. As the final common pathway in the brain for regulating reproduction, GnRH neurons receive signals from multiple cell types, and alterations in GnRH production impact reproductive competence. Historically, the paucity of GnRH neurons and their scattered distribution in the brain have limited the study of GnRH gene expression. With transgenic technology, newer model systems (such as immortalized GnRH-expressing cell lines and GnRH-reporter gene transgenic mice) have been developed, making molecular studies possible. This article provides an update on the molecular mechanisms responsible for the regulation of GnRH gene expression, focusing on tissue-specific expression and transcriptional regulation. After an overview of GnRH gene structure, synthesis, and secretion, the model systems for studying GnRH neurons are examined. The molecular mechanisms that translate physiologic stimuli, such as nutritional status or stress, into changes in GnRH expression will be reviewed, concentrating on the regulatory regions within the GnRH gene promoter and the critical transcription factors. PMID:17710727

  1. Hypovolemia Induced Orthostatic Hypotension in Presyncopal Astronauts and Normal Subjects Relates to Hypo-Sympathetic Responsiveness

    NASA Technical Reports Server (NTRS)

    Meck, Janice V.; Stenger, Michael B.; Platts, Steven H.; Ziegler, Michael G.

    2007-01-01

    Circulating blood volume is reduced during spaceflight, leaving astronauts hemodynamically compromised after landing. Because of this hypovolemia, crew members are able to withstand a postflight 10 minute upright tilt test only if they are able to mount a hyper-sympathetic response. Previous work from this laboratory has shown that about 30% of astronauts, primarily female, have postflight sympathetic responses to tilt that are equal to or less than their preflight responses and thus, they become presyncopal. Part of the mission of the cardiovascular lab at the Johnson Space Center is to identify susceptible crewmembers before flight so that individualized countermeasures can be prescribed. The goal of this study was to develop a ground based model of hypovolemia that could be used for this purpose We tested the hypothesis that hypovolemia alone, in the absence of spaceflight, would reproduce the landing day rate of presyncope during upright tilt in normal volunteers. Further, we hypothesized that, during hypovolemia, subjects who had sympathetic responses that were equal to or less than their normovolemic responses would become presyncopal during upright tilt tests. We studied 20 subjects, 13 male and 7 female, on two separate occasions: during normovolemia and hypovolemia. We induced hypovolemia with intravenous furosemide 40 hours prior to the experiment day, followed by a 10MEq Na diet. On the normovolemia and hypovolemia test days, plasma volume, tilt tolerance and supine and standing arterial pressure, heart rate and plasma norepinephrine levels were measured. A two factor, repeated measures analysis of variance was performed to examine the differences between group (presyncopal vs. non-presyncopal) and day (normovolemia vs. hypovolemia) effects. There were no differences in baseline arterial pressure between normovolemia and hypovolemia or between presyncopal and non-presyncopal groups, but heart rates were higher with hypovolemia in both groups (presyncopal

  2. University Loaned Normal Uranium Slug Disposition Study: University survey responses. Predecisional draft

    SciTech Connect

    Becker, G.W. Jr.

    1992-09-01

    During the 1950`s and 1960`s, the Atomic Energy Commission loaned rejected natural uranium slugs from the Savannah River Site to United States universities for use in subcritical assemblies. Currently, there are sixty-two universities holding 91,798 slugs, containing about 167 metric tons of natural uranium. It was originally planned that the universities would return the material to Fernald when they no longer required it. Fernald has not received slugs since it was shut down in 1988. The Department of Energy`s Office of Weapons and Materials Planning requested that the Planning Support Group develop information to assist them in facilitating the return of the unwanted slugs to one or more of their facilities and develop alternatives for the ultimate disposition of this material. This supplemental report to the University Loaned Normal Uranium Slug Disposition Study documents responses to and summarizes the results of a survey of fifty-eight universities. University contacts and survey responses covering loaned slug descriptions, historical information, radiological data, current status, and plans and schedules are documented.

  3. Cellular and humoral antibody responses of normal pastel and sapphire mink to goat erythrocytes.

    PubMed

    Lodmell, D L; Bergman, R K; Hadlow, W J; Munoz, J J

    1971-02-01

    This study was undertaken to determine whether normal sapphire and royal pastel mink differ immunologically at the cellular and humoral levels. Two days after primary intraperitoneal (ip) inoculation of goat erythrocytes (GE), essentially no 19 or 7S plaque-forming cells (PFC) per 10(6) cells were detected in spleen or in abdominal and peripheral lymph nodes of either color phase. On the 4th day, more 19S PFC were detected in pastel than in sapphire tissues; pastel tissues also contained 7S PFC, whereas essentially none was present in sapphires until the 6th day. After an ip booster inoculation, the number of PFC was markedly different between the two color phases. These differences were most apparent in spleen and peripheral lymph nodes. In parallel with differences observed in PFC responses between the color phases, total hemolysin and 2-mercaptoethanol-resistant hemolysin titers of pastels exceeded those of sapphires in all but one interval after the primary, and at every interval after the booster, inoculation. These data indicate that sapphire mink are not immunological cripples, nor are they immunologically hyperactive, but that differences do exist between sapphire and royal pastel mink, especially in the response to booster injections of GE. PMID:16557957

  4. Cellular and Humoral Antibody Responses of Normal Pastel and Sapphire Mink to Goat Erythrocytes

    PubMed Central

    Lodmell, D. L.; Bergman, R. K.; Hadlow, W. J.; Munoz, J. J.

    1971-01-01

    This study was undertaken to determine whether normal sapphire and royal pastel mink differ immunologically at the cellular and humoral levels. Two days after primary intraperitoneal (ip) inoculation of goat erythrocytes (GE), essentially no 19 or 7S plaque-forming cells (PFC) per 106 cells were detected in spleen or in abdominal and peripheral lymph nodes of either color phase. On the 4th day, more 19S PFC were detected in pastel than in sapphire tissues; pastel tissues also contained 7S PFC, whereas essentially none was present in sapphires until the 6th day. After an ip booster inoculation, the number of PFC was markedly different between the two color phases. These differences were most apparent in spleen and peripheral lymph nodes. In parallel with differences observed in PFC responses between the color phases, total hemolysin and 2-mercaptoethanol-resistant hemolysin titers of pastels exceeded those of sapphires in all but one interval after the primary, and at every interval after the booster, inoculation. These data indicate that sapphire mink are not immunological cripples, nor are they immunologically hyperactive, but that differences do exist between sapphire and royal pastel mink, especially in the response to booster injections of GE. PMID:16557957

  5. Analysis of the dynamic response of a supersonic inlet to flow-field perturbations upstream of the normal shock

    NASA Technical Reports Server (NTRS)

    Cole, G. L.; Willoh, R. G.

    1975-01-01

    A linearized mathematical analysis is presented for determining the response of normal shock position and subsonic duct pressures to flow-field perturbations upstream of the normal shock in mixed-compression supersonic inlets. The inlet duct cross-sectional area variation is approximated by constant-area sections; this approximation results in one-dimensional wave equations. A movable normal shock separates the supersonic and subsonic flow regions, and a choked exit is assumed for the inlet exit condition. The analysis leads to a closed-form matrix solution for the shock position and pressure transfer functions. Analytical frequency response results are compared with experimental data and a method of characteristics solution.

  6. Enhancement of thermal response of normal and malignant tissues by Corynebacterium parvum. [Mice

    SciTech Connect

    Urano, M.; Yamashita, T.; Suit, H.D.; Gerweck, L.E.

    1984-06-01

    Further studies were carried out on the combined effects of Corynebacterium parvum and hyperthermia on animal tissues and cultured Chinese hamster ovary cells. Experimental animals were C3Hf/Sed mice derived from a defined flora mouse colony. Tumors were eighth-generation isotransplants of a spontaneous fibrosarcoma, FSa-II. Hyperthermia was given by immersing the mouse foot or culture flasks in the constant temperature water bath. Present experiments include thermal enhancement of C. parvum at different temperatures, effect of the agent on the kinetics of thermal resistance, and the mechanism of the thermal enhancement. The thermal enhancement by C. parvum was independent of temperature in a range between 42.5 and 46.5 degrees, and it increased with decreasing temperature. The analysis of the Arrhenius plot suggested a comparable activation energy for combined treatments and for heat alone between 42.5 and 46.5 degrees. The thermal resistance developed very rapidly in both normal and tumor tissues. Systemic administration of C. parvum failed to modify the kinetics of thermal resistance. Several experiments were attempted in order to disclose the mechanism. A single injection of C. parvum-induced macrophages failed to enhance thermal response of the mouse foot, while 3 daily injections of the macrophages enhanced the response, indicating that the enhancement by C. parvum is at least partly attributed to the C. parvum-induced macrophages. Whole-body irradiation of 6 Gy and/or administration of anti-mouse T-cell serum and histamine failed to inhibit the C. parvum enhancement of thermal response. No thermal enhancement was observed for Chinese hamster ovary cells treated at 43.0 degrees in vitro with C. parvum or thiomersalate, a preservative supplemented in C. parvum, although cytotoxic effect was shown at a high concentration of thiomersalate.

  7. 'Getting back to normal' or 'a new type of normal'? A qualitative study of patients' responses to the existential threat of cancer.

    PubMed

    Baker, P; Beesley, H; Fletcher, I; Ablett, J; Holcombe, C; Salmon, P

    2016-01-01

    Existential concerns about cancer have been studied extensively in palliative care but less so in curative settings. The present report aims to describe ways in which patients viewed the continuity or discontinuity of their identity in the face of the mortal threat of cancer. Twenty-eight patients with breast, prostate or lung cancer attending pre-treatment, treatment or follow-up appointments were interviewed about their emotional experiences following diagnosis. Qualitative analysis followed an inductive, constant comparative approach. Patients spoke of 'getting back to normal', but presented two distinct accounts of 'normality'. Some, particularly those only recently diagnosed, maintained continuity to past identity by upholding previous routines, emphasising resilience and minimising the impact of cancer. Others talked of a new 'normality' discontinuous with their past. Most accounts, however, evidenced elements of continuity and discontinuity, often in ostensibly contradictory ways. We suggest that holding contradictory perspectives simultaneously characterises an intermediate stage of adjustment for some patients: between reliance on continuity with the past in the aftermath of diagnosis and, later, a sense of being a new person, changed by cancer. Practitioners should appreciate that patients' wishes for 'normality' can signify very different responses to cancer, and that holding such contradictory orientations is functional, not aberrant. PMID:25523386

  8. Tamoxifen Induces Expression of Immune Response-Related Genes in Cultured Normal Human Mammary Epithelial Cells

    PubMed Central

    Schild-Hay, Laura J.; Leil, Tarek A.; Divi, Rao L.; Olivero, Ofelia, A.; Weston, Ainsley; Poirier, Miriam C.

    2008-01-01

    Use of tamoxifen (TAM) is associated with a 50% reduction in breast cancer incidence and an increase in endometrial cancer incidence. Here, we documented TAM-induced gene expression changes in cultured normal human mammary epithelial cells (NHMEC strains numbered 5, 16 and 40), established from tissue taken at reduction mammoplasty from 3 individuals. Cells exposed to 0, 10 or 50 μM TAM for 48 hours were evaluated for (E)-α-(deoxyguanosin-N2-yl)-tamoxifen (dG-N2-TAM) adduct formation by TAM-DNA (DNA modified with dG-N2-TAM) chemiluminescence immunoassay (CIA), gene expression changes using NCI DNA-oligonucleotide microarray, and real time (RT)-PCR. At 48 hr, cells exposed to 10 μM and 50 μM TAM were 85.6% and 48.4% viable, respectively, and there were no measurable dG-N2-TAM adducts. For microarray, cells were exposed to 10 μM TAM and genes with expression changes of ≥ 3-fold were as follows: thirteen genes up-regulated and one down-related for strain 16; seventeen genes up-regulated for strain 5; and eleven genes up-regulated for strain 40. Interferon-inducible genes (IFITM1, IFIT1, IFNA1, MXI and GIP3), and a potassium ion channel (KCNJ1) were up-regulated in all 3 strains. No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. RT-PCR revealed up-regulation of interferon α (IFNA1) and confirmed the TAM-induced up-regulation of the genes identified by microarray, with the exception of GIP3 and MX1, which were not up-regulated in strain 40. Induction of interferon-related genes in the three NHMEC strains suggests that, in addition to hormonal effects, TAM exposure may enhance immune response in normal breast tissue. PMID:19155303

  9. Inhibitors of cell cycle checkpoints and DNA replication cause different responses in normal versus malignant urothelial cells

    PubMed Central

    Meuth, Mark

    2014-01-01

    S-phase checkpoints are triggered in tumor cells in response to DNA replication stress caused by the tumor microenvironment or oncogenes. A recent report from our laboratory showed that tumor cells and more normal epithelial cells have a very different response to replication stress. In this Author's View, the implications of this finding are discussed. PMID:27308366

  10. Successful use of a gonadotropin-releasing hormone (GnRH) analog for the treatment of tertiary hypogonadism (GnRH deficiency) in a 5-year-old Belgian Blue bull.

