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Sample records for cumulative glucocorticoid dose

  1. Determination of radionuclides and pathways contributing to cumulative dose

    Energy Technology Data Exchange (ETDEWEB)

    Napier, B.A.

    1992-12-01

    A series of scoping calculations has been undertaken to evaluate the absolute and relative contributions of different radionuclides and exposure pathways to doses that may have been received by individuals living in the vicinity of the Hanford Site. This scoping calculation (Calculation 004) examined the contributions of numerous radionuclides to cumulative dose via environmental exposures and accumulation in foods. Addressed in this calculation were the contributions to organ and effective dose of infants and adults from (1) air submersion and groundshine external dose, (2) inhalation, (3) ingestion of soil by humans, (4) ingestion of leafy vegetables, (5) ingestion of other vegetables and fruits, (6) ingestion of meat, (7) ingestion of eggs, and (8) ingestion of cows' milk from Feeding Regime 1, as described in calculation 002. This calculation specifically addresses cumulative radiation doses to infants and adults resulting from releases occurring over the period 1945 through 1972.

  2. Low-dose glucocorticoids in hyperandrogenism Efecto de bajas dosis de glucocorticoides en el hiperandrogenismo

    Directory of Open Access Journals (Sweden)

    Leonardo Rizzo

    2007-06-01

    Full Text Available To investigate the effect of low-doses of glucocorticoids on androgen and cortisol secretion during the course of the day, we evaluated clinical signs of hyperandrogenism and total, free and bioavailable testosterone, SHBG, and cortisol following two different protocols: A fourteen patients received betamethasone 0.6 mg/day (n=8 or methylprednisolone 4 mg/day (n=6, as single daily oral dose at 11.00 PM, during 30 days, B fourteen patients were evaluated under betamethasone 0.3 mg in a single daily dose at 11.00 PM during six months, 11 out of whom were re-evaluated six months later. Twenty eight women with hyperandrogenism were included and seven normal females were used as control. Blood samples were taken in follicular phase at 8 AM and 7 PM to determine SHBG, cortisol, total, free and bioavailable testosterone. In both protocols, a significant morning and evening decrease in cortisol and testosterone (pCon el objetivo de investigar el efecto de bajas dosis de glucocorticoides sobre la secreción de andrógenos y cortisol en el curso del día, evaluamos signos de hiperandrogenismo, testosterona total, libre y biodisponible y cortisol según dos protocolos diferentes: A catorce pacientes recibieron betametasona 0.6 mg/día (n= 8 o metilprednisolona 4 mg/día (n= 6 en dosis única cotidiana, a las 23 h, durante 30 días, B catorce pacientes fueron evaluadas bajo betametasona 0.3 mg en dosis única cotidiana a la 23 h, administrada durante 6 meses; de ellas, 11 pacientes fueron re-evaluadas 6 meses más tarde. Se incluyeron 28 mujeres con hiperandrogenismo y 7 controles normales. Se obtuvieron muestras de sangre en fase folicular a las 08:00 y 9:00 h para determinar SHBG, cortisol, testosterona total, libre y biodisponible. En ambos protocolos se observó una disminución significativa de cortisol y testosterona (p<0.05 a <0.01, más importante con betametasona (p<0.05. En el protocolo B, los niveles matutinos de SHBG aumentaron

  3. Role of sulfite additives in wine induced asthma: single dose and cumulative dose studies

    OpenAIRE

    Vally, H; Thompson, P.

    2001-01-01

    BACKGROUND—Wine appears to be a significant trigger for asthma. Although sulfite additives have been implicated as a major cause of wine induced asthma, direct evidence is limited. Two studies were undertaken to assess sulfite reactivity in wine sensitive asthmatics. The first study assessed sensitivity to sulfites in wine using a single dose sulfited wine challenge protocol followed by a double blind, placebo controlled challenge. In the second study a cumulative dose su...

  4. Chronic high-dose glucocorticoid therapy triggers the development of chronic organ damage and worsens disease outcome in systemic lupus erythematosus.

    Science.gov (United States)

    Tarr, Tünde; Papp, Gábor; Nagy, Nikolett; Cserép, Edina; Zeher, Margit

    2017-02-01

    Long-term survival of patients with systemic lupus erythematosus (SLE) improved worldwide; thus, prevention of cumulative organ damage became a major goal in disease management. The aim of our study was to investigate the chronic organ damages and their influence on disease outcome in SLE. We evaluated clinical conditions, laboratory findings and medications of 357 consecutive SLE patients and assessed their impact on Systemic Lupus Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and disease outcome. We detected one or more SDI scores in 77.87% of patients. Patients with disease duration of more than 10 years and subjects diagnosed at age above 40 had significantly higher SDI values. The most frequent damages were valvulopathies, cognitive dysfunction, angina pectoris and venous thrombosis. Higher cumulative glucocorticoid dose increased SDI, while chloroquin treatment was favourable for patients. Male gender, elevated SDI scores and higher cumulative doses of glucocorticoids increased mortality risk. Our data confirmed that disease duration, age at diagnosis and chronic high-dose glucocorticoid therapy have significant effects on the development of chronic organ damage. Higher SDI score is characterized with worse survival ratios. The most common chronic organ damages affected the cardiovascular or neuropsychiatric system. As long-term survival in SLE improves, it becomes increasingly important to identify the determinants of chronic organ damage. Most of the chronic organ damage occurs in the cardiovascular and the neuropsychiatric systems; thus, regular follow-up, screening and adequate therapy are essential for the best clinical outcome.

  5. Determination of radionuclides and pathways contributing to cumulative dose. Hanford Environmental Dose Reconstruction Project: Dose code recovery activities, Calculation 004

    Energy Technology Data Exchange (ETDEWEB)

    Napier, B.A.

    1992-12-01

    A series of scoping calculations has been undertaken to evaluate the absolute and relative contributions of different radionuclides and exposure pathways to doses that may have been received by individuals living in the vicinity of the Hanford Site. This scoping calculation (Calculation 004) examined the contributions of numerous radionuclides to cumulative dose via environmental exposures and accumulation in foods. Addressed in this calculation were the contributions to organ and effective dose of infants and adults from (1) air submersion and groundshine external dose, (2) inhalation, (3) ingestion of soil by humans, (4) ingestion of leafy vegetables, (5) ingestion of other vegetables and fruits, (6) ingestion of meat, (7) ingestion of eggs, and (8) ingestion of cows` milk from Feeding Regime 1, as described in calculation 002. This calculation specifically addresses cumulative radiation doses to infants and adults resulting from releases occurring over the period 1945 through 1972.

  6. Radiologic imaging in cystic fibrosis: cumulative effective dose and changing trends over 2 decades.

    LENUS (Irish Health Repository)

    O'Connell, Oisin J

    2012-06-01

    With the increasing life expectancy for patients with cystic fibrosis (CF), and a known predisposition to certain cancers, cumulative radiation exposure from radiologic imaging is of increasing significance. This study explores the estimated cumulative effective radiation dose over a 17-year period from radiologic procedures and changing trends of imaging modalities over this period.

  7. Mapping of the cumulative β-ray dose on the ground surface surrounding the Fukushima area

    Science.gov (United States)

    Endo, Satoru; Kajimoto, Tsuyoshi; Tanaka, Kenichi; Nguyen, Thanh T.; Hayashi, Gohei; Imanaka, Tetsuji

    2015-01-01

    A large amount of the fission products released by the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident on 11 March 2011 was deposited in a wide area from Tohoku to northern Kanto. A map of the estimated cumulative β-ray dose (70 μm dose equivalent) on the soil surface for one year after the FDNPP accident has been prepared using previously reported calculation methods and the 2-km mesh survey data by MEXT. From this map of estimated dose, areas with a high cumulative β-ray dose on the soil surface for one year after the FDNPP accident were found to be located in the Akogi-Teshichiro to Akogi-Kunugidaira region in Namie Town, and in the southern Futaba Town to the northern Tomioka Town region. The highest estimated cumulative β-ray dose was 710 mSv for one year at Akogi-Teshichiro, Namie Town. PMID:26519736

  8. Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2017-05-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to a single dose of betamethasone or placebo, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children underwent whole-body dual-energy radiograph absorptiometry at 6 to 8 years' corrected age. Of 212 eligible childhood survivors, 185 were studied (87%; 91 repeat betamethasone group; 94 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar whole-body bone mineral content (median repeat betamethasone: 553 g, interquartile range: 442-712 g; placebo: 567 g, interquartile range: 447-750 g; geometric mean ratio: 0.99; 95% confidence interval: 0.94-1.03, P = .55) and bone area (median repeat betamethasone 832 cm(2), interquartile range: 693-963 cm(2); placebo: 822 cm(2), interquartile range: 710-1020 cm(2); geometric mean ratio: 0.99, 95% confidence interval: 0.92-1.07, P = .75). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not alter bone mass in mid-childhood. Copyright © 2017 by the American Academy of Pediatrics.

  9. Treatment Of Pemphigus Vulgaris With Brief, High-Dose Intravenous Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Farshchian Mahmood

    2004-01-01

    Full Text Available Background: Glucocorticoid therapy remains the mainstay of treatment in pemphigus vulgaris although controversy exists about the optimal regiman. This study was conducted to compare the efficacy of routine oral prednisolone with high dose intravenous glucocorticoids in treatment of pemphigus vulgaris. Methods: A total of 55 patients with pemphigus vulgaris was enrolled in the study. The diagnosis of pemphigus vulgaris was confirmed histologically. The patients were divided into two groups: Group A (26 Patients was treated with high-dose intravenous glucocorticoids and group B or control group (29 patients was treated with routine oral prednisolone. Both groups were followed for at least 20 months after initiation of treatment. Results: The results showed complete clinical cure (without relapse in 20 months follow up in 81% of cases in group A and in 69% of cases in group B (p<0.05. The mean + SD prednisolone daily dose during the 20 months follow up after initiation of treatment was 12+0.38 for A and 15.3 + 1.33 for control group (p<0.05.

  10. Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6-11 years-old than cumulative high doses of inhaled terbutaline

    DEFF Research Database (Denmark)

    Kaae, Rikke; Agertoft, Lone; Pedersen, Sören

    2004-01-01

    OBJECTIVES: To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children. METHODS: Twenty boys and girls (6-11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxis......) 4.5 microg (F4.5) or terbutaline (Bricanyl) 500 microg (T500) were inhaled cumulatively via a dry powder inhaler (Turbuhaler) over 1 h (three patients) or 2.5 h (17 patients) and compared to a day of no treatment, in a randomised, double-blind (active treatments only), crossover trial. Blood...... pressure (BP), ECG, plasma potassium, glucose, lactate, and adverse events were monitored up to 10 h to assess tolerability and relative systemic dose potency. RESULTS: Formoterol and terbutaline had significant beta2-adrenergic effects on most outcomes. Apart from the effect on systolic BP, QRS duration...

  11. Cumulative Doses of T-Cell Depleting Antibody and Cancer Risk after Kidney Transplantation.

    Directory of Open Access Journals (Sweden)

    Jenny H C Chen

    Full Text Available T-cell depleting antibody is associated with an increased risk of cancer after kidney transplantation, but a dose-dependent relationship has not been established. This study aimed to determine the association between cumulative doses of T-cell depleting antibody and the risk of cancer after kidney transplantation. Using data from the Australian and New Zealand Dialysis and Transplant Registry between 1997-2012, we assessed the risk of incident cancer and cumulative doses of T-cell depleting antibody using adjusted Cox regression models. Of the 503 kidney transplant recipients with 2835 person-years of follow-up, 276 (55%, 209 (41% and 18 (4% patients received T-cell depleting antibody for induction, rejection or induction and rejection respectively. The overall cancer incidence rate was 1,118 cancers per 100,000 patient-years, with 975, 1093 and 1377 cancers per 100,000 patient-years among those who had received 1-5 doses, 6-10 doses and >10 doses, respectively. There was no association between cumulative doses of T cell depleting antibody and risk of incident cancer (1-5: referent, 6-10: adjusted hazard ratio (HR 1.19, 95%CI 0.48-2.95, >10: HR 1.42, 95%CI 0.50-4.02, p = 0.801. This lack of association is contradictory to our hypothesis and is likely attributed to the low event rates resulting in insufficient power to detect significant differences.

  12. Relative Pesticide and Exposure Route Contribution to Aggregate and Cumulative Dose in Young Farmworker Children

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    Asa Bradman

    2012-01-01

    Full Text Available The Child-Specific Aggregate Cumulative Human Exposure and Dose (CACHED framework integrates micro-level activity time series with mechanistic exposure equations, environmental concentration distributions, and physiologically-based pharmacokinetic components to estimate exposure for multiple routes and chemicals. CACHED was utilized to quantify cumulative and aggregate exposure and dose estimates for a population of young farmworker children and to evaluate the model for chlorpyrifos and diazinon. Micro-activities of farmworker children collected concurrently with residential measurements of pesticides were used in the CACHED framework to simulate 115,000 exposure scenarios and quantify cumulative and aggregate exposure and dose estimates. Modeled metabolite urine concentrations were not statistically different than concentrations measured in the urine of children, indicating that CACHED can provide realistic biomarker estimates. Analysis of the relative contribution of exposure route and pesticide indicates that in general, chlorpyrifos non-dietary ingestion exposure accounts for the largest dose, confirming the importance of the micro-activity approach. The risk metrics computed from the 115,000 simulations, indicate that greater than 95% of these scenarios might pose a risk to children’s health from aggregate chlorpyrifos exposure. The variability observed in the route and pesticide contributions to urine biomarker levels demonstrate the importance of accounting for aggregate and cumulative exposure in establishing pesticide residue tolerances in food.

  13. Usefulness of high doses of glucocorticoids and hyperbaric oxygen therapy in sudden sensorineural hearing loss treatment.

    Science.gov (United States)

    Narozny, Waldemar; Sicko, Zdzislaw; Przewozny, Tomasz; Stankiewicz, Czeslaw; Kot, Jacek; Kuczkowski, Jerzy

    2004-11-01

    We investigated the effect of pharmacologic (steroids, vasodilators, vitamins, and Betaserc) and hyperbaric oxygen therapy on patients with sudden sensorineural hearing loss. The pharmacologic arm of the study consisted of 52 patients with defined sudden sensorineural hearing loss treated simultaneously in the ENT Department and National Center for Hyperbaric Medicine of the Medical University of Gdansk, Poland, from 1997 to 2000 (Group A). The hyperbaric oxygen therapy consisted of exposure to 100% oxygen at a pressure of 250 kPa for a total of 60 minutes in a multiplace hyperbaric chamber. The control group included 81 patients with defined sudden sensorineural hearing loss treated in the ENT Department, Medical University of Gdansk, from 1980 to 1996 (Group B). Both groups were comparable regarding the age of the patients, season of hearing loss occurrence, tinnitus and vestibular symptom frequency, delay before therapy, and average threshold loss before the start of treatment. The treatment results (hearing gain) were estimated using pure-tone audiometry. We retrospectively analyzed the audiograms of all patients. Patients from Group A (blood flow-promoting drugs, glucocorticoids in high doses, betahistine, and hyperbaric oxygen therapy) showed significantly better recovery of hearing levels compared with those from Group B (blood flow-promoting drugs and glucocorticoids in low doses) at seven frequencies (500, 1,000, 2,000, 3,000, 4,000, 6,000, and 8,000 Hz) (p < 0.05) and four groups of frequencies (pure-tone average, high-tone average, pure middle-tone average, and overall average) (p < 0.05). Percentage hearing gain in all investigated frequencies was also better in Group A versus Group B, and the differences were statistically significant (p < 0.05). We conclude that hyperbaric oxygen therapy with high doses of glucocorticoids improves the results of conventional sudden sensorineural hearing loss treatment and should be recommended. In addition, the best

  14. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-02-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age. Copyright © 2015 by the American Academy of Pediatrics.

  15. Cumulative oxytocin dose during induction of labor according to maternal body mass index.

    Science.gov (United States)

    Roloff, Kristina; Peng, Sheppard; Sanchez-Ramos, Luis; Valenzuela, Guillermo J

    2015-10-01

    To determine the cumulative oxytocin dose needed to achieve vaginal delivery among obese and non-obese women. A retrospective study was undertaken of women with singleton, term (≥37 weeks) pregnancies who delivered at an institution in California, USA, between May 1 and July 31, 2012. Women were deemed to be obese when their body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) was 30 or above. Cumulative oxytocin doses were calculated for women who achieved vaginal delivery. Overall, 413 women were included. Among 357 women for whom BMI data were available, 204 (57.1%) were obese. Vaginal delivery was achieved in 379 women. Among women who received augmentation after spontaneous labor onset, obese women trended towards more cumulative oxytocin (minimum: 24.7 ± 100.5 mU among women with a BMI of 18.50-24.99; maximum: 1580.5 ± 2530.5 mU among women with a BMI of 35.00-39.99; P=0.086). Women who underwent induction of labor required significantly more oxytocin with increasing BMI class (Plabor. Obese women required a larger cumulative oxytocin dose to achieve vaginal birth during labor induction, but not during augmentation of labor. The physiology of spontaneous labor could supersede or influence the metabolic derangement facing obese patients undergoing induction of labor. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  16. Yearly reduction of glucocorticoid dose by 50% as tapering schedule achieves complete remission for 124 pemphigus vulgaris patients.

    Science.gov (United States)

    Wang, Mingyue; Gao, Yu; Peng, Yang; Zhao, Junyu; Chen, Xixue; Zhu, Xuejun

    2016-03-01

    Glucocorticoids are the first-line treatment for pemphigus vulgaris. Among 140 patients receiving systemic glucocorticoids, 124 patients achieved complete remission off or on a prednisone dose of ≤10 mg/day or less for 6 months or more. The mean average steroid controlling doses were 0.65, 0.62, 0.80, 1.08 and 1.38 mg/kg per day for the mucosal-dominant patients and the mild, moderate, severe and extensive cutaneous-involved patients, respectively (P pemphigus vulgaris within 3-6 years.

  17. Prenatal high-dose pyridoxine may prevent hypertension and syndrome X in-utero by protecting the fetus from excess glucocorticoid activity.

    Science.gov (United States)

    McCarty, M F

    2000-05-01

    The increased risk for hypertension, insulin resistance syndrome, and coronary events associated with small-for-gestational-age birth, has plausibly been attributed to excessive prenatal exposure to glucocorticoids; this may up-regulate glucocorticoid activity throughout life by permanently decreasing expression of hippocampal glucocorticoid receptors crucial for feedback control of cortisol secretion. Since pyridoxal phosphate is a safe physiological antagonist of glucocorticoid activity, it is proposed that prenatal supplementation with high-dose pyridoxine may counteract the adverse impact of glucocorticoids on fetal growth, as well as on subsequent cardiovascular risk.

  18. Evaluation of cumulative lead dose and longitudinal changes in structural MRI in former organolead workers

    Science.gov (United States)

    Schwartz, Brian S.; Caffo, Brian; Stewart, Walter F.; Hedlin, Haley; James, Bryan D.; Yousem, David; Davatzikos, Christos

    2010-01-01

    Objective We evaluated whether tibia lead was associated with longitudinal change in brain volumes and white matter lesions in male former lead workers and population-based controls in whom we have previously reported on the cognitive and structural consequences of cumulative lead dose. Methods We used linear regression to identify predictors of change in brain volumes and white matter lesion grade scores, using two MRIs an average of five years apart. Results On average, total brain volume declined almost 30 cm3, predominantly in gray matter. Increasing age at the first MRI was strongly associated with larger declines in volumes and greater increases in white matter lesion scores. Tibia lead was not associated with change in brain volumes or white matter lesion scores. Conclusions In former lead workers in whom cumulative lead dose was associated with progressive declines in cognitive function decades after occupational exposure had ended, cumulative lead dose was associated with earlier persistent effects on brain structure, but not with additional worsening over five years. PMID:20357679

  19. Therapeutic efficacy of small doses of colchicine combined with glucocorticoid for acute gouty arthritis

    Directory of Open Access Journals (Sweden)

    Ying LIU

    2015-10-01

    Full Text Available Objective To observe the clinical effect of small dose of colchicine combined with glucocorticoid for acute gouty arthritis. Methods Ninety-two patients with acute gouty arthritis were equally and randomly divided into small doses of colchicine combined with dexamethasone treatment group (treatment group and conventional large dose colchicine treatment group (control group between January 2009 and December 2013. The articular lesion scoring and clinical efficacy evaluation were performed at 3, 6, 12, 24, 48, and 72h after treatment. Erythrocyte sedimentation rate (ESR, white blood cells, hepatorenal function and glomerular filtration rate (GFR were determined before and 72h after treatment respectively. The gastrointestinal adverse events and recurrence rate were observed within one month after treatment. Results The articular lesion scores were significantly decreased at 6, 12, 48, and 72h after treatment in treatment group compared with control group (P0.05. Serum uric acid, glutamic-pyruvic transaminase in serum (SGPT, and GFR did not show any change before and 72h after the treatment, and there was also no significant difference between groups (P>0.05. The incidence of gastrointestinal adverse events were obviously higher in control group (76.1% compared with that of the treatment group (P<0.05, and the differences was statistically significant. There was no statistical difference in recurrence rate between the control group and treatment group after a follow-up of one month. Conclusions Compared with conventional large dose colchicine, small dose of colchicine combined with dexamethasone can more rapidly and effectively control acute gouty arthritis, with good tolerability and safety, thus being worthy of popularization clinically. DOI: 10.11855/j.issn.0577-7402.2015.08.10

  20. Estimation of the annual cumulative radiation dose received by the dentist in dental clinics in Chennai

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    Sanarpalayam Chinaswamy Selvamuthukumar

    2014-01-01

    Full Text Available Aim and Objectives: To estimate the annual cumulative radiation dose received by a dentist in a ′less than an ideally sized clinic′ in Chennai. The objective of the study is to estimate the annual cumulative radiation dose received by the dentist at various distances and various angulations from the x-ray tube. Study Design: The head of a mannequin model was mounted on the dental chair to simulate a patient′s head and three thermoluminescent dosimeter (TLD chips were kept at various distances and various angulations, at a constant height. The standard conventional intraoral dental radiographic unit was used, which was kept stationary, with a constant voltage of 70 Kv, 8 mA current, and a constant exposure time of 0.3 seconds. Ninety-two TLD chips were exposed 20 times a day with constant horizontal angulations for a period of one year. The reading from the TLD chips was obtained on a computer through a TLD Badge Reader. Statistical Analysis: Post Hoc tests and One-way analysis of variance (ANOVA were used. Results and Conclusion: A decreasing trend was obtained in the average radiation doses, as the distance increased from the x-ray source, and a highly significant difference in doses (P < 0.001% was found between 4 and 5.5 feet (ft. We found a minimum average radiation dose at an angle of 60° to 80° and behind the tube. The purpose of this study was to create awareness among dental professionals, who had ′less than an ideally sized clinic′. We recommend that the dentist follow guidelines suggested by the National Council on Radiation Protection and Measurements (NCRP, USA. From this study, it is clear that most clinics are of sizes that do not permit this distance (6 ft, and hence, it is recommended that they use suitable barriers.

  1. Age- and gender-specific estimates of cumulative CT dose over 5 years using real radiation dose tracking data in children

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eunsol; Goo, Hyun Woo; Lee, Jae-Yeong [University of Ulsan College of Medicine, Asan Medical Center, Department of Radiology and Research Institute of Radiology, Seoul (Korea, Republic of)

    2015-08-15

    It is necessary to develop a mechanism to estimate and analyze cumulative radiation risks from multiple CT exams in various clinical scenarios in children. To identify major contributors to high cumulative CT dose estimates using actual dose-length product values collected for 5 years in children. Between August 2006 and July 2011 we reviewed 26,937 CT exams in 13,803 children. Among them, we included 931 children (median age 3.5 years, age range 0 days-15 years; M:F = 533:398) who had 5,339 CT exams. Each child underwent at least three CT scans and had accessible radiation dose reports. Dose-length product values were automatically extracted from DICOM files and we used recently updated conversion factors for age, gender, anatomical region and tube voltage to estimate CT radiation dose. We tracked the calculated CT dose estimates to obtain a 5-year cumulative value for each child. The study population was divided into three groups according to the cumulative CT dose estimates: high, ≥30 mSv; moderate, 10-30 mSv; and low, <10 mSv. We reviewed clinical data and CT protocols to identify major contributors to high and moderate cumulative CT dose estimates. Median cumulative CT dose estimate was 5.4 mSv (range 0.5-71.1 mSv), and median number of CT scans was 4 (range 3-36). High cumulative CT dose estimates were most common in children with malignant tumors (57.9%, 11/19). High frequency of CT scans was attributed to high cumulative CT dose estimates in children with ventriculoperitoneal shunt (35 in 1 child) and malignant tumors (range 18-49). Moreover, high-dose CT protocols, such as multiphase abdomen CT (median 4.7 mSv) contributed to high cumulative CT dose estimates even in children with a low number of CT scans. Disease group, number of CT scans, and high-dose CT protocols are major contributors to higher cumulative CT dose estimates in children. (orig.)

  2. Analysis of Cumulative Dose to Implanted Pacemaker According to Various IMRT Delivery Methods: Optimal Dose Delivery Versus Dose Reduction Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jeong Woo; Hong, Se Mie [Dept. of Radiation Oncology, Konkuk University Medical Center, Seoul (Korea, Republic of)

    2011-11-15

    Cancer patients with implanted cardiac pacemaker occasionally require radiotherapy. Pacemaker may be damaged or malfunction during radiotherapy due to ionizing radiation or electromagnetic interference. Although radiotherapy should be planned to keep the dose to pacemaker as low as possible not to malfunction ideally, current radiation treatment planning (RTP) system does not accurately calculate deposited dose to adjacent field border or area beyond irradiated fields. In terms of beam delivery techniques using multiple intensity modulated fields, dosimetric effect of scattered radiation in high energy photon beams is required to be detailed analyzed based on measurement data. The aim of this study is to evaluate dose discrepancies of pacemaker in a RTP system as compared to measured doses. We also designed dose reduction strategy limited value of 2 Gy for radiation treatment patients with cardiac implanted pacemaker. Total accumulated dose of 145 cGy based on in-vivo dosimetry was satisfied with the recommendation criteria to prevent malfunction of pacemaker in SS technique. However, the 2 mm lead shielder enabled the scattered doses to reduce up to 60% and 40% in the patient and the phantom, respectively. The SS technique with the lead shielding could reduce the accumulated scattered doses less than 100 cGy. Calculated and measured doses were not greatly affected by the beam delivery techniques. In-vivo and measured doses on pacemaker position showed critical dose discrepancies reaching up to 4 times as compared to planned doses in RTP. The current SS technique could deliver lower scattered doses than recommendation criteria, but use of 2 mm lead shielder contributed to reduce scattered doses by 60%. The tertiary lead shielder can be useful to prevent malfunction or electrical damage of implanted pacemakers during radiotherapy. It is required to estimate more accurate scattered doses of the patient or medical device in RTP to design proper dose reduction strategy.

  3. Effect of low-dose glucocorticoid on corticosteroid insufficient patients with acute exacerbation of chronic obstructive pulmonary disease

    Institute of Scientific and Technical Information of China (English)

    袁光雄

    2014-01-01

    Objective To investigate the effect of low-dose glucocorticoid on prognosis of critical illness-related corticosteroid insufficient(CIRCI)patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD).Methods A total of 385 eligible patients met the criteria of AECOPD were admitted from January 2010 to December 2012.The AECOPD patients co-morbid with CIRCI screened by an adrenal corticotrophic hormone test within 12 hours after admission were randomly divided

  4. Clinical trials documenting the efficacy of low-dose glucocorticoids in rheumatoid arthritis.

    Science.gov (United States)

    Pincus, Theodore; Cutolo, Maurizio

    2015-01-01

    Twelve clinical trials have documented that prednisone or prednisolone in doses of 10 mg/day or less is efficacious to improve function, maintain status and/or slow radiographic progression in patients with rheumatoid arthritis (RA). An early trial reported by de Andrade et al. [Ann Rheum Dis 1964;23:158-162] in 1964 indicated that 5 mg of prednisolone at night was preferred to 5 mg of prednisone in the morning. Harris et al. [J Rheumatol 1983;10:713-721] documented the efficacy of 5 mg/day of prednisone in a non-double-blind trial in 1983. Two important trials in the 1990s by Kirwan [N Engl J Med 1995;333:142-146] using 7.5 mg/day, and the COBRA study by Boers et al. [Lancet 1997;350:309-318] with step-down from 60 mg rapidly tapered to 5 mg/day led to strong advocacy of low-dose glucocorticoids. In 2002, the first Utrecht Study [Ann Intern Med 2002;136:1-12] indicated that 10 mg/day prednisone slowed radiographic progression, a finding confirmed and extended in 2005 by Svensson et al. [Arthritis Rheum 2005;52:3360-3370] with 7.5 mg/day, and Wassenberg et al. [Arthritis Rheum 2005;52:3371-3380] with 5 mg/day of prednisolone. In 2008, Buttgereit et al. [Lancet 2008;371:205-214] reported CAPRA-1, which documented that modified-release prednisone or prednisolone taken at bedtime led to lower morning stiffness and IL-6 levels compared to usual morning prednisone. In 2009, Pincus et al. [Ann Rheum Dis 2009;68:1715-1720] reported a withdrawal clinical trial, in which patients who took 3 mg/day were gradually withdrawn to placebo, and dropped out at a significantly higher rate than control patients who were 'withdrawn' to prednisone. In 2012, a second Utrecht Study [Ann Intern Med 2012;156:329-339], CAMERA-II, documented that 10 mg of prednisone added to a 'treat-to-target' strategy with methotrexate provided incremental slowing of radiographic progression. An Italian study of patients with early RA who received step-up disease-modifying antirheumatic drug therapy over 2

  5. Prediction of the cumulated dose for external beam irradiation of prostate cancer patients with 3D-CRT technique

    Directory of Open Access Journals (Sweden)

    Giżyńska Marta

    2016-03-01

    Full Text Available Nowadays in radiotherapy, much effort is taken to minimize the irradiated volume and consequently minimize doses to healthy tissues. In our work, we tested the hypothesis that the mean dose distribution calculated from a few first fractions can serve as prediction of the cumulated dose distribution, representing the whole treatment. We made our tests for 25 prostate cancer patients treated with three orthogonal fields technique. We did a comparison of dose distribution calculated as a sum of dose distribution from each fraction with a dose distribution calculated with isocenter shifted for a mean setup error from a few first fractions. The cumulative dose distribution and predicted dose distributions are similar in terms of gamma (3 mm 3% analysis, under condition that we know setup error from seven first fractions. We showed that the dose distribution calculated for the original plan with the isocenter shifted to the point, defined as the original isocenter corrected of the mean setup error estimated from the first seven fractions supports our hypothesis, i.e. can serve as a prediction for cumulative dose distribution.

  6. Reduced peripheral expression of the glucocorticoid receptor α isoform in individuals with posttraumatic stress disorder: a cumulative effect of trauma burden.

    Directory of Open Access Journals (Sweden)

    Hannah Gola

    Full Text Available BACKGROUND: Posttraumatic stress disorder (PTSD is a serious psychiatric condition that was found to be associated with altered functioning of the hypothalamic-pituitary-adrenal (HPA axis and changes in glucocorticoid (GC responsiveness. The physiological actions of GCs are primarily mediated through GC receptors (GR of which isoforms with different biological activities exist. This study aimed to investigate whether trauma-experience and/or PTSD are associated with altered expression of GR splice variants. METHODS: GRα and GRβ mRNA expression levels were determined by real-time quantitative PCR in whole blood samples of individuals with chronic and severe forms of PTSD (n = 42 as well as in ethnically matched reference subjects (non-PTSD, n = 35. RESULTS: Individuals suffering from PTSD exhibited significantly lower expression of the predominant and functionally active GRα isoform compared to non-PTSD subjects. This effect remained significant when accounting for gender, smoking, psychotropic medication or comorbid depression. Moreover, the GRα expression level was significantly negatively correlated with the number of traumatic event types experienced, both in the whole sample and within the PTSD patient group. Expression of the less abundant and non-ligand binding GRβ isoform was comparable between patient and reference groups. CONCLUSIONS: Reduced expression of the functionally active GRα isoform in peripheral blood cells of individuals with PTSD seems to be a cumulative effect of trauma burden rather than a specific feature of PTSD since non-PTSD subjects with high trauma load showed an intermediate phenotype between PTSD patients and individuals with no or few traumatic experiences.

  7. Balancing the benefits and risks of low-dose glucocorticoid in rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Tânia Santiago

    2015-01-01

    Full Text Available Glucocorticoids have potent anti-inflammatory and immunomodulatory effects and are widely use in the management of rheumatoid arthritis in combination with other synthetic and with biological disease-modifying anti-rheumatic drugs. Concerns about the risk of adverse effects of glucocorticoids, especially if they are given at higher dosages and for a longer time, hamper their use despite the clear symptomatic and disease modifying benefits. However, the evidence base for these concerns for low dose glucocorticoid therapy is quite limited due to the scarcity of quality literature on its safety in rheumatoid arthritis. This review discusses the current understanding about their disease-modifying effects, toxicity data from recent trials and observational studies, recommendations for their management and the current efforts to improve the therapeutic ratio of glucocorticoid through the development of new formulations, such as modified-release prednisone. Introduction With over 60 years of experience, the number of patients treated with glucocorticoids (GCs, and the range of clinical applications are more extensive than with any other treatment. GCs represent a true anchor treatment for rheumatoid arthritis (RA. This is supported by data indicating that up to 60% of all patients with RA in Germany are treated with GCs at some time during the course of their disease (1. Similarly, 34 to 93% of all patients entering recent clinical trials of biologics, and thus with active disease, were receiving GCs at baseline (2. Such data are in contrast with the literature predominantly addressing the risks of these agents and the caution advised by every treatment recommendations. Clinicians, and presumably patients, seem thus to value the anti-inflammatory, immunosuppressive and disease-modifying therapeutic effects of GCs. In contrast, both the literature and the medical community seem to be split between those in favour and those against the use of low-dose

  8. Benchmark Dose Analysis from Multiple Datasets: The Cumulative Risk Assessment for the N-Methyl Carbamate Pesticides

    Science.gov (United States)

    The US EPA’s N-Methyl Carbamate (NMC) Cumulative Risk assessment was based on the effect on acetylcholine esterase (AChE) activity of exposure to 10 NMC pesticides through dietary, drinking water, and residential exposures, assuming the effects of joint exposure to NMCs is dose-...

  9. Estimated cumulative radiation dose received by diagnostic imaging during staging and treatment of operable Ewing sarcoma 2005-2012

    Energy Technology Data Exchange (ETDEWEB)

    Johnsen, Boel [Haukeland University Hospital, Centre for Nuclear Medicine and PET, Department of Radiology, P.O. Box 1400, Bergen (Norway); Fasmer, Kristine Eldevik [Haukeland University Hospital, Department of Oncology, Medical Physics Section, Bergen (Norway); Boye, Kjetil [Norwegian Radium Hospital, Oslo University Hospital, Department of Oncology, Oslo (Norway); Rosendahl, Karen; Aukland, Stein Magnus [Haukeland University Hospital, Department of Radiology, Paediatric Section, Bergen (Norway); University of Bergen, Department of Clinical Medicine, Bergen (Norway); Trovik, Clement [University of Bergen, Department of Clinical Medicine, Bergen (Norway); Haukeland University Hospital, Department of Surgery, Orthopaedic Section, Bergen (Norway); Biermann, Martin [Haukeland University Hospital, Centre for Nuclear Medicine and PET, Department of Radiology, P.O. Box 1400, Bergen (Norway); University of Bergen, Department of Clinical Medicine, Bergen (Norway)

    2017-01-15

    Patients with Ewing sarcoma are subject to various diagnostic procedures that incur exposure to ionising radiation. To estimate the radiation doses received from all radiologic and nuclear imaging episodes during diagnosis and treatment, and to determine whether {sup 18}F-fluorodeoxyglucose positron emission tomography - computed tomography ({sup 18}F-FDG PET-CT) is a major contributor of radiation. Twenty Ewing sarcoma patients diagnosed in Norway in 2005-2012 met the inclusion criteria (age <30 years, operable disease, uncomplicated chemotherapy and surgery, no metastasis or residual disease within a year of diagnosis). Radiation doses from all imaging during the first year were calculated for each patient. The mean estimated cumulative radiation dose for all patients was 34 mSv (range: 6-70), radiography accounting for 3 mSv (range: 0.2-12), CT for 13 mSv (range: 2-28) and nuclear medicine for 18 mSv (range: 2-47). For the patients examined with PET-CT, the mean estimated cumulative effective dose was 38 mSv, of which PET-CT accounted for 14 mSv (37%). There was large variation in number and type of examinations performed and also in estimated cumulative radiation dose. The mean radiation dose for patients examined with PET-CT was 23% higher than for patients not examined with PET-CT. (orig.)

  10. A methodology to split the total cumulative Hp(10) dose into the Hp(10) i doses received during various procedures performed by interventional cardiologist.

    Science.gov (United States)

    Domienik, Joanna

    2017-03-01

    The methodology describing how to split the cumulative Hp(10) dose of interventional cardiologists into Hp(10) i doses received during procedures of various types based on procedure-specific ELDO coefficients and Hp(3) doses per procedure is presented. The appropriate equations for Hp(10) i (Hp(10) for procedure type i), depending on the number of various procedure types (i  =  1 … 4) performed by a particular physician, are derived. The methodology can be applied to whole-body doses measured on the lead apron and therefore can be used for optimisation of work practices in those catheterisation labs where routine dosimeter is worn above the apron.

  11. Glucocorticoid therapy-induced memory deficits: acute versus chronic effects.

    Science.gov (United States)

    Coluccia, Daniel; Wolf, Oliver T; Kollias, Spyros; Roozendaal, Benno; Forster, Adrian; de Quervain, Dominique J-F

    2008-03-26

    Conditions with chronically elevated glucocorticoid levels are usually associated with declarative memory deficits. Considerable evidence suggests that long-term glucocorticoid exposure may cause cognitive impairment via cumulative and long-lasting influences on hippocampal function and morphology. However, because elevated glucocorticoid levels at the time of retention testing are also known to have direct impairing effects on memory retrieval, it is possible that such acute hormonal influences on retrieval processes contribute to the memory deficits found with chronic glucocorticoid exposure. To investigate this issue, we examined memory functions and hippocampal volume in 24 patients with rheumatoid arthritis who were treated either chronically (5.3 +/- 1.0 years, mean +/- SE) with low to moderate doses of prednisone (7.5 +/- 0.8 mg, mean +/- SE) or without glucocorticoids. In both groups, delayed recall of words learned 24 h earlier was assessed under conditions of either elevated or basal glucocorticoid levels in a double-blind, placebo-controlled crossover design. Although the findings in this patient population did not provide evidence for harmful effects of a history of chronic prednisone treatment on memory performance or hippocampal volume per se, acute prednisone administration 1 h before retention testing to either the steroid or nonsteroid group impaired word recall. Thus, these findings indicate that memory deficits observed under chronically elevated glucocorticoid levels result, at least in part, from acute and reversible glucocorticoid effects on memory retrieval.

  12. The acceleration of amygdala kindling epileptogenesis by chronic low-dose corticosterone involves both mineralocorticoid and glucocorticoid receptors.

    Science.gov (United States)

    Kumar, Gaurav; Couper, Abbie; O'Brien, Terence J; Salzberg, Michael R; Jones, Nigel C; Rees, Sandra M; Morris, Margaret J

    2007-08-01

    We have previously demonstrated that low-dose corticosterone (CS) administration, used as a model of the effect of chronic stress, accelerates epileptogenesis in the electrical amygdala kindling rat model of temporal lobe epilepsy (TLE). This current study examined the relative contributions to this effect of mineralocorticoid (MR) and glucocorticoid (GR) subtypes of glucocorticoid receptors. Female non-epileptic wistar rats 10-13 weeks of age were implanted with a bipolar electrode into the left amygdala. Five treatment groups were subjected to rapid amygdala kindling: water-control (n=9), CS treated (6 mg/100 ml added to drinking water; n=9), CS+spironolactone (MR antagonist, 50 mg/kg sc; n=9), CS+mifepristone (GR antagonist, 25 mg/kg sc; n=9), and CS+both antagonists (n=7). Rats were injected with vehicle or the relevant antagonist twice daily for the entire kindling period. Experimental groups differed significantly in the number of stimulations required to reach the 'fully kindled state' (Racine, 1972) ANOVA, F(4,38)=2.73, p=0.04). Amygdala kindling was accelerated in the CS-treated group compared with water controls (mean stimulations for full kindling: 45.2 vs. 86.5, pkindling rates in these groups not significantly different from water-treated subjects (p=0.26 and 0.29, respectively). The kindling rates in the MR and GR antagonist treatment groups did not significantly differ from each other (p=0.93), nor from the combined treatment group (mean stimulations: 62.8, p=0.59 and 0.54, respectively). This study demonstrates that activation of both high-affinity (MR) and low-affinity (GR) glucocorticoid receptors are involved in mediating CS-induced acceleration of amygdala kindling epileptogenesis.

  13. Postnatal glucocorticoid-induced hypomyelination, gliosis, neurologic deficits are dose-dependent, preparation-specific, and reversible

    Science.gov (United States)

    Zia, Muhammad TK; Vinukonda, Govindaiah; Vose, Linnea; Bhimavarapu, Bala B.R.; Iacobas, Sanda; Pandey, Nishi K.; Beall, Ann Marie; Dohare, Preeti; LaGamma, Edmund F.; Iacobas, Dumitru A.; Ballabh, Praveen

    2014-01-01

    Postnatal glucocorticoids (GCs) are widely used in the prevention of chronic lung disease in premature infants. Their pharmacologic use is associated with neurodevelopmental delay and cerebral palsy. However, the effect of GC dose and preparation (dexamethasone versus betamethasone) on short and long-term neurological outcomes remains undetermined, and the mechanisms of GC-induced brain injury are unclear. We hypothesized that postnatal GC would induce hypomyelination and motor impairment in a preparation- and dose-specific manner, and that GC receptor (GR) inhibition might restore myelination and neurological function in GC-treated animals. Additionally, GC-induced hypomyelination and neurological deficit might be transient. To test our hypotheses, we treated prematurely delivered rabbit pups with high (0.5 mg/kg/day) or low (0.2 mg/kg/day) doses of dexamethasone or betamethasone. Myelin basic protein (MBP), oligodendrocyte proliferation and maturation, astrocytes, transcriptomic profile, and neurobehavioral functions were evaluated. We found that high-dose GC treatment, but not low-dose, reduced MBP expression and impaired motor function at postnatal day 14. High-dose dexamethasone induced astrogliosis, betamethasone did not. Mifepristone, a GR antagonist, reversed dexamethasone-induced myelination, but not astrogliosis. Both GCs inhibited oligodendrocyte proliferation and maturation. Moreover, high-dose dexamethasone altered genes associated with myelination, cell-cycle, GR, and Mitogen-activated protein kinase. Importantly, GC-induced hypomyelination, gliosis, and motor-deficit, observed at day 14, completely recovered by day 21. Hence, high-dose, but not low-dose, postnatal GC causes reversible reductions in myelination and motor functions. GC treatment induces hypomyelination by GR-dependent genomic mechanisms, but astrogliosis by non-genomic mechanisms. GC-induced motor impairment and neurodevelopmental delay might be transient and recover spontaneously in

  14. A study of the relationship between peak skin dose and cumulative air kerma in interventional neuroradiology and cardiology

    Energy Technology Data Exchange (ETDEWEB)

    Neil, S; Padgham, C; Martin, C J [Health Physics, Gartnavel Royal Hospital, Glasgow G12 0XH (United Kingdom)

    2010-12-01

    A study of peak skin doses (PSDs) during neuroradiology and cardiology interventional procedures has been carried out using Gafchromic XR-RV2 film. Use of mosaics made from squares held in cling film has allowed doses to the head to be mapped successfully. The displayed cumulative air kerma (CAK) has been calibrated in terms of cumulative entrance surface dose (CESD) and results indicate that this can provide a reliable indicator of the PSD in neuroradiology. Results linking PSD to CESD for interventional cardiology were variable, but CAK is still considered to provide the best option for use as an indicator of potential radiation-induced effects. A CESD exceeding 3 Gy is considered a suitable action level for triggering follow-up of patients in neuroradiology and cardiology for possible skin effects. Application of dose action levels defined in this way would affect 8% of neurological embolisation procedures and 5% of cardiology ablation and multiple stent procedures at the hospitals where the investigations were carried out. A close relationship was observed between CESD and dose-area product (DAP) for particular types of procedure, and DAPs of 200-300 Gy cm{sup 2} could be used as trigger levels where CAK readings were not available. The DAP value would depend on the mean field size and would need to be determined for each application.

  15. Effect and its clinical significance of different dose of glucocorticoids on inflammation mediators in patients with acute exacerbation of chronic obstructive pulmonary diseases

    Institute of Scientific and Technical Information of China (English)

    钟佰强

    2014-01-01

    Objective To explore the effect and its clinical significance of different dose of glucocorticoids on inflammation mediators in patients with acute exacerbation of chronic obstructive pulmonary diseases.Methods 45 patients admitted to our hospitals from March 2007 to March 2011were randomly divided into 3 groups:methylprednisolone40 mg group(methylprednisolone 40mg,iv,qd),meth-

  16. Insulin dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: test of an algorithm [correction of analgoritm

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R; Christensen, Ann-Birgitte L; Hellmuth, Ellinor

    2002-01-01

    Poor glycemic control is often a serious clinical problem during glucocorticoid treatment for fetal lung maturation in pregnant women with diabetes. An algorithm for improved subcutaneous insulin treatment during glucocorticoid treatment in insulin-dependent diabetic women was developed and tested....

  17. Sci—Thur AM: YIS - 11: Estimation of Bladder-Wall Cumulative Dose in Multi-Fraction Image-Based Gynaecological Brachytherapy Using Deformable Point Set Registration

    Energy Technology Data Exchange (ETDEWEB)

    Zakariaee, R [Physics Department, University of British Columbia, Vancouver, BC (Canada); Brown, C J; Hamarneh, G [School of Computing Science, Simon Fraser University, Burnaby, BC (Canada); Parsons, C A; Spadinger, I [British Columbia Cancer Agency, Vancouver, BC (Canada)

    2014-08-15

    Dosimetric parameters based on dose-volume histograms (DVH) of contoured structures are routinely used to evaluate dose delivered to target structures and organs at risk. However, the DVH provides no information on the spatial distribution of the dose in situations of repeated fractions with changes in organ shape or size. The aim of this research was to develop methods to more accurately determine geometrically localized, cumulative dose to the bladder wall in intracavitary brachytherapy for cervical cancer. The CT scans and treatment plans of 20 cervical cancer patients were used. Each patient was treated with five high-dose-rate (HDR) brachytherapy fractions of 600cGy prescribed dose. The bladder inner and outer surfaces were delineated using MIM Maestro software (MIM Software Inc.) and were imported into MATLAB (MathWorks) as 3-dimensional point clouds constituting the “bladder wall”. A point-set registration toolbox for MATLAB, Coherent Point Drift (CPD), was used to non-rigidly transform the bladder-wall points from four of the fractions to the coordinate system of the remaining (reference) fraction, which was chosen to be the emptiest bladder for each patient. The doses were accumulated on the reference fraction and new cumulative dosimetric parameters were calculated. The LENT-SOMA toxicity scores of these patients were studied against the cumulative dose parameters. Based on this study, there was no significant correlation between the toxicity scores and the determined cumulative dose parameters.

  18. Clinical significance of cumulative biological effective dose and overall treatment time in the treatment of carcinoma cervix

    Directory of Open Access Journals (Sweden)

    Mandal Abhijit

    2007-01-01

    Full Text Available The purpose of this retrospective study is to report the radiotherapy treatment response of, and complications in, patients with cervical cancer on the basis of cumulative biologic effective dose (BED and overall treatment time (OTT. Sixty-four (stage II - 35/64; stage III - 29/64 patients of cervical cancer were treated with combination of external beam radiotherapy (EBRT and low dose rate intracavitary brachytherapy (ICBT. The cumulative BED was calculated at Point A (BED 10 ; and bladder, rectal reference points (BED 2.5 using the linear-quadratic BED equations. The local control (LC rate and 5-year disease-free survival (DFS rate in patients of stage II were comparable for BED 10 < 84.5 and BED 10 > 84.5 but were much higher for BED 10 > 84.5 than BED 10 < 84.5 ( P < 0.01 in stage III patients. In the stage II patients, The LC rate and 5-year DFS rate were comparable for OTT < 50 days and for OTT> 50 days but were much higher in stage III patients with OTT < 50 than OTT> 50 days ( P < 0.001. It was also observed that patients who received BED 2.5 < 105 had lesser rectal ( P < 0.001 and bladder complications than BED 2.5 > 105. Higher rectal complication-free survival (CFS R rate, bladder complication-free survival (CFS B rate and all-type late complication-free survival rate were observed in patients who received BED 2.5 < 105 than BED 2.5 > 105. A balanced, optimal and justified radiotherapy treatment schedule to deliver higher BED 10 (>84.5 and lower BED 2.5 (< 105 in lesser OTT (< 50 days is essential in carcinoma cervix to expect a better treatment outcome in all respects.

  19. Unified registration framework for cumulative dose assessment in cervical cancer across external beam radiotherapy and brachytherapy

    Science.gov (United States)

    Roy, Sharmili; Totman, John J.; Choo, Bok A.

    2016-03-01

    Dose accumulation across External Beam Radiotherapy (EBRT) and Brachytherapy (BT) treatment fractions in cervical cancer is extremely challenging due to structural dissimilarities and large inter-fractional anatomic deformations between the EBRT and BT images. The brachytherapy applicator and the bladder balloon, present only in the BT images, introduce missing structural correspondences for the underlying registration problem. Complex anatomical deformations caused by the applicator and the balloon, different rectum and bladder filling and tumor shrinkage compound the registration difficulties. Conventional free-form registration methods struggle to handle such topological differences. In this paper, we propose a registration pipeline that first transforms the original images to their distance maps based on segmentations of critical organs and then performs non-linear registration of the distance maps. The resulting dense deformation field is then used to transform the original anatomical image. The registration accuracy is evaluated on 27 image pairs from stage 2B-4A cervical cancer patients. The algorithm reaches a Hausdorff distance of close to 0:5 mm for the uterus, 2:2 mm for the bladder and 1:7 mm for the rectum when applied to (EBRT,BT) pairs, taken at time points more than three months apart. This generalized model-free framework can be used to register any combination of EBRT and BT images as opposed to methods in the literature that are tuned for either only (BT,BT) pair, or only (EBRT,EBRT) pair or only (BT,EBRT) pair. A unified framework for 3D dose accumulation across multiple EBRT and BT fractions is proposed to facilitate adaptive personalized radiation therapy.

  20. Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis

    DEFF Research Database (Denmark)

    Olsson, A; Oturai, Ditte Bang; Sørensen, P S;

    2015-01-01

    BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). OBJECTIVES: The objective of this paper is to assess bone mass in patients with MS and evaluate the importa......BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). OBJECTIVES: The objective of this paper is to assess bone mass in patients with MS and evaluate...... the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. METHODS: A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference...... population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. RESULTS: Osteopenia was present in 38...

  1. Risk of therapy-related leukaemia and preleukaemia after Hodgkin's disease. Relation to age, cumulative dose of alkylating agents, and time from chemotherapy

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, J; Specht, L; Larsen, S O;

    1987-01-01

    391 patients treated intensively for Hodgkin's disease were followed for up to 15 years to evaluate the risk of therapy-related acute non-lymphocytic leukaemia (t-ANLL) and preleukaemia. Only two independent factors, patient age and cumulative dose of alkylating agents, were related to the risk o...

  2. Dose-Response Relationship between Cumulative Occupational Lead Exposure and the Associated Health Damages: A 20-Year Cohort Study of a Smelter in China.

    Science.gov (United States)

    Wu, Yue; Gu, Jun-Ming; Huang, Yun; Duan, Yan-Ying; Huang, Rui-Xue; Hu, Jian-An

    2016-03-16

    Long-term airborne lead exposure, even below official occupational limits, has been found to cause lead poisoning at higher frequencies than expected, which suggests that China's existing occupational exposure limits should be reexamined. A retrospective cohort study was conducted on 1832 smelting workers from 1988 to 2008 in China. These were individuals who entered the plant and came into continuous contact with lead at work for longer than 3 months. The dose-response relationship between occupational cumulative lead exposure and lead poisoning, abnormal blood lead, urinary lead and erythrocyte zinc protoporphyrin (ZPP) were analyzed and the benchmark dose lower bound confidence limits (BMDLs) were calculated. Statistically significant positive correlations were found between cumulative lead dust and lead fumes exposures and workplace seniority, blood lead, urinary lead and ZPP values. A dose-response relationship was observed between cumulative lead dust or lead fumes exposure and lead poisoning (p lead dust and fumes doses were 0.68 mg-year/m³ and 0.30 mg-year/m³ for lead poisoning, respectively. The BMDLs of workplace airborne lead concentrations associated with lead poisoning were 0.02 mg/m³ and 0.01 mg/m³ for occupational exposure lead dust and lead fume, respectively. In conclusion, BMDLs for airborne lead were lower than occupational exposure limits, suggesting that the occupational lead exposure limits need re-examination and adjustment. Occupational cumulative exposure limits (OCELs) should be established to better prevent occupational lead poisoning.

  3. Chronic inflammation and low-dose glucocorticoid effects on glucose metabolism in premenopausal females with rheumatoid arthritis free of conventional metabolic risk factors.

    Science.gov (United States)

    Penesová, A; Rádiková, Z; Vlček, M; Kerlik, J; Lukáč, J; Rovenský, J; Imrich, R

    2013-01-01

    Chronic systemic inflammation is associated with increased cardiovascular mortality in patients with rheumatoid arthritis (RA). The aim of our study was to investigate association of glucose metabolism and inflammatory markers in a group of patients with rheumatoid arthritis free of other metabolic risk factors. Twenty-two premenopausal RA females (11 patients on low-dose GC (glucocorticoid therapy) and 15 age- and BMI-matched healthy females underwent the oral glucose tolerance test. The insulin sensitivity indices according Matsuda (ISI(MAT)) and Cederholm (ISI(CED)) as well as HOMA2 %S were calculated. Cytokines, lipid profile, non-esterified fatty acids (NEFA) and plasminogen activator inhibitor-1 (PAI-1) were measured in baseline blood samples. Despite elevated interleukin IL-6 and TNF alpha, glucose, insulin and C-peptide responses to oral glucose load as well as ISI(MAT), ISI(CED), PAI-1 and NEFA were comparable in both RA groups and healthy controls. HOMA2 %S correlated with disease activity. In conclusions, low-dose glucocorticoid treatment does not lead to glucose metabolism impairment in RA patients without other metabolic risk factors. Increased cardiovascular mortality and morbidity is probably due to a direct effect of systemic inflammation on myocardium and/or blood vessels.

  4. DOSE-RESPONSE MODELING FOR THE ASSESSMENT OF CUMULATIVE RISK DUE TO EXPOSURE TO N-METHYL CARBAMATE PESTICIDES

    Science.gov (United States)

    The US EPAs N-Methyl Carbamate Cumulative Risk Assessment (NMCRA) assesses the effect on acetylcholine esterase (AChE) activity of exposure to 10 N-methyl carbamate (NMC) pesticides through dietary, drinking water, and residential exposures.

  5. Unmasking of Partial Diabetes Insipidus during Stress but Not Maintenance Dosing of Glucocorticoids in an Infant with Septo-Optic Dysplasia

    Directory of Open Access Journals (Sweden)

    Loechner KarenJ

    2011-03-01

    Full Text Available Background. It is well acknowledged that glucocorticoid (GC replacement can unmask diabetes insipidus (DI in subjects with hypopituitarism. Objective. To increase the awareness and monitoring for transient and symptomatic DI in children with partial hypopituitarism during periods in which increased GC needs are required. Methods/Case. A 2-month-old female infant with septo-optic dysplasia (SOD; on thyroid and maintenance GC replacement therapy at 8 mg/m2/day developed transient DI during 2 separate episodes of stress (one hypothermia, one febrile when stress dosing of GC (25 mg/m2/day was instituted. Conclusion. Children not diagnosed with DI during initial evaluation for hypopituitarism may benefit from rescreening of serum sodium levels during acute periods of stress that demand "stress" GC dosing. This will permit treatment and/or increased vigilance for ensuing permanent DI.

  6. SU-E-J-106: The Use of Deformable Image Registration with Cone-Beam CT for a Better Evaluation of Cumulative Dose to Organs

    Energy Technology Data Exchange (ETDEWEB)

    Fillion, O; Gingras, L; Archambault, L [Universite Laval, Quebec, Quebec (Canada); Centre de recherche du CHU de Quebec, Quebec, Quebec (Canada); Centre de recherche sur le cancer, Quebec, Quebec (Canada)

    2015-06-15

    Purpose: The knowledge of dose accumulation in the patient tissues in radiotherapy helps in determining the treatment outcomes. This project aims at providing a workflow to map cumulative doses that takes into account interfraction organ motion without the need for manual re-contouring. Methods: Five prostate cancer patients were studied. Each patient had a planning CT (pCT) and 5 to 13 CBCT scans. On each series, a physician contoured the prostate, rectum, bladder, seminal vesicles and the intestine. First, a deformable image registration (DIR) of the pCTs onto the daily CBCTs yielded registered CTs (rCT) . This rCT combined the accurate CT numbers of the pCT with the daily anatomy of the CBCT. Second, the original plans (220 cGy per fraction for 25 fractions) were copied on the rCT for dose re-calculation. Third, the DIR software Elastix was used to find the inverse transform from the rCT to the pCT. This transformation was then applied to the rCT dose grid to map the dose voxels back to their pCT location. Finally, the sum of these deformed dose grids for each patient was applied on the pCT to calculate the actual dose delivered to organs. Results: The discrepancy between the planned D98 and D2 and these indices re-calculated on the rCT, are, on average, of −1 ± 1 cGy and 1 ± 2 cGy per fraction, respectively. For fractions with large anatomical motion, the D98 discrepancy on the re-calculated dose grid mapped onto the pCT can raise to −17 ± 4 cGy. The obtained cumulative dose distributions illustrate the same behavior. Conclusion: This approach allowed the evaluation of cumulative doses to organs with the help of uncontoured daily CBCT scans. With this workflow, the easy evaluation of doses delivered for EBRT treatments could ultimately lead to a better follow-up of prostate cancer patients.

  7. Serum Resistin Level and Progression of Atherosclerosis during Glucocorticoid Therapy for Systemic Autoimmune Diseases.

    Science.gov (United States)

    Tanaka, Nahoko; Masuoka, Shotaro; Kusunoki, Natsuko; Nanki, Toshihiro; Kawai, Shinichi

    2016-09-16

    Adipokines are important regulators of several processes, including inflammation and atherosclerosis. In patients with systemic autoimmune diseases, atherosclerosis is accelerated with higher cardiovascular morbidity and mortality. We prospectively investigated the association of adipokines and glucocorticoid therapy with progression of premature atherosclerosis in 38 patients starting glucocorticoid therapy for systemic autoimmune diseases. To detect premature atherosclerosis, carotid ultrasonography was performed at initiation of glucocorticoid therapy and after a mean three-year follow-up period. The ankle-brachial pressure index and cardio-ankle vascular index (CAVI) were measured. Serum adipokine levels were determined with enzyme-linked immunosorbent assay kits. Twenty-three patients (60.5%) had carotid artery plaque at baseline. The carotid artery intima-media thickness (IMT) increased significantly during follow-up. Glucocorticoids reduced the serum resistin level, while increasing serum leptin and high molecular weight-adiponectin. There was slower progression of atherosclerosis (carotid IMT and CAVI) at follow-up in patients with greater reduction of serum resistin and with higher cumulative prednisolone dose. In conclusion, progression of premature atherosclerosis occurred at an early stage of systemic autoimmune diseases before initiation of glucocorticoid therapy. Since resistin, an inflammation and atherosclerosis related adipokine, is reduced by glucocorticoids, glucocortidoid therapy may not accelerate atherosclerosis in patients with systemic autoimmune diseases.

  8. Current and historical individual data about exposure of workers in the rayon industry to carbon disulfide and their validity in calculating the cumulative dose.

    Science.gov (United States)

    Göen, Thomas; Schramm, Axel; Baumeister, Thomas; Uter, Wolfgang; Drexler, Hans

    2014-08-01

    The objective of the study was to investigate how exposure to carbon disulfide (CS2) in a rayon-manufacturing plant has changed within two decades and whether it is possible to calculate valid data for the individual cumulative exposure. The data for CS2 concentration in air and biological exposure monitoring (2-thio-1,3-thiaxolidine-4-carboxylic acid (TTCA) in urine) from two cross-sectional studies, performed in 1992 (n = 362) and 2009 (n = 212) in a German rayon-manufacturing plant, were compared to data obtained from company-internal measurements between the studies. Using the data from the cross-sectional studies and company-internal data, cumulative external exposure and the cumulative internal exposure were calculated for each worker. External and internal CS2 exposure of the employees decreased from 1992 (medians 4.0 ppm and 1.63 mgTTCA/g creatinine) to 2009 (medians 2.5 ppm and 0.86 mg/g). However, company-internal CS2 data do not show a straight trend for this period. The annual medians of the company-internal measurement of external exposure to CS2 have varied between 2.7 and 8.4 ppm, in which median values exceeded 5 ppm generally since 2000. The annual medians for the company-internal biomonitoring assessment ranged between 1.2 and 2.8 mg/g creatinine. The cumulative CS2 exposure ranged from 8.5 to 869.5 ppm years for external exposure and between 1.30 and 176.2 mg/g creatinine years for the internal exposure. Significant correlations were found between the current air pollution and the internal exposure in 2009 but also between the cumulative external and internal CS2 exposure. Current exposure data, usually collected in cross-sectional studies, rarely allow a reliable statement on the cumulative dose, because of higher exposure in the past and of fluctuating courses of exposure. On the other hand, company-internal exposure data may be affected by non-representative measurement strategies. Some verification of the reliability of

  9. Children and adolescents previously treated with glucocorticoids display lower verbal intellectual abilities

    DEFF Research Database (Denmark)

    Holm, Sara Krøis; Vestergaard, Martin; Madsen, Kathrine Skak

    2015-01-01

    /kg (range 21-723) and the mean time that had elapsed since treatment was three-and-a-half (standard deviation 2.2) years. Intellectual abilities were assessed with the Wechsler Intelligence Scale for Children and memory performance and behavioural problems with a pattern recognition memory task......AIM: Perinatal exposure to glucocorticoids has been associated with adverse cerebral effects, but little is known about their effect on cognitive development and exposure later in childhood. This study examined intellectual abilities, memory and behavioural problems in children previously treated...... with glucocorticoids. METHODS: We evaluated 38 children aged from seven to 16 years, who had been treated with glucocorticoids for rheumatic disease or nephrotic syndrome, together with 42 healthy controls matched for age, gender and parental education. The median cumulative dose of prednisolone equivalents was 158 mg...

  10. Successful treatment of Erdheim-Chester disease with combination of interleukin-1-targeting drugs and high-dose glucocorticoids.

    Science.gov (United States)

    Darstein, F; Kirschey, S; Heckl, S; Rahman, F; Schwarting, A; Schuchmann, M; Galle, P R; Zimmermann, T

    2014-01-01

    Erdheim-Chester disease (ECD) is a rare histocytic disorder. We report a case of a 45-year-old male ECD patient with severe clinical manifestation (urinary obstruction due to retroperitoneal mass with hydronephrosis, involvement of long bones) and central nervous system involvement (hemiparesis, aphasia and diabetes insipidus). Diagnosis was confirmed by typical clinical, radiological and histological findings. Under immunosuppressive therapy with prednisolone and interleukin-1A receptor antagonist (Anakinra, Kineret, Swedish Orphan Biovitrum AB, Stockholm, Sweden), a rapid improvement of the patients' symptoms and condition was observed. This is the first report of a successful combination therapy of Anakinra and glucocorticoids. Furthermore, current literature about ECD and treatment options are discussed. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

  11. Islet-cell dysfunction induced by glucocorticoid treatment

    DEFF Research Database (Denmark)

    van Raalte, Daniël H; Kwa, Kelly A A; van Genugten, Renate E

    2013-01-01

    Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system....

  12. Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner.

    Science.gov (United States)

    Munhoz, Carolina Demarchi; Sorrells, Shawn F; Caso, Javier R; Scavone, Cristoforo; Sapolsky, Robert M

    2010-10-13

    Although the anti-inflammatory actions of glucocorticoids (GCs) are well established, evidence has accumulated showing that proinflammatory GC effects can occur in the brain, in a poorly understood manner. Using electrophoretic mobility shift assay, real-time PCR, and immunoblotting, we investigated the ability of varying concentrations of corticosterone (CORT, the GC of rats) to modulate lipopolysaccharide (LPS)-induced activation of NF-κB (nuclear factor κB), expression of anti- and proinflammatory factors and of the MAP (mitogen-activated protein) kinase family [ERK (extracellular signal-regulated kinase), p38, and JNK/SAPK (c-Jun N-terminal protein kinase/stress-activated protein kinase)], and AKT. In the frontal cortex, elevated CORT levels were proinflammatory, exacerbating LPS effects on NF-κB, MAP kinases, and proinflammatory gene expression. Milder proinflammatory GCs effects occurred in the hippocampus. In the absence of LPS, elevated CORT levels increased basal activation of ERK1/2, p38, SAPK/JNK, and AKT in both regions. These findings suggest that GCs do not uniformly suppress neuroinflammation and can even enhance it at multiple levels in the pathway linking LPS exposure to inflammation.

