Testing the effects of long-acting steroids in edema and ecchymosis after closed rhinoplasty

PubMed Central

Gutierrez, Santiago; Wuesthoff, Carolina

2014-01-01

BACKGROUND: Steroids have proven to be of some benefit in rhinoplasty edema and ecchymosis when administered at a high and repeated dose. OBJECTIVE: To evaluate the effects of single-dose, long-acting intramuscular steroids on postoperative edema and ecchymosis after closed rhinoplasty with osteotomies compared with placebo. METHODS: A randomized, double-blinded, placebo-controlled trial was performed. Fifty-four patients were randomly assigned to two groups: 28 received a single dose of long-acting dexamethasone (mean [± SD] dose 16±4 mg) immediately before anesthetic induction; the remaining 26 received an intramuscular injection of saline solution. The same surgeon performed all surgeries, with patients under general anesthesia. Acetaminophen was the only analgesic used to control postoperative pain. High-resolution digital photographs were taken on postoperative days 1, 3, 7 and 14. Scoring was performed separately for eyelid swelling and ecchymosis by an independent observer using a graded scale (0 to 5) for edema and a scoring system (0 to 13) for ecchymosis. RESULTS: No statistically significant differences in terms of age, sex or amount of bleeding during surgery were found between the two groups. No statistically significant difference was observed in the decrease of both ecchymosis and edema between placebo and high-dose, long-acting dexamethasone. A statistically significant difference in operation time was found, favouring the steroid group. No severe complications were observed due to steroid use. DISCUSSION: Osteotomies are basically a form of (controlled) trauma, with considerable disruption of the abundant blood vessels in this facial region and, therefore, are associated with with undesirable effects. A recent meta-analysis failed to show benefits of the use of steroids after postoperative day 3. Only a trend toward reduction in edema and ecchymosis with the use of long-acting steroids compared with placebo was demonstrated in the present study. CONCLUSION: There was no benefit in administering single-dose, long-acting steroids in patients undergoing closed rhinoplasty with osteotomies. PMID:25114618

The Effects of Steroids on Coagulation Dysfunction Induced by Cardiopulmonary Bypass: A Steroids in Cardiac Surgery (SIRS) Trial Substudy.

PubMed

Paparella, Domenico; Parolari, Alessandro; Rotunno, Crescenzia; Vincent, Jessica; Myasoedova, Veronica; Guida, Pietro; De Palo, Micaela; Margari, Vito; Devereaux, Philip J; Lamy, Andre; Alamanni, Francesco; Yusuf, Salim; Whitlock, Richard

2017-01-01

Cardiopulmonary bypass (CPB) surgery, despite heparin administration, elicits activation of coagulation system resulting in coagulopathy. Anti-inflammatory effects of steroid treatment have been demonstrated, but its effects on coagulation system are unknown. The primary objective of this study is to assess the effects of methylprednisolone on coagulation function by evaluating thrombin generation, fibrinolysis, and platelet activation in high-risk patients undergoing cardiac surgery with CPB. The Steroids In caRdiac Surgery study is a double-blind, randomized, controlled trial performed on 7507 patients worldwide who were randomized to receive either intravenous methylprednisolone, 250 mg at anesthetic induction and 250 mg at initiation of CPB (n = 3755), or placebo (n = 3752). A substudy was conducted in 2 sites to collect blood samples perioperatively to measure prothrombin fragment 1.2 (PF1+2, thrombin generation), plasmin-antiplasmin complex (PAP, fibrinolysis), platelet factor 4 (PF4 platelet activation), and fibrinogen. Eighty-one patients were enrolled in the substudy (37 placebo vs 44 in treatment group). No difference in clinical outcome was detected, including postoperative bleeding and need for blood products transfusion. All patients showed changes of all plasma biomarkers with greater values than baseline in both groups. This reaction was attenuated significantly in the treatment group for PF1.2 (P = 0.040) and PAP (P = 0.042) values at the first intraoperative measurement. No difference between groups was detected for PF4. Methylprednisolone treatment attenuates activation of coagulation system in high-risk patients undergoing CPB surgery. Reduction of thrombin generation and fibrinolysis activation may lead to reduced blood loss after surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

1-Ene-steroid reductase of Mycobacterium sp. NRRL B-3805.

PubMed

Goren, T; Harnik, M; Rimon, S; Aharonowitz, Y

1983-12-01

The microbial enzymatic reduction of 1,4-androstadiene-3,17-dione (ADD) to 4-androstene-3,17-dione (AD), testosterone and 1-dehydrotestosterone (DHT) is described. Two reducing activities observed in washed cell suspensions and cell free extracts of Mycobacterium sp. NRRL B-3805 were found to account for these bioconversions. One was a 1-ene-steroid reductase and the other a 17-keto steroid reductase. The first reducing activity was found to appear in the soluble cell fraction whereas the latter could be precipitated by centrifugation. Maximum 1-ene-steroid reductase specific activity was achieved during the exponential growth phase of the organism and significantly increased upon induction with ADD. The 1-ene-steroid reductase was partially purified (30-fold) by ammonium sulfate fractionation, gel-filtration and ion-exchange chromatography, and was eluted from a Sephacryl S-300 column with an Mr = 115,000. The 1-ene-steroid reductase activity was NADPH-dependent and had specificity towards steroid compounds containing C-1,2 double bond with an apparent Km for ADD of 2.2 X 10(-5) M. The reverse reaction catalyzing C-1,2 dehydrogenation could not be detected in our preparations. The results suggest that in Mycobacterium sp NRRL B-3805 and B-3683 the steroid C-1,2 dehydrogenation and 1-ene reduction are two separable activities.

Crohn Disease: FDG PET/CT Before and After Initial Dose of Anti-Tumor Necrosis Factor Therapy to Predict Long-term Response.

PubMed

Epelboym, Yan; Shyn, Paul B; Chick, Jeffrey Forris Beecham; Hamilton, Matthew J; OʼConnor, Stacy D; Silverman, Stuart G; Kim, Chun K

2017-11-01

Clinical assessments of Crohn disease activity are limited in their capacity to assess treatment response to biologic therapy. The purpose of this study was to determine if changes in FDG activity between baseline PET and repeat PET performed prior to the second dose of induction anti-tumor necrosis factor (TNF) therapy correlate with clinical response. In this prospective, institutional review board-approved, Health Insurance Portability and Accountability Act-compliant pilot study of 8 adult patients with active Crohn disease, FDG activity before and 2 weeks after initiation of anti-TNF therapy was assessed using low-dose PET/CT. FDG activity was measured in the most inflamed bowel loop using an SUVratio (SUVmax/liver SUVmean). Changes in SUVratio were compared with a blinded gastroenterologist assessment of clinical response and steroid-free remission, as well as C-reactive protein (CRP), during a 12-month follow-up period. Of 8 patients, 7 showed FDG activity decline at 2 weeks, 5 of whom achieved a clinical response and steroid-free remission at 8, 26, and 52 weeks. The remaining 2 patients with FDG activity decline did not achieve a clinical response or steroid-free remission at these time points, but there were reductions in CRP. The 1 patient without FDG activity decline was a clinical nonresponder, had no reduction in CRP, and did not achieve steroid-free remission. A change in FDG activity at FDG PET/CT performed prior to the second induction dose of anti-TNF therapy has the potential to predict clinical response and steroid-free remission in patients with Crohn disease.

Enhanced cytogenetic and antineoplastic effects by the combined action of two esteric steroidal derivatives of nitrogen mustards.

PubMed

Papageorgiou, A; Nikolaropoulos, S S; Arsenou, E S; Karaberis, E; Mourelatos, D; Kotsis, A; Chryssogelou, E

1999-01-01

The authors studied the effect of two modified steroids containing different proportions (%) of alkylating agents alone or in combination on sister chromatid exchange (SCE) rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The two chemicals in mixtures enhance SCE induction and antitumor activity in a synergistic manner. The homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenyl acetic acid was found to be more effective than the homo-aza-steroidal ester of o-bis(2-chloroethyl)aminobenzoic acid in causing cytogenetic damage and antineoplastic activity. A correlation was observed between the magnitude of the SCE response and the depression of the cell proliferation index. The order of the antitumor effectiveness of the five different treatments tested coincided with the order of the cytogenetic effects they induced.

Sex steroid imbalances in the muricid Stramonita haemastoma from TBT contaminated sites.

PubMed

Rossato, M; Castro, I B; Paganini, C L; Colares, E P; Fillmann, G; Pinho, G L L

2016-04-01

Imposex incidence, organotin tissue levels, and sex steroid (free and esterified testosterone and estradiol) levels were assessed in Stramonita haemastoma from Babitonga Bay (Santa Catarina State, Southern Brazil). The imposex levels showed a reduction when compared to a previous evaluation performed in the same area. In spite of that, the detected imposex incidence indicated the occurrence of tributyltin (TBT) inputs that were still able to produce endocrine disruption in local gastropods. In addition, a high level of organotins was observed in tissues of imposexed females. These females also showed a hormonal imbalance, especially in the total testosterone/total estradiol ratio. These findings obtained under realistic field conditions suggest that the steroid pathway could be responsible by the imposex induction after exposure to TBT. In this case, measurements of sex steroid levels can be an additional evidence for monitoring sites and impose affected gastropod populations.

Etiology and treatment of hypogonadism in adolescents.

PubMed

Viswanathan, Vidhya; Eugster, Erica A

2009-12-01

Adequate functioning at all levels of the hypothalamic-pituitary-gonadal axis is necessary for normal gonadal development and subsequent sex steroid production. Deficiencies at any level of the axis can lead to a hypogonadal state. The causes of hypogonadism are heterogeneous and may involve any level of the reproductive system. This review discusses various causes of hypogonadism, describes the evaluation of hypogonadal states, and outlines treatment options for the induction of puberty in affected adolescents. Whereas some conditions are clearly delineated, the exact etiology and underlying pathogenesis of many disorders is unknown.

Update on the management of ulcerative colitis.

PubMed

Taba Taba Vakili, Sahar; Taher, Mohammad; Ebrahimi Daryani, Nasser

2012-01-01

The present treatment goals for inflammatory bowel diseases (IBD) especially ulcerative colitis (UC) include rapid induction of clinical remission, steroid-free maintenance of clinical remission, mucosal healing and improvement of quality of life in UC patients. Immunomodulators have been reserved for steroid- dependent or steroid- refractory UC patients. Among these agents, azathioprine/6-mercaptopurine should be used for maintenance of remission in quiescent UC. Calcineurin inhibitors can be prescribed as a short-term rescue therapy in steroid- refractory UC patients, but the long term efficacy of these agents remains unclear. According to retrospective studies, methotraxate is not recommended for inducing and maintaining remission in UC. Novel biological therapies targeting different specific immunological pathways continue to be developed and introduced for a variety of clinical scenarios in IBD. Infliximab is currently used for induction and maintenance therapy in patients who have moderately to severely active UC with an inadequate response to conventional agents such as aminosalicylates, corticosteroids, or immunomodulators. Other anti-TNF agents and biologic therapies are undergoing evaluation in clinical trials for their efficacy in IBD. Most patients who start biologics should continue treatment for the foreseeable future and potential consequences of discontinuation should be discussed with individual patients. Currently, data do not exist to administer biologics as first-line therapy in UC. Emerging data suggest that biologics may have the potential to prevent complications and limit disease progression. If such benefits are proven, biologics may be used in the future to modulate subclinical inflammation and to prevent the development of clinical disease.