    PubMed

    Contri, Alberto; Gloria, Alessia; Wegher, Laura; Carluccio, Augusto

    2012-01-01

    A bull was referred for a progressive oligoasthenotheratozoospermia that resulted in a unsuitable seminal quality for the cryopreservation. Breeding soundness evaluation results suggested gonadal dysfunction. Because of the lack of normal ranges for these hormones in the bull, in this study, the hypogonadism and the site of the dysfunction (hypothalamus) were diagnosed by the gonadotropin-releasing hormone (GnRH) stimulation test. The evaluation of pituitary and testicular responsiveness by a GnRH stimulating test revealed a responsiveness of the pituitary and testis, thus a secondary hypogonadism (hypothalamic hypogonadism) was postulated and a therapeutic approach based on the subcutaneous administration of GnRH analog was attempted. An increase in semen volume, concentration and sperm characteristics were detected 9 weeks after the start of the treatment, corroborating the hypothalamic origin of the disease and the useful of the GnRH therapy. PMID:22493993

  11. Modeling the response of normal and ischemic cardiac tissue to electrical stimulation

    NASA Astrophysics Data System (ADS)

    Kandel, Sunil Mani

    Heart disease, the leading cause of death worldwide, is often caused by ventricular fibrillation. A common treatment for this lethal arrhythmia is defibrillation: a strong electrical shock that resets the heart to its normal rhythm. To design better defibrillators, we need a better understanding of both fibrillation and defibrillation. Fundamental mysteries remain regarding the mechanism of how the heart responds to a shock, particularly anodal shocks and the resultant hyperpolarization. Virtual anodes play critical roles in defibrillation, and one cannot build better defibrillators until these mechanisms are understood. We are using mathematical modeling to numerically simulate observed phenomena, and are exploring fundamental mechanisms responsible for the heart's electrical behavior. Such simulations clarify mechanisms and identify key parameters. We investigate how systolic tissue responds to an anodal shock and how refractory tissue reacts to hyperpolarization by studying the dip in the anodal strength-interval curve. This dip is due to electrotonic interaction between regions of depolarization and hyperpolarization following a shock. The dominance of the electrotonic mechanism over calcium interactions implies the importance of the spatial distribution of virtual electrodes. We also investigate the response of localized ischemic tissue to an anodal shock by modeling a regional elevation of extracellular potassium concentration. This heterogeneity leads to action potential instability, 2:1 conduction block (alternans), and reflection-like reentry at the boarder of the normal and ischemic regions. This kind of reflection (reentry) occurs due to the delay between proximal and distal segments to re-excite the proximal segment. Our numerical simulations are based on the bidomain model, the state-of-the-art mathematical description of how cardiac tissue responds to shocks. The dynamic LuoRudy model describes the active properties of the membrane. To model ischemia

  12. Conservative management of a pituitary tumor during pregnancy following induction of ovulation with gonadotropins.

    PubMed

    Jewelewicz, R; Zimmerman, E A; Carmel, P W

    1977-01-01

    Ovulation induced with human menopausal gonadotropin-human chorionic gonadotropin in a 27-year-old woman who had been amenorrheic for 7 years resulted in pregnancy. Although pretreatment neurologic evaluation was normal, significant loss of vision was found at 30 weeks' gestation, and a skull x-ray revealed enlargement and erosion of the sella turcica. As an attempt to delay surgery, 12 mg of dexamethasone daily arrested further visual deterioration, and the pregnancy continued uneventful for 36 weeks, when triplets were born. Five days after delivery the visual fields were normal. Trans-sphenoidal resection of a prolactin-secreting chromophobe adenoma of the pituitary was carried out 6 months later. It is suggested that when disturbance in visual perception due to a pituitary tumor occurs during pregnancy, a course of high-dose corticosteroids with frequent monitoring of visual fields and acuity might be tried before surgical intervention. Although further rapid deterioration in vision may dictate immediate surgical decompression, conservative management may result in stabilization, allowing the patient to carry the pregnancy to term and obviating the need for emergency surgery. PMID:832714

  13. Radiation-quality dependent cellular response in mutation induction in normal human cells.

    PubMed

    Suzuki, Masao; Tsuruoka, Chizuru; Uchihori, Yukio; Kitamura, Hisashi; Liu, Cui Hua

    2009-09-01

    We studied cellular responses in normal human fibroblasts induced with low-dose (rate) or low-fluence irradiations of different radiation types, such as gamma rays, neutrons and high linear energy transfer (LET) heavy ions. The cells were pretreated with low-dose (rate) or low-fluence irradiations (approximately 1 mGy/7-8 h) of 137Cs gamma rays, 241Am-Be neutrons, helium, carbon and iron ions before irradiations with an X-ray challenging dose (1.5 Gy). Helium (LET = 2.3 keV/microm), carbon (LET = 13.3 keV/microm) and iron (LET = 200 keV/microm) ions were produced by the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. No difference in cell-killing effect, measured by a colony forming assay, was observed among the pretreatment with different radiation types. In mutation induction, which was detected in the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus to measure 6-thioguanine resistant clones, there was no difference in mutation frequency induced by the X-ray challenging dose between unpretreated and gamma-ray pretreated cells. In the case of the pretreatment of heavy ions, X-ray-induced mutation was around 1.8 times higher in helium-ion pretreated and 4.0 times higher in carbon-ion pretreated cells than in unpretreated cells (X-ray challenging dose alone). However, the mutation frequency in cells pretreated with iron ions was the same level as either unpretreated or gamma-ray pretreated cells. In contrast, it was reduced at 0.15 times in cells pretreated with neutrons when compared to unpretreated cells. The results show that cellular responses caused by the influence of hprt mutation induced in cells pretreated with low-dose-rate or low-fluence irradiations of different radiation types were radiation-quality dependent manner. PMID:19680011

  14. Middle latency auditory evoked responses in normal term infants: a longitudinal study.

    PubMed

    Rogers, S H; Edwards, D A; Henderson-Smart, D J; Pettigrew, A G

    1989-05-01

    Middle latency auditory evoked responses (MLAERs) were measured in 21 normal term infants, three to five days after birth and then at 6 weeks, 7 months and 1 year of age. A polyphasic waveform was elicited during natural sleep in all infants at each recording session by monaural click stimulation at a rate of 9 per second. A 70 dBHL stimulus was found to be optimal as the MLAER became less well defined when the stimulus intensity approached the threshold hearing level. The first 60 to 70 msec of the waveform was found to be most stable, with decreasing detectability of peaks at longer latencies. There was no change in wave latency or reproducibility of MLAERs recorded during different sleep states. Waves Po and Na showed a significant decrease in latency with increasing stimulus intensity at term and/or 6 weeks of age. This was not evident for the remainder of the waveform. Waves Po, Na, Pa, Nb, Pb and Nc exhibited significant decreases in latency with age, attaining values indistinguishable from adults by 7 months of age. PMID:2739875

  15. Responses to cochlear normalized speech stimuli in the auditory nerve of cat

    NASA Astrophysics Data System (ADS)

    Recio, Alberto; Rhode, William S.; Kiefte, Michael; Kluender, Keith R.

    2002-05-01

    Previous studies of auditory-nerve fiber (ANF) representation of vowels in cats and rodents (chinchillas and guinea pigs) have shown that, at amplitudes typical for conversational speech (60-70 dB), neuronal firing rate as a function of characteristic frequency alone provides a poor representation of spectral prominences (e.g., formants) of speech sounds. However, ANF rate representations may not be as inadequate as they appear. Here, it is investigated whether some of this apparent inadequacy owes to the mismatch between animal and human cochlear characteristics. For all animal models tested in earlier studies, the basilar membrane is shorter and encompasses a broader range of frequencies than that of humans. In this study, a customized speech synthesizer was used to create a rendition of the vowel [eh] with formant spacing and bandwidths that fit the cat cochlea in proportion to the human cochlea. In these vowels, the spectral envelope is matched to cochlear distance rather than to frequency. Recordings of responses to this cochlear normalized [eh] in auditory-nerve fibers of cats demonstrate that rate-based encoding of vowel sounds is capable of distinguishing spectral prominences even at 70-80-dB SPL. When cochlear dimensions are taken into account, rate encoding in ANF appears more informative than was previously believed.

  16. Optical spectroscopy of radiotherapy and photodynamic therapy responses in normal rat skin shows vascular breakdown products

    NASA Astrophysics Data System (ADS)

    Teles de Andrade, Cintia; Nogueira, Marcelo S.; Kanick, Stephen C.; Marra, Kayla; Gunn, Jason; Andreozzi, Jacqueline; Samkoe, Kimberley S.; Kurachi, Cristina; Pogue, Brian W.

    2016-03-01

    Photodynamic therapy (PDT) and radiotherapy are non-systemic cancer treatment options with different mechanisms of damage. So combining these techniques has been shown to have some synergy, and can mitigate their limitations such as low PDT light penetration or radiotherapy side effects. The present study monitored the induced tissue changes after PDT, radiotherapy, and a combination protocol in normal rat skin, using an optical spectroscopy system to track the observed biophysical changes. The Wistar rats were treated with one of the protocols: PDT followed by radiotherapy, PDT, radiotherapy and radiotherapy followed by PDT. Reflectance spectra were collected in order to observe the effects of these combined therapies, especially targeting vascular response. From the reflectance, information about oxygen saturation, met-hemoglobin and bilirubin concentration, blood volume fraction (BVF) and vessel radius were extracted from model fitting of the spectra. The rats were monitored for 24 hours after treatment. Results showed that there was no significant variation in the vessel size or BVF after the treatments. However, the PDT caused a significant increase in the met-hemoglobin and bilirubin concentrations, indicating an important blood breakdown. These results may provide an important clue on how the damage establishment takes place, helping to understand the effect of the combination of those techniques in order to verify the existence of a known synergistic effect.

  17. Identification and Validation of Reference Genes for Transcript Normalization in Strawberry (Fragaria × ananassa) Defense Responses

    PubMed Central

    Amil-Ruiz, Francisco; Garrido-Gala, José; Blanco-Portales, Rosario; Folta, Kevin M.; Muñoz-Blanco, Juan; Caballero, José L.

    2013-01-01

    Strawberry (Fragaria spp) is an emerging model for the development of basic genomics and recombinant DNA studies among rosaceous crops. Functional genomic and molecular studies involve relative quantification of gene expression under experimental conditions of interest. Accuracy and reliability are dependent upon the choice of an optimal reference control transcript. There is no information available on validated endogenous reference genes for use in studies testing strawberry-pathogen interactions. Thirteen potential pre-selected strawberry reference genes were tested against different tissues, strawberry cultivars, biotic stresses, ripening and senescent conditions, and SA/JA treatments. Evaluation of reference candidate’s suitability was analyzed by five different methodologies, and information was merged to identify best reference transcripts. A combination of all five methods was used for selective classification of reference genes. The resulting superior reference genes, FaRIB413, FaACTIN, FaEF1α and FaGAPDH2 are strongly recommended as control genes for relative quantification of gene expression in strawberry. This report constitutes the first systematic study to identify and validate optimal reference genes for accurate normalization of gene expression in strawberry plant defense response studies. PMID:23940602

  18. Glycemic response to selected sympathomimetics in stressed normal and goldthioglucose mice.

    PubMed

    Sandage, B W; Fletcher, H P

    1983-01-01

    Single intraperitoneal doses of phenylephrine (PE), phenylpropanolamine (PPA) and pseudoephedrine (PSD) have differing effects on blood glucose in stressed, normal and goldthioglucose (GTG) mice. PE in normal and GTG mice caused a pronounced but temporary rise in blood glucose while PPA failed to show a significant effect on resting blood glucose in either animal. PSD, in normal and GTG mice, caused a hyperglycemia at 2 h after treatment. Reduced stress conditions (nonrepeated orbital sinus blood sampling) or adrenalectomy eliminated the PSD delayed hyperglycemia in normal mice. PSD did not alter immunoreactive insulin levels at 2 h; however, PSD caused significantly higher corticosterone levels in normal and GTG mice at 2 h. PPA, which did not cause hyperglycemia, had no effect on corticosterone levels at 2 h in normal mice. PMID:6412256

  19. Power source effects of soft plasma jet and the differential response of skin cancer and normal cells

    NASA Astrophysics Data System (ADS)

    Taylor, Nathaniel; Dobrynin, Danil; Fridman, Alexander; Choi, Eun Ha

    2014-10-01

    The effects of pulsed power direct current energy sources were compared using an indirect discharge plasma jet applied to treat cancerous and normal skin cells. Two power supplies with different voltage and current profiles were compared and optimized through the measurement of physical parameters and evaluated through the treatment of skin cells using an atmospheric pressure nitrogen gas plasma jet. Plasma density and temperature, power output, gas output temperature, and reactive species production were measured. Cell morphology, viability, and ROS generation were investigated using staining. A differential response has been shown between the normal and cancerous cell lines. The cancer cells viability reduced while normal cells did not over the same treatment time.

  20. Influence of hormonal contraceptives on the pituitary response to LH/FSH-releasing hormone.

    PubMed

    Carol, W; Lauterbach, H; Klinger, G; Möller, R

    1978-03-01

    In the pre-ovulatory phase the absolute and relative LH increase was much greater than during the luteal phase and less pronounced in the early follicular phase of the normal cycle. FSH release was affected only during the pre-ovulatory period, where a retarded, 3- or 4-fold increase compared to basal levels was recorded. In the women taking oral contraceptives of the conventional type the first LH-RH test showed gonadotropin responses similar to those obtained during the luteal phase of the controls. The second test brought a significantly lower LH response, suggesting an increasing exogenous steroid inhibition at the pituitary level in the course of the therapeutic cycle. This inhibition seems to be reversed during the monthly tablet-free interval. A particularly small and retarded gonadotropin response was observed in patients taking Deposiston. These results are discussed as to their clinical significance. PMID:357145

  1. Ocular motor responses to abrupt interaural head translation in normal humans

    NASA Technical Reports Server (NTRS)

    Ramat, Stefano; Zee, David S.; Shelhamer, M. J. (Principal Investigator)

    2003-01-01

    We characterized the interaural translational vestibulo-ocular reflex (tVOR) in 6 normal humans to brief (approximately 200 ms), high-acceleration (0.4-1.4g) stimuli, while they fixed targets at 15 or 30 cm. The latency was 19 +/- 5 ms at 15-cm and 20 +/- 12 ms at 30-cm viewing. The gain was quantified using the ratio of actual to ideal behavior. The median position gain (at time of peak head velocity) was 0.38 and 0.37, and the median velocity gain, 0.52 and 0.62, at 15- and 30-cm viewing, respectively. These results suggest the tVOR scales proportionally at these viewing distances. Likewise, at both viewing distances, peak eye velocity scaled linearly with peak head velocity and gain was independent of peak head acceleration. A saccade commonly occurred in the compensatory direction, with a greater latency (165 vs. 145 ms) and lesser amplitude (1.8 vs. 3.2 deg) at 30- than 15-cm viewing. Even with saccades, the overall gain at the end of head movement was still considerably undercompensatory (medians 0.68 and 0.77 at 15- and 30-cm viewing). Monocular viewing was also assessed at 15-cm viewing. In 4 of 6 subjects, gains were the same as during binocular viewing and scaled closely with vergence angle. In sum the low tVOR gain and scaling of the response with viewing distance and head velocity extend previous results to higher acceleration stimuli. tVOR latency (approximately 20 ms) was lower than previously reported. Saccades are an integral part of the tVOR, and also scale with viewing distance.