  13. Double dose: the cumulative effect of TV viewing at home and in preschool on children's activity patterns and weight status.

    Science.gov (United States)

    Taverno Ross, Sharon; Dowda, Marsha; Saunders, Ruth; Pate, Russell

    2013-05-01

    Little is known about how screen-based sedentary behavior at home and in preschool influences children's health and activity patterns. The current study examined the individual and cumulative influence of TV viewing at home and in preschool on children's physical activity (PA) and weight status. Children (n = 339) attending 16 preschools in South Carolina were grouped into high and low TV groups based on parent report of children's TV viewing at home and director report of TV use/rules in preschool. T-tests and mixed model ANOVAs examined differences in weight status and PA (min/hr) by high and low TV groups. Results revealed that children who were classified as High TV both at home and in pre- school had significantly lower levels of moderate-to-vigorous PA compared with their Low TV counterparts (8.3 (0.3) min/hr vs. 7.6 (0.2) min/hr, p TV groups at home or in preschool when examined individually. These findings demonstrate the importance of total environmental TV exposure on preschooler's PA. Longitudinal and observational research to assess preschoolers' cumulative screen-based sedentary behavior and its relationship with PA and weight status is needed.

  14. Oral Calcidiol Is More Effective Than Cholecalciferol Supplementation to Reach Adequate 25(OH)D Levels in Patients with Autoimmune Diseases Chronically Treated with Low Doses of Glucocorticoids: A “Real-Life” Study

    Science.gov (United States)

    Ortego-Jurado, Miguel; Callejas-Rubio, José-Luis; Ríos-Fernández, Raquel; González-Moreno, Juan; González Ramírez, Amanda Rocío; González-Gay, Miguel A.; Ortego-Centeno, Norberto

    2015-01-01

    Glucocorticoids (GCs) are the cornerstone of the therapy in many autoimmune and inflammatory diseases. However, it is well known that their use is a double edged sword, as their beneficial effects are associated almost universally with unwanted effects, as, for example glucocorticoid-induced osteoporosis (GIO). Over the last years, several clinical practice guidelines emphasize the need of preventing bone mass loss and reduce the incidence of fractures associated with GC use. Calcium and vitamin D supplementation, as adjunctive therapy, are included in all the practice guidelines. However, no standard vitamin D dose has been established. Several studies with postmenopausal women show that maintaining the levels above 30–33 ng/mL help improve the response to bisphosphonates. It is unknown if the response is the same in GIO, but in the clinical practice the levels are maintained at around the same values. In this study we demonstrate that patients with autoimmune diseases, undergoing glucocorticoid therapy, often present suboptimal 25(OH)D levels. Patients with higher body mass index and those receiving higher doses of glucocorticoids are at increased risk of having lower levels of 25(OH)D. In these patients, calcidiol supplementations are more effective than cholecalciferol to reach adequate 25(OH)D levels. PMID:26124976

  15. Oral Calcidiol Is More Effective Than Cholecalciferol Supplementation to Reach Adequate 25(OHD Levels in Patients with Autoimmune Diseases Chronically Treated with Low Doses of Glucocorticoids: A “Real-Life” Study

    Directory of Open Access Journals (Sweden)

    Miguel Ortego-Jurado

    2015-01-01

    Full Text Available Glucocorticoids (GCs are the cornerstone of the therapy in many autoimmune and inflammatory diseases. However, it is well known that their use is a double edged sword, as their beneficial effects are associated almost universally with unwanted effects, as, for example glucocorticoid-induced osteoporosis (GIO. Over the last years, several clinical practice guidelines emphasize the need of preventing bone mass loss and reduce the incidence of fractures associated with GC use. Calcium and vitamin D supplementation, as adjunctive therapy, are included in all the practice guidelines. However, no standard vitamin D dose has been established. Several studies with postmenopausal women show that maintaining the levels above 30–33 ng/mL help improve the response to bisphosphonates. It is unknown if the response is the same in GIO, but in the clinical practice the levels are maintained at around the same values. In this study we demonstrate that patients with autoimmune diseases, undergoing glucocorticoid therapy, often present suboptimal 25(OHD levels. Patients with higher body mass index and those receiving higher doses of glucocorticoids are at increased risk of having lower levels of 25(OHD. In these patients, calcidiol supplementations are more effective than cholecalciferol to reach adequate 25(OHD levels.

  16. A population-based case-control study of Selective Serotonin Reuptake Inhibitors (SSRIs and breast cancer: The impact of duration of use, cumulative dose and latency

    Directory of Open Access Journals (Sweden)

    Lévesque LE

    2010-12-01

    Full Text Available Abstract Background Selective serotonin reuptake inhibitors (SSRIs, a popular class of antidepressants, may increase breast cancer risk by stimulating the secretion of prolactin, a potential tumour promoter. We evaluated the effects of duration of SSRI use, cumulative dose, and latency on the risk of breast cancer by conducting a population-based case-control study utilizing Saskatchewan health databases. Methods Cases included 1,701 women with primary invasive breast cancer diagnosed from 2003 to 2006, and controls consisted of 17,017 women, randomly selected from the population registry. Use of SSRIs was compiled using the Saskatchewan prescription database. Unconditional logistic regression was conducted to evaluate the impact of duration of combined SSRI use (total number of prescriptions dispensed, cumulative dose (total dosage received and timing of use (two or more years, two to seven years and more than seven years prior to index date on the risk of breast cancer. Results Overall, SSRI use was not associated with an increased risk of breast cancer regardless of our definition of cumulative use (total number of prescriptions dispensed and total dosage. In addition, our results indicate that prolonged SSRI use does not have a latent effect on breast cancer risk. Also, our findings are not suggestive of an increased risk of breast cancer with the use of individual SSRIs. Conclusions Our study improved upon most previous studies by having a longer follow-up period, a larger sample size of long-term SSRI users and consideration of risk during specific exposure time windows that take latency into account. Given the potential health benefits of using SSRIs, our results suggest that the issue of breast cancer risk may no longer be a concern for women requiring long-term SSRIs.

  17. Adrenal Insufficiency Caused by Locally Applied Glucocorticoids-Myth or Fact?

    DEFF Research Database (Denmark)

    Dinsen, Stina; Klose, Marianne; Rasmussen, Åse Krogh

    2015-01-01

    have been shown to cause adrenal suppression in 0-16% of patients. Glucocorticoid creams and nasal glucocorticoids can cause adrenal insufficiency, also when used within prescribed doses, but the frequency seems to be less than with inhaled glucocorticoids. Intraarticularly administered glucocorticoids...... can cause adrenal suppression after a single injection. The systemic effect of locally applied glucocorticoids depends on pharmacokinetic and -dynamic properties of the particular glucocorticoid as well as individual factors. Many of the symptoms in iatrogen adrenal insufficiency are unspecific...

  18. Osteoporosis inducida por glucocorticoides Glucocorticoid induced osteoporosis

    Directory of Open Access Journals (Sweden)

    R. Gutiérrez-Polo

    2003-01-01

    . Corticoid-induced osteoporosis is the main adverse event deriving from their systemic and long-term administration, being the most frequent cause of secondary osteoporosis. This implies an important health and socio-economic repercussion due to the complications it causes, such as fragility fractures, above all of vertebral origin, and the resultant functional incapacity. The bone loss is produced early, being greatest in the first few months of glucocorticoid use, in relation fundamentally to daily dose. The pathogenesis of this type of osteoporosis is multifactorial, but the inhibitory effect of corticoids on bone formation can be emphasised. The adequate management of this serious health problem requires an active attitude that is currently suboptimal. It involves similar diagnostic, preventive and therapeutic recommendations available for other, different causes of bone loss, but with certain particularities, especially including those referring to the self-management of corticosteroids. A multidisciplinary strategy is advisable, which has shown its effectiveness, mainly if it is carried out early, from the start of glucocorticoid therapy. Nevertheless, there are many questions to be clarified about aspects relating to therapy with corticosteroids in general, and to the osteoporosis caused by them in particular. What is needed is the evaluation and investigation of new treatments that will improve the effectiveness obtained with those in current use, in order to minimize the adverse consequences that glucocorticoid use has for the health of patients.

  19. Effect of low-dose glucocorticoids in septic shock%糖皮质激素治疗感染性休克的疗效

    Institute of Scientific and Technical Information of China (English)

    陈宏; 贾建国; 李非; 杨磊; 刘大川; 杨鹏; 孙家邦

    2008-01-01

    目的 探讨小剂量糖皮质激素对纠正感染性休克和改善患者预后的作用.方法 对2000年1月至2006年10月收治于首都医科大学宣武医院ICU的46例感染性休克患者进行回顾性研究.2000年1月至2002年10月收治的24例患者未接受糖皮质激素治疗,为对照组(n=24);2002年11月至2006年10月收治的22例患者接受了糖皮质激素治疗,为治疗组(n=22).除糖皮质激素应用外,两组患者在其他治疗方法上无明显差别.比较两组患者在纠正休克和转归方面的差异.结果 治疗组(72.73)在治疗第7天时休克纠正比率明显高于对照组(41.67)(P<0.05).治疗组治疗48~72 h后CRP明显低于对照组[(20.05±4.06)mg/dl vs.(23.55±4.93)mg/dl],而治疗3 d后APACHE Ⅱ也低于对照组[(16.76±4.87)vs.(21.45±4.02)].而两组患者在呼吸机治疗时间、住ICU时间、MODS发生率和死亡率方面差异无统计学意义(P>0.05).结论 对顽同性感染性休克患者应用小剂量糖皮质激素可有效地纠正休克,更早地撤离血管活性药物,并明显降低炎症反应程度,但其对患者的远期预后影响值得进一步研究.%Objective To study retrospectively the effects of low-dose glucocorticoids in outcomeof septic shock.Method The present stray was carried out by analysis of septic shock patients treated with norepinephrine or dopamine.A total of 46 patients with a confirmed diagnosis of septic shock admitted from January 2000 to October 2006 were divided into two groups:(1)ghcocorticoids treatment group(n=22),treated with glucocorticoids in addition to conventional treatment from November 2002 to October 2006;(2)conlrol group(n =24),only treated with routine treatment from January 2000 to October 2002.The differences in outcome were compared between the two groups.Results The duration of of vasopressor support was significantly shorter in treatment group com0~ed with control group.The percentage of shock reversal at 7 days was higher in

  20. Measurement of radiocesium concentration in trees using cumulative gamma radiation dose rate detection systems - A simple presumption for radiocesium concentration in living woods using glass-badge based gamma radiation dose rate detection system

    Energy Technology Data Exchange (ETDEWEB)

    Yoshihara, T.; Hashida, S.N. [Plant Molecular Biology, Laboratory of Environmental Science, Central Research Institute of Electric Power Industry (CRIEPI), 1646 Abiko, Chiba 270-1194 (Japan); Kawachi, N.; Suzui, N.; Yin, Y.G.; Fujimaki, S. [Radiotracer Imaging Gr., Quantum Beam Science Center, Japan Atomic Energy Agency (JAEA), 1233 Watanuki, Takasaki, Gunma 370-1292 (Japan); Nagao, Y.; Yamaguchi, M. [Takasaki Advanced Radiation Research Institute, Japan Atomic Energy Agency (JAEA), 1233 Watanuki, Takasaki, Gunma 370-1292 (Japan)

    2014-07-01

    Radiocesium from the severe accident at the Fukushima Dai-ichi Nuclear Power Plant on 11 March 2011 contaminates large areas. After this, a doubt for forest products, especially of mushroom, is indelible at the areas. Pruned woody parts and litters are containing a considerable amount of radiocesium, and generates a problem at incineration and composting. These mean that more attentive survey for each subject is expected; however, the present survey system is highly laborious/expensive and/or non-effective for this purpose. On the other hand, we can see a glass-badge based gamma radiation dose rate detection system. This system always utilized to detect a personal cumulative radiation dose, and thus, it is not suitable to separate a radiation from a specific object. However, if we can separate a radiation from a specific object and relate it with the own radiocesium concentration, it would enable us to presume the specific concentration with just an easy monitoring but without a destruction of the target nature and a complicated process including sampling, pre-treatment, and detection. Here, we present the concept of the measurement and results of the trials. First, we set glass-badges (type FS, Chiyoda Technol Corp., Japan) on a part of bough (approximately 10 cm in diameter) of Japanese flowering cherry trees (Prunus x yedoensis cv. Somei-Yoshino) with four different settings: A, a direct setting without any shield; B, a setting with an aluminum shield between bough and the glass-badge; C, a setting with a lead shield between bough and the glass-badge; D, a setting with a lead shield covering the glass-badge to shut the radiation from the surrounding but from bough. The deduction between the amount of each setting should separate a specific radiation of the bough from unlimited radiation from the surrounding. Even if the hourly dose rate is not enough to count the difference, a moderate cumulative dose would clear the difference. In fact, results demonstrated a

  1. Integration of kerma-area product and cumulative air kerma determination into a skin dose tracking system for fluoroscopic imaging procedures

    Science.gov (United States)

    Vijayan, Sarath; Shankar, Alok; Rudin, Stephen; Bednarek, Daniel R.

    2016-03-01

    The skin dose tracking system (DTS) that we developed provides a color-coded mapping of the cumulative skin dose distribution on a 3D graphic of the patient during fluoroscopic procedures in real time. The DTS has now been modified to also calculate the kerma area product (KAP) and cumulative air kerma (CAK) for fluoroscopic interventions using data obtained in real-time from the digital bus on a Toshiba Infinix system. KAP is the integral of air kerma over the beam area and is typically measured with a large-area transmission ionization chamber incorporated into the collimator assembly. In this software, KAP is automatically determined for each x-ray pulse as the product of the air kerma/ mAs from a calibration file for the given kVp and beam filtration times the mAs per pulse times the length and width of the beam times a field nonuniformity correction factor. Field nonuniformity is primarily the result of the heel effect and the correction factor was determined from the beam profile measured using radio-chromic film. Dividing the KAP by the beam area at the interventional reference point provides the area averaged CAK. The KAP and CAK per x-ray pulse are summed after each pulse to obtain the total procedure values in real-time. The calculated KAP and CAK were compared to the values displayed by the fluoroscopy machine with excellent agreement. The DTS now is able to automatically calculate both KAP and CAK without the need for measurement by an add-on transmission ionization chamber.

  2. Investigation of practical approaches to evaluating cumulative dose for cone beam computed tomography (CBCT) from standard CT dosimetry measurements: a Monte Carlo study

    Science.gov (United States)

    Abuhaimed, Abdullah; Martin, Colin J.; Sankaralingam, Marimuthu; Gentle, David J.

    2015-07-01

    A function called Gx(L) was introduced by the International Commission on Radiation Units and Measurements (ICRU) Report-87 to facilitate measurement of cumulative dose for CT scans within long phantoms as recommended by the American Association of Physicists in Medicine (AAPM) TG-111. The Gx(L) function is equal to the ratio of the cumulative dose at the middle of a CT scan to the volume weighted CTDI (CTDIvol), and was investigated for conventional multi-slice CT scanners operating with a moving table. As the stationary table mode, which is the basis for cone beam CT (CBCT) scans, differs from that used for conventional CT scans, the aim of this study was to investigate the extension of the Gx(L) function to CBCT scans. An On-Board Imager (OBI) system integrated with a TrueBeam linac was simulated with Monte Carlo EGSnrc/BEAMnrc, and the absorbed dose was calculated within PMMA, polyethylene (PE), and water head and body phantoms using EGSnrc/DOSXYZnrc, where the body PE body phantom emulated the ICRU/AAPM phantom. Beams of width 40-500 mm and beam qualities at tube potentials of 80-140 kV were studied. Application of a modified function of beam width (W) termed Gx(W), for which the cumulative dose for CBCT scans f (0) is normalized to the weighted CTDI (CTDIw) for a reference beam of width 40 mm, was investigated as a possible option. However, differences were found in Gx(W) with tube potential, especially for body phantoms, and these were considered to be due to differences in geometry between wide beams used for CBCT scans and those for conventional CT. Therefore, a modified function Gx(W)100 has been proposed, taking the form of values of f (0) at each position in a long phantom, normalized with respect to dose indices f 100(150)x measured with a 100 mm pencil ionization chamber within standard 150 mm PMMA phantoms, using the same scanning parameters, beam widths and positions within the phantom. f 100(150)x averages the dose resulting from

  3. Leukaemia and low dose radiation. Is there an association between leukaemia and cumulative external dose amongst the British Nuclear Fuel plc. (BNFL) workers?

    Energy Technology Data Exchange (ETDEWEB)

    McGeoghegan, D.; Binks, K. [Westlakes Scientific Consulting, Cumbria (United Kingdom)

    2000-05-01

    A detailed examination of the BNFL leukaemia data is presented, for the period 1941-1995, using the recently assembled company wide BNFL epidemiological database and the BNFL leukaemia case-control data set. The association of this occupationally exposed cohort is examined with respect to both leukaemia mortality and leukaemia morbidity. The excess relative risk for total leukaemia excluding chronic lymphatic leukaemia amongst the BNFL radiation workers was found to be 3.64 Sv{sup -1} (90% CI -0.13-11.22); for Sellafield and Springfields this figure was 7.99 Sv{sup -1} (90% CI 1.50-29.5) and -1.97 Sv{sup -1} (90% CI<-2.23-6.11) respectively. A 14-20% increase in risk is noted when dosimetry adjusted for measurement error, is used to determine the excess relative risk. The association between leukaemia and cumulative external radiation is found to be particularly associated with the Sellafield plant; the Springfields plant gave consistently negative risk estimates. (author)

  4. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation

    Science.gov (United States)

    Van Dongen, Hans P A.; Maislin, Greg; Mullington, Janet M.; Dinges, David F.

    2003-01-01

    OBJECTIVES: To inform the debate over whether human sleep can be chronically reduced without consequences, we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation. DESIGN: The chronic sleep restriction experiment involved randomization to one of three sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days. SETTING: Both experiments were conducted under standardized laboratory conditions with continuous behavioral, physiological and medical monitoring. PARTICIPANTS: A total of n = 48 healthy adults (ages 21-38) participated in the experiments. INTERVENTIONS: Noctumal sleep periods were restricted to 8 h, 6 h or 4 h per day for 14 days, or to 0 h for 3 days. All other sleep was prohibited. RESULTS: Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks. Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days, and did not significantly differentiate the 6 h and 4 h conditions. Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis--displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights. Comparison of chronic sleep restriction to total sleep deprivation showed that the latter resulted in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost. A statistical model revealed that, regardless of the mode of sleep deprivation, lapses in behavioral alertness

  5. Promoter region variation in NFE2L2 influences susceptibility to ototoxicity in patients exposed to high cumulative doses of cisplatin.

    Science.gov (United States)

    Spracklen, T F; Vorster, A A; Ramma, L; Dalvie, S; Ramesar, R S

    2016-07-26

    Ototoxicity is a disabling reaction to cisplatin chemotherapy. Much of the inter-individual variability in the development of hearing impairment among cisplatin-receiving patients has not been fully accounted for. In particular, little is known about the pharmacogenomics of cisplatin-induced ototoxicity. This study sought to investigate the role of variation in five candidate genes in a cohort of South African cancer patients. Five variants within the candidate genes were genotyped in 214 patients, of which SLC22A2 rs316019 and NFE2L2 rs6721961 associated with reduced rates of ototoxicity. In the patients who were exposed to cumulative cisplatin doses ⩾200 mg m(-)(2) (n=113), the variant rs6721961 associated with ototoxicity according to three different grading scales of hearing loss (ASHA, P=0.005; Chang, P=0.028; CTCAE, P=0.004). The NFE2L2 promotor variant rs6721961 may therefore be protective against hearing loss in cisplatin-receiving cancer patients.The Pharmacogenomics Journal advance online publication, 26 July 2016; doi:10.1038/tpj.2016.52.

  6. [Glucocorticoids in rheumatology].

    Science.gov (United States)

    Dziurla, R; Buttgereit, F

    2008-11-01

    Glucocorticoids (GC) are effective drugs which are often used in rheumatology. However, they have a considerable potential for frequent and sometimes serious side effects that restrict their use. Their mechanisms of action are either receptor dependent (specific) or independent (unspecific) on the genomic as well as the non-genomic level. Many adverse effects are predominantly caused by transactivation while the desired effects are mostly mediated by transrepression. Treatment strategies are sub-classified into low, medium, high, very high dose and pulse therapy based on criteria such as dose, indication, duration of treatment and potential risk of adverse events. The musculoskeletal, gastrointestinal, neuro-endocrino-immunological, opthalmological and neuropsychiatric systems are examples where adverse effects may occur.

  7. The Effect of Total Cumulative Dose, Number of Treatment Cycles, Interval between Injections, and Length of Treatment on the Frequency of Occurrence of Antibodies to Botulinum Toxin Type A in the Treatment of Muscle Spasticity

    Science.gov (United States)

    Bakheit, Abdel Magid O.; Liptrot, Anthea; Newton, Rachel; Pickett, Andrew M.

    2012-01-01

    A large cumulative dose of botulinum toxin type A (BoNT-A), frequent injections, a short interval between treatment cycles, and a long duration of treatment have all been suggested, but not confirmed, to be associated with a high incidence of neutralizing antibodies to the neurotoxin. The aim of this study was to investigate whether these…

  8. Analysis of bone metabolism during early stage and clinical benefits of early intervention with alendronate in patients with systemic rheumatic diseases treated with high-dose glucocorticoid: Early DIagnosis and Treatment of OsteopoRosis in Japan (EDITOR-J) study.

    Science.gov (United States)

    Tanaka, Yoshiya; Mori, Hiroko; Aoki, Takatoshi; Atsumi, Tatsuya; Kawahito, Yutaka; Nakayama, Hisanori; Tohma, Shigeto; Yamanishi, Yuji; Hasegawa, Hitoshi; Tanimura, Kazuhide; Negoro, Nobuo; Ueki, Yukitaka; Kawakami, Atsushi; Eguchi, Katsumi; Saito, Kazuyoshi; Okada, Yosuke

    2016-11-01

    We conducted a prospective multicenter study to assess early changes in the dynamics of bone metabolism in patients with systemic connective tissue diseases following commencement of high-dose glucocorticoid therapy and the benefits of early treatment with bisphosphonate and vitamin D analogue. The subjects of this randomized controlled trial were 106 female patients with systemic connective tissue diseases treated for the first time with glucocorticoids at doses equivalent to prednisolone ≥20 mg/day (age ≥ 18 years). One week after initiation of glucocorticoid therapy, patients were randomly assigned to treatment with alfacalcidol at 1 μg/day (n = 33), alendronate 35 mg/week (n = 37), and alfacalcidol plus alendronate (n = 36). The primary endpoints were changes in lumbar spine bone density at 6 months of treatment and the frequency of bone fracture at 12 months. Commencement of glucocorticoid therapy was associated with a rapid and marked bone resorption within 1 week. The combination of alfacalcidol and alendronate administered after the first week of glucocorticoid therapy halted the pathological processes affecting bone metabolism, increased bone density, and reduced the incidence of bone fracture over a period of 12 months. Taken together, the use of the combination of alfacalcidol and alendronate improved bone metabolism, increased bone density, and significantly reduced the incidence of bone fracture during 1-year high-dose glucocorticoid therapy.

  9. Cumulative radiation dose of multiple trauma patients during their hospitalization%多发伤患者住院期间X射线累积有效剂量研究

    Institute of Scientific and Technical Information of China (English)

    王志康; 孙建忠; 赵祖丹

    2012-01-01

    Objective To study the cumulative radiation dose of multiple trauma patients during their hospitalization and to analyze the dose influece factors.Methods The DLP for CT and DR were retrospectively collected from the patients during June,2009 and April,2011 at a university affiliated hospital.The cumulative radiation doses were calculated by summing typical effective doses of the anatomic regions scanned.Results The cumulative radiation doses of 113 patients were collected.The maximum,minimum and the mean values of cumulative effective doses were 153.3,16.48 mSv and(52.3 ± 26.6) mSv.Conclusions Multiple trauma patients have high cumulative radiation exposure.Therefore,the management of cumulative radiation doses should be enhanced.To establish the individualized radiation exposure archives will be helpful for the clinicians and technicians to make decision wheather to image again and how to select the imaging parameters.%目的 研究多发伤患者在院治疗期间的累积医疗X射线检查剂量,探讨其影响因素.方法 回顾性收集2009年6月至2011年4月在本院治疗患者的CT、DR检查记录,CT记录其DLP值,并用各部位转换系数算出有效剂量;DR参照以往研究各部位有效剂量数据.结果 共收集113位患者的X射线检查的累积剂量,剂量范围16.48~153.3 mSv,平均(52.3±26.6)mSv.结论 多发伤患者其累积X射线剂量处于较高的水平.应加强对医疗X射线检查的累积剂量管理,通过建立患者X射线辐射剂量档案管理可能使临床医生、检查技术员重视检查开单的选择以及检查参数的合理设置.

  10. A combined cumulative threshold spectra and digital reconstruction analysis reveal structural alterations of microglia within the prefrontal cortex following low-dose LPS administration.

    Science.gov (United States)

    Kongsui, R; Johnson, S J; Graham, B A; Nilsson, M; Walker, F R

    2015-12-01

    Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 μg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior.

  11. Catarata em corticoterapia sistêmica: prevalência e relação com tempo e dose cumulativa de glicocorticóides Corticosteroid therapy and cataract: prevalence and relation to time of use and cumulative dose

    Directory of Open Access Journals (Sweden)

    Fernanda Ziger

    2003-01-01

    Full Text Available OBJETIVO: O presente estudo teve por finalidade estudar a freqüência de catarata em pacientes reumáticos e usuários crônicos de corticóide, procurando-se correlacionar o seu aparecimento com tempo de uso, dose cumulativa total e doença de fundo. MÉTODOS: Foram estudados 27 pacientes reumáticos usuários crônicos de corticóide, com exame de lâmpada de fenda e calculado o tempo de uso e doses cumulativas de prednisona ou equivalente. RESULTADO: Encontrou-se freqüência de 18,52% de cataratas e não foi possível demonstrar correlação com dose cumulativa do medicamento (p=0,231 ou com o tipo de doença de fundo. Apesar do tempo médio de uso de corticóide ter sido maior entre os pacientes que apresentaram catarata, esta correlação não demostrou significância estatística (p=0,694. CONCLUSÃO: Os autores concluem que esta complicação é relativamente comum e que mais estudos são necessários para melhor entender o processo fisiopatológico implicado na sua formação.PURPOSE: To study cataract prevalence in rheumatic patients who used corticosteroid chronically and to correlate it with time and total corticosteroid dose as well as with the disease that required such treatment. METHODS: We studied 27 rheumatic patients regarding cataract using slit lamp and calculated the total dose of prednisone or equivalent steroids as well as the treatment time. RESULTS: We found an 18.52% prevalence and no correlation with cumulative dose (p=0.231 or with the underlying disease. Although the time of treatment was longer in the group with cataract, no statistically significant difference could be found (p=0.694. CONCLUSION: The authors conclude that cataract is a relativelly common complication of steroid use and that further studies are needed to understand the pathophysiologic process of its formation.

  12. Perioperative glucocorticoids in hip and knee surgery - benefit vs. harm?

    DEFF Research Database (Denmark)

    Lunn, T H; Kehlet, H

    2013-01-01

    with local glucocorticoid. All studies were small-sized and none sufficiently powered to meaningfully evaluate uncommon adverse events. Most of the local administration studies had poor scientific quality (high risk of bias). Due to clinical heterogeneity and poor scientific quality, no meta-analysis......Glucocorticoids are frequently used to prevent post-operative nausea and vomiting (PONV), and may be part of multimodal analgesic regimes. The objective of this review was to evaluate the overall benefit vs. harm of perioperative glucocorticoids in patients undergoing hip or knee surgery. A wide...... was performed. In conclusion, in addition to PONV reduction with low-dose systemic glucocorticoid, this review supports high-dose systemic glucocorticoid to ameliorate post-operative pain after hip and knee surgery. However, large-scale safety and dose-finding studies are warranted before final recommendations....

  13. Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4

    Directory of Open Access Journals (Sweden)

    Shin J. Lee

    2016-07-01

    Conclusions: Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies.

  14. Risk of therapy-related leukaemia and preleukaemia after Hodgkin's disease. Relation to age, cumulative dose of alkylating agents, and time from chemotherapy

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, J.; Specht, L.; Larsen, S.O.;

    1987-01-01

    .0% (SE 3.0) at 10 years after which time there were no further cases. Calculated from cessation of therapy with alkylating agents, however, the cumulative risk curve increased steeply during the first 1-2 years then gradually levelled out and no new cases were observed beyond 7 years. With a 15-year...

  15. Systematic review of the clinical effect of glucocorticoids on nonhematologic malignancy

    Directory of Open Access Journals (Sweden)

    Keith Bruce D

    2008-03-01

    Full Text Available Abstract Background Glucocorticoids are often used in the treatment of nonhematologic malignancy. This review summarizes the clinical evidence of the effect of glucocorticoid therapy on nonhematologic malignancy. Methods A systematic review of clinical studies of glucocorticoid therapy in patients with nonhematologic malignancy was undertaken. Only studies having endpoints of tumor response or tumor control or survival were included. PubMed, EMBASE, the Cochrane Register/Databases, conference proceedings (ASCO, AACR, ASTRO/ASTR, ESMO, ECCO and other resources were used. Data was extracted using a standard form. There was quality assessment of each study. There was a narrative synthesis of information, with presentation of results in tables. Where appropriate, meta-analyses were performed using data from published reports and a fixed effect model. Results Fifty four randomized controlled trials (RCTs, one meta-analysis, four phase l/ll trials and four case series met the eligibility criteria. Clinical trials of glucocorticoid monotherapy in breast and prostate cancer showed modest response rates. In advanced breast cancer meta-analyses, the addition of glucocorticoids to either chemotherapy or other endocrine therapy resulted in increased response rate, but not increased survival. In GI cancer, there was one RCT each of glucocorticoids vs. supportive care and chemotherapy +/- glucocorticoids; glucocorticoid effect was neutral. The only RCT found of chemotherapy +/- glucocorticoids, in which the glucocorticoid arm did worse, was in lung cancer. In glucocorticoid monotherapy, meta-analysis found that continuous high dose glucocorticoids had a detrimental effect on survival. The only other evidence, for a detrimental effect of glucocorticoid monotherapy, was in one of the two trials in lung cancer. Conclusion Glucocorticoid monotherapy has some benefit in breast and prostate cancer. In advanced breast cancer, the addition of glucocorticoids to other

  16. Glucocorticoid-Induced Osteoporosis

    Science.gov (United States)

    ... Cryopyrin-Associated Autoinflammatory Syndrome (CAPS) (Juvenile) Dermatomyositis (Juvenile) Familial Mediterranean Fever (Juvenile) Fibromyalgia Giant Cell Arteritis Glucocorticoid-induced Osteoperosis ...

  17. The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus

    Science.gov (United States)

    Mendoza-Pinto, Claudia; Garcia-Carrasco, Mario; Vallejo-Ruiz, Veronica; Taboada-Cole, Alejandro; Muñoz-Guarneros, Margarita; Solis-Poblano, Juan Carlos; Pezzat-Said, Elias; Aguilar-Lemarroy, Adriana; Jave-Suarez, Luis Felipe; de Lara, Luis Vazquez; Ramos-Alvarez, Gloria; Reyes-Leyva, Julio; Lopez-Colombo, Aurelio

    2013-01-01

    OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus-related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5±11.8 years and 9.7±5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2±11.2 vs. 44.2±11.5 years, respectively; p = 0.05), and patients with the virus had higher daily prednisone doses (12.8±6.8 vs. 9.7±6.7 mg, respectively; p = 0.01) and cumulative glucocorticoid doses (14.2±9.8 vs. 9.7±7.3 g, respectively; p = 0.005) compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03). In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus. PMID:24473503

  18. The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Claudia Mendoza-Pinto

    2013-12-01

    Full Text Available OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus-related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5±11.8 years and 9.7±5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2±11.2 vs. 44.2±11.5 years, respectively; p = 0.05, and patients with the virus had higher daily prednisone doses (12.8±6.8 vs. 9.7±6.7 mg, respectively; p = 0.01 and cumulative glucocorticoid doses (14.2±9.8 vs. 9.7±7.3 g, respectively; p = 0.005 compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03. In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus.

  19. Glucocorticoid feedback resistance.

    Science.gov (United States)

    De Kloet, E R; Vreugdenhil, E; Oitzl, M S; Joëls, M

    1997-01-01

    Glucocorticoid feedback resistance can be inherited or locally acquired. The implications of these two forms of resistance for disease are strikingly different. The inherited form is characterized by enhanced adrenocortical function and hypercorticism to compensate for a generalized deficit in the glucocorticoid receptor gene, but these individuals lack symptoms of Cushing's syndrome. By contrast, resistance acquired at the level of the hypothalamic corticotropin-releasing hormone (CRH) neurons is linked to hypercorticism, which is not compensatory but overexposes the rest of the body and the brain to glucocorticoids. This cell-specific glucocorticoid resistance can be acquired by genetically predisposed individuals failing to cope with (early) life events and causes enhanced vulnerability to disease-specific actions of glucocorticoids. (c) 1997, Elsevier Science Inc. (Trends Endocrinol Metab 1997; 8:26-33).

  20. Relation between treatment efficacy and cumulative dose of alpha interferon in chronic hepatitis B. European Concerted Action on Viral Hepatitis (Eurohep)

    DEFF Research Database (Denmark)

    Krogsgaard, K; Christensen, E; Bindslev, N;

    1996-01-01

    Alpha interferon (IFN) is an established treatment of chronic hepatitis B. The effect has been shown to be dose related, recommended dose regimens being associated with a doubling of the spontaneous, baseline HBeAg to anti-HBe seroconversion rate. However, the efficacy of IFN treatment in relation...

  1. Chronic Glucocorticoid Hypersecretion in Cushing's Syndrome Exacerbates Cognitive Aging

    Science.gov (United States)

    Michaud, Kathy; Forget, Helene; Cohen, Henri

    2009-01-01

    Cumulative exposure to glucocorticoid hormones (GC) over the lifespan has been associated with cognitive impairment and may contribute to physical and cognitive degeneration in aging. The objective of the present study was to examine whether the pattern of cognitive deficits in patients with Cushing's syndrome (CS), a disorder characterized by…

  2. Chronic Glucocorticoid Hypersecretion in Cushing's Syndrome Exacerbates Cognitive Aging

    Science.gov (United States)

    Michaud, Kathy; Forget, Helene; Cohen, Henri

    2009-01-01

    Cumulative exposure to glucocorticoid hormones (GC) over the lifespan has been associated with cognitive impairment and may contribute to physical and cognitive degeneration in aging. The objective of the present study was to examine whether the pattern of cognitive deficits in patients with Cushing's syndrome (CS), a disorder characterized by…

  3. Biological significance of glucocorticoid receptor beta

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Alternative splicing of the human glucocorticoid receptor (hGR) primary transcript produces two receptor isoforms, termed hGRα and hGRβ. hGRα is a ligand-activated transcription factor which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to specific glucocorticoid response element (GRE) DNA sequences. In contrast, hGRβ dose not bind glucocorticoids and is transcriptionally inactive. We demonstrate here that hGRβ inhibits the hormone-induced, hGRα-mediated stimulations of gene expression, including glucocorticoid-responsive reporter gene (cat) and endogenous p21 gene. We also demonstrate that hGRβ can inhibit hGRα-mediated regulation of proliferation and differentiation of a human osteosarcoma cell line (HOS-8603). Our studies on the expression of hGR mRNA in nephrotic syndrome patients indicate that the hGRα/hGRβ mRNA ratio in peripheral white blood cell of hormone-resistant patients is lower than that of hormone-sensitive patients and health volunteers. These results indicate that hGRβ may be a physiologically and pathophysiologically relevant endogenous inhibitor of hGRα

  4. Current concepts in glucocorticoid resistance.

    Science.gov (United States)

    Yang, Nan; Ray, David W; Matthews, Laura C

    2012-09-01

    Glucocorticoids (GCs) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to therapy. The high doses of GC required for less responsive patients means a high risk of developing very serious side effects. Variation in sensitivity between individuals can be due to a number of factors. Congenital, generalized GC resistance is very rare, and is due to mutations in the glucocorticoid receptor (GR) gene, the receptor that mediates the cellular effects of GC. A more common problem is acquired GC resistance. This localized, disease-associated GC resistance is a serious therapeutic concern and limits therapeutic response in patients with chronic inflammatory disease. It is now believed that localized resistance can be attributed to changes in the cellular microenvironment, as a consequence of chronic inflammation. Multiple factors have been identified, including alterations in both GR-dependent and -independent signaling downstream of cytokine action, oxidative stress, hypoxia and serum derived factors. The underlying mechanisms are now being elucidated, and are discussed here. Attempts to augment tissue GC sensitivity are predicted to permit safe and effective use of low-dose GC therapy in inflammatory disease.

  5. Glucocorticoid-Induced Osteoporosis

    Science.gov (United States)

    ... also is approved for treatment of glucocorticoid-induced osteoporosis. This manmade form of parathyroid hormone helps stimulate bone formation. Women planning a pregnancy should talk to their doctor about the pros ...

  6. An assessment of cumulative external doses from Chernobyl fallout for a forested area in Russia using the optically stimulated luminescence from quartz inclusions in bricks

    DEFF Research Database (Denmark)

    Ramzaev, V.; Bøtter-Jensen, Lars; Thomsen, Kristina Jørkov

    2008-01-01

    Optically stimulated luminescence (OSL) has been used for estimation of the accumulated doses in quartz inclusions obtained from two fired bricks, extracted in July 2004 from a building located in the forested surroundings of the recreational area Novie Bobovichi, the Bryansk Region, Russia...

  7. The Soft Cumulative Constraint

    CERN Document Server

    Petit, Thierry

    2009-01-01

    This research report presents an extension of Cumulative of Choco constraint solver, which is useful to encode over-constrained cumulative problems. This new global constraint uses sweep and task interval violation-based algorithms.

  8. Effects of multimodal analgesia with LowDose buprenorphine and meloxicam on fecal glucocorticoid metabolites after surgery in New Zealand white rabbits (Oryctolagus cuniculus).

    Science.gov (United States)

    Goldschlager, Gregg B; Gillespie, Virginia L; Palme, Rupert; Baxter, Mark G

    2013-09-01

    Despite the increasing use of rabbits as companion animals and models for biomedical research, rabbits have not been extensively studied to identify an efficacious postsurgical analgesic that does not cause systemic complications. The synergy of NSAID and systemic opioids is well-documented, and their combined use reduces the amount of either drug required for adequate analgesia. We measured fecal corticosterone metabolites (FCM) in rabbits after a minimally invasive vascular cut-down procedure. Rabbits received buprenorphine (0.03 mg/kg SC every 12 h for 3 d), meloxicam (0.2 mg/kg SC every 24 h for 3 d), buprenorphine-meloxicam (0.01 mg/kg-0.1 mg/kg SC every 24 h for 3 d), or a single dose of 0.5% bupivacaine (0.5 mL) infused locally at the incision site. By day 3 after surgery, buprenorphine, meloxicam, and bupivacaine groups showed elevated FCM levels, which continued to rise until day 7 and then gradually returned to baseline by day 28. In the buprenorphine-meloxicam group, FCM was relatively unchanged until day 3, when treatment was discontinued, and then began to rise. Rabbits in the buprenorphine-meloxicam group gained more weight over the 28-d study than did those in the other 3 treatment groups. This study shows that in rabbits low-dose buprenorphine administered with meloxicam effectively mitigates the FCM response that develops after surgery without the adverse effects associated with higher doses.

  9. Regulation of triglyceride metabolism by glucocorticoid receptor

    OpenAIRE

    Wang Jen-Chywan; Gray Nora E; Kuo Taiyi; Harris Charles A

    2012-01-01

    Abstract Glucocorticoids are steroid hormones that play critical and complex roles in the regulation of triglyceride (TG) homeostasis. Depending on physiological states, glucocorticoids can modulate both TG synthesis and hydrolysis. More intriguingly, glucocorticoids can concurrently affect these two processes in adipocytes. The metabolic effects of glucocorticoids are conferred by intracellular glucocorticoid receptors (GR). GR is a transcription factor that, upon binding to glucocorticoids,...

  10. Glucocorticoid Regulation of Reproduction.

    Science.gov (United States)

    Geraghty, Anna C; Kaufer, Daniela

    2015-01-01

    It is well accepted that stress, measured by increased glucocorticoid secretion, leads to profound reproductive dysfunction. In times of stress, glucocorticoids activate many parts of the fight or flight response, mobilizing energy and enhancing survival, while inhibiting metabolic processes that are not necessary for survival in the moment. This includes reproduction, an energetically costly procedure that is very finely regulated. In the short term, this is meant to be beneficial, so that the organism does not waste precious energy needed for survival. However, long-term inhibition can lead to persistent reproductive dysfunction, even if no longer stressed. This response is mediated by the increased levels of circulating glucocorticoids, which orchestrate complex inhibition of the entire reproductive axis. Stress and glucocorticoids exhibits both central and peripheral inhibition of the reproductive hormonal axis. While this has long been recognized as an issue, understanding the complex signaling mechanism behind this inhibition remains somewhat of a mystery. What makes this especially difficult is attempting to differentiate the many parts of both of these hormonal axes, and new neuropeptide discoveries in the last decade in the reproductive field have added even more complexity to an already complicated system. Glucocorticoids (GCs) and other hormones within the hypothalamic-pituitary-adrenal (HPA) axis (as well as contributors in the sympathetic system) can modulate the hypothalamic-pituitary-gonadal (HPG) axis at all levels-GCs can inhibit release of GnRH from the hypothalamus, inhibit gonadotropin synthesis and release in the pituitary, and inhibit testosterone synthesis and release from the gonads, while also influencing gametogenesis and sexual behavior. This chapter is not an exhaustive review of all the known literature, however is aimed at giving a brief look at both the central and peripheral effects of glucocorticoids on the reproductive function.

  11. Quantifying cutaneous adverse effects of systemic glucocorticoids in patients with rheumatoid arthritis: a cross-sectional cohort study.

    Science.gov (United States)

    Amann, Jonna; Wessels, Anne-Marie; Breitenfeldt, Friederike; Huscher, Dörte; Bijlsma, Johannes W J; Jacobs, Johannes W G; Buttgereit, Frank

    2017-01-01

    EULAR guidelines state that adverse effects (AEs) of glucocorticoid (GC) therapy should be considered and discussed with the patient before treatment is initiated. However, reliable quantitative data, especially on cutaneous AEs of low-to-medium dose GCs are lacking. We performed a study assessing the occurrence of cutaneous AEs of GCs and its association with current and cumulative GC doses in patients with rheumatoid arthritis (RA). In a cross-sectional study performed in 2 outpatient rheumatology centres, 381 RA patients were enrolled. They were classed into 4 groups, according their mean daily dose during the past 12 months: 0 mg (n=87), 7.5 mg (n=56) of prednisone equivalent. AEs of GC on the skin were assessed by physical examination using a predefined scoring system, and by patients' self-assessments. Data were analysed according GC dose categories and cumulative doses. Cushingoid habitus, easy bruising, skin atrophy, and impaired wound healing as reported by patients occurred significantly more frequently in those using a GC the past 12 months, compared to those not using a GC. At physicians' assessments, only Cushingoid habitus and ecchymosis were more prevalent in GC users. The prevalence of these AEs was statistically significantly positively associated with current and cumulative GC dose. There was low occurrence of abnormal stretch marks, acne, perioral dermatitis, alopecia and hirsutism, which were not correlated with GC use. Certain GC-associated cutaneous AEs are common in RA, but other AEs of GC occur infrequently at the low-to-medium GC doses used in RA.

  12. UBIQUITOUS POLLUTANTS FROM CUMULATIVE ...

    Science.gov (United States)

    The occurrence of pharmaceuticals and personal care products (PPCPS) as environmental pollutants is a multifaceted issue whose scope continues to become better delineated since the escalation of concerted attention beginning in the 1980s. PPCPs typically occur as trace environmental pollutants (primarily in surface but also in ground waters) as a result of their widespread, continuous, combined usage in a broad range of human and veterinary therapeutic activities and practices. With respect to the risk-assessment paradigm, the growing body of published work has focused primarily on the origin and occurrence of these substances. Comparatively less is known about human and ecological exposure, and even less about the known or even potential hazards associated with exposure to these anthropogenic substances, many of which are highly bioactive. The continually growing, worldwide importance of freshwater resources underscores the need for ensuring that any aggregate or cumulative impacts on water supplies and resultant potential for human or ecological exposure be minimized. This has prompted the more recent investigations on waste treatment processes for one of the major sources of environmental disposition, namely sewage. Despite the paucity of health effects data for long-term, simultaneous exposure to multiple xenobiotics (particularly PPCPS) at low doses (a major toxicological issue that can be described by the

  13. Is physiological glucocorticoid replacement important in children?

    Science.gov (United States)

    Porter, John; Blair, Joanne; Ross, Richard J

    2017-01-01

    Cortisol has a distinct circadian rhythm with low concentrations at night, rising in the early hours of the morning, peaking on waking and declining over the day to low concentrations in the evening. Loss of this circadian rhythm, as seen in jetlag and shift work, is associated with fatigue in the short term and diabetes and obesity in the medium to long term. Patients with adrenal insufficiency on current glucocorticoid replacement with hydrocortisone have unphysiological cortisol concentrations being low on waking and high after each dose of hydrocortisone. Patients with adrenal insufficiency complain of fatigue, a poor quality of life and there is evidence of poor health outcomes including obesity potentially related to glucocorticoid replacement. New technologies are being developed that deliver more physiological glucocorticoid replacement including hydrocortisone by subcutaneous pump, Plenadren, a once-daily modified-release hydrocortisone and Chronocort, a delayed and sustained absorption hydrocortisone formulation that replicates the overnight profile of cortisol. In this review, we summarise the evidence regarding physiological glucocorticoid replacement with a focus on relevance to paediatrics. PMID:27582458

  14. Cumulative mortality rates in Aedes polynesiensis after feeding on polynesian Wuchereria bancrofti carriers treated with single doses of ivermectin, diethylcarbamazine and placebo.

    Science.gov (United States)

    Cartel, J L; Sechan, Y; Spiegel, A; Nguyen, L; Barbazan, P; Martin, P M; Roux, J F

    1991-12-01

    During a therapeutic trial, batches of 672 to 1979 laboratory-bred Aedes polynesiensis, the mosquito vector of lymphatic filariasis in French Polynesia, were fed on Wuchereria bancrofti carriers one, three and six months after they had been treated with either single doses of ivermectin at 100 mcg/kg, diethylcarbamazine (DEC) at 3 and 6 mg/kg or placebo. High mortality rates were observed during the 15-day period following the blood-meal in mosquitoes fed on carriers treated with microfilaricidal drugs and were significantly higher in mosquitoes fed on carriers treated with ivermectin than in those fed on carriers treated with DEC. Though its intensity decreased with the passage of time, the phenomenon was observed in mosquitoes fed on carriers up to six months after treatment, especially in those fed on carriers treated with ivermectin. By decreasing the number of mosquitoes able to transmit the infection, this lethal effect on Ae. polynesiensis might represent an additional advantage of ivermectin in lymphatic filariasis control programs.

  15. Glucocorticoids and atrial natriuretic factor receptors on vascular smooth muscle.

    Science.gov (United States)

    Yasunari, K; Kohno, M; Murakawa, K; Yokokawa, K; Takeda, T

    1990-11-01

    The effect of glucocorticoids on the atrial natriuretic factor (ANF)-mediated formation of cyclic guanosine monophosphate (cGMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from the renal arteries of 14-week-old Wistar rats by the explant method. Micromolar concentrations of dexamethasone, given as pretreatment for 48 hours, suppressed the ANF-mediated response. The dexamethasone-induced suppression was detectable at 6 hours and reached a maximum 24 hours after administration in a dose-dependent manner. Inhibitors of protein synthesis blocked this effect of the glucocorticoid. The basal activity of guanylate cyclase in the dexamethasone-treated cells was lower than in the control cells. Other steroids having glucocorticoid action mimicked this suppression of the ANF-mediated response. This suppression was blocked by a glucocorticoid receptor antagonist. The results suggest that glucocorticoids suppress ANF-mediated cGMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis. Suppression of the ANF-mediated response may play a role in glucocorticoid-induced hypertension.

  16. New topology for soft switching converters: realization of a 2 kW converter which can operate under cumulated radiation doses comprised between 1 and 10 mega-rads; Nouvelle topologie de convertisseur a commutation douce: realisation d'un convertisseur 2 kW fonctionnant pour des doses de rayonnement cumulees comprises entre 1 et 10 Mega-rads

    Energy Technology Data Exchange (ETDEWEB)

    Marceau, M. [CEA/Saclay, Dept. d' Electronique et d' Instrumentation Nucleaire (DEIN), 91 - Gif-sur-Yvette (France); Huillet, H.; Ploquin, D. [Gaia Converter, 33 - Merignac (France)

    1998-11-01

    This paper presents a new topology of a patented power converter. This topology applies to DC-DC converters with soft switching operation. The power density reached is of about 4000 W/liter and the efficiency is greater than 90%. This converter, devoted to nuclear applications, has been dimensioned to be able to operate under cumulated radiation doses greater than 1 Mega rads. A functioning principle scheme and a brief description of the topology is reported in this short paper. (J.S.)

  17. First month prednisone dose predicts prednisone burden during the following 11 months: an observational study from the RELES cohort

    OpenAIRE

    2016-01-01

    Aim To study the influence of prednisone dose during the first month after systemic lupus erythematosus (SLE) diagnosis (prednisone-1) on glucocorticoid burden during the subsequent 11 months (prednisone-2–12). Methods 223 patients from the Registro Español de Lupus Eritematoso Sistémico inception cohort were studied. The cumulative dose of prednisone-1 and prednisone-2–12 were calculated and recoded into a four-level categorical variable: no prednisone, low dose (up to 7.5 mg/day), medium do...

  18. Glucocorticoid use and abuse in SLE.

    Science.gov (United States)

    Ruiz-Irastorza, Guillermo; Danza, Alvaro; Khamashta, Munther

    2012-07-01

    Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents. They act by two different mechanisms: the genomic and the non-genomic pathways. The genomic pathway is considered responsible for many adverse effects of GCs, most of them are time and dose dependent. Observational studies support a relationship between GCs and damage in SLE. GCs have been associated with the development of osteoporosis, osteonecrosis, cataracts, hyperglycaemia, coronary heart disease and cognitive impairment, among others. Although no clinical trial has compared high vs low doses of GCs, some studies have shown the efficacy of medium doses in severe forms of SLE. The dose below which treatment can be considered safe has not been defined, but daily doses <7.5 mg of prednisone seem to minimize adverse effects. Combination therapy with HCQ and the judicious use of immunosuppressive drugs help to keep prednisone therapy within those limits.

  19. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor

    DEFF Research Database (Denmark)

    Presman, Diego M; Ogara, M Florencia; Stortz, Martín;

    2014-01-01

    Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation wi...

  20. Population-based assessment of adverse events associated with long-term glucocorticoid use

    NARCIS (Netherlands)

    Curtis, [No Value; Westfall, AO; Allison, J; Bijlsma, JW; Freeman, A; George, [No Value; Kovac, SH; Spettell, CM; Saag, KG

    2006-01-01

    The frequency of many adverse events (AEs) associated with low-dose glucocorticoid use is unclear. We sought to determine the prevalence of glucocorticoid-associated AEs in a large US managed care population., Methods. Using linked administrative and pharmacy claims, adults receiving >= 60 days of g

  1. [The Influence of Glucocorticoids on the Healing Processes in the Gastric Mucosa].

    Science.gov (United States)

    Podvigina, T T; Filaretova, L P

    2016-01-01

    In this review, we analyzed the data of literature about the glucocorticoid influences on the gastric erosion and ulcer healing. The data show that multiple injections of glucocorticoids at pharmacological doses delay gastric erosion and ulcer healing. However, according to experimental results endogenic glucocorticoids, on the contrary, play significant role in maintenance of gastric mucosal integrity. Thus, glucocorticoids may have dual effect on healing of gastric injury: contribute to healing process or delay them. The initial glucocorticoid action is physiological and consists in a participation in healing processes what is considered as component gastroprotective action of these hormones. During a long-lasting action of glucocorticoids, the physiological effect can be transformed into pathological one, delaying erosion and ulcer healing, and this contributes to the ulcerogenic action of glucocorticods.

  2. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol

    Energy Technology Data Exchange (ETDEWEB)

    Stojanov, Dragan A. [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Clinical Center Nis, Center for Radiology, Nis (Serbia); Vojinovic, Slobodan; Ljubisavljevic, Srdjan [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Clinic for Neurology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-03-15

    To evaluate correlation between cumulative dose of gadobutrol and signal intensity (SI) within dentate nucleus and globus pallidus on unenhanced T1-weighted images in patients with relapsing-remitting multiple sclerosis (RRMS). Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios, and renal and liver functions, were evaluated after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. We compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections. Globus pallidus-to-thalamus (p = 0.025) and dentate nucleus-to-pons (p < 0.001) SI ratios increased after multiple gadobutrol administrations, correlated with the number of administrations (ρ = 0.263, p = 0.046, respectively) and depended on the length of administration (p = 0.017, p = 0.037, respectively). Patients receiving gadobutrol at 27 weeks showed the greatest increase in both SI ratios (p = 0.006; p = 0.014, respectively, versus 96-98 weeks). GGT increased at the end of the study (p = 0.004). In patients with RRMS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period caused greater SI increase. (orig.)

  3. Interaction of glucocorticoids with macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Werb, Z.; Foley, R.; Munck, A.

    1978-01-01

    The mononuclear phagocyte system plays a central role in mediating host responses in inflammation. Glucocorticoids have anti-inflammatory actions that may be of considerable importance in the therapeutic effects of these agents in chronic inflammation; it is possible that some of these effects are mediated through direct hormonal action on macrophages. Although the site of action of the glucocorticoids on macrophages has not been established, it has been shown that in many other glucocorticoid target systems the effects of glucocorticoids are mediated by specific macromolecular binding proteins, referred to as receptors. In this study we have established that monocytes and macophages contain saturable glucocorticoid-binding proteins, with specificity of binding for cortisol, corticosterone, and related synthetic steroids such as dexamethasone, and that they have dissociation constants for binding within physiological ranges.

  4. Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis

    NARCIS (Netherlands)

    Banciu, M.

    2007-01-01

    Glucocorticoids (GC) have inhibitory actions on solid tumor growth due to suppressive effects on tumor angiogenesis and inflammation. When evaluating the preclinical studies on solid tumor growth inhibition, it appears that GC-induced antitumor effects are achieved by using substantially higher dose

  5. Cumulative fatigue damage models

    Science.gov (United States)

    Mcgaw, Michael A.

    1988-01-01

    The problem of calculating expected component life under fatigue loading conditions is complicated by the fact that component loading histories contain, in many cases, cyclic loads of widely varying amplitudes. In such a case a cumulative damage model is required, in addition to a fatigue damage criterion, or life relationship, in order to compute the expected fatigue life. The traditional cumulative damage model used in design is the linear damage rule. This model, while being simple to use, can yield grossly unconservative results under certain loading conditions. Research at the NASA Lewis Research Center has led to the development of a nonlinear cumulative damage model, named the double damage curve approach (DDCA), that has greatly improved predictive capability. This model, which considers the life (or loading) level dependence of damage evolution, was applied successfully to two polycrystalline materials, 316 stainless steel and Haynes 188. The cumulative fatigue behavior of the PWA 1480 single-crystal material is currently being measured to determine the applicability of the DDCA for this material.

  6. [Systemic glucocorticoid therapy: associated measures].

    Science.gov (United States)

    Sailler, L; Pugnet, G; Arlet, P

    2013-05-01

    Long-term treatment with glucocorticoids results in many adverse effects. Prevention of osteoporosis is well codified, but prevention of other adverse effects is not. If there is some consensus on the prevention of glucocorticoid-induced adverse events, there are also many habits since interventional studies are lacking. A low caloric and low carbohydrate diet as well as a regular physical training are certainly necessary to avoid lipodystrophy, weight gain and diabetes mellitus. Some patients benefit from the repeated intervention of a dietetic or nutrition specialist. Physical training is often neglected though it is efficacious to limit severity of glucocorticoid-induced myopathy and probably to reduce vascular risk. Low sodium intake has no effect on lipodystrophy and its efficacy to prevent hypertension is doubtful. Benzodiazepines may be useful against anxiety, insomnia and nervousness when these symptoms are cumbersome. Anti-ulcer drugs are generally not indicated because glucocorticoids are not ulcerogenic. Hypokaliemia rarely occurs, so we prefer controlling serum potassium level 1 and 3 months after glucocorticoid initiation rather than systematically prescribe potassium supplementation. Patients on glucocorticoids are at increased risk for cardiovascular events. Due to the lack of studies specific to patients on long-term glucocorticoid therapy, the rules for the prescription of statins are the same as in the general population. There is no known prevention for cutaneous atrophy. However, use of adhesive tape should be strictly avoided when skin atrophy is severe. Prevention of infections is developed elsewhere.

  7. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

    Magnussen, Helgo; Disse, Bernd; Rodriguez-Roisin, Roberto

    2014-01-01

    BACKGROUND: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchod......BACKGROUND: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long......-acting bronchodilators has not been fully explored. METHODS: In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid...... fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric...

  8. Cumulative radiation exposure in children with cystic fibrosis.

    LENUS (Irish Health Repository)

    O'Reilly, R

    2010-02-01

    This retrospective study calculated the cumulative radiation dose for children with cystic fibrosis (CF) attending a tertiary CF centre. Information on 77 children with a mean age of 9.5 years, a follow up time of 658 person years and 1757 studies including 1485 chest radiographs, 215 abdominal radiographs and 57 computed tomography (CT) scans, of which 51 were thoracic CT scans, were analysed. The average cumulative radiation dose was 6.2 (0.04-25) mSv per CF patient. Cumulative radiation dose increased with increasing age and number of CT scans and was greater in children who presented with meconium ileus. No correlation was identified between cumulative radiation dose and either lung function or patient microbiology cultures. Radiation carries a risk of malignancy and children are particularly susceptible. Every effort must be made to avoid unnecessary radiation exposure in these patients whose life expectancy is increasing.

  9. Cumulative Timers for Microprocessors

    Science.gov (United States)

    Battle, John O.

    2007-01-01

    It has been proposed to equip future microprocessors with electronic cumulative timers, for essentially the same reasons for which land vehicles are equipped with odometers (total-distance-traveled meters) and aircraft are equipped with Hobbs meters (total-engine-operating time meters). Heretofore, there has been no way to determine the amount of use to which a microprocessor (or a product containing a microprocessor) has been subjected. The proposed timers would count all microprocessor clock cycles and could only be read by means of microprocessor instructions but, like odometers and Hobbs meters, could never be reset to zero without physically damaging the chip.

  10. Cumulative Vehicle Routing Problems

    OpenAIRE

    Kara, &#;mdat; Kara, Bahar Yeti&#;; Yeti&#;, M. Kadri

    2008-01-01

    This paper proposes a new objective function and corresponding formulations for the vehicle routing problem. The new cost function defined as the product of the distance of the arc and the flow on that arc. We call a vehicle routing problem with this new objective function as the Cumulative Vehicle Routing Problem (CumVRP). Integer programming formulations with O(n2) binary variables and O(n2) constraints are developed for both collection and delivery cases. We show that the CumVRP is a gener...

  11. Glucocorticoids, chronic stress, and obesity.

    Science.gov (United States)

    Dallman, Mary F; Pecoraro, Norman C; La Fleur, Susanne E; Warne, James P; Ginsberg, Abigail B; Akana, Susan F; Laugero, Kevin C; Houshyar, Hani; Strack, Alison M; Bhatnagar, Seema; Bell, Mary E

    2006-01-01

    Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a chronic stressor, the steroids act in brain in a feed-forward fashion to recruit a stress-response network that biases ongoing autonomic, neuroendocrine, and behavioral outflow as well as responses to novel stressors. We review evidence for the role of glucocorticoids in activating the central stress-response network, and for mediation of this network by corticotropin-releasing factor (CRF). We briefly review the effects of CRF and its receptor antagonists on motor outflows in rodents, and examine the effects of glucocorticoids and CRF on monoaminergic neurons in brain. Corticosteroids stimulate behaviors that are mediated by dopaminergic mesolimbic "reward" pathways, and increase palatable feeding in rats. Moreover, in the absence of corticosteroids, the typical deficits in adrenalectomized rats are normalized by providing sucrose solutions to drink, suggesting that there is, in addition to the feed-forward action of glucocorticoids on brain, also a feedback action that is based on metabolic well being. Finally, we briefly discuss the problems with this network that normally serves to aid in responses to chronic stress, in our current overindulged, and underexercised society.

  12. Glucocorticoid programming of neuroimmune function.

    Science.gov (United States)

    Walker, David J; Spencer, Karen A

    2017-07-17

    Throughout life physiological systems strive to maintain homeostasis and these systems are susceptible to exposure to maternal or environmental perturbations, particularly during embryonic development. In some cases, these perturbations may influence genetic and physiological processes that permanently alter the functioning of these physiological systems; a process known as developmental programming. In recent years, the neuroimmune system has garnered attention for its fundamental interactions with key hormonal systems, such as the hypothalamic pituitary adrenal (HPA) axis. The ultimate product of this axis, the glucocorticoid hormones, play a key role in modulating immune responses within the periphery and the CNS as part of the physiological stress response. It is well-established that elevated glucocorticoids induced by developmental stress exert profound short and long-term physiological effects, yet there is relatively little information of how these effects are manifested within the neuroimmune system. Pre and post-natal periods are prime candidates for manipulation in order to uncover the physiological mechanisms that underlie glucocorticoid programming of neuroimmune responses. Understanding the potential programming role of glucocorticoids may be key in uncovering vulnerable windows of CNS susceptibility to stressful experiences during embryonic development and improve our use of glucocorticoids as therapeutics in the treatment of neurodegenerative diseases. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  13. Examination of Glucocorticoid Treatment on Bone Marrow Stroma: Implications for Bone Disease and Applied Bone Regeneration

    OpenAIRE

    Porter, Ryan Michael

    2002-01-01

    Long-term exposure to pharmacological doses of glucocorticoids has been associated with the development of osteopenia and avascular necrosis. Bone loss may be partially attributed to a steroid-induced decrease in the osteoblastic differentiation of multipotent progenitor cells found in the bone marrow. In order to determine if there is a change in the osteogenic potential of the bone marrow stroma following glucocorticoid treatment, Sprague-Dawley rats were administered methylprednisolone f...

  14. Cumulative environmental effects. Summary

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-07-01

    This report presents a compilation of knowledge about the state of the environment and human activity in the Norwegian part of the North Sea and Skagerrak. The report gives an overview of pressures and impacts on the environment from normal activity and in the event of accidents. This is used to assess the cumulative environmental effects, which factors have most impact and where the impacts are greatest, and to indicate which problems are expected to be most serious in the future. The report is intended to provide relevant information that can be used in the management of the marine area in the future. It also provides input for the identification of environmental targets and management measures for the North Sea and Skagerrak.(Author)

  15. Suppressive effect of glucocorticoids on TNF-alpha production is associated with their clinical effect in multiple sclerosis.

    NARCIS (Netherlands)

    Winsen, L.M.L.; Polman, C.H.; Dijkstra, C.D.; Tilders, F.J.H.; Uitdehaag, B.M.J.

    2010-01-01

    A reduced sensitivity to glucocorticoids can affect the clinical effect of treatment with high-dose intravenous methylprednisolone in multiple sclerosis. We prospectively studied 27 multiple sclerosis patients who were treated with intravenous methylprednisolone. Before and after treatment in vitro

  16. Suppressive effect of glucocorticoids on TNF-alpha production is associated with their clinical effect in multiple sclerosis.

    NARCIS (Netherlands)

    Winsen, L.M.L.; Polman, C.H.; Dijkstra, C.D.; Tilders, F.J.H.; Uitdehaag, B.M.J.

    2010-01-01

    A reduced sensitivity to glucocorticoids can affect the clinical effect of treatment with high-dose intravenous methylprednisolone in multiple sclerosis. We prospectively studied 27 multiple sclerosis patients who were treated with intravenous methylprednisolone. Before and after treatment in vitro

  17. Glucocorticoids and nervous system plasticity

    Institute of Scientific and Technical Information of China (English)

    Kathryn M Madalena; Jessica K Lerch

    2016-01-01

    Glucocorticoid and glucocorticoid receptor (GC/GR) interactions alter numerous aspects of neuronal function. These consequences (e.g., anti-inlfammatoryvs. pro-inlfammatory) can vary depending on the duration of GC exposure or central nervous system (CNS) injury model. In this review we discuss how GC/GR interactions impact neuronal recovery after a central or peripheral nerve injury and discuss how GC exposure duration can produce divergent CNS neuronal growth responses. Finally we consider how new ifndings on gender speciifc immune cell responses after a nerve injury could intersect with GC/GR interactions to impact pain processing.