Thymoglobulin induction in liver transplant recipients with a tacrolimus, mycophenolate mofetil, and steroid immunosuppressive regimen: a five-year randomized prospective study.

PubMed

Boillot, Olivier; Seket, Belhassen; Dumortier, Jérôme; Pittau, Gabriella; Boucaud, Catherine; Bouffard, Yves; Scoazec, Jean-Yves

2009-11-01

This randomized, comparative study assessed the long-term efficacy and tolerability of thymoglobulin (TMG) induction in 93 liver transplant patients with an initial regimen of tacrolimus (Tac), mycophenolate mofetil (MMF), and steroids. Forty-four patients were randomly allocated to the TMG+ group, and 49 patients were randomly allocated to the TMG- group. In both groups, Tac was given orally at the initial daily dose of 0.075 mg/kg twice daily, and MMF was given at the initial daily dose of 2 g/day. Steroid withdrawal was planned at 3 months after liver transplantation. The results were evaluated with respect to acute rejection incidence, patient and graft survival, graft function, and medical complications until 5 years or death for all patients. No significant differences were found between groups for the incidence of acute rejection at 5 years (11.4% versus 14.3%), 5-year patient survival (77.3% versus 87.8%), graft function, or postoperative renal function. One patient in the TMG- group underwent retransplantation. There was no difference between groups with respect to the incidence of medical complications, excepted for a higher rate of leukopenia in the TMG+ group, during the 5-year follow-up. In conclusion, the results of this prospective randomized study suggest that the addition of TMG to a triple immunosuppressive regimen (Tac, MMF, and steroids) did not modify the incidence of acute rejection episodes or long-term survival and was responsible for increased leukopenia rates.

Budesonide for the Treatment of Ulcerative Colitis

PubMed Central

Abdalla, Maisa I.; Herfarth, Hans

2016-01-01

Introduction Budesonide is a synthetic corticosteroid characterized by enhanced topical potency and limited systemic bioavailability. Its use in ulcerative colitis (UC) was limited to rectal preparations until recently when the new oral budesonide formulation incorporating the multi-matrix system technology was introduced. The purpose of this review is to evaluate the current role of oral and rectal budesonide in managing UC patients Areas Covered In this paper, we described the chemical structure and pharmacologic characteristics of the different oral and rectal budesonide preparations, provided a summary of the published trials that evaluated the efficacy and safety of budesonide in UC, and discussed the current status of its use in this population Expert Opinion Budesonide is effective in inducing remission in a subset of patients with mild-moderate UC. Nevertheless, the current evidence suggests inferiority of oral budesonide to 5-aminosalisylates (5-ASA) and systemic steroids, whereas rectal applications are comparable to other rectal steroid preparations but still inferior to rectal 5-ASA. In clinical practice, several issues need clarification including, its exact position in the line of induction agents; the role of combining budesonide and 5-ASAs; the role of combining oral and rectal budesonide; and the role of budesonide in maintenance therapy. PMID:27157244

Budesonide for the treatment of ulcerative colitis.

PubMed

Abdalla, Maisa I; Herfarth, Hans

2016-08-01

Budesonide is a synthetic corticosteroid characterized by enhanced topical potency and limited systemic bioavailability. Its use in ulcerative colitis (UC) was limited to rectal preparations until recently when the new oral budesonide formulation incorporating the multi-matrix system technology was introduced. The purpose of this review is to evaluate the current role of oral and rectal budesonide in managing UC patients Areas covered: In this paper, we described the chemical structure and pharmacologic characteristics of the different oral and rectal budesonide preparations, provided a summary of the published trials that evaluated the efficacy and safety of budesonide in UC, and discussed the current status of its use in this population Expert opinion: Budesonide is effective in inducing remission in a subset of patients with mild-moderate UC. Nevertheless, the current evidence suggests inferiority of oral budesonide to 5-aminosalisylates (5-ASA) and systemic steroids, whereas rectal applications are comparable to other rectal steroid preparations, but still inferior to rectal 5-ASA. In clinical practice, several issues need clarification including, its exact position in the line of induction agents; the role of combining budesonide and 5-ASAs; the role of combining oral and rectal budesonide; and the role of budesonide in maintenance therapy.

Dissolution of steroid crystals in a nematic droplet: effect of rotation

NASA Astrophysics Data System (ADS)

Gvozdovskyy, I. A.; Terenetskaya, Irina P.; Reshetnyak, Victor Y.

2003-12-01

The nematic liquid crystals (LCs) can be converted into cholesteric LCs by different chiral dopants. For the first time the dynamics of a cholesteric phase induction was investigated on dissolution of the single steroid crystal (vitamin D isomers and relative compounds) at the nematic droplet and the new effect of the crystal rotation has been discovered. In all cases the correlation between the rotation direction and screw sense of the cholesteric helix was found. A theoretical model and interpretation of the rotation effect has been proposed.

Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia.

PubMed

Gonzalez-Ramella, O; Ortiz-Lazareno, P C; Jiménez-López, X; Gallegos-Castorena, S; Hernández-Flores, G; Medina-Barajas, F; Meza-Arroyo, J; Jave-Suárez, L F; Lerma-Díaz, J M; Sánchez-Zubieta, F; Bravo-Cuellar, A

2016-04-01

Pentoxifylline (PTX) has been shown to increase chemotherapy-induced apoptosis. A clinical trial was developed to evaluate the effect of the addition of PTX to the induction steroid window phase in children with acute lymphoblastic leukemia (ALL). Thirty-two children were enrolled on this study. Children with a new diagnosis of ALL were randomly assigned to receive prednisone (PRD) 40 mg/m(2)/day only during the 7-day treatment pre-phase (PRD group, 11 patients) or to receive PRD with PTX (10 mg/kg/day) (PTX group, 11 patients); the control group included children with normal bone marrow (10 patients). Bone marrow aspiration (BMA) was performed at diagnosis (day -7) in all groups, and at day 0 (end of PRD window) for patients with ALL (PRD and PTX groups). Apoptosis was evaluated by flow cytometry (FC) using Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) stains. Statistical analysis was performed using the Mann-Whitney U test. Apoptotic index at day -7 was similar in all groups. However, at day 0 post-treatment, apoptosis was significantly higher in the PTX group than in the PRD group (p < 0.001). There were no serious adverse effects associated with PTX. PTX potentiates blast apoptosis induced by PRD in children with ALL during steroid window phase.

Hochu-ekki-to Treatment Improves Reproductive and Immune Modulation in the Stress-Induced Rat Model of Polycystic Ovarian Syndrome.

PubMed

Park, Eunkuk; Choi, Chun Whan; Kim, Soo Jeong; Kim, Yong-In; Sin, Samkee; Chu, Jong-Phil; Heo, Jun Young

2017-06-13

The traditional herbal medicine, Hochu-ekki-to, has been shown to have preventive effects on viral infection and stress. This study aimed to evaluate the clinical effects of Hochu-ekki-to on two stress-related rat models of polycystic ovarian syndrome. Female Sprague-Dawley rats were divided into control and treatment groups, the latter of which were subjected to stress induced by exposure to adrenocorticotropic hormone (ACTH) or cold temperatures. After these stress inductions, rats were orally treated with dissolved Hochu-ekki-to once per day for 7 days. Rats subjected to the two different stressors exhibited upregulation of steroid hormone receptors (in ovaries) and reproductive hormones (in blood), and consequent stimulation of abnormal follicle development accompanied by elevation of Hsp 90 expression (in ovaries). Treatment with Hochu-ekki-to for 7 days after stress induction increased immune functions, reduced the stress-induced activation of Hsp 90, and normalized the levels of the tested steroid hormone receptors and reproductive hormones. Our findings suggest that stress stimulations may promote the activation of Hsp 90 via the dysregulation of steroid hormone receptors and reproductive hormones, but that post-stress treatment with Hochu-ekki-to improves reproductive and immune functions in the ovaries of stressed rats.

Induction of sister chromatid exchanges and cell division delays in human lymphocytes by the anti-tumour agent homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenoxy acetic acid.

PubMed

Tselepi, M R; Demopoulos, N A; Catsoulacos, P

1989-09-01

3 beta-Hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl) aminophenoxyacetate (NSC 294859) is a new modified steroidal alkylating agent. This compound was given by i.p. administration to mice bearing different types of tumour. It was found to exhibit good activity in L1210 and P388 leukaemias with maintenance of activity against advanced tumours. The treatment of colon 26 tumour and B16 melanoma resulted in positive antineoplastic activity. The drug was not shown to be active in a melphalan-resistant P388 line. In this study, NSC 294859 was found to be effective in causing statistically significant increases in sister-chromatid exchange (SCE) rates and cell division delays. The alkylating agent component, p-bis-(2-chloroethyl)aminophenoxy acetic acid, was shown to be less effective than the parent compound, while the modified steroid component, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam, showed no effect. There were no statistically significant differences among donors regarding the induction of SCEs and replication indices (RIs) for the compounds tested.

Induction prednisone dosing for childhood nephrotic syndrome: how low should we go?

PubMed

Sibley, Matthew; Roshan, Abishek; Alshami, Alanoud; Catapang, Marisa; Jöbsis, Jasper J; Kwok, Trevor; Polderman, Nonnie; Sibley, Jennifer; Matsell, Douglas G; Mammen, Cherry

2018-05-22

Historically, children with nephrotic syndrome (NS) across British Columbia (BC), Canada have been cared for without formal standardization of induction prednisone dosing. We hypothesized that local historical practice variation in induction dosing was wide and that children treated with lower doses had worse relapsing outcomes. This retrospective cohort study included 92 NS patients from BC Children's Hospital (1990-2010). We excluded secondary causes of NS, age < 1 year at diagnosis, steroid resistance, and incomplete induction due to early relapse. We explored cumulative induction dose and defined dosing quartiles. Relapsing outcomes above and below each quartile threshold were compared including total relapses in 2 years, time to first relapse, and proportions developing frequently relapsing NS (FRNS) or starting a steroid-sparing agent (SSA). Cumulative prednisone was widely distributed with approximated median, 1st, and 3rd quartile doses of 2500, 2000, and 3000 mg/m 2 respectively. Doses ≤ 2000 mg/m 2 showed significantly higher relapses (4.2 vs 2.7), shorter time to first relapse (61 vs 175 days), and higher SSA use (36 vs 14%) compared to higher doses. Doses ≤ 2500 mg/m 2 also showed significantly more relapses (3.9 vs 2.2), quicker first relapse (79 vs 208 days), and higher FRNS (37 vs 17%) and SSA use (28 vs 11%). Relapsing outcomes lacked statistical difference in ≤ 3000 vs > 3000 mg/m 2 doses. Results strongly justify our development of a standardized, province-wide NS clinical pathway to reduce practice variation and minimize under-treatment. The lowest induction prednisone dosing threshold to minimize future relapsing risks is likely between 2000 and 2500 mg/m 2 . Further prospective studies are warranted.

One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multicentre cohort study.