  2. Innate Immune Responses of Human Neonatal Cells to Bacteria from the Normal Gastrointestinal Flora

    PubMed Central

    Karlsson, Helen; Hessle, Christina; Rudin, Anna

    2002-01-01

    The hygiene hypothesis postulates that the prevalence of allergy has increased due to decreased microbial stimulation early in life, leading to delayed maturation of the immune system. The aim of this study was to examine the cytokine pattern produced from cord blood mononuclear cells relative to adult cells after stimulation with bacterial strains from the normal flora. Mononuclear cells from cord and adult blood samples were stimulated with the following bacteria: Bifidobacterium adolescentis, Enterococcus faecalis, Lactobacillus plantarum, Streptococcus mitis, Corynebacterium minutissimum, Clostridium perfringens, Bacteroides vulgatus, Escherichia coli, Pseudomonas aeruginosa, Veillonella parvula, and Neisseria sicca. The levels of interleukin 12 (IL-12), tumor necrosis factor alpha (TNF-α), IL-10, and IL-6 were measured by enzyme-linked immunosorbent assay. The TNF-α production was also analyzed after blocking CD14, Toll-like receptor 2 (TLR-2), and TLR-4 prior to stimulation with bacteria. The levels of IL-12 and TNF-α were similar in cord and adult cells. Gram-positive bacteria induced considerably higher levels of IL-12 and TNF-α than gram-negative bacteria in both cord and adult cells. The levels of IL-6 were significantly higher in newborns than in adults, whereas the levels of IL-10 were similar in newborns and adults. Gram-negative and gram-positive bacteria induced similar levels of IL-6 and IL-10 in cord cells. L. plantarum bound or signaled through CD14, TLR-2, and TLR-4, whereas E. coli acted mainly through CD14 and TLR-4. These results indicate that the innate immune response in newborns to commensal bacteria is strong and also suggest that different bacterial strains may have differential effects on the maturation of the immune system of infants. PMID:12438343

  3. Innate immune responses of human neonatal cells to bacteria from the normal gastrointestinal flora.

    PubMed

    Karlsson, Helen; Hessle, Christina; Rudin, Anna

    2002-12-01

    The hygiene hypothesis postulates that the prevalence of allergy has increased due to decreased microbial stimulation early in life, leading to delayed maturation of the immune system. The aim of this study was to examine the cytokine pattern produced from cord blood mononuclear cells relative to adult cells after stimulation with bacterial strains from the normal flora. Mononuclear cells from cord and adult blood samples were stimulated with the following bacteria: Bifidobacterium adolescentis, Enterococcus faecalis, Lactobacillus plantarum, Streptococcus mitis, Corynebacterium minutissimum, Clostridium perfringens, Bacteroides vulgatus, Escherichia coli, Pseudomonas aeruginosa, Veillonella parvula, and Neisseria sicca. The levels of interleukin 12 (IL-12), tumor necrosis factor alpha (TNF-alpha), IL-10, and IL-6 were measured by enzyme-linked immunosorbent assay. The TNF-alpha production was also analyzed after blocking CD14, Toll-like receptor 2 (TLR-2), and TLR-4 prior to stimulation with bacteria. The levels of IL-12 and TNF-alpha were similar in cord and adult cells. Gram-positive bacteria induced considerably higher levels of IL-12 and TNF-alpha than gram-negative bacteria in both cord and adult cells. The levels of IL-6 were significantly higher in newborns than in adults, whereas the levels of IL-10 were similar in newborns and adults. Gram-negative and gram-positive bacteria induced similar levels of IL-6 and IL-10 in cord cells. L. plantarum bound or signaled through CD14, TLR-2, and TLR-4, whereas E. coli acted mainly through CD14 and TLR-4. These results indicate that the innate immune response in newborns to commensal bacteria is strong and also suggest that different bacterial strains may have differential effects on the maturation of the immune system of infants. PMID:12438343

  4. Fluent and Disfluent Normal Speakers' Responses on a Synthetic Sentence Identification (SSI) Task.

    ERIC Educational Resources Information Center

    Nuck, Martha E.; And Others

    1987-01-01

    To evaluate the theory that central auditory processing deficits exist in the normally disfluent population, 40 adults were administered the Synthetic Sentence Identification-Ipsilateral Competing Message Measure. Results revealed a significant difference between the performance of fluent and disfluent normal speakers but not between ear…

  5. Normal mitogen-induced suppression of the interleukin-6 (IL-6) response and its deficiency in systemic lupus erythematosus

    SciTech Connect

    Warrington, R.J.; Rutherford, W.J. )

    1990-01-01

    A low-frequency suppressor-cell population in normal peripheral blood inhibits the B-cell CESS response to IL-6, following pokeweed mitogen stimulation. The suppression of IL-6 responsiveness is radiation sensitive, directed against CESS targets and not mediated by inhibition of IL-6 production, and associated with nonspecific cytotoxic activity against CESS targets. The generation of these cytolytic cells is also radiation sensitive. A correlation was found between PWM-induced cytotoxicity against CESS and the suppression of IL-6-dependent IgG production. But cytotoxicity toward CESS targets is not responsible for this suppression because IL-2 induces equivalent or greater nonspecific cytotoxicity against CESS in the total absence of suppression of CESS-derived IgG production and suppression is also induced by mitogen-activated PBL separated from CESS targets by a cell-impermeable membrane. This suppression was not mediated by TNF alpha/beta or IFN-gamma. In systemic lupus erythematosus, suppression of IL-6-dependent IgG production is impaired in patients with active disease (29.2 +/- 13.7%) compared to patients with inactive disease (70 +/- 19.5%) or normal controls (82.8 +/- 9.2%). There is also a defect in mitogen-induced nonspecific cytotoxicity in active SLE (specific lysis 15.1 +/- 3.5%, compared to 34 +/- 4% in normals). Pokeweed mitogen-activated PBL can therefore normally induce suppression of B-cell IL-6 responses and this response is deficient in lupus.

  6. Up-regulation of placental leptin by human chorionic gonadotropin.

    PubMed

    Maymó, Julieta L; Pérez Pérez, Antonio; Sánchez-Margalet, Víctor; Dueñas, José L; Calvo, Juan Carlos; Varone, Cecilia L

    2009-01-01

    Leptin, the 16,000 molecular weight protein product of the obese gene, was originally considered as an adipocyte-derived signaling molecule for the central control of metabolism. However, leptin has been suggested to be involved in other functions during pregnancy, particularly in placenta, in which it was found to be expressed. In the present work, we have found that recombinant human chorionic gonadotropin (hCG) added to BeWo choriocarcinoma cell line showed a stimulatory effect on endogenous leptin expression, when analyzed by Western blot. This effect was time and dose dependent. Maximal effect was achieved at hCG 100 IU/ml. Moreover, hCG treatment enhanced leptin promoter activity up to 12.9 times, evaluated by transient transfection with a plasmid construction containing different promoter regions and the reporter gene luciferase. This effect was dose dependent and evidenced with all the promoter regions analyzed, regardless of length. Similar results were obtained with placental explants, thus indicating physiological relevance. Because hCG signal transduction usually involves cAMP signaling, this pathway was analyzed. Contrarily, we found that dibutyryl cAMP counteracted hCG effect on leptin expression. Furthermore, cotransfection with the catalytic subunit of PKA and/or the transcription factor cAMP response element binding protein repressed leptin expression. Thereafter we determined that hCG effect could be partially blocked by pharmacologic inhibition of MAPK pathway with 50 microM PD98059 but not by the inhibition of the phosphatidylinositol 3-kinase pathway with 0.1 microm wortmannin. Moreover, hCG treatment promoted MAPK kinase and ERK1/ERK2 phosphorylation in placental cells. Finally, cotransfection with a dominant-negative mutant of MAPK blocked the hCG-mediated activation of leptin expression. In conclusion, we provide some evidence suggesting that hCG induces leptin expression in trophoblastic cells probably involving the MAPK signal transduction

  7. Species and community response to above normal precipitation following prolonged drought in the northern Mojave Desert

    SciTech Connect

    Schultz, B.W.; Ostler, W.K.

    1993-12-31

    Little information is available on how desert plant communities that are dominated by perennial species respond to normal and above normal precipitation following prolonged drought. Intuitively, one would expect total canopy cover to increase. Whether a concomitant increase in the density of perennial species also occurs is unknown. Even less is known about how individual species respond to above normal precipitation following drought. From 1987 through 1991 a prolonged drought occurred in much of the western United States, including the northern Mojave Desert. In March 1991 the northern Mojave Desert received well above normal precipitation. The following two winters (December--March) also had above normal precipitation (150 to 200 % of normal, unpublished data). Ongoing vegetation characterization studies by the US Department of Energy (DOE) at Yucca Mountain, Nevada, allowed EG&G Energy Measurements to collect data that could be used to infer how both vegetation associations and individual species respond to above normal precipitation following prolonged drought. This paper reports the preliminary results.

  8. Ventral frontal satiation-mediated responses to food aromas in obese and normal-weight women123

    PubMed Central

    Eiler, William JA; Dzemidzic, Mario; Case, K Rose; Armstrong, Cheryl LH; Mattes, Richard D; Cyders, Melissa A; Considine, Robert V; Kareken, David A

    2014-01-01

    Background: Sensory properties of foods promote and guide consumption in hunger states, whereas satiation should dampen the sensory activation of ingestive behaviors. Such activation may be disordered in obese individuals. Objective: Using functional magnetic resonance imaging (fMRI), we studied regional brain responses to food odor stimulation in the sated state in obese and normal-weight individuals targeting ventral frontal regions known to be involved in coding for stimulus reward value. Design: Forty-eight women (25 normal weight; 23 obese) participated in a 2-day (fed compared with fasting) fMRI study while smelling odors of 2 foods and an inedible, nonfood object. Analyses were conducted to permit an examination of both general and sensory-specific satiation (satiation effects specific to a given food). Results: Normal-weight subjects showed significant blood oxygen level–dependent responses in the ventromedial prefrontal cortex (vmPFC) to food aromas compared with responses induced by the odor of an inedible object. Normal-weight subjects also showed general (but not sensory-specific) satiation effects in both the vmPFC and orbitofrontal cortex. Obese subjects showed no differential response to the aromas of food and the inedible object when fasting. Within- and between-group differences in satiation were driven largely by changes in the response to the odor of the inedible stimulus. Responses to food aromas in the obese correlated with trait negative urgency, the tendency toward negative affect-provoked impulsivity. Conclusions: Ventral frontal signaling of reward value may be disordered in obesity, with negative urgency heightening responses to food aromas. The observed nature of responses to food and nonfood stimuli suggests that future research should independently quantify each to fully understand brain reward signaling in obesity. This trial was registered at clinicaltrials.gov as NCT02041039. PMID:24695888

  9. The effects of kisspeptin on gonadotropin release in non-human mammals.

    PubMed

    Abbara, Ali; Ratnasabapathy, Risheka; Jayasena, Channa N; Dhillo, Waljit S

    2013-01-01

    The Kiss1 gene encodes a 145-amino acid pre-peptide, kisspeptin, which is cleaved into smaller peptides of 54, 14, 13, and 10 amino acids. This chapter reviews in detail the effects of kisspeptin on gonadotropin secretion in non-human mammals. Studies of kisspeptin's effects have included both acute and chronic administration regimens via a number of administration routes. Acute kisspeptin stimulates gonadotropin secretion in a wide range of species of non-human mammals, including rats, mice, hamsters, sheep, pigs, goats, cows, horses, and monkeys. In general, the stimulatory effect of kisspeptin treatment is more pronounced for LH than FSH secretion. Kisspeptin is thought to exert its stimulatory effects on LH and FSH release via stimulation of GnRH release from the hypothalamus, since pre--administration of a GnRH antagonist prevents kisspeptin's stimulation of gonadotropin secretion. Although the kisspeptin receptor is also expressed on anterior pituitary cells of some species, and incubation of anterior pituitary cells with high concentrations of kisspeptin can stimulate in vitro LH release, the contribution of direct effects of kisspeptin on the pituitary is thought to be negligible in vivo. Continuous kisspeptin administration results in reduced sensitivity to the effects of kisspeptin, in some species. This desensitization is thought to occur at the level of the kisspeptin receptor, since the response of the pituitary gland to exogenous GnRH is maintained. Overall, the findings discussed in this chapter are invaluable to the understanding of the reproductive role of kisspeptin and the potential therapeutic uses of kisspeptin for the treatment of fertility disorders. PMID:23550002

  10. FMR1 gene CGG repeat variation within the normal range is not predictive of ovarian response in IVF cycles.

    PubMed

    Morin, Scott J; Tiegs, Ashley W; Franasiak, Jason M; Juneau, Caroline R; Hong, Kathleen H; Werner, Marie D; Zhan, Yiping; Landis, Jessica; Scott, Richard T

    2016-05-01

    The relationship between FMR1 CGG premutation status and decreased ovarian responsiveness is well established. The association between FMR1 CGG repeat number in the currently defined normal range (less than 45 repeats) and ovarian reserve, however, is controversial. This retrospective study examined whether variation in CGG repeat number in the normal range was associated with markers of ovarian response in IVF cycles. The first IVF cycle of 3006 patients with FMR1 CGG repeat analysis was examined. Only patients carrying two alleles with less than 45 CGG repeats were included for analysis. The CGG repeat number furthest from the modal peak was plotted against number of mature oocytes retrieved and no correlation was identified. Patients were also separated into biallelic genotype groups, based on the recently proposed narrower "new normal" range of 26-34 CGG repeats. A linear regression showed that none of the biallelic genotype groups were associated with a decreased oocyte yield. The euploidy rates after comprehensive chromosomal screening were equivalent among the genotype groups. No difference was found in the rate of cycle cancellation for poor response. Despite increasing use, FMR1 CGG repeats in the normal range cannot be used as a predictor of ovarian response to gonadotrophin stimulation. PMID:27013081

  11. Progestin Exposure Before Gonadotropin Stimulation Improves Embryo Development after In Vitro Fertilization in the Domestic Cat1

    PubMed Central

    Pelican, Katharine M.; Spindler, Rebecca E.; Pukazhenthi, Budhan S.; Wildt, David E.; Ottinger, Mary A.; Howard, JoGayle

    2010-01-01

    This study investigated the influence of progestin priming and ovarian quiescence on response to exogenous gonadotropin stimulation in the cat. Because a subpopulation of cats routinely ovulated spontaneously, there also was the opportunity to examine the ovary's reaction to the added impact of endogenously secreted progestagen. Queens were given 1) equine chorionic gonadotropin (eCG) plus human chorionic gonadotropin (hCG) only (control; n = 9 cats), 2) GnRH antagonist (antide) injections followed by eCG and hCG (n = 9), and 3) a progestin implant (levonorgestrel) followed by eCG and hCG (n = 9). Laparoscopy was used to assess ovarian activity and aspirate follicular oocytes that were graded on the basis of morphology. In five cats per treatment, half of the high-quality oocytes were assessed for glucose, pyruvate, and lactate metabolism as well as nuclear maturation. Remaining oocytes were inseminated in vitro, cultured, and examined at 72 h after insemination for cleavage. In the remaining four cats per treatment, all oocytes were inseminated in vitro and assessed at 72, 120, and 168 h after insemination for embryo developmental stage. Cats pretreated with progestin had more follicles and produced more embryos per donor (including at the combined morula/blastocyst stage) than controls or females treated with GnRH antagonist (P < 0.05). There were no differences among groups (P > 0.05) in oocyte carbohydrate metabolism, nuclear maturation metrics, or fertilization success, although there was a tendency toward improvements in all three (P < 0.2) in progestin-treated females. Interestingly, cats that spontaneously ovulated within 60 days of treatment onset also produced more embryos per cat than induced-ovulation counterparts (P < 0.05). Results indicate that prior exposure to exogenous progestin (via implant) or endogenous progestagen (via spontaneous ovulation) improves ovarian responsiveness to gonadotropins in the cat through a mechanism that is independent of

  12. The effect of Yohimbine, an alpha2 adrenergic receptor antagonist, on the growth hormone response to apomorphine in normal subjects.

    PubMed Central

    Lal, S; Thavundayil, J X; Krishnan, B; Nair, N P; Schwartz, G; Guyda, H

    1996-01-01

    Yohimbine HCl (16 mg po) administered 30 min before clonidine (CLON) (2 ug/kg infused over 10 min) (N = 5) or apomorphine HCl (Apo) (0.5 mg sc) (N = 10) antagonized the growth hormone (GH) response to CLON but had no effect on the GH response to Apo in normal men. This finding suggests that in humans, alpha2 adrenergic mechanisms do not modulate dopaminergic function, at least not in the hypothalamic-pituitary axis, and that the GH response to Apo is not mediated via an alpha2 adrenergic link. PMID:8820174

  13. Normalization of sonographical multifocal nerve enlargements in a MADSAM patient following a good clinical response to intravenous immunoglobulin.