  18. Is There a Renaissance of Glucocorticoids in Rheumatoid Arthritis?

    Science.gov (United States)

    Kirwan, J R; Gunasekera, Wma

    2017-08-07

    The first therapeutic use of glucocorticoids was in a patient with severe rheumatoid arthritis and the symptomatic benefit was astounding. Adverse effects from increasingly large doses led to them being overshadowed, dismissed as inappropriate treatment, and ignored for 20 years - but in the last 2 decades, the accumulating evidence and clinical practice suggest there is a justified renaissance in their use as a first-line treatment. © 2017 ASCPT.

  19. Maintenance hemodialysis patients have high cumulative radiation exposure.

    LENUS (Irish Health Repository)

    Kinsella, Sinead M

    2010-10-01

    Hemodialysis is associated with an increased risk of neoplasms which may result, at least in part, from exposure to ionizing radiation associated with frequent radiographic procedures. In order to estimate the average radiation exposure of those on hemodialysis, we conducted a retrospective study of 100 patients in a university-based dialysis unit followed for a median of 3.4 years. The number and type of radiological procedures were obtained from a central radiology database, and the cumulative effective radiation dose was calculated using standardized, procedure-specific radiation levels. The median annual radiation dose was 6.9 millisieverts (mSv) per patient-year. However, 14 patients had an annual cumulative effective radiation dose over 20 mSv, the upper averaged annual limit for occupational exposure. The median total cumulative effective radiation dose per patient over the study period was 21.7 mSv, in which 13 patients had a total cumulative effective radiation dose over 75 mSv, a value reported to be associated with a 7% increased risk of cancer-related mortality. Two-thirds of the total cumulative effective radiation dose was due to CT scanning. The average radiation exposure was significantly associated with the cause of end-stage renal disease, history of ischemic heart disease, transplant waitlist status, number of in-patient hospital days over follow-up, and death during the study period. These results highlight the substantial exposure to ionizing radiation in hemodialysis patients.

  20. 不同剂量糖皮质激素在急性低频下降型感音神经性聋治疗中的疗效差异%Outcome in patients with acute low-tone sensorineural hearing loss by administration of different doses of glucocorticoids

    Institute of Scientific and Technical Information of China (English)

    惠莲; 于刚; 杨宁; 姜学钧

    2012-01-01

    Objective: Aimed to compare the outcome in patients with acute low-tone sensorineural hearing loss (ALHL) treated with different doses of glucocorticoids. Method: Fifty-four ALHL patients were randomly divided into no-prednisone group(n=: ten) , low-dose prednisone groupCn = 22) and high-dose prednisone group(n = 22). AH patients were treated for ten days and followed up for six months from the initial examination. Result;The cure rates (complete recovery) were 30. 0%, 59. 1%. 90. 9% respectively and the improved rates (complete recovery and partial recovery) were 40.0%, 86.4%. 95.5% respectively in the three groups of no prednisone group, low-dose prednisone group and high-dose prednisone group. The low-dose prednisone group therapy for ALHL showed significant improved rates than the no prednisone group(P<0. 05). The high-dose prednisone group therapy for ALHL showed significant cure rates than the low-dose prednisone group (P<0. 05). Conclusion; High-dose glucocorticoids is more effective than low dose. It is suggested that the etiology of ALHL is related with both an en-dolymphatic hydrops and an autoimmunological mechanism.%目的:探讨不同剂量糖皮质激素在治疗急性低频下降型感音神经性聋(ALHL)中的疗效差异.方法:选取54例(54耳)ALHL患者,随机分为无泼尼松组(10例)、低剂量泼尼松组(22例)和高剂量泼尼松组(22例),治疗10d,并随访6个月.结果:无泼尼松组、低剂量泼尼松组和高剂量泼尼松组痊愈率分别为30.0%、59.1%、90.9%,高、低剂量组比较差异有统计学意义(P<0.05);改善率分别为40.0%、86.4%、95.5%,低剂量、高剂量泼尼松组与无泼尼松组比较均差异有统计学意义(均P<0.05).结论:用糖皮质激素治疗ALHL疗效显著,高剂量优于低剂量,提示该病与内淋巴水肿和患者自身免疫机制可能相关.

  1. Glucocorticoids and dopamine-1 receptors on vascular smooth muscle cells.

    Science.gov (United States)

    Yasunari, K; Kohno, M; Balmforth, A; Murakawa, K; Yokokawa, K; Kurihara, N; Takeda, T

    1989-06-01

    The effect of glucocorticoids on the dopamine (DA)-mediated cyclic adenosine monophosphate (cAMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from renal arteries of 14-week-old Wistar-Kyoto rats by explant method. Micromolar concentrations of dexamethasone (DEX) pretreatment for 48 hours potentiated DA-mediated response without any change of affinity constant. However, micromolar concentrations of aldosterone pretreatment for 48 hours had almost no effect on DA-mediated response. The DEX-induced facilitation began at 6 hours and reached maximum at 24 hours after DEX administration in a dose-dependent manner. Inhibitors of protein and RNA synthesis blocked this glucocorticoid effect. The basal activity of adenylate cyclase in DEX-treated cells was twofold higher than that in control cells. Treatment of VSMC with DEX increased cholera toxin-stimulated and forskolin-stimulated adenylate cyclase activity. However, pertussis toxin treatment did not augment or reduce the effect of DEX treatment. These results suggest that glucocorticoids increase DA-mediated cAMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis and that the activation of the catalytic unit may play some role in this facilitation.

  2. Repetitive prenatal glucocorticoids increase lung endothelial nitric oxide synthase expression in ovine fetuses delivered at term.

    Science.gov (United States)

    Grover, T R; Ackerman, K G; Le Cras, T D; Jobe, A H; Abman, S H

    2000-07-01

    Antenatal administration of glucocorticoids has been shown to improve postnatal lung function after preterm birth in the ovine fetus. Mechanisms of steroid-induced lung maturation include increased surfactant production and altered parenchymal lung structure. Whether steroid treatment also affects lung vascular function is unclear. Because nitric oxide contributes to the fall in pulmonary vascular resistance at birth, we hypothesized that the improvement of postnatal lung function of preterm lambs after treatment with prenatal glucocorticoids may be in part caused by an increase in endothelial nitric oxide synthase (eNOS) activity. To determine whether glucocorticoid treatment increases lung eNOS expression, we measured eNOS protein content by Western blot analysis of distal lung homogenates and immunostaining of formalin-fixed lungs from ovine fetuses delivered at preterm and term gestation after prenatal administration of glucocorticoids. Treatment protocols were followed in which ewes were treated with intramuscular betamethasone (0.5 mg/kg) at single or multiple doses at weekly intervals, and fetuses were delivered at 125, 135, or 145 d gestation. All groups were compared with saline-treated controls. Western blot analysis of whole lung homogenates demonstrated a 4-fold increase in eNOS protein content in lambs treated with repetitive doses of glucocorticoids and delivery at term (145 d; p preterm ages (125 and 135 d). Immunostaining showed eNOS predominantly in the vascular endothelium in all vessel sizes. Pattern of staining was not altered by treatment with antenatal glucocorticoids. We conclude that maternal treatment with glucocorticoids increases lung eNOS content after multiple doses and delivery at term gestation. We speculate that antenatal glucocorticoids may up-regulate eNOS but that the timing and duration of steroid administration appears to be critical to this response.

  3. Overexpression of Glucocorticoid Receptor β Enhances Myogenesis and Reduces Catabolic Gene Expression

    Directory of Open Access Journals (Sweden)

    Terry D. Hinds

    2016-02-01

    Full Text Available Unlike the glucocorticoid receptor α (GRα, GR β (GRβ has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GRα as the mediator of glucocorticoid-induced skeletal muscle loss. Because GRβ causes glucocorticoid resistance, targeting GRβ may be beneficial in impairing muscle loss as a result of GRα activity. The purpose of this study was to determine how the overexpression of GRβ affects myotube formation and dexamethasone (Dex responsiveness. We measured GR isoform expression in C2C12 muscle cells in response to Dex and insulin, and through four days of myotube formation. Next, lentiviral-mediated overexpression of GRβ in C2C12 was performed, and these cells were characterized for cell fusion and myotube formation, as well as sensitivity to Dex via the expression of ubiquitin ligases. GRβ overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GRβ overexpressing myotubes had an increased fusion index. Myotubes overexpressing GRβ had lower forkhead box O3 (Foxo3a mRNA levels and a blunted muscle atrophy F-box/Atrogen-1 (MAFbx and muscle ring finger 1 (MuRF1 response to Dex. We showed that GRβ may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GRβ levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids.

  4. Epigenetic programming by stress and glucocorticoids along the human lifespan.

    Science.gov (United States)

    Zannas, A S; Chrousos, G P

    2017-03-14

    Psychosocial stress triggers a set of behavioral, neural, hormonal, and molecular responses that can be a driving force for survival when adaptive and time-limited, but may also contribute to a host of disease states if dysregulated or chronic. The beneficial or detrimental effects of stress are largely mediated by the hypothalamic-pituitary axis, a highly conserved neurohormonal cascade that culminates in systemic secretion of glucocorticoids. Glucocorticoids activate the glucocorticoid receptor, a ubiquitous nuclear receptor that not only causes widespread changes in transcriptional programs, but also induces lasting epigenetic modifications in many target tissues. While the epigenome remains sensitive to stressors throughout life, we propose two key principles that may govern the epigenetics of stress and glucocorticoids along the lifespan: first, the presence of distinct life periods, during which the epigenome shows heightened plasticity to stress exposure, such as in early development and at advanced age; and, second, the potential of stress-induced epigenetic changes to accumulate throughout life both in select chromatin regions and at the genome-wide level. These principles have important clinical and translational implications, and they show striking parallels with the existence of sensitive developmental periods and the cumulative impact of stressful experiences on the development of stress-related phenotypes. We hope that this conceptual mechanistic framework will stimulate fruitful research that aims at unraveling the molecular pathways through which our life stories sculpt genomic function to contribute to complex behavioral and somatic phenotypes.Molecular Psychiatry advance online publication, 14 March 2017; doi:10.1038/mp.2017.35.

  5. Glucocorticoids in early rheumatoid arthritis

    NARCIS (Netherlands)

    Everdingen, Amalia A. van

    2002-01-01

    For 50 years, glucocorticoids (GC) are used for symptomatic treatment of rheumatoid arthritis (RA). In the last decade, results from clinical studies of treatment with GC as additional therapy to long-acting antirheumatic drugs in patients with early RA suggested also disease-modifying properties of

  6. Glucocorticoid programming of intrauterine development.

    Science.gov (United States)

    Fowden, A L; Valenzuela, O A; Vaughan, O R; Jellyman, J K; Forhead, A J

    2016-07-01

    Glucocorticoids (GCs) are important environmental and maturational signals during intrauterine development. Toward term, the maturational rise in fetal glucocorticoid receptor concentrations decreases fetal growth and induces differentiation of key tissues essential for neonatal survival. When cortisol levels rise earlier in gestation as a result of suboptimal conditions for fetal growth, the switch from tissue accretion to differentiation is initiated prematurely, which alters the phenotype that develops from the genotype inherited at conception. Although this improves the chances of survival should delivery occur, it also has functional consequences for the offspring long after birth. Glucocorticoids are, therefore, also programming signals that permanently alter tissue structure and function during intrauterine development to optimize offspring fitness. However, if the postnatal environmental conditions differ from those signaled in utero, the phenotypical outcome of early-life glucocorticoid receptor overexposure may become maladaptive and lead to physiological dysfunction in the adult. This review focuses on the role of GCs in developmental programming, primarily in farm species. It examines the factors influencing GC bioavailability in utero and the effects that GCs have on the development of fetal tissues and organ systems, both at term and earlier in gestation. It also discusses the windows of susceptibility to GC overexposure in early life together with the molecular mechanisms and long-term consequences of GC programming with particular emphasis on the cardiovascular, metabolic, and endocrine phenotype of the offspring.

  7. Mode of Glucocorticoid Actions in Airway Disease

    Directory of Open Access Journals (Sweden)

    Kazuhiro Ito

    2006-01-01

    Full Text Available Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5% of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR, which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.

  8. Curative effect of various doses of glucocorticoid on children inphase 2 of hand-foot-mouth disease%不同剂量糖皮质激素治疗小儿重症手足口病2期的疗效观察

    Institute of Scientific and Technical Information of China (English)

    樊婷婷; 潘家华

    2012-01-01

    Objective To discuss the therapeutic effect of 3 doses glucocorticoid impaction in the treatment of hand-foot-mouth disease phase 2. Methods The sick children with HFMD of neurological involvement hospitalized from May to July in 2011 were enrolled into the study. All cases received ribavirin and therapies based on their symptoms, while 33 cases received high dose methylprednisolone 10 ~ 15 mg · Kg-1 · D-1 ,24 cases received small methylprednisolone 1 ~2 mg · Kg-1 · D-1 ,and another 24 cases received no methylprednisolone. The curative effect of the three groups were investigated. Results The CNS involvement duration , time of staying in hospital in 3 groups were not significantly different ( P > 0. 05 ). But the febrile duration is shorter in the non- hormone group than those of other groups,which demonstrated a significant difference ( P <0.05 ). Eighty-one recruited cased with HFMD of neurological involvement were recovered, and no cases developed into neurogenic pulmonary edema or congestive heart failure during the treatment. Conclusion Small dose glucocorticoid can reduce the fever duration, which lightens the suffering of sick children and anxiety of parents. But glucocorticoid in the therapy of HFMD phase 2 can not shorten the course and improves prognosis.%目的 探讨不同剂量静脉注射糖皮质激素治疗小儿重症手足口病2期的疗效.方法 以2011年5月~7月确诊累及神经系统的手足口病重症患儿为研究对象,回顾性分析全部患儿在利巴韦林10 mg·kg-1·d-1抗病毒及对症支持治疗的基础上,加用不同剂量甲基强的松龙:大剂量组(A组)10~15 mg·kg-1·d-1;小剂量组(B组) 1~2 mg·kg-1·d-1;无激素使用组(C组);比较三组临床治疗效果.结果 三组患儿神经系统受累时间、住院天数差异无统计学意义(P>0.05).无激素使用组(C组)发热持续时间比激素使用组(A、B组)长,差异有统计学意义(P<0.05),但A、B组间差异无统计学意义(P>0

  9. Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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    Ricardo P. P. Moreira

    2011-01-01

    Full Text Available INTRODUCTION: 21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed. OBJECTIVE: The present study aimed to evaluate the association between polymorphic variants involved inglucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients. METHODS: We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels. RESULTS: The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19%, 11.3% and 3.8% of the patients, respectively. The mean ± SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9 ± 0.8 and 19.5 ± 3.2 mg/m²/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose. CONCLUSION: Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed, the CYP3A7*1C allele accounted for 20% of the variability in the cortisone acetate dose. The analysis of genes involved in glucocorticoid metabolism may be useful in the optimization of treatment of 21-hydroxylase deficiency.

  10. Aging, glucocorticoids and developmental programming.

    Science.gov (United States)

    Zambrano, E; Reyes-Castro, L A; Nathanielsz, P W

    2015-06-01

    Glucocorticoids are pleiotropic regulators of multiple cell types with critical roles in physiological systems that change across the life-course. Although glucocorticoids have been associated with aging, available data on the aging trajectory in basal circulating glucocorticoids are conflicting. A literature search reveals sparse life-course data. We evaluated (1) the profile of basal circulating corticosterone across the life-course from weaning (postnatal day-PND 21), young adult PND 110, adult PND 450, mature adult PND 650 to aged phase PND 850 in a well-characterized homogeneous rat colony to determine existence of significant changes in trajectory in the second half of life; (2) sex differences; and (3) whether developmental programming of offspring by exposure to maternal obesity during development alters the later-life circulating corticosterone trajectory. We identified (1) a fall in corticosterone between PND 450 and 650 in both males and females (p point data set, corticosterone fell at a similar age but from higher levels in male and female offspring of obese mothers. In all four groups studied, there was a second half of life fall in corticosterone. Higher corticosterone levels in offspring of obese mothers may play a role in their shorter life-span, but the age-associated fall occurs at a similar time to control offspring. Although even more life-course time-points would be useful, a five life-course time-point analysis provides important new information on normative and programmed aging of circulating corticosterone.

  11. Dopamine DA1 receptors on vascular smooth muscle cells are regulated by glucocorticoid and sodium chloride.

    Science.gov (United States)

    Yasunari, K; Kohno, M; Yokokawa, K; Horio, T; Takeda, T

    1994-09-01

    The modulation of dopamine DA1 receptors of cultured rat renal arterial smooth muscle cells by glucocorticoid and sodium chloride was studied. At a concentration of 10 nM, the synthetic glucocorticoid dexamethasone increased maximum receptor binding but had no effect on the dissociation constant. However, the maximum binding of [3H]Sch-23390 in cells treated with 100 mM sodium chloride did not change. However, the dissociation constant for DA1 receptor was increased by adding sodium chloride. The glucocorticoid effect on DA1 of arterial smooth muscle cells became apparent after hours of incubation in the presence of the steroid and was significantly inhibited by cycloheximide (10 micrograms/ml) or by the glucocorticoid receptor antagonist RU-38486, indicating that the effect required protein synthesis through glucocorticoid receptors. Treatment of cells with 1 microM dexamethasone for 24 h increased basal and DA1-stimulated adenylate cyclase activity. Basal adenylate cyclase was decreased by sodium chloride in a dose-dependent manner. These results suggest differential control of DA1 receptors on vascular smooth muscle cells by glucocorticoid or sodium chloride.

  12. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells

    NARCIS (Netherlands)

    S.W. Paugh (Steven); E.J. Bonten (Erik J.); D. Savic (Daniel); L.B. Ramsey (Laura B.); W.E. Thierfelder (William E.); P. Gurung (Prajwal); R.K.S. Malireddi (R. K. Subbarao); M. Actis (Marcelo); A. Mayasundari (Anand); J. Min (Jaeki); D.R. Coss (David R.); L.T. Laudermilk (Lucas T.); J.C. Panetta (John); J.R. McCorkle (J. Robert); Y. Fan (Yiping); K.R. Crews (Kristine R.); G. Stocco (Gabriele); M.R. Wilkinson (Mark R.); A.M. Ferreira (Antonio M.); C. Cheng (Cheng); W. Yang (Wenjian); S.E. Karol (Seth E.); C.A. Fernandez (Christian A.); B. Diouf (Barthelemy); C. Smith (Colton); J.K. Hicks (J Kevin); A. Zanut (Alessandra); A. Giordanengo (Audrey); D.J. Crona; J.J. Bianchi (Joy J.); L. Holmfeldt (Linda); C.G. Mullighan (Charles); M.L. den Boer (Monique); R. Pieters (Rob); S. Jeha (Sima); T.L. Dunwell (Thomas L.); F. Latif (Farida); D. Bhojwani (Deepa); W.L. Carroll (William L.); C.-H. Pui (Ching-Hon); R.M. Myers (Richard M.); R.K. Guy (R Kiplin); T.-D. Kanneganti (Thirumala-Devi); M.V. Relling (Mary); W.E. Evans (William)

    2015-01-01

    textabstractGlucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia ce

  13. Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL

    NARCIS (Netherlands)

    Tissing, Wim J. E.; Meijerink, Jules P. P.; Brinkhof, Bas; Broekhuis, Mathilde J. C.; Menezes, Renee X.; den Boer, Monique L.; Pieters, Rob

    2006-01-01

    Glucocorticoid (GC) resistance is an adverse prognostic factor in childhood acute lymphoblastic leukemia (ALL), but little is known about causes of GC resistance. Up-regulation of the glucocorticoid receptor (GR) has been suggested as an essential step to the induction of apoplosis in leukemic cells

  14. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    multifactorial, and likely due to disease, as well as the two study drugs enzalutamide and mifepristone . from There have been no dose limiting toxicities ...AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined

  15. Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model.

    Science.gov (United States)

    Liu, Chengcheng; Janke, Laura J; Kawedia, Jitesh D; Ramsey, Laura B; Cai, Xiangjun; Mattano, Leonard A; Boyd, Kelli L; Funk, Amy J; Relling, Mary V

    2016-01-01

    Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.

  16. Pharmacology of glucocorticoids in rheumatoid arthritis

    NARCIS (Netherlands)

    Spies, Cornelia M.; Bijlsma, Johannes W. J.; Burmester, Gerd-Ruediger; Buttgereit, Frank

    2010-01-01

    Glucocorticoids (GCs) provide one of the most effective treatments for rheumatoid arthritis (RA); however, their long-term use is marred by undesired side effects. Increased understanding of the mechanisms of glucocorticoid action enables the development of novel drugs, such as SEGRAs or liposomal g

  17. Glucocorticoid pulsatility : implications for brain functioning

    NARCIS (Netherlands)

    Sarabdjitsingh, Ratna Angela

    2010-01-01

    Pronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body’s major neuroendocrine axes, were already demonstrated several decades ago. Until now, the clinical relevance of the pulsatile nature of glucocorticoids

  18. Mineral bone density comparative assessment in patients with systemic lupus erythematosus treated and not treated with glucocorticoids

    Directory of Open Access Journals (Sweden)

    L A Archakova

    2004-01-01

    Full Text Available Objective. To compare bone mineral density (BMD in pts with systemic lupus erythematosus (SLE, treated and untreated by glucocorticoids (GC. Matherial and Methods. 30 females with reliable SLE were examined (APA, 1982, 15 had GC (prednisolone 7.5-60mg/day, median cumulative dose 10.7±6.6g (1st group, 15 others did not take GC (2nd group. Groups were comparable by age, SLE course duration, body weight. All were females with normal menses period. BMD was assessed in low back vertebral region and femoral neck in standard projections on dichromatic X-ray densitometer QDR-1000 Plus (Hologic, USA in absolute values (g/cm2 and T-index. Results. BMD in low back was statistically reliably lower in the 1st group as compared with the 2nd (0,918±0,118 and 1,036±0,156; p=0,027. In the left femoral neck there were no differences in mineralization of bone tissue (0,769±0,167 and 0,807±0,227; p=0,568, BMD decreasing in the studied bone region reliably prevailed among pts of the 1st group (n=ll as compared with the 2nd (n=2 (p=0.003. Conclusion. SLE pis treated by GC demonstrated reliably lower indices of BMD in LI-L4 as compared with pts who were not treated by GC.

  19. GLUCOCORTICOIDS IN THE THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS

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    T. M. Reshetnyak

    2014-07-01

    Full Text Available Despite a more than fifty-year period after the introduction of glucocorticoids (GCs into therapeutic practice; they have headed the list of anti-inflammatory drugs so far. The paper analyzes current views on the terminology of GCs, mechanism of action, standardization of indications for their use in systemic lupus erythematosus, choice of a dose and a regimes of the drugs, as well as the rates of their decrease; the authors also review Russian and foreign literature on this problem and their own data.

  20. GLUCOCORTICOIDS IN THE THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS

    Directory of Open Access Journals (Sweden)

    T. M. Reshetnyak

    2013-01-01

    Full Text Available Despite a more than fifty-year period after the introduction of glucocorticoids (GCs into therapeutic practice; they have headed the list of anti-inflammatory drugs so far. The paper analyzes current views on the terminology of GCs, mechanism of action, standardization of indications for their use in systemic lupus erythematosus, choice of a dose and a regimes of the drugs, as well as the rates of their decrease; the authors also review Russian and foreign literature on this problem and their own data.

  1. Glucocorticoids and inflammation: a double-headed sword in depression? How do neuroendocrine and inflammatory pathways interact during stress to contribute to the pathogenesis of depression?

    Science.gov (United States)

    Horowitz, M A; Zunszain, P A; Anacker, C; Musaelyan, K; Pariante, C M

    2013-01-01

    Both glucocorticoids and inflammation have been implicated in the pathogenesis of depression. There is a large body of literature indicating that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor (GR) dysfunction are present in a significant proportion of depressed patients. There is also evidence of increased inflammatory processes in depressed populations, with higher levels of cytokines being a prominent finding - including raised levels of IL-6, and IL-1. These findings appear difficult to reconcile given the well-recognised property of glucocorticoids as prominent anti-inflammatory molecules. There are three potential solutions posed to this dilemma. Firstly, it has been argued that the glucocorticoid system and the inflammatory system exist in balance with one another and chronic stress can disrupt this balance in favour of inflammatory processes at the expense of glucocorticoid signalling. It has also been suggested that glucocorticoids have more complex actions than typically thought, and, in low levels can actually be pro-inflammatory, rather than universally anti-inflammatory. Lastly, it is possible that inflammation and glucocorticoid signalling may act on the same processes and structures without direct interaction to give rise to cumulative damage. Improved understanding of this interaction will allow further progress in determining targets for treatment.

  2. The Radiology of Vertebral Fractures in Childhood Osteoporosis Related to Glucocorticoid Administration.

    Science.gov (United States)

    Lentle, Brian; Ma, Jinhui; Jaremko, Jacob L; Siminoski, Kerry; Matzinger, Mary Ann; Shenouda, Nazih; Konji, Victor N; Ward, Leanne M

    2016-01-01

    A number of unusual conditions cause decreased bone mass and density in children and these may be associated with low-trauma fractures. However, a series of reports have more recently identified that children with chronic disease sustain vertebral fractures (VFs) much more often than had been suspected. The common denominator involved is glucocorticoid (GC) administration, although other factors such as disease activity come into play. This review will focus on the imaging findings in this form of secondary osteoporosis. Spinal fractures in children have been found to correlate with back pain. At the same time, up to 2/3 of children with VFs in the GC-treated setting are asymptomatic, underscoring the importance of routine surveillance in at-risk children. Other predictors of prevalent and incident VFs include GC exposure (average daily and cumulative dose), declines in lumbar spine bone mineral density Z-scores and increases in body mass index Z-scores, as well as increases in disease activity scores. The imaging diagnosis of osteoporotic VFs in children is made differently from that in adults because immature vertebral bodies continue to ossify during growth. Thus, it is not possible to assess the vertebral end plates or periphery until late, as enchondral ossification extends centripetally within the centrum. Diagnosis, therefore, is much more dependent upon changes in shape than on loss of structural integrity, which may have a more prominent diagnostic role in adults. However, children have a unique ability to model (a growth-dependent process) and thereby reshape previously fractured vertebral bodies. If the underlying disease is successfully treated and the child has sufficient residual growth potential, this means that, on one hand, treatment of the bone disease may be of more limited duration, and, as a last recourse, the diagnosis may be apparent retrospectively. Copyright © 2015 International Society for Clinical Densitometry. Published by Elsevier Inc

  3. Common Infections in Patients Prescribed Systemic Glucocorticoids in Primary Care: A Population-Based Cohort Study.

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    Laurence Fardet

    2016-05-01

    Full Text Available Little is known about the relative risk of common bacterial, viral, fungal, and parasitic infections in the general population of individuals exposed to systemic glucocorticoids, or about the impact of glucocorticoid exposure duration and predisposing factors on this risk.The hazard ratios of various common infections were assessed in 275,072 adults prescribed glucocorticoids orally for ≥15 d (women: 57.8%, median age: 63 [interquartile range 48-73] y in comparison to those not prescribed glucocorticoids. For each infection, incidence rate ratios were calculated for five durations of exposure (ranging from 15-30 d to >12 mo, and risk factors were assessed. Data were extracted from The Health Improvement Network (THIN primary care database. When compared to those with the same underlying disease but not exposed to glucocorticoids, the adjusted hazard ratios for infections with significantly higher risk in the glucocorticoid-exposed population ranged from 2.01 (95% CI 1.83-2.19; p < 0.001 for cutaneous cellulitis to 5.84 (95% CI 5.61-6.08; p < 0.001 for lower respiratory tract infection (LRTI. There was no difference in the risk of scabies, dermatophytosis and varicella. The relative increase in risk was stable over the durations of exposure, except for LRTI and local candidiasis, for which it was much higher during the first weeks of exposure. The risks of infection increased with age and were higher in those with diabetes, in those prescribed higher glucocorticoid doses, and in those with lower plasma albumin level. Most associations were also dependent on the underlying disease. A sensitivity analysis conducted on all individuals except those with asthma or chronic obstructive pulmonary disease produced similar results. Another sensitivity analysis assessing the impact of potential unmeasured confounders such as disease severity or concomitant prescription of chemotherapy suggested that it was unlikely that adjusting for these potential

  4. 长期口服小剂量糖皮质激素有效预防多发性硬化复发1例并文献复习%Long term oral administration of low-dose glucocorticoids for prevention of multiple sclerosis recurrence:a case report and literature review

    Institute of Scientific and Technical Information of China (English)

    黄鑫; 刘建国; 戚晓昆

    2016-01-01

    Objective To analyze the safety and effectiveness of long-term oral administra-tion of low-dose glucocorticoids therapy on multiple sclerosis ( MS) and provide reference for therapy in remission stage of MS. Methods A retrospective analysis was performed evaluating one MS pa-tient in our hospital, who was given oral prednisolone acetate of 25 mg/d for 12 years. Clinical chara-cteristics and treatment details were analyzed and related literature was reviewed and discussed. Re-sults The patient had≥4 times of clinical recurrence (1996, 2002, 2003, 2015) and≥2 objec-tive clinical evidence (periventricular, juxta cortical, and cervical spinal cord), corresponding to RRMS diagnosis criteria. In remission period after the second attack long-term oral prednisolone ace-tate of 25 mg/d were taken without progression or deterioration ( except for recurrence after a cold in 2015) . No obvious adverse reaction happened. Conclusion Long term oral administration of low-dose glucocorticoids can be used as a safe and simple method for the prevention of recurrence of re-lapsing-remitting MS recurrence.%目的:研究长期口服小剂量糖皮质激素治疗多发性硬化( multiple sclerosis,MS)的安全性和有效性,为指导MS缓解期治疗提供参考依据。方法回顾性分析1例确诊MS患者缓解期经口服醋酸泼尼松龙片25 mg/d、治疗12年的临床资料,分析患者病例特点及诊治经验,并文献复习。结果患者≥4次临床发作(1996年、2002年、2003年、2015年),≥2个客观临床证据(首次发病颈椎MRI示第4颈椎水平脊髓内长T1、长T2异常信号且呈斑片状强化,第3次复发头颅MRI示脑室周围、近皮质、颈髓多发斑片状病灶),诊断复发-缓解型MS( relapsing-remitting multiple sclerosis,RRMS)明确。于第2次发作后缓解期内长期口服醋酸泼尼松龙片25 mg/d,病情无进展或恶化(除2015年感冒后复发外),未见明显不良反应。结论长期口服小剂量糖皮质激素

  5. Ex vivo stimulation of whole blood as a means to determine glucocorticoid sensitivity

    Directory of Open Access Journals (Sweden)

    Burnsides C

    2012-08-01

    Full Text Available Christopher Burnsides,1,* Jacqueline Corry,1,* Jacob Alexander,1 Catherine Balint,1 David Cosmar,1 Gary Phillips,2 Jeanette I Webster Marketon1,31Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Center for Biostatistics, 3Institute for Behavioral Medicine Research, Wexner Medical Center at The Ohio State University, Columbus, OH, USA*JC and CB have equally contributed to this workPurpose: Glucocorticoids are commonly prescribed to treat a number of diseases including the majority of inflammatory diseases. Despite considerable interpersonal variability in response to glucocorticoids, an insensitivity rate of about 30%, and the risk of adverse side effects of glucocorticoid therapy, currently no assay is performed to determine sensitivity.Patients and methods: Here we propose a whole blood ex vivo stimulation assay to interrogate known glucocorticoid receptor (GR up- and downregulated genes to indicate glucocorticoid sensitivity. We have chosen to employ real-time PCR in order to provide a relatively fast and inexpensive assay.Results: We show that the GR-regulated genes, GILZ and FKBP51, are upregulated in whole blood by treatment with dexamethasone and that LPS-induction of cytokines (IL-6 and TNFα are repressed by dexamethasone in a dose responsive manner. There is considerable interpersonal variability in the maximum induction of these genes but little variation in the EC50 and IC50 concentrations. The regulation of the GR-induced genes differs throughout the day whereas the suppression of LPS-induced cytokines is not as sensitive to time of day.Conclusion: In all, this assay would provide a method to determine glucocorticoid receptor responsiveness in whole blood.Keywords: glucocorticoid responsiveness, gene regulation, nuclear receptor, GILZ, FKBP51, cytokines

  6. Risk Factors for Infection in Patients with Remitted Rheumatic Diseases Treated with Glucocorticoids

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    Matsumoto,Yoshinori

    2011-10-01

    Full Text Available It is well known that infection is one of the major causes of morbidity and mortality in rheumatic disease patients treated with high-dose glucocorticoids, especially in the early phase after achievement of disease remission. The aim of this study was to identify the risk factors for infection, with a focus on the dose of glucocorticoids administered, following the achievement of disease remission in rheumatic diseases patients. We retrospectively analyzed the medical records of rheumatic disease patients who had been treated with glucocorticoids. The primary endpoint was the incidence rate of infection during a period from 1 to 2 months after the commencement of treatment. From April 2006 to March 2010, 19 of 92 patients suffered from infection during the observation period. Age≧65 yrs, presence of interstitial pneumonia, diagnosis of systemic vasculitis and serum creatinine level≧2.0mg/dl were found to be univariate predictors for infection. However, only the presence of interstitial pneumonia was an independent risk factor for infection (HR=4.50, 95%CI=1.65 to 14.44 by the Cox proportional hazard model. Even after achievement of clinical remission, careful observation is needed for patients with interstitial pneumonia, more so than for those receiving high-dose glucocorticoids.

  7. Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice.

    Science.gov (United States)

    van der Geest, Rick; Ouweneel, Amber B; van der Sluis, Ronald J; Groen, Albert K; Van Eck, Miranda; Hoekstra, Menno

    2016-09-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18±5ng/ml vs 472±58ng/ml; Phypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Cumulant expansions for atmospheric flows

    CERN Document Server

    Ait-Chaalal, Farid; Meyer, Bettina; Marston, J B

    2015-01-01

    The equations governing atmospheric flows are nonlinear, and consequently the hierarchy of cumulant equations is not closed. But because atmospheric flows are inhomogeneous and anisotropic, the nonlinearity may manifests itself only weakly through interactions of mean fields with disturbances such as thermals or eddies. In such situations, truncations of the hierarchy of cumulant equations hold promise as a closure strategy. We review how truncations at second order can be used to model and elucidate the dynamics of turbulent atmospheric flows. Two examples are considered. First, we study the growth of a dry convective boundary layer, which is heated from below, leading to turbulent upward energy transport and growth of the boundary layer. We demonstrate that a quasilinear truncation of the equations of motion, in which interactions of disturbances among each other are neglected but interactions with mean fields are taken into account, can successfully capture the growth of the convective boundary layer. Seco...

  9. Electro-cumulation CNF project

    CERN Document Server

    Grishin, V G

    2000-01-01

    bound or free ion current within solid substances; non-plain symmetry; cumulation of the ion interaction. Experimental result: an Ice SuperPolarization. Cold nuclear fusion ? At http://www.shortway.to/to2084 . Keywords: ion, current, solid, symmetry, cumulation, cold nuclear fusion, polarization, depolarization, ionic conductor, superionic conductor, ice, crystal, strain, V-center, V-centre, doped crystal, interstitial impurity, intrinsic color center, high pressure technology, Bridgman, experiment, crowdion, dielectric, proton, layer, defect, lattice, dynamics, electromigration, mobility, muon catalysis, concentration, doping, dopant, conductivity, pycnonuclear reaction, permittivity, dielectric constant, point defects, interstitials, polarizability, imperfection, defect centers, glass, epitaxy, sodium hydroxide, metallic substrate, crystallization, point, tip, susceptibility, ferroelectric, ordering, force, correlation, collective, shift, distortion, coalescence, crowdions, electrolysis.

  10. Involvement of the insular cortex in regulating glucocorticoid effects on memory consolidation of inhibitory avoidance training

    Directory of Open Access Journals (Sweden)

    Raquel eFornari

    2012-03-01

    Full Text Available Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor agonist RU 28362 (3 or 10 ng in 0.5 l infused bilaterally into the IC of male Sprague-Dawley rats immediately after one-trial inhibitory avoidance training dose-dependently enhanced 48-h retention performance. Moreover, training on the inhibitory avoidance task increased neuronal activity of the IC, as assessed by an increased number of cells expressing immunoreactivity for phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2. However, systemic administration of a memory-enhancing dose of corticosterone (1 mg/kg after inhibitory avoidance training rapidly reduced the number of pERK1/2-positive cells in the IC, suggesting that glucocorticoid administration reduces overall neuronal activity of the IC. To investigate which components of the inhibitory avoidance training experience were influenced by the intra-IC glucocorticoid administration, in the last experiment rats were trained on a modified inhibitory avoidance task in which context exposure and footshock training occur on two sequential days. RU 28362 administration into the IC enhanced later retention when infused immediately after either the context or footshock training. Thus, these findings indicate that the IC mediates glucocorticoid effects on the consolidation of memory of different components of inhibitory avoidance training and suggest that the IC might be an important element of the rodent brain network involved in emotional regulation of learning and memory.

  11. Genetics Home Reference: familial glucocorticoid deficiency

    Science.gov (United States)

    ... certain hormones called glucocorticoids . These hormones, which include cortisol and corticosterone, aid in immune system function, play ... If left untreated, hypoglycemia can lead to seizures, learning difficulties, and other neurological problems. Hypoglycemia that is ...

  12. Glucocorticoid receptor-dependent gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Phillip Phuc Le

    2005-08-01

    Full Text Available While the molecular mechanisms of glucocorticoid regulation of transcription have been studied in detail, the global networks regulated by the glucocorticoid receptor (GR remain unknown. To address this question, we performed an orthogonal analysis to identify direct targets of the GR. First, we analyzed the expression profile of mouse livers in the presence or absence of exogenous glucocorticoid, resulting in over 1,300 differentially expressed genes. We then executed genome-wide location analysis on chromatin from the same livers, identifying more than 300 promoters that are bound by the GR. Intersecting the two lists yielded 53 genes whose expression is functionally dependent upon the ligand-bound GR. Further network and sequence analysis of the functional targets enabled us to suggest interactions between the GR and other transcription factors at specific target genes. Together, our results further our understanding of the GR and its targets, and provide the basis for more targeted glucocorticoid therapies.

  13. Molecular mechanisms of glucocorticoid receptor signaling

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR. Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.

  14. Glucocorticoid-induced osteoporosis in rheumatic diseases

    NARCIS (Netherlands)

    Nijs, Ronny Nicolaas Johannes Theodorus Lambertus de

    2005-01-01

    Glucocorticoids (GCs) are widely used in medicine for their immunosuppressive and anti-inflammatory effects. They are prescribed to patients with systemic inflammatory diseases and are frequently used in the fields of internal medicine (rheumatology, hematology, pulmonology, gastroenterology, etc),

  15. Cumulative Paired φ-Entropy

    Directory of Open Access Journals (Sweden)

    Ingo Klein

    2016-07-01

    Full Text Available A new kind of entropy will be introduced which generalizes both the differential entropy and the cumulative (residual entropy. The generalization is twofold. First, we simultaneously define the entropy for cumulative distribution functions (cdfs and survivor functions (sfs, instead of defining it separately for densities, cdfs, or sfs. Secondly, we consider a general “entropy generating function” φ, the same way Burbea et al. (IEEE Trans. Inf. Theory 1982, 28, 489–495 and Liese et al. (Convex Statistical Distances; Teubner-Verlag, 1987 did in the context of φ-divergences. Combining the ideas of φ-entropy and cumulative entropy leads to the new “cumulative paired φ-entropy” ( C P E φ . This new entropy has already been discussed in at least four scientific disciplines, be it with certain modifications or simplifications. In the fuzzy set theory, for example, cumulative paired φ-entropies were defined for membership functions, whereas in uncertainty and reliability theories some variations of C P E φ were recently considered as measures of information. With a single exception, the discussions in the scientific disciplines appear to be held independently of each other. We consider C P E φ for continuous cdfs and show that C P E φ is rather a measure of dispersion than a measure of information. In the first place, this will be demonstrated by deriving an upper bound which is determined by the standard deviation and by solving the maximum entropy problem under the restriction of a fixed variance. Next, this paper specifically shows that C P E φ satisfies the axioms of a dispersion measure. The corresponding dispersion functional can easily be estimated by an L-estimator, containing all its known asymptotic properties. C P E φ is the basis for several related concepts like mutual φ-information, φ-correlation, and φ-regression, which generalize Gini correlation and Gini regression. In addition, linear rank tests for scale that

  16. Glucocorticoids are ineffective in alcoholic hepatitis

    DEFF Research Database (Denmark)

    Christensen, E; Gluud, C

    1995-01-01

    The aim of this study was to perform a meta-analysis of controlled clinical trials of glucocorticoid treatment in clinical alcoholic hepatitis, adjusting for prognostic variables and their possible interaction with therapy, because these trials have given appreciably different results. Weighted...... may be different (beneficial or harmful) in special patient subgroups. These results do not support the routine use of glucocorticoids in patients with alcoholic hepatitis, including those with encephalopathy. Whether other subgroups may benefit needs further investigation using the individual patient...

  17. The Algebra of the Cumulative Percent Operation.

    Science.gov (United States)

    Berry, Andrew J.

    2002-01-01

    Discusses how to help students avoid some pervasive reasoning errors in solving cumulative percent problems. Discusses the meaning of ."%+b%." the additive inverse of ."%." and other useful applications. Emphasizes the operational aspect of the cumulative percent concept. (KHR)

  18. Adaptive strategies for cumulative cultural learning.

    Science.gov (United States)

    Ehn, Micael; Laland, Kevin

    2012-05-21

    The demographic and ecological success of our species is frequently attributed to our capacity for cumulative culture. However, it is not yet known how humans combine social and asocial learning to generate effective strategies for learning in a cumulative cultural context. Here we explore how cumulative culture influences the relative merits of various pure and conditional learning strategies, including pure asocial and social learning, critical social learning, conditional social learning and individual refiner strategies. We replicate the Rogers' paradox in the cumulative setting. However, our analysis suggests that strategies that resolved Rogers' paradox in a non-cumulative setting may not necessarily evolve in a cumulative setting, thus different strategies will optimize cumulative and non-cumulative cultural learning.

  19. "Buddha's Light" of Cumulative Particles

    CERN Document Server

    Kopeliovich, Vladimir B; Potashnikova, Irina K

    2014-01-01

    We show analytically that in the cumulative particles production off nuclei multiple interactions lead to a glory-like backward focusing effect. Employing the small phase space method we arrived at a characteristic angular dependence of the production cross section $d\\sigma \\sim 1/ \\sqrt {\\pi - \\theta}$ near the strictly backward direction. This effect takes place for any number $n\\geq 3 $ of interactions of rescattered particle, either elastic or inelastic (with resonance excitations in intermediate states), when the final particle is produced near corresponding kinematical boundary. Such a behaviour of the cross section near the backward direction is in qualitative agreement with some of available data.

  20. A Resource Cost Aware Cumulative

    Science.gov (United States)

    Simonis, Helmut; Hadzic, Tarik

    We motivate and introduce an extension of the well-known cumulative constraint which deals with time and volume dependent cost of resources. Our research is primarily interested in scheduling problems under time and volume variable electricity costs, but the constraint equally applies to manpower scheduling when hourly rates differ over time and/or extra personnel incur higher hourly rates. We present a number of possible lower bounds on the cost, including a min-cost flow, different LP and MIP models, as well as greedy algorithms, and provide a theoretical and experimental comparison of the different methods.

  1. Decreased use of glucocorticoids in biological-experienced patients with rheumatoid arthritis who initiated intravenous abatacept: results from the 2-year ACTION study

    Science.gov (United States)

    Alten, Rieke; Nüßlein, Hubert; Galeazzi, Mauro; Lorenz, Hanns-Martin; Nurmohamed, Michael T; Bensen, William G; Burmester, Gerd R; Peter, Hans-Hartmut; Pavelka, Karel; Chartier, Mélanie; Poncet, Coralie; Rauch, Christiane; Elbez, Yedid; Le Bars, Manuela

    2016-01-01

    Introduction Prolonged glucocorticoid use may increase the risk of adverse safety outcomes, including cardiovascular events. The European League Against Rheumatism and the Canadian Rheumatology Association advise tapering glucocorticoid dose as rapidly as clinically feasible. There is a paucity of published data on RA that adequately describe concomitant treatment patterns. Methods ACTION (AbataCepT In rOutiNe clinical practice) is a non-interventional cohort study of patients from Europe and Canada that investigated the long-term retention of intravenous abatacept in clinical practice. We assessed concomitant glucocorticoids in patients with established RA who had participated in ACTION and received ≥1 biological agent prior to abatacept initiation. Results The analysis included 1009 patients. Glucocorticoids were prescribed at abatacept initiation in 734 (72.7%) patients at a median 7.5 mg/day dose (n=692). Of the patients who remained on abatacept at 24 months, 40.7% were able to decrease their dose of glucocorticoids, including 26.9% who decreased their dose from >5 mg/day to ≤5 mg/day. Conclusion Reduction and/or cessation of glucocorticoid therapy is possible with intravenous abatacept in clinical practice. PMID:26925253

  2. Glucocorticoids decrease astrocyte numbers by reducing glucocorticoid receptor expression in vitro and in vivo.

    Science.gov (United States)

    Unemura, Kazuhiro; Kume, Toshiaki; Kondo, Minami; Maeda, Yuki; Izumi, Yasuhiko; Akaike, Akinori

    2012-01-01

    Glucocorticoids are stress hormones released from the adrenal cortex and their concentration is controlled by the hypothalamic-pituitary-adrenal axis. In this study, we investigated the effect of glucocorticoids on the number of astrocytes and glucocorticoid receptor (GR) expression in vitro and in vivo. Proliferation of cultured astrocytes was reduced following treatment with corticosterone and dexamethasone for 72 h. Corticosterone and dexamethasone also reduced GR expression in astrocytes. RU486, a GR antagonist, inhibited the reduction in both astrocyte proliferation and GR expression. Furthermore, GR knockdown by siRNA inhibited astrocyte proliferation. We also examined the effect of excessive glucocorticoid release on GR expression and the number of astrocytes in vivo by administering adrenocorticotropic hormone to rats for 14 days. GR expression was reduced in the prefrontal cortex and hippocampus and the number of astrocytes was reduced in the frontal cortex. Overall, our results suggest that glucocorticoids decrease the number of astrocytes by reducing GR expression.

  3. 职业性噪声聋的发生、发展规律及与累积噪声暴露剂量的关系研究%The occurrence and development of occupational noise deafness and its relationship with the cumulative noise exposure dose

    Institute of Scientific and Technical Information of China (English)

    王雪琴

    2015-01-01

    Objective: To analyze and investigate the occurrence and development of occupational noise deafness and its re-lationship with the cumulative noise exposure dose (CNE).Methods:Randomly selecting a city and medium-sized enterprises 120 workers and management are as the research object, to the enterprise operating environment noise monitoring, investigation object were measured by pure tone threshold audiometry, calculating the cumulative noise exposure, to investigate the occurrence and occupational noise induced hearing loss.Results: The noise pressure level of the examination site was higher than that in other places; when the CNE increases, high-frequency loss, language frequency loss detection rate had significant difference; oc-cupational noise induced deafness related to rate and development and CNE, to 100 dB (a) years as threshold.Conclusion:The cumulative noise exposure dose and occupational noise induced deafness, the law of development there is a certain relationship, early detection threshold anomaly or high frequency audibility threshold change of patients,, improve efficiency and patient quality of life.%目的:分析和探讨职业性噪声聋的发生、发展规律及与累积噪声暴露剂量(CNE)的关系。方法随机选取某城市中型企业中120名工人及管理者作为研究对象,对企业作业环境噪音进行监测,组织调查对象进行纯音听阈测定,计算累积噪声暴露剂量,探讨与职业性噪声聋的发生、发展规律的关系。结果检查现场噪声声压级均高于其他场所;当CNE升高时,高频损失、语频损失检出率差异明显;职业性噪声聋发生率及发展与CNE有关,以100dB(A)年为阈值。结论累积噪声暴露剂量与职业性噪声聋的发生、发展规律存在一定的关系,早期发现听阈异常或高频听阈改变的患者,及时控制职业噪音暴露量,并按规定调离噪声作业岗位,避免病情进一步发展,提高患者工作效率和生活质量。

  4. Glucocorticoids affect the metabolism of bone marrow stromal cells and lead to osteonecrosis of the femoral head: a review

    Institute of Scientific and Technical Information of China (English)

    TAN Gang; KANG Peng-de; PEI Fu-xing

    2012-01-01

    Objective To review the recent developments in the mechanisms of glucocorticoids induced osteonecrosis of femoral head (ONFH) and introduce a new theory of ONFH.Data sources Both Chinese- and English-language literatures were searched using MEDLINE (1997-2011),Pubmed (1997-2011 ) and the Index of Chinese-language Literature (1997-2011 ).Study selection Data from published articles about mechanisms of glucocorticoids induced ONFH in recent domestic and foreign literature were selected.Data extraction Data were mainly extracted from 61 articles which are listed in the reference section of this review.Results Glucocorticoids are steroid hormones secreted by the adrenal cortex that play a pivotal role in the regulation of a variety of developmental,metabolic and immune functions.However,high dose of exogenous glucocorticoids usage is the most common non-traumatic cause of ON FH.Glucocorticoids can affect the metabolisms of osteoblasts,osteoclasts,bone marrow stromal cells and adipocytes which decrease osteoblasts formation but increase adipocytes formation and cause ONFH finally.Conclusions Glucocorticoids affect the differentiation of mesenchymal stem cells,through activating or inhibiting the related transcript regulators of osteogenesis and adipogenesis.At last,the size and volume of mesenchymal stem cells derived adipocytes will increase amazingly,but the osteoblasts will be decreased obviously.In the meantime,the activity of the osteoclasts will be activated.So,these mechanisms work together and lead to ONFH.

  5. A paradox of cumulative culture.

    Science.gov (United States)

    Kobayashi, Yutaka; Wakano, Joe Yuichiro; Ohtsuki, Hisashi

    2015-08-21

    Culture can grow cumulatively if socially learnt behaviors are improved by individual learning before being passed on to the next generation. Previous authors showed that this kind of learning strategy is unlikely to be evolutionarily stable in the presence of a trade-off between learning and reproduction. This is because culture is a public good that is freely exploited by any member of the population in their model (cultural social dilemma). In this paper, we investigate the effect of vertical transmission (transmission from parents to offspring), which decreases the publicness of culture, on the evolution of cumulative culture in both infinite and finite population models. In the infinite population model, we confirm that culture accumulates largely as long as transmission is purely vertical. It turns out, however, that introduction of even slight oblique transmission drastically reduces the equilibrium level of culture. Even more surprisingly, if the population size is finite, culture hardly accumulates even under purely vertical transmission. This occurs because stochastic extinction due to random genetic drift prevents a learning strategy from accumulating enough culture. Overall, our theoretical results suggest that introducing vertical transmission alone does not really help solve the cultural social dilemma problem. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.

    Science.gov (United States)

    Paugh, Steven W; Bonten, Erik J; Savic, Daniel; Ramsey, Laura B; Thierfelder, William E; Gurung, Prajwal; Malireddi, R K Subbarao; Actis, Marcelo; Mayasundari, Anand; Min, Jaeki; Coss, David R; Laudermilk, Lucas T; Panetta, John C; McCorkle, J Robert; Fan, Yiping; Crews, Kristine R; Stocco, Gabriele; Wilkinson, Mark R; Ferreira, Antonio M; Cheng, Cheng; Yang, Wenjian; Karol, Seth E; Fernandez, Christian A; Diouf, Barthelemy; Smith, Colton; Hicks, J Kevin; Zanut, Alessandra; Giordanengo, Audrey; Crona, Daniel; Bianchi, Joy J; Holmfeldt, Linda; Mullighan, Charles G; den Boer, Monique L; Pieters, Rob; Jeha, Sima; Dunwell, Thomas L; Latif, Farida; Bhojwani, Deepa; Carroll, William L; Pui, Ching-Hon; Myers, Richard M; Guy, R Kiplin; Kanneganti, Thirumala-Devi; Relling, Mary V; Evans, William E

    2015-06-01

    Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases.

  7. NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells

    Science.gov (United States)

    Paugh, Steven W.; Bonten, Erik J.; Savic, Daniel; Ramsey, Laura B.; Thierfelder, William E.; Gurung, Prajwal; Malireddi, R. K. Subbarao; Actis, Marcelo; Mayasundari, Anand; Min, Jaeki; Coss, David R.; Laudermilk, Lucas T.; Panetta, John C.; McCorkle, J. Robert; Fan, Yiping; Crews, Kristine R.; Stocco, Gabriele; Wilkinson, Mark R.; Ferreira, Antonio M.; Cheng, Cheng; Yang, Wenjian; Karol, Seth E.; Fernandez, Christian A.; Diouf, Barthelemy; Smith, Colton; Hicks, J. Kevin; Zanut, Alessandra; Giordanengo, Audrey; Crona, Daniel; Bianchi, Joy J.; Holmfeldt, Linda; Mullighan, Charles G.; den Boer, Monique L.; Pieters, Rob; Jeha, Sima; Dunwell, Thomas L.; Latif, Farida; Bhojwani, Deepa; Carroll, William L.; Pui, Ching-Hon; Myers, Richard M.; Guy, R. Kiplin; Kanneganti, Thirumala-Devi; Relling, Mary V.; Evans, William E.

    2015-01-01

    Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444 newly diagnosed ALL patients, revealing significantly higher expression of caspase 1 (CASP1) and its activator NLRP3 in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of CASP1 and NLRP3 promoters. Over-expression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1 overexpressing ALL. Our findings establish a new mechanism by which the NLRP3/CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on glucocorticoid transcriptional response suggests this mechanism could also modify glucocorticoid effects in other diseases. PMID:25938942

  8. Adverse Consequences of Glucocorticoid Medication : Psychological, Cognitive, and Behavioral Effects

    NARCIS (Netherlands)

    Judd, Lewis L.; Schettler, Pamela J.; Brown, E. Sherwood; Wolkowitz, Owen M.; Sternberg, Esther M.; Bender, Bruce G.; Bulloch, Karen; Cidlowski, John A.; de Kloet, E. Ronald; Fardet, Laurence; Joëls, Marian; Leung, Donald Y. M.; McEwen, Bruce S.; Roozendaal, Benno; Van Rossum, Elisabeth F. C.; Ahn, Junyoung; Brown, David W.; Plitt, Aaron; Singh, Gagandeep

    2014-01-01

    Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as

  9. Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects

    NARCIS (Netherlands)

    Judd, L.L.; Schettler, P.J.; Brown, E.S.; Wolkowitz, O.M.; Sternberg, E.M.; Bender, B.G.; Bulloch, K.; Cidlowski, J.A.; Kloet, E.R. de; Fardet, L.; Joels, M.; Leung, D.Y.; McEwen, B.S.; Roozendaal, B.; Rossum, E.F. van; Ahn, J.; Brown, D.W.; Plitt, A.; Singh, G.

    2014-01-01

    Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as

  10. Glucocorticoids and the regulation of memory in health and disease

    NARCIS (Netherlands)

    de Quervain, Dominique J. -F; Aerni, Amanda; Schelling, Gustav; Roozendaal, Benno

    2009-01-01

    Over the last decades considerable evidence has accumulated indicating that glucocorticoids - stress hormones released from the adrenal cortex - are crucially involved in the regulation of memory. Specifically, glucocorticoids have been shown to enhance memory consolidation of emotionally arousing e

  11. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

    Damsted, Sara K.; Born, A P; Paulson, Olaf B

    2011-01-01

    of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids....... Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular...

  12. Glucocorticoid control of gene transcription in neural tissue

    NARCIS (Netherlands)

    Morsink, Maarten Christian

    2007-01-01

    Glucocorticoid hormones exert modulatory effects on neural function in a delayed genomic fashion. The two receptor types that can bind glucocorticoids, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), are ligand-inducible transcription factors. Therefore, changes in gene exp

  13. Perinatal glucocorticoid treatment and perspectives for antioxidat therapy

    NARCIS (Netherlands)

    Tijsseling, D.

    2014-01-01

    Pre- and postnatal glucocorticoids are a life-saving therapy for prematurely born infants. However, glucocorticoids also trigger unwanted side effects. In part I we investigated the effects of antenatal glucocorticoids on hippocampal development. First in a mice model using a clinically relevant dos

  14. Glucocorticoid-induced myopathy: Pathophysiology, diagnosis, and treatment

    Directory of Open Access Journals (Sweden)

    Anu Gupta

    2013-01-01

    Full Text Available Glucocorticoid-induced myopathy is the most common type of drug-induced myopathy. Nearly 60% of patients with Cushing′s syndrome have muscle weakness. Glucocorticoid-induced muscle atrophy affects mainly fast-twitch glycolytic muscle fibers (type IIb fibers. This brief review will discuss the pathophysiology behind glucocorticoid-induced myopathy, along with diagnostic features and treatment.

  15. Perinatal glucocorticoid treatment and perspectives for antioxidat therapy

    NARCIS (Netherlands)

    Tijsseling, D.

    2014-01-01

    Pre- and postnatal glucocorticoids are a life-saving therapy for prematurely born infants. However, glucocorticoids also trigger unwanted side effects. In part I we investigated the effects of antenatal glucocorticoids on hippocampal development. First in a mice model using a clinically relevant dos

  16. Glucocorticoid receptor haplotype and metabolic syndrome : the Lifelines cohort study

    NARCIS (Netherlands)

    Wester, Vincent L.; Koper, Jan W.; van den Akker, Erica L. T.; Franco, Oscar H.; Stolk, Ronald P.; van Rossum, Elisabeth F. C.

    2016-01-01

    Objective: An excess of glucocorticoids (Cushing's syndrome) is associated with metabolic syndrome (MetS) features. Several single-nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene influence sensitivity to glucocorticoids and have been associated with aspects of MetS. However,

  17. Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome.

    Science.gov (United States)

    Cuzzoni, Eva; De Iudicibus, Sara; Franca, Raffaella; Stocco, Gabriele; Lucafò, Marianna; Pelin, Marco; Favretto, Diego; Pasini, Andrea; Montini, Giovanni; Decorti, Giuliana

    2015-01-01

    Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in their efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.

  18. GLUCOCORTICOID-INDUCED OSTEOPOROSIS: PATHOGENESIS, PREVENTION, TREATMENT

    Directory of Open Access Journals (Sweden)

    Irina Aleksandrovna Baranova

    2010-06-01

    Full Text Available Osteoporosis (OP is a serious problem to patients who have long taken glucocorticoids. In the past two decade, much knowledge has been accumulated about the epidemiology of the disease and drugs with proven efficacy for its prevention and treatment have emerged. However, a large number of studies suggest that there is a serious shortage in care to patients with glucocorticoid-induced OP, which calls for effective measures to bring the real level of its prevention and treatment in compliance with the current clinical guidelines

  19. GLUCOCORTICOID-INDUCED OSTEOPOROSIS: PATHOGENESIS, PREVENTION, TREATMENT

    Directory of Open Access Journals (Sweden)

    Irina Aleksandrovna Baranova

    2010-01-01

    Full Text Available Osteoporosis (OP is a serious problem to patients who have long taken glucocorticoids. In the past two decade, much knowledge has been accumulated about the epidemiology of the disease and drugs with proven efficacy for its prevention and treatment have emerged. However, a large number of studies suggest that there is a serious shortage in care to patients with glucocorticoid-induced OP, which calls for effective measures to bring the real level of its prevention and treatment in compliance with the current clinical guidelines

  20. Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin

    OpenAIRE

    Klopot, Anna; Baida, Gleb; Bhalla, Pankaj; Haegeman, Guy; Budunova, Irina

    2015-01-01

    Background: Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not prom...

  1. Mechanism of anti-inflammatory action of glucocorticoids: re-evaluation of vascular constriction hypothesis.

    OpenAIRE

    1981-01-01

    1 The question whether constriction of local vessels is essential for the anti-inflammatory action of glucocorticoids in carrageenin-induced granulomatous inflammation was studied. 2 The vasodilator prostaglandin E1 injection into the granuloma pouch fluid increased the exudation of plasma protein into the granuloma tissue. 3 Noradrenaline significantly reduced plasma exudation, possibly through alpha-adrenoceptor stimulation. 4 Cortisol and dexamethasone in doses sufficient to inhibit vascul...

  2. Association between Glucocorticoid-Induced Osteoporosis and Myasthenia Gravis: A Cross-Sectional Study.

    Directory of Open Access Journals (Sweden)

    Shingo Konno

    Full Text Available To investigate the association between glucocorticoid-induced osteoporosis and myasthenia gravis (MG using a cross-sectional survey in Japan.We studied 363 patients with MG (female 68%; mean age, 57 ± 16 years who were followed at six Japanese centers between April and July 2012. We evaluated the clinical information of MG and fractures, bone markers, and radiological assessment. Quality of life was measured using an MG-specific battery, MG-QOL15.Glucocorticoids were administered in 283 (78% of 363 MG patients. Eighteen (6% of 283 MG patients treated with prednisolone had a history of osteoporotic fractures. The duration of glucocorticoid therapy, but not the dose of prednisolone, was associated with the osteoporotic fractures in MG patients. Bone mineral density was significantly decreased in the MG patients with fractures. The multivariate analyses showed that the total quantitative MG score was the only independent factor associated with osteoporotic fractures (OR = 1.30, 95% CI 1.02-1.67, p = 0.03. MG patients who had experienced fractures reported more severe difficulties in activities of daily living.Glucocorticoid-induced osteoporosis aggravates quality of life in patients with MG.

  3. Disrupted secretory activation of the mammary gland after antenatal glucocorticoid treatment in sheep.

    Science.gov (United States)

    Henderson, Jennifer J; Hartmann, Peter E; Moss, Timothy J M; Doherty, Dorota A; Newnham, John P

    2008-11-01

    Antenatal glucocorticoids are administered to women at risk of preterm delivery to prevent neonatal respiratory morbidity. The effects of exogenous glucocorticoids on the development of lactation are unknown. This study investigated the effects of a single dose of antenatal glucocorticoids on secretory activation in sheep before and after parturition. Pregnant ewes (N=36) were randomised to receive either medroxyprogesterone acetate (MPA) at 118 days of pregnancy and betamethasone at 125 days (BETA group), MPA at 118 days and saline at 125 days (MPA group) or saline at 118 and 125 days (SALINE group). The concentration of lactose, progesterone, cortisol and prolactin in maternal plasma was measured during pregnancy. After term parturition, the concentration of lactose in milk and maternal plasma was measured daily for 5 days. Lambs were weighed at birth and at 5 days of age; milk volume was measured on day 5. The concentration of lactose in maternal plasma increased significantly after betamethasone administration, corresponding to a fall in plasma progesterone. No changes in lactose were observed in MPA or SALINE ewes. Transient decreases in cortisol and increases in prolactin were observed in the BETA group, but not in either the MPA or SALINE group. After parturition, BETA ewes experienced reduced milk yield and lamb weight gain, and delayed increases in milk lactose levels compared with MPA and saline controls. This study demonstrated that, in sheep, antenatal glucocorticoid administration disrupted secretory activation, causing precocious mammary secretion before parturition and compromising postpartum milk production and lamb growth.

  4. Fast effects of glucocorticoids on memory-related network oscillations in the mouse hippocampus.

    Science.gov (United States)

    Weiss, E K; Krupka, N; Bähner, F; Both, M; Draguhn, A

    2008-05-01

    Transient or lasting increases in glucocorticoids accompany deficits in hippocampus-dependent memory formation. Recent data indicate that the formation and consolidation of declarative and spatial memory are mechanistically related to different patterns of hippocampal network oscillations. These include gamma oscillations during memory acquisition and the faster ripple oscillations (approximately 200 Hz) during subsequent memory consolidation. We therefore analysed the effects of acutely applied glucocorticoids on network activity in mouse hippocampal slices. Evoked field population spikes and paired-pulse responses were largely unaltered by corticosterone or cortisol, respectively, despite a slight increase in maximal population spike amplitude by 10 microm corticosterone. Several characteristics of sharp waves and superimposed ripple oscillations were affected by glucocorticoids, most prominently the frequency of spontaneously occurring sharp waves. At 0.1 microm, corticosterone increased this frequency, whereas maximal (10 microm) concentrations led to a reduction. In addition, gamma oscillations became slightly faster and less regular in the presence of high doses of corticosteroids. The present study describes acute effects of glucocorticoids on sharp wave-ripple complexes and gamma oscillations in mouse hippocampal slices, revealing a potential background for memory deficits in the presence of elevated levels of these hormones.

  5. Determination of Glucocorticoids in UPLC-MS in Environmental Samples from an Occupational Setting

    Directory of Open Access Journals (Sweden)

    Enrico Oddone

    2015-01-01

    Full Text Available Occupational exposures to glucocorticoids are still a neglected issue in some work environments, including pharmaceutical plants. We developed an analytical method to quantify simultaneously 21 glucocorticoids using UPLC coupled with mass spectrometry to provide a basis to carry out environmental monitoring. Samples were taken from air, hand-washing tests, pad-tests and wipe-tests. This paper reports the contents of the analytical methodology, along with the results of this extensive environmental and personal monitoring of glucocorticoids. The method in UPLC-MS turned out to be suitable and effective for the aim of the study. Wipe-test and pad-test desorption was carried out using 50 mL syringes, a simple technique that saves time without adversely affecting analyte recovery. Results showed a widespread environmental pollution due to glucocorticoids. This is of particular concern. Evaluation of the dose absorbed by each worker and identification of a biomarker for occupational exposure will contribute to assessment and prevention of occupational exposure.