PubMed

Amiot, A; Serrero, M; Peyrin-Biroulet, L; Filippi, J; Pariente, B; Roblin, X; Buisson, A; Stefanescu, C; Trang-Poisson, C; Altwegg, R; Marteau, P; Vaysse, T; Bourrier, A; Nancey, S; Laharie, D; Allez, M; Savoye, G; Moreau, J; Vuitton, L; Viennot, S; Aubourg, A; Pelletier, A-L; Bouguen, G; Abitbol, V; Gagniere, C; Bouhnik, Y

2017-08-01

We recently showed that vedolizumab is effective in patients with Crohn's disease (CD) and ulcerative colitis (UC) with prior anti-TNF failure in a multicentre compassionate early-access programme before marketing authorisation was granted to vedolizumab. To assess effectiveness and safety of vedolizumab at week 54 in patients UC and CD. Between June and December 2014, 173 patients with Crohn's disease (CD) and 121 with ulcerative colitis (UC) were treated with vedolizumab induction therapy. Among those 294 patients, 272 completed the induction period and were evaluated at the week 14 visit (161 patients with CD and 111 with UC). Disease activity was assessed using the Harvey-Bradshaw Index for CD and the partial Mayo Clinic score for UC. The primary outcome was steroid-free clinical remission at week 54. At week 54, steroid-free clinical remission rates at week 54 were 27.2% and 40.5% in patients with CD and UC respectively. In addition, the sustained steroid-free clinical remission (from week 14 to week 54) rates were 8.1% and 19.0% respectively. No deaths were observed. Severe adverse events occurred in 17 (7.2%) patients, including six (2.5%) leading to vedolizumab discontinuation. Vedolizumab is able to maintain steroid-free clinical remission in up to one-third of patients with UC and CD at week 54 with a reasonable safety profile. A significant number of patients experienced loss of response during the first year of treatment, particularly in patients with CD. © 2017 John Wiley & Sons Ltd.

Treatment of inflammatory bowel disease: A review of medical therapy

PubMed Central

Kozuch, Patricia L; Hanauer, Stephen B

2008-01-01

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC. PMID:18200659

Etiology and treatment of hypogonadism in adolescents.

PubMed

Viswanathan, Vidhya; Eugster, Erica A

2011-10-01

Adequate functioning at all levels of the hypothalamic-pituitary-gonadal axis is necessary for normal gonadal development and subsequent sex steroid production. Deficiencies at any level of the axis can lead to a hypogonadal state. The causes of hypogonadism are heterogeneous and may involve any level of the reproductive system. This review discusses various causes of hypogonadism, describes the evaluation of hypogonadal states, and outlines treatment options for the induction of puberty in affected adolescents. Whereas some conditions are clearly delineated, the exact etiology and underlying pathogenesis of many disorders is unknown. Copyright © 2011 Elsevier Inc. All rights reserved.

TAC-TIC use of tacrolimus-based regimens in lupus nephritis

PubMed Central

Bredewold, Obbo W; Trompet, Stella; Huizinga, Tom W J; Rabelink, Ton J; de Craen, Anton J M; Teng, Y K Onno

2016-01-01

Current guidelines do not mention tacrolimus (TAC) as a treatment option and no consensus has been reported on the role of TAC in lupus nephritis (LN). The present study aimed to guide clinical judgement on the use of TAC in patients with LN. A meta-analysis was performed for clinical studies investigating TAC regimens in LN on the basis of treatment target (induction or maintenance), concomitant immunosuppression and quality of the data. 23 clinical studies performed in patients with LN were identified: 6 case series, 9 cohort studies, 2 case-control studies and 6 randomised controlled trials (RCTs). Of the 6 RCTs, 5 RCTs investigated TAC regimens as induction treatment and 1 RCT as maintenance treatment. Five RCTs investigated TAC in combination with steroids and 2 TAC with mycophenolate plus steroids. All RCTs were performed in patients of Asian ethnicity. In a meta-analysis, TAC regimens achieved a significantly higher total response (relative risk (RR) 1.23, 95% CI 1.12 to 1.34, p<0.05) and significantly higher complete response (RR 1.48, 95% CI 1.23 to 1.77, p<0.05). The positive outcome was predominantly defined by the largest RCT investigating TAC with mycophenolate plus steroids. Regarding safety, the occurrence of leucopoenia was significantly lower, while the occurrence of increased creatine was higher. Clinical studies on TAC regimens for LN are limited to patients of Asian ethnicity and hampered by significant heterogeneity. The positive results on clinical efficacy of TAC as induction treatment in LN cannot be extrapolated beyond Asian patients with LN. Therefore, further confirmation in multiethnic, randomised trials is mandatory. Until then, TAC can be considered in selected patients with LN. PMID:28123768

Single-shot antithymocyte globulin (ATG) induction for pancreas/kidney transplantation: ATG-Fresenius versus Thymoglobulin.

PubMed

Schulz, T; Papapostolou, G; Schenker, P; Kapischke, M

2005-03-01

Single-shot antithymocyte globulin (ATG) prior to reperfusion followed by tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisolone (PRD) is an established induction therapy in simultaneous pancreas kidney transplant (SPK) recipients. We retrospectively analyzed 6-month data from 105 patients who received their first SPK. From January 1996 to December 2000, ATG-Fresenius was used. Since January 2001, Thymoglobulin has been administered. In the first group, 58 patients were treated with ATG-Fresenius (4-6 mg/kg body weight). In the second group, 47 patients received Thymoglobulin (1.5-2.5 mg/kg body weight). HLA-mismatch was comparable. After an observation period of 6 months, patients, kidney, and pancreas graft survival is 98.3%, 96.6%, and 93.1% in group I and 97.9%, 97.9%, and 85.1% in group II, respectively. In each group, one death with functioning graft (DWFG) was observed. Twenty (34.5%) acute rejection episodes (AR) were observed (18 patients) in group I. They were treated with steroids (n = 16) or steroids/OKT3 (n = 4). One kidney graft failure was observed due to rejection and one due to DWFG. Four pancreas grafts were lost (thrombosis, n = 2; AR, n = 1; DWFG, n = 1). In group II, 15 AR (31.9%) were seen in 12 patients and were treated with steroids (n = 12), steroids/ATG (n = 1), or steroids/OKT3 (n = 2). Seven pancreas (thrombosis, n = 5; rejection, n = 1; DWFG, n = 1) and one kidney (DWFG, n = 1) graft losses occurred. These data clearly establish that single-shot ATG prior to reperfusion, followed by TAC, MMF, and PRD results in a low incidence of AR (34.5% in group I and 31.9% in group II) after SPK. Only 6.9% (group I) and 6.4% (group II) of the patients received antibodies for rejection treatment.

Improving Performance Efficiency in the Warfighter

DTIC Science & Technology

2007-12-01

knockout teaches us about GnRH activity: hypogonadal mice and neuronal grafts. Hormones and Behavior 31:212-220. 20. Wu, T.J., M.J. Gibson, A.J...Silverman (1996) FOS expression in grafted gonadotropin- releasing hormone neurons in the hypogonadal mouse: mating and steroid induction. Journal of

Marked elevation of serum macrophage migration inhibitory factor levels in patients with pemphigus vulgaris.

PubMed

Namazi, Mohammad Reza; Fallahzadeh, Mohammad Kazem; Shaghelani, Hassan; Kamali-Sarvestani, Eskandar

2010-02-01

There is ample evidence for involvement of macrophage migration inhibitory factor (MIF) in autoimmune and inflammatory diseases. The aim of this study was to determine whether MIF levels were raised in the sera of patients with pemphigus vulgaris (PV). Serum MIF levels were measured using ELISA method in 22 patients with active PV and 21 age- and sex-matched healthy controls and the results were compared with each other. The mean serum MIF levels was significantly higher in PV patients than in control subjects (11.99 +/- 1.63 pg/m vs. 1.83 +/- 0.22 pg/ml; P-value = 0.0001). Elevated MIF levels in the sera of PV patients could participate in disease induction by activation of T cells as well as induction of autoantibody production by B cells. Given that MIF counter-regulates the effects of steroids, MIF antagonists may prove to be very effective, novel steroid-sparing agents for this life-threatening conundrum.

Synergistic induction of cytogenetic damage by the homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid in combination with caffeine in human lymphocytes in vitro and in Ehrlich ascites tumour cells in vivo.

PubMed

Petrou, C; Mourelatos, D; Dozi-Vassiliades, J; Catsoulacos, P

1990-02-01

We studied the effects of caffeine alone or in combination with homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid (ASE, NSC 290205) on the frequency of SCEs and lymphocyte proliferation kinetics. Caffeine was found to act synergistically with ASE on the induction of SCEs when the two components were administered in combination. Caffeine was also found to act synergistically with ASE in inducing cell-division delays. Enhanced cytogenetic damage by ASE was observed when Ehrlich ascites tumour cells (EAT cells) were exposed in vivo to caffeine. ASE alone or in combination with caffeine caused a dose-dependent increase in SCE rates and cell-division delays. SCEs were demonstrated in EAT-bearing mice, by the i.p. injection of BrdUrd adsorbed onto activated charcoal, 1 h after the i.p. injection of ASE and/or caffeine.

Synergistic antineoplastic and cytogenetic effects by the combined action of two homo-aza-steroidal esters of nitrogen mustards on P388 and L1210 leukaemias in vivo and in vitro.

PubMed

Nikolaropoulos, S; Tsavdaridis, D; Arsenou, E; Papageorgiou, A; Karaberis, E; Mourelatos, D

2000-01-01

In order to increase the damaging effects on specific DNA sequences and decrease the subsequent toxicity, the use of homo-aza-steroidal esters of nitrogen mustards is already known. Two specific homo-aza-steroidal esters were mixed at different proportions and the resultant final mixtures were tested in vivo and in vitro. The effects of these on P388 and L1210 leukaemias, on SCE rates and on human lymphocyte proliferation kinetics were studied. The results demonstrate that the combined substances enhanced SCE induction (p < 0.05) and antitumour activity (p < 0.02) in a synergistic manner. A correlation was observed (p < 0.001) between the magnitude of the SCE response and the depression of the cell proliferation index.

No-load sirolimus with tacrolimus and steroids is safe and effective in renal transplantation.

PubMed

Tellis, V; Schechner, R; Mallis, M; Rosegreen, S; Glicklich, D; Moore, N; Greenstein, S

2005-03-01

Basiliximab (BX) induction, tacrolimus (TAC), and steroids have sharply reduced acute cellular rejection at our institution. However, late graft loss has continued, for which sirolimus (SL) was introduced into the protocol. From July 1, 2001 to December 31, 2003, 152 live donor (LD) renal transplant recipients received TAC (level 15 to 20 ng/mL) and steroids, with BX induction. One hundred twenty-two patients (Group 1) received SL (3 mg/d African-americans; 2 mg/d for others) starting on days 2 and 3. The SL level was adjusted to 8 to 10 ng/d, usually by weeks 3 to 4 posttransplant. The TAC doses were then progressively reduced. Records were reviewed for demographics, immunosuppressive drug levels, serum cholesterol and blood pressure, and complications. Graft and patient survival rates were calculated. Comparison was made to 53 LD recipients transplanted from July 1, 1998, to June 30, 2001 (Group 2) receiving BX, steroids and TAC, without SL. Recipients of deceased donor kidneys were excluded because of variability in kidney quality, ischemic time, and patient management. Demographics were similar between groups: African Americans, 25% to 35%; mean age 36 years; mean HLA mismatch 3.7. Wound problems and infection were minimal in both groups. Mean serum creatinine and cholesterol and systolic and diastolic blood pressure measured periodically up to 1 year were similar, as was the incidence of rejection. In 25% of patients, SL was discontinued. Gradual introduction of SL appears to be associated with minimal wound problems. With more aggressive reduction in TAC, better renal function, and better long-term graft survival may be attainable. We currently lower TAC levels to 5 ng/mL by 3 months.