    PubMed

    Tanaka, Kanta; Ota, Natsuko; Harada, Yuzuru; Wada, Ikko; Suenaga, Toshihiko

    2016-09-01

    Focal nerve enlargements at sites of conduction blocks can be visualized sonographically in patients with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). However, little is known about association between nerve morphological changes and treatment responses. Here we present a 73-year-old female MADSAM patient whose sonographical multifocal nerve enlargements normalized following a good treatment response. She was admitted to our department with progressive asymmetrical muscle weakness and sensory disturbances for 6 months. Ultrasonography revealed multifocal nerve enlargements at sites of electrophysiological demyelination. Intravenous immunoglobulin improved her symptoms and electrophysiological abnormalities. Six months later, ultrasonography revealed normalization of multifocal nerve enlargements. Contrary to our observations, one previous report described a MADSAM patient with persistent nerve enlargements at the sites of resolved conduction blocks. In this earlier patient, however, the time from onset to remission was approximately 30 months. Morphological changes of nerve enlargements in MADSAM may vary with treatment response. PMID:27460345

  14. Inhibition of P450 aromatase enhances gonadotropin secretion in early and midpubertal boys: evidence for a pituitary site of action of endogenous E.

    PubMed

    Wickman, S; Dunkel, L

    2001-10-01

    In early pubertal boys, E concentrations are very low. We studied the role and site of action of endogenous E in the regulation of gonadotropin secretion in early and midpubertal boys by inhibiting the action of E with a potent and specific P450 aromatase inhibitor, letrozole. A total of 35 boys who were referred to us because of suspicion of delayed puberty were included in the study. The boys were in either early or midpuberty, and they composed 3 groups: 10 boys did not receive any treatment, 12 boys received T alone, and 13 boys received T and letrozole. In the untreated group during the 5-month follow-up, no changes were observed in 17beta-E2, T, basal gonadotropin, or inhibin B concentrations or in the GnRH-induced gonadotropin responses. In the T-treated group during the 5-month treatment, the T concentration increased by 55% (P < 0.05), and the 17beta-E2 concentration increased by 130% (P < 0.02). Concurrently, basal gonadotropin concentrations were suppressed, but the GnRH-induced gonadotropin responses and the inhibin B concentration remained unchanged. In the T- plus letrozole-treated group during the 5-month treatment, an increase in T concentration of 606% was observed (P < 0.001), but the 17beta-E2 concentration remained unchanged. The changes in the 17beta-E2 concentration within 5 months in the untreated and the T- plus letrozole-treated groups were different (P < 0.02), indicating significant inhibition of endogenous E synthesis during letrozole treatment. During the T plus letrozole treatment, basal gonadotropin concentration, the GnRH-induced LH response, and inhibin B concentration increased, and the GnRH-induced FSH response did not change significantly. Serum nocturnal gonadotropin pulses were determined in 5 boys treated with T and in 5 boys treated with T plus letrozole. In the T- plus letrozole-treated group, the nocturnal LH pulse amplitude increased, and the LH pulse frequency and interpulse interval remained unchanged. In conclusion, in

  15. Gonadotropin releasing hormone (GnRH)--a novel olfactory stimulant in fish.

    PubMed

    Andersen, O; Døving, K B

    1991-08-01

    The aim of this study was to elucidate the putative role of the gonadotropin releasing hormone (GnRH or LHRH) as an olfactory stimulant in fish. We report for the first time extreme sensitivity of the olfactory organ in the rainbow trout (Oncorhynchus mykiss) to GnRH. Recordings of the electroolfactogram (EOG) showed an electrophysiological response to 10(-16) M GnRH four times the amplitude of the response to a fresh water control stimulus. By stimulating the olfactory epithelium with several GnRH analogs and fragments of the decapeptide, the biologically active region of GnRH could be partly elucidated. The response profile of GnRH differed from that of the positive control odorant L-alanine, suggesting that separate receptors or receptor cells are involved. We propose that this potent odorant may act as a reproductive pheromone in fish. PMID:1912479

  16. The molecular and cellular response of normal and progressed human bronchial epithelial cells to HZE particles

    NASA Astrophysics Data System (ADS)

    Story, Michael; Ding, Liang-Hao; Minna, John; Park, Seong-mi; Larsen, Jill

    We have used a model of non-oncogenically immortalized normal human bronchial epithelial cells to determine the response of such cells to particles found outside the protection of the earth’s electromagnetic field. We have identified an enhanced frequency of cellular transformation, as measured by growth in soft agar, for both 56Fe and 28Si (1 GeV/n) that is maximal (4-6 fold) at 0.25 Gy and 0.40 Gy, respectively. At 4 months post-irradiation 38 individual soft agar clones were isolated. These clones were characterized extensively for cellular and molecular changes. Gene expression analysis suggested that these clones had down-regulated several genes associated with anti-oxidant pathways including GLS2, GPX1 and 4, SOD2, PIG3, and NQO1 amongst others. As a result, many of these transformed clones were exposed to high levels of intracellular radical oxygen species (ROS), although there appeared not to be any enhanced mitochondrial ROS. DNA repair pathways associated with ATM/ATR signaling were also upregulated. However, these transformants do not develop into tumors when injected into immune-compromised mice, suggesting that they have not progressed sufficiently to become oncogenic. Therefore we chose 6 soft agar clones for continuous culture for an additional 14 months. Amongst the 6 clones, only one clone showed any significant change in phenotype. Clone 3kt-ff.2a, propagated for 18 months, were 2-fold more radioresistant, had a shortened doubling time and the background rate of transformation more than doubled. Furthermore, the morphology of transformed clones changed. Clones from this culture are being compared to the original clone as well as the parental HBEC3KT and will be injected into immune-compromised mice for oncogenic potential. Oncogenically progressed HBECs, HBEC3KT cells that overexpress a mutant RAS gene and where p53 has been knocked down, designated HBEC3KTR53, responded quite differently to HZE particle exposure. First, these cells are more

  17. International Adoption in the U. S: Traumatic Stress and Normal Developmental Responses

    ERIC Educational Resources Information Center

    Wolfgang, Jeff Drayton

    2011-01-01

    The purpose of this paper is to present a review of literature on internationally adopted children in the U.S. that provides context, references for normal development, and describes traumatic stress with children. This gives counselors and other professionals who work with young children and families of international adoption a conceptual…

  18. Using an APOS Framework to Understand Teachers' Responses to Questions on the Normal Distribution

    ERIC Educational Resources Information Center

    Bansilal, Sarah

    2014-01-01

    This study is an exploration of teachers' engagement with concepts embedded in the normal distribution. The participants were a group of 290 in-service teachers enrolled in a teacher development program. The research instrument was an assessment task that can be described as an "unknown percentage" problem, which required the…

  19. Differential responsiveness of normal and simian virus 40-transformed human fibroblast cells to interferon-gamma.

    PubMed

    Karasaki, Y; Katoh, T; Higashi, K; Gotoh, S

    1992-06-01

    The effect of interferon-gamma (IFN-gamma) on epidermal growth factor (EGF) receptor binding and the proliferation of normal and simian virus 40 (SV40)-transformed human fibroblast cells was compared under identical culture conditions. IFN-gamma induced an enhancement of EGF binding to normal cells, whereas it decreased the EGF binding to SV40-transformed cells. Half-maximal enhancement occurred at 72 h after the normal cells were exposed to 10 U/ml of IFN-gamma, and maximal stimulation was obtained at about 10(2) U/ml of IFN-gamma at 72 h. On the other hand, half-maximal reduction was observed for SV40-transformed cells at less than 10 U/ml of IFN-gamma at 72 h, and maximal reduction was obtained at around 10(3) U/ml of IFN-gamma at 72 h. Scatchard analysis indicated that the number of EGF binding sites of normal and SV40-transformed cells was calculated to be 1.6 x 10(5) and 0.88 x 10(5) per cell, respectively, and was little altered by IFN-gamma treatment. The dissociation constant (Kd) of normal cells, however, decreased from 4.5 nM (control) to 2.0 nM (IFN-gamma-treated), while the Kd of SV40-transformed cells increased from 3.6 nM (control) to 17.0 nM (IFN-gamma-treated). The immunoprecipitation of 125I-labeled EGF-bound EGF receptors with anti-receptor antiserum indicated that a 72-h IFN-gamma treatment did not induce a conformational alteration in the EGF receptors of both normal and transformed cells. The DNA synthesis of normal cells was enhanced by EGF, and IFN-gamma treatment potentiated the effect of EGF on DNA synthesis, probably due to the increased binding affinity of EGF to the cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1640119

  20. Modulation of rat testes lipid composition by hormones: Effect of PRL (prolactin) and hCG (human chorionic gonadotropin)

    SciTech Connect

    Sebokova, E.; Wierzbicki, A.; Clandinin, M.T. )

    1988-10-01

    The effect of prolactin (PRL) and human chorionic gonadotropin (hCG) administration for 7 days on the composition and function of rat testicular plasma membrane was investigated. Refractory state in Leydig cells desensitized by hCG decreased the binding capacity for {sup 125}I-labeled hCG and also luteinizing hormone (LH)-induced adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) and testosterone production. In testicular membranes of hCG-treated animals, a depletion of cholesterol and an increase in total phospholipid content was observed after gonadotropin injection, thereby decreasing the cholesterol-to-phospholipid ratio. Injection of high doses of PRL had no effect on the binding capacity or affinity of the LH-hCG receptor but decreased the response of Leydig cells to LH in terms of cAMP and testosterone synthesis. PRL also increased total and esterified cholesterol and decreased free cholesterol and membrane phospholipid content. The fatty acid composition of testicular lipids was significantly and selectively influenced by both hormonal treatments. These observations suggest that metabolism of cholesterol and long-chain polyunsaturated fatty acids in testicular tissue is affected by chorionic gonadotropin and PRL and may provide the mechanism for regulating steroidogenic functions.

  1. Photoperiod-gonadotropin mismatches induced by treatment with acyline or FSH in Siberian hamsters: impacts on ovarian structure and function.

    PubMed

    Zysling, D A; Park, S-U; McMillan, E L; Place, N J

    2012-11-01

    Many seasonal breeders time their reproductive efforts to specific times of the year to ensure adequate resources for the production and care of young. For long-day (LD) breeders, females born before the summer solstice (LDs) reach sexual maturity quickly and often breed that same year, whereas females born after the summer solstice (short days (SDs)) may delay reproductive development to the following spring when environmental conditions are favorable for reproduction. In Siberian hamsters, development in SD is associated with structural and functional differences in the ovary compared with females held in LD, including a greater number of primordial follicles and an abundance of hypertrophied granulosa cells (HGCs), which are immunoreactive for anti-Müllerian hormone. The goal of this study was to determine whether SD-induced gonadotropin suppression is responsible for these phenotypic differences. Gonadotropin levels were suppressed in LD hamsters using the GNRH antagonist acyline. Conversely, to determine whether the SD ovarian phenotype is completely reversed by gonadotropin stimulation, recombinant human FSH (rhFSH) was administered. Our treatments were successful in mimicking FSH concentrations of the opposite photoperiod, but they did not produce a comparable change in the ovarian phenotype. Most notable was the lack of HGCs in the ovaries of acyline-treated LD females. Similarly, HGCs were maintained in the ovaries of SD females treated with rhFSH. Our data suggest that gonadotropins alone do not account for the SD ovarian phenotype. Future studies will determine whether SD-induced changes in other factors underlie these phenotypic changes. PMID:22936286

  2. Optimisation of an oviposition protocol employing human chorionic and pregnant mare serum gonadotropins in the Barred Frog Mixophyes fasciolatus (Myobatrachidae)

    PubMed Central

    2012-01-01

    Background Protocols for the hormonal induction of ovulation and oviposition are essential tools for managing threatened amphibians with assisted reproduction, but responses vary greatly between species and even broad taxon groups. Consequently, it is necessary to assess effectiveness of such protocols in representative species when new taxa become targets for induction. The threatened genus Mixophyes (family Myobatrachidae) has amongst the highest proportion of endangered species of all the Australian amphibians. This study developed and optimised the induction of oviposition in a non-threatened member of this taxon, the great barred frog (Mixophyes fasciolatus). Methods Gravid female M. fasciolatus were induced to oviposit on one or more occasions by administration of human chorionic gonadotropin (hCG) with or without priming with pregnant mare serum gonadotropin (PMSG). Treatments involved variations in hormone doses and combinations (administered via injection into the dorsal lymph sacs), and timing of administration. Pituitary homogenates from an unrelated bufonid species (Rhinella marina) were also examined with hCG. Results When injected alone, hCG (900 to 1400 IU) induced oviposition. However, priming with two time dependent doses of PMSG (50 IU, 25 IU) increased responses, with lower doses of hCG (200 IU). Priming increased response rates in females from around 30% (hCG alone) to more than 50% (p = 0.035), and up to 67%. Increasing the interval between the first PMSG dose and first hCG dose from 3 to 6 days also produced significant improvement (p<0.001). Heterologous pituitary extracts administered with hCG were no more effective than hCG alone (p = 0.628). Conclusions This study found that M. fasciolatus is amongst the few amphibian species (including Xenopus (Silurana) and some bufonids) that respond well to the induction of ovulation utilising mammalian gonadotropins (hCG). The optimal protocol for M. fasciolatus involved two priming doses of

  3. Homologous radioimmunoassay for canine thyrotropin: response of normal and x-irradiated dogs to propylthiouracil

    SciTech Connect

    Quinlan, W.J.; Michaelson, S.

    1981-03-01

    A RIA for canine TSH (cTSH) was developed using a double antibody method. Rabbit anti-cTSH antisera was slightly cross-reactive with ovine TSH. No evidence of cross-reactivity was noted with human, bovine, rat TSH, or ovine LH. Serum cTSH in euthyroid dogs was 7.0 +- 0.9 ng/ml. Normal and x-irradiated (localized to the thyroid or cranium) dogs received 334 mg propylthiouracil (PTU) im in oil daily for 1 week as a goitrogenic challenge. A significant increase in cTSH was noted in normal dogs and in two of four dogs that received 1000 rads to the thyroid. No significant increase was observed in cTSH in any of the dogs previously given either 100 or 1000 rads to the head. Although serum T/sub 3/ and T/sub 4/ were only slightly decreased in thyroid-irradiated dogs, a significant decrease in T/sub 3/ was observed in both normal and x-irradiated dogs maintained on PTU for 1 week. The inability of head x-irradiated dogs to respond to PTU, as evidenced by the lack of increased cTSH, suggests that moderate to high doses of x irradiation can impair the ability of the hypothalamic-hypophysial-thyroid axis to respond to a goitrogenic challenge.