  6. BClI polymorphism of the glucocorticoid receptor gene is associated with increased obesity, impaired glucose metabolism and dyslipidaemia in patients with Addison's disease.

    Science.gov (United States)

    Giordano, Roberta; Marzotti, Stefania; Berardelli, Rita; Karamouzis, Ioannis; Brozzetti, Annalisa; D'Angelo, Valentina; Mengozzi, Giulio; Mandrile, Giorgia; Giachino, Daniela; Migliaretti, Giuseppe; Bini, Vittorio; Falorni, Alberto; Ghigo, Ezio; Arvat, Emanuela

    2012-12-01

    Although glucocorticoids are essential for health, several studies have shown that glucocorticoids replacement in Addison's disease might be involved in anthropometric and metabolic impairment, with increased cardiovascular risk, namely if conventional doses are used. As the effects of glucocorticoids are mediated by the glucocorticoid receptor, encoded by NR3C1 gene, different polymorphisms in the NR3C1 gene have been linked to altered glucocorticoid sensitivity in general population as well as in patients with obesity or metabolic syndrome. We investigated the impact of glucocorticoid receptor gene polymorphisms, including the BclI, N363S and ER22/23EK variants, on anthropometric parameters (BMI and waist circumference), metabolic profile (HOMA, OGTT and serum lipids) and ACTH levels in 50 patients with Addison's disease (34 women and 16 men, age 20-82 year) under glucocorticoids replacement. Neither N363S nor ER22/23EK variants were significantly associated with anthropometric, metabolic or hormonal parameters, while patients carrying the homozygous BclI polymorphism GG (n = 4) showed higher (P Addison's disease and may contribute, along with other factors, to the increase in central adiposity, impaired glucose metabolism and dyslipidaemia. © 2012 Blackwell Publishing Ltd.

  7. Glucocorticoid-induced apoptosis and cellular mechanisms of myopathy.

    Science.gov (United States)

    Dirks-Naylor, Amie J; Griffiths, Carrie L

    2009-10-01

    Glucocorticoid-induced myopathy is a common side effect of chronic glucocorticoid therapy. Several mechanisms are currently being examined as ways in which glucocorticoid-induced myopathy occurs. These include apoptotic signaling through mitochondrial-mediated and Fas-mediated apoptosis, the role of the proteosome, the suppression of the IGF-1 signaling, and the role of ceramide in glucocorticoid-induced apoptosis and myopathy. It is difficult to differentiate which mechanism may be the initiating event responsible for the induction of apoptosis; however, all of the mechanisms play a vital role in glucocorticoid-induced myopathy.

  8. Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications.

    Science.gov (United States)

    Sapolsky, R M; Pulsinelli, W A

    1985-09-27

    Sustained exposure to glucocorticoids, the adrenocortical stress hormones, is toxic to neurons, and such toxicity appears to play a role in neuron loss during aging. Previous work has shown that glucocorticoids compromise the capacity of neurons to survive a variety of metabolic insults. This report extends those observations by showing that ischemic injury to neurons in rat brain is also potentiated by exposure to high physiological titers of glucocorticoids and is attenuated by adrenalectomy. The synergy between ischemic and glucocorticoid brain injury was seen even when glucocorticoid levels were manipulated after the ischemic insult. Pharmacological interventions that diminish the adrenocortical stress response may improve neurological outcome from stroke or cardiac arrest.

  9. Dosing schedule-dependent attenuation of dexamethasone-induced muscle atrophy in mice.

    Science.gov (United States)

    Nakao, Reiko; Yamamoto, Saori; Yasumoto, Yuki; Oishi, Katsutaka

    2014-05-01

    Many inflammatory and autoimmune diseases are treated using synthetic glucocorticoids. However, excessive glucocorticoid can often cause unpredictable effects including muscle atrophy. Endogenous glucocorticoid levels robustly fluctuate in a circadian manner and peak just before the onset of the active phase in both humans and nocturnal rodents. The present study determines whether muscle atrophy induced by exogenous glucocorticoid can be avoided by optimizing dosing times. We administered single daily doses of the glucocorticoid analog dexamethasone (Dex) to mice for 10 days at the times of day corresponding to peak (early night) or trough (early morning) endogenous glucocorticoid levels. Administration at the acrophase of endogenous glucocorticoids significantly attenuated Dex-induced wasting of the gastrocnemius (Ga) and tibialis anterior (TA) muscles that comprise mostly fast-twitch muscle fibers. Real-time RT-PCR revealed that the Dex-induced mRNA expression of genes encoding the atrophy-related ubiquitin ligases Muscle Atrophy F-box (Fbxo32, also known as MAFbx/Atrogin-1) and Muscle RING finger 1 (Trim63, also known as MuRF1) in the Ga and TA muscles was significantly attenuated by Dex when administered during the early night. Dex negligibly affected the weight of the soleus (So) muscle that mostly comprises slow-twitch muscle fibers, but significantly and similarly decreased the weight of the spleen at both dosing times. These results suggest that glucocorticoid-induced muscle atrophy can be attenuated by optimizing the dosing schedule.

  10. New possibilities for the treatment of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    I.A. Baranova

    2014-01-01

    Full Text Available Glucocorticoid-induced osteoporosis (GIO is the most common cause of secondary osteoporosis (OP and a main cause of drug-induced OP. Fractures of the skeleton are registered in 30–50% of patients who have taken oral glucocorticoids (GCs for a long time, during which the frac- tures develop with the use of any daily GC dose and with higher bone mineral density (BMD than in postmenopausal OP. In patients who have taken oral GCs long or in high daily doses, decrease of BMD and low bone tissue quality leading to fractures are largely associated with the reduction of bone formation. This gives proof to the administration of antiosteoporotic agents that enhance the formation of bone during its remodeling. Teriparatide, a recombinant human parathyroid hormone, enhances osteoblast function, decreases the apoptosis of osteoblasts and osteocytes, increases the differentiation of osteoblast precursors, and can prevent the negative effect of exogenous GCs on bone. According to clinical trials results, teriparatide treatment increases BMD and reduces the risk of vertebral fractures in patients who have taken oral GCs long. In accordance of the clinical recommendations for the diagnosis, prevention, and treatment of GIO, which have been developed by the Russian Osteoporosis Association jointly with the Association of Rheumatologists of Russia and the Russian Respiratory Society, teriparatide is the drug of first choice for the treatment of GIO in men and women at high risk for fractures (with the history of fragility fractures or having high FRAX 10-year absolute fracture risk. Teriparatide may be prescribed in case of previous antiosteoporotic treatment failure (new fractures occurring during treatment and/or continuing to decrease BMD, as well as when other drugs to treat OP are intolerable or when there are contraindications to their use. 

  11. Glucocorticoid Regulation of the Vitamin D Receptor

    Science.gov (United States)

    Hidalgo, Alejandro A.; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and Dex induce VDR- and glucocorticoid receptor (GR)-mediated transcription respectively, indicating both hormone receptors are active in SCC. Pre-treatment with Dex increases VDR-mediated transcription at the human CYP24A1 promoter. Whereas, pre-treatment with other steroid hormones, including dihydrotestosterone and R1881, has no effect on VDR-mediated transcription. Real-time PCR indicates treatment with Dex increases Vdr transcripts in a time-dependent manner, suggesting Dex may directly regulate expression of Vdr. Numerous putative glucocorticoid response elements (GREs) were found in the Vdr gene. Chromatin immunoprecipitation (ChIP) assay demonstrated GR binding at several putative GREs located within the mouse Vdr gene. However, none of the putative GREs studied increase GR-mediated transcription in luciferase reporter assays. In an attempt to identify the response element responsible for Vdr transcript regulation, future studies will continue to analyze newly identified GREs more distal from the Vdr gene promoter. PMID:20398752

  12. [Oral glucocorticoids for acute rhinosinusitis: an RCT

    NARCIS (Netherlands)

    Venekamp, R.P.; Bonten, M.J.; Rovers, M.M.; Verheij, T.J.; Sachs, A.P.

    2013-01-01

    OBJECTIVE: To determine the efficacy of a short course of oral glucocorticoids in adult patients with acute rhinosinusitis. DESIGN: A double blind, placebo-controlled, randomized study conducted in 54 general practices in the Netherlands from December 2008 to March 2011 (NTR1295; http://www.trialreg

  13. Activated glucocorticoid and eicosanoid pathways in endometriosis.

    Science.gov (United States)

    Monsivais, Diana; Bray, Jeffrey D; Su, Emily; Pavone, Mary Ellen; Dyson, Matthew T; Navarro, Antonia; Kakinuma, Toshiyuki; Bulun, Serdar E

    2012-07-01

    To define altered gene expression networks in endometriosis. Experiments using endometriotic tissues and primary cells. Division of Reproductive Biology Research, Northwestern University. Premenopausal women. Matched samples of eutopic endometrium and ovarian endometriosis (n = 8 patients) were analyzed by microarray and verified in a separate set of tissues (n = 6 patients). Experiments to define signaling pathways were performed in primary endometriotic stromal cells (n = 12 patients). Using a genome-wide in vivo approach, we identified 1,366 differentially expressed genes and a new gene network favoring increased glucocorticoid levels and action in endometriosis. Transcript and protein levels of 11β-hydroxysteroid dehydrogenase (HSD11B1), which produces cortisol, the biologically active glucocorticoid, were strikingly higher, whereas messenger RNA (mRNA) levels of the cortisol-degrading HSD11B2 enzyme were significantly lower in endometriotic tissue. Glucocorticoid receptor mRNA and protein levels were significantly higher in endometriosis. The inflammatory cytokine tumor necrosis factor robustly induced mRNA and protein levels of HSD11B1 and glucocorticoid receptor but suppressed HSD11B2 mRNA in primary endometriotic stromal cells, suggesting that tumor necrosis factor stimulates cortisol production and action. We also uncovered a subset of genes critical for prostaglandin synthesis and degradation, which favor high eicosanoid levels and activity in endometriosis. The proinflammatory milieu of the endometriotic lesion stimulates cortisol synthesis and action in endometriotic lesions. Published by Elsevier Inc.

  14. Glucocorticoid receptor knockdown and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Hooijdonk, Leonarda Wilhelmina Antonia van

    2010-01-01

    The research in this thesis is aimed at the elucidation of the role of the glucocorticoid receptor (GR) in hippocampal neuroplasticity and functioning. To achieve this, we have developed a novel method to specifically knockdown GR in a discrete cell population of the mouse brain. In this thesis I r

  15. Effects of glucocorticoid and glucocorticoid receptors on stress-induced neurogenesis suppression

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Jiapei Dai; Dan Liu; Shangxun Li; Yiwu Zhou

    2010-01-01

    Studies have shown that cerebral ischemia activates neurogenesis and that stress inhibits neurogenesis.However,the role of stress hormone levels on neurogenesis following cerebral ischemia remains poorly understood.The present study explored the possible regulatory mechanisms of adult neurogenesis under pathological conditions by examining changes and regulation of glucocorticoid receptors in adult rats subjected to transient unilateral middle cerebral artery suture occlusion.Corticosterone levels gradually increased following middle cerebral artery occlusion,and the number of glucocorticoid receptor-positive cells decreased.The number of5-bromodeoxyuridine-and nestin-positive cells significantly increased at 1 and 2 weeks after ischemia.A large number of doublecortin-positive cells migrated from the hippocampus to the cortex.At 3 weeks post-surgery,the number of 5-bromodeoxyuridine-and nestin-positive cells significantly reduced in the subventricular zone.Increased corticosterone levels decreased vascular endothelial cell proliferation and neurogenesis,and the number of glucocorticoid receptor-positive cells decreased.In the sham surgery group,vascular endothelial cell proliferation related to post-ischemic cerebral rehabilitation was not detected.Corticosterone levels increased,but the number and distribution of glucocorticoid receptor-positive cells were not changed.However,normal neuregenesis and migration of neural stem cells existed in the adult rat brain in the sham surgery group.Results suggested that glucocorticoid receptors influenced neurogenesis and were negatively regulated by glucocorticoid levels following focal cerebral ischemia and reperfusion.

  16. ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.

    Science.gov (United States)

    Nixon, Mark; Mackenzie, Scott D; Taylor, Ashley I; Homer, Natalie Z M; Livingstone, Dawn E; Mouras, Rabah; Morgan, Ruth A; Mole, Damian J; Stimson, Roland H; Reynolds, Rebecca M; Elfick, Alistair P D; Andrew, Ruth; Walker, Brian R

    2016-08-17

    The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgens while achieving physiological glucocorticoid replacement. However, current glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess androgens almost invariably induce adverse metabolic effects. Although both cortisol and corticosterone are glucocorticoids that circulate in human plasma, any physiological role for corticosterone has been neglected. In the brain, the adenosine 5'-triphosphate-binding cassette transporter ABCB1 exports cortisol but not corticosterone. Conversely, ABCC1 exports corticosterone but not cortisol. We show that ABCC1, but not ABCB1, is expressed in human adipose and that ABCC1 inhibition increases intracellular corticosterone, but not cortisol, and induces glucocorticoid-responsive gene transcription in human adipocytes. Both C57Bl/6 mice treated with the ABCC1 inhibitor probenecid and FVB mice with deletion of Abcc1 accumulated more corticosterone than cortisol in adipose after adrenalectomy and corticosteroid infusion. This accumulation was sufficient to increase glucocorticoid-responsive adipose transcript expression. In human adipose tissue, tissue corticosterone concentrations were consistently low, and ABCC1 mRNA was up-regulated in obesity. To test the hypothesis that corticosterone effectively suppresses adrenocorticotropic hormone (ACTH) without the metabolic adverse effects of cortisol, we infused cortisol or corticosterone in patients with Addison's disease. ACTH suppression was similar, but subcutaneous adipose transcripts of glucocorticoid-responsive genes were higher after infusion with cortisol rather than with corticosterone. These data indicate that corticosterone may be a metabolically favorable alternative to cortisol for glucocorticoid replacement therapy when ACTH suppression is desirable, as in congenital adrenal hyperplasia, and justify development of a pharmaceutical preparation

  17. Impacto da atividade inflamatória e uso de glicocorticóide nas variáveis nutricionais da artrite idiopática juvenil Impact of inflammatory activity and glucocorticoid use in the nutritional variables of juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Letícia Souza Bisotto

    2005-10-01

    Full Text Available OBJETIVO: avaliar o estado nutricional na artrite idiopática juvenil (AIJ, a influência da atividade inflamatória e o uso de glicocorticóide. MÉTODOS: foram estudados 116 pacientes com AIJ diagnosticados segundo os critérios da ILAR/1997. Subtipo e atividade da doença foram determinados por reumatologistas pediátricos, e a dose cumulativa de glicocorticóide foi revisada nos prontuários dos pacientes. Foram determinados os percentis do índice de massa corporal (IMC e da prega cutânea tricipital (PCT e o escore Z da estatura, de acordo com a OMS. Considerou-se baixo peso e baixa adiposidade quando o IMC e a PCT apresentavam-se abaixo do percentil 5. Baixa estatura foi definida por escore Z de estatura para idade menor do que -2. O nível sérico de IGF-1 foi medido por meio de radioimunoensaio. RESULTADOS: as prevalências de baixo peso, baixa adiposidade e baixa estatura foram 16,4%, 20,7% e 10,4%, respectivamente. Níveis séricos reduzidos de IGF-1 foram observados em 14 pacientes (12,1%. Os fatores negativamente associados com o escore Z da estatura na análise de regressão multivariável foram: duração da doença (coeficiente parcial de correlação, intervalo de confiança de 95%: -0,370, -0,527 a -0,188: pOBJECTIVE: To assess the nutritional status in juvenile idiopathic arthritis (JIA and the influence of inflammatory activity and glucocorticoid use. METHODS: One hundred and sixteen patients were evaluated. Disease subtype and disease activity were defined by the attending physician, and the cumulative glucocorticoid dose was recorded by chart review. The percentiles of body mass index (BMI and triceps skinfold (TSF and the Z-score for height were determined: low weight and low adiposity were diagnosed when BMI and TSF were below the 5th percentile. Short stature was defined by a Z-score of height for age < -2. The serum level of IGF-I was measured by radioimmunoassay. RESULTS: The prevalences of low weight, low adiposity

  18. Cumulate Fragments in Silicic Ignimbrites

    Science.gov (United States)

    Bachmann, O.; Ellis, B. S.; Wolff, J.

    2014-12-01

    Increasingly, studies are concluding that silicic ignimbrites are the result of the amalgamation of multiple discrete magma batches. Yet the existence of discrete batches presents a conundrum for magma generation and storage; if silicic magma batches are not generated nearly in situ in the upper crust, they must traverse, and reside within, a thermally hostile environment with large temperature gradients, resulting in low survivability in their shallow magmatic hearths. The Snake River Plain (Idaho, USA) is a type example of this 'multi-batch' assembly with ignimbrites containing multiple populations of pyroxene crystals, glass shards, and crystal aggregates. The ubiquitous crystal aggregates hint at a mechanism to facilitate the existence of multiple, relatively small batches of rhyolite in the upper crust. These aggregates contain the same plagioclase, pyroxene, and oxide mineral compositions as single phenocrysts of the same minerals in their host rocks, but they have significantly less silicic bulk compositions and lack quartz and sanidine, which occur as single phenocrysts in the deposits. This implies significant crystallization followed by melt extraction from mushy reservoir margins. The extracted melt then continues to evolve (crystallizing sanidine and quartz) while the melt-depleted margins provide an increasingly rigid and refractory network segregating the crystal-poor batches of magma. The hot, refractory, margins insulate the crystal-poor lenses, allowing (1) extended residence in the upper crust, and (2) preservation of chemical heterogeneities among batches. In contrast, systems that produce cumulates richer in low-temperature phases (quartz, K-feldspars, and/or biotite) favour remelting upon recharge, leading to less segregation of eruptible melt pockets and the formation of gradationally zoned ignimbrites. The occurrence of similar crystal aggregates from a variety of magmatic lineages suggests the generality of this process.

  19. Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE).

    Science.gov (United States)

    Han, Thang S; Krone, Nils; Willis, Debbie S; Conway, Gerard S; Hahner, Stefanie; Rees, D Aled; Stimson, Roland H; Walker, Brian R; Arlt, Wiebke; Ross, Richard J

    2013-06-01

    Quality of life (QoL) has been variously reported as normal or impaired in adults with congenital adrenal hyperplasia (CAH). To explore the reasons for this discrepancy we investigated the relationship between QoL, glucocorticoid treatment and other health outcomes in CAH adults. Cross-sectional analysis of 151 adults with 21-hydroxylase deficiency aged 18-69 years in whom QoL (assessed using the Short Form Health Survey), glucocorticoid regimen, anthropometric and metabolic measures were recorded. Relationships were examined between QoL, type of glucocorticoid (hydrocortisone, prednisolone and dexamethasone) and dose of glucocorticoid expressed as prednisolone dose equivalent (PreDEq). QoL was expressed as z-scores calculated from matched controls (14,430 subjects from UK population). Principal components analysis (PCA) was undertaken to identify clusters of associated clinical and biochemical features and the principal component (PC) scores used in regression analysis as predictor of QoL. QoL scores were associated with type of glucocorticoid treatment for vitality (P=0.002) and mental health (P=0.011), with higher z-scores indicating better QoL in patients on hydrocortisone monotherapy (Padults with CAH. Intervention trials are required to establish whether choice of glucocorticoid treatment and/or weight loss can improve QoL in CAH adults.

  20. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2014-12-01

    combination of mifepristone and enzalutamide has been well tolerated with no dose limiting toxicities . The current cohort has dose- escalated the...Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer...Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0021 5c. PROGRAM ELEMENT

  1. Cumulative human impacts on marine predators

    DEFF Research Database (Denmark)

    Maxwell, Sara M; Hazen, Elliott L; Bograd, Steven J

    2013-01-01

    Stressors associated with human activities interact in complex ways to affect marine ecosystems, yet we lack spatially explicit assessments of cumulative impacts on ecologically and economically key components such as marine predators. Here we develop a metric of cumulative utilization and impact...

  2. Downregulation of cholesteryl ester transfer protein by glucocorticoids: a randomised study on HDL.

    Science.gov (United States)

    Werumeus Buning, Jorien; Dimova, Lidya G; Perton, Frank G; Tietge, Uwe J F; van Beek, André P; Dullaart, Robin P F

    2017-07-01

    High density lipoprotein (HDL) cholesterol is not decreased in hypercortisolism despite high triglycerides, which may be ascribed to effects on the cholesteryl ester transfer protein (CETP) pathway. We explored if CETP mRNA expression is modulated by glucocorticoid treatment in vitro. Effects of doubling the hydrocortisone (HCT) replacement dose on plasma CETP activity, and HDL characteristics were tested in patients with secondary adrenal insufficiency. Human THP-1 macrophages were incubated with corticosterone in vitro in the presence or absence of a liver X receptor (LXR) agonist, followed by determination of CETP mRNA levels by quantitative real-time PCR. In addition, a randomised double-blind cross-over study was performed in 47 patients with secondary adrenal insufficiency (university medical setting; 10 weeks exposure to a higher HCT dose (0·4-0·6 mg/kg body weight) vs. 10 weeks of a lower HCT dose (0·2-0·3 mg/kg body weight). Corticosterone dose dependently decreased CETP mRNA in THP-1 macrophages. Corticosterone also decreased CETP mRNA expression after LXR pretreatment. In patients, CETP activity decreased with doubling of the HCT dose (P = 0·049), coinciding with an increase in HDL cholesterol, apolipoprotein A-I and the HDL cholesterol/apolipoprotein A-I ratio (reflecting HDL size; P HDL cholesterol/apolipoprotein A-I ratio was correlated with the decrease in plasma CETP activity (r = -0·442, P = 0·002). Glucocorticoids downregulate CETP gene expression in a human macrophage cell system. In line, a higher glucocorticoid replacement dose decreases plasma CETP activity in patients, thereby contributing to higher HDL cholesterol and an increase in estimated HDL size. © 2017 Stichting European Society for Clinical Investigation Journal Foundation.

  3. Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A.

    Science.gov (United States)

    Schewitz-Bowers, Lauren P; Lait, Philippa J P; Copland, David A; Chen, Ping; Wu, Wenting; Dhanda, Ashwin D; Vistica, Barbara P; Williams, Emily L; Liu, Baoying; Jawad, Shayma; Li, Zhiyu; Tucker, William; Hirani, Sima; Wakabayashi, Yoshiyuki; Zhu, Jun; Sen, Nida; Conway-Campbell, Becky L; Gery, Igal; Dick, Andrew D; Wei, Lai; Nussenblatt, Robert B; Lee, Richard W J

    2015-03-31

    Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

  4. Familial glucocorticoid deficiency presenting with generalized hyperpigmentation in an Egyptian child: a case report

    Directory of Open Access Journals (Sweden)

    Metwalley Kotb A

    2012-04-01

    Full Text Available Abstract Introduction Familial glucocorticoid deficiency, or hereditary unresponsiveness to adrenocorticotropic hormone, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. It may present in infancy or early childhood with hyperpigmentation, failure to thrive, recurrent infections, hypoglycemic attacks and convulsions that may result in coma or death. Here, we report the case of an 18-month-old Egyptian boy with familial glucocorticoid deficiency. Case presentation An 18-month-old Egyptian boy was referred to our institution for evaluation of generalized hyperpigmentation of the body associated with recurrent convulsions; one of his siblings, who had died at the age of nine months, also had generalized hyperpigmentation of the body. The initial clinical examination revealed generalized symmetrical deep hyperpigmentation of the body as well as hypotonia, normal blood pressure and normal male genitalia. He had low blood glucose and cortisol levels, normal aldosterone and high adrenocorticotropic hormone levels. Based on the above mentioned data, a provisional diagnosis of familial glucocorticoid deficiency was made, which was confirmed by a molecular genetics study. Oral hydrocortisone treatment at a dose of 10 mg/m2/day was started. The child was followed up after two months of treatment; the hyperpigmentation has lessened in comparison with his initial presentation and his blood sugar and cortisol levels were normalized. Conclusion Familial glucocorticoid deficiency is a rare, treatable disease that can be easily missed due to nonspecific presentations. The consequences of delayed diagnosis and treatment are associated with high rates of morbidity and mortality.

  5. Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach.

    Science.gov (United States)

    de Quervain, Dominique J-F; Margraf, Jürgen

    2008-04-07

    Post-traumatic stress disorder (PTSD) and phobias belong to the most common anxiety disorders and to the most common psychiatric illnesses in general. In both disorders, aversive memories are thought to play an important role in the pathogenesis and symptomatology. Previously, we have reported that elevated glucocorticoid levels inhibit memory retrieval in animals and healthy humans. We therefore hypothesized that the administration of glucocorticoids might also inhibit the retrieval of aversive memory, thereby reducing symptoms in patients with PTSD and phobias. In recent clinical studies, we found first evidence to support this hypothesis. In patients with PTSD, low-dose cortisol treatment for one month reduced symptoms of traumatic memories without causing adverse side effects. Furthermore, we found evidence for a prolonged effect of the cortisol treatment. Persistent retrieval and reconsolidation of traumatic memories is a process that keeps these memories vivid and thereby the disorder alive. By inhibiting memory retrieval, cortisol may weaken the traumatic memory trace, and thus reduce symptoms even beyond the treatment period. In patients with social phobia, we found that a single oral administration of cortisone 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation-, exposure-, and recovery phase of the stressor. In subjects with spider phobia, repeated oral administration of cortisol 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again two days after the last cortisol administration, indicating that cortisol facilitated the extinction of phobic fear. In conclusion, by a common mechanism of reducing the retrieval of aversive memories, glucocorticoids may be suited for the treatment of PTSD as well as phobias. More studies are needed to further evaluate the therapeutic efficacy of

  6. Vasopressin and angiotensin II in reflex regulation of ACTH, glucocorticoids, and renin: effect of water deprivation

    Science.gov (United States)

    Brooks, V. L.; Keil, L. C.

    1992-01-01

    Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS).

  7. Duration of Suppression of Adrenal Steroids after Glucocorticoid Administration

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    John S. Fuqua

    2010-01-01

    Full Text Available Hydrocortisone has long been the treatment of choice for congenital adrenal hyperplasia (CAH. However, treatment with this medication remains problematic. Patients with 21-hydroxylase deficiency CAH have significant diurnal variation in the secretion of 17-hydroxyprogesterone (17OHP. When considering treatment strategies, this variation must be considered along with the pharmacokinetic and pharmacodynamic properties of exogenous glucocorticoids. Orally administered hydrocortisone is highly bioavailable, but it has a short time to maximum concentration (Tmax⁡ and half life (T1/2. While prednisone has a somewhat longer Tmax⁡ and T1/2, they remain relatively short. There have been several studies of the pharmacodynamics of hydrocortisone. We present data indicating that the maximum effect of hydrocortisone in CAH patients is seen 3 hours after a morning dose. After an evening dose, suppression of adrenal hormones continues until approximately 0500 the next day. In both situations, however, there is a large degree of intersubject variability. These data are consistent with earlier published studies. Use of alternate specimen types, possibly in conjunction with delayed release hydrocortisone preparations under development, may allow the practitioner to design a medication regimen that provides improved control of androgen secretion. Whatever dosing strategy is used, clinical judgment is required to ensure the best outcome.

  8. Glucocorticoid activity detected by in vivo zebrafish assay and in vitro glucocorticoid receptor bioassay at environmental relevant concentrations.

    Science.gov (United States)

    Chen, Qiyu; Jia, Ai; Snyder, Shane A; Gong, Zhiyuan; Lam, Siew Hong

    2016-02-01

    Glucocorticoids are pharmaceutical contaminants of emerging concern due to their incomplete removal during wastewater treatment, increased presence in aquatic environment and their biological potency. The zebrafish is a popular model for aquatic toxicology and environmental risk assessment. This study aimed to determine if glucocorticoids at environmental concentrations would perturb expression of selected glucocorticoid-responsive genes in zebrafish and to investigate their potentials as an in vivo zebrafish assay in complementing in vitro glucocorticoid receptor bioassay. The relative expression of eleven glucocorticoid-responsive genes in zebrafish larvae and liver of adult male zebrafish exposed to three representative glucocorticoids (dexamethasone, prednisolone and triamcinolone) was determined. The expression of pepck, baiap2 and pxr was up-regulated in zebrafish larvae and the expression of baiap2, pxr and mmp-2 was up-regulated in adult zebrafish exposed to glucocorticoids at concentrations equivalent to total glucocorticoids reported in environmental samples. The responsiveness of the specific genes were sufficiently robust in zebrafish larvae exposed to a complex environmental sample detected with in vitro glucocorticoid activity equivalent to 478 pM dexamethasone (DEX-EQ) and confirmed to contain low concentration (0.2 ng/L or less) of the targeted glucocorticoids, and possibly other glucocorticoid-active compounds. The findings provided in vivo relevance to the in vitro glucocorticoid activity and suggested that the environmental sample can perturb glucocorticoid-responsive genes in its original, or half the diluted, concentration as may be found in the environment. The study demonstrated the important complementary roles of in vivo zebrafish and in vitro bioassays coupled with analytical chemistry in monitoring environmental glucocorticoid contaminants.

  9. Chronic treatment with glucocorticoids alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous agmatine and arginine decarboxylase levels.

    Science.gov (United States)

    Zhu, Meng-Yang; Wang, Wei-Ping; Huang, Jingjing; Regunathan, Soundar

    2007-12-01

    In the present study, we examined the possible effect of chronic treatment with glucocorticoids on the morphology of the rat brain and levels of endogenous agmatine and arginine decarboxylase (ADC) protein, the enzyme essential for agmatine synthesis. Seven-day treatment with dexamethasone, at a dose (10 and 50 mug/kg/day) associated to stress effects contributed by glucocorticoids, did not result in obvious morphologic changes in the medial prefrontal cortex and hippocampus, as measured by immunocytochemical staining with beta-tubulin III. However, 21-day treatment (50 mug/kg/day) produced noticeable structural changes such as the diminution and disarrangement of dendrites and neurons in these areas. Simultaneous treatment with agmatine (50 mg/kg/day) prevented these morphological changes. Further measurement with HPLC showed that endogenous agmatine levels in the prefrontal cortex and hippocampus were significantly increased after 7-day treatments with dexamethasone in a dose-dependent manner. On the contrary, 21-day treatment with glucocorticoids robustly reduced agmatine levels in these regions. The treatment-caused biphasic alterations of endogenous agmatine levels were also seen in the striatum and hypothalamus. Interestingly, treatment with glucocorticoids resulted in a similar change of ADC protein levels in most brain areas to endogenous agmatine levels: an increase after 7-day treatment versus a reduction after 21-day treatment. These results demonstrated that agmatine has neuroprotective effects against structural alterations caused by glucocorticoids in vivo. The parallel alterations in the endogenous agmatine levels and ADC expression in the brain after treatment with glucocorticoids indicate the possible regulatory effect of these stress hormones on the synthesis and metabolism of agmatine in vivo.

  10. Ethanol regulation of serum glucocorticoid kinase 1 expression in DBA2/J mouse prefrontal cortex.

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    Blair N Costin

    Full Text Available BACKGROUND: We previously identified a group of glucocorticoid-responsive genes, including Serum Glucocorticoid kinase 1 (Sgk1, regulated by acute ethanol in prefrontal cortex of DBA2/J mice. Acute ethanol activates the hypothalamic pituitary adrenal axis (HPA causing release of glucocorticoids. Chronic ethanol dysregulates the HPA response in both humans and rodents, possibly contributing to important interactions between stress and alcoholism. Because Sgk1 regulates ion channels and learning and memory, we hypothesized that Sgk1 contributes to HPA-dependent acute and adaptive neuronal responses to ethanol. These studies characterized acute and chronic ethanol regulation of Sgk1 mRNA and protein and their relationship with ethanol actions on the HPA axis. RESULTS: Acute ethanol increased Sgk1 mRNA expression in a dose and time dependent manner. Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the Sgk1 promoter; adrenalectomy blocked ethanol induction of Sgk1 mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and Sgk1 induction by acute ethanol. SGK1 protein had complex temporal responses to acute ethanol with rapid and transient increases in Ser422 phosphorylation at 15 min. following ethanol administration. This activating phosphorylation had functional consequences, as suggested by increased phosphorylation of the known SGK1 target, N-myc downstream-regulated gene 1 (NDRG1. After repeated ethanol administration during locomotor sensitization, basal SGK1 protein phosphorylation increased despite blunting of Sgk1 mRNA induction by ethanol. CONCLUSIONS: These results suggest that HPA axis and glucocorticoid receptor signaling mediate acute ethanol induction of Sgk1 transcription in mouse prefrontal cortex. However, acute ethanol also causes complex changes in SGK1 protein expression and

  11. Adverse events of glucocorticoids during treatment of rheumatoid arthritis: lessons from cohort and registry studies.

    Science.gov (United States)

    W J Bijlsma, Johannes; Buttgereit, Frank

    2016-12-01

    Glucocorticoids have now been used for >65 years in the treatment of RA. There is good evidence for their disease-modifying effect, especially in early RA. When used in a dosage of 7.5-10 mg/day, most adverse effects can be handled quite well, although monitoring for and awareness of infections are important. Adverse events may have been overreported, due to bias by indication, but pose an important drawback in the use of these very effective anti-inflammatory and immune-modulatory drugs. Daily dosages >7.5-10 mg and use for a prolonged period (years) of time are associated with a dose-dependent increased mortality. Still, the benefit:risk ratio for low-dosage glucocorticoid in patients with RA is acceptable and in many ways is comparable with other synthetic and biologic DMARDs.

  12. Hormones, stress, and cognition: The effects of glucocorticoids and oxytocin on memory

    Science.gov (United States)

    Wirth, Michelle M.

    2014-01-01

    Hormones have nuanced effects on learning and memory processes. The degree and direction of the effect (e.g., is memory impaired or enhanced?) depends on the dose, type and stage of memory, and type of material being learned, among other factors. This review will focus on two specific topics within the realm of effects of hormones on memory: (1) How glucocorticoids (the output hormones of the hypothalamic-pituitary-adrenal axis) affect long-term memory consolidation, retrieval, and working memory, with a focus on neural mechanisms and effects of emotion; and (2) How oxytocin affects memory, with emphasis on a speculative hypothesis that oxytocin might exert its myriad effects on human social cognition and behavior via impacts on more general cognitive processes. Oxytocin-glucocorticoid interactions will be briefly addressed. These effects of hormones on memory will also be considered from an evolutionary perspective. PMID:25893159

  13. Vertebral histomorphometry in a child with glucocorticoid-induced osteoporosis.

    Science.gov (United States)

    Hatakeyama, Yuji; Miyakoshi, Naohisa; Kasukawa, Yuji; Watanabe, Arata; Hirayama, Masashi; Senma, Seietsu; Ono, Iwao; Shimada, Yoichi

    2012-08-01

    Vertebral fractures are an under-recognized problem in children with glucocorticoid-induced osteoporosis (GIO). They cause severe back pain and spinal column deformity with a decrease of quality of life. For evaluating the bone mass, bone mineral density measurements have been widely carried out using dual energy X-ray absorptiometry. However, bone histomorphometric analyses of GIO in children are scarce. Bone histomorphometric analyses of vertebral bodies have not been reported. Our aim is to report the first bone histomorphometric data for vertebrae from an autopsied child with GIO. A 15-year-old girl with systemic lupus erythematosus was started on a daily oral dose of 10 mg of prednisolone at 6 years of age. She presented with back pain from 12 years of age. Magnetic resonance imaging at 14 years of age showed a compression fracture of the first lumbar (L1) vertebral body. At 15 years of age, she died of heart failure owing to pulmonary hypertension. Collapsed (L1) and non-collapsed (seventh thoracic vertebrae; T7) vertebral bodies were autopsied for bone histomorphometry and compared. T7 showed severe osteoporosis (bone volume, 4.99%; trabecular thickness, 59 µm; trabecular separation, 1,134 µm). Compared with T7, L1 showed increased bone volume (33.9%) and trabecular thickness (77 µm), and decreased trabecular separation (156 µm) owing to the impact of the vertebral fracture. The bone formation and bone resorption parameters were comparable between the two vertebrae. These histological findings suggest that severe osteoporosis developed after long-term glucocorticoid administration, and that the remodeling activities were similar in the fractured and non-fractured vertebrae.

  14. Antenatal glucocorticoid treatment affects hippocampal development in mice.

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    Cornelle W Noorlander

    Full Text Available Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

  15. Antenatal glucocorticoid treatment affects hippocampal development in mice.

    Science.gov (United States)

    Noorlander, Cornelle W; Tijsseling, Deodata; Hessel, Ellen V S; de Vries, Willem B; Derks, Jan B; Visser, Gerard H A; de Graan, Pierre N E

    2014-01-01

    Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

  16. Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy.

    Science.gov (United States)

    Hapgood, Janet P; Avenant, Chanel; Moliki, Johnson M

    2016-09-01

    Pharmacological doses of glucocorticoids (GCs), acting via the glucocorticoid receptor (GR) to repress inflammation and immune function, remain the most effective therapy in the treatment of inflammatory and immune diseases. Since many patients on GC therapy exhibit GC resistance and severe side-effects, much research is focused on developing more selective GCs and combination therapies, with greater anti-inflammatory potency. GCs mediate their classical genomic transcriptional effects by binding to the cytoplasmic GR, followed by nuclear translocation and modulation of transcription of target genes by direct DNA binding of the GR or its tethering to other transcription factors. Recent evidence suggests, however, that the responses mediated by the GR are much more complex and involve multiple parallel mechanisms integrating simultaneous signals from other receptors, both in the absence and presence of GCs, to shift the sensitivity of a target cell to GCs. The level of cellular stress, immune activation status, or the cell cycle phase may be crucial for determining GC sensitivity and GC responsiveness as well as subcellular localization of the GR and GR levels. Central to the development of new drugs that target GR signaling alone or as add-on therapies, is an in-depth understanding of the molecular mechanisms of GC-independent GR desensitization, priming and activation of the unliganded GR, as well as synergy and cross-talk with other signaling pathways. This review will discuss the information currently available on these topics and their relevance to immunotherapy, as well as identify unanswered questions and future areas of research.

  17. Preventive Effects of Nitroglycerine on Glucocorticoid-induced Osteoporosis in Growing Rats

    Institute of Scientific and Technical Information of China (English)

    LI Yuming; LI Yongguo; YANG Weihong

    2007-01-01

    The preventive effects of nitroglycerine (NG) on glucocorticoid-induced osteoporosis in growing rats were studied. Three-month-old female Wistar rats were randomly divided into control group (CON), dexamethasone group (DXM), DXM plus a low dose NG group (NG-L), DXM plus a middle dose NG group (NG-M) and DXM plus a high dose NG group (NG-H), 8 rats in each group. The rat model of osteoporosis was developed by intramuscular injection of dexamethasone twice a week. NG 0.2, 0.4 and 1.0 mg/kg was administered by oral gavages to the treatment groups every day for 12 weeks. Rats in CON group and DXM group were treated with normal saline of the same amount. After the treatment, the bone mineral density (BMD) and bone metabolism-associated bio-chemical markers were determined. Compared with CON group, BMD of lumbar spine and femur in DXM group was decreased significantly (P<0.05 and P<0.01 respectively), blood BGP levels and NO levels reduced (both P<0.01), and TRAP level increased (P<0.05). As compared with DXM group, BMD, serum BGP and NO were increased, and TRAP decreased in NG-L group and NG-M group, but had no significant difference in comparison to CON group. All the markers other than se- rum NO and TRAP levels had no significant difference between NG-H group and DXM group.It was concluded that low or middle doses of NG could prevent glucocorticoid-induced bone loss in growing rats, but high dose of NG could not. Supplement with NO donor could be considered as a preventive treatment for glucocorticoid-induced osteoporosis in a developing skeleton.

  18. Nonlinear cumulative damage model for multiaxial fatigue

    Institute of Scientific and Technical Information of China (English)

    SHANG De-guang; SUN Guo-qin; DENG Jing; YAN Chu-liang

    2006-01-01

    On the basis of the continuum fatigue damage theory,a nonlinear uniaxial fatigue cumulative damage model is first proposed.In order to describe multiaxial fatigue damage characteristics,a nonlinear multiaxial fatigue cumulative damage model is developed based on the critical plane approach,The proposed model can consider the multiaxial fatigue limit,mean hydrostatic pressure and the unseparated characteristic for the damage variables and loading parameters.The recurrence formula of fatigue damage model was derived under multilevel loading,which is used to predict multiaxial fatigue life.The results showed that the proposed nonlinear multiaxial fatigue cumulative damage model is better than Miner's rule.

  19. Common Infections in Patients Prescribed Systemic Glucocorticoids in Primary Care: A Population-Based Cohort Study

    Science.gov (United States)

    Fardet, Laurence; Petersen, Irene; Nazareth, Irwin

    2016-01-01

    Background Little is known about the relative risk of common bacterial, viral, fungal, and parasitic infections in the general population of individuals exposed to systemic glucocorticoids, or about the impact of glucocorticoid exposure duration and predisposing factors on this risk. Methods and Findings The hazard ratios of various common infections were assessed in 275,072 adults prescribed glucocorticoids orally for ≥15 d (women: 57.8%, median age: 63 [interquartile range 48–73] y) in comparison to those not prescribed glucocorticoids. For each infection, incidence rate ratios were calculated for five durations of exposure (ranging from 15–30 d to >12 mo), and risk factors were assessed. Data were extracted from The Health Improvement Network (THIN) primary care database. When compared to those with the same underlying disease but not exposed to glucocorticoids, the adjusted hazard ratios for infections with significantly higher risk in the glucocorticoid-exposed population ranged from 2.01 (95% CI 1.83–2.19; p < 0.001) for cutaneous cellulitis to 5.84 (95% CI 5.61–6.08; p < 0.001) for lower respiratory tract infection (LRTI). There was no difference in the risk of scabies, dermatophytosis and varicella. The relative increase in risk was stable over the durations of exposure, except for LRTI and local candidiasis, for which it was much higher during the first weeks of exposure. The risks of infection increased with age and were higher in those with diabetes, in those prescribed higher glucocorticoid doses, and in those with lower plasma albumin level. Most associations were also dependent on the underlying disease. A sensitivity analysis conducted on all individuals except those with asthma or chronic obstructive pulmonary disease produced similar results. Another sensitivity analysis assessing the impact of potential unmeasured confounders such as disease severity or concomitant prescription of chemotherapy suggested that it was unlikely that

  20. Glucocorticoids reduce phobic fear in humans.

    Science.gov (United States)

    Soravia, Leila M; Heinrichs, Markus; Aerni, Amanda; Maroni, Caroline; Schelling, Gustav; Ehlert, Ulrike; Roozendaal, Benno; de Quervain, Dominique J-F

    2006-04-04

    Phobias are characterized by excessive fear, cued by the presence or anticipation of a fearful situation. Whereas it is well established that glucocorticoids are released in fearful situations, it is not known whether these hormones, in turn, modulate perceived fear. As extensive evidence indicates that elevated glucocorticoid levels impair the retrieval of emotionally arousing information, they might also inhibit retrieval of fear memory associated with phobia and, thereby, reduce phobic fear. Here, we investigated whether acutely administrated glucocorticoids reduced phobic fear in two double-blind, placebo-controlled studies in 40 subjects with social phobia and 20 subjects with spider phobia. In the social phobia study, cortisone (25 mg) administered orally 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation, exposure, and recovery phase of the stressor. Moreover, the stress-induced release of cortisol in placebo-treated subjects correlated negatively with fear ratings, suggesting that endogenously released cortisol in the context of a phobic situation buffers fear symptoms. In the spider phobia study, repeated oral administration of cortisol (10 mg), but not placebo, 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again 2 days after the last cortisol administration, suggesting that cortisol may also have facilitated the extinction of phobic fear. Cortisol treatment did not reduce general, phobia-unrelated anxiety. In conclusion, the present findings in two distinct types of phobias indicate that glucocorticoid administration reduces phobic fear.

  1. Glucocorticoids in endodontics: an online study guide.

    Science.gov (United States)

    2008-05-01

    The Editorial Board of the Journal of Endodontics has developed a literature-based study guide of topical areas related to endodontics. This study guide is intended to give the reader a focused review of the essential endodontic literature and does not cite all possible articles related to each topic. Although citing all articles would be comprehensive, it would defeat the idea of a study guide. This section will cover the use of glucocorticoids in endodontics.

  2. Recent progress in the discovery of novel glucocorticoid receptor modulators.

    Science.gov (United States)

    Takahashi, Hidenori; Razavi, Hossein; Thomson, David

    2008-01-01

    Glucocorticoids have been used in modern clinical practice for over fifty years. Although they have demonstrated potent anti-inflammatory and immunosuppressive activities, their association with debilitating and life-threatening side effects has been a major drawback. Recent insights into glucocorticoid biology have lent support to the hypothesis that the glucocorticoid anti-inflammatory activities could be dissociated from their adverse side effects. Inspired by these biological findings, the search for dissociated glucocorticoid receptor agonists has intensified. Antag-onists of the glucocorticoid receptor that offer therapeutic benefits for the treatment of diseases such as diabetes have also been pursued. These efforts have been partly focused on the development of tissue, especially liver, selective glucocor-ticoid receptor antagonists, which are thought to have improved safety profiles. This review offers a summary of the research and development activities in this field and covers journal and patent publications from 2003 to March 2006.

  3. The glucocorticoid receptor: a revisited target for toxins.

    Science.gov (United States)

    Marketon, Jeanette I Webster; Sternberg, Esther M

    2010-06-01

    The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy.

  4. Glucocorticoid-induced osteoporosis: 2013 update.

    Science.gov (United States)

    Mazzantini, M; Di Munno, O

    2014-01-01

    Glucocorticoids are the most common cause of secondary osteoporosis leading to the so-called glucocorticoid-induced osteoporosis (GIO). A treatment with 10 mg/d of prednisone or equivalent for more than 3 months leads to a 7-fold increase in hip fractures and a 17-fold increase in vertebral fractures. The difference between bone quantity and quality in GIO makes bone mineral density measurements inadequate to detect patients at risk of fracture. The adverse effects of glucocorticoids on the skeleton derive from a direct impact on bone cells with a severe impairment of mechanical competence. Crucial to prevention of GIO is early timing of intervention. The World Health Organization has adopted a fracture prevention algorithm (FRAX) intended to estimate fracture risk in GIO. The American College of Rhematology modified its prevention and treatment guidelines taking into account the individual risk of fracture calculated in GIO on the basis of the FRAX algorithm. Recently, also a joint Guideline Working Group of the International Osteoporosis Foundation (IOF) and the European Calcified Tissue Society (ECTS) published a framework for the development of national guidelines for the management of GIO. Bisphosphonates are the first-line drugs to treat GIO; teriparatide counteracts several fundamental pathophysiologic aspects of GIO; denosumab is useful in patients with renal failure and in potentially pregnant young women. Vertebroplasty and kyphoplasty may be less beneficial in GIO than in primary involutional osteoporosis.

  5. Biochemical endpoints of glucocorticoid hormone action

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    Young, D.A.; Nicholson, M.L.; Guyette, W.A.; Giddings, S.J.; Mendelsohn, S.L.; Nordeen, S.K.; Lyons, R.T.

    1978-01-01

    Both the rapidly evolving metabolic effects of glucocorticoids and the more slowly developing lethal actions appear to be initiated via the synthesis of new mRNAs and proteins. The chronic suppression of cell growth may be the consequence of suppression of overall rates of protein synthesis (and probably RNA and DNA synthesis as well) that in turn may represent the cellular response to the small changes in ratios of adenine nucleotides that result from the suppression of oxidative ATP production. The inhibition of glucose transport may also play a role here to prevent a compensatory increase in glycolytic ATP production. Some other hormone actions, the decrease in the ability of cells to concentrate AIB and the increase in nuclear fragility are unrelated to, and evolve separately from, the hormonal inhibitions on energy production. Cell killing is not the result of suppression of protein synthesis, nor of hormone-induced increases in calcium uptake. While the mechanisms are unknown, the increase in nuclear fragility appears to be the earliest measure of their operation. In tumor cells resistance to lethal actions of glucocorticoids may emerge via the selection of cells with hardier membranes, that are better able to withstand the intracellular destructive events set in motion by high levels of glucocorticoids.

  6. Cumulative risk: toxicity and interactions of physical and chemical stressors.

    Science.gov (United States)

    Rider, Cynthia V; Boekelheide, Kim; Catlin, Natasha; Gordon, Christopher J; Morata, Thais; Selgrade, Maryjane K; Sexton, Kenneth; Simmons, Jane Ellen

    2014-01-01

    Recent efforts to update cumulative risk assessment procedures to incorporate nonchemical stressors ranging from physical to psychosocial reflect increased interest in consideration of the totality of variables affecting human health and the growing desire to develop community-based risk assessment methods. A key roadblock is the uncertainty as to how nonchemical stressors behave in relationship to chemical stressors. Physical stressors offer a reasonable starting place for measuring the effects of nonchemical stressors and their modulation of chemical effects (and vice versa), as they clearly differ from chemical stressors; and "doses" of many physical stressors are more easily quantifiable than those of psychosocial stressors. There is a commonly held belief that virtually nothing is known about the impact of nonchemical stressors on chemically mediated toxicity or the joint impact of coexposure to chemical and nonchemical stressors. Although this is generally true, there are several instances where a substantial body of evidence exists. A workshop titled "Cumulative Risk: Toxicity and Interactions of Physical and Chemical Stressors" held at the 2013 Society of Toxicology Annual Meeting provided a forum for discussion of research addressing the toxicity of physical stressors and what is known about their interactions with chemical stressors, both in terms of exposure and effects. Physical stressors including sunlight, heat, radiation, infectious disease, and noise were discussed in reference to identifying pathways of interaction with chemical stressors, data gaps, and suggestions for future incorporation into cumulative risk assessments.

  7. Cumulative cultural learning: Development and diversity.

    Science.gov (United States)

    Legare, Cristine H

    2017-07-24

    The complexity and variability of human culture is unmatched by any other species. Humans live in culturally constructed niches filled with artifacts, skills, beliefs, and practices that have been inherited, accumulated, and modified over generations. A causal account of the complexity of human culture must explain its distinguishing characteristics: It is cumulative and highly variable within and across populations. I propose that the psychological adaptations supporting cumulative cultural transmission are universal but are sufficiently flexible to support the acquisition of highly variable behavioral repertoires. This paper describes variation in the transmission practices (teaching) and acquisition strategies (imitation) that support cumulative cultural learning in childhood. Examining flexibility and variation in caregiver socialization and children's learning extends our understanding of evolution in living systems by providing insight into the psychological foundations of cumulative cultural transmission-the cornerstone of human cultural diversity.

  8. Dibutyltin disrupts glucocorticoid receptor function and impairs glucocorticoid-induced suppression of cytokine production.

    Directory of Open Access Journals (Sweden)

    Christel Gumy

    Full Text Available BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK and tyrosine-aminotransferase (TAT and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6 and TNF-alpha production in lipopolysaccharide (LPS-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.

  9. Calculating Cumulative Binomial-Distribution Probabilities

    Science.gov (United States)

    Scheuer, Ernest M.; Bowerman, Paul N.

    1989-01-01

    Cumulative-binomial computer program, CUMBIN, one of set of three programs, calculates cumulative binomial probability distributions for arbitrary inputs. CUMBIN, NEWTONP (NPO-17556), and CROSSER (NPO-17557), used independently of one another. Reliabilities and availabilities of k-out-of-n systems analyzed. Used by statisticians and users of statistical procedures, test planners, designers, and numerical analysts. Used for calculations of reliability and availability. Program written in C.

  10. METHOTREXATE IN THE TREATMENT OF GLUCOCORTICOID-DEPENDENT ASTHMA

    Institute of Scientific and Technical Information of China (English)

    王国杨; 朱利文; 姚婉贞; 赵呜武

    2001-01-01

    To study how low-dose of methotrexate affects steroid use, asthma symptom scores and pulmonary function in glucocorticoid-dependent asthmatic patients.Methods 13 patients with severe, steroid-dependent asthma were enrolled in the prospective study, who received weekly oral methotrexate 20 mg for 12 months. Of these 13 patients, 12 finished 12 monthcourseResults The mean prednisone dose reduced from 20.63mg/d to 7.71mg/d (P<0.001) in the 12 patients treated with long-term methotrexate: Eight patients discontinued the regular use of prednisone, 10 patients reduced predaisone dosage by more than 50%. Measurement of forced vital capacity(FVC) and forced expiratory volume in one second (FEV1) showed that there was no deterioration due to methotrexate treatment and steroid reduction. Mean daily symptom scores for cough, wheezing, shortness of breath, and chest tightness remained unchanged.Conclusion Our study provides evidence supporting the long-term efficacy and safety of methotrexate in patients with severe bronchial asthma.

  11. Cumulative cultural evolution: the role of teaching.

    Science.gov (United States)

    Castro, Laureano; Toro, Miguel A

    2014-04-21

    In humans, cultural transmission occurs usually by cumulative inheritance, generating complex adaptive behavioral features. Cumulative culture requires key psychological processes (fundamentally imitation and teaching) that are absent or impoverished in non-human primates. In this paper we analyze the role that teaching has played in human cumulative cultural evolution. We assume that a system of cumulative culture generates increasingly adaptive behaviors, that are also more complex and difficult to imitate. Our thesis is that, as cultural traits become more complex, cumulative cultural transmission requires teaching to ensure accurate transmission from one generation to the next. In an increasingly complex cultural environment, we consider that individuals commit errors in imitation. We develop a model of cumulative cultural evolution in a changing environment and show that these errors hamper the process of cultural accumulation. We also show that a system of teaching between parents and offspring that increases the fidelity of imitation unblocks the accumulation and becomes adaptive whenever the gain in fitness compensates the cost of teaching.

  12. Human cumulative culture: a comparative perspective.

    Science.gov (United States)

    Dean, Lewis G; Vale, Gill L; Laland, Kevin N; Flynn, Emma; Kendal, Rachel L

    2014-05-01

    Many animals exhibit social learning and behavioural traditions, but human culture exhibits unparalleled complexity and diversity, and is unambiguously cumulative in character. These similarities and differences have spawned a debate over whether animal traditions and human culture are reliant on homologous or analogous psychological processes. Human cumulative culture combines high-fidelity transmission of cultural knowledge with beneficial modifications to generate a 'ratcheting' in technological complexity, leading to the development of traits far more complex than one individual could invent alone. Claims have been made for cumulative culture in several species of animals, including chimpanzees, orangutans and New Caledonian crows, but these remain contentious. Whilst initial work on the topic of cumulative culture was largely theoretical, employing mathematical methods developed by population biologists, in recent years researchers from a wide range of disciplines, including psychology, biology, economics, biological anthropology, linguistics and archaeology, have turned their attention to the experimental investigation of cumulative culture. We review this literature, highlighting advances made in understanding the underlying processes of cumulative culture and emphasising areas of agreement and disagreement amongst investigators in separate fields.

  13. Transforming growth factor-alpha abrogates glucocorticoid-stimulated tight junction formation and growth suppression in rat mammary epithelial tumor cells.

    Science.gov (United States)

    Buse, P; Woo, P L; Alexander, D B; Cha, H H; Reza, A; Sirota, N D; Firestone, G L

    1995-03-24

    The glucocorticoid and transforming growth factor-alpha (TGF-alpha) regulation of growth and cell-cell contact was investigated in the Con8 mammary epithelial tumor cell line derived from a 7,12-dimethylbenz(alpha)anthracene-induced rat mammary adenocarcinoma. In Con8 cell monolayers cultured on permeable filter supports, the synthetic glucocorticoid, dexamethasone, coordinately suppressed [3H]thymidine incorporation, stimulated monolayer transepithelial electrical resistance (TER), and decreased the paracellular leakage of [3H]inulin or [14C]mannitol across the monolayer. These processes dose dependently correlated with glucocorticoid receptor occupancy and function. Constitutive production of TGF-alpha in transfected cells or exogenous treatment with TGF-alpha prevented the glucocorticoid growth suppression response and disrupted tight junction formation without affecting glucocorticoid responsiveness. Treatment with hydroxyurea or araC demonstrated that de novo DNA synthesis is not a requirement for the growth factor disruption of tight junctions. Immunofluorescence analysis revealed that the ZO-1 tight junction protein is localized exclusively at the cell periphery in dexamethasone-treated cells and that TGF-alpha caused-ZO-1 to relocalize from the cell periphery back to a cytoplasmic compartment. Taken together, our results demonstrate that glucocorticoids can coordinately regulate growth inhibition and cell-cell contact of mammary tumor cells and that TGF-alpha, can override both effects of glucocorticoids. These results have uncovered a novel functional "cross-talk" between glucocorticoids and TGF-alpha which potentially regulates the proliferation and differentiation of mammary epithelial cells.

  14. Assessment of the Prevalence and Risk Factors Associated With Glucocorticoid-Induced Diabetes Mellitus in Pemphigus Vulgaris Patients

    Directory of Open Access Journals (Sweden)

    Abbas Darjani

    2017-08-01

    Full Text Available Pemphigus vulgaris is a chronic autoimmune disease and glucocorticoids are one of the main treatments. Our study investigates the prevalence and associated factors of glucocorticoid-induced diabetes mellitus in these patients under different glucocorticoid regimens. 36 patients with first diagnosed Pemphigus vulgaris based on pathological and direct immunofluorescence findings who had received different glucocorticoid regimens (1-2 mg/kg oral or 1-2 mg/kg oral with 1g methylprednisolone pulse daily for 3 consecutive days with or without azathioprine were evaluated during 2014-2016. Our study found that 22.2% of patients had impaired fasting glucose and incidence of corticosteroid-induced diabetes mellitus was 22.2% with no difference between oral and pulse therapy of corticosteroid. The first day after pulse therapy 19 patients of 21 had post bolus hyperglycemia that 36% of them became diabetic after 8 weeks. None of the variables, including age, BMI, HbA1c, LDL, HDL, TG, cholesterol, family history and blood pressure were associated with diabetes. Pretreatment FBS was the factor that would increase the likelihood of glucocorticoid-induced diabetes mellitus, 42.2% of patients with pretreatment FBS 100-126 developed diabetes in comparison with 17.2% in normal pretreatment FBS. Although the group who received azathioprine was associated with increased incidence of diabetes, the overall corticosteroid dose in this group was significantly higher than the other group (P=0.012, and controversy with other studies could be because of difference in corticosteroid dosage and small number of patients. The incidence of diabetes was not different between the group with glucocorticoid pulses and oral prednisolone without pulse therapy. Higher pretreatment FBS can be related to increased incidence of diabetes, but results from this study due to small number of patients are preliminary and multicenter studies are needed.

  15. The Regulation of Muscle Mass by Endogenous Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Daniel L Marks

    2015-02-01

    Full Text Available Glucocorticoids are highly conserved fundamental regulators of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, glucocorticoids are released from the adrenal gland, rapidly mobilizing energy from carbohydrate, fat and protein stores. In the case of inflammation, mobilized protein is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilization can lead to a p rofound depletion of energy stores. Skeletal muscle represents the major body store of protein, and can become substantially atrophied under conditions of chronic inflammation. Glucocorticoids elicit the atrophy of muscle by increasing the rate of protein degradation by the ubiquitin-proteasome system and autophagy lysosome system. Protein synthesis is also suppressed at the level of translational initiation, preventing the production of new myofibrillar protein. Glucocorticoids also antagonize the action of anabolic regulators such as insulin further exacerbating the loss of protein and muscle mass. The loss of muscle mass in the context of chronic disease is a key feature of cachexia and contributes substantially to morbidity and mortality. A growing body of evidence demonstrates that glucocorticoid signaling is a common mediator of wasting, irrespective of the underlying initiator or disease state. This review will highlight fundamental mechanisms of glucocorticoid signaling and detail the mechanisms of glucocorticoid-induced muscle atrophy. Additionally, the evidence for glucocorticoids as a driver of muscle wasting in numerous disease states will be discussed. Given the burden of wasting diseases and the nodal nature of glucocorticoid signaling, effective anti-glucocorticoid therapy would be a valuable clinical tool. Therefore, the progress and potential pitfalls in the development of glucocorticoid antagonists for muscle wasting will

  16. The regulation of muscle mass by endogenous glucocorticoids.

    Science.gov (United States)

    Braun, Theodore P; Marks, Daniel L

    2015-01-01

    Glucocorticoids are highly conserved fundamental regulators of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, glucocorticoids are released from the adrenal gland, rapidly mobilizing energy from carbohydrate, fat and protein stores. In the case of inflammation, mobilized protein is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilization can lead to a profound depletion of energy stores. Skeletal muscle represents the major body store of protein, and can become substantially atrophied under conditions of chronic inflammation. Glucocorticoids elicit the atrophy of muscle by increasing the rate of protein degradation by the ubiquitin-proteasome system and autophagy lysosome system. Protein synthesis is also suppressed at the level of translational initiation, preventing the production of new myofibrillar protein. Glucocorticoids also antagonize the action of anabolic regulators such as insulin further exacerbating the loss of protein and muscle mass. The loss of muscle mass in the context of chronic disease is a key feature of cachexia and contributes substantially to morbidity and mortality. A growing body of evidence demonstrates that glucocorticoid signaling is a common mediator of wasting, irrespective of the underlying initiator or disease state. This review will highlight fundamental mechanisms of glucocorticoid signaling and detail the mechanisms of glucocorticoid-induced muscle atrophy. Additionally, the evidence for glucocorticoids as a driver of muscle wasting in numerous disease states will be discussed. Given the burden of wasting diseases and the nodal nature of glucocorticoid signaling, effective anti-glucocorticoid therapy would be a valuable clinical tool. Therefore, the progress and potential pitfalls in the development of glucocorticoid antagonists for muscle wasting will be discussed.

  17. Clinical experience with daily doses of misonidazole

    Energy Technology Data Exchange (ETDEWEB)

    Kogelnik, H.D.; Reinartz, G.; Szepesi, T.; Seitz, W.; Wurst, F.; Mamoli, B.; Wessely, P.; Stark, H.

    1980-11-01

    In this pilot study daily low doses of misonidazole (in the range of 1 to 2 g) up to cumulative doses between 7 and 19 g/m/sup 2/ were used. Serum levels were analysed at different times after administration and according to several dose regimens. We related the cumulative doses to the incidence and severity of the observed peripheral neuropathies. The aim was to find an effective daily low-dose schedule of misonidazole with a clinically acceptable incidence of side effects. Some impressive clinical responses were observed.

  18. Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.

    NARCIS (Netherlands)

    H. Russcher (Henk); P. Smit (Pauline); E.L.T. van den Akker (Erica); E.F.C. van Rossum (Liesbeth); A.O. Brinkmann (Albert); F.H. de Jong (Frank); S.W.J. Lamberts (Steven); J.W. Koper (Jan)

    2005-01-01

    textabstractCONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND DESIGN

  19. Glucocorticoid receptors in Epstein-Barr virus-transformed lymphocytes from patients with glucocorticoid resistance and a glucocorticoid-resistant New World primate species.

    Science.gov (United States)

    Tomita, M; Brandon, D D; Chrousos, G P; Vingerhoeds, A C; Foster, C M; Fowler, D; Loriaux, D L; Lipsett, M B

    1986-06-01

    Members of a previously reported family with glucocorticoid resistance and several New World primates have high plasma cortisol concentrations without any signs of glucocorticoid excess. The glucocorticoid receptor in circulating leukocytes and cultured skin fibroblasts from these patients and the animals is characterized by a decreased affinity for dexamethasone. On the other hand, the cell content of receptor is similar to that of corresponding tissues of normal humans. Detailed biochemical-biophysical studies of the glucocorticoid receptor in this familial syndrome and animal model became possible with the use of Epstein-Barr virus-transformed lymphocyte lines. Cell lines from patients with this syndrome and from the marmoset (Saguinus oedipus) contained decreased amounts of glucocorticoid receptors with concomitant decreases in nuclear receptor content compared to cultured Epstein-Barr virus-transformed lymphocytes from normal human subjects. This may reflect diminished induction of glucocorticoid receptor during viral transformation of cells from the patients and the animal model. Receptors from a severely affected glucocorticoid-resistant patient and the marmoset had decreased affinity for dexamethasone. Evidence for a mild affinity defect of the glucocorticoid receptor in a patient with asymptomatic glucocorticoid resistance was obtained by increased hormone-receptor dissociation at an elevated temperature. Thermal stability, mero-receptor formation, thermal activation of cytosolic receptor, and mol wt of receptors from all cell lines were normal. Only the receptors of the severely affected patient had a discernible defect in temperature-induced activation of intact cells. We conclude that the major detectable change in the receptor in both the patients and the animal model is the decreased affinity for glucocorticoid. Viral receptor induction is decreased in both patient and marmoset cells. The physiological relevance of this phenomenon is not known. Gross

  20. Progesterone inhibits glucocorticoid-dependent aromatase induction in human adipose fibroblasts.

    Science.gov (United States)

    Schmidt, M; Renner, C; Löffler, G

    1998-09-01

    In fibroblasts derived from human adipose tissue, aromatase induction is observed after exposure to 1 microM cortisol in the presence of serum or platelet-derived growth factor (PDGF). Progesterone suppresses this induction in a dose-dependent manner, 10 microM resulting in complete inhibition. A reduced cortisol concentration (0.1 microM) concomitantly reduces the progesterone concentration required for effective inhibition (10-100 nM). This effect of progesterone is specific, as neither the release of cellular enzymes nor aromatase induction by dibutyryl-cAMP, which acts independently from cortisol, are affected. However, the inhibitory effect of progesterone requires its presence throughout the induction period. Kinetic studies in intact cells reveal a reduced number of aromatase active sites upon progesterone treatment, whereas progesterone at near-physiological concentration (100 nM) does not inhibit aromatase activity in isolated microsomes. Semi-quantitative reverse transcriptase PCR analysis shows reduced amounts of aromatase mRNA in progesterone-treated cells, indicating specific inhibition of the glucocorticoid-dependent pathway of aromatase induction. The inhibitory effect of progesterone is not blocked by the anti-progestin ZK114043, excluding action via progesterone receptors and indicating competition for the glucocorticoid receptor. Progesterone must be considered a potential physiological inhibitor of glucocorticoid-dependent aromatase induction in adipose tissue. It is proposed that it is a suppressor of aromatase induction in adipose tissue in premenopausal women.