Interactions of the interferon system with cellular metabolism

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1986-01-01

The results of studies concerning the interaction of the interferon (Inf) system with the activities of carcinogens, tumor promoters, and cytochrome P-450 are presented. The results show that the addition of a tumor promoter (TPA or 4-O-methyl-TPA) to a tissue culture enhances virus-induced Inf-gamma production, suggesting a potential value of tumor promoters in the biosynthesis of commercial Inf. On the other hand, the carcinogens were reported to inhibit the induction of Inf-alpha/beta in cultured cells and in intact animals (with no effect on the administered or preformed Inf). The demonstration of a correlation between the carcinogenic potential of a compound and its inhibitive effect on Inf production suggests a possible use of the Inf production assay in the evaluation of the carcinogenicity of chemicals. In addition, it was shown that the induction of Inf-alpha/beta as well as the administration of this Inf depresses the levels of rat liver cytochrome P-450 which is responsible for binding lipophilic drugs, steroids, and carcinogens, thus increasing the toxicity of the respective chemical.

ALTERED SERUM SEX STEROIDS AND VITELLOGENIN INDUCTION IN WALLEYE (STIZOSTEDION VITREUM) COLLECTED NEAR A METROPOLITAN SEWAGE TREATMENT PLANT

EPA Science Inventory

Feral, male walleye collected from the Mississippi River below the St. Paul metropolitan sewage treatment plant (STP) contained measurable levels of the estrogen-inducible, female egg protein, vitellogenin. These same fish showed significantly decreased serum androgen and signifi...

Brain feminization requires active repression of masculinization via DNA methylation

PubMed Central

Nugent, Bridget M.; Wright, Christopher L.; Shetty, Amol C.; Hodes, Georgia E.; Lenz, Kathryn M.; Mahurkar, Anup; Russo, Scott J.; Devine, Scott E.; McCarthy, Margaret M.

2015-01-01

The developing mammalian brain is destined for a female phenotype unless exposed to gonadal hormones during a perinatal sensitive period. It has been assumed that the undifferentiated brain is masculinized by direct induction of transcription by ligand-activated nuclear steroid receptors. We found that a primary effect of gonadal steroids in the highly sexually-dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression. Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in females. Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice. RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females. Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation. PMID:25821913

Resolution of Graves' disease after renal transplantation.

PubMed

Lee, Yvonne; Butani, Lavjay; Glaser, Nicole; Nguyen, Stephanie

2016-06-01

We report a case of an adolescent boy with Down's syndrome and ESRD on hemodialysis who developed mild Graves' disease that was not amenable to radioablation, surgery, or ATDs. After 14 months of observation without resolution of Graves' disease, he successfully received a DDRT with a steroid minimization protocol. Thymoglobulin and a three-day course of steroids were used for induction and he was started on tacrolimus, MMF, and pravastatin for maintenance transplant immunosuppression. One month after transplantation, all biochemical markers and antibody profiling for Graves' disease had resolved and remain normal one yr later. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Is the efficacy of successful infliximab induction therapy maintained for one year lasting without retreatment in different behavior types of Crohn's disease?

PubMed

Molnár, T; Farkas, K; Miheller, P; Nyári, T; Szepes, Z; Herszényi, L; Müzes, Gy; Nagy, F; Tulassay, Zs; Wittmann, T

2008-12-01

The high cost of infliximab inhibits the regular retreatment of all patients in Hungary with Crohn's disease (CD) after beneficial induction therapy. This study is set out to evaluate the medium-term efficacy of induction therapy with infliximab without retreatment in CD patients with chronic activity and/or fistulae refractory to conventional therapy. A retrospective 1-year review was undertaken of all CD patients with successfully induced remission or fistula closure with 3 infusions of infliximab. Infliximab was administered in a dose of 5 mg/kg 3 times, in weeks 0, 2 and 6. Clinical remission was defined as symptom resolution and an estimated Crohn's Disease Activity Index (CDAI) <150 and complete fistula closure. We evaluated the clinical response, the estimated CDAI, the number of draining fistulae, the dosages of steroid and immunosuppressive drugs at 6 and 12 months after the last infusion, and the needs for hospitalization and surgical intervention during this period. Breslow (Generalized Wilcoxon) test was used as the statistical method. The data of the 50 patients (19 luminal, 31 fistulizing disease; average age 29. 3 [13-59] years, disease localization: 23 colon, 13 ileum, 13 ileocolon, 1 duodenum) were suitable for analysis. Infliximab induction therapy without retreatment resulted in a beneficial effect lasting for at least 1 year in 22 of the 50 patients (44%). 11 of the 19 patients (57.9%) with luminal disease remained in steroid-free complete remission, while the fistulae persisted closed in only 11 of the 31 patients (35.5%) (p<0.05). Infliximab induction therapy alone may result in sustained remission mainly in patients with luminal disease. These results suggest the need for maintenance therapy with infliximab after successful therapy induction in patients with fistulae, while luminal CD patients could possibly participate in regular retreatment only if needed. If these data are confirmed, this modification of the therapeutic procedure could well increase the cost-effectiveness of infliximab.

Birdsong and the neural production of steroids

PubMed Central

Remage-Healey, Luke; London, Sarah E.; Schinger, Barney A.

2009-01-01

The forebrain circuits involved in singing and audition (the ‘song system’) in songbirds exhibit a remarkable capacity to synthesize and respond to steroid hormones. This review considers how local brain steroid production impacts the development, sexual differentiation, and activity of song system circuitry. The songbird forebrain contains all of the enzymes necessary for the de novo synthesis of steroids - including neuroestrogens - from cholesterol. Steroid production enzymes are found in neuronal cell bodies, but they are also expressed in pre-synaptic terminals in the song system, indicating a novel mode of brain steroid delivery to local circuits. The song system expresses nuclear hormone receptors, consistent with local action of brain-derived steroids. Local steroid production also occurs in brain regions that do not express nuclear hormone receptors, suggesting a non-classical mode-of-action. Recent evidence indicates that local steroid levels can change rapidly within the forebrain, in a manner similar to traditional neuromodulators. Lastly, we consider growing evidence for modulatory interactions between brain-derived steroids and neurotransmitter/neuropeptide networks within the song system. Songbirds have therefore emerged as a rich and powerful model system to explore the neural and neurochemical regulation of social behavior. PMID:19589382

Steroid hormone receptor status defines the MMTV promoter chromatin structure in vivo.

PubMed

Archer, T K; Fryer, C J; Lee, H L; Zaniewski, E; Liang, T; Mymryk, J S

1995-06-01

The ability to respond to small signalling molecules such as steroid hormones is important for many physiological processes. Steroid hormones act through a group of high affinity receptors that regulate transcription by binding to hormone response elements (HREs) located within the promoters of target genes, which themselves are organized with nuclear proteins to form chromatin. To dissect the mechanisms(s) of steroid hormone action we have used the steroid inducible mouse mammary tumor virus (MMTV) promoter as a model system. The MMTV promoter is assembled into a phased array of nucleosomes that are specifically positioned in rodent cells. Induction of transcription by glucocorticoids is accompanied by the appearance of a hypersensitive region in the proximal promoter which allows the hormone dependent assembly of a preinitiation complex including transcription factors such as nuclear factor 1 (NF1) and the octamer transcription factor (OTF). Surprisingly, when introduced by transient transfection, the progesterone receptor (PR) is unable to activate this promoter in vivo, a finding that may result from its inability to alter MMTV promoter chromatin. In an attempt to investigate the failure of the PR to activate the promoter, we have stably introduced the MMTV promoter into human T47D breast cancer cells that express high levels of the PR. In contrast to what has been observed previously in rodent cells, the MMTV templates resident in human breast cancer cells adopt a novel and constitutively open chromatin structure. The constitutively open chromatin structure is accompanied by the hormone independent loading of transcription factors including the PR and NF1. In T47D cells that stably express the glucocorticoid receptor, the MMTV promoter responds to glucocorticoids, but not progestins, and displays glucocorticoid induced restriction enzyme hypersensitivity and transcription factor loading. These findings suggest that the organization of the MMTV chromatin structure is dependent upon the cell type and receptor status of the recipient cell into which the MMTV promoter is stably introduced.

Predictive risk factors for failure to induction therapy of lupus nephritis in a cohort of Colombian patients.

PubMed

Pinto Peñaranda, Luis Fernando; Castro Mercado, Inis Lizeth; Duque Caballero, Vladimir; Márquez Hernández, Javier Darío; Velásquez Franco, Carlos Jaime

2014-01-01

To determine the predictors of failure to obtain remission after induction therapy for proliferative lupus nephritis in a group of northwestern Colombian patients. A retrospective study was conducted. We included patients with systemic lupus erythematosus according to the American College of Rheumatology criteria who had nephritis confirmed by renal biopsy. We followed 84 patients: 88.1% female, and 11.9% male. The mean age at diagnosis of systemic lupus erythematosus was 27.5±11.8 years (9-70). The average time between diagnosis of systemic lupus erythematosus and proliferative nephritis onset was 13.6 months (0-168). Histopathologic type: iv (78.57%), iii (15.47%), iii-iv/v (5.96%). Activity index: 6.7±4.6. Chronicity index: 2±2.7. 24-hour proteinuria (mg): 6,164 (130-18,100). Baseline creatinine: 1.14 mg/dL (0.43-7.4). Induction therapy: Steroids (100%), cyclophosphamide (76.2%) and mycophenolate mofetil (23.8%). At six months, 56% of individuals failed to achieve partial or complete remission. Predictors of failure to induction therapy were, in accordance with the bivariate analysis (OR; 95%CI): creatinine level more than 1.2mg/dL (10.8; 3.18-36.84; P<.005), nephrotic range proteinuria (11.9; 3.09-45.8; P<.001), and an activity index above 8 (5.04; 1.7-14.3; P<.001). In the multivariate analysis, only baseline creatinine higher than 1.2mg/dL (10.92; 2.65-45.02; P=.001), and nephrotic range proteinuria (9.81; 1.85-52.04; P=.007) were significant. A significant percentage of Colombian patients fail to achieve remission of proliferative lupus nephritis after six months of treatment. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Use of orbital floor steroids in the management of patients with uniocular non-necrotising scleritis.

PubMed Central

Hakin, K N; Ham, J; Lightman, S L

1991-01-01

Most cases of non-necrotising scleritis can be successfully treated with non-steroidal anti-inflammatory drugs. If these are ineffective, then high-dose systemic corticosteroids, with all their attendant side-effects, are usually required. We have used orbital floor injections of depot steroid in the management of nine patients with non-necrotising scleritis in an attempt to avoid the use of systemic steroids, or to allow the dose of steroids to be reduced while maintaining disease control. A temporary reduction in inflammation was achieved in all cases, which allowed the use of systemic steroids to be avoided altogether in two patients and delayed in the others. Non-steroidal anti-inflammatory drugs and systemic corticosteroids remain the mainstay of treatment for non-necrotising scleritis, but orbital floor injections may be a useful adjunct in certain cases. Images PMID:2043574

[Clinical Evaluation of Diagnostic and Treatment Protocol of Idiopathic Retroperitoneal Fibrosis Incorporating Consideration of Possible IgG4-Related Disease].