  4. Regulation of the tidal volume and ventilatory responses to CO2 in normal man and in scoliosis.

    PubMed

    Kafer, E R

    1981-01-01

    The variation of the ventilatory response to CO2 and its pattern among normals and in the presence of pulmonary disease is wide. In normal subjects the relationship between the slopes of the ventilatory (delta V/delta PCO2), tidal volume (delta VT/delta PCO2) and the frequency (delta f/delta PCO2) responses and body size, metabolic rate, resting ventilation and pattern, lung volumes or mechanical properties of the respiratory system have only been demonstrated in a few studies. In idiopathic scoliosis there is a positive correlation between the delta V/delta PCO2 and delta VT/delta PCO2 and body size, resting ventilation and tidal volume, lung volumes and compliance of the respiratory system. Although there were significant correlations between the delta V/delta PCO2 and the delta VT/delta PCO2 and th delta f/delta PCO2 the correlation between the delta VT/delta PCO2 and delta f/delta PCO2 was not significant. Correlations between the delta f/delta PCO2 and lung volumes, compliance or body size were also not significant. Therefore variation in the frequency response to CO2 contribute to the variation between individuals of the delta V/delta PCO2 and this variation is unrelated to respiratory mechanics or body size. We conclude that in human studies any examination of possible relationships between ventilatory response to CO2 and body size, lung volumes and mechanics should examine separately the tidal volume and frequency response to CO2. We postulate that the tidal volume response is the most appropriate variable to normalize for lung volumes, e.g., vital capacity (delta VT/VC/delta/ PCO2). PMID:6781570

  5. Fluorodeoxyglucose Positron Emission Tomography Response and Normal Tissue Regeneration After Stereotactic Body Radiotherapy to Liver Metastases

    SciTech Connect

    Stinauer, Michelle A.; Diot, Quentin; Westerly, David C.; Schefter, Tracey E.; Kavanagh, Brian D.

    2012-08-01

    Purpose: To characterize changes in standardized uptake value (SUV) in positron emission tomography (PET) scans and determine the pace of normal tissue regeneration after stereotactic body radiation therapy (SBRT) for solid tumor liver metastases. Methods and Materials: We reviewed records of patients with liver metastases treated with SBRT to {>=}40 Gy in 3-5 fractions. Evaluable patients had pretreatment PET and {>=}1 post-treatment PET. Each PET/CT scan was fused to the planning computed tomography (CT) scan. The maximum SUV (SUV{sub max}) for each lesion and the total liver volume were measured on each PET/CT scan. Maximum SUV levels before and after SBRT were recorded. Results: Twenty-seven patients with 35 treated liver lesions were studied. The median follow-up was 15.7 months (range, 1.5-38.4 mo), with 5 PET scans per patient (range, 2-14). Exponential decay curve fitting (r=0.97) showed that SUV{sub max} declined to a plateau of 3.1 for controlled lesions at 5 months after SBRT. The estimated SUV{sub max} decay half-time was 2.0 months. The SUV{sub max} in controlled lesions fluctuated up to 4.2 during follow-up and later declined; this level is close to 2 standard deviations above the mean normal liver SUV{sub max} (4.01). A failure cutoff of SUV{sub max} {>=}6 is twice the calculated plateau SUV{sub max} of controlled lesions. Parenchymal liver volume decreased by 20% at 3-6 months and regenerated to a new baseline level approximately 10% below the pretreatment level at 12 months. Conclusions: Maximum SUV decreases over the first months after SBRT to plateau at 3.1, similar to the median SUV{sub max} of normal livers. Transient moderate increases in SUV{sub max} may be observed after SBRT. We propose a cutoff SUV{sub max} {>=}6, twice the baseline normal liver SUV{sub max}, to score local failure by PET criteria. Post-SBRT values between 4 and 6 would be suspicious for local tumor persistence or recurrence. The volume of normal liver reached nadir 3

  6. Analytic calculation of second-order electric response properties with the normalized elimination of the small component (NESC) method

    NASA Astrophysics Data System (ADS)

    Zou, Wenli; Filatov, Michael; Cremer, Dieter

    2012-08-01

    Analytic second derivatives of the relativistic energy for the calculation of electric response properties are derived utilizing the normalized elimination of the small component (NESC) method. Explicit formulas are given for electric static dipole polarizabilities and infrared intensities by starting at the NESC representation of electric dipole moments. The analytic derivatives are implemented in an existing NESC program and applied to calculate dipole moments, polarizabilities, and the infrared spectra of gold- and mercury-containing molecules as well as some actinide molecules. Comparison with experiment reveals the accuracy of NESC second order electric response properties.

  7. Hormones in Synergy: Regulation of the Pituitary Gonadotropin Genes

    PubMed Central

    Thackray, Varykina G.; Mellon, Pamela L.; Coss, Djurdjica

    2009-01-01

    The precise interplay of hormonal influences that governs gonadotropin hormone production by the pituitary includes endocrine, paracrine and autocrine actions of hypothalamic gonadotropin-releasing hormone (GnRH), activin and steroids. However, most studies of hormonal regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the pituitary gonadotrope have been limited to analyses of the isolated actions of individual hormones. LHβ and FSHβ subunits have distinct patterns of expression during the menstrual/estrous cycle as a result of the integration of activin, GnRH, and steroid hormone action. In this review, we focus on studies that delineate the interplay among these hormones in the regulation of LHβ and FSHβ gene expression in gonadotrope cells and discuss how signaling cross-talk contributes to differential expression. We also discuss how recent technological advances will help identify additional factors involved in the differential hormonal regulation of LH and FSH. PMID:19747958

  8. Binding sites for gonadotropins in human postmenopausal ovaries

    SciTech Connect

    Nakano, R.; Shima, K.; Yamoto, M.; Kobayashi, M.; Nishimori, K.; Hiraoka, J.

    1989-02-01

    The binding of human LH and human FSH to postmenopausal ovarian tissue from 21 patients with cervical carcinoma was analyzed. The binding sites for FSH and LH were demonstrated in postmenopausal ovarian tissue. The surface-binding sites for gonadotropins were localized in the cells of cortical stroma of the postmenopausal ovary. In addition, diffuse cytoplasmic staining of endogenous estrogen and 3 beta-hydroxysteroid dehydrogenase activity were detected immunohistochemically and histochemically in the cells of the cortical stroma. Electron microscopic study also suggested steroidogenic function in the cells of the cortical stroma. The results of the present study suggest that postmenopausal ovaries contain specific binding sites for pituitary gonadotropins and play a role in ovarian steroidogenesis.

  9. Ecological comparison of cellular stress responses among populations – normalizing RT-qPCR values to investigate differential environmental adaptations

    PubMed Central

    2013-01-01

    Background Rising temperatures and other environmental factors influenced by global climate change can cause increased physiological stress for many species and lead to range shifts or regional population extinctions. To advance the understanding of species’ response to change and establish links between individual and ecosystem adaptations, physiological reactions have to be compared between populations living in different environments. Although changes in expression of stress genes are relatively easy to quantify, methods for reliable comparison of the data remain a contentious issue. Using normalization algorithms and further methodological considerations, we compare cellular stress response gene expression levels measured by RT-qPCR after air exposure experiments among different subpopulations of three species of the intertidal limpet Nacella. Results Reference gene assessment algorithms reveal that stable reference genes can differ among investigated populations and / or treatment groups. Normalized expression values point to differential defense strategies to air exposure in the investigated populations, which either employ a pronounced cellular stress response in the inducible Hsp70 forms, or exhibit a comparatively high constitutive expression of Hsps (heat shock proteins) while showing only little response in terms of Hsp induction. Conclusions This study serves as a case study to explore the methodological prerequisites of physiological stress response comparisons among ecologically and phylogenetically different organisms. To improve the reliability of gene expression data and compare the stress responses of subpopulations under potential genetic divergence, reference gene stability algorithms are valuable and necessary tools. As the Hsp70 isoforms have been shown to play different roles in the acute stress responses and increased constitutive defenses of populations in their different habitats, these comparative studies can yield insight into

  10. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

    PubMed Central

    Lee, Alice W.; Tyrer, Jonathan P.; Doherty, Jennifer A.; Stram, Douglas A.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Vergote, Ignace; Van Nieuwenhuysen, Els; Lambrechts, Diether; Wicklund, Kristine G.; Eilber, Ursula; Wang-Gohrke, Shan; Chang-Claude, Jenny; Rudolph, Anja; Sucheston-Campbell, Lara; Odunsi, Kunle; Moysich, Kirsten B.; Shvetsov, Yurii B.; Thompson, Pamela J.; Goodman, Marc T.; Wilkens, Lynne R.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B.; Bogdanova, Natalia; Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto; Edwards, Robert P.; Kelley, Joseph L.; Harter, Philipp; Schwaab, Ira; Heitz, Florian; du Bois, Andreas; Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y.; Hogdall, Estrid; Kjaer, Susanne K.; Jensen, Allan; Vierkant, Robert A.; Cunningham, Julie M.; Goode, Ellen L.; Fridley, Brooke L.; Southey, Melissa C.; Giles, Graham G.; Bruinsma, Fiona; Wu, Xifeng; Hildebrandt, Michelle A.T.; Lu, Karen; Liang, Dong; Bisogna, Maria; Levine, Douglas A.; Weber, Rachel Palmieri; Schildkraut, Joellen M.; Iversen, Edwin S.; Berchuck, Andrew; Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.; Poole, Elizabeth M.; Olson, Sara H.; Orlow, Irene; Bandera, Elisa V.; Bjorge, Line; Tangen, Ingvild L.; Salvesen, Helga B.; Krakstad, Camilla; Massuger, Leon F.A.G.; Kiemeney, Lambertus A.; Aben, Katja K.H.; van Altena, Anne M.; Bean, Yukie; Pejovic, Tanja; Kellar, Melissa; Le, Nhu D.; Cook, Linda S.; Kelemen, Linda E.; Brooks-Wilson, Angela; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Yang, Hannah; Nedergaard, Lotte; Lundvall, Lene; Hogdall, Claus; Song, Honglin; Campbell, Ian G.; Eccles, Diana; Glasspool, Rosalind; Siddiqui, Nadeem; Carty, Karen; Paul, James; McNeish, Iain A.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Whittemore, Alice S.; McLaughlin, John R.; Risch, Harvey A.; Phelan, Catherine M.; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Ramus, Susan J.; Gentry-Maharaj, Aleksandra; Harrington, Patricia; Pike, Malcolm C.; Modugno, Francesmary; Rossing, Mary Anne; Ness, Roberta B.; Pharoah, Paul D.P.; Stram, Daniel O.; Wu, Anna H.; Pearce, Celeste Leigh

    2016-01-01

    Objective Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. PMID:25528498

  11. Prolonged gonadotropin stimulation is associated with decreased ART success

    PubMed Central

    Chuang, Meleen; Zapantis, Athena; Taylor, Martina; Jindal, Sangita K.; Neal-Perry, Genevieve S.; Lieman, Harry J.

    2010-01-01

    Purpose To evaluate whether the duration of gonadotropin stimulation predicts the likelihood of live birth after ART. Methods All IVF or ICSI cycles using fresh autologous oocytes at our institution between January 2004 and December 2007 were analyzed. Results Out of 699 cycles resulting in oocyte retrieval, 193 produced a live birth (27.6%). Women who achieved a live birth had a significantly shorter stimulation phase (11.1 vs. 11.5 days, respectively). Multivariable analysis suggested that 13 days or longer of stimulation decreased the likelihood of a live birth by 53% as compared to cycles that were 10–12 days long (odds ratio [OR] 0.47; 95% confidence interval [CI]: 0.30–0.75) after adjustment for female age, maximum historical FSH, total dose of gonadotropin received, oocytes retrieved, embryos transferred, antagonist suppression and PCOS diagnosis. Conclusions Prolonged duration of gonadotropin stimulation is an independent negative predictor of ART success in our cohort. PMID:20821043

  12. An essential single domain response regulator required for normal cell division and differentiation in Caulobacter crescentus.

    PubMed Central

    Hecht, G B; Lane, T; Ohta, N; Sommer, J M; Newton, A

    1995-01-01

    Signal transduction pathways mediated by sensor histidine kinases and cognate response regulators control a variety of physiological processes in response to environmental conditions. Here we show that in Caulobacter crescentus these systems also play essential roles in the regulation of polar morphogenesis and cell division. Previous studies have implicated histidine kinase genes pleC and divJ in the regulation of these developmental events. We now report that divK encodes an essential, cell cycle-regulated homolog of the CheY/Spo0F subfamily and present evidence that this protein is a cognate response regulator of the histidine kinase PleC. The purified kinase domain of PleC, like that of DivJ, can serve as an efficient phosphodonor to DivK and as a phospho-DivK phosphatase. Based on these and earlier genetic results we propose that PleC and DivK are members of a signal transduction pathway that couples motility and stalk formation to completion of a late cell division cycle event. Gene disruption experiments and the filamentous phenotype of the conditional divK341 mutant reveal that DivK also functions in an essential signal transduction pathway required for cell division, apparently in response to another histidine kinase. We suggest that phosphotransfer mediated by these two-component signal transduction systems may represent a general mechanism regulating cell differentiation and cell division in response to successive cell cycle checkpoints. Images PMID:7664732

  13. Comparison of normal and asthmatic subjects' responses to sulfate pollutant aerosols

    SciTech Connect

    Utell, M.J.; Morrow, P.E.; Hyde, R.W.

    1980-01-01

    Epidemiological studies support an association between elevated levels of sulfates and acute respiratory disease. To determine if these pollutants produce airway hyperreactivity, 16 normal and 17 asthmatic subjects inhaled a control NaCl aerosol and the following sulfates: ammonium sulfate, sodium bisulfate, ammonium bisulfate, and sulfuric acid. A Lovelace generator produced particles with an average MMAD of approx. 1.0 ..mu..m (sigma/sub g/ approx. = 2.0) and concentrations of 0.1 and 1.0 mg/m/sup 3/. By double-blind randomization, all subjects breathed these aerosols for a 16-minute period. To determine if sulfate inhalation caused increased reactivity to a known bronchoconstrictor, all subjects inhaled carbachol following each 16-minute exposure. Before, during, and after exposure, pulmonary function studies were performed. When compared to NaCl, sulfate (1 mg/m/sup 3/) produced significant reductions in airway conductance and flow rates in asthmatics. The two most sensitive asthmatics demonstrated changes even at 0.1 mg/m/sup 3/ sulfate. To a far more significant degree, the bronchoconstrictor action of carbachol was potentiated by sulfates more or less in relation to their acidity in normals and asthmatics.

  14. Auditory Brainstem Responses from Children Three Months to Three Years of Age: Normal Patterns of Response II.

    ERIC Educational Resources Information Center

    Gorga, Michael P.; And Others

    1989-01-01

    Auditory brainstem responses (ABR) were measured in 535 children from 3 months to 3 years of age. Results suggested that changes in wave V latency with age are due to central (neural) factors and that age-appropriate norms should be used in evaluations of ABR latencies in children. (Author/DB)

  15. 77 FR 55481 - Withdrawal of Approval of New Animal Drug Applications; Chorionic Gonadotropin; Naloxone...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-10

    ...; Chorionic Gonadotropin; Naloxone; Oxymorphone; Oxytocin AGENCY: Food and Drug Administration, HHS. ACTION... Pharmaceuticals hydrochloride) Inc., 100 Painters Injection. Dr., Chadds Ford, PA 19317. 046-822 VETOCIN...

  16. Differential Molecular Stress Responses to Low Compared to High Doses of Ionizing Radiation in Normal Human Fibroblasts

    PubMed Central

    Velegzhaninov, Ilya O.; Shadrin, Dmitry M.; Pylina, Yana I.; Ermakova, Anastasia V.; Shostal, Olga A.; Belykh, Elena S.; Kaneva, Anna V.; Ermakova, Olga V.