  1. Glucocorticoids aggravate retrograde memory deficiency associated with traumatic brain injury in rats.

    Science.gov (United States)

    Chen, Xin; Zhang, Ke-Li; Yang, Shu-Yuan; Dong, Jing-Fei; Zhang, Jian-Ning

    2009-02-11

    Administration of glucocorticoid to patients with head injury has previously been demonstrated to impair memory. We hypothesize that glucocorticoids promote post-traumatic hippocampal apoptosis, resulting in retrograde memory deficiency associated with traumatic brain injury (TBI). In the present study, we tested this hypothesis by measuring spatial memory deficiency in rats subjected to fluid percussion injury (FPI) and receiving dexamethasone (DXM at 0.5-10 mg/kg) or methylprednisolone (MP at 5-30 mg/kg); we also examined neuronal apoptosis in hippocampus. Adult male Wistar rats were trained for the acquisition of spatial memory, then subjected to FPI and tested for spatial reference memory on post-injury days 7 and 14 using the Morris Water Maze. Brain tissue from injured rats was examined 24 h to 2 weeks after injury. The percent time in the goal quadrant, which measures spatial reference memory, was significantly lower in injured rats receiving either high-dose DXM or MP than in control groups. TUNEL-positive cells in hippocampus were first detected 24 h post-injury, plateauing at 48h. The number of TUNEL-positive cells was significantly higher in injured rats treated with either DXM or MP. The data suggest that glucocorticoid therapy for TBI may increase neuronal apoptosis in hippocampus and, as a result, aggravate retrograde memory deficits induced by TBI.

  2. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients

    Directory of Open Access Journals (Sweden)

    Wen-biao ZHAO

    2014-10-01

    Full Text Available Objective To observe the effect of glucocorticoid inhalation on the clinical symptoms and pulmonary fibrosis index in ARDS patients. Methods Fifty-three ARDS patients admitted to ICU of Songjiang District Center Hospital of Shanghai from Dec. 2011 to Jun. 2013 were randomly divided into two groups. Group A (n=29 received conventional therapy, and group B (n=24 was given glucocorticoid inhalation treatment (budesonide, 2 mg, 1/12 h, for 12 days on the basis of the conventional therapy. The oxygenation index, time of extubation, changes in pulmonary fibrosis index, including collagen Ⅰ(Co Ⅰ, Ⅲ procollagen peptide (PⅢP and transforming growth factor (TGF-β1 were compared between the two groups, and the incidence of common adverse reactions were analyzed. Results The oxygenation index of patients in group B was significantly improved on the 15th day compared with group A (P0.05. Conclusion A small dose of glucocorticoids introduced by inhalation can improve the oxygenation index and pulmonary fibrosis level without increasing common adverse reactions, suggesting that the inhalation of corticosteroid may be a clinically safe and effective way in patients with ARDS. DOI: 10.11855/j.issn.0577-7402.2014.09.13

  3. New selective glucocorticoid receptor modulators reverse amyloid-β peptide-induced hippocampus toxicity.

    Science.gov (United States)

    Pineau, Fanny; Canet, Geoffrey; Desrumaux, Catherine; Hunt, Hazel; Chevallier, Nathalie; Ollivier, Matthias; Belanoff, Joseph K; Givalois, Laurent

    2016-09-01

    In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-β peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Predicting Cumulative Incidence Probability by Direct Binomial Regression

    DEFF Research Database (Denmark)

    Scheike, Thomas H.; Zhang, Mei-Jie

    Binomial modelling; cumulative incidence probability; cause-specific hazards; subdistribution hazard......Binomial modelling; cumulative incidence probability; cause-specific hazards; subdistribution hazard...

  5. Stepping stones in the path of glucocorticoid-driven apoptosis of lymphoid cells

    Institute of Scientific and Technical Information of China (English)

    E.Brad Thompson

    2008-01-01

    Cumulative work on glucocorticoid (GC) regulation of genes in lymphoid cell cultures has revealed that apoptotic sensitivity to GCs depends on sufficient active GC receptors in the cells.The actions of the ligand-driven GC receptor that lead to apoptosis depend on interactions with other major cell.signaling systems,including the MAPK pathways,the cA P/PKA pathway,the hedgehogpathway,the mTORsystem and the c-myc system.The balance between these systems determines whether a given cell responds to GCs by undergoing apoptosis.A central core of networked genes may be found under GC control in many types of malignant,GCsensitive cells.The partial core list identified should be tested in clinical cell samples from hematologic malignancies.

  6. Cell cycle phase regulates glucocorticoid receptor function.

    Directory of Open Access Journals (Sweden)

    Laura Matthews

    Full Text Available The glucocorticoid receptor (GR is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1. Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G(1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase. The impact of cell cycle-driven GR trafficking on a panel of glucocorticoid actions was profiled. In G2/M-enriched cells there was marked prolongation of glucocorticoid-induced ERK activation. This was accompanied by DNA template-specific, ligand-independent GR transactivation. Using chimeric and domain-deleted receptors we demonstrate that this transactivation effect is mediated by the AF1 transactivation domain. AF-1 harbours multiple phosphorylation sites, which are consensus sequences for kinases including CDKs, whose activity changes during the cell cycle. In G2/M there was clear ligand independent induction of GR phosphorylation on residues 203 and 211, both of which are phosphorylated after ligand activation. Ligand-independent transactivation required induction of phospho-S211GR but not S203GR, thereby directly linking cell cycle driven GR modification with altered GR function. Cell cycle phase therefore regulates GR localisation and post-translational modification which selectively impacts GR activity. This suggests that cell cycle phase is an important determinant in the cellular response to Gc, and that mitotic index contributes to tissue Gc sensitivity.

  7. Glucocorticoids decrease Treg cell numbers in lungs of allergic mice.

    Science.gov (United States)

    Olsen, P C; Kitoko, J Z; Ferreira, T P; de-Azevedo, C T; Arantes, A C; Martins, Μ A

    2015-01-15

    Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients.

  8. Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis.

    Science.gov (United States)

    Conrad, Cheryl D

    2008-01-01

    The hippocampus, a limbic structure important in learning and memory, is particularly sensitive to chronic stress and to glucocorticoids. While glucocorticoids are essential for an effective stress response, their oversecretion was originally hypothesized to contribute to age-related hippocampal degeneration. However, conflicting findings were reported on whether prolonged exposure to elevated glucocorticoids endangered the hippocampus and whether the primate hippocampus even responded to glucocorticoids as the rodent hippocampus did. This review discusses the seemingly inconsistent findings about the effects of elevated and prolonged glucocorticoids on hippocampal health and proposes that a chronic stress history, which includes repeated elevation of glucocorticoids, may make the hippocampus vulnerable to potential injury. Studies are described to show that chronic stress or prolonged exposure to glucocorticoids can compromise the hippocampus by producing dendritic retraction, a reversible form of plasticity that includes dendritic restructuring without irreversible cell death. Conditions that produce dendritic retraction are hypothesized to make the hippocampus vulnerable to neurotoxic or metabolic challenges. Of particular interest is the finding that the hippocampus can recover from dendritic retraction without any noticeable cell loss. When conditions surrounding dendritic retraction are present, the potential for harm is increased because dendritic retraction may persist for weeks, months or even years, thereby broadening the window of time during which the hippocampus is vulnerable to harm, called the 'glucocorticoid vulnerability hypothesis'. The relevance of these findings is discussed with regard to conditions exhibiting parallels in hippocampal plasticity, including Cushing's disease, major depressive disorder (MDD), and post-traumatic stress disorder (PTSD).

  9. Glucocorticoids facilitate the retention of acquired immobility during forced swimming

    NARCIS (Netherlands)

    Veldhuis, H D; De Korte, C C; De Kloet, E R

    1985-01-01

    The adrenalectomy-induced decrease in the level of immobility during a 5 min retest period in the Porsolt swimming test could be reversed by glucocorticoids administered s.c. 15 min after the initial forced swimming exposure. The synthetic glucocorticoids dexamethasone and RU 28362 were active in

  10. Exogenous Glucocorticoids Decrease Subgenual Cingulate Activity Evoked by Sadness

    Science.gov (United States)

    Sudheimer, Keith D; Abelson, James L; Taylor, Stephan F; Martis, Brian; Welsh, Robert C; Warner, Christine; Samet, Mira; Manduzzi, Andrea; Liberzon, Israel

    2013-01-01

    The glucocorticoid hormone cortisol is known to have wide-ranging effects on a variety of physiological systems, including the morphology and physiology of the amygdala and hippocampus. Disruptions of cortisol regulation and signaling are also linked with psychiatric disorders involving emotional disturbances. Although there is much evidence to suggest a relationship between cortisol signaling and the brain physiology underlying emotion, few studies have attempted to test for direct effects of cortisol on the neurophysiology of emotion. We administered exogenous synthetic cortisol (hydrocortisone, HCT) using two different dosing regimens (25 mg/day over 4 days, 100 mg single dose), in a double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study. During fMRI scanning, healthy subjects viewed images designed to induce happy, sad, and neutral emotional states. Subjective emotional reactions were collected for each experimental stimulus after fMRI scanning. Mood ratings were also collected throughout the 4 days of the study. Both dose regimens of HCT resulted in decreased subgenual cingulate activation during sadness conditions. The 25 mg/day regimen also resulted in higher arousal ratings of sad stimuli. No effects of HCT were observed on any mood ratings. Few reliable effects of HCT were observed on brain activity patterns or subjective emotional responses to stimuli that were not sad. The inhibitory effects of cortisol on sadness-induced subgenual cingulate activity may have critical relevance to the pathophysiology of major depression, as both subgenual hyperactivity and decreased sensitivity to cortisol signaling have been documented in patients with depression. PMID:23303057

  11. Glucocorticoid-related genetic susceptibility for Alzheimer's disease.

    Science.gov (United States)

    de Quervain, Dominique J-F; Poirier, Raphael; Wollmer, M Axel; Grimaldi, Luigi M E; Tsolaki, Magdalini; Streffer, Johannes R; Hock, Christoph; Nitsch, Roger M; Mohajeri, M Hasan; Papassotiropoulos, Andreas

    2004-01-01

    Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for Alzheimer's disease (AD). We analyzed single-nucleotide polymorphisms in 10 glucocorticoid-related genes in a population of 814 AD patients and unrelated control subjects. Set-association analysis revealed that a rare haplotype in the 5' regulatory region of the gene encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) was associated with a 6-fold increased risk for sporadic AD. Results of a reporter-gene assay indicated that the rare risk-associated haplotype altered HSD11B1 transcription. HSD11B1 controls tissue levels of biologically active glucocorticoids and thereby influences neuronal vulnerability. Our results indicate that a functional variation in the glucocorticoid system increases the risk for AD, which may have important implications for the diagnosis and treatment of this disease.

  12. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

    Damsted, Sara K.; Born, A P; Paulson, Olaf B;

    2011-01-01

    of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids...... reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported....... Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular...

  13. Cumulative Culture and Future Thinking: Is Mental Time Travel a Prerequisite to Cumulative Cultural Evolution?

    Science.gov (United States)

    Vale, G. L.; Flynn, E. G.; Kendal, R. L.

    2012-01-01

    Cumulative culture denotes the, arguably, human capacity to build on the cultural behaviors of one's predecessors, allowing increases in cultural complexity to occur such that many of our cultural artifacts, products and technologies have progressed beyond what a single individual could invent alone. This process of cumulative cultural evolution…

  14. Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14-17 year-old adolescents.

    NARCIS (Netherlands)

    Wolbeek, M. ter; Sonneville, L.M. de; Vries, W.B. de; Kavelaars, A.; Veen, S.; Kornelisse, R.F.; Weissenbruch, M. van; Baerts, W.; Liem, K.D.; Bel, F. van; Heijnen, C.J.

    2013-01-01

    OBJECTIVE: To reduce the risk of bronchopulmonary dysplasia, preterm infants receive neonatal treatment with glucocorticoids, mostly dexamethasone (DEX). Compared to current protocols, treatment regimens of the late 1980s - early 1990s prescribed high doses of DEX for an extensive period up to 6 wee

  15. A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo

    NARCIS (Netherlands)

    Huizenga, NATM; Koper, JW; De Lange, P; Pols, HAP; Stolk, RP; Burger, H; Grobbee, DE; Brinkmann, AO; De Jong, FH; Lamberts, SWJ

    1998-01-01

    We investigated whether a polymorphism at nucleotide position 1220, resulting in an asparagine-to-serine change at codon 363 in the glucocorticoid receptor (GR) gene is associated with an altered sensitivity to glucocorticoids. In a group of 216 elderly persons, 13 heterozygotes for the N363S polymo

  16. Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    C.P. Fitzsimons; J. Herbert; M. Schouten; O.C. Meijer; P.J. Lucassen; S. Lightman

    2016-01-01

    Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free horm

  17. High cumulative insulin exposure : a risk factor of atherosclerosis in type 1 diabetes?

    NARCIS (Netherlands)

    Muis, MJ; Bots, ML; Bilo, HJG; Hoogma, RPLM; Hoekstra, JBL; Grobbee, DE; Stolk, RP

    Background: Since insulin therapy might have an atherogenic effect, we studied the relationship between cumulative insulin dose and atherosclerosis in type 1 diabetes. We have focused on patients with type 1 diabetes instead of type 2 diabetes to minimise the effect of insulin resistance as a

  18. Effects of exposure, diet, and thermoregulation on fecal glucocorticoid measures in wild bears.

    Directory of Open Access Journals (Sweden)

    Jeff Stetz

    Full Text Available We examined fecal glucocorticoid (fGC measures of nutrition and thermoregulatory demands on wild bears in Glacier National Park, Montana, and assessed how these measures changed in samples left in the field. Both ambient temperature and exposure can impact thermoregulation and sample degradation. Bear diets vary markedly with season, affecting body condition and thus fGC. We collected fecal samples during September and October, 2001, when ambient temperatures ranged from 30°C to -5°C. We collected half of each sample immediately and left the other half in its original location for 1-28 days. We used generalized linear models (GLM to first predict fGC concentrations in fresh samples based on proxies of nutrition, ambient temperature, thermal exposure, and precipitation. These same covariates were then used to predict degradation-based differences in fGC concentrations between the paired sample halves. Variation in fGC was predicted by diet, Julian date, aspect, and the interaction between Julian date and aspect in both fresh and exposed samples. Cumulative precipitation was also a significant predictor of fGC concentrations in the exposed samples, independent of time, indicating that precipitation contributes to sample degradation but not enough to mask effects of other environmental factors on fGC concentrations. Differences between sample halves were only predicted by cumulative precipitation and exposure time; cumulative precipitation decreased, whereas exposure time increased, fGC concentrations in the exposed sample halves. Results indicate that fGC can provide reliable indices of nutrition and thermoregulatory demands in bears and that sample degradation impacts on these relations are minimal and can be virtually eliminated by controlling for cumulative precipitation over the estimated exposure times.

  19. Glucocorticoid-induced osteoporosis: 2013 update

    Directory of Open Access Journals (Sweden)

    M. Mazzantini

    2014-07-01

    Full Text Available Glucocorticoids are the most common cause of secondary osteoporosis leading to the so-called glucocorticoidinduced osteoporosis (GIO. A treatment with 10 mg/d of prednisone or equivalent for more than 3 months leads to a 7-fold increase in hip fractures and a 17-fold increase in vertebral fractures. The difference between bone quantity and quality in GIO makes bone mineral density measurements inadequate to detect patients at risk of fracture. The adverse effects of glucocorticoids on the skeleton derive from a direct impact on bone cells with a severe impairment of mechanical competence. Crucial to prevention of GIO is early timing of intervention. The World Health Organization has adopted a fracture prevention algorithm (FRAX intended to estimate fracture risk in GIO. The American College of Rhematology modified its prevention and treatment guidelines taking into account the individual risk of fracture calculated in GIO on the basis of the FRAX algorithm. Recently, also a joint Guideline Working Group of the International Osteoporosis Foundation (IOF and the European Calcified Tissue Society (ECTS published a framework for the development of national guidelines for the management of GIO. Bisphosphonates are the first-line drugs to treat GIO; teriparatide counteracts several fundamental pathophysiologic aspects of GIO; denosumab is useful in patients with renal failure and in potentially pregnant young women. Vertebroplasty and kyphoplasty may be less beneficial in GIO than in primary involutional osteoporosis.

  20. Comparison of Glucocorticoid (Budesonide) and Antileukotriene (Montelukast) Effect in Patients with Bronchial Asthma Determined with Body Plethysmography

    Science.gov (United States)

    Lajqi, Njomza; Ilazi, Ali; Kastrati, Bashkim; Islami, Hilmi

    2015-01-01

    Objective: Effect of glucocorticoids-budesonide and antileukotriene–montelukast in patients with bronchial asthma and bronchial increased reactivity was studied in this work. Methods: Parameters of the lung function are determined with Body plethysmography. Raw and ITGV were registered and specific resistance (SRaw) was also calculated. Results: Results of this research, in patients with bronchial asthma, indicate that glucocorticoids – budesonide (Pulmicort; 2 × 2 mg inh) has significant action (p< 0.01) on reduction of the specific resistance (SRaw) of airways, applied to the same patients 3 days after administration of montelukast, at home (2 × 10 mg). Three days after administration of the montelukast, antileukotriene medicine, at home, on the fourth day same patients administered a capsule of montelukast, 10 mg dose per os, and significantly (p < 0.05) reduced the increased bronchomotor tonus; and the effect of the control with salbutamol (beta2-adrenergic agonist) is effective in removal of the increased bronchomotor tonus, causing significant decrease of the resistance (Raw), respectively of the specific resistance (SRaw), (p < 0, 01). Conclusion: This suggests that the bronchodilator effect of glucocorticoids is more powerful than of the leukotriene, because glucocorticoids terminate the early stage of chemical mediator release (prostaglandins PgD2, SRS, and leukotriene LTC4, LTD4, LTE4 and Cytokinins also etc.) as powerful bronchoconstriction substances, whilst antileukotriene substances does not have this feature. PMID:26862243

  1. Is cumulated pyrethroid exposure associated with prediabetes?

    DEFF Research Database (Denmark)

    Hansen, Martin Rune; Jørs, Erik; Lander, Flemming;

    2014-01-01

    , cumulative exposure) was assessed from questionnaire data. Participants were asked about symptoms of diabetes. Blood samples were analyzed for glycosylated hemoglobin (HbA1c), a measure of glucose regulation. No association was found between pyrethroid exposure and diabetes symptoms. The prevalence...

  2. Cumulative Disadvantage among the Highly Ambitious.

    Science.gov (United States)

    McClelland, Katherine

    1990-01-01

    Using a social reproduction theory framework, analyzes the process by which high school seniors aspiring to high-level positions are sorted out after graduation. Analyzes early educational attainments and changes in occupational expectations. Shows a process of cumulative disadvantage in which White males are more likely to achieve their goals.…

  3. Pavlovian conditioning and cumulative reinforcement rate.

    Science.gov (United States)

    Harris, Justin A; Patterson, Angela E; Gharaei, Saba

    2015-04-01

    In 5 experiments using delay conditioning of magazine approach with rats, reinforcement rate was varied either by manipulating the mean interval between onset of the conditioned stimulus (CS) and unconditioned stimulus (US) or by manipulating the proportion of CS presentations that ended with the US (trial-based reinforcement rate). Both manipulations influenced the acquisition of responding. In each experiment, a specific comparison was made between 2 CSs that differed in their mean CS-US interval and in their trial-based reinforcement rate, such that the cumulative reinforcement rate-the cumulative duration of the CS between reinforcements-was the same for the 2 CSs. For example, a CS reinforced on 100% of trials with a mean CS-US interval of 60 s was compared with a CS reinforced on 33% of trials and a mean duration of 20 s. Across the 5 experiments, conditioning was virtually identical for the 2 CSs with matched cumulative reinforcement rate. This was true as long as the timing of the US was unpredictable and, thus, response rates were uniform across the length of the CS. We conclude that the effects of CS-US interval and of trial-based reinforcement rate are reducible entirely to their common effect on cumulative reinforcement rate. We discuss the implications of this for rate-based, trial-based, and real-time associative models of conditioning.

  4. An Axiomatization of Cumulative Prospect Theory

    NARCIS (Netherlands)

    Wakker, P.P.; Tversky, A.

    1993-01-01

    This paper presents a method for axiomatizing a variety of models for decision making under uncertainty, including Expected Utility and Cumulative Prospect Theory. This method identifies, for each model, the situations that permit consistent inferences about the ordering of value differences. Exampl

  5. Cumulative Disadvantage among the Highly Ambitious.

    Science.gov (United States)

    McClelland, Katherine

    1990-01-01

    Using a social reproduction theory framework, analyzes the process by which high school seniors aspiring to high-level positions are sorted out after graduation. Analyzes early educational attainments and changes in occupational expectations. Shows a process of cumulative disadvantage in which White males are more likely to achieve their goals.…

  6. Relationship between Glucocorticoid-induced Osteoporosis and Vitamine D Receptor Genotypes

    Institute of Scientific and Technical Information of China (English)

    李裕明; 徐琳; 沈凌迅; 余立凯; 陈璐璐

    2002-01-01

    Summary: By means of polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) assay, the association between vitamine D receptor (VDR) genotypes and bone min-eral density (BMD) in the patients receiving long-term glucocorticoid therapy was studied. Theclinical data and blood of 71 patients with rheumatosis who received long-term glucocorticoid ther-apy were collected. BMD was measured by dual-energy X-ray absorptimometry. VDR gene frag-ment (about 185 bp) was amplified by PCR from the extracted genomic DNA, then digested withrestriction endonuclease Bsm I. The genotypes were evaluated based on the fragment length fol-lowing endonuclease digestion and the association between genotypes and BMD or Z-score valueswas analyzed. Among the 71 cases, the detected genotypes were Bb and bb with the distributionfrequency being 11.3 % and 88. 7 % respectively. The distribution frequency of the alleles was inagreement with the Hardy-Weinberg equilibrium. There was no significant difference between thetwo genotypes in age, gender, body mass index (BMI), disease duration, disease types, time ofglucocorticoid administration and cumulative dosage (P>0.05). Osteoporosis rate of the patientswith Bb or bb genotype was 37. 5 % and 33. 3 % respectively, with the difference being not signif-icant (x2=0. 05, P=0. 8). The BMD and Z-score values at lumbar spine and femur in two geno-types were not similar, but the difference had no significant (P>0. 05). The distribution frequen-cy of bb type of VDR genotypes in Hah populations of China was more prevalent, followed by Bband bb types in turn. In the patients receiving long-term glucocorticoid therapy, there was no sig-nificant difference in BMD between Bb and bb genotypes. The data suggest that the VDR geno-types may not be means of identifying patients at greater risk of glucocorticoid-induced osteoporo-sis, which await to be further confirmed by a large sample size.

  7. Neural regulation of the stress response: glucocorticoid feedback mechanisms

    Directory of Open Access Journals (Sweden)

    J.P. Herman

    2012-04-01

    Full Text Available The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA axis, driven by a neural signal originating in the paraventricular nucleus (PVN. Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

  8. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia

    Science.gov (United States)

    Tosello, Valeria; Herranz, Daniel; Ambesi-Impiombato, Alberto; Da Silva, Ana Carolina; Sanchez-Martin, Marta; Perez-Garcia, Arianne; Rigo, Isaura; Castillo, Mireia; Indraccolo, Stefano; Cross, Justin R; de Stanchina, Elisa; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M; Tallman, Martin S; Basso, Giuseppe; Meijerink, Jules P; Cordon-Cardo, Carlos; Califano, Andrea; Ferrando, Adolfo A.

    2013-01-01

    SUMMARY Glucocorticoid resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy and effectively reverses glucocorticoid resistance in vitro and in vivo. PMID:24291004

  9. Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene

    Energy Technology Data Exchange (ETDEWEB)

    Karl, M.; Lamberts, S.W.J.; Detera-Wadleigh, S.D.; Encio, I.J.; Stratakis, C.A.; Hurley, D.M.; Accili, D.; Chrousos, G.P. (National Institutes of Health, Bethesda, MD (United States) Erasmus Univ. of Rotterdam (Netherlands))

    1993-03-01

    The clinical syndrome of generalized, compensated glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hyper- or hypocortisolism, and manifestations of androgen and/or mineralocorticoid excess. This condition results from partial failure of the glucocorticoid receptor (GR) to modulate transcription of its target genes. The authors studied the molecular mechanisms of this syndrome in a Dutch kindred, whose affected members had hypercortisolism and approximately half of normal GRs, and whose proband was a young woman with manifestations of hyperandrogenism. Using the polymerase chain reaction to amplify and sequence each of the nine exons of the GR gene [alpha], along with their 5[prime]- and 3[prime]-flanking regions, the authors identified a 4-base deletion at the 3[prime]-boundary of exon 6 in one GR allele ([Delta][sub 4]), which removed a donor splice site in all three affected members studied. In contrast, the sequence of exon 6 in the two unaffected siblings was normal. A single nucleotide substitution causing an amino acid substitution in the amino terminal domain of the GR (asparagine to serine, codon 363) was also discovered in exon 2 of the other allele (G[sub 1220]) in the proband, in one of her affected brothers and in her unaffected sister. This deletion in the glucocorticoid receptor gene was associated with the expression of only one allele and a decrease of GR protein by 50% in affected members of this glucocorticoid resistant family. The mutation identified in exon 2 did not segregate with the disease and appears to be of no functional significance. The presence of the null allele was apparently compensated for by increased cortisol production at the expense of concurrent hyperandrogenism. 40 refs., 3 figs.

  10. Iatrogenic Cushing's Syndrome Due to Topical Ocular Glucocorticoid Treatment.

    Science.gov (United States)

    Fukuhara, Daisuke; Takiura, Toshihiko; Keino, Hiroshi; Okada, Annabelle A; Yan, Kunimasa

    2017-02-01

    Iatrogenic Cushing's syndrome (CS) is a severe adverse effect of systemic glucocorticoid (GC) therapy in children, but is extremely rare in the setting of topical ocular GC therapy. In this article, we report the case of a 9-year-old girl suffering from idiopathic uveitis who developed CS due to topical ocular GC treatment. She was referred to the ophthalmology department with a complaint of painful eyes, at which time she was diagnosed with bilateral iridocyclitis and started on a treatment of betamethasone sodium phosphate eye drops. Six months after the initiation of topical ocular GC treatment, she was referred to our pediatric department with stunted growth, truncal obesity, purple skin striate, buffalo hump, and moon face. Because her serum cortisol and plasma adrenocorticotropic hormone levels were undetectable, she was diagnosed with iatrogenic CS. After the doses of topical ocular GC were reduced, the clinical symptoms of CS were improved. The fact that the amount of topical ocular GC with our patient was apparently less than that of similar previous cases tempted us to perform genetic analysis of her NR3C1 gene. We found that our patient had a single heterozygous nucleotide substitution in the 3' untranslated region of the NR3C1 gene, which may explain why she developed CS. However, additional investigations are required to determine if our findings can be extrapolated to other patients. In conclusion, clinicians should be aware that even extremely low doses of topical ocular steroid therapy can cause iatrogenic CS. Copyright © 2017 by the American Academy of Pediatrics.

  11. Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration.

    Science.gov (United States)

    Starkman, Monica N

    2013-09-01

    This article reviews the neuropsychiatric presentations elicited by spontaneous hypercortisolism and exogenous supraphysiologic glucocorticoids. Patients with Cushing disease and syndrome develop a depressive syndrome: irritable and depressed mood, decreased libido, disrupted sleep and cognitive decrements. Exogenous short-term glucocorticoid administration may elicit a hypomanic syndrome with mood, sleep and cognitive disruptions. Treatment options are discussed. Brain imaging and neuropsychological studies indicate elevated cortisol and other glucocorticoids are especially deleterious to hippocampus and frontal lobe. The research findings also shed light on neuropsychiatric abnormalities in conditions that have substantial subgroups exhibiting elevated and dysregulated cortisol: aging, major depressive disorder and Alzheimer's disease.

  12. Addison disease in patients treated with glucocorticoid therapy.

    LENUS (Irish Health Repository)

    Cronin, C C

    2012-02-03

    Acute adrenal crisis in patients with unrecognized chronic adrenocortical failure is difficult to diagnose and potentially fatal. We describe 2 patients with acute adrenal crisis whose diagnoses were hindered because of concomitant glucocorticoid treatment. Acute adrenal insufficiency is primarily a state of mineralocorticoid deficiency. Prednisolone and prednisone, the most frequently prescribed anti-inflammatory corticosteroid agents, have minimal mineralocorticoid activity. Several conditions that may be treated with pharmacological glucocorticoids are associated with an increased risk of Addison disease. An acute adrenal crisis, against which concurrent glucocorticoid therapy does not confer adequate protection, may develop in such patients.

  13. Effect of acute adrenalectomy on rat liver glucocorticoid receptor

    Directory of Open Access Journals (Sweden)

    Isenović Esma R.

    2006-01-01

    Full Text Available In order to improve current clinical treatment of human hypocortisolism, it is necessary to understand molecular aspects of this pathophysiology. In this study liver tissues from male Wistar rats were used as an experimental model to study structural and functional properties of glucocorticoid receptor (GR in the absence of glucocorticoid hormones (GC. Results show that acute adrenalectomy (ADX significantly increases the number of GR binding sites and GR protein content. In addition, acute ADX stimulates increase in stability of the GR, decrease in stability of the glucocorticoid- receptor complex (G-R, and changes in accumulation of the G-R complex in nuclei and its cellular distribution. .

  14. Glucocorticoids and prostate cancer treatment:friend or foe?

    Institute of Scientific and Technical Information of China (English)

    Bruce Montgomery; Heather H Cheng; James Drechsler; Elahe A Mostaghel

    2014-01-01

    Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo-and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of deifning their contribution to the biology of prostate cancer.

  15. Glucocorticoid-induced hypertension and cardiac injury: effects of mineralocorticoid and glucocorticoid receptor antagonism.

    Science.gov (United States)

    Hattori, Takuya; Murase, Tamayo; Iwase, Erika; Takahashi, Keiji; Ohtake, Masafumi; Tsuboi, Koji; Ohtake, Mayuko; Miyachi, Masaaki; Murohara, Toyoaki; Nagata, Kohzo

    2013-02-01

    Glucocorticoids are widely administered for the treatment of various disorders, although their long-term use results in adverse effects associated with glucocorticoid excess. We investigated the pathophysiological roles of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the cardiac changes induced by exogenous corticosterone in rats. Corticosterone or vehicle was injected twice daily in rats from 8 to 12 weeks of age. The effects of the GR antagonist RU486, the MR antagonist spironolactone, or both agents on corticosterone action were also determined. Corticosterone induced hypertension, left ventricular (LV) fibrosis, and LV diastolic dysfunction. Neither RU486 nor spironolactone affected corticosterone-induced hypertension, whereas spironolactone, but not RU486, attenuated the effects of corticosterone on LV fibrosis and diastolic function. Corticosterone also increased cardiac oxidative stress and inflammation in a manner sensitive to spironolactone but not to RU486. The corticosterone-induced LV atrophy was not affected by either RU486 or spironolactone. Our results implicate MRs in the cardiac fibrosis and diastolic dysfunction, but not MRs or GRs in the cardiac atrophy, induced by corticosterone. Neither MRs nor GRs appear to contribute to corticosterone-induced hypertension.

  16. 9β Polymorphism of the Glucocorticoid Receptor Gene Appears to Have Limited Impact in Patients with Addison’s Disease

    Science.gov (United States)

    Ross, Ian Louis; Dandara, Collet; Swart, Marelize; Lacerda, Miguel; Schatz, Desmond; Blom, Dirk Jacobus

    2014-01-01

    Background Addison’s disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9β polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. Materials and Methods 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. Results Genotype data for the 9β polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9β polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. Conclusions This study did not identify any associations between the 9β polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD. PMID:24466047

  17. 9β Polymorphism of the glucocorticoid receptor gene appears to have limited impact in patients with Addison's disease.

    Directory of Open Access Journals (Sweden)

    Ian Louis Ross

    Full Text Available BACKGROUND: Addison's disease (AD has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9β polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. MATERIALS AND METHODS: 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. RESULTS: Genotype data for the 9β polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003, increased triglycerides (p = 0.002, reduced HDLC (p<0.001 an elevated highly sensitive C-reactive protein (p = 0.01, compared with controls. The 9β polymorphism (at least one G allele was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. CONCLUSIONS: This study did not identify any associations between the 9β polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD.

  18. Glucocorticoid receptors in murine erythroleukaemic cells

    Energy Technology Data Exchange (ETDEWEB)

    Hammond, K.D.; Torrance, J.M.; DiDomenico, M.

    1987-01-01

    Glucocorticoid receptors in murine erythroleukaemic cells were studied in relation to hexamethylene bisacetamide (HMBA) induced differentiation. Specific binding of dexamethasone was measured. A single class of saturable, high affinity binding sites was demonstrated in intact cells; with cell homogenates or fractions binding was low and could not be reliably quantified. Receptor binding in whole cell suspensions was lower in cells which had been treated with HMBA (36.5 +/- 8.2 pmol/g protein) than in untreated controls (87.9 +/- 23.6 pmol/g protein); dissociation constants were similar in treated (2.7 nM) and untreated cells (2.5 nM). Dexamethasone, hydrocortisone, corticosterone and progesterone competed with tritium-labelled dexamethasone for receptor binding sites; cortisone, deoxycorticosterone and oestradiol had little effect.

  19. Local glucocorticoid production in the thymus.

    Science.gov (United States)

    Talaber, Gergely; Jondal, Mikael; Okret, Sam

    2015-11-01

    Besides generating immunocompetent T lymphocytes, the thymus is an established site of de novo extra-adrenal glucocorticoid (GC) production. Among the compartments of the thymus, both stromal thymic epithelial cells (TECs) and thymocytes secrete biologically active GCs. Locally produced GCs secreted by the various thymic cellular compartments have been suggested to have different impact on thymic homeostasis. TEC-derived GCs may regulate thymocyte differentiation whereas thymocyte-derived GCs might regulate age-dependent involution. However the full biological significance of thymic-derived GCs is still not fully understood. In this review, we summarize and describe recent advances in the understanding of local GC production in the thymus and immunoregulatory steroid production by peripheral T cells and highlight the possible role of local GCs for thymus function.

  20. Glucocorticoids and central nervous system inflammation.

    Science.gov (United States)

    Dinkel, Klaus; Ogle, William O; Sapolsky, Robert M

    2002-12-01

    Glucocorticoids (GCs) are well known for their anti-inflammatory and immunosuppressive properties in the periphery and are therefore widely and successfully used in the treatment of autoimmune diseases, chronic inflammation, or transplant rejection. This led to the assumption that GCs are uniformly anti-inflammatory in the periphery and the central nervous system (CNS). As a consequence, GCs are also used in the treatment of CNS inflammation. There is abundant evidence that an inflammatory reaction is mounted within the CNS following trauma, stroke, infection, and seizure, which can augment the brain damage. However an increasing number of studies indicate that the concept of GCs being universally immunosuppressive might be oversimplified. This article provides a review of the current literature, showing that under certain circumstances GCs might fail to have anti-inflammatory effects and sometimes even enhance inflammation.

  1. Animal models of glucocorticoid-induced glaucoma.

    Science.gov (United States)

    Overby, Darryl R; Clark, Abbot F

    2015-12-01

    Glucocorticoid (GC) therapy is widely used to treat a variety of inflammatory diseases and conditions. While unmatched in their anti-inflammatory and immunosuppressive activities, GC therapy is often associated with the significant ocular side effect of GC-induced ocular hypertension (OHT) and iatrogenic open-angle glaucoma. Investigators have generated GC-induced OHT and glaucoma in at least 8 different species besides man. These models mimic many features of this condition in man and provide morphologic and molecular insights into the pathogenesis of GC-OHT. In addition, there are many clinical, morphological, and molecular similarities between GC-induced glaucoma and primary open-angle glaucoma (POAG), making animals models of GC-induced OHT and glaucoma attractive models in which to study specific aspects of POAG.

  2. Glucocorticoid programing of the mesopontine cholinergic system.

    Science.gov (United States)

    Borges, Sónia; Coimbra, Bárbara; Soares-Cunha, Carina; Ventura-Silva, Ana P; Pinto, Luisa; Carvalho, Miguel M; Pêgo, José-Miguel; Rodrigues, Ana João; Sousa, Nuno

    2013-01-01

    Stress perception, response, adaptation, and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids (GCs) is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programing intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety, and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to GCs (in utero glucocorticoid exposure, iuGC) present hyperanxiety, increased fear behavior, and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22 kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT), in the initiation of 22 kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT) expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individual stress vulnerability threshold.

  3. Glucocorticoid programming of the mesopontine cholinergic system

    Directory of Open Access Journals (Sweden)

    Sónia eBorges

    2013-12-01

    Full Text Available Stress perception, response, adaptation and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programming intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to glucocorticoids (iuGC present hyperanxiety, increased fear behaviour and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT and pedunculopontine tegmental nucleus (PPT, in the initiation of 22kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individuals stress vulnerability threshold.

  4. Inflammation in Parkinson's disease: role of glucocorticoids.

    Science.gov (United States)

    Herrero, María-Trinidad; Estrada, Cristina; Maatouk, Layal; Vyas, Sheela

    2015-01-01

    Chronic inflammation is a major characteristic feature of Parkinson's disease (PD). Studies in PD patients show evidence of augmented levels of potent pro-inflammatory molecules e.g., TNF-α, iNOS, IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergic neurons are particularly vulnerable to activated glia releasing these toxic factors. Recent genetic studies point to the role of immune system in the etiology of PD, thus in combination with environmental factors, both peripheral and CNS-mediated immune responses could play important roles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are known to mediate chronic inflammation, the roles of other immune-competent cells are less well understood. Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis. Glucocorticoids (GCs) released from adrenal glands upon stimulation of HPA axis, in response to either cell injury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both through direct transcriptional action on target genes and by indirectly inhibiting transcriptional activities of transcriptional factors such as NF-κB, AP-1 or interferon regulatory factors. In PD patients, the HPA axis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GR function in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucial effect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover, GCs are also known to regulate human brain vasculature as well as blood brain barrier (BBB) permeability, any dysfunction in their actions may influence infiltration of cytotoxic molecules resulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation of glucocorticoid receptor actions is likely important in dopamine neuron degeneration through establishment of chronic

  5. Effects of Chronic Psychosocial Stress on Reduction of Basal Glucocorticoid Levels and Suppression of Glucocorticoid Levels Following Dexamethasone Administration in Animal Model of PTSD

    Directory of Open Access Journals (Sweden)

    Ana Starcevic

    2014-03-01

    Conclusion: Significant changes in HPA activity, reductions in basal glucocorticoid levels and enhanced dexamethasone induced inhibition of glucocorticoid levels have been manifested. All of this is manifested in PTSD patients also as many other stress induces changes.

  6. Complexity and demographic explanations of cumulative culture.

    Directory of Open Access Journals (Sweden)

    Adrien Querbes

    Full Text Available Formal models have linked prehistoric and historical instances of technological change (e.g., the Upper Paleolithic transition, cultural loss in Holocene Tasmania, scientific progress since the late nineteenth century to demographic change. According to these models, cumulation of technological complexity is inhibited by decreasing--while favoured by increasing--population levels. Here we show that these findings are contingent on how complexity is defined: demography plays a much more limited role in sustaining cumulative culture in case formal models deploy Herbert Simon's definition of complexity rather than the particular definitions of complexity hitherto assumed. Given that currently available empirical evidence doesn't afford discriminating proper from improper definitions of complexity, our robustness analyses put into question the force of recent demographic explanations of particular episodes of cultural change.

  7. Avoiding Program-Induced Cumulative Overload (PICO).

    Science.gov (United States)

    Orr, Robin; Knapik, Joseph J; Pope, Rodney

    2016-01-01

    This article defines the concept of program-induced cumulative overload (PICO), provides examples, and advises ways to mitigate the adverse effects. PICO is the excessive cumulative physical workload that can be imparted to military personnel by a military training program with an embedded physical training component. PICO can be acute (accumulating within a single day) or chronic (accumulating across the entirety of the program) and results in adverse outcomes for affected personnel, including detrimental fatigue, performance degradation, injuries, or illness. Strategies to mitigate PICO include focusing administration and logistic practices during the development and ongoing management of a trainee program and implementing known musculoskeletal injury prevention strategies. More training is not always better, and trainers need to consider the total amount of physical activity that military personnel experience across both operational training and physical training if PICO is to be mitigated.

  8. Sharing a quota on cumulative carbon emissions

    Science.gov (United States)

    Raupach, Michael R.; Davis, Steven J.; Peters, Glen P.; Andrew, Robbie M.; Canadell, Josep G.; Ciais, Philippe; Friedlingstein, Pierre; Jotzo, Frank; van Vuuren, Detlef P.; Le Quéré, Corinne

    2014-10-01

    Any limit on future global warming is associated with a quota on cumulative global CO2 emissions. We translate this global carbon quota to regional and national scales, on a spectrum of sharing principles that extends from continuation of the present distribution of emissions to an equal per-capita distribution of cumulative emissions. A blend of these endpoints emerges as the most viable option. For a carbon quota consistent with a 2 °C warming limit (relative to pre-industrial levels), the necessary long-term mitigation rates are very challenging (typically over 5% per year), both because of strong limits on future emissions from the global carbon quota and also the likely short-term persistence in emissions growth in many regions.

  9. Structural Vibration Monitoring Using Cumulative Spectral Analysis

    Directory of Open Access Journals (Sweden)

    Satoru Goto

    2013-01-01

    Full Text Available This paper describes a resonance decay estimation for structural health monitoring in the presence of nonstationary vibrations. In structural health monitoring, the structure's frequency response and resonant decay characteristics are very important for understanding how the structure changes. Cumulative spectral analysis (CSA estimates the frequency decay by using the impulse response. However, measuring the impulse response of buildings is impractical due to the need to shake the building itself. In a previous study, we reported on system damping monitoring using cumulative harmonic analysis (CHA, which is based on CSA. The current study describes scale model experiments on estimating the hidden resonance decay under non-stationary noise conditions by using CSA for structural condition monitoring.

  10. Cumulative carbon emissions and the Green Paradox

    OpenAIRE

    Ploeg, Frederick Van der

    2013-01-01

    The green paradox states that a gradually more ambitious climate policy such as a renewables subsidy or an anticipated carbon tax induces fossil fuel owners to extract more rapidly and accelerate global warming. However, if extraction becomes more costly as reserves are depleted, such policies also shorten the fossil fuel era, induce more fossil fuel to be left in the earth, and thus curb cumulative carbon emissions. These consequences are relevant, as global warming depends primarily on cumu...

  11. Expansive Soil Crack Depth under Cumulative Damage

    Directory of Open Access Journals (Sweden)

    Bei-xiao Shi

    2014-01-01

    Full Text Available The crack developing depth is a key problem to slope stability of the expansive soil and its project governance and the crack appears under the roles of dry-wet cycle and gradually develops. It is believed from the analysis that, because of its own cohesion, the expansive soil will have a certain amount of deformation under pulling stress but without cracks. The soil body will crack only when the deformation exceeds the ultimate tensile strain that causes cracks. And it is also believed that, due to the combined effect of various environmental factors, particularly changes of the internal water content, the inherent basic physical properties of expansive soil are weakened, and irreversible cumulative damages are eventually formed, resulting in the development of expansive soil cracks in depth. Starting from the perspective of volumetric strain that is caused by water loss, considering the influences of water loss rate and dry-wet cycle on crack developing depth, the crack developing depth calculation model which considers the water loss rate and the cumulative damages is established. Both the proposal of water loss rate and the application of cumulative damage theory to the expansive soil crack development problems try to avoid difficulties in matrix suction measurement, which will surely play a good role in promoting and improving the research of unsaturated expansive soil.

  12. EPA Workshop on Epigenetics and Cumulative Risk ...

    Science.gov (United States)

    Agenda Download the Workshop Agenda (PDF) The workshop included presentations and discussions by scientific experts pertaining to three topics (i.e., epigenetic changes associated with diverse stressors, key science considerations in understanding epigenetic changes, and practical application of epigenetic tools to address cumulative risks from environmental stressors), to address several questions under each topic, and included an opportunity for attendees to participate in break-out groups, provide comments and ask questions. Workshop Goals The workshop seeks to examine the opportunity for use of aggregate epigenetic change as an indicator in cumulative risk assessment for populations exposed to multiple stressors that affect epigenetic status. Epigenetic changes are specific molecular changes around DNA that alter expression of genes. Epigenetic changes include DNA methylation, formation of histone adducts, and changes in micro RNAs. Research today indicates that epigenetic changes are involved in many chronic diseases (cancer, cardiovascular disease, obesity, diabetes, mental health disorders, and asthma). Research has also linked a wide range of stressors including pollution and social factors with occurrence of epigenetic alterations. Epigenetic changes have the potential to reflect impacts of risk factors across multiple stages of life. Only recently receiving attention is the nexus between the factors of cumulative exposure to environmental

  13. Effect of glucocorticoid on prostaglandin E1 mediated cyclic AMP formation by vascular smooth muscle cells.

    Science.gov (United States)

    Yasunari, K; Kohno, M; Murakawa, K; Yokokawa, K; Takeda, T

    1988-12-01

    The effect of glucocorticoid on the prostaglandin E1 (PGE1)-mediated cyclic AMP (cAMP) formation by vascular smooth muscle cells (VSMC) from renal arteries (RA) was studied in rats. Dexamethasone (DEX) at concentrations ranging from 10(-10) to approximately 10(-8) mol/l dose-dependently potentiates the PGE1-mediated response. This facilitation began at 6 h and reached its maximum after 24 h of DEX administration. Aldosterone (10(-6) mol/l) did not affect the dose-response curve of PGE1. Inhibitors of protein and RNA synthesis blocked this glucocorticoid effect. The basal activity of adenylate cyclase in DEX-treated cells was twice as high as in control cells. Treatment of VSMC with DEX increased cholera toxin- and pertussis toxin-stimulated adenylate cyclase activity. DEX treatment also augments forskolin-stimulated adenylate cyclase activity. These results suggest that DEX increases PGE1-mediated cAMP formation of VSMC from RA through a mechanism that involves the induction of protein synthesis, and that the activation of the catalytic unit may play some role in this facilitating process.

  14. Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS.

    Directory of Open Access Journals (Sweden)

    Julie E Goodwin

    Full Text Available Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.

  15. Hypersensitivity Reactions from Excipients in Systemic Glucocorticoid Formulations

    DEFF Research Database (Denmark)

    Calogiuri, Gianfranco; Garvey, Lene H; Romita, Paolo

    2016-01-01

    Glucocorticoids are the most widely used drugs for the treatment of hypersensitivity, however these drugs themselves and the excipients contained in commercial corticosteroid formulations are able to induce severe immediate-type hypersensitivity reactions. Reactions involving excipients have been...

  16. The impact of insulin resistance, gender, genes, glucocorticoids and ...

    African Journals Online (AJOL)

    The impact of insulin resistance, gender, genes, glucocorticoids and ethnicity on body ... The metabolic consequences of obesity are highly dependent on body fat ... it has been suggested that insulin sensitivity at the level of the adipocyte may ...

  17. Endothelial glucocorticoid receptor suppresses atherogenesis--brief report.

    Science.gov (United States)

    Goodwin, Julie E; Zhang, Xinbo; Rotllan, Noemi; Feng, Yan; Zhou, Han; Fernández-Hernando, Carlos; Yu, Jun; Sessa, William C

    2015-04-01

    The purpose of this study was to determine the role of the endothelial glucocorticoid receptor in the pathogenesis of atherosclerosis. Control mice and mice lacking the endothelial glucocorticoid receptor were bred onto an Apoe knockout background and subjected to high-fat diet feeding for 12 weeks. Assessment of body weight and total cholesterol and triglycerides before and after the diet revealed no differences between the 2 groups of mice. However, mice lacking the endothelial glucocorticoid receptor developed more severe atherosclerotic lesions in the aorta, brachiocephalic artery, and aortic sinus, as well as a heightened inflammatory milieu as evidenced by increased macrophage recruitment in the lesions. These data suggest that the endothelial glucocorticoid receptor is important for tonic inhibition of inflammation and limitation of atherosclerosis progression in this model. © 2015 American Heart Association, Inc.

  18. Glucocorticoids induce autophagy in rat bone marrow mesenchymal stem cells

    DEFF Research Database (Denmark)

    Wang, L.; Fan, J.; Lin, Y. S.;

    2015-01-01

    and their responses to diverse stimuli, however, the role of autophagy in glucocorticoidinduced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy......Glucocorticoidinduced osteoporosis (GIOP) is a widespread clinical complication following glucocorticoid therapy. This irreversible damage to boneforming and resorbing cells is essential in the pathogenesis of osteoporosis. Autophagy is a physiological process involved in the regulation of cells...

  19. The regulation of muscle mass by endogenous glucocorticoids

    OpenAIRE

    2015-01-01

    Glucocorticoids are highly conserved fundamental regulators of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, glucocorticoids are released from the adrenal gland, rapidly mobilizing energy from carbohydrate, fat and protein stores. In the case of inflammation, mobilized protein is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilizatio...

  20. Cumulative stress in research animals: Telomere attrition as a biomarker in a welfare context?

    Science.gov (United States)

    Bateson, Melissa

    2016-02-01

    Progress in improving animal welfare is currently limited by the lack of objective methods for assessing lifetime experience. I propose that telomere attrition, a cellular biomarker of biological age, provides a molecular measure of cumulative experience that could be used to assess the welfare impact of husbandry regimes and/or experimental procedures on non-human animals. I review evidence from humans that telomere attrition is accelerated by negative experiences in a cumulative and dose-dependent manner, but that this attrition can be mitigated or even reversed by positive life-style interventions. Evidence from non-human animals suggests that despite some specific differences in telomere biology, stress-induced telomere attrition is a robust phenomenon, occurring in a range of species including mice and chickens. I conclude that telomere attrition apparently integrates positive and negative experience in an accessible common currency that translates readily to novel species--the Holy Grail of a cumulative welfare indicator.

  1. Glucocorticoids and the regulation of memory in health and disease.

    Science.gov (United States)

    de Quervain, Dominique J-F; Aerni, Amanda; Schelling, Gustav; Roozendaal, Benno

    2009-08-01

    Over the last decades considerable evidence has accumulated indicating that glucocorticoids - stress hormones released from the adrenal cortex - are crucially involved in the regulation of memory. Specifically, glucocorticoids have been shown to enhance memory consolidation of emotionally arousing experiences, but impair memory retrieval and working memory during emotionally arousing test situations. Furthermore, growing evidence indicates that these different glucocorticoid effects all depend on emotional arousal-induced activation of noradrenergic transmission within the basolateral complex of the amygdala (BLA) and on interactions of the BLA with other brain regions, such as the hippocampus and neocortical regions. Here we review findings from both animal and human experiments and present an integrated perspective of how these opposite glucocorticoid effects might act together to serve adaptive processing of emotionally significant information. Furthermore, as intense emotional memories also play a crucial role in the pathogenesis and symptomatology of anxiety disorders, such as posttraumatic stress disorder (PTSD) or phobias, we discuss to what extent the basic findings on glucocorticoid effects on emotional memory might have implications for the understanding and treatment of these clinical conditions. In this context, we review data suggesting that the administration of glucocorticoids might ameliorate chronic anxiety by reducing retrieval of aversive memories and enhancing fear extinction.

  2. Differential effects of glucocorticoids on energy homeostasis in Syrian hamsters.

    Science.gov (United States)

    Solomon, Matia B; Sakai, Randall R; Woods, Stephen C; Foster, Michelle T

    2011-08-01

    Syrian hamsters, like many humans, increase food intake and body adiposity in response to stress. We hypothesized that glucocorticoids (cortisol and corticosterone) mediate these stress-induced effects on energy homeostasis. Because Syrian hamsters are dual secretors of cortisol and corticosterone, differential effects of each glucocorticoid on energy homeostasis were investigated. First, adrenal intact hamsters were injected with varying physiological concentrations of cortisol, corticosterone, or vehicle to emulate our previously published defeat regimens (i.e., 1 injection/day for 5 days). Neither food intake nor body weight was altered following glucocorticoid injections. Therefore, we investigated the effect of sustained glucocorticoid exposure on energy homeostasis. This was accomplished by implanting hamsters with supraphysiological steady-state pellets of cortisol, corticosterone, or cholesterol as a control. Cortisol, but not corticosterone, significantly decreased food intake, body mass, and lean and fat tissue compared with controls. Despite decreases in body mass and adiposity, cortisol significantly increased circulating free fatty acids, triglyceride, cholesterol, and hepatic triglyceride concentrations. Although corticosterone did not induce alterations in any of the aforementioned metabolic end points, Syrian hamsters were responsive to the effects of corticosterone since glucocorticoids both induced thymic involution and decreased adrenal mass. These findings indicate that cortisol is the more potent glucocorticoid in energy homeostasis in Syrian hamsters. However, the data suggest that cortisol alone does not mediate stress-induced increases in food intake or body mass in this species.

  3. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants

    Science.gov (United States)

    Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoi...

  4. Comparison of different glucocorticoid regimens in the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

    Directory of Open Access Journals (Sweden)

    T P Ajish

    2014-01-01

    Full Text Available Background: There are recommendations regarding the total dose of hydrocortisone to be administered in the treatment of classical congenital adrenal hyperplasia (CAH to achieve the twin objectives of glucocorticoid replacement and control of hyperandrogenism. However, there is evidence gap regarding the breakup, timing and type of the steroid regimen. Objectives: Efficacy of three different glucocorticoid regimens having the same total dose of steroid, differing in either the timing or type of evening steroid administered, in achieving biochemical control of the disease was assessed. Materials and Methods: The study was done in 13 prepubertal children with classical CAH over a 6-month period with 2 months devoted to each regimen. We used a prospective cross-over design using 10-15 mg/m 2 total dose of hydrocortisone. Two-fifths of the total dose of hydrocortisone was administered in the morning and one-fifth of the total dose was administered at noon in all the regimens. The regimens differed in the timing of the evening dose of hydrocortisone, 06.00-07.00 pm in regimen 1 and 09.00-10.00 pm in regimen 2. The third regimen had the evening dose of hydrocortisone replaced by an equivalent dose of prednisolone suspension which was administered at 10.00 pm. Serum 17-hydroxyprogesterone and testosterone levels were compared to assess the efficacy of treatment regimens. Results: The three different regimens were found to be similar in their ability to control 17-hydroxyprogesterone and testosterone levels. The percentage of patients with predefined criteria for biochemically controlled disease was similar in all the three regimens. However, there was a trend toward better control of 17-hydroxyprogesterone levels in patients receiving evening dose of prednisolone. Conclusions: There is no significant advantage in administering the hydrocortisone dose late at night in patients with classical CAH.

  5. Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics.

    Science.gov (United States)

    Kalafatakis, Konstantinos; Russell, Georgina M; Zarros, Apostolos; Lightman, Stafford L

    2016-02-01

    Glucocorticoids mediate plethora of actions throughout the human body. Within the brain, they modulate aspects of immune system and neuroinflammatory processes, interfere with cellular metabolism and viability, interact with systems of neurotransmission and regulate neural rhythms. The influence of glucocorticoids on memory and emotional behaviour is well known and there is increasing evidence for their involvement in many neuropsychiatric pathologies. These effects, which at times can be in opposing directions, depend not only on the concentration of glucocorticoids but also the duration of their presence, the temporal relationship between their fluctuations, the co-influence of other stimuli, and the overall state of brain activity. Moreover, they are region- and cell type-specific. The molecular basis of such diversity of effects lies on the orchestration of the spatiotemporal interplay between glucocorticoid- and mineralocorticoid receptors, and is achieved through complex dynamics, mainly mediated via the circadian and ultradian pattern of glucocorticoid secretion. More sophisticated methodologies are therefore required to better approach the study of these hormones and improve the effectiveness of glucocorticoid-based therapeutics.

  6. Post-training glucocorticoid receptor activation during Pavlovian conditioning reduces Pavlovian-instrumental transfer in rats.

    Science.gov (United States)

    Pielock, Steffi M; Sommer, Susanne; Hauber, Wolfgang

    2013-03-01

    Considerable evidence suggests that glucocorticoid receptor activation can enhance memory consolidation in Pavlovian learning tasks. For instance, post-training injections of the synthetic glucocorticoid receptor agonist dexamethasone increased conditioned responding to reward-predictive Pavlovian stimuli. Here we explored whether post-training dexamethasone injections can enhance appetitive Pavlovian learning and amplify the ability of Pavlovian stimuli to invigorate instrumental behaviour, a phenomenon termed Pavlovian-instrumental transfer (PIT). Animals were given 8 training days with two sessions per day, an instrumental training session in the morning and a Pavlovian training session in the afternoon. Dexamethasone or vehicle injections were administered daily immediately after Pavlovian training sessions. In a subsequent transfer test, we measured the general PIT effect, i.e. the enhancement of lever pressing for expected reward during presentation of an appetitive Pavlovian stimulus predictive for the same reward. Repeated high-dose (1.2 mg/kg, i.p.) dexamethasone injections elicited pronounced body weight loss, markedly reduced instrumental performance and left Pavlovian learning unaltered, whereas repeated low-dose (3 μg/kg, i.p.) dexamethasone injections inhibited body weight gain, slightly reduced instrumental performance and left Pavlovian learning unaltered during training. Importantly, in rats subjected to high- and low-dose dexamethasone injections, the overall response rates and the PIT effect were reduced in the transfer test. Thus, dexamethasone given after Pavlovian training was not able to amplify the invigorating effects of Pavlovian stimuli on instrumental action. Considerable evidence suggests that body weight changes after repeated low- and high-dose dexamethasone treatment as observed here are associated with muscle atrophy that could impair response capabilities. However, our data suggest that impaired response capabilities are not a

  7. Cumulative risks of foster care placement for Danish children

    National Research Council Canada - National Science Library

    Fallesen, Peter; Emanuel, Natalia; Wildeman, Christopher

    2014-01-01

    Although recent research suggests that the cumulative risk of foster care placement is far higher for American children than originally suspected, little is known about the cumulative risk of foster...

  8. Recursive Numerical Evaluation of the Cumulative Bivariate Normal Distribution

    CERN Document Server

    Meyer, Christian

    2010-01-01

    We propose an algorithm for evaluation of the cumulative bivariate normal distribution, building upon Marsaglia's ideas for evaluation of the cumulative univariate normal distribution. The algorithm is mathematically transparent, delivers competitive performance and can easily be extended to arbitrary precision.

  9. Climate mitigation: sustainable preferences and cumulative carbon

    Science.gov (United States)

    Buckle, Simon

    2010-05-01

    We develop a stylized AK growth model with both climate damages to ecosystem goods and services and sustainable preferences that allow trade-offs between present discounted utility and long-run climate damages. The simplicity of the model permits analytical solutions. Concern for the long-term provides a strong driver for mitigation action. One plausible specification of sustainable preferences leads to the result that, for a range of initial parameter values, an optimizing agent would choose a level of cumulative carbon dioxide (CO2) emissions independent of initial production capital endowment and CO2 levels. There is no technological change so, for economies with sufficiently high initial capital and CO2 endowments, optimal mitigation will lead to disinvestment. For lower values of initial capital and/or CO2 levels, positive investment can be optimal, but still within the same overall level of cumulative emissions. One striking aspect of the model is the complexity of possible outcomes, in addition to these optimal solutions. We also identify a resource constrained region and several regions where climate damages exceed resources available for consumption. Other specifications of sustainable preferences are discussed, as is the case of a hard constraint on long-run damages. Scientists are currently highlighting the potential importance of the cumulative carbon emissions concept as a robust yet flexible target for climate policymakers. This paper shows that it also has an ethical interpretation: it embodies an implicit trade off in global welfare between present discounted welfare and long-term climate damages. We hope that further development of the ideas presented here might contribute to the research and policy debate on the critical areas of intra- and intergenerational welfare.

  10. Anti-inflammatory glucocorticoid drugs: reflections after 60 years.

    Science.gov (United States)

    Whitehouse, Michael W

    2011-02-01

    This review considers the problem of the serious concomitant side effects of powerful anti-inflammatory drugs modelled upon the principal human glucocorticoid hormone, cortisol. The very nature of the original bio-assays to validate their cortisol-like hormonal and anti-inflammatory activities ensured that pleiotropic toxins were selected for clinical studies. Other complicating factors have been (1) considerable reliance on bio-assays conducted in laboratory animals that primarily secrete corticosterone, not cortisol, as their principal anti-inflammatory adrenal hormone; (2) some differences in the binding of xenobiotic cortisol analogues (vis á vis cortisol) to transport proteins, detoxifying enzymes and even some intra-cellular receptors; (3) the "rogue" properties of these hormonal xenobiotics, acting independently of--but still able to suppress--hormonal mechanisms regulating endogenous cortisol; and (4) problems of intrinsic/acquired "steroid resistance", diminishing their clinical efficacy, but not necessarily all their toxicities. The rather gloomy conclusion is that devising new drugs to reproduce the effect of multi-potent hormones may be a recipe for disaster, in contexts other than simply remedying an endocrine deficiency. Promising new developments include "designed" combination therapies that allow some reduction in total steroid doses (and hopefully their side effects); sharpening strategies to limit the actual duration of steroid administration; and resurgent interest in searching for more selective analogues (both steroidal and non-steroid) with less harmful side effects. Some oversights and neglected areas of research are also considered. Overall, it now seems timely to engage in some drastic rethinking about (retaining?) these "licensed toxins" as fundamental therapies for chronic inflammation.

  11. Long and Short Term Cumulative Structural Priming Effects

    OpenAIRE

    Kaschak, Michael P.; Kutta, Timothy J.; Coyle, Jacqueline M.

    2012-01-01

    We present six experiments that examine cumulative structural priming effects (i.e., structural priming effects that accumulate across many utterances). Of particular interest is whether (1) cumulative priming effects transfer across language production tasks and (2) the transfer of cumulative priming effects across tasks persists over the course of a week. Our data suggest that cumulative structural priming effects do transfer across language production tasks (e.g., from written stem complet...

  12. Preserved cumulative semantic interference despite amnesia

    Directory of Open Access Journals (Sweden)

    Gary Michael Oppenheim

    2015-05-01

    As predicted by Oppenheim et al’s (2010 implicit incremental learning account, WRP’s BCN RTs demonstrated strong (and significant repetition priming and semantic blocking effects (Figure 1. Similar to typical results from neurally intact undergraduates, WRP took longer to name pictures presented in semantically homogeneous blocks than in heterogeneous blocks, an effect that increased with each cycle. This result challenges accounts that ascribe cumulative semantic interference in this task to explicit memory mechanisms, instead suggesting that the effect has the sort of implicit learning bases that are typically spared in hippocampal amnesia.

  13. Cumulant matching for independent source extraction.

    Science.gov (United States)

    Phlypo, Ronald; Zarzoso, Vicente; Comon, Pierre; Lemahieu, Ignace

    2008-01-01

    In this work we show how one can make use of priors on signal statistics under the form of cumulant guesses to extract an independent source from an observed mixture. The advantage of using statistical priors on the signal lies in the fact that no specific knowledge is needed about its temporal behavior, neither about its spatial distribution. We show that these statistics can be obtained either by reasoning on the theoretical values of a supposed waveform, either by using a subset of the observations from which we know that their statistics are merely hindered by interferences. Results on an electro-cardiographic recording confirm the above assumptions.

  14. A Missing Link in the Evolution of the Cumulative Recorder

    Science.gov (United States)

    Asano, Toshio; Lattal, Kennon A.