PubMed

Iyoki, Takaya; Maehana, Takeshi; Tanaka, Toshiaki; Yamamoto, Motohisa; Takahashi, Hiroki; Masumori, Naoya

2017-11-01

About half of idiopathic retroperitoneal fibrosis might be classified as a IgG4-related disease, a newly characterized disease that is especially known to be sensitive to steroid therapy. We developed a new protocol for diagnosis and treatment of retroperitoneal fibrosis, which included aggressive diagnosis of IgG4- related disease. We retrospectively reviewed 22 cases with idiopathic retroperitoneal fibrosis that were diagnosed and treated according to our protocol. Of them, 10 patients (45.5%) had no evidence of IgG4- related disease (non-IgG4RD group), whereas 12 patients (54.5%) were diagnosed with IgG4-related disease (IgG4RD group). All patients received steroid therapy, and 13 patients (59.1%) underwent ureteral stenting or received prednisolone (PNS). There was no severe adverse event and planned steroid therapy was completed in all patients. In principle, maintenance steroid therapy was continued after induction therapy in the IgG4RD group, whereas steroid therapy was discontinued in the non-IgG4RD group. Regression of retroperitoneal plaque was achieved in all 22 patients. Four (57.1%) out of 7 patients and 3 (50.0%) out of 6 patients achieved freedom from ureteral stent or PNS in the non-IgG4RD group and IgG4RD group, respectively. All 3 patients with PNS became catheter-free after treatment, whereas only 4 (40.0%) of the 10 patients withureteral stent could become stent-free. Steroid therapy could be discontinued in 7 patients (70.0%) in the non-IgG4RD group. The results of this study suggest that similar efficacy of steroid therapy can be expected in the non-IgG4RD group and IgG4RD group.

Steroid profiling in H295R cells to identify chemicals potentially disrupting the production of adrenal steroids.

PubMed

Strajhar, Petra; Tonoli, David; Jeanneret, Fabienne; Imhof, Raphaella M; Malagnino, Vanessa; Patt, Melanie; Kratschmar, Denise V; Boccard, Julien; Rudaz, Serge; Odermatt, Alex

2017-04-15

The validated OECD test guideline 456 based on human adrenal H295R cells promotes measurement of testosterone and estradiol production as read-out to identify potential endocrine disrupting chemicals. This study aimed to establish optimal conditions for using H295R cells to detect chemicals interfering with the production of key adrenal steroids. H295R cells' supernatants were characterized by liquid chromatography-mass spectrometry (LC-MS)-based steroid profiling, and the influence of experimental conditions including time and serum content was assessed. Steroid profiles were determined before and after incubation with reference compounds and chemicals to be tested for potential disruption of adrenal steroidogenesis. The H295R cells cultivated according to the OECD test guideline produced progestins, glucocorticoids, mineralocorticoids and adrenal androgens but only very low amounts of testosterone. However, testosterone contained in Nu-serum was metabolized during the 48h incubation. Thus, inclusion of positive and negative controls and a steroid profile of the complete medium prior to the experiment (t=0h) was necessary to characterize H295R cells' steroid production and indicate alterations caused by exposure to chemicals. Among the tested chemicals, octyl methoxycinnamate and acetyl tributylcitrate resembled the corticosteroid induction pattern of the positive control torcetrapib. Gene expression analysis revealed that octyl methoxycinnamate and acetyl tributylcitrate enhanced CYP11B2 expression, although less pronounced than torcetrapib. Further experiments need to assess the toxicological relevance of octyl methoxycinnamate- and acetyl tributylcitrate-induced corticosteroid production. In conclusion, the extended profiling and appropriate controls allow detecting chemicals that act on steroidogenesis and provide initial mechanistic evidence for prioritizing chemicals for further investigations. Copyright © 2017 Elsevier B.V. All rights reserved.

Differential Responses of Brain, Gonad and Muscle Steroid Levels to Changes in Social Status and Sex in a Sequential and Bidirectional Hermaphroditic Fish

PubMed Central

Lorenzi, Varenka; Earley, Ryan L.; Grober, Matthew S.

2012-01-01

Sex steroids can both modulate and be modulated by behavior, and their actions are mediated by complex interactions among multiple hormone sources and targets. While gonadal steroids delivered via circulation can affect behavior, changes in local brain steroid synthesis also can modulate behavior. The relative steroid load across different tissues and the association of these levels with rates of behavior have not been well studied. The bluebanded goby (Lythrypnus dalli) is a sex changing fish in which social status determines sexual phenotype. We examined changes in steroid levels in brain, gonad and body muscle at either 24 hours or 6 days after social induction of protogynous sex change, and from individuals in stable social groups not undergoing sex change. For each tissue, we measured levels of estradiol (E2), testosterone (T) and 11-ketotestosterone (KT). Females had more T than males in the gonads, and more E2 in all tissues but there was no sex difference in KT. For both sexes, E2 was higher in the gonad than in other tissues while androgens were higher in the brain. During sex change, brain T levels dropped while brain KT increased, and brain E2 levels did not change. We found a positive relationship between androgens and aggression in the most dominant females but only when the male was removed from the social group. The results demonstrate that steroid levels are responsive to changes in the social environment, and that their concentrations vary in different tissues. Also, we suggest that rapid changes in brain androgen levels might be important in inducing behavioral and/or morphological changes associated with protogynous sex change. PMID:23251444

Sources, mechanisms, and fate of steroid estrogens in wastewater treatment plants: a mini review.

PubMed

Ting, Yien Fang; Praveena, Sarva Mangala

2017-04-01

Steroid estrogens, such as estrone (E 1 ), 17β-estradiol (E 2 ), estriol (E 3 ), and 17α-ethinylestradiol (EE 2 ), are natural and synthetic hormones released into the environment through incomplete sewage discharge. This review focuses on the sources of steroid estrogens in wastewater treatment plants (WWTPs). The mechanisms and fate of steroid estrogens throughout the entire wastewater treatment system are also discussed, and relevant information on regulatory aspects is given. Municipal, pharmaceutical industry, and hospitals are the main sources of steroid estrogens that enter WWTPs. A typical WWTP comprises primary, secondary, and tertiary treatment units. Sorption and biodegradation are the main mechanisms for removal of steroid estrogens from WWTPs. The fate of steroid estrogens in WWTPs depends on the types of wastewater treatment systems. Steroid estrogens in the primary treatment unit are removed by sorption onto primary sludge, followed by sorption onto micro-flocs and biodegradation by microbes in the secondary treatment unit. Tertiary treatment employs nitrification, chlorination, or UV disinfection to improve the quality of the secondary effluent. Activated sludge treatment systems for steroid estrogens exhibit a removal efficiency of up to 100%, which is higher than that of the trickling filter treatment system (up to 75%). Moreover, the removal efficiency of advance treatment systems exceeds 90%. Regulatory aspects related to steroid estrogens are established, especially in the European Union. Japan is the only Asian country that implements a screening program and is actively involved in endocrine disruptor testing and assessment. This review improves our understanding of steroid estrogens in WWTPs, proposes main areas to be improved, and provides current knowledge on steroid estrogens in WWTPs for sustainable development.

Sex and Stress Hormone Influences on the Expression and Activity of Brain-Derived Neurotrophic Factor

PubMed Central

Carbone, David L.; Handa, Robert J.

2012-01-01

The neurotrophin, brain-derived neurotrophic factor (BDNF), is recognized as a key component in the regulation of central nervous system ontogeny, homeostasis and adult neuroplasticity. The importance of BDNF in central nervous system development and function is well documented by numerous reports from animal studies linking abnormal BDNF signaling to metabolic disturbances and anxiety or depressive-like behavior. Despite the diverse roles for BDNF in nearly all aspects of central nervous system physiology, the regulation of BDNF expression, as well as our understanding of the signaling mechanisms associated with this neurotrophin, remains incomplete. However, links between sex hormones such as estradiol and testosterone, as well as endogenous and synthetic glucocorticoids, have emerged as important mediators of BDNF expression and function. Examples of such regulation include brain region-specific induction of Bdnf mRNA in response to estradiol. Additional studies have also documented regulation of the expression of the high-affinity BDNF receptor TrkB by estradiol, thus implicating sex steroids not only in the regulation of BDNF expression, but on mechanisms of signaling associated with it. In addition to gonadal steroids, further evidence also suggests functional interaction between BDNF and glucocorticoids, such as in the regulation of corticotrophin-releasing hormone and other important neuropeptides. In this review, we provide an overview of the roles played by selected sex or stress hormones in the regulation of BDNF expression and signaling in the central nervous system PMID:23211562

Expression analysis of cyp11a1 during gonadal development, recrudescence and after hCG induction and sex steroid analog treatment in the catfish, Clarias batrachus.

PubMed

Rajakumar, Anbazhagan; Senthilkumaran, Balasubramanian

2014-10-01

In teleosts, the levels of steroids are critical for sexual development and hence, expression of steroidogenic enzyme genes and specific substrate availability are indispensable for gonadal steroidogenesis. Early stages of steroidogenesis specifically cholesterol to pregnenolone conversion by Cyp11a1 is crucial for estradiol and testosterone biosynthesis. Based on this, in this study, full length cDNA of cyp11a1 (2581bp) was cloned from catfish testis to investigate the importance of Cyp11a1 by analyzing the expression of cyp11a1 during gonadal development, seasonal reproductive cycle, after human chorionic gonadotropin (hCG) induction and sex steroid analog treatment. Phylogenetic analysis revealed that the Cyp11a1 is more conserved across teleosts. Tissue distribution analysis showed that the cyp11a1 expression was higher in the testis followed by the brain, head kidney, muscle and ovary compared to other tissues analyzed. High expression of cyp11a1 in the head kidney and muscle revealed that Cyp11a1 could potentially regulate the extra-gonadal and/or circulating steroid levels in teleosts. Developing and mature testes showed higher expression of cyp11a1 than the ovary of corresponding age group. Further, cyp11a1 expression was found to be higher during pre-spawning and spawning phases of testicular cycle and was upregulated by hCG, in vivo and in vitro, which indicates the possible regulation by gonadotropin. Exposure of methyltestosterone (1μg/L) and ethinylestradiol (1μg/L) for 21days during catfish testicular development showed lower cyp11a1 expression levels in the testis and brain indicating a certain feedback intervention. These results suggest possible role for Cyp11a1 in the testis development and recrudescence. Copyright © 2014 Elsevier Inc. All rights reserved.

Efficacy and safety of thymoglobulin induction as an alternative approach for steroid-free maintenance immunosuppression in pediatric renal transplantation.