    2015-01-01

    Understanding the mechanisms producing low dose ionizing radiation specific biological effects represents one of the major challenges of radiation biology. Although experimental evidence does suggest that various molecular stress response pathways may be involved in the production of low dose effects, much of the detail of those mechanisms remains elusive. We hypothesized that the regulation of various stress response pathways upon irradiation may differ from one another in complex dose-response manners, causing the specific and subtle low dose radiation effects. In the present study, the transcription level of 22 genes involved in stress responses were analyzed using RT-qPCR in normal human fibroblasts exposed to a range of gamma-doses from 1 to 200 cGy. Using the alkali comet assay, we also measured the level of DNA damages in dose-response and time-course experiments. We found non-linear dose responses for the repair of DNA damage after exposure to gamma-radiation. Alterations in gene expression were also not linear with dose for several of the genes examined and did not follow a single pattern. Rather, several patterns could be seen. Our results suggest a complex interplay of various stress response pathways triggered by low radiation doses, with various low dose thresholds for different genes. PMID:26675169

  17. Immunity to Brugia pahangi in athymic nude and normal mice: eosinophilia, antibody and hypersensitivity responses.

    PubMed

    Vickery, A C; Vincent, A L

    1984-11-01

    Congenitally athymic nude (nu/nu) mice, immunologically reconstituted by thymus grafting before inoculation with infective larvae, and mice heterozygous for the nu gene (nu/+), mounted potent protective humoral and cellular immune responses to Brugia pahangi. Although responses were not identical, both groups of mice produced IgM, IgG and IgE antibodies specific for adult worm antigen (S-Ag) present in a crude aqueous extract, made immediate and delayed hypersensitivity footpad swelling responses when challenged with S-Ag and eliminated their infection in the early larval stages. Heterozygotes also exhibited a marked eosinophilia which peaked coincident with larval killing. In contrast, thymus grafting of patent nudes had no effect upon microfilaraemias or adult worm burdens and did not completely protect against a challenge larval inoculum although antibodies specific for S-Ag were produced. With the occasional exceptions of moderate immediate footpad swelling and very low titres of IgM specific for S-Ag, no specific immune responses to B. pahangi were found in ungrafted nude mice which allowed full development of adult worms and supported patent infections. PMID:6522098

  18. Effect of retinol on the hyperthermal response of normal tissue in vivo

    SciTech Connect

    Rogers, M.A.; Marigold, J.C.L.; Hume, S.P.

    1983-07-01

    The effect of prior administration of retinol, a membrane labilizer, on the in vivo hyperthermal response of lysosomes was investigated in the mouse spleen using a quantitative histochemical assay for the lysosomal enzyme acid phosphatase. A dose of retinol which had no effect when given alone enhanced the thermal response of the lysosome, causing an increase in lysosomal membrane permeability. In contrast, the same dose of retinol had no effect on the gross hyperthermal response of mouse intestine; a tissue which is relatively susceptible to hyperthermia. Thermal damage to intestine was assayed directly by crypt loss 1 day after treatment or assessed as thermal enhancement of x-ray damage by counting crypt microcolonies 4 days after a combined heat and x-ray treatment. Thus, although the hyperthermal response of the lysosome could be enhanced by the administration of retinol, thermal damage at a gross tissue level appeared to be unaffected, suggesting that lysosomal membrane injury is unlikely to be a primary event in hyperthermal cell killing.

  19. The effect of retinol on the hyperthermal response of normal tissue in vivo

    SciTech Connect

    Rogers, M.A.; Marigold, J.C.; Hume, S.P.

    1983-07-01

    The effect of prior administration of retinol, a membrane labilizer, on the in vivo hyperthermal response of lysosomes was investigated in the mouse spleen using a quantitative histochemical assay for the lysosomal enzyme acid phosphatase. A dose of retinol which had no effect when given alone enhanced the thermal response of the lysosome, causing an increase in lysosomal membrane permeability. In contrast, the same dose of retinol had no effect on the gross hyperthermal response of mouse intestine; a tissue which is relatively susceptible to hyperthermia. Thermal damage to intestine was assayed directly by crypt loss 1 day after treatment or assessed as thermal enhancement of X-ray damage by counting crypt microcolonies 4 days after a combined heat and X-ray treatment. Thus, although the hyperthermal response of the lysosome could be enhanced by the administration of retinol, thermal damage at a gross tissue level appeared to be unaffected, suggesting that lysosomal membrane injury is unlikely to be a primary event in hyperthermal cell killing.

  20. SENSITIVITY OF NORMAL THEORY METHODS TO MODEL MISSPECIFICATION IN THE CALCULATION OF UPPER CONFIDENCE LIMITS ON THE RISK FUNCTION FOR CONTINUOUS RESPONSES. (R825385)

    EPA Science Inventory

    Normal theory procedures for calculating upper confidence limits (UCL) on the risk function for continuous responses work well when the data come from a normal distribution. However, if the data come from an alternative distribution, the application of the normal theory procedure...

  1. Hypovolemia Induced Orthostatic Hypotension in Presyncopal Astronauts and Normal Subjects Related to Hypoadrenergic Responsiveness

    NASA Technical Reports Server (NTRS)

    Meck, Janice V.; Platts, Steven H.; Waters, Wendy W.; Shi, Shang-Jin; Hayashi, Yuho; Perez, Sondra A.; Ziegler, Michael G.

    2006-01-01

    Circulating blood volume is reduced during spaceflight, making astronauts hemodynamically compromised. After landing, astronauts separate into two groups. One group compensates for the hypovolemia with a hyper-sympathetic response during upright tilt testing and can complete a tilt test with few symptoms. The other group is unable to mount a hyper-sympathetic response and experiences orthostatic hypotension and presyncope during upright tilt tests. We tested the hypothesis that hypovolemia alone, in the absence of spaceflight, also would cause subjects to separate into presyncopal and non-presyncopal groups according to their sympathetic responses during tilt. We studied 20 subjects, including 10 veteran astronauts, on three occasions. On Days 1 (normovolemia) and 3 (hypovolemia), plasma volume, tilt tolerance and supine and standing plasma norepinephrine levels were measured. Forty hours prior to Day 3, subjects were given intravenous furosemide, followed by 36 hours of a 10MEq Na diet. Statistical comparisons were made between normovolemia and hypovolemia responses. This protocol reproduced landing day tilt test outcomes with 100% fidelity in the astronauts. Similarly to patterns reported after flight, non-presyncopal subjects had greater norepinephrine responses to tilt during hypovolemia compared to normovolemia (580 plus or minus 79 vs. 298 plus or minus 37 pg/ml, P less than 0.05), but presyncopal subjects had no increase (180 plus or minus 44 vs. 145 plus or minus 32 pg/ml, P=NS). This model can be used to predict astronauts who will become presyncopal on landing day, so that prospective, individualized countermeasures can be developed. Within patient populations, it can be used to study the interaction of volemic state and the sympathetic nervous system.

  2. Oxygen saturation response to exercise in healthy pregnant women: a simple protocol and normal range

    PubMed Central

    Langford, Edward; Khwanda, Ahmad; Langford, Kate

    2010-01-01

    Measurement of oxygen saturation on excercise, using a pulse oximeter, has been advocated in the assessment of women with shortness of breath in pregnancy. However, there is currently no standard protocol for this. The aims of this study were to determine the normal range for oxygen saturation at rest and on moderate exercise in healthy women from 24 weeks gestation and to evaluate a simple, widely applicable exercise protocol in which women walked at their own pace for 100 metres then up two flights of stairs. The protocol achieved 60–85% maximum predicted heart rate in 99% of women at a median gestation of 31+3 weeks, with a wide range of Hb and BMI. There was a mean 0.3% fall in oxygen saturation on exertion but oxygen saturation did not fall below 95% in any of the women.

  3. Strategies for optimizing the response of cancer and normal tissues to radiation

    PubMed Central

    Moding, Everett J.; Kastan, Michael B.; Kirsch, David G.

    2014-01-01

    Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their treatment, and the majority of these patients are treated with curative intent. Despite recent advances in the planning of radiation treatment and the delivery of image-guided radiation therapy, acute toxicity and potential long-term side effects often limit the ability to deliver a sufficient dose of radiation to control tumours locally. In the past two decades, a better understanding of the hallmarks of cancer and the discovery of specific signalling pathways by which cells respond to radiation have provided new opportunities to design molecularly targeted therapies to increase the therapeutic window of radiation therapy. Here, we review efforts to develop approaches that could improve outcomes with radiation therapy by increasing the probability of tumour cure or by decreasing normal tissue toxicity. PMID:23812271

  4. Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia

    PubMed Central

    Hillman, Robert S.

    1969-01-01

    Erythropoiesis in normal man was studied during periods of phlebotomy-induced anemia of varying severity. This study permitted a comparison of marrow production measurements over a wide range of marrow production levels. As long as the serum iron remained above 50 μg/100 ml, measurements of plasma iron turnover provided an excellent index of marrow production at all levels of red cell production. In contrast, the absolute reticulocyte count demonstrated a poor correlation with the other measurements. This was shown to be the result of a prolongation of the time required for circulating reticulocytes to lose their reticulum, which correlated with the severity of the anemia. For the clinical application of the reticulocyte count as a measurement of marrow production, an adjustment must be made for this alteration in the circulating reticulocyte maturation time. PMID:5773082

  5. Normally Occurring Human Anti-GM1 Immunoglobulin M Antibodies and the Immune Response to Bacteria

    PubMed Central

    Alaniz, María E.; Lardone, Ricardo D.; Yudowski, Silvia L.; Farace, María I.; Nores, Gustavo A.

    2004-01-01

    Anti-GM1 antibodies of the immunoglobulin M (IgM) isotype are normal components of the antibody repertoire of adult human serum. Using a sensitive high-performance thin-layer chromatography (HPTLC) immunostaining assay, we found that these antibodies were absent in the umbilical vein and children <1 month of age but could be detected after 1 month of age. Although most of the children older than 6 months of age were positive, there were still a few negative children. The appearance of anti-GM1 IgM antibodies showed a perfect concordance with two well-characterized antibacterial antibodies, anti-Forssman and anti-blood group A, which indicates a similar origin. We also studied IgM reactivity with lipopolysaccharides (LPSs) from gram-negative bacteria isolated from stool samples from healthy babies and from Escherichia coli HB101 in serum from individuals of different ages. We found a positive reaction with both LPSs in all the children more than 1 month of age analyzed, even in those that were negative for anti-GM1 antibodies. Anti-GM1 IgM antibodies were purified from adult serum by affinity chromatography and tested for the ability to bind LPSs from different bacteria. This highly specific preparation showed reactivity only with LPS from a strain of Campylobacter jejuni isolated from a patient with diarrhea. We conclude that normally occurring IgM antibodies are generated after birth, probably during the immune defense against specific bacterial strains. PMID:15039337

  6. Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man.

    PubMed

    Davis, S N; Galassetti, P; Wasserman, D H; Tate, D

    2000-01-01

    Significant, sexual dimorphisms exist in counterregulatory responses to commonly occurring stresses, such as hypoglycemia, fasting, and cognitive testing. The question of whether counterregulatory responses differ during exercise in healthy men and women remains controversial. The aim of this study was to determine whether a sexual dimorphism exists in neuroendocrine, metabolic, or cardiovascular responses to prolonged moderate exercise. Sixteen healthy (eight men and eight women) subjects matched for age (28+/-2 yr), body mass index (22+/-1 kg/m2), nutrient intake, and spectrum of physical fitness were studied in a randomized fashion during 90 min of exercise on a cycle ergometer at 80% of their anaerobic threshold (approximately 50% VO2 max). Respiratory quotient and oxygen consumption relative to body weight were identical in men and women. Glycemia was equated (5.3+/-0.2 mmol/L) during exercise via an exogenous glucose infusion. Gender had significant effects on counterregulatory responses during exercise. Arterialized epinephrine (1.05+/-0.2 vs. 0.45+/-0.04 nmol/L), norepinephrine (9.2+/-1.1 vs. 5.8+/-1.1 nmol/L), and pancreatic polypeptide (52+/-6 vs. 37+/-6 pmol/L) were significantly (P<0.01) increased in men compared to women, respectively. Plasma glucagon, cortisol, and GH levels responded similarly in men and women. Insulin values were higher at baseline in men and fell by a greater amount to reach similar levels during exercise compared to those in women. Endogenous glucose production, measured with [3-3H]glucose was similar in men and women. Carbohydrate oxidation was significantly increased in men relative to women (21.2+/-2 vs. 15.6+/-2 mg/kg fat free mass x min; P<0.05). Despite reduced sympathetic nervous system (SNS) drive, lipolytic responses were increased in women. Arterialized blood glycerol (215+/-30 vs. 140+/-20 micromol/L), beta-hydroxybutyrate (54+/-9 vs. 25+/-10 micromol/L), and plasma nonesterified fatty acids (720+/-56 vs. 469

  7. Dynamic responses of a semi-type offshore floating wind turbine during normal state and emergency shutdown

    NASA Astrophysics Data System (ADS)

    Hu, Zhi-qiang; Li, Liang; Wang, Jin; Hu, Qiu-hao; Shen, Ma-cheng

    2016-03-01

    This paper addresses joint wind-wave induced dynamic responses of a semi-type offshore floating wind turbine (OFWT) under normal states and fault event conditions. The analysis in this paper is conducted in time domain, using an aero-hydro-servo-elastic simulation code-FAST. Owing to the unique viscous features of the reference system, the original viscous damping model implemented in FAST is replaced with a quadratic one to gain an accurate capture of viscous effects. Simulation cases involve free-decay motion in still water, steady motions in the presence of regular waves and wind as well as dynamic response in operational sea states with and without wind. Simulations also include the cases for transient responses induced by fast blade pitching after emergency shutdown. The features of platform motions, local structural loads and a typical mooring line tension force under a variety of excitations are obtained and investigated.

  8. Ethanol Extract of Hedyotis diffusa Willd Affects Immune Responses in Normal Balb/c Mice In Vivo.

    PubMed

    Kuo, Yu-Jui; Lin, Jing-Pin; Hsiao, Yung-Ting; Chou, Guan-Ling; Tsai, Yu-Hsiang; Chiang, Su-Yin; Lin, Jaung-Geng; Chung, Jing-Gung

    2015-01-01

    Numerous clinical anticancer drugs are obtained from natural plants and Hedyotis diffusa Willd (EEHDW) has been used as a major component in Traditional Chinese medicine formulas since a long time. Ethanol extracts of EEHDW have been shown to possess various biological activities including anticancer function in vitro. Our earlier studies have shown that EEHDW affects immune responses in WEHI-3-generated leukemia mice, but EEHDW has not been reported to affect immune responses in a normal mouse model. Herein, we investigated whether EEHDW could affect immune responses on normal murine cells in vivo. Normal BALB/c mice were orally treated with or without EEHDW at 0, 16, 32, and 64 mg/kg or 32 mg/kg by i.p. for 3 weeks, then were weighed, and blood, liver and spleen samples were collected for further experiments. Results indicated that EEHDW did not significantly affect body and liver weight but significantly increased the spleen weight by i.p. treatment when compared to control groups. Flow cytometric assays indicated that EEHDW promoted CD11b levels at 16, 32 and 64 mg/kg oral treatment, CD19 levels at 16, 32, 64 mg/kg oral treatment and i.p. treatment, and Mac-3 levels at 16, 32 and 64 mg/kg oral treatment, however, it did not significantly affect the levels of CD3. Oral treatment with 16 and 32 mg/kg of EEHDW significantly decreased macrophage phagocytosis from PBMC; 32 mg/kg of EEHDW by i.p. treatment significantly increased phagocytosis activity of macrophages obtain from the peritoneal cavity. EEHDW at 32 mg/kg by i.p. treatment led to an increase of NK cell activities compared to oil control groups. EEHDW at 32 mg/kg of EEHDW by i.p. treatment increased B- and T-cell proliferation. Based on these observations, EEHDW seems to have promoted immune responses in this murine model. PMID:26130790

  9. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.