    2012-01-01

    A recently recovered cumulative recorder provides a missing link in the evolution of the cumulative recorder from a modified kymograph to a reliably operating, scientifically and commercially successful instrument. The recorder, the only physical evidence of such an early precommercial cumulative recorder yet found, was sent to Keio University in…

  15. Original and cumulative prospect theory: a discussion of empirical differences

    NARCIS (Netherlands)

    P.P. Wakker; H. Fennema

    1997-01-01

    This note discusses differences between prospect theory and cumulative prospect theory. It shows that cumulative prospect theory is not merely a formal correction of some theoretical problems in prospect theory, but it also gives different predictions. Experiments are described that favor cumulative

  16. Salivary cortisol day curves in assessing glucocorticoid replacement therapy in Addison's disease.

    Science.gov (United States)

    Smans, Lisanne; Lentjes, Eef; Hermus, Ad; Zelissen, Pierre

    2013-01-01

    Patients with Addison's disease require lifelong treatment with glucocorticoids. At present, no glucocorticoid replacement therapy (GRT) can exactly mimic normal physiology. As a consequence, under- and especially overtreatment can occur. Suboptimal GRT may lead to various side effects. The aim of this study was to investigate the use of salivary cortisol day curves (SCDC) in the individual adjustment of GRT in order to approach normal cortisol levels as closely as possible, reduce over- and underreplacement and study the short-term effects on quality of life (QoL). Twenty patients with Addison's disease were included in this prospective study. A SCDC was obtained and compared to normal controls; general and disease specific QoL-questionnaires were completed. Based on SCDC assessment of over- and undertreatment (calculated as duration (h) × magnitude (nmol/L) at different time points, glucocorticoid dose and regime were adjusted. After 4 weeks SCDC and QoL assessment were repeated and the effect of adjusting GRT was analysed. At baseline, underreplacement was present in 3 and overreplacement in 18 patients; total calculated overreplacement was 32.8 h.nmol/L. Overreplacement decreased significantly to 13.3 h. nmol/L (p =0.005) after adjustment of GRT. Overreplacement was found particularly in the afternoon and evening. After reducing overreplacement in the evening, complaints about sleep disturbances significantly decreased. Individual adjustment of GRT based on SCDC to approach normal cortisol concentrations during the day can reduce overreplacement, especially in the evening. This can lead to a reduction of sleep disturbances and fatigue in patients with Addison's disease. A SCDC is a simple and patient-friendly tool for adjusting GRT and can be useful in the follow-up of patients with Addison's disease.

  17. Effect of high-dose preoperative methylprednisolone on pain and recovery after total knee arthroplasty: a randomized, placebo-controlled trial

    DEFF Research Database (Denmark)

    Lunn, Troels; Kristensen, Billy Bjarne; Andersen, Lasse

    2011-01-01

    Total knee arthroplasty (TKA) is associated with severe pain and inflammation despite an extensive multimodal analgesic approach, but the effect of high-dose glucocorticoid administration has not been studied....

  18. Glucocorticoids enhance extinction-based psychotherapy.

    Science.gov (United States)

    de Quervain, Dominique J-F; Bentz, Dorothée; Michael, Tanja; Bolt, Olivia C; Wiederhold, Brenda K; Margraf, Jürgen; Wilhelm, Frank H

    2011-04-19

    Behavioral exposure therapy of anxiety disorders is believed to rely on fear extinction. Because preclinical studies have shown that glucocorticoids can promote extinction processes, we aimed at investigating whether the administration of these hormones might be useful in enhancing exposure therapy. In a randomized, double-blind, placebo-controlled study, 40 patients with specific phobia for heights were treated with three sessions of exposure therapy using virtual reality exposure to heights. Cortisol (20 mg) or placebo was administered orally 1 h before each of the treatment sessions. Subjects returned for a posttreatment assessment 3-5 d after the last treatment session and for a follow-up assessment after 1 mo. Adding cortisol to exposure therapy resulted in a significantly greater reduction in fear of heights as measured with the acrophobia questionnaire (AQ) both at posttreatment and at follow-up, compared with placebo. Furthermore, subjects receiving cortisol showed a significantly greater reduction in acute anxiety during virtual exposure to a phobic situation at posttreatment and a significantly smaller exposure-induced increase in skin conductance level at follow-up. The present findings indicate that the administration of cortisol can enhance extinction-based psychotherapy.

  19. Effects of glucocorticoids on human brown adipocytes.

    Science.gov (United States)

    Barclay, Johanna L; Agada, Hadiya; Jang, Christina; Ward, Micheal; Wetzig, Neil; Ho, Ken K Y

    2015-02-01

    Clinical cases of glucocorticoid (GC) excess are characterized by increased fat mass and obesity through the accumulation of white adipocytes. The effects of GCs on growth and function of brown adipose tissue are unknown and may contribute to the negative energy balance observed clinically. This study aims to evaluate the effect of GCs on proliferation, differentiation, and metabolic function of brown adipocytes. Human brown adipocytes sourced from supraclavicular fat biopsies were grown in culture and differentiated to mature adipocytes. Human white adipocytes sourced from subcutaneous abdominal fat biopsies were cultured as controls. Effects of dexamethasone on growth, differentiation (UCP1, CIDEA, and PPARGC1A expression), and function (oxygen consumption rate (OCR)) of brown adipocytes were quantified. Dexamethasone (1 μM) significantly stimulated the proliferation of brown preadipocytes and reduced that of white preadipocytes. During differentiation, dexamethasone (at 0.1, 1, and 10 μM) stimulated the expression of UCP1, CIDEA, and PPARGC1A in a concentration-dependent manner and enhanced by fourfold to sixfold the OCR of brown adipocytes. Isoprenaline (100 nM) significantly increased (POCR of brown adipocytes. These effects were significantly reduced (Pbiology of human brown adipose tissue (BAT) and for the involvement of the BAT system in the metabolic manifestation of Cushing's syndrome. © 2015 Society for Endocrinology.

  20. Glucocorticoids in the treatment of rheumatoid arthritis.

    Science.gov (United States)

    Bijlsma, Johannes W J; Jacobs, Johannes W G; Buttgereit, Frank

    2015-01-01

    Glucocorticoids (GC) are now being used for over 65 years in the treatment of rheumatoid arthritis (RA). There is by now good evidence for their disease modifying effect, especially in early RA. When used in a dosage of 7.5-10 mg most adverse effects can be quite well handled, though monitoring and awareness for infections are important. The CAMERA II study is discussed, in which patients with early RA were treated with a tight control scheme of climbing dosages of methotrexate plus either 10 mg prednisone daily or placebo. After the two years of the trial, 70% of the patients treated with tight control strategy without GC had no erosions versus 82% of the patients treated with additional prednisone. Remission was reached more often and earlier on in the strategy with prednisone compared to the strategy with placebo. It may be suggested that GC have a greater beneficial effect on joint structure than can be explained by their anti-inflammatory effects only.

  1. Effects of Heat Shock on Glucocorticoid Receptor

    Institute of Scientific and Technical Information of China (English)

    宋亮年

    1994-01-01

    The changes of glucocorticoid receptor (GR) during the heat shock response have been studied using a human osteosarcoma cell line (HOS-8603) as the model. The expression of the heat shock protein 70 (hsp70) mRNA in HOS-8603 cells has been enhanced markedly after a heat treatment at 43 ℃ for 30 min. A mild thermal pretreatment (42℃ for 1 h) protects the HOS-8603 cells against a subsequent heat challenge (46℃). This induced thermotolerance is reflected by the increase of cell viability of HOS-8603 cells. The GR binding activity in HOS-8603 cells decreased rapidly after the heat treatment at 43℃; only 42. 61% of controls were detected 60 min after the heat treatment. However, there was no significant change in the dissociation constant value (Kd). These results indicate that the heat shock induce not only the heat shock mRNA expression, but also the rapid reduction in GR binding activity, suggesting that there might be a functional relationship between GR action and the heat shock response.

  2. Glucocorticoid regulation of astrocytic fate and function.

    Directory of Open Access Journals (Sweden)

    Shuang Yu

    Full Text Available Glial loss in the hippocampus has been suggested as a factor in the pathogenesis of stress-related brain disorders that are characterized by dysregulated glucocorticoid (GC secretion. However, little is known about the regulation of astrocytic fate by GC. Here, we show that astrocytes derived from the rat hippocampus undergo growth inhibition and display moderate activation of caspase 3 after exposure to GC. Importantly, the latter event, observed both in situ and in primary astrocytic cultures is not followed by either early- or late-stage apoptosis, as monitored by stage I or stage II DNA fragmentation. Thus, unlike hippocampal granule neurons, astrocytes are resistant to GC-induced apoptosis; this resistance is due to lower production of reactive oxygen species (ROS and a greater buffering capacity against the cytotoxic actions of ROS. We also show that GC influence hippocampal cell fate by inducing the expression of astrocyte-derived growth factors implicated in the control of neural precursor cell proliferation. Together, our results suggest that GC instigate a hitherto unknown dialog between astrocytes and neural progenitors, adding a new facet to understanding how GC influence the cytoarchitecture of the hippocampus.

  3. Cumulative Environmental Management Association : Wood Buffalo Region

    Energy Technology Data Exchange (ETDEWEB)

    Friesen, B. [Syncrude Canada Ltd., Edmonton, AB (Canada)

    2001-07-01

    The recently announced oil sands development of the Wood Buffalo Region in Alberta was the focus of this power point presentation. Both mining and in situ development is expected to total $26 billion and 2.6 million barrels per day of bitumen production. This paper described the economic, social and environmental challenges facing the resource development of this region. In addition to the proposed oil sands projects, this region will accommodate the needs of conventional oil and gas production, forestry, building of pipelines and power lines, municipal development, recreation, tourism, mining exploration and open cast mining. The Cumulative Environmental Management Association (CEMA) was inaugurated as a non-profit association in April 2000, and includes 41 members from all sectors. Its major role is to ensure a sustainable ecosystem and to avoid any cumulative impacts on wildlife. Other work underway includes the study of soil and plant species diversity, and the effects of air emissions on human health, wildlife and vegetation. The bioaccumulation of heavy metals and their impacts on surface water and fish is also under consideration to ensure the quality and quantity of surface water and ground water. 3 figs.

  4. Cumulative environmental management and the oil sands

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-07-01

    In response to concerns regarding the cumulative environmental impacts of oil sands development within the Athabasca oil sands deposit, the government of Alberta established a Regional Sustainable Development Strategy (RSDS) to balance development with environmental protection. The environmental issues identified through the RSDS were addressed by the Cumulative Environmental Management Association (CEMA). CEMA's boundary is the Wood Buffalo region of northeastern Alberta. It identifies existing and future environmental effects in the region and proposes recommendations to regulatory bodies for reducing environmental impacts associated with oil sands development. This presentation outlined some of the 55 stakeholder representatives of CEMA, including Alberta government departments associated with resource development, oil sand developers within the region, and Aboriginal communities and First Nations. These stakeholders provide input on sector priorities and agree on environmental thresholds. Established working groups also address technical and scientific research issues identified in the RSDS such as sustainable ecosystems; surface waters; trace metals and air contaminants; nitrogen oxides and sulphur dioxides; and land reclamation. To date, CEMA has submitted more than 50 reports and has made 4 major environmental recommendations for trace metal management, ecosystem management tools, a framework for acid deposition management, and a landscape design checklist. tabs., figs.

  5. Higher Order Cumulants in Colorless Partonic Plasma

    CERN Document Server

    Cherif, S; Ladrem, M

    2016-01-01

    Any physical system considered to study the QCD deconfinement phase transition certainly has a finite volume, so the finite size effects are inevitably present. This renders the location of the phase transition and the determination of its order as an extremely difficult task, even in the simplest known cases. In order to identify and locate the colorless QCD deconfinement transition point in finite volume $T_{0}(V)$, a new approach based on the finite-size cumulant expansion of the order parameter and the $\\mathscr{L}_{m,n}$-Method is used.We have shown that both cumulants of higher order and their ratios, associated to the thermodynamical fluctuations of the order parameter, in QCD deconfinement phase transition behave in a particular enough way revealing pronounced oscillations in the transition region. The sign structure and the oscillatory behavior of these in the vicinity of the deconfinement phase transition point might be a sensitive probe and may allow one to elucidate their relation to the QCD phase...

  6. Innovativeness, population size and cumulative cultural evolution.

    Science.gov (United States)

    Kobayashi, Yutaka; Aoki, Kenichi

    2012-08-01

    Henrich [Henrich, J., 2004. Demography and cultural evolution: how adaptive cultural processes can produce maladaptive losses-the Tasmanian case. Am. Antiquity 69, 197-214] proposed a model designed to show that larger population size facilitates cumulative cultural evolution toward higher skill levels. In this model, each newborn attempts to imitate the most highly skilled individual of the parental generation by directly-biased social learning, but the skill level he/she acquires deviates probabilistically from that of the exemplar (cultural parent). The probability that the skill level of the imitator exceeds that of the exemplar can be regarded as the innovation rate. After reformulating Henrich's model rigorously, we introduce an overlapping-generations analog based on the Moran model and derive an approximate formula for the expected change per generation of the highest skill level in the population. For large population size, our overlapping-generations model predicts a much larger effect of population size than Henrich's discrete-generations model. We then investigate by way of Monte Carlo simulations the case where each newborn chooses as his/her exemplar the most highly skilled individual from among a limited number of acquaintances. When the number of acquaintances is small relative to the population size, we find that a change in the innovation rate contributes more than a proportional change in population size to the cumulative cultural evolution of skill level.

  7. Is uveitis associated with topiramate use? A cumulative review

    Directory of Open Access Journals (Sweden)

    Goldberg JL

    2016-08-01

    Full Text Available Jeffrey L Goldberg,1 Amy G Lau,2 Bo Fan,2 Lisa Ford,3 Howard E Greenberg3 1Byers Eye Institute, Stanford University, Palo Alto, CA, 2Janssen Research & Development, LLC, Horsham, PA, 3Janssen Research & Development, LLC, Titusville, NJ, USA Abstract: Occasional reports of uveitis following topiramate use necessitated an investigation of relevant cases from safety databases and published biomedical literature. Data mining of the Food and Drug Administration Adverse Event Reporting System and cumulative review of cases from the global safety database (sponsor database and published literature were conducted to assess association between topiramate use and uveitis. The Food and Drug Administration Adverse Event Reporting System search identified disproportional reporting of uveitis (n=23 and related terms (choroidal detachment, n=25; iridocyclitis, n=17. The postmarketing reporting frequency of uveitis and related events from the global safety database and based on an estimated topiramate exposure of 11,185,740 person-years from launch to April 2015 was 0.38 per 100,000 person-years and assigned as very rare. A total of 14 potential uveitis cases were identified from the cumulative review. Seven of these 14 cases were complicated by inadequate documentation, appearance of uveitic signs following drug withdrawal, or concurrent use of other sulfonamides. In acute angle-closure glaucoma and uveal effusions cases, insufficient evidence for underlying inflammation suggested that uveitis was not a component. Only seven of 14 cases were well documented, potentially topiramate-associated uveitis cases. Uveitis may occur in the setting of topiramate use only in very rare instances. Current evidence did not reveal a dose- or duration-dependent relationship between uveitis and topiramate use. Keywords: topiramate, uveitis, acute angle-closure glaucoma, drug safety, Food and Drug Administration Adverse Event Reporting System, postmarketing 

  8. Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation.

    Science.gov (United States)

    Lambert, W Marcus; Xu, Chong-Feng; Neubert, Thomas A; Chao, Moses V; Garabedian, Michael J; Jeanneteau, Freddy D

    2013-09-01

    Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.

  9. Inhibition of dehydration-induced water intake by glucocorticoids is associated with activation of hypothalamic natriuretic peptide receptor-A in rat.

    Directory of Open Access Journals (Sweden)

    Chao Liu

    Full Text Available Atrial natriuretic peptide (ANP provides a potent defense mechanism against volume overload in mammals. Its primary receptor, natriuretic peptide receptor-A (NPR-A, is localized mostly in the kidney, but also is found in hypothalamic areas involved in body fluid volume regulation. Acute glucocorticoid administration produces potent diuresis and natriuresis, possibly by acting in the renal natriuretic peptide system. However, chronic glucocorticoid administration attenuates renal water and sodium excretion. The precise mechanism underlying this paradoxical phenomenon is unclear. We assume that chronic glucocorticoid administration may activate natriuretic peptide system in hypothalamus, and cause volume depletion by inhibiting dehydration-induced water intake. Volume depletion, in turn, compromises renal water excretion. To test this postulation, we determined the effect of dexamethasone on dehydration-induced water intake and assessed the expression of NPR-A in the hypothalamus. The rats were deprived of water for 24 hours to have dehydrated status. Prior to free access to water, the water-deprived rats were pretreated with dexamethasone or vehicle. Urinary volume and water intake were monitored. We found that dexamethasone pretreatment not only produced potent diuresis, but dramatically inhibited the dehydration-induced water intake. Western blotting analysis showed the expression of NPR-A in the hypothalamus was dramatically upregulated by dexamethasone. Consequently, cyclic guanosine monophosphate (the second messenger for the ANP content in the hypothalamus was remarkably increased. The inhibitory effect of dexamethasone on water intake presented in a time- and dose-dependent manner, which emerged at least after 18-hour dexamethasone pretreatment. This effect was glucocorticoid receptor (GR mediated and was abolished by GR antagonist RU486. These results indicated a possible physiologic role for glucocorticoids in the hypothalamic control of

  10. Cumulative ionizing radiation exposure in patients with end stage kidney disease: a 6-year retrospective analysis.

    LENUS (Irish Health Repository)

    Coyle, Joe

    2011-08-13

    OBJECTIVE: To quantify cumulative exposure to ionizing radiation in patients with end stage kidney disease (ESKD). To investigate factors which may be independently associated with risk of high cumulative effective dose (CED). MATERIALS AND METHODS: The study had local institutional review board ethical approval. We conducted a retrospective study of 394 period prevalent ESKD patients attending a single tertiary referral centre between 2004 and 2009. Patient demographics were obtained from case records. Details of radiological investigations were obtained from the institutional radiology computerized database. CED was calculated using standard procedure specific radiation levels. High exposure was defined as CED > 50 mSv, an exposure which has been reported to increase cancer mortality by 5%. Data were compared using Pearson χ(2) and Mann-Whitney U test or Kruskal-Wallis tests. RESULTS: 394 patients were followed for a median of 4 years (1518 patient years follow-up). Of these 63% were male. Seventeen percent of patients had a CED of >50 mSv. Computed tomography (CT) accounted for 9% of total radiological studies\\/procedures while contributing 61.4% of total study dose. Median cumulative dose and median dose per patient year were significantly higher in the hemodialysis (HD) group (15.13 and 5.79 mSv, respectively) compared to the post-transplant group (2.9 and 0.52 mSv, respectively) (P < 0.001). CONCLUSION: ESKD patients are at risk of cumulative exposure to significant levels of diagnostic radiation. The majority of this exposure is imparted as a result of CT examinations to patients in the HD group.

  11. Glucocorticoid-induced osteoporosis: an update on effects and management.

    Science.gov (United States)

    Buehring, Bjoern; Viswanathan, Ravi; Binkley, Neil; Busse, William

    2013-11-01

    Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  12. Glucocorticoid influence on prognosis of idiopathic sudden sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Eduardo Amaro Bogaz

    2014-06-01

    Full Text Available INTRODUCTION: Idiopathic Sudden Sensorineural Hearing Loss (ISSHL is defined when a loss of at least 30 dB occurs in over 3 continuous frequencies, in up to 72 hours, of which etiology is not established, despite adequate investigation. Different types of treatment regimens have been proposed, but only glucocorticoids have shown some evidence of benefit in the literature. OBJECTIVE: To analyze whether the type of treatment or time of treatment with glucocorticoids have any influence on hearing recovery in ISSHL. METHODS: Observational retrospective cohort study. One hundred twenty-seven patients with ISSHL, treated at outpatient clinics between the years 2000 and 2010, were studied. We evaluated the prognostic correlation of the type of treatment and time to treatment with glucocorticoids and ISSHL. RESULTS: The absolute hearing gain and the relative hearing gain was as follows: 23.6 dB and 37.2%. Complete recovery was observed in 15.7% of patients, significant recovery in 27.6% and recovery in 57.5%. CONCLUSION: In this study, there was no difference between the use and nonuse of glucocorticoids in hearing improvement. However, when started within seven days after onset, the use of glucocorticoids was a factor of better prognosis.

  13. Glucocorticoid and progesterone receptors in yolk sac placenta.

    Science.gov (United States)

    Carbone, J P; Baldridge, R C; Magen, A B; Andrew, C L; Koszalka, T R; Brent, R L

    1986-01-01

    The parietal yolk sac (PYS) of the rat fetus at the 14th day of gestation contains glucocorticoid as well as progesterone receptors; both are present in the trophoblast cell layer. Following heat activation the receptors are capable of binding to deoxyribonucleic acid- (DNA-)cellulose. Glucocorticoid receptors, but not progesterone receptors, are also present in the visceral yolk sac (VYS) at the 14th day of gestation. Greater amounts (some 250 femtomoles/mg cytosol protein) of a glucocorticoid receptor are present in the VYS on the 17th day of gestation. The Kd is approximately 4 X 10(-9) M; following activation it also binds to DNA-cellulose. The elution pattern of the activated VYS receptor from diethylaminoethyl-(DEAE-)Sephadex, however, is similar to that found with kidney and colon rather than that of liver (i.e., it resembles corticosteroid binder IB rather than binder II) indicating a possible role in transport. Although the receptors are separate entities, progesterone competes as effectively as corticosterone for binding to the glucocorticoid receptors in both the PYS and and VYS, thus raising the question of the possible effect of changes in progesterone concentrations on the functioning of glucocorticoids during development.

  14. The role of glucocorticoid receptor (GR) polymorphisms in human erythropoiesis.

    Science.gov (United States)

    Varricchio, Lilian; Migliaccio, Anna Rita

    2014-01-01

    Glucocorticoids are endogenous steroid hormones that regulate several biological functions including proliferation, differentiation and apoptosis in numerous cell types in response to stress. Synthetic glucocorticoids, such as dexamethasone (Dex) are used to treat a variety of diseases ranging from allergy to depression. Glucocorticoids exert their effects by passively entering into cells and binding to a specific Glucocorticoid Receptor (GR) present in the cytoplasm. Once activated by its ligand, GR may elicit cytoplasmic (mainly suppression of p53), and nuclear (regulation of transcription of GR responsive genes), responses. Human GR is highly polymorphic and may encode > 260 different isoforms. This polymorphism is emerging as the leading cause for the variability of phenotype and response to glucocorticoid therapy observed in human populations. Studies in mice and clinical observations indicate that GR controls also the response to erythroid stress. This knowledge has been exploited in-vivo by using synthetic GR agonists for treatment of the erythropoietin-refractory congenic Diamond Blackfan Anemia and in-vitro to develop culture conditions that may theoretically generate red cells in numbers sufficient for transfusion. However, the effect exerted by GR polymorphism on the variability of the phenotype of genetic and acquired erythroid disorders observed in the human population is still poorly appreciated. This review will summarize current knowledge on the biological activity of GR and of its polymorphism in non-hematopoietic diseases and discuss the implications of these observations for erythropoiesis.

  15. Safety of glucocorticoids can be improved by lower yet still effective dosages of liposomal steroid formulations in murine antigen-induced arthritis: comparison of prednisolone with budesonide.

    Science.gov (United States)

    Hofkens, Wouter; van den Hoven, Jolanda M; Pesman, Gerard J; Nabbe, Karin C; Sweep, Fred C; Storm, Gert; van den Berg, Wim B; van Lent, Peter L

    2011-09-20

    The goal of this study was to compare the effects of liposomal and free glucocorticoid formulations on joint inflammation and activity of the hypothalamic-pituitary-adrenal (HPA) axis during experimental antigen-induced arthritis (AIA). A dose of 10mg/kg liposomal prednisolone phosphate (PLP) gave a suppression of the HPA-axis, as measured by plasma corticosterone levels in mice with AIA and in naïve mice. In a subsequent dose-response study, we found that a single dose of 1mg/kg liposomal prednisolone phosphate (PLP) was still equally effective in suppressing joint inflammation as 4 repeated once-daily injections of 10mg/kg free PLP. Moreover, the 1mg/kg liposomal PLP dose gave 22% less suppression of corticosterone levels than 10mg/kg of liposomal PLP at day 14 of the AIA. In order to further optimize liposomal glucocorticoids, we compared liposomal PLP with liposomal budesonide phosphate (BUP) (1mg/kg). At 1 day after treatment, liposomal BUP gave a significantly stronger suppression of joint swelling than liposomal PLP (lip. BUP 98% vs. lip. PLP 79%). Both formulations also gave a strong and lasting suppression of synovial infiltration in equal amounts. However, at day 21 after AIA, liposomal PLP still significantly suppressed corticosterone levels, whereas this suppression was not longer statistically significant for liposomal BUP. Liposomal delivery improves the safety of glucocorticoids by allowing for lower effective dosing. The safety of liposomal glucocorticoid may be further improved by encapsulating BUP rather than PLP. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. Repeated Radionuclide therapy in metastatic paraganglioma leading to the highest reported cumulative activity of 131I-MIBG

    Directory of Open Access Journals (Sweden)

    Ezziddin Samer

    2012-01-01

    Full Text Available Abstract 131I-MIBG therapy for neuroendocrine tumours may be dose limited. The common range of applied cumulative activities is 10-40 GBq. We report the uneventful cumulative administration of 111 GBq (= 3 Ci 131I-MIBG in a patient with metastatic paraganglioma. Ten courses of 131I-MIBG therapy were given within six years, accomplishing symptomatic, hormonal and tumour responses with no serious adverse effects. Chemotherapy with cisplatin/vinblastine/dacarbazine was the final treatment modality with temporary control of disease, but eventually the patient died of progression. The observed cumulative activity of 131I-MIBG represents the highest value reported to our knowledge, and even though 12.6 GBq of 90Y-DOTATOC were added intermediately, no associated relevant bone marrow, hepatic or other toxicity were observed. In an individual attempt to palliate metastatic disease high cumulative activity alone should not preclude the patient from repeat treatment.

  17. Salivary cortisol day curves in assessing glucocorticoid replacement therapy in Addison's disease

    NARCIS (Netherlands)

    Smans, L.; Lentjes, E.G.W.M.; Hermus, A.R.; Zelissen, P.

    2013-01-01

    OBJECTIVE: Patients with Addison's disease require lifelong treatment with glucocorticoids. At present, no glucocorticoid replacement therapy (GRT) can exactly mimic normal physiology. As a consequence, under- and especially overtreatment can occur. Suboptimal GRT may lead to various side effects.

  18. Salivary cortisol day curves in assessing glucocorticoid replacement therapy in Addison's disease

    NARCIS (Netherlands)

    Smans, L.; Lentjes, E.G.W.M.; Hermus, A.R.; Zelissen, P.

    2013-01-01

    OBJECTIVE: Patients with Addison's disease require lifelong treatment with glucocorticoids. At present, no glucocorticoid replacement therapy (GRT) can exactly mimic normal physiology. As a consequence, under- and especially overtreatment can occur. Suboptimal GRT may lead to various side effects. T

  19. Glomerular Glucocorticoid Receptors Expression and Clinicopathological Types of Childhood Nephrotic Syndrome.

    Science.gov (United States)

    Gamal, Yasser; Badawy, Ahlam; Swelam, Salwa; Tawfeek, Mostafa S K; Gad, Eman Fathalla

    2017-02-01

    Glucocorticoids are primary therapy of idiopathic nephrotic syndrome (INS). However, not all children respond to steroid therapy. We assessed glomerular glucocorticoid receptor expression in fifty-one children with INS and its relation to response to steroid therapy and to histopathological type. Clinical, laboratory and glomerular expression of glucocorticoid receptors were compared between groups with different steroid response. Glomerular glucocorticoid expression was slightly higher in controls than in minimal change early responders, which in turn was significantly higher than in minimal change late responders. There was significantly lower glomerular glucocorticoid receptor expression in steroid-resistance compared to early responders, late responders and controls. Glomerular glucocorticoid expression was significantly higher in all minimal change disease (MCD) compared to focal segmental glomerulosclerosis. In INS, response to glucocorticoid is dependent on glomerular expression of receptors and peripheral expression. Evaluation of glomerular glucocorticoid receptor expression at time of diagnosis of NS can predict response to steroid therapy.

  20. ROLE OF THE ENDOCANNABINOID SYSTEM IN REGULATING GLUCOCORTICOID EFFECTS ON MEMORY FOR EMOTIONAL EXPERIENCES

    NARCIS (Netherlands)

    Atsak, P.; Roozendaal, B.; Campolongo, P.

    2012-01-01

    Glucocorticoids, stress hormones released from the adrenal cortex, have potent modulatory effects on emotional memory. Whereas early studies focused mostly on the detrimental effects of chronic stress and glucocorticoid exposure on cognitive performance and the classic genomic pathways that mediate

  1. Glucocorticoid effects on hippocampal protein synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Schlatter, L.K.

    1988-01-01

    Following subcutaneous injection of rats with 5 mg corticosterone, hippocampal slices in vitro show increased ({sup 35}S)-methionine labeling of a cytosolic protein with an apparent molecular weight (M{sub r}) of 35,000 and an isoelectric point (IEP) of 6.6. This labeling is temporally consistent with a transcriptional event, and is steroid- and tissue-specific. The pear serum concentration of steroid occurs one hour or less following the injection. Maximal labeling of this protein is reached whenever serum corticosterone values are approximately 100 ng/ml. When endogenous corticosterone levels are elevated to 100 ng/ml through stressors or exogenous ACTH injections the same maximal increase in synthesis of the 35,000 M{sub r} protein is observed. Adrenalectomy prevents the observed response from occurring following stressor application or ACTH injections. Comparison of the increases observed after administration of the type 2 receptor agonist RU 28362 and aldosterone, which has a higher affinity for the type 1 receptor, shows a 50-fold greater sensitivity of the response to the type 2 receptor agonist. Synthesis of this protein following serum increases of steroid possibly correlates to the theorized function of the type 2 receptor feedback regulation. The similar protein in the liver has an IEP of 6.8 and a slightly higher M{sub r}. A second hippocampal protein with an M{sub r} of 46,000 and an IEP of 6.2 is also increased in labeling. Two additional liver proteins, one of Mr 53,000 (IEP of 6.2) and the other with an M{sub r} of 45,000 (IEP of 8.7-7.8) are increased in the liver following glucocorticoid administration.

  2. RELATIONSHIP OF SERUM ADIPONECTIN LEVELS WITH ADIPOSITY, GLUCOCORTICOIDS, LEPTIN AND INSULIN

    Institute of Scientific and Technical Information of China (English)

    杨颖; 唐金凤; 汪启迪; 李凤英; 顾卫琼; 洪洁; 张一波; 周丽斌; 李荣英; 陈名道

    2005-01-01

    Objective To investigate the relationship between serum adiponectin levels with adiposity,glucocorticoids , insulin and leptin in Cushing' s syndrome, obesity and non-obese subjects. Methods The serum adiponectin concentrations were measured in 104 non-obese and 57 overweight or obese (BMI≥25) subjects by RIA. 15 patients with Cushing's syndrome, 10 with obesity and 9 non-obese subjects were investigated, with their serum adiponectin, glucocorticoids, insulin and leptin levels measured at 8: 00, 12: 00, 16: 00, 20: 00, 24: 00 and 3:00. Dexamethasone suppression tests in both obesity and Cushing's syndrome were performed at the dose of lmg,2mg and 5mg. Results The serum adiponectin concentrations in non-obese were (10.15±6.33) mg/L in male and (13.82 ±6. 09 ) mg/L in female, and those in overweight or obese ones were(5. 78 ±3.55)mg/L in male and (8. 13 ± 4. 32 ) mg/L in female. In both men and women, the fasting adiponectin levels in overweight or obese subjects were lower than those of the non-obese ones, and serum adiponectin concentrations were significantly nagetively correlated with BMI, % Fat and waist circumference. The circadian rhythmicity of adiponectin was not distinct, but the adiponectin levels in obesity were lower than those of the non-obese subjects at all 6 time spots. The serum adiponectin area under curve (AUC) were significantly nagetively correlated with BMI, waist circumference and insulin AUC. The adiponectin levels with dexamethasone administration for a short-term both at higher doses and lower doses did not change, but was decreased after surgery. Conclusion Adiponectin is a hormone secreted by adipocytes which may intimately related to obese and insulin resistance. Therefore, any treatment that could be used to increase adiponectin should be beneficial. Neither long-term endogenous hyper-glucocorticoid nor short-term dexamethasone administration may affect the adiponectin levels, and similarly, no change with elevated postprandial

  3. DHEA modulates the effect of cortisol on RACK1 expression via interference with the splicing of the glucocorticoid receptor

    Science.gov (United States)

    Pinto, Antonella; Malacrida, Beatrice; Oieni, Jacopo; Serafini, Melania Maria; Davin, Annalisa; Galbiati, Valentina; Corsini, Emanuela; Racchi, Marco

    2015-01-01

    Background and Purpose Dehydroepiandrosterone (DHEA) is thought to be an anti-glucocorticoid hormone known to be fully functional in young people but deficient in aged humans. Our previous data suggest that DHEA not only counteracts the effect of cortisol on RACK1 expression, a protein required both for the correct functioning of immune cells and for PKC-dependent pathway activation, but also modulates the inhibitory effect of cortisol on LPS-induced cytokine production. The purpose of this study was to investigate the effect of DHEA on the splicing mechanism of the human glucocorticoid receptor (GR). Experimental Approach The THP1 monocytic cell line was used as a cellular model. Cytokine production was measured by specific elisa. Western blot and real-time RT-PCR were used, where appropriate, to determine the effect of DHEA on GRs, serine/arginine-rich proteins (SRp), and RACK1 protein and mRNA. Small-interfering RNA was used to down-regulate GRβ. Key Results DHEA induced a dose-related up-regulation of GRβ and GRβ knockdown completely prevented DHEA-induced RACK1 expression and modulation of cytokine release. Moreover, we showed that DHEA influenced the expression of some components of the SRps found within the spliceosome, the main regulators of the alternative splicing of the GR gene. Conclusions and Implications These data contribute to our understanding of the mechanism of action of DHEA and its effect on the immune system and as an anti-glucocorticoid agent. PMID:25626076

  4. Glucocorticoids specifically enhance L-type calcium current amplitude and affect calcium channel subunit expression in the mouse hippocampus.

    Science.gov (United States)

    Chameau, Pascal; Qin, Yongjun; Spijker, Sabine; Smit, August Benjamin; Smit, Guus; Joëls, Marian

    2007-01-01

    Previous studies have shown that corticosterone enhances whole cell calcium currents in CA1 pyramidal neurons, through a pathway involving binding of glucocorticoid receptor homodimers to the DNA. We examined whether glucocorticoids show selectivity for L- over N-type of calcium currents. Moreover, we addressed the putative gene targets that eventually lead to the enhanced calcium currents. Electrophysiological recordings were performed in nucleated patches that allow excellent voltage control. Calcium currents in these patches almost exclusively involve N- and L-type channels. We found that L- but not N-type calcium currents were largely enhanced after treatment with a high dose of corticosterone sufficient to activate glucocorticoid receptors. Voltage dependency and kinetic properties of the currents were unaffected by the hormone. Nonstationary noise analysis suggests that the increased current is not caused by a larger unitary conductance, but rather to a doubling of the number of functional channels. Quantitative real-time PCR revealed that transcripts of the Ca(v)1 subunits encoding for the N- or L-type calcium channels are not upregulated in the mouse CA1 area; instead, a strong, direct, and consistent upregulation of the beta4 subunit was observed. This indicates that the corticosteroid-induced increase in number of L-type calcium channels is not caused by a simple transcriptional regulation of the pore-forming subunit of the channels.

  5. The effectiveness of synthetic glucocorticoids on the disease course, treatment, and outcome of severe sepsis and septic shock

    Directory of Open Access Journals (Sweden)

    Jelena Dumančić

    2016-03-01

    Full Text Available Due to the high morbidity and mortality rates, severe sepsis and septic shock, present a major global public health problem. The treatment and management of severe sepsis and septic shock is based on a set of international guidelines called the Surviving sepsis campaign (SSC. SSC guidelines suggest the use of hydrocortisone at a dose of 200 mg IV in adult patients with septic shock refractory to fluid resuscitation and vasopressors. During the last century, the importance of cortisol as an essential hormone at times of stress, such as septic shock, has been recognized. Therefore, the therapeutic use of synthetic glucocorticoids has been the subject of many studies during the last few decades but their results are not consistent. Two of the largest studies (CORTICUS and French study showed different effects of synthetic glucocorticoids on mortality rates, but they both showed a significantly shorter duration of septic shock. There is an ongoing large, multicenter, double-blind, randomized study (ADRENAL study and its primary goal is to assess the impact of hydrocortisone therapy on 90-day survival rate. It is expected that the results of this study might provide answers to the questions raised by previously conducted studies. This review will summarize the pathophysiology of sepsis and septic shock and the role of cortisol in its development, and will highlight the most important clinical studies pertaining to synthetic glucocorticoid administration in sepsis and septic shock.

  6. Ion cumulation by conical cathode electrolysis.

    CERN Document Server

    Grishin, V G

    2002-01-01

    Results of solid-state sodium stearate electrolysis with conical and cylindrical cathodes is presented here. Both electric measurement and conical samples destruction can be explained if a stress developing inside the conical sample is much bigger than in the cylindrical case and there is its unlimited amplification along cone slopes. OTHER KEYWORDS: ion, current, solid, symmetry, cumulation, polarization, depolarization, ionic conductor,superionic conductor, ice, crystal, strain, V-center, V-centre, doped crystal, interstitial impurity, intrinsic color center, high pressure technology, Bridgman, anvil, experiment, crowdion, dielectric, proton, layer, defect, lattice, dynamics, electromigration, mobility, muon catalysis, concentration, doping, dopant, conductivity, pycnonuclear reaction, permittivity, dielectric constant, point defects, interstitials, polarizability, imperfection, defect centers, glass, epitaxy, sodium hydroxide, metallic substrate, crystallization, point, tip, susceptibility, ferroelectric, ...

  7. [Cumulative trauma disorders: work or professional disease?].

    Science.gov (United States)

    de Carvalho, Marcus Vitor Diniz; Cavalcanti, Francisco Ivo Dantas; Soriano, Evelyne Pessoa; de Miranda, Hênio Ferreira

    2009-06-01

    This study aimed at reviewing the Brazilian legislation applied to occupational health. It refers to the diseases embodied in the Repetition Strain Injury (RSI) and Cumulative Trauma Disorders (CTD) regarded as work or professional diseases. This analysis allowed to perform the historical evolution of legislation concerning the issue, noting that the state of the art of regulation on RSI-CTD is anchored in specific regulation present in the Normative Instruction 98/2003, that establishes the diagnostic criteria and classification of RSI-CTD. It was concluded that according to the existing legislation in Brazil, the pathologies related to RSI-CTD are considered as work diseases and their legal effects are similar to the work-related accidents.

  8. The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone

    DEFF Research Database (Denmark)

    Ding, Ming; Danielsen, Carl C; Overgaard, Søren

    mechanical properties in the glucocorticoid-2. In conclusion, 7 months glucocorticoid treatment with malnutrition had significant impact on cortical microarchitecture of sheep femur midshaft. These changes occurred particularly 3 months after the glucocorticoid cessation suggesting a delayed effect......The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone – Validation of large animal model for tissue engineering and biomaterial research Ming Ding,1* Carl Christian Danielsen,2 Søren Overgaard1 1Orthopaedic Research Laboratory...

  9. Hippocampal neuronal nitric oxide synthase mediates the stress-related depressive behaviors of glucocorticoids by downregulating glucocorticoid receptor.

    Science.gov (United States)

    Zhou, Qi-Gang; Zhu, Li-Juan; Chen, Chen; Wu, Hai-Yin; Luo, Chun-Xia; Chang, Lei; Zhu, Dong-Ya

    2011-05-25

    The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO(-))/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO(-) donor into hippocampus caused depressive-like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.

  10. Glucocorticoids and the Brain: Neural Mechanisms Regulating the Stress Response.

    Science.gov (United States)

    Shirazi, Shawn N; Friedman, Aaron R; Kaufer, Daniela; Sakhai, Samuel A

    2015-01-01

    In this chapter, we describe the central role of the brain in the glucocorticoid mediated stress response. We describe the mechanisms by which the brain gauges the severity of stress, mechanisms of hypothalamic-pituitary-adrenal axis (HPA) regulation, and how various sub-systems of the brain respond to glucocorticoid (GC) signaling to regulate stress behavior. In particular, we focus on the hippocampus, pre-frontal cortex, and amygdala, where GCs can induce a series of changes. Finally, we briefly discuss an apparent paradox in GC signaling: while exposure to glucocorticoids promotes the survival of an organism during acute stress, these same hormones in chronic excess can also cause damage and promote illness.

  11. Differential effects of stress and glucocorticoids on adult neurogenesis.

    Science.gov (United States)

    Schoenfeld, Timothy J; Gould, Elizabeth

    2013-01-01

    Stress is known to inhibit neuronal growth in the hippocampus. In addition to reducing the size and complexity of the dendritic tree, stress and elevated glucocorticoid levels are known to inhibit adult neurogenesis. Despite the negative effects of stress hormones on progenitor cell proliferation in the hippocampus, some experiences which produce robust increases in glucocorticoid levels actually promote neuronal growth. These experiences, including running, mating, enriched environment living, and intracranial self-stimulation, all share in common a strong hedonic component. Taken together, the findings suggest that rewarding experiences buffer progenitor cells in the dentate gyrus from the negative effects of elevated stress hormones. This chapter considers the evidence that stress and glucocorticoids inhibit neuronal growth along with the paradoxical findings of enhanced neuronal growth under rewarding conditions with a view toward understanding the underlying biological mechanisms.

  12. Suppression of glucocorticoid secretion enhances cholinergic transmission in rat hippocampus.

    Science.gov (United States)

    Mizoguchi, Kazushige; Shoji, Hirotaka; Ikeda, Ryuji; Tanaka, Yayoi; Maruyama, Wakako; Tabira, Takeshi

    2008-08-15

    We previously demonstrated that suppression of glucocorticoid secretion by adrenalectomy (ADX) impaired prefrontal cortex-sensitive working memory, but not reference memory. Since the cholinergic system in the hippocampus is also involved in these memories, we examined the effects of glucocorticoid suppression on cholinergic transmission in the rat hippocampus. A microdialysis study revealed that ADX did not affect the basal acetylcholine release, but enhanced the KCl-evoked response. This enhanced response was reversed by the corticosterone replacement treatment. The extracellular choline concentrations increased under both basal and KCl-stimulated conditions in the ADX rats, and these increases were also reversed by the corticosterone replacement. These results indicate that suppression of glucocorticoid secretion enhances cholinergic transmission in the hippocampus in response to stimuli. It is possible that this enhanced cholinergic transmission may not contribute to the ADX-induced working memory impairment, but it may be involved in maintenance of reference memory.

  13. Glucocorticoid receptors in monocytes in type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Damm, P; Binder, C

    1989-01-01

    Glucocorticoid receptor binding characteristics were investigated in 8 males with poorly controlled Type 1 diabetes mellitus and 14 healthy males. The cell type studied was monocytes, and a method for correction for heterogeneity in glucocorticoid binding in a mononuclear leucocyte population...... or with HbA1c. In conclusion, no major abnormalities in glucocorticoid receptor binding characteristics could be demonstrated in Type 1 diabetes mellitus....... was introduced. The number of receptors and the dissociation constant KD were, respectively, 13,699 and 2.93 X 10(-8) mol/l for the control group and 15,788 and 2.75 X 10(-8) mol/l for diabetics (p greater than 0.05). In diabetics, KD correlated negatively with blood glucose (r = 0.762, p less than 0...

  14. Membrane glucocorticoid receptor activation induces proteomic changes aligning with classical glucocorticoid effects.

    Science.gov (United States)

    Vernocchi, Sara; Battello, Nadia; Schmitz, Stephanie; Revets, Dominique; Billing, Anja M; Turner, Jonathan D; Muller, Claude P

    2013-07-01

    Glucocorticoids exert rapid nongenomic effects by several mechanisms including the activation of a membrane-bound glucocorticoid receptor (mGR). Here, we report the first proteomic study on the effects of mGR activation by BSA-conjugated cortisol (Cort-BSA). A subset of target proteins in the proteomic data set was validated by Western blot and we found them responding to mGR activation by BSA-conjugated cortisol in three additional cell lines, indicating a conserved effect in cells originating from different tissues. Changes in the proteome of BSA-conjugated cortisol treated CCRF-CEM leukemia cells were associated with early and rapid pro-apoptotic, immune-modulatory and metabolic effects aligning with and possibly "priming" classical activities of the cytosolic glucocorticoid receptor (cGR). PCR arrays investigating target genes of the major signaling pathways indicated that the mGR does not exert its effects through the transcriptional activity of any of the most common kinases in these leukemic cells, but RhoA signaling emerged from our pathway analysis. All cell lines tested displayed very low levels of mGR on their surface. Highly sensitive and specific in situ proximity ligation assay visualized low numbers of mGR even in cells previously thought to be mGR negative. We obtained similar results when using three distinct anti-GR monoclonal antibodies directed against the N-terminal half of the cGR. This strongly suggests that the mGR and the cGR have a high sequence homology and most probably originate from the same gene. Furthermore, the mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay. Our results indicate however that Cav-1 is not necessary for membrane localization of the GR since CCRF-CEM and Jurkat cells have a functional mGR, but did not express this caveolar protein. However, if expressed, this membrane protein

  15. Effects of glucocorticoids on traumatic brain injury related critical illness-related corticosteroid insufficiency

    Institute of Scientific and Technical Information of China (English)

    ZHAO Zi-long; CHEN Xin; ZHU Hui; ZHANG Bao-liang; CHAI Yan; LI Xin-yuan; DONG Jing-fei

    2013-01-01

    Background Traumatic brain injury (TBI) is a heterogeneous condition that can lead to critical LLLness-related corticosteroid insufficiency (CIRCI) causing a high mortality and morbidity.Glucocorticoids were widely used in the clinical management of TBI,but their benefit has been challenged in some studies and their efficacy,especially for treating CIRCI in TBI patients,remains unclear.Methods We conducted a meta-analysis of published data to determine if the controversy is related to clinical dosing and timing of glucocorticoids (GCs) application.We analyzed published reports in four databases (MEDLINE,EMBASE,the Cochrane Controlled Trials Register,and CBMdisc).The published data were stratified into not only low-and high-dose GCs group but also short-and long-term GCs group to compare their effectiveness in improving TBI outcomes.Results We totally identified 16 reports.For low-dose patients,the pooled relative risks (RRs) for two clinical outcomes of death or a combination of death and severe disability were 0.95 (95% confidence interval (CI):0.80 to 1.13) and 0.95 (95% CI:0.83 to 1.09),respectively.The risks for infection and gastrointestinal bleeding were 0.85 (95% CI:0.50 to 1.45) and 0.64 (95% Cl:0.15 to 2.70),respectively.For high-dose group,the pooled RR of death is 1.14 (95% Cl:1.06 to 1.21).The pooled RRs for infection and gastrointestinal bleeding for the high-dose patients were 1.04 (95% CI:0.93 to 1.15) and 1.26 (95% CI:0.92 to 1.75),respectively.For long-term use group,the pooled RRs for two clinical outcomes of death or a combination of death and severe disability were 0.98 (95% CI:0.87 to 1.12) and 1.00 (95% CI:0.90 to 1.11),respectively.The risks for infection and gastrointestinal bleeding were 0.88 (95% CI:0.71 to 1.11) and 0.96 (95% CI:0.35 to 2.66),respectively.For short-term use group,the pooled RR of death is 1.15 (95% CI:1.07 to 1.23),and importantly the effects on infections were beneficial in terms of TBI patients

  16. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself

    DEFF Research Database (Denmark)

    Dinsen, Stina; Baslund, Bo; Klose, Marianne;

    2013-01-01

    Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficul...

  17. LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function

    NARCIS (Netherlands)

    Hoekstra, Menno; Korporaal, Suzanne J. A.; van der Sluis, Ronald J.; Hirsch-Reinshagen, Veronica; Bochem, Andrea E.; Wellington, Cheryl L.; Van Berkel, Theo J. C.; Kuivenhoven, Jan Albert; Van Eck, Miranda

    2013-01-01

    containing lipoproteins can provide cholesterol for synthesis of glucocorticoids. Here we assessed adrenal glucocorticoid function in LCAT knockout (KO) mice to determine the specific contribution of HDL-cholesteryl esters to adrenal glucocorticoid output in vivo. LCAT KO mice exhibit an 8-fold high

  18. Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity.

    Science.gov (United States)

    Suri, D; Vaidya, V A

    2013-06-01

    Glucocorticoids serve as key stress response hormones that facilitate stress coping. However, sustained glucocorticoid exposure is associated with adverse consequences on the brain, in particular within the hippocampus. Chronic glucocorticoid exposure evokes neuronal cell damage and dendritic atrophy, reduces hippocampal neurogenesis and impairs synaptic plasticity. Glucocorticoids also alter expression and signaling of the neurotrophin, brain-derived neurotrophic factor (BDNF). Since BDNF is known to promote neuroplasticity, enhance cell survival, increase hippocampal neurogenesis and cellular excitability, it has been hypothesized that specific adverse effects of glucocorticoids may be mediated by attenuating BDNF expression and signaling. The purpose of this review is to summarize the current state of literature examining the influence of glucocorticoids on BDNF, and to address whether specific effects of glucocorticoids arise through perturbation of BDNF signaling. We integrate evidence of glucocorticoid regulation of BDNF at multiple levels, spanning from the well-documented glucocorticoid-induced changes in BDNF mRNA to studies examining alterations in BDNF receptor-mediated signaling. Further, we delineate potential lines of future investigation to address hitherto unexplored aspects of the influence of glucocorticoids on BDNF. Finally, we discuss the current understanding of the contribution of BDNF to the modulation of structural and functional plasticity by glucocorticoids, in particular in the context of the hippocampus. Understanding the mechanistic crosstalk between glucocorticoids and BDNF holds promise for the identification of potential therapeutic targets for disorders associated with the dysfunction of stress hormone pathways.

  19. Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma.

    Science.gov (United States)

    Thomas, Alexandra L; Coarfa, Cristian; Qian, Jun; Wilkerson, Joseph J; Rajapakshe, Kimal; Krett, Nancy L; Gunaratne, Preethi H; Rosen, Steven T

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3'-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death.

  20. Glucocorticoids, master modulators of the thymic catecholaminergic system?

    Directory of Open Access Journals (Sweden)

    I. Pilipović

    Full Text Available There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg·100 g body weight-1·day-1 for 4 days. The effects of β-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRαβhigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20 = 10.92, P < 0.01; for CD4-CD8+ F (1,20 = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRαβhigh thymocyte ratio (3.41 ± 0.21 in non-adrenalectomized rats vs 2.90 ± 0.31 in adrenalectomized rats, P < 0.05 were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only β-adrenoceptor- but also α-adrenoceptor-mediated modulation of thymopoiesis.

  1. Glucocorticoids, master modulators of the thymic catecholaminergic system?

    Directory of Open Access Journals (Sweden)

    I. Pilipović

    2010-03-01

    Full Text Available There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg·100 g body weight-1·day-1 for 4 days. The effects of β-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRαβhigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20 = 10.92, P < 0.01; for CD4-CD8+ F (1,20 = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRαβhigh thymocyte ratio (3.41 ± 0.21 in non-adrenalectomized rats vs 2.90 ± 0.31 in adrenalectomized rats, P < 0.05 were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only β-adrenoceptor- but also α-adrenoceptor-mediated modulation of thymopoiesis.

  2. Glucocorticoids regulate the expression of the mouse urocortin II gene: a putative connection between the corticotropin-releasing factor receptor pathways.

    Science.gov (United States)

    Chen, Alon; Vaughan, Joan; Vale, Wylie W

    2003-08-01

    Peptides encoded by the urocortin II (Ucn II) gene were recently identified as new members of the corticotropin-releasing factor (CRF) family. Ucn II is a specific ligand for the type 2 CRF receptor. Using RT-PCR, DNA sequencing, and immunofluorescence staining, we report the expression of Ucn II mRNA in several human and mouse (m) neuronal cell lines. Using these neuronal cell lines, we provide evidence that exposure to glucocorticoid hormones increases mUcn II mRNA expression and promoter activation. The effect of glucocorticoids on mUcn II mRNA expression was tested in the Ucn II/glucocorticoid receptor-positive cell line NG108-15. The results demonstrate that mUcn II mRNA expression is up-regulated by dexamethasone in a dose- and time-dependent fashion. Computer analysis revealed the presence of 14 putative half-palindrome glucocorticoid response element sequences within 1.2 kb of the mUcn II 5' flanking region. Transfections with different fragments of the 5'-flanking region of the mUcn II gene fused to a luciferase reporter gene showed a promoter-dependent expression of the reporter gene and regulation by dexamethasone. Promoter deletion studies clarify the sufficient putative glucocorticoid response element site mediating this effect. The steroid hormone antagonist RU486 blocked the effect of dexamethasone on mUcn II mRNA expression and promoter activation, suggesting a direct glucocorticoid receptor-mediated effect of dexamethasone on mUcn II mRNA expression. Ucn II is expressed in vivo in the hypothalamus, brainstem, olfactory bulb, and pituitary. Low levels were also detected in the mouse cortex, hippocampus, and spinal cord. We demonstrated that mUcn II gene transcription was stimulated by glucocorticoid administration in vivo and inhibited by removal of glucocorticoids by adrenalectomy. Administration of dexamethasone to mice resulted in an increase of mUcn II levels in the hypothalamus and brainstem but not in the olfactory bulb region 12 h following

  3. The role of glucocorticoids, catecholamines and endocannabinoids in the development of traumatic memories and posttraumatic stress symptoms in survivors of critical illness.

    Science.gov (United States)

    Hauer, Daniela; Kaufmann, Ines; Strewe, Claudia; Briegel, Isabel; Campolongo, Patrizia; Schelling, Gustav

    2014-07-01

    -induced temporary impairment in traumatic memory retrieval which has previously been demonstrated in both rats and humans. The hypothesis that stress doses of glucocorticoids or the pharmacologic manipulation of glucocorticoid-endocannabinoid interaction during traumatic memory consolidation and retrieval could be useful for prophylaxis and treatment of PTSD after critical illness should be tested in larger controlled studies.

  4. The role of glucocorticoids in sodium retention in cirrhotic patients

    DEFF Research Database (Denmark)

    Hansen, Martin Højmark; Kristensen, Steffen Skott; Schaffalitzky de Muckadell, Ove B

    2012-01-01

    Abstract Objective. Cirrhotic patients have an increased ratio of urinary cortisol to cortisone metabolites, indicating decreased renal 11-β-hydroxysteroid dehydrogenase type-2 activity. This suggests that cortisol - by activation of the mineralocorticoid receptor - may contribute to the abnormal...... sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. Methods. A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout....... Conclusion. These results indicate that endogenous glucocorticoids contribute to the sodium retention in patients with alcoholic cirrhosis of the liver....

  5. The mechanisms of the relationship between glucocorticoids and cardiovascular diseases

    Institute of Scientific and Technical Information of China (English)

    Ejder Kardesoglu; Zafer Isilak; Omer Uz; Turgay Celik

    2010-01-01

    @@ To the editor: We have enjoyed reading an original article by Ji et al,1 entitled Influence of drug treatment on glucocorticoid receptor levels in patients with coronary heart disease, published in a recent issue of the Chinese Medical Journal. Herein, 80 patients with coronary artery disease were divided into four groups according to given drugs, and glucocorticoid (GC) receptor protein levels in peripheral blood lymphocytes were investigated before and I month after treatment in each group. In groups receiving beta blocker and nifedipine, increased levels were observed. They proposed that these increased levels might account for antiinflammatory effects of these drugs.

  6. Evaluation of the endogenous glucocorticoid hypothesis of denervation atrophy

    Science.gov (United States)

    Konagaya, Masaaki; Konagaya, Yoko; Max, Stephen R.

    1988-01-01

    The effects are studied of the oral administration of RU38486, a potent selective glucocorticoid antagonist, on muscle weight, non-collagen protein content, and selected enzyme activities (choline acetyltransferase, glucose 6-phosphate dehydrogenase, and glutamine synthetase) following denervation of rat skeletal muscle. Neither decreases in muscle weight, protein content, and choline acetyltransferase activity, nor increases in the activities of glucose 6-phosphate dehydrogernase and glutamine synthetase were affected by RU38486. These data do not support the hypothesis that denervation atrophy results from enhanced sensitivity of muscle to endogenous glucocorticoids.

  7. Glucocorticoid receptor effects on the immune system and infl ammation

    OpenAIRE

    Akker, Erica

    2008-01-01

    textabstractThomas Addison’s discovery in the mid-1800s that the adrenal cortex was essential for survival preceded by nearly a century the demonstration that this gland produced at least two distinct hormones, each essential for normal life. How glucocorticoids sustained life remained a mystery for decades. In 1949 glucocorticoids were found to have powerful anti-infl ammatory activity, a discovery which led to their use as “miracle drugs” in many diseases 1. Since their introduction in 1948...

  8. Radiation dose monitoring in the clinical routine

    Energy Technology Data Exchange (ETDEWEB)

    Guberina, Nika [UK Essen (Germany). Radiology

    2017-04-15

    Here we describe the first clinical experiences regarding the use of an automated radiation dose management software to monitor the radiation dose of patients during routine examinations. Many software solutions for monitoring radiation dose have emerged in the last decade. The continuous progress in radiological techniques, new scan features, scanner generations and protocols are the primary challenge for radiation dose monitoring software systems. To simulate valid dose calculations, radiation dose monitoring systems have to follow current trends and stay constantly up-to-date. The dose management software is connected to all devices at our institute and conducts automatic data acquisition and radiation dose calculation. The system incorporates 18 virtual phantoms based on the Cristy phantom family, estimating doses in newborns to adults. Dose calculation relies on a Monte Carlo simulation engine. Our first practical experiences demonstrate that the software is capable of dose estimation in the clinical routine. Its implementation and use have some limitations that can be overcome. The software is promising and allows assessment of radiation doses, like organ and effective doses according to ICRP 60 and ICRP 103, patient radiation dose history and cumulative radiation doses. Furthermore, we are able to determine local diagnostic reference doses. The radiation dose monitoring software systems can facilitate networking between hospitals and radiological departments, thus refining radiation doses and implementing reference doses at substantially lower levels.

  9. Colonic resection with early discharge after combined subarachnoid-epidural analgesia, preoperative glucocorticoids, and early postoperative mobilization and feeding in a pulmonary high-risk patient

    DEFF Research Database (Denmark)

    Møiniche, S; Dahl, J B; Rosenberg, J

    1994-01-01

    BACKGROUND AND OBJECTIVES. A pulmonary high-risk patient undergoing right hemicolectomy for cancer was treated with a combination of intense afferent neural block with subarachnoid-epidural local anesthetics followed by continuous epidural analgesia, preoperative high-dose glucocorticoids......) with unchanged pulmonary function. Nocturnal episodic oxygen desaturation, hyperthermia, and postoperative fatigue were prevented. Defecation occurred on the first postoperative day and oral caloric intake was normal after 24 hours with no postoperative weight loss. Self care was normalized on the third...

  10. Bronchiolitis obliterans organizing pneumonia during low-dose amiodarone therapy

    NARCIS (Netherlands)

    Jessurun, GAJ; Hoogenberg, K; Crijns, HJGM

    1997-01-01

    Two cases of amiodarone-induced pulmonary toxicity during a relatively short period of low-dose amiodarone treatment are reported. The toxicity risk of amiodarone is determined by cumulative factors in individual patients.

  11. Bronchiolitis obliterans organizing pneumonia during low-dose amiodarone therapy

    NARCIS (Netherlands)

    Jessurun, GAJ; Hoogenberg, K; Crijns, HJGM

    Two cases of amiodarone-induced pulmonary toxicity during a relatively short period of low-dose amiodarone treatment are reported. The toxicity risk of amiodarone is determined by cumulative factors in individual patients.

  12. Long and Short Term Cumulative Structural Priming Effects.

    Science.gov (United States)

    Kaschak, Michael P; Kutta, Timothy J; Coyle, Jacqueline M

    We present six experiments that examine cumulative structural priming effects (i.e., structural priming effects that accumulate across many utterances). Of particular interest is whether (1) cumulative priming effects transfer across language production tasks and (2) the transfer of cumulative priming effects across tasks persists over the course of a week. Our data suggest that cumulative structural priming effects do transfer across language production tasks (e.g., from written stem completion to picture description, and from picture description to written stem completion), but only when both tasks are presented in the same experimental session. When cumulative priming effects are established in one task, and the second (changed) task is not presented until a week later, the cumulative priming effects are not observed.

  13. Why Veterinary Medical Educators Should Embrace Cumulative Final Exams.

    Science.gov (United States)

    Royal, Kenneth D

    2017-01-03

    The topic of cumulative final examinations often elicits polarizing opinions from veterinary medical educators. While some faculty prefer cumulative finals, there are many who perceive these types of examinations as problematic. Specifically, faculty often cite cumulative examinations are more likely to cause students' greater stress, which may in turn result in negative student evaluations of teaching. Cumulative finals also restrict the number of items one may present to students on most recent material. While these cited disadvantages may have some merit, the advantages of cumulative examinations far exceed the disadvantages. The purpose of this article is to discuss the advantages of cumulative examinations with respect to learning evidence, grade/score validity, fairness issues, and implications for academic policy.

  14. Alendronate-Related Femoral Fracture in a premenopausal glucocorticoid treated patient.

    Science.gov (United States)

    Mobini, Maryam

    2014-01-01

    Alendronate is a bisphosphonate that is approved to reduce bone loss in glucocorticoid treated patients. In this paper, we present a case of femoral fracture following the use of Alendronate. A- 46 year old woman who was a known case of hemolytic anemia has been treated by prednisolone (with different doses from 7.5 to 75 mg/day), calcium-D 500 mg/day and alendronate 70 mg/week for 3 years. Despite improvement of bone density, she experienced a low truama femoral shaft fracture. This case shows a rare complication of treatment by alendronate. It may be needed to evaluate patients with long term usage of bisphosphonates for cortical thickness.

  15. Molecular mechanisms of glucocorticoid receptor signaling Mecanismos moleculares de señalización del receptor de glucocorticoides

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR. Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.Esta revisión destaca los más recientes hallazgos sobre los mecanismos moleculares del receptor de glucocorticoides (GR. La mayoría de los efectos de los glucocorticoides son mediados por los GR intracelulares presentes en casi todos los tejidos y controlan la activación transcripcional por mecanismos directos e indirectos. Las respuestas a los glucocorticoides son específicas para cada gen y tejido. Los GR se asocian en forma selectiva con ligandos producidos en la glándula adrenal, corticosteroides, en respuesta a cambios neuroendocrinos. La interacción del ligando con el GR promueve: a la unión del GR a elementos genómicos de respuesta a glucocorticoides, modulando la transcripción; b la interacción de monómeros del GR con otros factores de transcripción activados por otras vías, llevando a la transrepresión. El GR regula un amplio espectro de funciones fisiológicas, incluyendo la

  16. Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients.

    Science.gov (United States)

    Behan, Lucy-Ann; Rogers, Bairbre; Hannon, Mark J; O'Kelly, Patrick; Tormey, William; Smith, Diarmuid; Thompson, Christopher J; Agha, Amar

    2011-10-01

    The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15-30 mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. Primarily to define the hydrocortisone regimen which results in a 24 h cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). Ten male hypopituitary patients with severe ACTH deficiency (basal cortisol <100 nm and peak response to stimulation <400 nm) were enrolled in a prospective, randomized, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24 h serum cortisol sampling and QoL assessment with the Short Form 36 (SF36) and the Nottingham Health Profile (NHP) questionnaires. Free cortisol was calculated using Coolen's equation. All results were compared to those of healthy, matched controls. Corticosteroid binding globulin (CBG) was significantly lower across all dose regimens compared to controls (P < 0·05). The lower dose regimen C (10 mg mane/5 mg tarde) produced a 24 h free cortisol profile (FCP) which most closely resembled that of controls. Both regimen A(20 mg mane/10 mg tarde) and B(10 mg mane/10 mg tarde) produced supraphysiological post-absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (P < 0·001). The lower dose of hydrocortisone (10 mg/5 mg) produces a more physiological cortisol profile, without compromising QoL, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality. © 2011 Blackwell Publishing Ltd.

  17. Optimising glucocorticoid replacement therapy in severely adrenocorticotropin (ACTH) deficient hypopituitary male patients.

    LENUS (Irish Health Repository)

    Behan, Lucy-Ann

    2011-04-18

    Context:  The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15mg to 30mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. Objective:  Primarily to define the hydrocortisone regimen which results in a 24hour cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). Design:  10 male hypopituitary patients with severe ACTH deficiency (basal cortisol <100nM and peak response to stimulation <400nM) were enrolled in a prospective, randomised, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24hour serum cortisol sampling and QoL assessment with the Short Form 36 and the Nottingham Health Profile questionnaires. Free cortisol was calculated using Coolen\\'s equation. All results were compared to those of healthy, matched controls. Results:  CBG was significantly lower across all dose regimens compared to controls (p<0.05). The lower dose regimen C(10mg mane\\/5mg tarde) produced a 24hour free cortisol profile which most closely resembled that of controls. Both regimen A(20mg mane\\/10mg tarde) and B(10mg mane\\/10mg tarde) produced supraphysiological post-absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (p<0.001). Conclusions:  The lower dose of HC(10mg\\/5mg) produces a more physiological cortisol profile, without compromising quality of life, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality.

  18. Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients.

    LENUS (Irish Health Repository)

    Behan, Lucy-Ann

    2012-02-01

    BACKGROUND: The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15-30 mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. OBJECTIVE: Primarily to define the hydrocortisone regimen which results in a 24 h cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). DESIGN: Ten male hypopituitary patients with severe ACTH deficiency (basal cortisol <100 nm and peak response to stimulation <400 nm) were enrolled in a prospective, randomized, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24 h serum cortisol sampling and QoL assessment with the Short Form 36 (SF36) and the Nottingham Health Profile (NHP) questionnaires. Free cortisol was calculated using Coolen\\'s equation. All results were compared to those of healthy, matched controls. RESULTS: Corticosteroid binding globulin (CBG) was significantly lower across all dose regimens compared to controls (P < 0.05). The lower dose regimen C (10 mg mane\\/5 mg tarde) produced a 24 h free cortisol profile (FCP) which most closely resembled that of controls. Both regimen A(20 mg mane\\/10 mg tarde) and B(10 mg mane\\/10 mg tarde) produced supraphysiological post-absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (P < 0.001). CONCLUSIONS: The lower dose of hydrocortisone (10 mg\\/5 mg) produces a more physiological cortisol profile, without compromising QoL, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality.