PubMed

Li, Li; Chaudhuri, Abanti; Chen, Amery; Zhao, Xinmeng; Bezchinsky, Maria; Concepcion, Waldo; Salvatierra, Oscar; Sarwal, Minnie M

2010-12-27

Given the recent withdrawal of daclizumab (DAC), the safety and efficacy of thymoglobulin (TMG) was tested as an alternative induction agent for steroid-free (SF) immunosuppression in pediatric kidney transplant recipients. Thirteen pediatric renal transplant recipients meeting defined high-risk criteria at transplantation were offered TMG induction and SF immunosuppression with maintenance mycophenolate mofetil and tacrolimus between October 2008 and January 2010. Patients were closely monitored at baseline, 3, 6, 9, and 12 months posttransplant for protocol biopsy and clinical outcomes. Outcomes were compared with 13 consecutively transplanted low-risk patients receiving an established DAC-based SF protocol (Sarwal et al., WA, American Transplant Congress 2003). There was a significant trend for overall decrease in the absolute lymphocyte counts in TMG group (F=5.86, mixed model group effect P=0.02), predominately at 3 months compared with DAC group (0.7±0.6 vs. 2.1±1.0, P=0.0004); however, lymphocyte count was recovered and was back to reference range by 6 months in TMG. There was trend toward more subclinical cytomegalovirus (15% vs. 0%) and BK viremia (17% vs. 0%) in the TMG group, with no differences in the incidence of subclinical Epstein Barr virus viremia (23% vs. 31%) or clinical viral disease. Mean graft function was excellent, and with a minimum follow-up of 6 months, there were no episodes of acute rejection. TMG seems to be a safe alternative induction strategy in patients for SF immunosuppression in pediatric renal transplantation. Extended follow-up and greater enrollment are necessary to fully explore the impact of TMG dosing on viral replication posttransplantation.

Campath-1H (alemtuzumab) as an induction agent for the prevention of graft rejection and preservation of renal function in kidney transplant patients: Philippine 3-year follow-up.

PubMed

Muñoz, A S; Cabanayan-Casasola, C B; Danguilan, R A; Padua, F B; Ona, E T

2008-09-01

The purpose of this study was to evaluate the safety and efficacy of induction with Campath-1H with low-dose cyclosporine (CsA) monotherapy using outcome measures of acute rejection episodes (ARE), chronic allograft nephropathy (CAN), graft and patient survivals, as well as malignancies and infections. Fourteen kidney transplant recipients were randomized to receive either Campath 1H induction with CsA monotherapy (9 patients) or immunosuppression with CsA, azathioprine, and steroids (5 patients). Campath (20 mg IV) was administered within 6 hours after the anastomosis and repeated 24 hours later. Cyclosporine was started 72 hours after the first Campath dose (10 mg/kg on the first day, then 4 mg/kg/d), seeking to achieve target trough CsA levels of 90 to 110 ng/mL. This is a 3-year follow-up of the 9 patients who received Campath-1H induction. Six of 9 (67%) patients developed ARE (borderline ARE to Banff IB) in the Campath group compared with 1 of 5 (20%) in the other group (ARE Banff IIA). They all received methylprednisolone for 3 days with good responses. One of the 6 patients in the Campath group with ARE also displayed CAN and was converted to sirolimus; 2 others had mycophenolate mofetil and steroids added to their immunosuppression after the ARE. Creatinine levels ranged from 1 to 1.7 mg/dL at 24 to 36 months posttransplantation in both groups. Among the Campath group, 1 patient died 6 months posttransplantation with sepsis secondary to infectious diarrhea. Upper respiratory tract infections comprised the majority of infections at 24 to 36 months. No malignancies were observed. Three years posttransplantation, patients given Campath induction with CsA monotherapy showed a greater incidence of ARE, although renal function remained comparable to CsA-azathioprine-prednisone therapy. AREs were easily reversed with steriods. Infections were minor.

Advanced Running Performance by Genetic Predisposition in Male Dummerstorf Marathon Mice (DUhTP) Reveals Higher Sterol Regulatory Element-Binding Protein (SREBP) Related mRNA Expression in the Liver and Higher Serum Levels of Progesterone

PubMed Central

Brenmoehl, Julia; Walz, Christina; Ponsuksili, Siriluck; Schwerin, Manfred; Fuellen, Georg; Hoeflich, Andreas

2016-01-01

Long-term-selected DUhTP mice represent a non-inbred model for inborn physical high-performance without previous training. Abundance of hepatic mRNA in 70-day male DUhTP and control mice was analyzed using the Affymetrix mouse array 430A 2.0. Differential expression analysis with PLIER corrected data was performed using AltAnalyze. Searching for over-representation in biochemical pathways revealed cholesterol metabolism being most prominently affected in DUhTP compared to unselected control mice. Furthermore, pathway analysis by AltAnalyze plus PathVisio indicated significant induction of glycolysis, fatty acid synthesis and cholesterol biosynthesis in the liver of DUhTP mice versus unselected control mice. In contrast, gluconeogenesis was partially inactivated as judged from the analysis of hepatic mRNA transcript abundance in DUhTP mice. Analysis of mRNA transcripts related to steroid hormone metabolism inferred elevated synthesis of progesterone and reduced levels of sex steroids. Abundance of steroid delta isomerase-5 mRNA (Hsd3b5, FC 4.97) was increased and steroid 17-alpha-monooxygenase mRNA (Cyp17a1, FC -11.6) was massively diminished in the liver of DUhTP mice. Assessment of steroid profiles by LC-MS revealed increased levels of progesterone and decreased levels of sex steroids in serum from DUhTP mice versus controls. Analysis of hepatic mRNA transcript abundance indicates that sterol regulatory element-binding protein-1 (SREBP-1) may play a major role in metabolic pathway activation in the marathon mouse model DUhTP. Thus, results from bioinformatics modeling of hepatic mRNA transcript abundance correlated with direct steroid analysis by mass spectrometry and further indicated functions of SREBP-1 and steroid hormones for endurance performance in DUhTP mice. PMID:26799318

Induction of osteoporosis with its influence on osteoporotic determinants and their interrelationships in rats by DEXA.

PubMed

Heiss, Christian; Govindarajan, Parameswari; Schlewitz, Gudrun; Hemdan, Nasr Y A; Schliefke, Nathalie; Alt, Volker; Thormann, Ulrich; Lips, Katrin Susanne; Wenisch, Sabine; Langheinrich, Alexander C; Zahner, Daniel; Schnettler, Reinhard

2012-06-01

As women are the population most affected by multifactorial osteoporosis, research is focused on unraveling the underlying mechanism of osteoporosis induction in rats by combining ovariectomy (OVX) either with calcium, phosphorus, vitamin C and vitamin D2/D3 deficiency, or by administration of glucocorticoid (dexamethasone). Different skeletal sites of sham, OVX-Diet and OVX-Steroid rats were analyzed by Dual Energy X-ray Absorptiometry (DEXA) at varied time points of 0, 4 and 12 weeks to determine and compare the osteoporotic factors such as bone mineral density (BMD), bone mineral content (BMC), area, body weight and percent fat among different groups and time points. Comparative analysis and interrelationships among osteoporotic determinants by regression analysis were also determined. T scores were below-2.5 in OVX-Diet rats at 4 and 12 weeks post-OVX. OVX-diet rats revealed pronounced osteoporotic status with reduced BMD and BMC than the steroid counterparts, with the spine and pelvis as the most affected skeletal sites. Increase in percent fat was observed irrespective of the osteoporosis inducers applied. Comparative analysis and interrelationships between osteoporotic determinants that are rarely studied in animals indicate the necessity to analyze BMC and area along with BMD in obtaining meaningful information leading to proper prediction of probability of osteoporotic fractures. Enhanced osteoporotic effect observed in OVX-Diet rats indicates that estrogen dysregulation combined with diet treatment induces and enhances osteoporosis with time when compared to the steroid group. Comparative and regression analysis indicates the need to determine BMC along with BMD and area in osteoporotic determination.

An Approach to Greater Specificity for Glucocorticoids

PubMed Central

Chow, Carson C.; Simons, S. Stoney

2018-01-01

Glucocorticoid steroids are among the most prescribed drugs each year. Nonetheless, the many undesirable side effects, and lack of selectivity, restrict their greater usage. Research to increase glucocorticoid specificity has spanned many years. These efforts have been hampered by the ability of glucocorticoids to both induce and repress gene transcription and also by the lack of success in defining any predictable properties that control glucocorticoid specificity. Correlations of transcriptional specificity have been observed with changes in steroid structure, receptor and chromatin conformation, DNA sequence for receptor binding, and associated cofactors. However, none of these studies have progressed to the point of being able to offer guidance for increased specificity. We summarize here a mathematical theory that allows a novel and quantifiable approach to increase selectivity. The theory applies to all three major actions of glucocorticoid receptors: induction by agonists, induction by antagonists, and repression by agonists. Simple graphical analysis of competition assays involving any two factors (steroid, chemical, peptide, protein, DNA, etc.) yields information (1) about the kinetically described mechanism of action for each factor at that step where the factor acts in the overall reaction sequence and (2) about the relative position of that step where each factor acts. These two pieces of information uniquely provide direction for increasing the specificity of glucocorticoid action. Consideration of all three modes of action indicate that the most promising approach for increased specificity is to vary the concentrations of those cofactors/pharmaceuticals that act closest to the observed end point. The potential for selectivity is even greater when varying cofactors/pharmaceuticals in conjunction with a select class of antagonists. PMID:29593646

Gender and oral contraceptive steroids as determinants of drug glucuronidation: effects on clofibric acid elimination.

PubMed Central

Miners, J O; Robson, R A; Birkett, D J

1984-01-01

The disposition of clofibric acid, a drug metabolised largely by glucuronidation, was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Clofibric acid plasma clearance was not significantly different in males compared to the control female group but was 48% greater (P less than 0.01) in women receiving OCS compared to non-pill using females. This difference was due to an alteration in clofibric acid metabolic clearance as there were no differences between the groups in clofibric acid free fraction. Along with previous data the results suggest that induction of drug glucuronidation by OCS may be of clinical importance, although any sex-related differences are unlikely to be of clinical significance. PMID:6487463

Identification of a new steroid degrading bacterial strain H5 from the Baltic Sea and isolation of two estradiol inducible genes.

PubMed

Sang, Yingying; Xiong, Guangming; Maser, Edmund

2012-03-01

The presence of steroid hormones in the aquatic environment is potentially threatening the population dynamics of all kinds of sea animals and public health. Environmental estrogens in water have been reported to be associated with abnormal sexual development and abnormal feminizing responses in some animals. New approaches for the bioremediation of steroid hormones from the environment are therefore urgently sought. We have previously isolated a steroid degrading bacterial strain (H5) from the Baltic Sea, at Kiel, Germany. In the present investigation, 16S rRNA analysis showed that marine strain H5 belongs to the genus Vibrio, family Vibrionaceae and class Gamma-Proteobacteria. To enable identification of steroid inducible genes from bacterial strain H5, a library was constructed of H5 chromosomal DNA fragments cloned into a fluorescent reporter (pKEGFP-2). A reporter plasmid pK3α-4.6-EGFP3 containing the estrogen-inducible gene 3α-hydroxysteroid dehydrogenase/carbonyl reductase (3α-HSD/CR) from Comamonas testosteroni (C. testosteroni) was created as a positive control. Steroid induction could be detected by a microplate fluorescence reader, when the plasmids were transformed into Escherichia coli (E. coli) HB101 cells. With our meta-genomic pKEGFP-2 approach, we identified two estradiol-inducible genes from marine strain H5, which are obviously involved in steroid degradation. Sequencing of the pKEGFP-2 inserts and data base research at NCBI revealed that one gene corresponds to 3-ketosteroid-delta-1-dehydrogenase from several Mycobacterium strains, while the other showed high similarity to carboxylesterase in Sebadella termitidis and Brachyspira murdochii. Both 3-ketosteroid-delta-1-dehydrogenase and carboxylesterase are one of the first enzymes in steroid degradation. In addition, we identified a strain H5 specific DNA sequence of 480bp which allows sensitive PCR detection and quantification of strain H5 bacteria in "unknown" seawater samples. Currently, the exact characterization and systematic classification of the marine steroid degrading bacterial strain H5 is envisaged, which might be used for the bioremediation of steroid contaminations in seawater. Article from a special issue on steroids and microorganisms. Copyright © 2011 Elsevier Ltd. All rights reserved.