    PubMed

    Tolaney, Sara M; Boucher, Yves; Duda, Dan G; Martin, John D; Seano, Giorgio; Ancukiewicz, Marek; Barry, William T; Goel, Shom; Lahdenrata, Johanna; Isakoff, Steven J; Yeh, Eren D; Jain, Saloni R; Golshan, Mehra; Brock, Jane; Snuderl, Matija; Winer, Eric P; Krop, Ian E; Jain, Rakesh K

    2015-11-17

    Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning. PMID:26578779

  10. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

    PubMed Central

    Tolaney, Sara M.; Boucher, Yves; Duda, Dan G.; Martin, John D.; Seano, Giorgio; Ancukiewicz, Marek; Barry, William T.; Goel, Shom; Lahdenrata, Johanna; Isakoff, Steven J.; Yeh, Eren D.; Jain, Saloni R.; Golshan, Mehra; Brock, Jane; Snuderl, Matija; Winer, Eric P.; Krop, Ian E.; Jain, Rakesh K.

    2015-01-01

    Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning. PMID:26578779

  11. Control of the head in response to tilt of the body in normal and labyrinthine-defective human subjects.

    PubMed

    Kanaya, T; Gresty, M A; Bronstein, A M; Buckwell, D; Day, B

    1995-12-15

    1. Head movement responses to discrete, unpredictable tilts of the trunk from earth upright were studied in normal and labyrinthine-defective (LD) subjects. Tilts of the seated, restrained trunk, were delivered in pitch and roll about head-centred axes and approximated raised cosine displacements with peak amplitudes of 20-30 deg and durations of 1.5-2 s. Subjects performed mental arithmetic with eyes closed or read earth-fixed text. 2. At the onset of tilt the head momentarily lagged behind the trunk because of inertia. Subsequently, head control varied widely with three broad types: (i) head relatively fixed to the trunk (in normal subjects and some patients); (ii) head unstable, falling in the direction of gimbal tilt (typical of acute patients for pitch motion); (iii) compensatory head movement in the opposite direction to gimbal tilt (observed consistently in normal subjects and in well-adapted patients). 3. EMG was well developed in subjects with compensatory head movement and consisted of an initial burst of activity at minimum latencies of 25-50 ms (means 72-108 ms), followed by a prolonged peak; both occurring in the 'side up' neck muscles, appropriate for righting the head. These muscles are shortened during the initial head lag so the responses cannot be stretch reflexes. In normal subjects their origin is predominantly labyrinthine but in patients they may be an 'unloading response' of the neck. 4. Head stability in space was superior with the visual task for all subjects but vision only partially compensated for labyrinthine signals in unstable patients. 5. Modelling the responses to tilt suggests that, in LD subjects, the short-latency burst could be driven by signals from the neck of the relative acceleration between head and trunk tilt. The longer latency EMG could be driven by a signal of head tilt in space. Normally, this signal is probably otolithic. In patients it could be synthesized from summing proprioceptive signals of position of head on

  12. Normal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases

    SciTech Connect

    Howells, Christopher C.; Stinauer, Michelle A.; Diot, Quentin; Westerly, David C.; Schefter, Tracey E.; Kavanagh, Brian D.; Miften, Moyed

    2012-11-01

    Purpose: To evaluate the temporal dose response of normal liver tissue for patients with liver metastases treated with stereotactic body radiation therapy (SBRT). Methods and Materials: Ninety-nine noncontrast follow-up computed tomography (CT) scans of 34 patients who received SBRT between 2004 and 2011 were retrospectively analyzed at a median of 8 months post-SBRT (range, 0.7-36 months). SBRT-induced normal liver tissue density changes in follow-up CT scans were evaluated at 2, 6, 10, 15, and 27 months. The dose distributions from planning CTs were mapped to follow-up CTs to relate the mean Hounsfield unit change ({Delta}HU) to dose received over the range 0-55 Gy in 3-5 fractions. An absolute density change of 7 HU was considered a significant radiographic change in normal liver tissue. Results: Increasing radiation dose was linearly correlated with lower post-SBRT liver tissue density (slope, -0.65 {Delta}HU/5 Gy). The threshold for significant change (-7 {Delta}HU) was observed in the range of 30-35 Gy. This effect did not vary significantly over the time intervals evaluated. Conclusions: SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue that is characterized by a decrease of >7 HU in liver density for doses >30-35 Gy.

  13. Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. I. Normal responses

    NASA Technical Reports Server (NTRS)

    Minor, L. B.; Lasker, D. M.; Backous, D. D.; Hullar, T. E.; Shelhamer, M. J. (Principal Investigator)

    1999-01-01

    The horizontal angular vestibuloocular reflex (VOR) evoked by high-frequency, high-acceleration rotations was studied in five squirrel monkeys with intact vestibular function. The VOR evoked by steps of acceleration in darkness (3,000 degrees /s(2) reaching a velocity of 150 degrees /s) began after a latency of 7.3 +/- 1.5 ms (mean +/- SD). Gain of the reflex during the acceleration was 14.2 +/- 5.2% greater than that measured once the plateau head velocity had been reached. A polynomial regression was used to analyze the trajectory of the responses to steps of acceleration. A better representation of the data was obtained from a polynomial that included a cubic term in contrast to an exclusively linear fit. For sinusoidal rotations of 0.5-15 Hz with a peak velocity of 20 degrees /s, the VOR gain measured 0.83 +/- 0.06 and did not vary across frequencies or animals. The phase of these responses was close to compensatory except at 15 Hz where a lag of 5.0 +/- 0.9 degrees was noted. The VOR gain did not vary with head velocity at 0.5 Hz but increased with velocity for rotations at frequencies of >/=4 Hz (0. 85 +/- 0.04 at 4 Hz, 20 degrees /s; 1.01 +/- 0.05 at 100 degrees /s, P < 0.0001). No responses to these rotations were noted in two animals that had undergone bilateral labyrinthectomy indicating that inertia of the eye had a negligible effect for these stimuli. We developed a mathematical model of VOR dynamics to account for these findings. The inputs to the reflex come from linear and nonlinear pathways. The linear pathway is responsible for the constant gain across frequencies at peak head velocity of 20 degrees /s and also for the phase lag at higher frequencies being less than that expected based on the reflex delay. The frequency- and velocity-dependent nonlinearity in VOR gain is accounted for by the dynamics of the nonlinear pathway. A transfer function that increases the gain of this pathway with frequency and a term related to the third power of head

  14. Normal Brain Response to Propofol in Advance of Recovery from Unresponsive Wakefulness Syndrome

    PubMed Central

    Blain-Moraes, Stefanie; Boshra, Rober; Ma, Heung Kan; Mah, Richard; Ruiter, Kyle; Avidan, Michael; Connolly, John F.; Mashour, George A.

    2016-01-01

    Up to 40% of individuals with unresponsive wakefulness syndrome (UWS) actually might be conscious. Recent attempts to detect covert consciousness in behaviorally unresponsive patients via neurophysiological patterns are limited by the need to compare data from brain-injured patients to healthy controls. In this report, we pilot an alternative within-subject approach by using propofol to perturb the brain state of a patient diagnosed with UWS. An auditory stimulation series was presented to the patient before, during, and after exposure to propofol while high-density electroencephalograph (EEG) was recorded. Baseline analysis revealed residual markers in the continuous EEG and event-related potentials (ERPs) that have been associated with conscious processing. However, these markers were significantly distorted by the patient’s pathology, challenging the interpretation of their functional significance. Upon exposure to propofol, changes in EEG characteristics were similar to what is seen in healthy individuals and ERPs associated with conscious processing disappeared. At the 1-month follow up, the patient had regained consciousness. We offer three alternative explanations for these results: (1) the patient was covertly consciousness, and was anesthetized by propofol administration; (2) the patient was unconscious, and the observed EEG changes were a propofol-specific phenomenon; and (3) the patient was unconscious, but his brain networks responded normally in a way that heralded the possibility of recovery. These alternatives will be tested in a larger study, and raise the intriguing possibility of using a general anesthetic as a probe of brain states in behaviorally unresponsive patients. PMID:27313518

  15. Hematological and clinical responses to combined mitoxantrone and cyclophosphamide administration to normal cats.

    PubMed Central

    Henry, C J; Brewer, W G; Royer, N S

    1994-01-01

    The purpose of this study was to examine the feasibility of a combination chemotherapy protocol ("CYCLONE") in cats, utilizing mitoxantrone and cyclophosphamide. Three normal adult cats were administered mitoxantrone (6.5 mg/m2 intravenously) and cyclophosphamide (100 mg/m2 intravenously) every 21 days for a total of three doses. Individual white blood cell count nadirs (range, 2.0-9.5 x 10(9)/L) and neutrophil count nadirs (range, 0.3 to 5.0 x 10(9)/L) occurred between days 2 and 10 after each dose of chemotherapy. Mean white blood cell count nadirs (range of mean, 5.5 to 8.4 x 10(9)/L) occurred between days 6 and 8, as did the mean neutrophil count nadir (range of mean, 1.7-4.0 x 10(9)/L). Side effects were limited to transient appetite suppression in one cat and loose stools in two cats. Myelosuppression and gastrointestinal side effects were comparable to those observed with single-agent mitoxantrone protocols. Further investigation of this protocol is warranted. PMID:7866961

  16. Differences in the responses of heterozygous carriers of colorblindness and normal controls to briefly presented stimuli.

    PubMed

    Cohn, S A; Emmerich, D S; Carlson, E A

    1989-01-01

    Two experiments were conducted in order to investigate the possible effects of X-inactivation (Lyon, 1961) on female carriers of colorblindness. The results of the first experiment, like those of Grützner et al. (1976), were consistent with the prediction of the Lyon (1961) hypothesis that the retinas of female carriers are composed of mosaic patches of colorblind and normal areas. In this first experiment, rows and columns of colored spots were presented tachistoscopically, and subjects were asked to identify the colors of the spots. In the second experiment, plates from the Ishihara test of colorblindness were presented tachistoscopically and subjects were asked to identify the number which was embedded in the pattern of colored dots. Both experiments support the Lyon hypothesis in that female carriers were found to have more difficulty in perceiving patterns of colored stimuli than did control subjects, and they suggest that the amount of time that a carrier has to scan colored stimuli plays an important role in her ability to accurately perceive them. PMID:2800352

  17. Comparison of Therapeutic Response and Clinical Outcome between HCV Patients with Normal and Abnormal Alanine Transaminase Levels

    PubMed Central

    Wu, Cheng-Kung; Chang, Kuo-Chin; Tseng, Po-Lin; Lu, Sheng-Nan; Chen, Chien-Hung; Wang, Jing-Houng; Lee, Chuan-Mo; Lin, Ming-Tsung; Yen, Yi-Hao; Hung, Chao-Hung; Hu, Tsung-Hui

    2016-01-01

    Background and Aims Patients with chronic hepatitic C (HCV) infection and normal serum alanine transaminase (ALT) levels were considered to have mild disease. In Taiwan, these patients were not suggested for interferon (IFN) based therapies. The aim of study is to compare therapeutic outcomes between HCV patients with normal and elevated ALT levels. Methods We conducted a retrospective study on 3241 HCV patients treated by IFN based therapies. Patients with normal ALT levels were classified as group A (n = 186) while those with elevated ALT levels were group B (n = 3055). Results At baseline, incidence of diabetes mellitus, low platelet counts and cirrhosis were significantly higher in group B patients. The sustained virologic response (SVR) rate was comparable between the 2 groups (65.3% vs. 65.3%, P = .993). But significantly higher incidence of HCC development after HCV treatment was observed in group B (7.4% vs. 3.2%, P = .032). No significant differences with respect to the outcome of liver decompensation, spontaneous bacterial peritonitis, and mortality were noted between 2 groups. Multivariate analysis showed younger age, female gender, non-HCV genotype 1, lower viral load, higher platelet counts and non-cirrhosis were favorable factors for achieving SVR, rather than ALT levels. Further analysis revealed older age, cirrhosis, lower platelet levels and non- peg-interferon treatment are risk factors of HCC development. Conclusions HCV patients with normal ALT levels had similar response to antiviral therapy and low rate of HCC development after therapy. Antiviral therapies begun at early course of HCV infection may be beneficial to prevent disease progression. PMID:26968010

  18. Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

    PubMed Central

    Hou, Jue; Wang, Fan; Kong, Peizhong; Yu, Peter K. N.; Wang, Hongzhi; Han, Wei

    2015-01-01

    Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose. PMID:25886619

  19. Normal or defective immune response to Hepatitis B vaccine in patients with diabetes and celiac disease.

    PubMed

    Zanoni, Giovanna; Contreas, Giovanna; Valletta, Enrico; Gabrielli, Oretta; Mengoli, Carlo; Veneri, Dino

    2015-01-01

    A defective production of protective levels of antibodies to Hepatitis B (HB) vaccine is reported to occur in 4-10% of healthy subjects and a correlation with the presence of specific human leukocyte antigen (HLA) molecules, including DQ2, which also confers genetic predisposition to celiac disease (CD) and type I diabetes mellitus (T1DM), has been suggested.   The aim of this study was to analyze the serological response to HB vaccine and measles-containing vaccines in 69 diabetic patients (T1DM), 42 patients with celiac disease (CD) and 79 healthy control subjects (CT). The median interval between the third dose of HB vaccine and serum collection was 6.8, 3.5, and 4.7 years for T1DM, CD and CT groups, respectively. 50/69 (72%) T1DM patients, 32/42 (76%) CD patients and 61/79 (77%) CT subjects showed protective anti-HBs antibodies after vaccination, with no statistically significant difference. On the contrary, a lower statistically significant difference was found in the mean HBsAb level of T1DM subjects when compared with the other two groups. No correlation between HLA DQ2 expression in T1DM and vaccine response was detected. The comparison of serological response to measles after vaccination also showed no statistically significant differences in the three groups. Contrasting results between these data and those reported in the literature might be due to differences in the time intervals between vaccination and testing. Prospective studies in pathological and healthy groups with the same age at HBV vaccination and with the same time interval for blood sample collection to determine antibody titers are necessary in order to provide more conclusive data. PMID:25483516

  20. The Alpha-Melanocyte-Stimulating Hormone Suppresses TLR2-Mediated Functional Responses through IRAK-M in Normal Human Keratinocytes

    PubMed Central

    Ryu, Sunhyo; Johnson, Andrew; Park, Yoonkyung; Kim, Beomjoon; Norris, David; Armstrong, Cheryl A.; Song, Peter I.