  19. Analysis of experimental data on correlations between cumulative particles

    Energy Technology Data Exchange (ETDEWEB)

    Vlasov, A.V.; Doroshkevich, E.A.; Leksin, G.A. [Institute of Theoretical and Experimental Physics, Moscow (Russian Federation)] [and others

    1995-04-01

    Experimental data on correlations between cumulative particles are analyzed. A space-time and energy-transfer pattern of hadron-nucleus interaction based on both correlation data and data on the inclusive spectra of cumulative particles is considered. A new variable that is convenient for describing the production of cumulative particles is proposed using the concept of symmetry between the one-particle and multiparticle distributions. 32 refs., 9 figs., 1 tab.

  20. Glucocorticoids Protect Neonatal Rat Brain in Model of Hypoxic-Ischemic Encephalopathy (HIE)

    Science.gov (United States)

    Harding, Benjamin; Conception, Katherine; Li, Yong; Zhang, Lubo

    2016-01-01

    Hypoxic-ischemic encephalopathy (HIE) resulting from asphyxia in the peripartum period is the most common cause of neonatal brain damage and can result in significant neurologic sequelae, including cerebral palsy. Currently therapeutic hypothermia is the only accepted treatment in addition to supportive care for infants with HIE, however, many additional neuroprotective therapies have been investigated. Of these, glucocorticoids have previously been shown to have neuroprotective effects. HIE is also frequently compounded by infectious inflammatory processes (sepsis) and as such, the infants may be more amenable to treatment with an anti-inflammatory agent. Thus, the present study investigated dexamethasone and hydrocortisone treatment given after hypoxic-ischemic (HI) insult in neonatal rats via intracerebroventricular (ICV) injection and intranasal administration. In addition, we examined the effects of hydrocortisone treatment in HIE after lipopolysaccharide (LPS) sensitization in a model of HIE and sepsis. We found that dexamethasone significantly reduced rat brain infarction size when given after HI treatment via ICV injection; however it did not demonstrate any neuroprotective effects when given intranasally. Hydrocortisone after HI insult also significantly reduced brain infarction size when given via ICV injection; and the intranasal administration showed to be protective of brain injury in male rats at a dose of 300 µg. LPS sensitization did significantly increase the brain infarction size compared to controls, and hydrocortisone treatment after LPS sensitization showed a significant decrease in brain infarction size when given via ICV injection, as well as intranasal administration in both genders at a dose of 300 µg. To conclude, these results show that glucocorticoids have significant neuroprotective effects when given after HI injury and that these effects may be even more pronounced when given in circumstances of additional inflammatory injury, such

  1. Analysis of Memory Codes and Cumulative Rehearsal in Observational Learning

    Science.gov (United States)

    Bandura, Albert; And Others

    1974-01-01

    The present study examined the influence of memory codes varying in meaningfulness and retrievability and cumulative rehearsal on retention of observationally learned responses over increasing temporal intervals. (Editor)

  2. Continuously Cumulating Meta-Analysis and Replicability.

    Science.gov (United States)

    Braver, Sanford L; Thoemmes, Felix J; Rosenthal, Robert

    2014-05-01

    The current crisis in scientific psychology about whether our findings are irreproducible was presaged years ago by Tversky and Kahneman (1971), who noted that even sophisticated researchers believe in the fallacious Law of Small Numbers-erroneous intuitions about how imprecisely sample data reflect population phenomena. Combined with the low power of most current work, this often leads to the use of misleading criteria about whether an effect has replicated. Rosenthal (1990) suggested more appropriate criteria, here labeled the continuously cumulating meta-analytic (CCMA) approach. For example, a CCMA analysis on a replication attempt that does not reach significance might nonetheless provide more, not less, evidence that the effect is real. Alternatively, measures of heterogeneity might show that two studies that differ in whether they are significant might have only trivially different effect sizes. We present a nontechnical introduction to the CCMA framework (referencing relevant software), and then explain how it can be used to address aspects of replicability or more generally to assess quantitative evidence from numerous studies. We then present some examples and simulation results using the CCMA approach that show how the combination of evidence can yield improved results over the consideration of single studies.

  3. Glucocorticoid receptor effects on the immune system and infl ammation

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica)

    2008-01-01

    textabstractThomas Addison’s discovery in the mid-1800s that the adrenal cortex was essential for survival preceded by nearly a century the demonstration that this gland produced at least two distinct hormones, each essential for normal life. How glucocorticoids sustained life remained a mystery for

  4. Stress, glucocorticoids and absences in a genetic epilepsy model

    NARCIS (Netherlands)

    Tolmacheva, E.A.; Oitzl, M.S.; Luijtelaar, E.L.J.M. van

    2012-01-01

    Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij ra

  5. The Glucocorticoid Receptor Controls Hepatic Dyslipidemia through Hes1

    NARCIS (Netherlands)

    Lemke, U.; Krones-Herzig, A.; Berriel Diaz, M.; Narvekar, P.; Ziegler, A.; Vegiopoulos, A.; Cato, A.C.B.; Bohl, S.; Klingmüller, U.; Screaton, R.A.; Müller-Decker, K.; Kersten, A.H.; Herzig, S.

    2008-01-01

    Aberrant accumulation of lipids in the liver (¿fatty liver¿ or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of

  6. Glucocorticoid therapy for hypotension in the cardiac intensive care unit

    NARCIS (Netherlands)

    Millar, K. J.; Thiagarajan, R. R.; Laussen, P. C.

    2007-01-01

    In recent years, it has been our practice to treat persistent hypotension in the cardiac intensive care unit with glucocorticoids. We undertook a retrospective review in an attempt to identify predictors of a hemodynamic response to steroids and of survival in these patients. Patients who had receiv

  7. Brief report: Glucocorticoid receptor polymorphism affects transrepression but not transactivation

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica); H. Russcher (Henk); E.F.C. van Rossum (Liesbeth); A.O. Brinkmann (Albert); F.H. de Jong (Frank); A.C.S. Hokken-Koelega (Anita); H.A.P. Pols (Huib); J.W. Koper (Jan); S.W.J. Lamberts (Steven)

    2006-01-01

    textabstractContext: Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC

  8. Mineralocorticoid and glucocorticoid receptor antagonists in animal models of anxiety

    NARCIS (Netherlands)

    Korte, SM; KorteBouws, GAH; Koob, GF; DeKloet, ER; Bohus, B

    1996-01-01

    The behavioral effects of intracerebroventricular (ICV) administration of a specific mineralocorticoid receptor (MR) antagonist [RU28318 (10-50 ng/2 mu l)], a glucocorticoid receptor (GR) antagonist [RU38486 (1-50 ng/2 mu l)], or both antagonists (50 ng/2 mu l), were studied in two different animal

  9. Novel pathways for glucocorticoid effects on neutrophils in chronic inflammation.

    Science.gov (United States)

    Goulding, N J; Euzger, H S; Butt, S K; Perretti, M

    1998-10-01

    Neutrophils have been implicated in mediating much of the tissue damage associated with chronic inflammatory diseases such as rheumatoid arthritis, where they are involved in destruction of both cartilage and bone. Glucocorticoids are powerful anti-inflammatory agents, often used in the treatment of this autoimmune disease. They exert significant inhibitory effects on neutrophil activation and functions, such as chemotaxis, adhesion, transmigration, apoptosis, oxidative burst, and phagocytosis. The mechanisms by which glucocorticoids exert these effects on neutrophils are unclear. Evidence from studies of inflammation in human subjects and animal models suggests that annexin-I an endogenous, glucocorticoid-induced protein also known as lipocortin-1, has a pivotal role in modulating neutrophil activation, transmigratory, and phagocytic functions. Furthermore, we present evidence for altered neutrophil functions in rheumatoid arthritis that correspond to a significantly reduced capacity of these cells to bind annexin-I. A proposed novel pathway for glucocorticoid actions on neutrophils involving annexin-I could explain the development of chronic neutrophil activation in diseases such as rheumatoid arthritis.

  10. Glucocorticoids boost stimulus-response memory formation in humans.

    Science.gov (United States)

    Guenzel, Friederike M; Wolf, Oliver T; Schwabe, Lars

    2014-07-01

    Stress affects memory beyond hippocampus-dependent spatial or episodic memory processes. In particular, stress may influence also striatum-dependent stimulus-response (S-R) memory processes. Rodent studies point to an important role of glucocorticoids in the modulation of S-R memory. However, whether glucocorticoids influence S-R memory processes in humans is still unknown. Therefore, we examined in the current experiment the impact of glucocorticoids on the formation of S-R memories in humans. For this purpose, healthy men and women received either hydrocortisone or a placebo 45 min before completing an S-R association learning task and an S-R navigation task. In addition, participants performed also a virtual spatial navigation task and a spatial navigation task in a real environment. Memory of all four learning tasks was tested one week later. Our data showed that hydrocortisone before learning enhanced memory of the S-R association learning task. Moreover, hydrocortisone enhanced the memory of the virtual spatial navigation task, mainly in women. Memory performance in the other tasks remained unaffected by hydrocortisone. These findings provide first evidence that glucocorticoids may facilitate S-R memory formation processes in humans.

  11. Glucocorticoid-induced myopathy in the intensive care unit

    DEFF Research Database (Denmark)

    Eddelien, Heidi Shil; Hoffmeyer, Henrik Westy; Lund, Eva Charlotte Løbner

    2015-01-01

    Glucocorticoids (GC) are used for intensive care unit (ICU) patients on several indications. We present a patient who was admitted to the ICU due to severe respiratory failure caused by bronchospasm requiring mechanical ventilation and treated with methylprednisolone 240 mg/day in addition...

  12. Loss of the podocyte glucocorticoid receptor exacerbates proteinuria after injury.

    Science.gov (United States)

    Zhou, Han; Tian, Xuefei; Tufro, Alda; Moeckel, Gilbert; Ishibe, Shuta; Goodwin, Julie

    2017-08-29

    Nephrotic syndrome is a common disorder in adults and children whose etiology is largely unknown. Glucocorticoids remain the mainstay of therapy in most cases, though their mechanism of action remains poorly understood. Emerging evidence suggests that immunomodulatory therapies used in nephrotic syndrome directly target the podocytes. To study how steroids directly affect the podocytes in the treatment of proteinuria, we created a mouse model with podocyte-specific deletion of the glucocorticoid receptor. The podocyte-specific glucocorticoid receptor (GR) knockout mice had similar renal function and protein excretion compared to wild type. However, after glomerular injury induced by either LPS or nephrotoxic serum, the podocyte GR knockout mice demonstrated worsened proteinuria compared to wild type. Ultrastructural examination of podocytes confirmed more robust foot process effacement in the knockout animals. Expression of several key slit diaphragm protein was down regulated in pGR KO mice. Primary podocytes isolated from wild type and podocyte GR knockout mice showed similar actin stress fiber staining patterns in unstimulated conditions. Yet, when exposed to LPS, GR knockout podocytes demonstrated fewer stress fibers and impaired migration compared to wild type podocytes. We conclude that the podocyte glucocorticoid receptor is important for limiting proteinuria in settings of podocyte injury.

  13. Effect of Calpain inhibitor I on glucocorticoid receptor-dependent degradation and its transactivation ability

    Institute of Scientific and Technical Information of China (English)

    程晓刚; 粟永萍; 罗成基; 刘晓宏

    2004-01-01

    Objective: To investigate the effect of Calpain inhibitor I on glucocorticoid receptor-dependent proteasomal degradation and its transcriptional activity. Methods: After Raw-264.7 cells were treated with Calpain inhibitor I, dexamethasone, or both for about 12 h, the change of glucocorticoid receptor was detected by western blot analysis. COS-7 cells were transfected with PRsh-GRα expression vector and glucocorticoid-responsive receptor pMAMneo-CAT, then the effect of Calpain inhibitor I on glucocorticoid receptor transcriptional activation ability was determined by CAT activity. Results: The glucocorticoid receptor levels decreased after RAW-264.7 cells were treated with dexamethasone for 12 hours, which effect can be inhibited by Calpain inhibitor I to some extent. CAT activity assay showed that Calpain inhibitor I enhance glucocorticoid receptor transcriptional activity. Conclusion: Calpain inhibitor I can inhibit the down-regulation of dexamethasone on glucocoaicoid receptor, and enhances glucocorticoid receptor transactivation ability.

  14. The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone.

    Science.gov (United States)

    Ding, Ming; Danielsen, Carl Christian; Overgaard, Søren

    2012-06-01

    In this study, 18 female skeletally mature sheep were randomly allocated into three groups of six each. Group 1 (glucocorticoid-1) received prednisolone treatment (0.60 mg/kg/day, five times weekly) for 7 months. Group 2 (glucocorticoid-2) received the same treatment regime followed by observation of 3 months without treatment. Group 3 was left untreated and served as controls. All sheep received a restricted diet with low calcium and phosphorus. At sacrifice, cortical bone samples from the femur midshaft of each sheep were harvested, micro-CT scanned and subjected to three-point bending and tensile strength testing. Bone collagen and mineral were determined. Cortical porosity was significantly increased in the glucocorticoid-2 compared with the glucocorticoid-1 and control groups. Apparent density was significantly decreased in the glucocorticoid-2 compared with the glucocorticoid-1 group. Collagen content was significantly increased in the glucocorticoid-2 compared with the glucocorticoid-1 and control groups. Bone mineral content did not differ between the groups. Neither the three-point bending mechanical properties nor the tensile mechanical properties differed significantly between the groups, while there was a trend towards decreasing bending mechanical properties in the glucocorticoid-2 group. In conclusion, 7 months of glucocorticoid treatment with malnutrition had a significant impact on the cortical microarchitecture of the sheep femur midshaft. These observed changes occurred 3 months after glucocorticoid cessation, suggesting a delayed effect of glucocorticoid on cortical bone. Thus, changes in cortical bone beyond cancellous bone might further increase fracture risk in patients treated with glucocorticoids. This model might be used as a glucocorticoid-induced osteoporotic model for orthopaedic biomaterial, joint prosthesis and medical device researches.

  15. 合并慢性阻塞性肺疾病的糖尿病患者短期应用糖皮质激素治疗后血糖升高的特点及胰岛素剂量调整方案%Characteristics of glucose changes and adjustment scheme of insulin doses in diabetic patients complicated with chronic obstructive pulmonary disease after short term use of glucocorticoid

    Institute of Scientific and Technical Information of China (English)

    于红

    2015-01-01

    Objective To explore the characteristics of glucose changes and adjustment scheme of insulin doses in diabetic patients complicated with chronic obstructive pulmonary disease (COPD) after short term use of glucocorticoid.Methods Totally 60 diabetic patients complicated with COPD from June 2010 to June 2014 were enrolled and randomly divided into observation 1 group and observation 2 group; in addition,30 COPD patients without diabetes were selected as control group.Salbutamol was inhaled in observation 1 group; salbutamol was inhaled and methylprednisolone was intravenously dropped (40 mg,8:00 AM,1 time/d) in observation 2 group and observation group; the treatment lasted for 5 days.The characteristics of glucose changes were observed through continuous glucose monitor system and the adjustment scheme of insulin dose was recorded.Results The total cholesterol,triacylglycerol,hemoglobin A1c (HbA1c) in observation 1 group and observation 2 group were significantlyhigher than those in control group [(5.8 ±2.1) mmol/L,(5.6 ± 2.1) mmol/L vs (4.8 ± 0.8) mmol/L; (2.68±0.51) mmol/L,(2.71 ±0.43) mmol/L vs (1.34±0.26) mmol/L; (7.3±2.5)%,(7.4 ± 2.5) % vs (5.3 ± 1.3) %] (P < 0.05) ; no significant differences were found between observation 1 group and observation 2 group (P >0.05).The characteristics of blood glucose changes in the first 24 h showed that the area under the curve of blood glucose ≥ 11.1 mmol/L,fasting blood glucose,24 h average blood glucose in observation 2 group were significantly higher than those in observation 1 group and control group[(4.06 ± 1.21) vs (0.17 ± 0.06),(0.21 ±0.08); (7.0±2.8) mmol/L vs (6.0±1.2),(4.1 ±1.0) mmol/L; (11.6±4.4) vs (4.9± 1.0),(4.4 ± 1.0) mmol/L] (P < 0.05) ; the peak glucose after breakfast in observation 1 and observation 2 groups were significantly higher than that in control group [(11.0 ± 3.1),(11.4 ± 3.3) mmol/L vs (7.1 ± 0.8) mmol/L] (P < 0.05) but no significant difference was found

  16. Cumulative Effect of Depression on Dementia Risk

    Directory of Open Access Journals (Sweden)

    J. Olazarán

    2013-01-01

    Full Text Available Objective. To analyze a potential cumulative effect of life-time depression on dementia and Alzheimer’s disease (AD, with control of vascular factors (VFs. Methods. This study was a subanalysis of the Neurological Disorders in Central Spain (NEDICES study. Past and present depression, VFs, dementia status, and dementia due to AD were documented at study inception. Dementia status was also documented after three years. Four groups were created according to baseline data: never depression (nD, past depression (pD, present depression (prD, and present and past depression (prpD. Logistic regression was used. Results. Data of 1,807 subjects were investigated at baseline (mean age 74.3, 59.3% women, and 1,376 (81.6% subjects were evaluated after three years. The prevalence of dementia at baseline was 6.7%, and dementia incidence was 6.3%. An effect of depression was observed on dementia prevalence (OR [CI 95%] 1.84 [1.01–3.35] for prD and 2.73 [1.08–6.87] for prpD, and on dementia due to AD (OR 1.98 [0.98–3.99] for prD and OR 3.98 [1.48–10.71] for prpD (fully adjusted models, nD as reference. Depression did not influence dementia incidence. Conclusions. Present depression and, particularly, present and past depression are associated with dementia at old age. Multiple mechanisms, including toxic effect of depression on hippocampal neurons, plausibly explain these associations.

  17. Cumulative social disadvantage and child health.

    Science.gov (United States)

    Bauman, Laurie J; Silver, Ellen J; Stein, Ruth E K

    2006-04-01

    Disparities in child health are a major public health concern. However, it is unclear whether these are predominantly the result of low income, race, or other social risk factors that may contribute to their health disadvantage. Although others have examined the effects of the accumulation of risk factors, this methodology has not been applied to child health. We tested 4 social risk factors (poverty, minority race/ethnicity, low parental education, and not living with both biological parents) to assess whether they have cumulative effects on child health and examined whether access to health care reduced health disparities. We analyzed data on 57,553 children low parental education, and single-parent household) were consistently associated with child health. These were summed, generating the Social Disadvantage Index (range: 0-3). A total of 43.6% of children had no social disadvantages, 30.8% had 1, 15.6% had 2, and 10.0% had all 3. Compared with those with no social disadvantages, the odds ratios (ORs) of being in "good, fair, or poor health" (versus "excellent or very good") were 1.95 for 1 risk, 3.22 for 2 risks, and 4.06 for 3 risks. ORs of having a chronic condition increased from 1.25 (1 risk) to 1.60 (2 risks) to 2.11 (3 risks). ORs for activity limitation were 1.51 (1 risk) to 2.14 (2 risks) and 2.88 (3 risks). Controlling for health insurance did not affect these findings. The accumulation of social disadvantage among children was strongly associated with poorer child health and having insurance did not reduce the observed health disparities.

  18. The Role of S-Palmitoylation of the Human Glucocorticoid Receptor (hGR) in Mediating the Nongenomic Glucocorticoid Actions.

    Science.gov (United States)

    Nicolaides, Nicolas C; Kino, Tomoshige; Roberts, Michael L; Katsantoni, Eleni; Sertedaki, Amalia; Moutsatsou, Paraskevi; Psarra, Anna-Maria G; Chrousos, George P; Charmandari, Evangelia

    2017-01-01

    Many rapid nongenomic glucocorticoid actions are mediated by membrane-bound glucocorticoid receptors (GRs). S-palmitoylation is a lipid post-translational modification that mediates the membrane localization of some steroid receptors. A highly homologous amino acid sequence (663YLCM KTLLL671) is present in the ligand-binding domain of hGRα, suggesting that hGRα might also undergo S-palmitoylation. To investigate the role of the motif 663YLCMKTLLL671 in membrane localization of the hGRα and in mediating rapid nongenomic glucocorticoid signaling. We showed that the mutant receptors hGRαY663A, hGRαC665A and hGRαLL670/671AA, and the addition of the palmitoylation inhibitor 2-bromopalmitate did not prevent membrane localization of hGRα and co-localization with caveolin-1, and did not influence the biphasic activation of mitogen-activated protein kinase (MAPK) signaling pathway in the early time points. Finally, the hGRα was not shown to undergo S-palmitoylation. The motif 663YLCMKTLLL671 does not play a role in membrane localization of hGRα and does not mediate the nongenomic glucocorticoid actions.

  19. Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene

    NARCIS (Netherlands)

    N.A.T.M. Huizenga (Nannette); P. de Lange (Pieter); J.W. Koper (Jan); W.W. de Herder (Wouter); R. Abs; J.H. Kasteren; F.H. de Jong (Frank); S.W.J. Lamberts (Steven)

    2000-01-01

    textabstractCortisol resistance (CR) is a rare disease characterized by a generalized reduced sensitivity of end-organs to the actions of glucocorticoids (GCs). GC effects are mediated by the GC receptor (GR). The molecular alterations in CR described thus far were loca

  20. A systematic review of the effect of oral glucocorticoids on energy intake, appetite, and body weight in humans.

    Science.gov (United States)

    Berthon, Bronwyn S; MacDonald-Wicks, Lesley K; Wood, Lisa G

    2014-03-01

    Obesity is a serious risk factor for chronic disease, and commonly prescribed oral glucocorticoids (OCS) may be contributing to the prevalence of obesity. The objective of this review was to assess the impact of OCS on obesity in humans through effects on body weight (BW), energy intake, appetite, and body composition. An electronic search of English language peer-reviewed studies from 1973 up to March 2012 was conducted using Medline, CINAHL, EMBASE, and Cochrane databases. Original studies that addressed the effects of OCS on appetite, energy intake, BW, or body composition in adults were considered eligible. Data from 21 studies with objectively measured outcomes were extracted and assessed for quality using standardized tools. The publication year varied from 1986 to 2013, and the sample size, from 6 to 189. Energy intake was measured in 6 studies; BW, in 19 studies; energy expenditure, in 3 studies; body composition, in 6 studies; and appetite was evaluated in 3 studies. Short-term oral glucocorticoid therapy may result in small increases in energy intake but does not appear to result in increased BW, possibly due to an increase in energy expenditure. Long-term therapy may result in clinically significant weight gain. Within-subject variation due to metabolism and physical activity levels confounds the relationship. A dose-response relationship of oral glucocorticoid therapy on energy intake, appetite, BW, or body composition was not found. Additional well-designed, double-blind, placebo-controlled clinical trials that use standardized doses of OCS and assess the effects on appetite, energy intake, BW, and composition are strongly justified to confirm the findings of this review.

  1. The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test.

    Science.gov (United States)

    Solomon, Matia B; Wulsin, Aynara C; Rice, Taylor; Wick, Dayna; Myers, Brent; McKlveen, Jessica; Flak, Jonathan N; Ulrich-Lai, Yvonne; Herman, James P

    2014-04-01

    Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10mg/kg), CORT 108297 (30mg/kg and 60mg/kg), imipramine (10mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.

  2. A Framework for Treating Cumulative Trauma with Art Therapy

    Science.gov (United States)

    Naff, Kristina

    2014-01-01

    Cumulative trauma is relatively undocumented in art therapy practice, although there is growing evidence that art therapy provides distinct benefits for resolving various traumas. This qualitative study proposes an art therapy treatment framework for cumulative trauma derived from semi-structured interviews with three art therapists and artistic…

  3. Cumulative Effects of Human Activities on Marine Mammal Populations

    Science.gov (United States)

    2015-09-30

    1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Cumulative Effects of Human Activities on Marine Mammal ...marine mammals . OBJECTIVES The National Academies of Sciences, Engineering, and Medicine has convened a volunteer committee that will...Review the present scientific understanding of cumulative effects of anthropogenic stressors on marine mammals with a focus on anthropogenic sound

  4. A Framework for Treating Cumulative Trauma with Art Therapy

    Science.gov (United States)

    Naff, Kristina

    2014-01-01

    Cumulative trauma is relatively undocumented in art therapy practice, although there is growing evidence that art therapy provides distinct benefits for resolving various traumas. This qualitative study proposes an art therapy treatment framework for cumulative trauma derived from semi-structured interviews with three art therapists and artistic…

  5. Cumulative Estrogen Exposure and Prospective Memory in Older Women

    Science.gov (United States)

    Hesson, Jacqueline

    2012-01-01

    This study looked at cumulative lifetime estrogen exposure, as estimated with a mathematical index (Index of Cumulative Estrogen Exposure (ICEE)) that included variables (length of time on estrogen therapy, age at menarche and menopause, postmenopausal body mass index, time since menopause, nulliparity and duration of breastfeeding) known to…

  6. Comparing two different superovulation protocols on ovarian activity and fecal glucocorticoid levels in the brown brocket deer (Mazama gouazoubira).

    Science.gov (United States)

    Zanetti, Eveline S; Munerato, Marina S; Cursino, Marina S; Duarte, José Maurício B

    2014-03-19

    Stress is a limiting factor in assisted reproduction in wild animals maintained in captivity. However, the knowledge of assisted reproduction techniques for wild animals is useful for future in situ and ex situ conservation programs. Thus, this study evaluated the ovulation rate, presence of functional corpora lutea and fecal glucocorticoid levels following treatments promoting superovulation in captive brown brocket deer. The crossover design used six hinds, allocated to two groups (n=6): eCG Treatment, CIDR for 8 days, followed by 0.25 mg of EB on day 0, 700 IU of eCG on day 4 following device insertion and 265 mug of PGF2alfa on day 8; and FSH Treatment, CIDR for 7.5 days, followed by 0.25 mg of EB on day 0, 130 mg of FSH in 8 equal doses and 265 mug of PGF2alfa on day 7.5. Induced adrenal activity and treatment efficacy were evaluated by corpora lutea (CL) counts and fecal glucocorticoid and progestin concentration (ng/g feces) analyses for five different phases: Pre, two days before treatment; Early, first four days of treatment; Late, last four days of treatment; Total, entire treatment period; and Post, five days posttreatment. eCG Treatment resulted in the highest number of CL (P lower than 0.05). There was no significant difference for fecal glucocorticoid concentrations in five different time periods between the treatments; however Pre fecal glucocorticoid concentrations (90.06+/-19.64) were significantly different from Late (200.76+/-26.39) within FSH Treatment. The mean fecal progestin concentration and mean ovulation rate were higher in eCG Treatment (4293.69+/-769.47, 7.0+/-1.8) than in FSH Treatment (1571.26+/-240.28, 2.6+/-0.8) (P lower than or equal to 0.05). Although the eCG Treatment induced a good superovulatory response, with the formation of functional corpora lutea, we cannot yet affirm that we have established a suitable protocol for induction of SOV in the species M. gouazoubira because approximately 65% of the deer showed premature

  7. EULAR recommendation for the management of rheumatoid arthritis (2013: glucocorticoid use

    Directory of Open Access Journals (Sweden)

    N.V. Chichasova

    2014-01-01

    Full Text Available The role of glucocorticoids (GCs in the current strategy of treating rheumatoid arthritis (RA according to the EULAR 2013 recommendation is discussed. The main studies focused on GCs since they started to be used to treat RA are reviewed. The difficulties, advantages, and draw- backs of using GCs to treat RA, as well as possibilities to affect progression of destruction in small joints of the hands and feet, are discussed. Since new data have recently been obtained, EULAR recommendations 2013 for the management of RA patients states the following for GCs: «The use low doses of GCs (combined with one or several disease-modifying anti-rheumatic drugs should be considered as a component of the treatment strategy during the first six months of the disease». It is particularly emphasized that GCs should be abandoned as soon as it is pos- sible from the clinical viewpoint. The term «low dose of GC» means prednisolone prescribed at a dose ≤7.5 mg/day. 

  8. Rapid Nongenomic Glucocorticoid Actions in Male Mouse Hypothalamic Neuroendocrine Cells Are Dependent on the Nuclear Glucocorticoid Receptor

    Science.gov (United States)

    Nahar, Jebun; Haam, Juhee; Chen, Chun; Jiang, Zhiying; Glatzer, Nicholas R.; Muglia, Louis J.; Dohanich, Gary P.; Herman, James P.

    2015-01-01

    Corticosteroids act classically via cognate nuclear receptors to regulate gene transcription; however, increasing evidence supports rapid, nontranscriptional corticosteroid actions via activation of membrane receptors. Using whole-cell patch clamp recordings in hypothalamic slices from male mouse genetic models, we tested for nongenomic glucocorticoid actions at glutamate and gamma aminobutyric acid (GABA) synapses in hypothalamic neuroendocrine cells, and for their dependence on the nuclear glucocorticoid receptor (GR). In enhanced green fluorescent protein-expressing CRH neurons of the paraventricular nucleus (PVN) and in magnocellular neurons of the PVN and supraoptic nucleus (SON), dexamethasone activated postsynaptic membrane-associated receptors and G protein signaling to elicit a rapid suppression of excitatory postsynaptic inputs, which was blocked by genetic deletion of type I cannabinoid receptors and a type I cannabinoid receptor antagonist. In magnocellular neurons, dexamethasone also elicited a rapid nitric oxide-dependent increase in inhibitory postsynaptic inputs. These data indicate a rapid, synapse-specific glucocorticoid-induced retrograde endocannabinoid signaling at glutamate synapses and nitric oxide signaling at GABA synapses. Unexpectedly, the rapid glucocorticoid effects on both excitatory and inhibitory synaptic transmission were lost with conditional deletion of GR in the PVN and SON in slices from a single minded-1-cre-directed conditional GR knockout mouse. Thus, the nongenomic glucocorticoid actions at glutamate and GABA synapses on PVN and SON neuroendocrine cells are dependent on the nuclear GR. The nuclear GR, therefore, is responsible for transducing the rapid steroid response at the membrane, or is either a critical component in the signaling cascade or regulates a critical component of the signaling cascade of a distinct membrane GR. PMID:26061727

  9. Lattice QCD results on cumulant ratios at freeze-out

    CERN Document Server

    Karsch, Frithjof

    2016-01-01

    Ratios of cumulants of net proton-number fluctuations measured by the STAR Collaboration show strong deviations from a skellam distribution, which should describe thermal properties of cumulant ratios, if proton-number fluctuations are generated in equilibrium and a hadron resonance gas (HRG) model would provide a suitable description of thermodynamics at the freeze-out temperature. We present some results on sixth order cumulants entering the calculation of the QCD equation of state at non-zero values of the baryon chemical potential (mu_B) and discuss limitations on the applicability of HRG thermodynamics deduced from a comparison between QCD and HRG model calculations of cumulants of conserved charge fluctuations. We show that basic features of the $\\mu_B$-dependence of skewness and kurtosis ratios of net proton-number fluctuations measured by the STAR Collaboration resemble those expected from a O(mu_B^2) QCD calculation of the corresponding net baryon-number cumulant ratios.

  10. A new family of cumulative indexes for measuring scientific performance.

    Directory of Open Access Journals (Sweden)

    Marcin Kozak

    Full Text Available In this paper we propose a new family of cumulative indexes for measuring scientific performance which can be applied to many metrics, including h index and its variants (here we apply it to the h index, h(2 index and Google Scholar's i10 index. These indexes follow the general principle of repeating the index calculation for the same publication set. Using bibliometric data and reviewer scores for accepted and rejected fellowship applicants we examine how valid the cumulative variant is compared to the original variant. These analyses showed that the cumulative indexes result in higher correlations with the reviewer scores than their original variants. Thus, the cumulative indexes better reflect the assessments by peers than the original variants and are useful extensions of the original indexes. In contrast to many other measures of scientific performance proposed up to now, the cumulative indexes seem not only to be effective, but they are also easy to understand and calculate.

  11. Glucocorticoid Induced Cerebellar Toxicity in the Developing Neonate: Implications for Glucocorticoid Therapy during Bronchopulmonary Dysplasia

    Directory of Open Access Journals (Sweden)

    Kevin K. Noguchi

    2014-01-01

    Full Text Available Prematurely born infants commonly suffer respiratory dysfunction due to the immature state of their lungs. As a result, clinicians often administer glucocorticoid (GC therapy to accelerate lung maturation and reduce inflammation. Unfortunately, several studies have found GC therapy can also produce neuromotor/cognitive deficits and selectively stunt the cerebellum. However, despite its continued use, relatively little is known about how exposure to this hormone might produce neurodevelopmental deficits. In this review, we use rodent and human research to provide evidence that GC therapy may disrupt cerebellar development through the rapid induction of apoptosis in the cerebellar external granule layer (EGL. The EGL is a transient proliferative region responsible for the production of over 90% of the neurons in the cerebellum. During normal development, endogenous GC stimulation is thought to selectively signal the elimination of the EGL once production of new neurons is complete. As a result, GC therapy may precociously eliminate the EGL before it can produce enough neurons for normal cerebellar function. It is hoped that this review may provide information for future clinical research in addition to translational guidance for the safer use of GC therapy.

  12. A bivariate optimal replacement policy with cumulative repair cost limit under cumulative damage model

    Indian Academy of Sciences (India)

    MIN-T SAI LAI; SHIH-CHIH CHEN

    2016-05-01

    In this paper, a bivariate replacement policy (n, T) for a cumulative shock damage process is presented that included the concept of cumulative repair cost limit. The arrival shocks can be divided into two kinds of shocks. Each type-I shock causes a random amount of damage and these damages are additive. When the total damage exceeds a failure level, the system goes into serious failure. Type-II shock causes the system into minor failure and such a failure can be corrected by minimal repair. When a minor failure occurs, the repaircost will be evaluated and minimal repair is executed if the accumulated repair cost is less than a predetermined limit L. The system is replaced at scheduled time T, at n-th minor failure, or at serious failure. The long-term expected cost per unit time is derived using the expected costs as the optimality criterion. The minimum-cost policy is derived, and existence and uniqueness of the optimal n* and T* are proved. This bivariate optimal replacement policy (n, T) is showed to be better than the optimal T* and the optimal n* policy.

  13. Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells.

    Science.gov (United States)

    Dong, Hongli; Carlton, Michael E; Lerner, Adam; Epstein, Paul M

    2015-01-01

    Stimulation of cAMP signaling induces apoptosis in glucocorticoid-sensitive and resistant CEM leukemic and MM.1 multiple myeloma cell lines, and this effect is enhanced by dexamethasone in both glucocorticoid-sensitive cell types and in glucocorticoid-resistant CEM cells. Expression of the mRNA for the glucocorticoid receptor alpha (GR) promoters 1A3, 1B and 1C, expression of mRNA and protein for GR, and the BH3-only proapoptotic proteins, Bim and Bad, and the phosphorylation state of Bad were examined following stimulation of the cAMP and glucocorticoid signaling pathways. Expression levels of GR promoters were increased by cAMP and glucocorticoid signaling, but GR protein expression was little changed in CEM and decreased in MM.1 cells. Stimulation of these two signaling pathways induced Bim in CEM cells, induced Bad in MM.1 cells, and activated Bad, as indicated by its dephosphorylation on ser112, in both cell types. This study shows that leukemic and multiple myeloma cells, including those resistant to glucocorticoids, can be induced to undergo apoptosis by stimulating the cAMP signaling pathway, with enhancement by glucocorticoids, and the mechanism by which this occurs may be related to changes in Bim and Bad expression, and in all cases, to activation of Bad.

  14. Longhi Games, Internal Reservoirs, and Cumulate Porosity

    Science.gov (United States)

    Morse, S. A.

    2009-05-01

    Fe in plagioclase at an early age, T-rollers (or not) on the Di-Trid boundary in Fo-Di-Sil, the mantle solidus, origins of anorthosites, esoteric uses of Schreinemakers rules and many more topics are all fresh and pleasant memories of John Longhi's prolific and creative work. The Fram-Longhi experimental effect of pressure on plagioclase partitioning with liquid in mafic rocks became essential to an understanding of multiphase Rayleigh fractionation of plagioclase in big layered intrusions. Only by using the pressure effect could I find a good equation through the data for the Kiglapait intrusion, and that result among others required the existence with probability 1.0 of an internal reservoir (Morse, JPet 2008). Knowledge of cumulate porosity is a crucial key to the understanding of layered igneous rocks. We seek both the initial (inverse packing fraction) and residual porosity to find the time and process path from sedimentation to solidification. In the Kiglapait Lower Zone we have a robust estimate of mean residual porosity from the modes of the excluded phases augite, oxides, sulfide, and apatite. To this we apply the maximum variance of plagioclase composition (the An range) to find an algorithm that extends through the Upper Zone and to other intrusions. Of great importance is that all these measurements were made in grain mounts concentrated from typically about 200 g of core or hand specimen, hence the represented sample volume is thousands of times greater than for a thin section. The resulting distribution and scatter of the An range is novel and remarkable. It is V-shaped in the logarithmic representation of stratigraphic height, running from about 20 mole % at both ends (base to top of the Layered Series) to near-zero at 99 PCS. The intercept of the porosity-An range relation gives An range = 3.5 % at zero residual porosity. Petrographic analysis reveals that for PCS less than 95 and greater than 99.9, the An range is intrinsic, i.e. pre-cumulus, for

  15. Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison's disease on glucocorticoid and mineralocorticoid replacement therapy.

    Science.gov (United States)

    Camozzi, Valentina; Betterle, Corrado; Frigo, Anna Chiara; Zaccariotto, Veronica; Zaninotto, Martina; De Caneva, Erica; Lucato, Paola; Gomiero, Walter; Garelli, Silvia; Sabbadin, Chiara; Salvà, Monica; Costa, Miriam Dalla; Boscaro, Marco; Luisetto, Giovanni

    2017-08-09

    to assess bone damage and metabolic abnormalities in patients with Addison's disease given replacement doses of glucocorticoids and mineralocorticoids. A total of 87 patients and 81 age-matched and sex-matched healthy controls were studied. The following parameters were measured: urinary cortisol, serum calcium, phosphorus, creatinine, 24-h urinary calcium excretion, bone alkaline phosphatase, parathyroid hormone, serum CrossLaps, 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D. Clear vertebral images were obtained with dual-energy X-ray absorptiometry in 61 Addison's disease patients and 47 controls and assessed using Genant's classification. Nineteen Addison's disease patients (31.1%) had at least one morphometric vertebral fracture, as opposed to six controls (12.8%, odds ratio 3.09, 95% confidence interval 1.12-8.52). There were no significant differences in bone mineral density parameters at any site between patients and controls. In Addison's disease patients, there was a positive correlation between urinary cortisol and urinary calcium excretion. Patients with fractures had a longer history of disease than those without fractures. Patients taking fludrocortisone had a higher bone mineral density than untreated patients at all sites except the lumbar spine. Addison's disease patients have more fragile bones irrespective of any decrease in bone mineral density. Supra-physiological doses of glucocorticoids and longer-standing disease (with a consequently higher glucocorticoid intake) might be the main causes behind patients' increased bone fragility. Associated mineralocorticoid treatment seems to have a protective effect on bone mineral density.

  16. Reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test as a marker for glucocorticoid sensitivity in children with asthma.

    Science.gov (United States)

    Willemsen, R H; van Leeuwen, L; Voorend-van Bergen, T A S; de Rijke, Y B; Pijnenburg, M W; van den Akker, E L T

    2016-01-01

    Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment in children. However, there is considerable inter-individual variation in glucocorticoid sensitivity, leading to over- as well as undertreatment. A simple and fast test to predict glucocorticoid sensitivity would enable more tailored therapy in children with asthma. To study reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test (DST) with salivary cortisol levels as marker for glucocorticoid sensitivity in asthmatic children. 23 children with atopic asthma were recruited for two overnight 0.25 mg DST's, 1 month apart. Baseline cortisol levels correlated well between both tests. However, cortisol levels, change in cortisol levels or fractional suppression of cortisol levels after dexamethasone did not correlate between the two tests. Bland-Altman plots showed that the difference in salivary cortisol levels between test 1 and 2 of an individual patient could go up to 12 nmol/l, which is a clinically relevant difference. ICS dose did not correlate with baseline cortisol levels, height and BMI SDS. The low-dose salivary DST test in its current form is not suitable for use in clinical practice in children with asthma, due to low reproducibility. Therefore, studies using the 0.25 mg salivary DST should be interpreted cautiously.

  17. Persistent glucocorticoid resistance in systemic lupus erythematosus patients during clinical remission.

    Science.gov (United States)

    Melo, A K G; Melo, M R; Saramago, A B A; Demartino, G; Souza, B D B; Longui, C A

    2013-06-20

    Glucocorticoids (GCs) are key drugs in the treatment of systemic lupus erythematosus (SLE). GC dose reduction during remission is related to disease activity, GC dose used, length of treatment, and individual GC sensitivity. We compared GC receptor α (GRα) isoform and nuclear factor kappaB (NF-κB) messenger RNA quantitation and in vivo GC sensitivity between SLE patients during remission and healthy controls. We performed a cross-sectional study of 19 women aged 22-49 years, including 9 SLE patients in clinical remission taking ≤5 mg prednisone and 10 matched controls. We evaluated GC sensitivity using 2 cortisol suppression tests: a very-low-dose intravenous dexamethasone suppression test (VLD-IV-DST) and a low-dose oral dexamethasone suppression test. GRα and NF-κB mRNA were quantified using real-time polymerase chain reaction. Although basal cortisol and adrenocorticotropic hormone levels were similar between the groups, the percentage of cortisol reduction after the VLD-IV-DST was 56% lower in SLE patients than in controls (P = 0.014). GRα and NF-κB gene expression levels were similar between the groups. The low-dose oral dexamethasone test caused intense cortisol suppression in all individuals, limiting the ability of this test to discriminate individual GC sensitivity. A positive correlation was found between the extent of cortisol suppression in vivo (VLD-IV-DST) and the number of days elapsed since the last flare of lupus activity. Despite clinical remission, SLE patients displayed partial GC resistance recognized by the VLD-IV-DST. The mechanism of this resistance is unrelated to altered GRα and NF-κB mRNA expression.

  18. Cumulative stress and autonomic dysregulation in a community sample.

    Science.gov (United States)

    Lampert, Rachel; Tuit, Keri; Hong, Kwang-Ik; Donovan, Theresa; Lee, Forrester; Sinha, Rajita

    2016-05-01

    Whether cumulative stress, including both chronic stress and adverse life events, is associated with decreased heart rate variability (HRV), a non-invasive measure of autonomic status which predicts poor cardiovascular outcomes, is unknown. Healthy community dwelling volunteers (N = 157, mean age 29 years) participated in the Cumulative Stress/Adversity Interview (CAI), a 140-item event interview measuring cumulative adversity including major life events, life trauma, recent life events and chronic stressors, and underwent 24-h ambulatory ECG monitoring. HRV was analyzed in the frequency domain and standard deviation of NN intervals (SDNN) calculated. Initial simple regression analyses revealed that total cumulative stress score, chronic stressors and cumulative adverse life events (CALE) were all inversely associated with ultra low-frequency (ULF), very low-frequency (VLF) and low-frequency (LF) power and SDNN (all p stress and chronic stress each was significantly associated with SDNN and ULF even after the highly significant contributions of age and sex, with no other covariates accounting for additional appreciable variance. For VLF and LF, both total cumulative stress and chronic stress significantly contributed to the variance alone but were not longer significant after adjusting for race and health behaviors. In summary, total cumulative stress, and its components of adverse life events and chronic stress were associated with decreased cardiac autonomic function as measured by HRV. Findings suggest one potential mechanism by which stress may exert adverse effects on mortality in healthy individuals. Primary preventive strategies including stress management may prove beneficial.

  19. Methods of calculating radiation absorbed dose.

    Science.gov (United States)

    Wegst, A V

    1987-01-01

    The new tumoricidal radioactive agents being developed will require a careful estimate of radiation absorbed tumor and critical organ dose for each patient. Clinical methods will need to be developed using standard imaging or counting instruments to determine cumulated organ activities with tracer amounts before the therapeutic administration of the material. Standard MIRD dosimetry methods can then be applied.

  20. The glucocorticoid/aggression relationship in animals and humans: an analysis sensitive to behavioral characteristics, glucocorticoid secretion patterns, and neural mechanisms.

    Science.gov (United States)

    Haller, József

    2014-01-01

    Glucocorticoids control a wide array of biological processes from glucose homeostasis to neuronal function. The mechanisms mediating their effects are similarly varied and include rapid and transient nongenomic effects on calcium trafficking, various neurotransmitter receptors, and other membrane/cytoplasmic proteins, as well as slowly developing but durable genomic effects that are mediated by a large number of glucocorticoid-sensitive genes that are affected after variable lag-times. Given this complexity, we suggest that the aggression/glucocorticoid relationship cannot be reduced to the simple "stimulation/inhibition" question. Here, we review the effects of glucocorticoids on aggression by taking into account the complexities of glucocorticoid actions. Acute and chronic effects were differentiated because these are mediated by different mechanisms. The effects of chronic increases and decreases in glucocorticoid production were discussed separately, because the activation of mechanisms that are not normally activated and the loss of normal functions should not be confounded. Findings in healthy/normal subjects and those obtained in subjects that show abnormal forms of behavior or psychopathologies were also differentiated, because the effects of glucocorticoids are indirect, and largely depend on the properties of neurons they act upon, which are altered in subjects with psychopathologies. In addition, the conditions of glucocorticoid measurements were also thoroughly evaluated. Although the role of glucocorticoids in aggression is perceived as controversial by many investigators, a detailed analysis that is sensitive to glucocorticoid and behavioral measure as well as to the mediating mechanism suggests that this role is rather clear-cut; moreover, there is a marked similarity between animal and human findings.

  1. Clinical observation of alprostadil combined with glucocorticoids on acute optic neuritis

    Directory of Open Access Journals (Sweden)

    Ke-Shun Fan

    2015-09-01

    Full Text Available AIM: To study the clinical effect of alprostadil combined with glucocorticoids in the treatment of acute optic neuritis(AON.METHODS: Seventy patients(70 eyeswith AON from January, 2012 to June, 2014 were randomly divided into two groups. 35 patients in observation group were used 10ug alprostadil with 10mL normal saline(NSby intravenous injection, once/d for 7d/one treatment course, and 10mL NS was used by intravenous injection in 35 patients of control group. Besides, the two groups were treated with the combined therapy as follows: 20mg methylprednisolone was injected periglomerularly beside the eyeballs, once /3d for 3 times; 800~1 000mg of methylprednisolone through intravenous drip for 3d, once/d; after 3d, oral administration of prednisone acetate for 1wk, 1mg/(kg·d; after 1wk, the dose decreased to 5mg/wk until withdraw. Simultaneously, oral administration of ranitidine capsules, calcium carbonate and vitamin D3 tablets were combined in the supportive treament. The differences of curative effect between two groups were comparatively analyzed.RESULTS: In the observation group, 25 eyes(71.4%were markedly effective, 7 eyes(20.0%were valid and 3 eyes(8.6%were invalid, and the total effective rate was 91.4%. In the control group, 15 eyes(42.9%were markedly effective, 14 eyes(40.0%were valid and 6 eyes(17.1%were invalid, and the total effective rate was 82.9%. The difference of total effective rate between the two groups was not statistically significant(P=0.477, but there was a significant difference in markedly effective rate between the two groups(χ2=5.833, P=0.016.CONCLUSION: Alprostadil combined with glucocorticoids is effective for AON, and it is worth of advocation.

  2. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

    Science.gov (United States)

    Buckley, Lenore; Guyatt, Gordon; Fink, Howard A; Cannon, Michael; Grossman, Jennifer; Hansen, Karen E; Humphrey, Mary Beth; Lane, Nancy E; Magrey, Marina; Miller, Marc; Morrison, Lake; Rao, Madhumathi; Robinson, Angela Byun; Saha, Sumona; Wolver, Susan; Bannuru, Raveendhara R; Vaysbrot, Elizaveta; Osani, Mikala; Turgunbaev, Marat; Miller, Amy S; McAlindon, Timothy

    2017-08-01

    To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. This guideline provides direction for clinicians and patients making treatment decisions. Clinicians

  3. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Sheela Vyas

    2016-01-01

    Full Text Available Stress and stress hormones, glucocorticoids (GCs, exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer’s (AD and Parkinson’s (PD diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

  4. The transcriptomics of glucocorticoid receptor signaling in developing zebrafish.

    Directory of Open Access Journals (Sweden)

    Dinushan Nesan

    Full Text Available Cortisol is the primary corticosteroid in teleosts that is released in response to stressor activation of the hypothalamus-pituitary-interrenal axis. The target tissue action of this hormone is primarily mediated by the intracellular glucocorticoid receptor (GR, a ligand-bound transcription factor. In developing zebrafish (Danio rerio embryos, GR transcripts and cortisol are maternally deposited into the oocyte prior to fertilization and influence early embryogenesis. To better understand of the molecular mechanisms involved, we investigated changes in the developmental transcriptome prior to hatch, in response to morpholino oligonucleotide knockdown of GR using the Agilent zebrafish microarray platform. A total of 1313 and 836 mRNA transcripts were significantly changed at 24 and 36 hours post fertilization (hpf, respectively. Functional analysis revealed numerous developmental processes under GR regulation, including neurogenesis, eye development, skeletal and cardiac muscle formation. Together, this study underscores a critical role for glucocorticoid signaling in programming molecular events essential for zebrafish development.

  5. The glucocorticoid receptor: cause of or cure for obesity?

    Science.gov (United States)

    John, Kezia; Marino, Joseph S; Sanchez, Edwin R; Hinds, Terry D

    2016-02-15

    Glucocorticoid hormones (GCs) are important regulators of lipid metabolism, promoting lipolysis with acute treatment but lipogenesis with chronic exposure. Conventional wisdom posits that these disparate outcomes are mediated by the classical glucocorticoid receptor GRα. There is insufficient knowledge of the GC receptors (GRα and GRβ) in metabolic conditions such as obesity and diabetes. We present acute models of GC exposure that induce lipolysis, such as exercise, as well as chronic-excess models that cause obesity and lipid accumulation in the liver, such as hepatic steatosis. Alternative mechanisms are then proposed for the lipogenic actions of GCs, including induction of GC resistance by the GRβ isoform, and promotion of lipogenesis by GC activation of the mineralocorticoid receptor (MR). Finally, the potential involvement of chaperone proteins in the regulation of adipogenesis is considered. This reevaluation may prove useful to future studies on the steroidal basis of adipogenesis and obesity. Copyright © 2016 the American Physiological Society.

  6. Effects of glucocorticoids on apoptosis and clearance of apoptotic cells.

    Science.gov (United States)

    McColl, Aisleen; Michlewska, Sylwia; Dransfield, Ian; Rossi, Adriano G

    2007-08-17

    The glucocorticoid (GC) drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR) primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed.

  7. Effects of Glucocorticoids on Apoptosis and Clearance of Apoptotic Cells

    Directory of Open Access Journals (Sweden)

    Aisleen McColl

    2007-01-01

    Full Text Available The glucocorticoid (GC drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed.

  8. Glucocorticoid suppresses steroidogenesis in rat progenitor Leydig cells.

    Science.gov (United States)

    Xiao, Ye-Chen; Huang, Ya-Dong; Hardy, Dianne O; Li, Xiao-Kun; Ge, Ren-Shan

    2010-01-01

    Glucocorticoid (GC) inhibits testosterone production in adult Leydig cells by the glucocorticoid receptor (GR). However, whether GC affects the development of Leydig cells is unclear. The goal of the present study is to investigate the effects of GC on steroidogenesis of rat progenitor Leydig cells (PLCs) in vitro. Dexamethasone (DEX) inhibited androsterone (AO) production in PLCs. The GR antagonist RU38486 reversed the DEX-induced inhibition of AO, whereas the mineralocorticoid receptor antagonist RU28318 did not. RU38486 also reversed DEX-induced reductions in steady-state mRNA levels of steroidogenic acute regulatory protein (Star) and 3β-hydroxysteroid dehydrogenase 1 (Hsd3b1). Steroidogenic acute regulatory protein (StAR) protein expression and 3β-hydroxysteroid dehydrogenase (3βHSD) enzyme activity were affected similarly. These results show that GCs inhibit steroidogenesis of PLCs by suppression of StAR and 3βHSD via a GR-mediated mechanism.

  9. Entanglement entropy and particle number cumulants of disordered fermions

    Science.gov (United States)

    Burmistrov, I. S.; Tikhonov, K. S.; Gornyi, I. V.; Mirlin, A. D.

    2017-08-01

    We study the entanglement entropy and particle number cumulants for a system of disordered noninteracting fermions in d dimensions. We show, both analytically and numerically, that for a weak disorder the entanglement entropy and the second cumulant (particle number variance) are proportional to each other with a universal coefficient. The corresponding expressions are analogous to those in the clean case but with a logarithmic factor regularized by the mean free path rather than by the system size. We also determine the scaling of higher cumulants by analytical (weak disorder) and numerical means. Finally, we predict that the particle number variance and the entanglement entropy are nonanalytic functions of disorder at the Anderson transition.

  10. Glucocorticoids modulate human brown adipose tissue thermogenesis in vivo

    OpenAIRE

    Scotney, Hannah; Symonds, Michael E; Law, James; Budge, Helen; Sharkey, Don; Manolopoulos, Konstantinos N.

    2017-01-01

    Introduction: Brown adipose tissue (BAT) is a thermogenic organ with substantial metabolic capacity and has important roles in the maintenance of body weight and metabolism. Regulation of BAT is primarily mediated through the ß-adrenoceptor (ß-AR) pathway. The in vivo endocrine regulation of this pathway in humans is unkown. The objective of our study was to assess the in vivo BAT temperature responses to acute glucocorticoid administration.\\ud Methods: We studied 8 healthy male volunteers, n...

  11. Locomotor therapy with extended-release crystalline glucocorticoids

    Directory of Open Access Journals (Sweden)

    Vladimir Vasilyevich Badokin

    2013-01-01

    Full Text Available Topical glucocorticoid (GC therapy for locomotor diseases is an extremely important component of a comprehensive program to treat inflammatory and, to a lesser extent, degenerative diseases. It reduces the time of hospitalization by 5—10 days in this category of patients, has a prompt and potent anti-inflammatory effect, and shows predictable efficiency. This therapy shows good tolerability and high safety and prevents serious adverse reactions to GC treatment.

  12. Glucocorticoid hormone resistance during primate evolution: receptor-mediated mechanisms.

    Science.gov (United States)

    Chrousos, G P; Renquist, D; Brandon, D; Eil, C; Pugeat, M; Vigersky, R; Cutler, G B; Loriaux, D L; Lipsett, M B

    1982-03-01

    The concentrations of total and protein-unbound plasma cortisol of New World monkeys are higher than those of Old World primates and prosimians. The urinary free-cortisol excretion also is increased markedly. However, there is no physiologic evidence of increased cortisol effect. These findings suggest end-organ resistance to glucocorticoids. This was confirmed by showing that the hypothalamic-pituitary adrenal axis is resistant to suppression by dexamethasone. To study this phenomenon, glucocorticoid receptors were examined in circulating mononuclear leukocytes and cultured skin fibroblasts from both New and Old World species. The receptor content is the same in all species, but the New World monkeys have a markedly decreased binding affinity for dexamethasone. Thus, the resistance of these species to the action of cortisol is due to the decreased binding affinity of the glucocorticoid receptor. This presumed mutation must have occurred after the bifurcation of Old and New World primates (approximately 60 x 10(6) yr ago) and before the diversion of the New World primates from each other (approximately 15 x 10(6) yr ago).

  13. Cannabinoids and glucocorticoids modulate emotional memory after stress.

    Science.gov (United States)

    Akirav, Irit

    2013-12-01

    Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Proposed glucocorticoid-mediated zinc signaling in the hippocampus.

    Science.gov (United States)

    Takeda, Atsushi; Tamano, Haruna

    2012-07-01

    Corticosteroid hormones are secreted from the adrenal glands in hourly pulses and signal the hippocampus for the development and function. In contrast, the stress-induced rise in corticosteroid concentrations has a profound effect on emotional arousal, motivational processes and cognitive performance. This rise is required as the stress response to maintain homeostasis in the living body or restore it. However, abnormal rise in corticosteroid concentrations is a disadvantage to the hippocampus. Corticosteroid-glutamatergic interactions during information processing are proposed as a potential model to explain many of the diverse actions of corticosteroids in synaptic plasticity such as long-term potentiation and cognition. Because zincergic neurons are a subtype of glutamatergic neurons and release Zn(2+) and glutamate into the synaptic cleft, it is possible that homeostasis of synaptic Zn(2+), in addition to homeostasis of glutamate, is modified by glucocorticoids, followed by the changes in cognitive function and stress response. Zn(2+) signal participates in cognitive and emotional behavior in cooperation with signaling of glucocorticoids and glutamate, while can disadvantageously act on the hippocampus under sever stress circumstances. This paper analyzes the actions of glucocorticoid-mediated Zn(2+) signal in the hippocampus under stressful circumstances and its significance in both hippocampal function and dysfunction.

  15. Glucocorticoids play a key role in circadian cell cycle rhythms.

    Directory of Open Access Journals (Sweden)

    Thomas Dickmeis

    2007-04-01

    Full Text Available Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary-adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part.

  16. Glucocorticoids entrain molecular clock components in human peripheral cells.

    Science.gov (United States)

    Cuesta, Marc; Cermakian, Nicolas; Boivin, Diane B

    2015-04-01

    In humans, shift work induces a desynchronization between the circadian system and the outside world, which contributes to shift work-associated medical disorders. Using a simulated night shift experiment, we previously showed that 3 d of bright light at night fully synchronize the central clock to the inverted sleep schedule, whereas the peripheral clocks located in peripheral blood mononuclear cells (PBMCs) took longer to reset. This underlines the need for testing the effects of synchronizers on both the central and peripheral clocks. Glucocorticoids display circadian rhythms controlled by the central clock and are thought to act as synchronizers of rodent peripheral clocks. In the present study, we tested whether the human central and peripheral clocks were sensitive to exogenous glucocorticoids (Cortef) administered in the late afternoon. We showed that 20 mg Cortef taken orally acutely increased PER1 expression in PBMC peripheral clocks. After 6 d of Cortef administration, the phases of central markers were not affected, whereas those of PER2-3 and BMAL1 expression in PBMCs were shifted by ∼ 9.5-11.5 h. These results demonstrate, for the first time, that human peripheral clocks are entrained by glucocorticoids. Importantly, they suggest innovative interventions for shift workers and jet-lag travelers, combining synchronizing agents for the central and peripheral clocks.

  17. EPA's SHEDS-multimedia model: children's cumulative pyrethroid exposure estimates and evaluation against NHANES biomarker data.

    Science.gov (United States)

    Xue, Jianping; Zartarian, Valerie; Tornero-Velez, Rogelio; Tulve, Nicolle S

    2014-12-01

    The U.S. EPA's SHEDS-Multimedia model was applied to enhance the understanding of children's exposures and doses to multiple pyrethroid pesticides, including major contributing chemicals and pathways. This paper presents combined dietary and residential exposure estimates and cumulative doses for seven commonly used pyrethroids, and comparisons of model evaluation results with NHANES biomarker data for 3-PBA and DCCA metabolites. Model input distributions were fit to publicly available pesticide usage survey data, NHANES, and other studies, then SHEDS-Multimedia was applied to estimate total pyrethroid exposures and doses for 3-5 year olds for one year variability simulations. For dose estimations we used a pharmacokinetic model and two approaches for simulating dermal absorption. SHEDS-Multimedia predictions compared well to NHANES biomarker data: ratios of 3-PBA observed data to SHEDS-Multimedia modeled results were 0.88, 0.51, 0.54 and 1.02 for mean, median, 95th, and 99th percentiles, respectively; for DCCA, the ratios were 0.82, 0.53, 0.56, and 0.94. Modeled time-averaged cumulative absorbed dose of the seven pyrethroids was 3.1 nmol/day (versus 8.4 nmol/day for adults) in the general population (residential pyrethroid use and non-use homes) and 6.7 nmol/day (versus 10.5 nmol/day for adults) in the simulated residential pyrethroid use population. For the general population, contributions to modeled cumulative dose by chemical were permethrin (60%), cypermethrin (22%), and cyfluthrin (16%); for residential use homes, contributions were cypermethrin (49%), permethrin (29%), and cyfluthrin (17%). The primary exposure route for 3-5 year olds in the simulated residential use population was non-dietary ingestion exposure; whereas for the simulated general population, dietary exposure was the primary exposure route. Below the 95th percentile, the major exposure pathway was dietary for the general population; non-dietary ingestion was the major pathway starting below

  18. Glucocorticoid Receptor-Mediated Repression of Pro-Inflammatory Genes in Rheumatoid Arthritis

    Science.gov (United States)

    2015-10-01

    1 AWARD NUMBER: W81XWH-14-1-0314 TITLE: Glucocorticoid Receptor-Mediated Repression of Pro-Inflammatory Genes in Rheumatoid Arthritis ...19 Sep 2015 4. TITLE AND SUBTITLE Glucocorticoid Receptor-Mediated Repression of Pro- Inflammatory Genes in Rheumatoid Arthritis 5a. CONTRACT NUMBER... arthritis (RA) patients rely on glucocorticoids (GCs) at some point during the disease. GCs signal through the GC receptor (GR), a transcription factor that

  19. Evidence that the modulator of the glucocorticoid-receptor complex is the endogenous molybdate factor.

    OpenAIRE

    Bodine, P V; Litwack, G

    1988-01-01

    We have recently purified the modulator of the glucocorticoid-receptor complex from rat liver. Purified modulator inhibits glucocorticoid-receptor complex activation and stabilizes the steroid-binding ability of the unoccupied glucocorticoid receptor. Since these activities are shared by exogenous sodium molybdate, modulator appears to be the endogenous factor that sodium molybdate mimics. In this report, we present additional evidence for the mechanism of action of purified modulator. (i) Mo...

  20. Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure.

    Science.gov (United States)

    Sloboda, Deborah M; Moss, Timothy J M; Li, Shaofu; Matthews, Stephen G; Challis, John R G; Newnham, John P

    2008-05-01

    To determine the expression of glucocorticoid metabolizing and action genes in the hippocampus of fetal, neonatal, and adult sheep. Pregnant ewes (or their fetuses) received intramuscular injections of saline or betamethasone (BETA, 0-5 mg/kg) at 104, 111, 118, and/or 125 days of gestation (dG). Hippocampal tissue was collected prior to (75, 84, and 101 dG), during (109 and 116 dG), or after (121, 132, and 146 dG; 6 and 12 postnatal weeks; 3.5 years of age) saline or BETA injections. Hippocampal glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and 11beta-hydroxysteroid dehydrogenase (11betaHSD)1 and 11betaHSD2 mRNA levels were determined using qRT-PCR. Control animals late in gestation demonstrated a decrease in mRNA encoding GR and 11betaHSD1, whereas 11betaHSD2 was undetectable, consistent with a damping of the negative feedback influence of circulating or locally produced cortisol on the hypothalamic-pituitary-adrenal (HPA) axis. BETA-administration had transient effects on fetal GR and MR, and early in postnatal life (12 weeks of age) 11betaHSD1 mRNA was increased. Hippocampal MR mRNA was elevated in adult offspring exposed to either one or four doses of maternal BETA (Pglucocorticoid negative feedback, facilitating increased preterm HPA activity and parturition. Adult offspring of BETA-treated mothers demonstrated increased MR and 11betaHSD2 mRNA, therefore it appears that exposure of fetus to high levels of synthetic glucocorticoids may have long-lasting effects on the hippocampal expression of HPA-related genes into adulthood.

  1. Online Scheduling in Manufacturing A Cumulative Delay Approach

    CERN Document Server

    Suwa, Haruhiko

    2013-01-01

    Online scheduling is recognized as the crucial decision-making process of production control at a phase of “being in production" according to the released shop floor schedule. Online scheduling can be also considered as one of key enablers to realize prompt capable-to-promise as well as available-to-promise to customers along with reducing production lead times under recent globalized competitive markets. Online Scheduling in Manufacturing introduces new approaches to online scheduling based on a concept of cumulative delay. The cumulative delay is regarded as consolidated information of uncertainties under a dynamic environment in manufacturing and can be collected constantly without much effort at any points in time during a schedule execution. In this approach, the cumulative delay of the schedule has the important role of a criterion for making a decision whether or not a schedule revision is carried out. The cumulative delay approach to trigger schedule revisions has the following capabilities for the ...

  2. Cumulative Risks of Foster Care Placement for Danish Children

    DEFF Research Database (Denmark)

    Fallesen, Peter; Emanuel, Natalia; Wildeman, Christopher

    2014-01-01

    Although recent research suggests that the cumulative risk of foster care placement is far higher for American children than originally suspected, little is known about the cumulative risk of foster care placement in other countries, which makes it difficult to gauge the degree to which factor...... is for Danish children. Results suggest that at the beginning of the study period (in 1998) the cumulative risk of foster care placement for Danish children was roughly in line with the risk for American children. Yet, by the end of the study period (2010), the risk had declined to half the risk for American...... foster care placement is salient in other contexts. In this article, we provide companion estimates to those provided in recent work on the US by using Danish registry data and synthetic cohort life tables to show how high and unequally distributed the cumulative risk of foster care placement...