Non-steroidal Anti-inflammatory Drugs Attenuate Hyperalgesia and Block Upregulation of Trigeminal Ganglionic Sodium Channel 1.7 after Induction of Temporomandibular Joint Inflammation in Rats.

PubMed

Bi, Rui Yun; Ding, Yun; Gan, Ye Hua

2016-03-01

To investigate the association between the analgesic effect of non-steroidal antiinflammatory drugs (NSAIDs) and sodium channel 1.7 (Nav1.7) expression in the trigeminal ganglion (TG). Temporomandibular joint (TMJ) inflammation was induced by complete Freund's adjuvant (CFA) in female rats. Ibuprofen, diclofenac sodium and meloxicam were given intragastrically before induction of TMJ inflammation. Histopathological evaluation and scoring of TMJ inflammation was used to evaluate the level of inflammation. The head withdrawal threshold and food intake were measured to evaluate TMJ nociceptive responses. The mRNA and protein expression of trigeminal ganglionic Nav1.7 was examined using real-time polymerase chain reaction and western blot. Twenty-four hours after the injection of CFA into the TMJs, NSAIDs attenuated hyperalgesia of inflamed TMJ and simultaneously blocked inflammation-induced upregulation of Nav1.7 mRNA and protein expression in the TG. However, ibuprofen and diclofenac sodium slightly attenuated TMJ inflammation and meloxicam did not affect TMJ inflammation. Attenuation of hyperalgesia of inflamed TMJ by NSAIDs might be associated with their role in blocking upregulation of trigeminal ganglionic Nav1.7.

Efficacy and tolerance of systemic steroids in sciatica: a systematic review and meta-analysis.

PubMed

Roncoroni, Cécile; Baillet, Athan; Durand, Marjorie; Gaudin, Philippe; Juvin, Robert

2011-09-01

The efficacy of pharmacological interventions in sciatica is limited and the use of systemic steroids is still controversial. We aimed at evaluating the efficacy and tolerance of systemic steroids in sciatica. A systematic literature search was performed in the Medline, Embase and Cochrane databases until February 2010. Randomized placebo-controlled trials evaluating the efficacy and the tolerance of systemic steroids in sciatica were included. Efficacy and tolerance were assessed using the relative risk (RR) and 95% CI with the inverse variance method (RR > 1 means that the event is more likely to occur in the steroid group). We explored the heterogeneity between the studies using subgroup analysis. Seven studies (383 patients) were included. The difference in the rate of responders between both groups was not statistically significant (RR = 1.22, 95% CI 0.96, 1.56). The rate of adverse events was 13.3% for the patients in the steroid group and 6.6% for the placebo group (RR = 2.01, 95% CI 1.06, 3.80). The number needed to harm was 20 (95% CI 10, ∞). Twenty (15.3%) patients in the steroid group and seven (5.7%) patients in the placebo group underwent surgery. A trend towards a higher requirement for spinal surgery was observed in the steroid group (RR = 1.14, 95% CI 0.74, 1.75). The methodological quality slightly influenced the results. We did not find any publication bias. Steroid efficacy is not superior to the placebo in sciatica, but it has more side effects. The tolerance : efficacy ratio indicates against the use of systemic steroids in sciatica.

Different glucocorticoids vary in their genomic and non-genomic mechanism of action in A549 cells

PubMed Central

Croxtall, Jamie D; van Hal, Peter Th W; Choudhury, Qam; Gilroy, Derek W; Flower, Rod J

2002-01-01

We have examined the effects of 12 glucocorticoids as inhibitors of A549 cell growth. Other than cortisone and prednisone, all the glucocorticoids inhibited cell growth and this was strongly correlated (r=0.91) with inhibition of prostaglandin (PG)E2 formation. The molecular mechanism by which the active steroids prevented PGE2 synthesis was examined and three groups were identified. Group A drugs did not inhibit arachidonic acid release but inhibited the induction of COX2. Group B drugs were not able to inhibit the induction of COX2 but inhibited arachidonic acid release through suppression of cPLA2 activation. Group C drugs were apparently able to bring about both effects. The inhibitory actions of all steroids was dependent upon glucocorticoid receptor occupation since RU486 reversed their effects. However, group A acted through the NF-κB pathway to inhibit COX2 as the response was blocked by the inhibitor geldanamycin which prevents dissociation of GR and the effect was blocked by APDC, the NF-κB inhibitor. On the other hand, the group B drugs were not inhibited by NF-κB inhibitors or geldanamycin but their effect was abolished by the src inhibitor PP2. Group C drugs depended on both pathways. In terms of PGE2 generation, there is clear evidence of two entirely separate mechanisms of glucocorticoid action, one of which correlates with NF-κB mediated genomic actions whilst the other, depends upon rapid effects on a cell signalling system which does not require dissociation of GR. The implications for these findings are discussed. PMID:11815387

Rituximab in systemic lupus erythematosus and lupus nephritis.

PubMed

Beckwith, Hannah; Lightstone, Liz

2014-01-01

Treatment options for systemic lupus erythematosus (SLE) and lupus nephritis (LN) have high associated morbidity and mortality. Side effects, particularly from long-term corticosteroid usage, limit patient adherence, with subsequent impacts on treatment efficacy. In addition, a subset of patients with SLE/LN fails to respond to current standard immunotherapy. There is an urgent need to develop steroid-sparing treatment regimens as well as novel therapies for the management of refractory disease. Rituximab is a chimeric mouse/human monoclonal antibody directed against the B cell CD20 receptor. It has been used in the treatment of non-Hodgkin's lymphoma for over 30 years and has an excellent safety profile. Recent work has demonstrated a role for B cell depletion therapy in the management of autoimmune disease, and the efficacy of rituximab in many observational studies in SLE and LN has been noted. Unfortunately, two large randomised controlled trials evaluating rituximab for the treatment of renal and non-renal lupus failed to meet their primary endpoints. Reasons for this have been discussed extensively within the medical community with a general consensus that trial design (steroid use, trial size and endpoints used) was the principal reason for the failures. Despite the lack of trial evidence, clinical experience means many physicians firmly believe in the value of rituximab in SLE/LN treatment and have continued to use it in their clinical practice. Recent work has demonstrated the efficacy of rituximab as a steroid-sparing agent and as an alternative therapeutic option for refractory SLE/LN. There are two further rituximab randomised controlled trials planned/started in LN – one using a steroid-minimising regimen with rituximab for induction and one evaluating rituximab for LN refractory to 6 months standard of care treatment. Rituximab remains a problematic drug in lupus and LN – it is a biologically plausible agent with a huge amount of supportive anecdotal clinical data. Yet the completed trials have been negative to date despite clinical experience strongly suggesting efficacy. It is hoped that the two new trials will determine the role for rituximab, at least in LN. © 2014 S. Karger AG, Basel.

Systemic steroids in the treatment of psoriasis: what is fact, what is fiction?

PubMed

Mrowietz, U; Domm, S

2013-08-01

The use of systemic steroids in the treatment of psoriasis is not recommended by dermatological textbooks and guidelines because of the risk of disease deterioration after dose reduction or withdrawal. In contrast to these recommendations, a recent analysis using data from a German nationwide healthcare insurance revealed that systemic steroids were the most frequently prescribed drugs for psoriasis by general practitioners, internal medicine physicians and dermatologists. As there is an obvious discrepancy between the use of systemic steroids for psoriasis and the reported adverse effects, a non-systematic literature search starting 1950 until today was performed to address beneficial and adverse effect of systemic steroids in psoriasis. Non-systematic literature search. Regarding the widespread use of systemic steroids in psoriasis and other medical conditions taking the high prevalence of psoriasis of 2-3% at least in Caucasians into consideration, there is a remarkable lack of literature addressing adverse effects such as rebound, pustular or erythrodermic flares or even new occurrence of psoriasis in patients with a negative disease history. A re-evaluation of the treatment of psoriasis and/or psoriatic arthritis with systemic steroids is necessary. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

Changes in hepatic levels of tyrosine aminotransferase messenger RNA during induction by hydrocortisone. [Xenopus laevis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nickol, J.M.; Lee, K.L.; Kenney, F.T.

Messenger RNA specific for tyrosine aminotransferase was quantitated by microinjection into oocytes of Xenopus laevis. The heterologously translated enzyme was identified by specific immunoprecipitation and found to be identical with authentic aminotransferase by several criteria. The level of functional message present in rat liver increases during hydrocortisone induction, and this increase is directly proportional to the increased rate of synthesis of the enzyme. Kinetic analysis of the changes in tyrosine aminotransferase mRNA levels during induction and withdrawal indicates that the steroid does not affect the stability of the message, which has a half-life of approximately 1.2 h. Hydrocortisone, therefore, actsmore » to increase the rate of synthesis of the specific messenger by stimulating either its transcription or processing to functional mRNA.« less

Role of Neuroactive Steroids in the Peripheral Nervous System

PubMed Central

Melcangi, Roberto Cosimo; Giatti, Silvia; Pesaresi, Marzia; Calabrese, Donato; Mitro, Nico; Caruso, Donatella; Garcia-Segura, Luis Miguel

2011-01-01

Several reviews have so far pointed out on the relevant physiological and pharmacological role exerted by neuroactive steroids in the central nervous system. In the present review we summarize observations indicating that synthesis and metabolism of neuroactive steroids also occur in the peripheral nerves. Interestingly, peripheral nervous system is also a target of their action. Indeed, as here reported neuroactive steroids are physiological regulators of peripheral nerve functions and they may also represent interesting therapeutic tools for different types of peripheral neuropathy. PMID:22654839

Adhesive blood microsampling systems for steroid measurement via LC-MS/MS in the rat.

PubMed

Heussner, Kirsten; Rauh, Manfred; Cordasic, Nada; Menendez-Castro, Carlos; Huebner, Hanna; Ruebner, Matthias; Schmidt, Marius; Hartner, Andrea; Rascher, Wolfgang; Fahlbusch, Fabian B

2017-04-01

Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) allows for the direct analysis of multiple hormones in a single probe with minimal sample volume. Rodent-based animal studies strongly rely on microsampling, such as the dry blood spot (DBS) method. However, DBS suffers the drawback of hematocrit-dependence (non-volumetric). Hence, novel volumetric microsampling techniques were introduced recently, allowing sampling of fixed accurate volumes. We compared these methods for steroid analysis in the rat to improve inter-system comparability. We analyzed steroid levels in blood using the absorptive microsampling devices Whatman® 903 Protein Saver Cards, Noviplex™ Plasma Prep Cards and the Mitra™ Microsampling device and compared the obtained results to the respective EDTA plasma levels. Quantitative steroid analysis was performed via LC-MS/MS. For the determination of the plasma volume factor for each steroid, their levels in pooled blood samples from each human adults and rats (18weeks) were compared and the transferability of these factors was evaluated in a new set of juvenile (21days) and adult (18weeks) rats. Hematocrit was determined concomitantly. Using these approaches, we were unable to apply one single volume factor for each steroid. Instead, plasma volume factors had to be adjusted for the recovery rate of each steroid and device individually. The tested microsampling systems did not allow the use of one single volume factor for adult and juvenile rats based on an unexpectedly strong hematocrit-dependency and other steroid specific (pre-analytic) factors. Our study provides correction factors for LC-MS/MS steroid analysis of volumetric and non-volumetric microsampling systems in comparison to plasma. It argues for thorough analysis of chromatographic effects before the use of novel volumetric systems for steroid analysis. Copyright © 2017 Elsevier Inc. All rights reserved.