    2015-01-01

    Alpha-melanocyte stimulating hormone (α-MSH) is a highly conserved 13-aa neuropeptide derived from pro-opiomelanocortin by post-translational processing, which has been reported to exhibit potent anti-inflammatory activity and a wide range of immunosuppressive activities in the skin. However, the regulatory effect of α-MSH is not completely clear in cutaneous innate immunity. In this study, we investigate the functional regulation of α-MSH in TLR2-mediated inflammatory responses in normal human keratinocytes (HKs). α-MSH pretreatment down-regulated the Staphylococcus aureus LTA-induced expression of both TLR2 and IL-8 as well as NF-κB nuclear translocation in HK cells. The inhibitory effect of α-MSH was blocked by agouti signaling protein (ASP), an α-MSH receptor-1 antagonist. To investigate the mechanism of this response in more detail, siRNA of IRAK-M, a negative regulator of TLR signaling, was utilized in these studies. The α-MSH suppressive effect on IL-8 production and NF-κB transactivation was inhibited by IRAK-M siRNA transfection in HK cells. These results indicate that α-MSH is capable of suppressing keratinocyte TLR2-mediated inflammatory responses induced by S. aureus-LTA, thus demonstrating another novel immunomodulatory activity of α-MSH in normal human keratinocytes. PMID:26309029

  1. The Alpha-Melanocyte-Stimulating Hormone Suppresses TLR2-Mediated Functional Responses through IRAK-M in Normal Human Keratinocytes.

    PubMed

    Ryu, Sunhyo; Johnson, Andrew; Park, Yoonkyung; Kim, Beomjoon; Norris, David; Armstrong, Cheryl A; Song, Peter I

    2015-01-01

    Alpha-melanocyte stimulating hormone (α-MSH) is a highly conserved 13-aa neuropeptide derived from pro-opiomelanocortin by post-translational processing, which has been reported to exhibit potent anti-inflammatory activity and a wide range of immunosuppressive activities in the skin. However, the regulatory effect of α-MSH is not completely clear in cutaneous innate immunity. In this study, we investigate the functional regulation of α-MSH in TLR2-mediated inflammatory responses in normal human keratinocytes (HKs). α-MSH pretreatment down-regulated the Staphylococcus aureus LTA-induced expression of both TLR2 and IL-8 as well as NF-κB nuclear translocation in HK cells. The inhibitory effect of α-MSH was blocked by agouti signaling protein (ASP), an α-MSH receptor-1 antagonist. To investigate the mechanism of this response in more detail, siRNA of IRAK-M, a negative regulator of TLR signaling, was utilized in these studies. The α-MSH suppressive effect on IL-8 production and NF-κB transactivation was inhibited by IRAK-M siRNA transfection in HK cells. These results indicate that α-MSH is capable of suppressing keratinocyte TLR2-mediated inflammatory responses induced by S. aureus-LTA, thus demonstrating another novel immunomodulatory activity of α-MSH in normal human keratinocytes. PMID:26309029

  2. Variability in coronary hemodynamics in response to ergonovine in patients with normal coronary arteries and atypical chest pain

    SciTech Connect

    Schwartz, A.B.; Donmichael, T.A.; Botvinick, E.H.; Ishimori, T.; Parmley, W.W.; Chatterjee, K.

    1983-03-01

    Because an increase in coronary vascular resistance in response to ergonovine maleate has been suggested as a possible diagnostic aid for variant angina, changes were evaluated in coronary hemodynamics and serial myocardial thallium-201 perfusion scans in 15 patients without angina and with normal coronary arteries in response to ergonovine (0.05, 0.10 and 0.20 mg intravenously). For the group, heart rate-blood pressure product increased significantly (p less than 0.001) without any change in coronary sinus flow, coronary vascular resistance, myocardial oxygen extraction, arterial-coronary sinus oxygen difference and lactate extraction. In 7 of 15 patients, however, coronary vascular resistance increased (mean 39%, range 11 to 75%, probability (p) less than 0.001), and coronary sinus flow decreased (14%, p less than 0.001), despite an increase in heart rate-blood pressure product (36%, p less than 0.02). No electrocardiographic, metabolic or thallium-201 scan abnormalities occurred. Therefore, significant increases in coronary vascular resistance in response to ergonovine may occur in patients with normal coronary arteries and atypical chest pain.

  3. Abnormal response to DNA crosslinking agents of Fanconi anemia fibroblasts can be corrected by transfection with normal human DNA.

    PubMed

    Diatloff-Zito, C; Papadopoulo, D; Averbeck, D; Moustacchi, E

    1986-09-01

    Primary skin fibroblast cell lines from patients with Fanconi anemia were cotransfected with UV-irradiated pSV2neo plasmids and high molecular weight DNA from normal human cells. Restoration of a normal cellular resistance to mitomycin C (MMC) was observed provided that a Fanconi anemia cell line is selected for DNA-mediated transformation (neo gene) and that at least two successive rounds of transfection are performed. Cells were selected by taking advantage of the higher proliferation rate and plating efficiency of the MMC resistant transformants. As estimated from reconstruction experiments, the frequency of transfer of MMC resistance lies between 1 and 30 X 10(-7). The MMC resistance phenotype was maintained for at least 10 generations following transfection. Evidence for DNA-mediated transformation also includes the recovery of a normal pattern of DNA semiconservative synthesis after treatment with 8-methoxypsoralen and 365-nm UV irradiation, and the presence of exogenous pSV2neo DNA sequences was shown by Southern blot analysis. The acquired MMC resistance is probably due to the presence of DNA from normal cells. Indeed, sensitivity to MMC was maintained when Fanconi anemia cells were cotransfected with the UV-irradiated pSV2neo plasmid mixed with their own DNA or with yeast or salmon sperm DNA. These negative results also render unlikely the selection of spontaneous MMC resistant revertants in transfection of Fanconi anemia cells with normal DNA. These experiments establish the prerequisites for the isolation of the gene(s) involved in the response to DNA crosslinking lesions in human cells. PMID:3092225

  4. The Human Vertical Translation Vestibulo-ocular Reflex (tVOR): Normal and Abnormal Responses

    PubMed Central

    Liao, Ke; Walker, Mark F.; Joshi, Anand; Reschke, Millard; Strupp, Michael; Leigh, R. John

    2010-01-01

    Geometric considerations indicate that the human translational vestibulo-ocular reflex (tVOR) should have substantially different properties than the angular vestibulo-ocular reflex (aVOR). Specifically, tVOR cannot simultaneously stabilize images of distant and near objects on the retina. Most studies make the tacit assumption that tVOR acts to stabilize foveal images even though, in humans, tVOR is reported to compensate for less than 60% of foveal image motion. We have determined that the compensation gain (eye rotational velocity / required eye rotational velocity to maintain foveal target fixation) of tVOR is held steady at ~ 0.6 during viewing of either near or distant targets during vertical (bob) translations in ambient illumination. We postulate that tVOR evolved not to stabilize the image of the target on the fovea, but rather to minimize retinal image motion between objects lying in different depth planes, in order to optimize motion parallax information. Such behavior is optimized when binocular visual cues of both far and distant targets are available in ambient light. Patients with progressive supranuclear palsy or cerebellar ataxia show impaired ability to increase tVOR responses appropriately when they view near targets. In cerebellar patients, impaired ability to adjust tVOR responses to viewing conditions occurs despite intact ability to converge at near. Loss of the ability to adjust tVOR according to viewing conditions appears to represent a distinct disorder of vestibular function. PMID:19645882

  5. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-01

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. PMID:27574304

  6. Serum Acylated Ghrelin Concentrations in Response to Short-Term Overfeeding in Normal Weight, Overweight, and Obese Men

    PubMed Central

    Wadden, Danny; Cahill, Farrell; Amini, Peyvand; Randell, Edward; Vasdev, Sudesh; Yi, Yanqing; Zhang, Weizhen; Sun, Guang

    2012-01-01

    Background Ghrelin, an orexigenic gut hormone secreted primarily from the stomach, is involved in energy homeostasis. However, little data is available regarding its response to energy surplus and the development of human obesity. Objective The present study investigated the response of circulating acylated ghrelin to a 7-day positive energy challenge. Design A total of 68 healthy young men were overfed 70% more calories than required, for 1-week. Subjects were classified based on percent body fat (measured by dual-energy X-ray absorptiometry) as normal weight, overweight, and obese. Serum acylated ghrelin concentration was measured before and after the positive energy challenge. Additionally, the relationship between acylated ghrelin and obesity-related phenotypes including weight, body mass index, percent body fat, cholesterol, HDL-c, LDL-c, glucose, insulin and homeostasis model assessment of insulin resistance and β-cell function at baseline and change due to overfeeding, were assessed. Results Contrary to our expectations, serum acylated ghrelin was significantly increased in response to overfeeding and the increase was independent of obesity status. There was no significant difference in fasting acylated ghrelin between normal weight, overweight, and obese men at baseline. Acylated ghrelin was negatively correlated with weight and BMI for normal weight and with BMI in overweight men. Also ghrelin was correlated with change in weight and BMI in overweight (negative relationship) and obese (positive relationship) groups. Conclusion Our results showed that circulating acylated ghrelin was increased after a 7-day positive energy challenge regardless of adiposity status. However, acylated ghrelin was correlated with change in weight and BMI in opposing directions, in overweight and obese subjects respectively, thus dependent on obesity status. PMID:23029221

  7. Chemiluminescent responses of alveolar macrophages from normal and Mycobacterium bovis BCG-vaccinated rabbits as a function of age.

    PubMed Central

    Chida, K; Myrvik, Q N; Leake, E S; Gordon, M R; Wood, P H; Ricardo, M J

    1987-01-01

    Luminol-dependent chemiluminescence (CL) responses of alveolar macrophages (AM) from normal and Mycobacterium bovis BCG-vaccinated infant and adult rabbits were compared. AM from 1-, 7-, and 14-day-old normal rabbits exhibited much lower peak CL responses than did AM from 28- and 42-day-old normal animals as well as rabbits 2 to 3 or 5 to 6 months and 1 to 2 years of age. The most striking differences among AM from infant and adult rabbits were noted when AM were obtained from 28-day-old and 5- to 6-month old rabbits 21 days after the rabbits were immunized with 200 micrograms of BCG intravenously. In this case, AM from 5- to 6-month-old animals gave peak counts per minute of 400,000 to 500,000 whereas AM from 28-day-old rabbits vaccinated with BCG (harvested at 49 days of age) gave peak counts per minute of only 40,715 +/- 2,688. These data reveal that AM from neonatal animals are grossly deficient as responders to phorbol myristate acetate-induced CL. This deficiency, which improved with age, is still apparent in AM from 28-day-old animals. The data also reveal that BCG vaccination of 28-day-old animals yields AM that are poor responders to phorbol myristate acetate compared with AM from BCG-vaccinated animals 2 to 3 and 5 to 6 months of age. AM from animals vaccinated with BCG at 28 days of age contained fewer and smaller electron-dense lysosomelike structures than did AM from adult rabbits similarly vaccinated. These findings provide an explanation for the difficulties infants have in developing effective cell-mediated immune responses against intracellular parasites. Images PMID:3553004

  8. Activation of the Innate Immune Response against DENV in Normal Non-Transformed Human Fibroblasts

    PubMed Central

    Bustos-Arriaga, José; García-Machorro, Jazmín; León-Juárez, Moisés; García-Cordero, Julio; Santos-Argumedo, Leopoldo; Flores-Romo, Leopoldo; Méndez-Cruz, A. René; Juárez-Delgado, Francisco J.; Cedillo-Barrón, Leticia

    2011-01-01

    Background When mosquitoes infected with DENV are feeding, the proboscis must traverse the epidermis several times (“probing”) before reaching a blood vessel in the dermis. During this process, the salivary glands release the virus, which is likely to interact first with cells of the various epidermal and dermal layers, cells which could be physiologically relevant to DENV infection and replication in humans. However, important questions are whether more abundant non-hematopoietic cells such as fibroblasts become infected, and whether they play any role in antiviral innate immunity in the very early stages of infection, or even if they might be used by DENV as primary replication cells. Methodology/Principal Findings Fibroblasts freshly released from healthy skin and infected 12 hours after their isolation show a positive signal for DENV. In addition, when primary skin fibroblast cultures were established and subsequently infected, we showed DENV-2 antigen-positive intracellular signal at 24 hours and 48 hours post-infection. Moreover, the fibroblasts showed productive infection in a conventional plaque assay. The skin fibroblasts infected with DENV-2 underwent potent signaling through both TLR3 and RIG- 1, but not Mda5, triggering up-regulation of IFNβ, TNFα, defensin 5 (HB5) and β defensin 2 (HβD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 (IRF7), when compared with mock-infected fibroblasts. Conclusions/Significance In this work, we demonstrated the high susceptibility to DENV infection by primary fibroblasts from normal human skin, both in situ and in vitro. Our results suggest that these cells may contribute to the pro-inflammatory and anti-viral microenvironment in the early stages of interaction with DENV-2. Furthermore, the data suggest that fibroblast may also be used as a primary site of DENV replication and provide viral

  9. The tumor suppressor p53 induces expression of the pregnancy-supporting human chorionic gonadotropin (hCG) CGB7 gene

    PubMed Central

    Sohr, Sindy

    2011-01-01

    Successful pregnancy requires a functionally normal blastocyst encountering a receptive maternal endometrium. Interestingly, the cell cycle regulator and tumor suppressor p53 has been reported to support reproduction in mice by regulating the expression of the leukemia inhibitory factor gene in the maternal endometrium. However, in humans the hormonal system orchestrating successful pregnancy is considerably different from rodents. Particularly, the primatespecific dimeric glycoprotein hormone human chorionic gonadotropin (hCG) is essential for blastocyst implantation and maintenance of early human pregnancy. Here we provide evidence that p53 selectively induces expression of the hCGβ7 (CGB7) gene. None of the other CGB genes was found to be regulated by p53. We show that expression of the CGB7 gene is upregulated upon p53 induction in human HFF, HCT116 and DLD1 cells as well as in cell preparations enriched in human primary first-trimester trophoblasts. The increase in CGB7 levels upon doxorubicin treatment is lost after siRNA-directed knockdown of p53. Furthermore, we describe CGB7 as a direct transcriptional target gene of p53 by identifying a p53-responsive element in the CGB7 promoter using reporter assays, electrophoretic mobility shift assays and chromatin immunoprecipitations. With these results we provide a new link between p53 transcriptional activity and human reproduction. PMID:22032922

  10. The Cervico-Ocular Reflex of normal human subjects in response to transient and sinusoidal trunk rotations

    NASA Technical Reports Server (NTRS)

    Sawyer, Robert N., Jr.; Thurston, Stephen E.; Becker, Keith R.; Ackley, Charles V.; Seidman, Scott H.; Leigh, R. John

    1994-01-01

    We used the magnetic search coil technique to measure the horizontal cervico-ocular reflex (COR) of 8 subjects in response to transient or sinusoidal (0.1-1.0 Hz) trunk rotations while their heads were firmly immobilized. Although we were able to resolve eye rotations of less than 0.05 deg, the COR was hardly measurable (gain was always less than 0.07). This finding, made with the most precise measurement technique used to date, suggests that the COR makes a negligible contribution to the stability of gaze in normal subjects during natural activities.