  3. Mapping cumulative human impacts in the eastern North Sea

    DEFF Research Database (Denmark)

    Stock, A.; Andersen, Jesper; Heinänen, S.

    of the MSFD; and 3) to deepen the understanding of how errors in expert judgment affect the resulting cumulative human impact maps by means of Monte Carlo simulations. We combined existing data sets on the spatial distribution of 33 anthropogenic stressors (linked to the MSFD pressures) and 28 key habitats....... In contrast, the predicted impacts for much of the Norwegian EEZ and areas far offshore were lower. The Monte Carlo simulations confirmed earlier findings that mapping cumulative impacts is generally "robust", but also showed that specific combinations of errors can seriously change local and regional...... on marine ecosystems have only recently been developed. The aims of our study were: 1) to develop a map of cumulative human impacts for the Danish, Swedish, Norwegian and German parts of the Greater North Sea; 2) to adjust the existing methods for mapping cumulative human impacts to fit the requirements...

  4. Cumulative Production Per Township - SaMiRa

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — This dataset contains a selected township grid within the Sagebrush Mineral Resource Assessment project (SaMiRa) study area attributed with cumulative oil and gas...

  5. Macroscopic cumulative fatigue damage of material under nonsymmetrical cycle

    Institute of Scientific and Technical Information of China (English)

    盖秉政

    2002-01-01

    Hashin's macroscopic theory of fatigue damage is further discussed and a new method has been proposed for prediction of cumulative fatigue damage of material and its lifetime under nonsymmetrical cyclic loading.

  6. Translation-Invariant Representation for Cumulative Foot Pressure Images

    CERN Document Server

    Zheng, Shuai; Tan, Tieniu

    2010-01-01

    Human can be distinguished by different limb movements and unique ground reaction force. Cumulative foot pressure image is a 2-D cumulative ground reaction force during one gait cycle. Although it contains pressure spatial distribution information and pressure temporal distribution information, it suffers from several problems including different shoes and noise, when putting it into practice as a new biometric for pedestrian identification. In this paper, we propose a hierarchical translation-invariant representation for cumulative foot pressure images, inspired by the success of Convolutional deep belief network for digital classification. Key contribution in our approach is discriminative hierarchical sparse coding scheme which helps to learn useful discriminative high-level visual features. Based on the feature representation of cumulative foot pressure images, we develop a pedestrian recognition system which is invariant to three different shoes and slight local shape change. Experiments are conducted on...

  7. Glucocorticoids: structure, signaling and molecular mechanisms in the treatment of diabetic retinopathy and diabetic macular edema.

    Science.gov (United States)

    Zhang, X; Wang, N; Schachat, A P; Bao, S; Gillies, M C

    2014-03-01

    Diabetic retinopathy (DR) is one of the leading causes of blindness in the working population worldwide. Vascular leakage, angiogenesis and neuronal degeneration are key features of DR. Current effective interventions for DR include treatment of systemic risk factors such as elevated blood glucose, blood pressure and dyslipidemia. Ocular treatments include vascular endothelial growth factor A (VEGF-A) inhibitors, laser photocoagulation and surgery. While anti-VEGF therapy has become as first-line treatment for diabetic macular edema (DME) that causes reduced vision, intravitreal glucocorticoids also have been shown to be efficacious in this situation. It has been reported that all the major pathological processes of DR are susceptible to glucocorticoid treatment. The effects of glucocorticoids on vascular leakage and angiogenesis may be mediated through their well established anti-inflammatory role. Alternatively, glucocorticoids may affect other mechanisms known to be activated in DR. Potential mechanisms for the anti-inflammatory effects of glucocorticoids include blockage of cytokine production and inhibition of leukocyte adhesion induced by VEGF-A. Glucocorticoids decrease the expression of VEGF-A directly, and increase the production, or decrease phosphorylation, of tight junction-associated proteins. Glucocorticoids have also been shown to be neuroprotective, in contrast to VEGF-A inhibitors which animal studies suggest may be neurotoxic. This review outlines the biological properties of synthetic glucocorticoids, with particular emphasis on the potential beneficial effect of combining glucocorticoids with anti-VEGF treatment for DME and DR.

  8. Glucocorticoids and insulin both modulate caloric intake through actions on the brain.

    Science.gov (United States)

    Dallman, Mary F; Warne, James P; Foster, Michelle T; Pecoraro, Norman C

    2007-09-01

    Glucocorticoids act primarily in a feed-forward fashion on brain to activate CNS pathways that implement wanting appropriate to physiological needs. Thus, depending on the available conditions, elevated glucocorticoids may augment the behavioural want to run, fight or feed. Although glucocorticoids stimulate intake of chow, fat and sucrose, insulin appears to sculpt calorie-associated desires toward foods high in fat, acting through hepatic branch afferents of the vagus nerve. Both conditions of reduced food allowance and chronic stress excite glucocorticoid-augmented central neural networks that may lead toward ultimate abdominal obesity.

  9. Glucocorticoid receptor-mediated induction of glutamine synthetase in skeletal muscle cells in vitro

    Science.gov (United States)

    Max, Stephen R.; Thomas, John W.; Banner, Carl; Vitkovic, Ljubisa; Konagaya, Masaaki

    1987-01-01

    The regulation by glucocorticoids of glutamine synthetase in L6 muscle cells in culture is studied. Glutamine synthetase activity was strikingly enhanced by dexamethasone. The dexamethasone-mediated induction of glutamine synthetase activity was blocked by RU38486, a glucocorticoid antagonist, indicating the involvement of intracellular glucocorticoid receptors in the induction process. RU38486 alone was without effect. Northern blot analysis revealed that dexamethasone-mediated enhancement of glutamine synthetase activity involves increased levels of glutamine synthetase mRNA. Glucocorticoids regulate the expression of glutamine synthetase mRNA in cultured muscle cells via interaction with intracellular receptors. Such regulation may be relevant to control of glutamine production by muscle.

  10. Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain.

    Science.gov (United States)

    Moisan, M P; Minni, A M; Dominguez, G; Helbling, J C; Foury, A; Henkous, N; Dorey, R; Béracochéa, D

    2014-03-01

    Corticosteroid binding globulin (CBG) is a glycoprotein synthesized in liver and secreted in the blood where it binds with a high affinity but low capacity glucocorticoid hormones, cortisol in humans and corticosterone in laboratory rodents. In mammals, 95% of circulating glucocorticoids are bound to either CBG (80%) or albumin (15%) and only the 5% free fraction is able to enter the brain. During stress, the concentration of glucocorticoids rises significantly and the free fraction increases even more because CBG becomes saturated. However, glucocorticoids unbound to CBG are cleared from the blood more quickly. Our studies on mice totally devoid of CBG (Cbg k.o.) showed that during stress these mutant mice display a lower rise of glucocorticoids than the wild-type controls associated with altered emotional reactivity. These data suggested that CBG played a role in the fast actions of glucocorticoids on behavior. Further analyses demonstrated that stress-induced memory retrieval impairment, an example of the fast action of glucocorticoids on the brain is abolished in the Cbg k.o. mice. This effect of stress on memory retrieval could be restored in the Cbg k.o. mice by infusing corticosterone directly in the hippocampus. The mechanisms explaining these effects involved an increased clearance but no difference in corticosterone production. Thus, CBG seems to have an important role in maintaining in blood a glucocorticoid pool that will be able to access the brain for the fast effects of glucocorticoids.

  11. Some Characterization Results on Dynamic Cumulative Residual Tsallis Entropy

    Directory of Open Access Journals (Sweden)

    Madan Mohan Sati

    2015-01-01

    Full Text Available We propose a generalized cumulative residual information measure based on Tsallis entropy and its dynamic version. We study the characterizations of the proposed information measure and define new classes of life distributions based on this measure. Some applications are provided in relation to weighted and equilibrium probability models. Finally the empirical cumulative Tsallis entropy is proposed to estimate the new information measure.

  12. Steps and pips in the history of the cumulative recorder.

    OpenAIRE

    Lattal, Kennon A.

    2004-01-01

    From its inception in the 1930s until very recent times, the cumulative recorder was the most widely used measurement instrument in the experimental analysis of behavior. It was an essential instrument in the discovery and analysis of schedules of reinforcement, providing the first real-time analysis of operant response rates and patterns. This review traces the evolution of the cumulative recorder from Skinner's early modified kymographs through various models developed by Skinner and his co...

  13. [Glucocorticoid-induced osteoporosis and rheumatic diseases. Pathogenesis, prevention and treatment].

    Science.gov (United States)

    Di Munno, Ombretta; Delle Sedie, Andrea

    2006-01-01

    Glucocorticoids (GC) are diffusely used to treat a wide variety of inflammatory and autoimmune disorders, including rheumatic diseases. GC-induced osteoporosis (GIO) is the most common and serious side-effect for patients receiving GC. Loss of bone mineral density (BMD) is greatest in the first few months of GC use; fracture (Fx) risk is significantly increased at the spine and hip on doses even as low as 2.5 mg of prednisolone daily; Fx risk increases rapidly from the onset of therapy and, for a given BMD, is higher in GIO than in postmenopausal OP. General measures to reduce bone loss include use of the lowest effective dose; consideration of alternative routes of administration; adequate calcium and vitamin D supplementation. Today, results from large randomised controlled clinical trials provide evidence that bone loss and Fx may be prevented through the use of bone sparing agents (hormone therapy, bisphosphonates, PTH 1-34). Bisphosphonates (alendronate, risedronate) are first-choice therapy for the prevention and treatment of GIO; patients at high risk for Fx, for example those in post-menopausal status or aged > or =65 years and those with a prior fragility Fx, should be advised to start bone-protective therapy at the time of starting GC. Due to the prevalence of GC use, it is imperative that there be a greater awareness of GIO and of therapies that may be offered to patients both for prevention and treatment.

  14. Effects of glucocorticoid treatment on focal and systemic bone loss in rheumatoid arthritis.

    Science.gov (United States)

    Di Munno, O; Delle Sedie, A

    2008-07-01

    Rheumatoid arthritis (RA) is characterized by an extensive dysregulation in skeletal homeostasis recognized as 1) focal articular bone erosions, 2) iuxta-articular osteopenia, 3) systemic osteoporosis (OP) and fractures, as is well documented in both cross-sectional and prospective studies. The disease activity, as a consequence of new insights into the complex interaction between bone cells and a variety of cells of the immune system, has emerged as the main responsible for both focal and systemic bone loss. Given this background, the therapeutic approach to RA has become more aggressive, and a more widespread use of low-dose glucocorticoids (GC), recently categorized as disease modifying antirheumatic drugs (DMARD) because of their additional joint sparing effect on the long-term, has also been recommended from the early stages. Addressing the effects of GC on systemic bone loss in RA, GC are considered, in addition to inflammation and inactivity, the major risk factors for OP and fractures. As a consequence, among the most recent recommendations (i.e. dosing, timing, and tapering strategies) for patients receiving GC for more than 3 months, prevention and treatment of GC-induced OP (i.e. calcium, vitamin D, and bisphosphonates) are included. However, innovative GC, characterized by a more favorable risk/benefit profile such as selective GC receptor agonists (SEGRA), are currently in the pipeline. This article reviews the major points of evidence so far available, regarding the effects of GC on focal and systemic bone loss.

  15. Glucocorticoid-induced osteoporosis and rheumatic diseases. Pathogenesis, prevention and treatment

    Directory of Open Access Journals (Sweden)

    Andrea Delle Sedie

    2011-09-01

    Full Text Available Glucocorticoids (GC are diffusely used to treat a wide variety of inflammatory and autoimmune disorders, including rheumatic diseases. GC-induced osteoporosis (GIO is the most common and serious side-effect for patients receiving GC. Loss of bone mineral density (BMD is greatest in the first few months of GC use; fracture (Fx risk is significantly increased at the spine and hip on doses even as low as 2.5 mg of prednisolone daily; Fx risk increases rapidly from the onset of therapy and, for a given BMD, is higher in GIO than in postmenopausal OP. General measures to reduce bone loss include use of the lowest effective dose; consideration of alternative routes of administration; adequate calcium and vitamin D supplementation. Today, results from large randomised controlled clinical trials provide evidence that bone loss and Fx may be prevented through the use of bone sparing agents (hormone therapy, bisphosphonates, PTH 1-34. Bisphosphonates (alendronate, risedronate are first-choice therapy for the prevention and treatment of GIO; patients at high risk for Fx, for example those in post-menopausal status or aged ³65 years and those with a prior fragility Fx, should be advised to start bone-protective therapy at the time of starting GC. Due to the prevalence of GC use, it is imperative that there be a greater awareness of GIO and of therapies that may be offered to patients both for prevention and treatment

  16. TCR-mediated activation promotes GITR upregulation in T cells and resistance to glucocorticoid-induced death.

    Science.gov (United States)

    Zhan, Yifan; Funda, David P; Every, Alison L; Fundova, Petra; Purton, Jared F; Liddicoat, Douglas R; Cole, Timothy J; Godfrey, Dale I; Brady, Jamie L; Mannering, Stuart I; Harrison, Leonard C; Lew, Andrew M

    2004-09-01

    T lymphocytes (pivotal in many inflammatory pathologies) are targets for glucocorticoid hormone (GC). How TCR-mediated activation and GC signaling via glucocorticoid receptor (GR) impact on T-cell fates is not fully defined. We delineated here the expression of a recently identified glucocorticoid-induced TNF receptor (GITR) induced by GC and by TCR-mediated T-cell activation in GC receptor (GR)-deficient mice (GR-/-). We also compared the action of GC on GITR+ and GITR- T cells by monitoring apoptosis, proliferation and cytokine production stimulated by anti-CD3 antibody. By using GR-/- mice, we observed that the development of GITR+ T cells (both in thymus and periphery) is not dependent upon GR signaling. This contradicts the implication of GITR's name reflecting GC induction. TCR-mediated T-cell activation induced GITR expression in both GR+/+ and GR-/- cells. Somewhat unexpectedly, there was very modest GITR upregulation on GR+/+ T cells by a range of GC doses (10(-8) to 10(-6) M). Constitutive expression of GITR by a subset of CD4+ cells did not significantly render them resistant to GC-induced cell death. However, TCR-induced GITR upregulation on GR+/+ T cells was correlated with resistance to GC-mediated apoptosis suggesting that GITR, in conjunction with other (as yet unidentified) TCR-induced factors, protects T cells from apoptosis. Thus, even though GC is a potent inducer of apoptosis of T cells, activated T cells are resistant to GC-mediated killing. Meanwhile, although GC suppressed anti-CD3-induced cytokine production, cell proliferation was unaffected by GC in GR+/+ mice. GR deficiency has no effect on anti-CD3-induced cytokine production and proliferation. Our findings also have implications for GC treatment in that it would be more difficult to abrogate an ongoing T-cell mediated inflammatory response than to prevent its induction.

  17. Genistein inhibits glucocorticoid amplification in adipose tissue by suppression of 11β-hydroxysteroid dehydrogenase type 1.

    Science.gov (United States)

    Tagawa, Noriko; Kubota, Sayaka; Kobayashi, Yoshiharu; Kato, Ikuo

    2015-01-01

    Excess glucocorticoids promote visceral obesity, hyperlipidemia, and insulin resistance. The main regulator of intracellular glucocorticoid levels is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoids into bioactive forms such as cortisol in humans and corticosterone in rodents. Hexose-6-phosphate dehydrogenase (H6PD), which is colocalized with 11β-HSD1 in the intralumen of the endoplasmic reticulum, supplies a crucial coenzyme, NADPH, for full reductase activity of 11β-HSD1. Therefore, it is possible that inhibition of 11β-HSD1 will become a considerable medical treatment for metabolic diseases including obesity and diabetes. Genistein, a soy isoflavone, has received attention for its therapeutic potential for obesity, diabetes, and cardiovascular disease, and has been proposed as a promising compound for the treatment of metabolic disorders. However, the mechanisms underlying the pleiotropic anti-obesity effects of genistein have not been fully clarified. Here, we demonstrate that genistein was able to inhibit 11β-HSD1 and H6PD activities within 10 or 20min, in dose- and time-dependent manners. Inhibition of 11β-HSD2 activity was not observed in rat kidney microsomes. The inhibition was not reversed by two estrogen receptor antagonists, tamoxifen and ICI182,780. A kinetic study revealed that genistein acted as a non-competitive inhibitor of 11β-HSD1, and its apparent Km value for 11-dehydrocorticosterone was 0.5μM. Genistein also acted as a non-competitive inhibitor of H6PD, and its apparent Km values for G6P and NADP were 0.9 and 3.3μM, respectively. These results suggest that genistein may exert its inhibitory effect by interacting with these enzymes. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Glucocorticoid-mediated repression of T-cell receptor signalling is impaired in glucocorticoid receptor exon 2-disrupted mice.

    Science.gov (United States)

    Liddicoat, Douglas R; Purton, Jared F; Cole, Timothy J; Godfrey, Dale I

    2014-02-01

    Studies using glucocorticoid receptor exon 2-disrupted knockout (GR2KO) mice provided strong evidence against an obligatory role for glucocorticoid receptor (GR) signalling in T-cell selection. These mice express a truncated form of the GR that is incapable of transmitting a range of glucocorticoid (GC)-induced signals, including GC-induced thymocyte death. However, one study that suggested that truncated GR function is preserved in the context of GR-mediated repression of T-cell activation-induced genes, challenged earlier conclusions derived from the use of these mice. Because GR versus T-cell receptor (TCR) signalling cross-talk is the means by which GCs are hypothesized to have a role in T-cell selection, we reassessed the utility of GR2KO mice to study the role of the GR in this process. Here, we show that GR-mediated repression of TCR signalling is impaired in GR2KO T cells in terms of TCR-induced activation, proliferation and cytokine production. GC-induced apoptosis was largely abolished in peripheral T cells, and induction of the GC-responsive molecule, interleukin-7 receptor, was also severely reduced in GR2KO thymocytes. Together, these data strongly re-affirm conclusions derived from earlier studies of these mice that the GR is not obligatory for normal T-cell selection.

  19. Childhood Cumulative Risk Exposure and Adult Amygdala Volume and Function.

    Science.gov (United States)

    Evans, Gary W; Swain, James E; King, Anthony P; Wang, Xin; Javanbakht, Arash; Ho, S Shaun; Angstadt, Michael; Phan, K Luan; Xie, Hong; Liberzon, Israel

    2016-06-01

    Considerable work indicates that early cumulative risk exposure is aversive to human development, but very little research has examined the neurological underpinnings of these robust findings. This study investigates amygdala volume and reactivity to facial stimuli among adults (mean 23.7 years of age, n = 54) as a function of cumulative risk exposure during childhood (9 and 13 years of age). In addition, we test to determine whether expected cumulative risk elevations in amygdala volume would mediate functional reactivity of the amygdala during socioemotional processing. Risks included substandard housing quality, noise, crowding, family turmoil, child separation from family, and violence. Total and left hemisphere adult amygdala volumes were positively related to cumulative risk exposure during childhood. The links between childhood cumulative risk exposure and elevated amygdala responses to emotionally neutral facial stimuli in adulthood were mediated by the corresponding amygdala volumes. Cumulative risk exposure in later adolescence (17 years of age), however, was unrelated to subsequent adult amygdala volume or function. Physical and socioemotional risk exposures early in life appear to alter amygdala development, rendering adults more reactive to ambiguous stimuli such as neutral faces. These stress-related differences in childhood amygdala development might contribute to the well-documented psychological distress as a function of early risk exposure.

  20. From image-guided radiotherapy to dose-guided radiotherapy; De la radiotherapie guidee par l'image a la radiotherapie guidee par la dose

    Energy Technology Data Exchange (ETDEWEB)

    Cazoulat, G.; Lesaunier, M.; Simon, A.; Haigron, P.; Acosta, O. [Inserm, U642, 35000 Rennes (France); LTSI, universite de Rennes-1, 35000 Rennes (France); Louvel, G.; Chajon, E.; Leseur, J. [Centre Eugene-Marquis, rue de La-Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes cedex (France); Lafond, C.; De Crevoisier, R. [Inserm, U642, 35000 Rennes (France); LTSI, universite de Rennes-1, 35000 Rennes (France); Centre Eugene-Marquis, rue de La-Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes cedex (France)

    2011-12-15

    Purpose. - In case of tumour displacement, image-guided radiotherapy (IGRT) based on the use of cone beam CT (tomographie conique) allows replacing the tumour under the accelerator by rigid registration. Anatomical deformations require however re-planning, involving an estimation of the cumulative dose, session after session. This is the objective of this study. Patients and methods. - Two examples of arc-intensity modulated radiotherapy are presented: a case of prostate cancer (total dose = 80 Gy) with tomographie conique (daily prostate registration) and one head and neck cancer (70 Gy). For the head and neck cancer, the patient had a weekly scanner allowing a dose distribution calculation. The cumulative dose was calculated per voxel on the planning CT after deformation of the dose distribution (with trilinear interpolation) following the transformation given by a non-rigid registration step (Demons registration method) from: either the tomographie conique (prostate), or the weekly CT. The cumulative dose was eventually compared with the planned dose. Results. - In cases of prostate irradiation, the 'cumulative' dose corresponded to the planned dose to the prostate. At the last week of irradiation, it was above the planned dose for the rectum and bladder. The volume of rectal wall receiving more than 50 Gy (V50) was 20% at the planning and 26% at the end of treatment, increasing the risk of rectal toxicity (NTCP) of 14%. For the bladder wall, V50 were 73% and 82%, respectively. In head and neck, the 'cumulative' dose to the parotid exceeded the planned dose (mean dose increasing from 46 Gy to 54 Gy) from the 5. week of irradiation on, suggesting the need for re-planning within the first 5 weeks of radiotherapy. Conclusion. - The deformable registration estimates the cumulative dose delivered in the different anatomical structures. Validation on digital and physical phantoms is however required before clinical evaluation. (authors)

  1. Retrospective study of cumulative diagnostic radiation exposure during childhood in patients with spina bifida.

    Science.gov (United States)

    Smookler, Gregory; Deavenport-Saman, Alexis

    2015-10-01

    The Biological Effects of Ionizing Radiation Committee of the National Academy of Sciences in 2005 and other expert panels have warned that risk of cancer increases with higher doses of radiation. Children with spina bifida and hydrocephalus have far greater exposure to radiation than the average person, starting almost directly after birth and continuing throughout their lifetimes. The purpose of this study was to estimate the amount of ionizing radiation that patients with spina bifida and hydrocephalus are exposed to during childhood from diagnostic imaging. Thirty patients, ages 18 years or older, with spina bifida and hydrocephalus were randomly selected from a spina bifida clinic and their radiology records were reviewed. Descriptive analyses were conducted. The total radiation exposure was then calculated for the study group, and the mean effective dose per patient was determined. In the study group, during their first 18 years, each patient had a mean of 55.1 studies and a median of 45 radiologic studies, a mean of 9.6 brain CT scans, and a mean cumulative effective dose of 81.9 mSv (2.6 mSv/patient/year over 18 years) and a median cumulative effective dose of 77.2 mSV of accumulated radiation exposure (4.5 mSv/patient/year over 18 years). Clinicians should recognize that increased radiation exposure puts patients with spina bifida and hydrocephalus at higher risk for cancer. The population of children and adults with spina bifida and hydrocephalus should be surveyed for incidence of cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Cumulative radiation exposure and cancer risk of patients with ischemic heart diseases from diagnostic and therapeutic imaging procedures

    Energy Technology Data Exchange (ETDEWEB)

    Brix, Gunnar, E-mail: gbrix@bfs.de [Department of Medical and Occupational Radiation Protection, Federal Office for Radiation Protection, Ingoldstädter Landstraße 1, D-85764 Oberschleissheim (Germany); Berton, Marc, E-mail: marcberton@web.de [Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim (Germany); Nekolla, Elke, E-mail: enekolla@bfs.de [Department of Medical and Occupational Radiation Protection, Federal Office for Radiation Protection, Ingoldstädter Landstraße 1, D-85764 Oberschleissheim (Germany); Lechel, Ursula, E-mail: ulechel@bfs.de [Department of Medical and Occupational Radiation Protection, Federal Office for Radiation Protection, Ingoldstädter Landstraße 1, D-85764 Oberschleissheim (Germany); Schegerer, Alexander, E-mail: aschegerer@bfs.de [Department of Medical and Occupational Radiation Protection, Federal Office for Radiation Protection, Ingoldstädter Landstraße 1, D-85764 Oberschleissheim (Germany); Süselbeck, Tim, E-mail: Tim.Sueselbeck@umm.de [Department of Cardiology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim (Germany); Fink, Christian, E-mail: Christian.Fink@umm.de [Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim (Germany)

    2013-11-01

    Objectives: To present a detailed analysis of the cumulative radiation exposure and cancer risk of patients with ischemic heart diseases (IHD) from diagnostic and therapeutic imaging. Methods: For 1219 IHD patients, personal and examination data were retrieved from the information systems of a university hospital. For each patient, cumulative organ doses and the corresponding effective dose (E{sup ¯}) resulting from all imaging procedures performed within 3 months before and 12 months after the date of the diagnosis were calculated. The cumulative lifetime attributable risk (LAR{sup ¯}) of the patients to be diseased by radiation-related cancer was estimated using sex-, age-, and organ-specific risk models. Results: Among the 3870 procedures performed in the IHD patients, the most frequent were radiographic examinations (52.4%) followed by coronary catheter angiographies and percutaneous cardiac interventions (41.3%), CT scans (3.9%), and perfusion SPECT (2.3%). 87% of patient exposure resulted from heart catheter procedures. E{sup ¯} and LAR{sup ¯} were significantly higher in males than females (average, 13.3 vs. 10.3 mSv and 0.09 vs. 0.07%, respectively). Contrary to the effective dose, the cancer risk decreased markedly for both sexes with increasing age. Conclusions: Although IHD patients were partially exposed to considerable amounts of radiation, estimated LAR{sup ¯}s were small as compared to their baseline risk to develop cancer in the remaining life.

  3. Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis

    OpenAIRE

    Kavanaugh, Arthur; Wells, Alvin F

    2014-01-01

    Glucocorticosteroids (GCs) have been employed extensively for the treatment of rheumatoid arthritis (RA) and other autoimmune and systemic inflammatory disorders. Their use is supported by extensive literature and their utility is reflected in their incorporation into current treatment guidelines for RA and other conditions. Nevertheless, there is still some concern regarding the long-term use of GCs because of their potential for clinically important adverse events, particularly with an exte...

  4. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT

    National Research Council Canada - National Science Library

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-01-01

    .... We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial...

  5. Unilateral adrenal tumor, erectile dysfunction and infertility in a patient with 21-hydroxylase deficiency: effects of glucocorticoid treatment and surgery.

    Science.gov (United States)

    Scaroni, C; Favia, G; Lumachi, F; Opocher, G; Bonanni, G; Mantero, F; Armanini, D

    2003-02-01

    In untreated congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHDS) the presence of adrenal and testicular tumors had been described; however little is known about the effect of the enzymatic defect on fertility in males. We studied a male adult patient affected by 21OHDS for infertility, after a long period of discontinuation of glucocorticoid therapy and then during resumption of treatment and 8 months after monoadrenalectomy. The initial spermatic count revealed azoospermia and testicular needle aspiration showed a cytological picture consistent with prepuberty. The morphofunctional study revealed a right adrenal mass with reduced uptake at radioscan. Treatment was resumed with onset of impotency, which improved after reduction of the dose of glucocorticoids. The patient was monoadrenalectomised and his spermatic count increased. The patient shows that corticosteroid therapy in 21OHDS should be continued lifelong to avoid adrenal hyperplasia with possible areas of autonomy and to allow regular fertility. Impotence during treatment is probably due to a decrease of excessive adrenal androgens while testicular androgen production is still suppressed.

  6. Current practice of glucocorticoid replacement therapy and patient-perceived health outcomes in adrenal insufficiency - a worldwide patient survey

    Directory of Open Access Journals (Sweden)

    Forss M

    2012-06-01

    Full Text Available Abstract Background The aim was to survey current practice in glucocorticoid replacement therapy and self-perceived health outcomes in patients with adrenal insufficiency. Methods Participants were recruited via patient organizations to respond anonymously to a web-based survey developed by clinical experts. Unique entries were set up for each patient organization enabling geographical localization of the entries. Results 1245 participants responded (primary adrenal insufficiency: 84%; secondary adrenal insufficiency: 11%; unsure: 5%. Therapies included hydrocortisone (75%, prednisone/prednisolone (11%, cortisone acetate (6% and dexamethasone (4%. Dosing regimens were once daily (10%, twice daily (42%, thrice daily (32% or other (17%. Compromised subjective health necessitating changes to physical activity or social-, work- or family life was reported by 64% of the participants. 40% of the participants reported absence from work/school in the last 3 months. Irrespective of diagnosis, 76% were concerned about long-term side-effects of therapy, mainly osteoporosis (78%, obesity (64% and cardiovascular morbidity (46%. 38% of the participants had been hospitalized in the last year. Conclusions Glucocorticoid replacement therapy among the respondents consisted primarily of hydrocortisone administered twice or thrice daily. A majority reported impact of their disease or treatment on subjective health requiring alterations in e.g. physical activity or family life. Three quarters reported concerns about long-term side-effects of the treatment. These data demonstrate - from the patients' perspective - a need for improvement in the management of adrenal insufficiency.

  7. The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement.

    Science.gov (United States)

    Swords, F M; Carroll, P V; Kisalu, J; Wood, P J; Taylor, N F; Monson, J P

    2003-11-01

    11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) converts inactive cortisone to active cortisol. 11 beta HSD1 activity is increased in GH deficiency and inhibited by GH and IGF-I in acromegaly. However it is not known whether these changes in cortisol metabolism exert significant effects during hydrocortisone therapy, and the effect has not been studied in patients taking cortisone acetate. We have studied the effect of GH induced 11 beta HSD1 inhibition in hypopituitary adults with severe GH deficiency to determine whether this inhibition has a different magnitude of effect when patients are taking different forms of glucocorticoid replacement therapy. We have taken the ratio of 11-hydroxy/11-oxo cortisol metabolites (Fm/Em), an established measure of net 11 beta HSD activity to reflect the likely balance of cortisol to cortisone exposure in tissues expressing 11 beta HSD1, principally the liver and adipose tissue. We recruited 10 hypopituitary adults all on established glucocorticoid replacement therapy, but who were not receiving GH. Patients were treated with their standard hydrocortisone therapy for one week and an equivalent dose of cortisone acetate in its place for one week in random order. Serial serum cortisol assessments and urine steroid profiles were performed on each treatment. All patients were then established on GH therapy for at least three months before the two-week cycle was repeated. Fm/Em was also measured in a control population (20F, 20M). Prior to GH, the ratio Fm/Em was greater with hydrocortisone compared with cortisone acetate replacement (1.17 +/- 0.28 and 0.52 +/- 0.09 respectively, P cortisol/cortisone did not change indicating unchanged 11 beta HSD2 activity. Mean circulating cortisol also fell in all subjects after GH. This effect was greater during cortisone acetate treatment (-18.7%, P tissue exposure to glucocorticoid is supra-physiological in hypopituitary patients with untreated GH deficiency taking hydrocortisone

  8. Cumulative risks of foster care placement for Danish children.

    Science.gov (United States)

    Fallesen, Peter; Emanuel, Natalia; Wildeman, Christopher

    2014-01-01

    Although recent research suggests that the cumulative risk of foster care placement is far higher for American children than originally suspected, little is known about the cumulative risk of foster care placement in other countries, which makes it difficult to gauge the degree to which factor foster care placement is salient in other contexts. In this article, we provide companion estimates to those provided in recent work on the US by using Danish registry data and synthetic cohort life tables to show how high and unequally distributed the cumulative risk of foster care placement is for Danish children. Results suggest that at the beginning of the study period (in 1998) the cumulative risk of foster care placement for Danish children was roughly in line with the risk for American children. Yet, by the end of the study period (2010), the risk had declined to half the risk for American children. Our results also show some variations by parental ethnicity and sex, but these differences are small. Indeed, they appear quite muted relative to racial/ethnic differences in these risks in the United States. Last, though cumulative risks are similar between Danish and American children (especially at the beginning of the study period), the age-specific risk profiles are markedly different, with higher risks for older Danish children than for older American children.

  9. Latino Mothers' Cumulative Food Insecurity Exposure and Child Body Composition.

    Science.gov (United States)

    Hernandez, Daphne C

    2016-01-01

    To document whether an intergenerational transmission of food insecurity is occurring by assessing low-income foreign-born Latino mothers' experiences with food insecurity as none, once (either childhood or adulthood) or twice (during both childhood and adulthood). Also the association between maternal cumulative food insecurity and children's body composition was examined. Maternal self-reported surveys on retrospective measures of food insecurity during childhood, current measures of food insecurity, and demographics were collected from Houston-area community centers (N = 96). Children's body mass index (BMI) and waist circumference (WC) were directly assessed. Covariate-adjusted logistic regression models analyzed the association between cumulative food insecurity experiences and children's body composition. Fifty-eight percent of mothers experienced food insecurity both as a child and as an adult and 31% of the mothers experienced food insecurity either as a child or adult. Maternal cumulative exposure to food insecurity was unrelated to BMI but was negatively related to elevated WC. Although an intergenerational transmission of food insecurity does exist, maternal cumulative exposure to food insecurity does not impact children's body composition negatively in the short term. Studying the long-term effects of cumulative food insecurity exposure can provide information for the development and timing of obesity interventions.

  10. USING CUMULATIVE NUMBER DENSITIES TO COMPARE GALAXIES ACROSS COSMIC TIME

    Energy Technology Data Exchange (ETDEWEB)

    Behroozi, Peter S.; Wechsler, Risa H. [Kavli Institute for Particle Astrophysics and Cosmology, SLAC National Accelerator Laboratory, Stanford, CA 94305 (United States); Marchesini, Danilo [Department of Physics and Astronomy, Tufts University, Medford, MA 02155 (United States); Muzzin, Adam [Leiden Observatory, Leiden University, P.O. Box 9513, 2300 RA Leiden (Netherlands); Papovich, Casey [Department of Physics and Astronomy, Texas A and M University, College Station, TX 77843 (United States); Stefanon, Mauro [Physics and Astronomy Department, University of Missouri, Columbia, MO 65211 (United States)

    2013-11-01

    Comparing galaxies across redshifts at fixed cumulative number density is a popular way to estimate the evolution of specific galaxy populations. This method ignores scatter in mass accretion histories and galaxy-galaxy mergers, which can lead to errors when comparing galaxies over large redshift ranges (Δz > 1). We use abundance matching in the ΛCDM paradigm to estimate the median change in cumulative number density with redshift and provide a simple fit (+0.16 dex per unit Δz) for progenitors of z = 0 galaxies. We find that galaxy descendants do not evolve in the same way as galaxy progenitors, largely due to scatter in mass accretion histories. We also provide estimates for the 1σ range of cumulative number densities corresponding to galaxy progenitors and descendants. Finally, we discuss some limits on cumulative number density comparisons, which arise due to difficulties measuring physical quantities (e.g., stellar mass) consistently across redshifts. A public tool to calculate cumulative number density evolution for galaxies, as well as approximate halo masses, is available online.

  11. Impact of Stress and Glucocorticoids on Schema-Based Learning.

    Science.gov (United States)

    Kluen, Lisa Marieke; Nixon, Patricia; Agorastos, Agorastos; Wiedemann, Klaus; Schwabe, Lars

    2016-12-14

    Pre-existing knowledge, a 'schema', facilitates the encoding, consolidation, and retrieval of schema-relevant information. Such schema-based memory is key to every form of education and provides intriguing insights into the integration of new information and prior knowledge. Stress is known to have a critical impact on memory processes, mainly through the action of glucocorticoids and catecholamines. However, whether stress and these major stress mediators affect schema-based learning is completely unknown. To address this question, we performed two experiments, in which participants acquired a schema on day 1 and learned schema-related as well as schema-unrelated information on day 2. In the first experiment, participants underwent a stress or control manipulation either immediately or about 25 min before schema-based memory testing. The second experiment tested whether glucocorticoid and/or noradrenergic activation is sufficient to modulate schema-based memory. To this end, participants received orally a placebo, hydrocortisone, the α2-adrenoceptor-antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs, before completing the schema-based memory test. Our data indicate that stress, irrespective of the exact timing of the stress exposure, impaired schema-based learning, while leaving learning of schema-unrelated information intact. A very similar effect was obtained after hydrocortisone, but not yohimbine, administration. These data show that stress disrupts participants' ability to benefit from prior knowledge during learning and that glucocorticoid activation is sufficient to produce this effect. Our findings provide novel insights into the impact of stress and stress hormones on the dynamics of human memory and have important practical implications, specifically for educational contexts.Neuropsychopharmacology advance online publication, 14 December 2016; doi:10.1038/npp.2016.256.

  12. Adrenal glucocorticoids regulate adipsin gene expression in genetically obese mice.

    Science.gov (United States)

    Spiegelman, B M; Lowell, B; Napolitano, A; Dubuc, P; Barton, D; Francke, U; Groves, D L; Cook, K S; Flier, J S

    1989-01-25

    Adipsin expression at the protein and mRNA levels is greatly reduced in several distinct syndromes of obesity in the mouse: genetic obesity due to the db/db and ob/ob genes, and a chemically induced model secondary to neonatal exposure to monosodium glutamate. We considered first the possibility that the adipsin gene might be identical to the db or ob locus and the lowered expression of this protein might result from a mutation in this gene. We show here that the adipsin structural gene is located on chromosome 10 and hence is physically distinct from any obesity genes so far identified in the mouse. A major role for the adrenal gland and adrenal glucocorticoids in the aberrant regulation of adipsin in these models of obesity is indicated by several experiments. Adrenalectomy of the ob/ob mouse raises the circulating levels of adipsin protein and the amount of this mRNA in epididymal fat pads (5-fold), although neither is increased to the levels seen in lean controls. Exogenous administration of corticosterone completely blocks the effects of adrenalectomy on adipsin, suggesting that the effect of this endocrine ablation is through reduction of adrenal glucocorticoids. Corticosterone administration also causes suppression in the levels of adipsin mRNA and protein in lean mice, although this decrease is never as severe as that seen in obese mice. The effect of exogenous corticosterone in lean mice occurs within 2 days and hence is not secondary to the obesity which these hormones eventually elicit. These results indicate that glucocorticoids can regulate adipsin expression in vivo and strongly suggest that the hyperglucocorticoid state seen in certain obese models plays a significant role in lowering adipsin mRNA and protein levels. Quantitative analysis of these experiments suggests that other as yet unknown neuroendocrine factors also function to suppress adipsin in obesity.

  13. Specific regulatory motifs predict glucocorticoid responsiveness of hippocampal gene expression.

    Science.gov (United States)

    Datson, N A; Polman, J A E; de Jonge, R T; van Boheemen, P T M; van Maanen, E M T; Welten, J; McEwen, B S; Meiland, H C; Meijer, O C

    2011-10-01

    The glucocorticoid receptor (GR) is an ubiquitously expressed ligand-activated transcription factor that mediates effects of cortisol in relation to adaptation to stress. In the brain, GR affects the hippocampus to modulate memory processes through direct binding to glucocorticoid response elements (GREs) in the DNA. However, its effects are to a high degree cell specific, and its target genes in different cell types as well as the mechanisms conferring this specificity are largely unknown. To gain insight in hippocampal GR signaling, we characterized to which GRE GR binds in the rat hippocampus. Using a position-specific scoring matrix, we identified evolutionary-conserved putative GREs from a microarray based set of hippocampal target genes. Using chromatin immunoprecipitation, we were able to confirm GR binding to 15 out of a selection of 32 predicted sites (47%). The majority of these 15 GREs are previously undescribed and thus represent novel GREs that bind GR and therefore may be functional in the rat hippocampus. GRE nucleotide composition was not predictive for binding of GR to a GRE. A search for conserved flanking sequences that may predict GR-GRE interaction resulted in the identification of GC-box associated motifs, such as Myc-associated zinc finger protein 1, within 2 kb of GREs with GR binding in the hippocampus. This enrichment was not present around nonbinding GRE sequences nor around proven GR-binding sites from a mesenchymal stem-like cell dataset that we analyzed. GC-binding transcription factors therefore may be unique partners for DNA-bound GR and may in part explain cell-specific transcriptional regulation by glucocorticoids in the context of the hippocampus.

  14. Glucocorticoids Enhance Taste Aversion Memory via Actions in the Insular Cortex and Basolateral Amygdala

    Science.gov (United States)

    Miranda, Maria Isabel; Quirarte, Gina L.; Rodriguez-Garcia, Gabriela; McGaugh, James L.; Roozendaal, Benno

    2008-01-01

    It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function.…

  15. Fecal glucocorticoid response to environmental stressors in green iguanas (Iguana iguana)

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Timm, Jeanette; Ibsen, Ida

    2012-01-01

    Quantification of glucocorticoid metabolites in feces has been shown to be a powerful tool in evaluating well-being in vertebrates. Little is known however about the hypothalamic–pituitary–adrenal axis response to stressors, and consequent glucocorticoid excretion, in reptiles. In a longitudinal...

  16. Influence of drug treatment on glucocorticoid receptor levels in patients with coronary heart disease

    Institute of Scientific and Technical Information of China (English)

    JI Hong; GUO Wei-zao; YAN Zhi-hong; LI Di; LU Cui-lian

    2010-01-01

    Background Glucocorticoid signaling exerts major roles in inflammation, metabolism and depression, which are three crucial factors accompanying or underlying coronary heart disease. Although accumulating evidence indicates the influence of glucocorticoids on the pathology and treatment of coronary heart disease, there is still a dearth of pharmaceutical mechanisms for this relationship. This study aimed to investigate the influence of drug treatment on glucocorticoid receptor levels in coronary heart disease.Methods Eighty hospitalized patients (average age (59.0 7.5) years, 46 male and 34 female) with coronary heart disease were categorized into four groups with 20 members in each according to one of the four drugs they were treated with. The four drugs were: nitrated derivative isosorbide dinitrate, the beta-adrenergic receptor blocker metoprolol, the calcium antagonist nifedipine, and the HMG-CoA reductase inhibitor lovastatin. Glucocorticoid receptor protein levels of peripheral blood lymphocytes were tested using immunoblotting analysis before and after one month of treatment. Results Immunoblotting analysis showed increased glucocorticoid receptor levels after treatment with metoprolol and nifedipine. There were no statistically significant changes of glucocorticoid receptor levels after treatment with isosorbide dinitrate or lovastatin, although there were trends of up-regulation of glucocorticoid receptor expression after both treatments.Conclusions Both the beta-blocker and the calcium blocker can increase glucocorticoid receptor levels after chronic administration. This effect suggests a mechanism for their anti-inflammatory and other therapeutic roles for coronary heart disease and comorbid disorders.

  17. Allelic polymorphism of glucocorticoid receptor NR3C1 (GR: from molecular biology to clinical implications

    Directory of Open Access Journals (Sweden)

    Orlovsky M. A.

    2012-09-01

    Full Text Available Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is focused on the molecular biology and clinical implications of glucocorticoid receptor gene polymorphism.

  18. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress.

    NARCIS (Netherlands)

    Oomen, C.A.; Mayer, J.L.; de Kloet, E.R.; Joëls, M.; Lucassen, P.J.

    2007-01-01

    In rodents, stress suppresses adult neurogenesis. This is thought to involve activation of glucocorticoid receptors in the brain. In the present study, we therefore questioned whether glucocorticoid receptor blockade by mifepristone can normalize the effects of chronic stress on adult neurogenesis.

  19. Instructions for producing a mouse model of glucocorticoid-induced osteoporosis

    DEFF Research Database (Denmark)

    Thiele, S.; Baschant, U.; Rauch, A.

    2014-01-01

    with a compromised bone quality and an increased fracture risk. At the cellular level, glucocorticoids suppress bone formation and stimulate bone resorption, which leads to loss of bone mass. To investigate the underlying mechanisms and new therapeutic strategies, the in vivo model for glucocorticoid-induced bone...

  20. Glucocorticoids Enhance Taste Aversion Memory via Actions in the Insular Cortex and Basolateral Amygdala

    Science.gov (United States)

    Miranda, Maria Isabel; Quirarte, Gina L.; Rodriguez-Garcia, Gabriela; McGaugh, James L.; Roozendaal, Benno

    2008-01-01

    It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function.…

  1. Tolloid-like 1 is negatively regulated by stress and glucocorticoids.

    Science.gov (United States)

    Tamura, Goichiro; Olson, Dawne; Miron, Joel; Clark, Timothy G

    2005-12-14

    Glucocorticoids affect a variety of tissues to enable the organism to adapt to the stress. Hippocampal neurons contain glucocorticoid receptors and respond to elevated glucocorticoid levels by down-regulating the HPA axis. Chronically, however, stress is deleterious to hippocampal neurons. Chronically elevated levels of glucocorticoids result in a decrease in the number of dendritic spines, reduced axonal growth and synaptogenesis, and decreased neurogenesis in the hippocampus. Tolloid-like 1 (Tll-1) is a metalloprotease that potentiates the activity of the bone morphogenetic proteins (BMPs). Neurogenesis in the hippocampus of both developing and adult mammals requires BMPs. In this study, we demonstrate that Tll-1 expression is increased in mice that have increased neurogenesis. The Tll-1 promoter contains glucocorticoid response elements which are capable of binding to purified glucocorticoid receptor. Glucocorticoids decrease Tll-1 expression in vitro. Finally, prenatal stress leads to a decrease in Tll-1 mRNA expression in the hippocampus of adult female mice that is not observed in adult male mice indicating that Tll-1 expression is differentially regulated in males and females. The results of this study indicate that Tll-1 is responsive to glucocorticoids and this mechanism might influence neurogenesis in the hippocampus.

  2. Long-term effects of perinatal glucocorticoid treatment on the heart

    NARCIS (Netherlands)

    Vries, W.B. de

    2006-01-01

    Long-term effects of perinatal glucocorticoid treatment on the heart Chronic lung disease in the extremely preterm baby is still a major complication in neonatal intensive care medicine. Perinatal (ante- and neonatal) glucocorticoids are widely used to prevent severe infant respiratory syndrome and

  3. Behavioral neuroadaptation to alcohol : from glucocorticoids to histone acetylation

    Directory of Open Access Journals (Sweden)

    Daniel Beracochea

    2016-10-01

    Full Text Available A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic-pituitary-adrenal (HPA axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit including the prefrontal cortex, the hippocampus and the amygdala. These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally amygdala hyperactivity coupled with a hypofunction of the prefrontal cortex and the hippocampus. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately, leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcohol-induced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as CREB (cAMP response element binding protein and chromatin remodeling due to post-translational modifications of histone proteins. We describe the role of prefrontal-hippocampus-amygdala circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region-specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes on how persistently increased glucocorticoid levels in prefrontal cortex may be involved in

  4. Glucocorticoid receptor gene polymorphism and juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Scheplyagina Larisa A

    2011-01-01

    Full Text Available Abstract Background The glucocorticoid receptor gene (NR3C1 has been suggested as a candidate gene affecting juvenile idiopathic arthritis (JIA course and prognosis. The purpose of this study is to investigate the glucocorticoid receptor gene BclI polymorphism (rs41423247 in JIA patients, the gene's role in susceptibility to juvenile idiopathic arthritis, and its associations with JIA activity, course and bone mineralization. Methods One hundred twenty-two Caucasian children with JIA and 143 healthy ethnically matched controls were studied. We checked markers of clinical and laboratory activity: morning stiffness, Ritchie Articular Index (RAI, swollen joint count (SJC, tender joint count (TJC, physician's visual analog scale (VAS, hemoglobin level (Hb, leukocyte count (L, platelet count (Pl, Westergren erythrocyte sedimentation rate (ESR, C-reactive protein (CRP, albumin, DAS and DAS28. Bone mineralization was measured by dual-energy X-ray absorptiometry (DXA of lumbar spine L1-L4. Assessments of bone metabolism included osteocalcin, C-terminal telopeptide (CTT, parathyroid hormone (PTH, total and ionized calcium, inorganic phosphate and total alkaline phosphatase (TAP. BclI polymorphism was genotyped by polymerase chain reaction restriction fragment length polymorphism. Results No association was observed between glucocorticoid receptor gene polymorphism and the presence or absence of JIA. In girls with JIA, the presence of the G allele was associated with an unfavorable arthritis course, a younger age of onset of arthritis (p = 0.0017, and higher inflammatory activity. The higher inflammatory activity was demonstrated by the following: increased time of morning stiffness (p = 0.02, VAS (p = 0.014, RAI (p = 0.048, DAS (p = 0.035, DAS28 (p = 0.05, Pl (p = 0.003, L (p = 0.046, CRP (p = 0.01. In addition, these patients had bone metabolism disturbances as follows: decreased BA (p = 0.0001, BMC (p = 0.00007, BMD (0.005 and Z score (p = 0.002; and

  5. Bone loss during simulated weightlessness - Is it glucocorticoid mediated?

    Science.gov (United States)

    Bikle, D. D.; Halloran, B. P.; Cone, C. M.; Morey-Holton, E.

    1985-01-01

    Elevating the hindquarters of a rat by the tail unweights the hind limbs but maintains normal weight-bearing by the forelimbs. This maneuver leads to a decrease in bone mass and calcium content in the unweighted bones (e.g., tibia and L1 vertebra), but not in the normally weighted bones (e.g., humerus and mandible). Potentially, the stress of the maneuver, mediated by increased glucocorticoid production and secretion, could explain the decreased bone formation, rather than the skeletal unweighting per se. To test this possibility, the effects of adrenalectomy on the response of bone to the unweighting of the hind limbs of normal rats were evaluated.

  6. Behavioral Neuroadaptation to Alcohol: From Glucocorticoids to Histone Acetylation

    Science.gov (United States)

    Mons, Nicole; Beracochea, Daniel

    2016-01-01

    A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic–pituitary–adrenal axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents) from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit, including the prefrontal cortex (PFC), the hippocampus (HPC), and the amygdala (AMG). These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally AMG hyperactivity coupled with a hypofunction of the PFC and the HPC. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcohol-induced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as [cAMP response element-binding protein (CREB)] and chromatin remodeling due to posttranslational modifications of histone proteins. We describe the role of prefrontal–HPC–AMG circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region-specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes how persistently increased glucocorticoid levels in PFC may be involved in mediating working memory impairments and

  7. Radiation Dose Risk and Diagnostic Benefit in Imaging Investigations

    CERN Document Server

    Dobrescu, Lidia

    2015-01-01

    The paper presents many facets of medical imaging investigations radiological risks. The total volume of prescribed medical investigations proves a serious lack in monitoring and tracking of the cumulative radiation doses in many health services. Modern radiological investigations equipment is continuously reducing the total dose of radiation due to improved technologies, so a decrease in per caput dose can be noticed, but the increasing number of investigations has determined a net increase of the annual collective dose. High doses of radiation are cumulated from Computed Tomography investigations. An integrated system for radiation safety of the patients investigated by radiological imaging methods, based on smart cards and Public Key Infrastructure allow radiation absorbed dose data storage.

  8. Maternal glucocorticoid elevation and associated blood metabonome changes might be involved in metabolic programming of intrauterine growth retardation in rats exposed to caffeine prenatally

    Energy Technology Data Exchange (ETDEWEB)

    Kou, Hao; Liu, Yansong; Liang, Gai; Huang, Jing; Hu, Jieqiong; Yan, You-e; Li, Xiaojun [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Yu, Hong; He, Xiaohua; Zhang, Baifang [Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071 (China); Zhang, Yuanzhen [Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071 (China); Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Feng, Jianghua, E-mail: jianghua.feng@xmu.edu.cn [Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005 (China); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071 (China)

    2014-03-01

    Our previous studies demonstrated that prenatal caffeine exposure causes intrauterine growth retardation (IUGR), fetuses are over-exposed to high levels of maternal glucocorticoids (GC), and intrauterine metabolic programming and associated metabonome alteration that may be GC-mediated. However, whether maternal metabonomes would be altered and relevant metabolite variations might mediate the development of IUGR remained unknown. In the present studies, we examined the dose- and time-effects of caffeine on maternal metabonome, and tried to clarify the potential roles of maternal GCs and metabonome changes in the metabolic programming of caffeine-induced IUGR. Pregnant rats were treated with caffeine (0, 20, 60 or 180 mg/kg · d) from gestational days (GD) 11 to 20, or 180 mg/kg · d caffeine from GD9. Metabonomes of maternal plasma on GD20 in the dose–effect study and on GD11, 14 and 17 in the time–course study were analyzed by {sup 1}H nuclear magnetic resonance spectroscopy, respectively. Caffeine administration reduced maternal weight gains and elevated both maternal and fetal corticosterone (CORT) levels. A negative correlation between maternal/fetal CORT levels and fetal bodyweight was observed. The maternal metabonome alterations included attenuated metabolism of carbohydrates, enhanced lipolysis and protein breakdown, and amino acid accumulation, suggesting GC-associated metabolic effects. GC-associated metabolite variations (α/β-glucoses, high density lipoprotein-cholesterol, β-hydroxybutyrate) were observed early following caffeine administration. In conclusion, prenatal caffeine exposure induced maternal GC elevation and metabonome alteration, and maternal GC and relevant discriminatory metabolites might be involved in the metabolic programming of caffeine-induced IUGR. - Highlights: • Prenatal caffeine exposure elevated maternal blood glucocorticoid levels. • Prenatal caffeine exposure altered maternal blood metabonomes. • Maternal

  9. High faecal glucocorticoid levels predict mortality in ring-tailed lemurs (Lemur catta)

    Science.gov (United States)

    Ethan Pride, R

    2005-01-01

    Glucocorticoid levels are commonly used as measures of stress in wild animal populations, but their relevance to individual fitness in a wild population has not been demonstrated. In this study I followed 93 ring-tailed lemurs (Lemur catta) at Berenty Reserve in Madagascar, collecting 1089 faecal samples from individually recognized animals, and recording their survival over a 2 year period. I evaluated faecal glucocorticoid levels as predictors of individual survival to the end of the study. Animals with high glucocorticoid levels had a significantly higher mortality rate. This result suggests that glucocorticoid measures can be useful predictors of individual survival probabilities in wild populations. The ‘stress landscape’ indicated by glucocorticoid patterns may approximate the fitness landscape to which animals adapt. PMID:17148128

  10. Cumulative Trauma Among Mayas Living in Southeast Florida.

    Science.gov (United States)

    Millender, Eugenia I; Lowe, John

    2016-01-04

    Mayas, having experienced genocide, exile, and severe poverty, are at high risk for the consequences of cumulative trauma that continually resurfaces through current fear of an uncertain future. Little is known about the mental health and alcohol use status of this population. This correlational study explored t/he relationship of cumulative trauma as it relates to social determinants of health (years in the United States, education, health insurance status, marital status, and employment), psychological health (depression symptoms), and health behaviors (alcohol use) of 102 Guatemalan Mayas living in Southeast Florida. The results of this study indicated that, as specific social determinants of health and cumulative trauma increased, depression symptoms (particularly among women) and the risk for harmful alcohol use (particularly among men) increased. Identifying risk factors at an early stage before serious disease or problems are manifest provides room for early screening leading to early identification, early treatment, and better outcomes.

  11. Analysis of sensory ratings data with cumulative link models

    DEFF Research Database (Denmark)

    Christensen, Rune Haubo Bojesen; Brockhoff, Per B.

    2013-01-01

    Examples of categorical rating scales include discrete preference, liking and hedonic rating scales. Data obtained on these scales are often analyzed with normal linear regression methods or with omnibus Pearson chi2 tests. In this paper we propose to use cumulative link models that allow...... for regression methods similar to linear models while respecting the categorical nature of the observations. We describe how cumulative link models are related to the omnibus chi2 tests and how they can lead to more powerful tests in the non-replicated setting. For replicated categorical ratings data we present...... a quasi-likelihood approach and a mixed effects approach both being extensions of cumulative link models. We contrast population-average and subject-specific interpretations based on these models and discuss how different approaches lead to different tests. In replicated settings, naive tests that ignore...

  12. Cumulative pion production via successive collisions in nuclear medium

    CERN Document Server

    Motornenko, A

    2016-01-01

    Production of pions in proton-nucleus (p+A) reactions outside of a kinematical boundary of proton-nucleon collisions, the so-called cumulative effect, is studied. The kinematical restrictions on pions emitted in backward direction in the target rest frame are analyzed. It is shown that cumulative pion production requires a presence of massive baryonic resonances that are produced during successive collisions of projectile with nuclear nucleons. After each successive collision the mass of created resonance may increase and, simultaneously, its longitudinal velocity decreases. Simulations within Ultra relativistic Quantum Molecular Dynamics model reveals that successive collisions of baryonic resonances with nuclear nucleons plays the dominant role in cumulative pion production in p+A reactions.

  13. Solid-state electro-cumulation effect numerical simulation

    CERN Document Server

    Grishin, V G

    2001-01-01

    It is an attempt to simulate as really as possible a crystal's interatomic interaction under conditions of "Solid-state electro-cumulation (super-polarization) effect". Some theoretical and experimental reasons to believe that within solid substances an interparticles interaction could concentrate from the surface to a centre were given formerly. Now, numerical results show the conditions that could make the cumulation more effective. Another keywords: ion, current, solid, symmetry, cumulation, polarization, depolarization, ionic conductor,superionic conductor, ice, crystal, strain, V-center, V-centre, doped crystal, interstitial impurity, intrinsic color center, high pressure technology, Bridgman, anvil, experiment, crowdion, dielectric, proton, layer, defect, lattice, dynamics, electromigration, mobility, muon catalysis, concentration, doping, dopant, conductivity, pycnonuclear reaction, permittivity, dielectric constant, point defects, interstitials, polarizability, imperfection, defect centers, glass, epi...

  14. Association between diastolic blood pressure and cumulative work time

    Directory of Open Access Journals (Sweden)

    Ricardo Cordeiro

    1999-01-01

    Full Text Available Diastolic blood pressure was viewed as a generic indicator of aging, and its association with cumulative work time was studied after controlling for age as a potential confounding factor. The study was conducted among production line workers at a Brazilian tannery in July 1993. The association between diastolic blood pressure and cumulative work time was verified by fitting a second-order linear regression model, where diastolic blood pressure was a function of worker's age and cumulative work time. By fitting the model, one can predict that, in the beginning of working life at the tannery, on average each 1-year period is associated with an increase of about 1.5 mmHg in diastolic blood pressure. The fit obtained highlights one component directly associated with work as part of the rate of pressure increase in the study group. This component is twice as high as that directly associated with age.

  15. Baltic Sea biodiversity status vs. cumulative human pressures

    DEFF Research Database (Denmark)

    Andersen, Jesper H.; Halpern, Benjamin S.; Korpinen, Samuli

    2015-01-01

    Abstract Many studies have tried to explain spatial and temporal variations in biodiversity status of marine areas from a single-issue perspective, such as fishing pressure or coastal pollution, yet most continental seas experience a wide range of human pressures. Cumulative impact assessments have...... been developed to capture the consequences of multiple stressors for biodiversity, but the ability of these assessments to accurately predict biodiversity status has never been tested or ground-truthed. This relationship has similarly been assumed for the Baltic Sea, especially in areas with impaired...... status, but has also never been documented. Here we provide a first tentative indication that cumulative human impacts relate to ecosystem condition, i.e. biodiversity status, in the Baltic Sea. Thus, cumulative impact assessments offer a promising tool for informed marine spatial planning, designation...

  16. Session: What do we know about cumulative or population impacts

    Energy Technology Data Exchange (ETDEWEB)

    Kerlinger, Paul; Manville, Al; Kendall, Bill

    2004-09-01

    This session at the Wind Energy and Birds/Bats workshop consisted of a panel discussion followed by a discussion/question and answer period. The panelists were Paul Kerlinger, Curry and Kerlinger, LLC, Al Manville, U.S. Fish and Wildlife Service, and Bill Kendall, US Geological Service. The panel addressed the potential cumulative impacts of wind turbines on bird and bat populations over time. Panel members gave brief presentations that touched on what is currently known, what laws apply, and the usefulness of population modeling. Topics addressed included which sources of modeling should be included in cumulative impacts, comparison of impacts from different modes of energy generation, as well as what research is still needed regarding cumulative impacts of wind energy development on bird and bat populations.

  17. Cumulant dynamics in a finite population linkage equilibrium theory

    CERN Document Server

    Rattray, M; Rattray, Magnus; Shapiro, Jonathan L.

    1999-01-01

    The evolution of a finite population at linkage equilibrium is described in terms of the dynamics of phenotype distribution cumulants. This provides a powerful method for describing evolutionary transients and we elucidate the relationship between the cumulant dynamics and the diffusion approximation. A separation of time-scales between the first and higher cumulants for low mutation rates is demonstrated in the diffusion limit and provides a significant simplification of the dynamical system. However, the diffusion limit may not be appropriate for strong selection as the standard Fisher-Wright model of genetic drift can break down in this case. Two novel examples of this effect are considered: we shown that the dynamics may depend on the number of loci under strong directional selection and that environmental variance results in a reduced effective population size. We also consider a simple model of a changing environment which cannot be described by a diffusion equation and we derive the optimal mutation ra...

  18. Effect of correlation on cumulants in heavy-ion collisions

    CERN Document Server

    Mishra, D K; Netrakanti, P K

    2015-01-01

    We study the effects of correlation on cumulants and their ratios of net-proton multiplicity distribution which have been measured for central (0-5\\%) Au+Au collisions at Relativistic Heavy Ion Collider (RHIC). This effect has been studied assuming individual proton and anti-proton distributions as Poisson or Negative Binomial Distribution (NBD). In-spite of significantly correlated production due to baryon number, electric charge conservation and kinematical correlations of protons and anti-protons, the measured cumulants of net-proton distribution follow the independent production model. In the present work we demonstrate how the introduction of correlations will affect the cumulants and their ratios for the difference distributions. We have also demonstrated this study using the proton and anti-proton distributions obtained from HIJING event generator.

  19. Comparing the effects of two inhaled glucocorticoids on allergen-induced bronchoconstriction and markers of systemic effects, a randomised cross-over double-blind study

    Directory of Open Access Journals (Sweden)

    Lötvall Jan

    2011-10-01

    Full Text Available Abstract Background Inhaled glucocorticoids are efficient in protecting against asthma exacerbations, but methods to compare their efficacy vs systemic effects have only been attempted in larger multi-centre studies. The aim of the current study was therefore to directly compare the effects of two separate inhaled glucocorticoids, mometasone and budesonide, to compare the effects on the early and late asthmatic responses to inhaled allergen in patients with mild allergic asthma, and sputum eosinophils, and to relate the clinical positive effects to any systemic effects observed. Methods Twelve patients with documented early and late asthmatic responses (EAR and LAR to inhaled allergen at a screening visit were randomized in a double-blind fashion to treatment with mometasone (200 μg × 2 or 400 μg × 2, budesonide (400 μg × 2 or placebo in a double-blind crossover fashion for a period of seven days. Challenge with the total allergen dose causing both an EAR and LAR was given on the last day of treatment taken in the morning. Lung function was assessed using FEV1, and systemic glucocorticoid activity was quantified using 24 h urinary cortisol. Results Mometasone and budesonide attenuate both EAR and LAR to allergen to a similar degree. No significant dose-related effects on the lung function parameters were observed. Both treatments reduced the relative amount of sputum eosinophils (% after allergen. At the dose of 800 μg daily, mometasone reduced 24 h urinary cortisol by approximately 35%. Both drugs were well tolerated. Conclusions Mometasone and budesonide are equieffective in reducing early and late asthmatic responses induced by inhaled allergen challenge. Mometasone 800 μg given for seven days partially affects the HPA axis.

  20. Impact of glucocorticoid hormones on adipokine secretion and human adipose tissue metabolism.

    Science.gov (United States)

    Fain, John N

    2013-08-01

    The glucocorticoid hormones alter the metabolism of the adipose tissue after an approximately 2-h lag period. The effects are mediated through the nuclear receptors that alter the expression of a wide variety of genes through the mechanisms that are similar to those seen in the other cells. There are many direct metabolic effects of the glucocorticoids on the adipose tissue metabolism, and every year, new effects are added to the list of proteins whose expression is influenced by the glucocorticoids. Furthermore, some enzymatic processes are affected by these hormones only in the presence of the other hormones such as growth hormone (GH) or insulin. Most of the effects of the glucocorticoids are on the gene transcription, and the effects on the mRNA are reflected in the altered levels of the target proteins. The glucocorticoids enhance the leptin release, while reducing that of the inflammatory adipokines and stimulating that of the lipoprotein lipase (LPL) in the presence of insulin. The activity of 11β-hydroxysteroid dehydrogenase type 1 (HSD1) is enhanced by the glucocorticoids along with that of α1 glycoprotein 1 and serum amyloid A release by the adipose tissue. In contrast, the tumor necrosis factor α (TNF)-stimulated lipolysis in the adipose tissue is blocked by the glucocorticoids. It is still unclear which, if any, of these effects account for the insulin resistance due to the glucocorticoids in the adipose tissue. However, recent work suggests that, at least in mice, the reduction in the osteocalcin release by the osteoblasts in the presence of the glucocorticoids accounts for much of the in vivo insulin resistance. In summary, there are multiple direct effects of the glucocorticoids, both anti-inflammatory and proinflammatory, on the adipose tissue.