Effective prescribing in steroid allergy: controversies and cross-reactions.

PubMed

Browne, Fiona; Wilkinson, S Mark

2011-01-01

Contact allergy to topical corticosteroids should be considered in all patients who do not respond to, or are made worse by, the use of topical steroids. The incidence of steroid allergy in such patients is reported as 9% to 22% in adult patients and in 25% of children. It can often go undiagnosed for a long time in patients with a long history of dermatologic conditions and steroid use. Although rare, both immediate and delayed-type hypersensitivity reactions have been reported to systemic corticosteroids with an incidence of 0.3%. Reported reactions range from localized eczematous eruptions to systemic reactions, anaphylaxis, and even death. Delayed type reactions to systemically administered steroids may present as a generalized dermatitis, an exanthematous eruption, or occasionally, with blistering or purpura. In this contribution, we clarify the issues surrounding the pathogenesis of steroid allergy, cover the importance of cross-reactions, and describe strategies for the investigation and management for patients with suspected steroid allergy. Copyright © 2011 Elsevier Inc. All rights reserved.

Protective Actions of 17β-Estradiol and Progesterone on Oxidative Neuronal Injury Induced by Organometallic Compounds

PubMed Central

Ishihara, Yasuhiro; Takemoto, Takuya; Yamazaki, Takeshi

2015-01-01

Steroid hormones synthesized in and secreted from peripheral endocrine glands pass through the blood-brain barrier and play a role in the central nervous system. In addition, the brain possesses an inherent endocrine system and synthesizes steroid hormones known as neurosteroids. Increasing evidence shows that neuroactive steroids protect the central nervous system from various harmful stimuli. Reports show that the neuroprotective actions of steroid hormones attenuate oxidative stress. In this review, we summarize the antioxidative effects of neuroactive steroids, especially 17β-estradiol and progesterone, on neuronal injury in the central nervous system under various pathological conditions, and then describe our recent findings concerning the neuroprotective actions of 17β-estradiol and progesterone on oxidative neuronal injury induced by organometallic compounds, tributyltin, and methylmercury. PMID:25815107

Second-generation corticosteroids for the treatment of Crohn's disease and ulcerative colitis: more effective and less side effects?

PubMed

De Cassan, Chiara; Fiorino, Gionata; Danese, Silvio

2012-01-01

Systemic corticosteroids are highly effective at inducing clinical remission in cases of acute exacerbation of Crohn's disease (CD) and ulcerative colitis (UC); however, their use is limited by their frequent and sometimes severe side effects. Thus, a second generation of corticosteroids with less systemic effects has been developed. This review analyzed all of the studies on the new formulations of steroids with limited absorption (budesonide, budesonide MMX®, beclomethasone dipropionate and erythrocyte-mediated delivery of dexamethasone) in patients with CD and UC. All relevant articles published in English between September 1960 and April 2011 were reviewed. Budesonide is superior to placebo, and as effective as systemic corticosteroids in inducing clinical remission in patients with ileo-colonic CD, but evidence of mucosal healing is limited. When administered as an MMX formula, budesonide can also effectively induce clinical remission in patients with UC, but budesonide alone is not effective in maintaining clinical remission in CD or UC. Beclomethasone dipropionate seems to be effective in patients with mild-to-moderate left-sided and extensive UC, while data on erythrocyte-mediated delivery of dexamethasone are encouraging but still limited. The safety profile for all these products is good but more studies are needed. Steroids remain the mainstay for the induction of clinical remission in cases of acute relapse of both CD and UC. Second-generation corticosteroids are an interesting alternative, with the advantage of high topical activity, less systemic toxicity and limited side effects. Copyright © 2012 S. Karger AG, Basel.

Comparative study of sister chromatid exchange induction and antitumor effects by homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]butyric acid.

PubMed

Camoutsis, C; Catsoulacos, D; Karayiann, V; Papageorgiou, A; Mourelatos, D; Mioglou, E; Kritsi, Z; Nikolaropoulos, S

2001-01-01

The present work was undertaken in order to test the hypothesis that the Sister Chromatid Exchange (SCE) assay in vitro can be used for the prediction of in vivo tumor response to newly synthesized potential chemotherapeutics. The effect of three homo-aza-steroidal esters containing the -CONH- in the steroidal nucleus, 1, 2, and 3 on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The three substances induced statistically significant enhancement of SCEs and of cell division delays. Compounds 1 and 3 were identified, on a molar basis, as more effective inducers of SCEs and of cell division delays compared with compound 2. Compounds 1 and 3 had upon both experimental tumors better therapeutic effects compared with compound 2 at equitoxic doses. Therefore, the order of the antitumor effectiveness of the three compounds coincided with the order of the cytogenetic effects they induced.

Perioperative systemic steroid for rapid recovery in total knee and hip arthroplasty: a systematic review and meta-analysis of randomized trials.

PubMed

Yue, Chen; Wei, Rong; Liu, Youwen

2017-06-27

Perioperative systemic steroid administration for rapid recovery in total knee and hip arthroplasty (TKA/THA) is an important and controversial topic. We conducted this systematic review and meta-analysis to evaluate the overall benefits and harms of perioperative systemic steroid in patients undergoing TKA and THA. A comprehensive search was performed on PubMed, OVID, and Web of Science databases, and a systematic approach was carried out starting from the PRISMA recommendations. Relevant randomized controlled trials (RCTs) were selected. The risk of bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions version. Data were extracted and meta-analyzed or qualitatively synthesized for all the outcomes. Data were extracted from 11 trials involving 774 procedures. Meta-analysis showed that high-dose systemic steroid (dexamethasone > 0.1 mg/kg) rather than low dose is effective to reduce postoperative nausea and vomiting and postoperative acute pain (within 24 h). In addition, systemic steroid is associated within faster functional rehabilitation and greater inflammation control. On the other hand, systemic steroid is associated with a higher level of postoperative serum glucose on the operation day. The complications between groups are similarly low. Our study suggests that by providing lower incidence of postoperative nausea and vomiting and less postoperative acute pain, high-dose systemic steroid plays a critical role in rapid recovery to TKA and THA. The preliminary results also show the superior possibility of systemic steroid in functional rehabilitation and inflammation control. More large, high-quality studies that investigate the safety and dose-response relationship are necessary.

Induction of osteoporosis with its influence on osteoporotic determinants and their interrelationships in rats by DEXA

PubMed Central

Heiss, Christian; Govindarajan, Parameswari; Schlewitz, Gudrun; Hemdan, Nasr Y.A.; Schliefke, Nathalie; Alt, Volker; Thormann, Ulrich; Lips, Katrin Susanne; Wenisch, Sabine; Langheinrich, Alexander C.; Zahner, Daniel; Schnettler, Reinhard

2012-01-01

Summary Background As women are the population most affected by multifactorial osteoporosis, research is focused on unraveling the underlying mechanism of osteoporosis induction in rats by combining ovariectomy (OVX) either with calcium, phosphorus, vitamin C and vitamin D2/D3 deficiency, or by administration of glucocorticoid (dexamethasone). Material/Methods Different skeletal sites of sham, OVX-Diet and OVX-Steroid rats were analyzed by Dual Energy X-ray Absorptiometry (DEXA) at varied time points of 0, 4 and 12 weeks to determine and compare the osteoporotic factors such as bone mineral density (BMD), bone mineral content (BMC), area, body weight and percent fat among different groups and time points. Comparative analysis and interrelationships among osteoporotic determinants by regression analysis were also determined. Results T scores were below-2.5 in OVX-Diet rats at 4 and 12 weeks post-OVX. OVX-diet rats revealed pronounced osteoporotic status with reduced BMD and BMC than the steroid counterparts, with the spine and pelvis as the most affected skeletal sites. Increase in percent fat was observed irrespective of the osteoporosis inducers applied. Comparative analysis and interrelationships between osteoporotic determinants that are rarely studied in animals indicate the necessity to analyze BMC and area along with BMD in obtaining meaningful information leading to proper prediction of probability of osteoporotic fractures. Conclusions Enhanced osteoporotic effect observed in OVX-Diet rats indicates that estrogen dysregulation combined with diet treatment induces and enhances osteoporosis with time when compared to the steroid group. Comparative and regression analysis indicates the need to determine BMC along with BMD and area in osteoporotic determination. PMID:22648240

Rapid Steroid Hormone Actions Initiated at the Cell Surface and the Receptors that Mediate Them with an Emphasis on Recent Progress in Fish Models

PubMed Central

Thomas, Peter

2011-01-01

In addition to the classic genomic mechanism of steroid action mediated by activation of intracellular nuclear receptors, there is now extensive evidence that steroids also activate receptors on the cell surface to initiate rapid intracellular signaling and biological responses that are often nongenomic. Recent progress in our understanding of rapid, cell surface-initiated actions of estrogens, progestins, androgens and corticosteroids and the identities of the membrane receptors that act as their intermediaries is briefly reviewed with a special emphasis on studies in teleost fish. Two recently discovered novel proteins with seven-transmembrane domains, G protein-coupled receptor 30 (GPR30), and membrane progestin receptors (mPRs) have the ligand binding and signaling characteristics of estrogen and progestin membrane receptors, respectively, but their functional significance is disputed by some researchers. GPR30 is expressed on the cell surface of fish oocytes and mediates estrogen inhibition of oocyte maturation. mPRα is also expressed on the oocyte cell surface and is the intermediary in progestin induction of oocyte maturation in fish. Recent results suggest there is cross-talk between these two hormonal pathways and that there is reciprocal down-regulation of GPR30 and mPRα expression by estrogens and progestins at different phases of oocyte development to regulate the onset of oocyte maturation. There is also evidence in fish that mPRs are involved in progestin induction of sperm hypermotility and anti-apoptotic actions in ovarian follicle cells. Nonclassical androgen and corticosteroid actions have also been described in fish models but the membrane receptors mediating these actions have not been identified. PMID:22154643

Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways.

PubMed

Mijatovic, Tatjana; Kiss, Robert

2013-03-01

Many cancer patients fail to respond to chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli or the acquisition of the multidrug resistant phenotype during chronic treatment. Previous data from our groups and from others point to the sodium/potassium pump (the Na+/K+-ATPase, i.e., NaK) with its highly specific ligands (i.e., cardiotonic steroids) as a new target for combating cancers associated with dismal prognoses, including gliomas, melanomas, non-small cell lung cancers, renal cell carcinomas, and colon cancers. Cardiotonic steroid-mediated Na+/K+-ATPase targeting could circumvent various resistance pathways. The most probable pathways include the involvement of Na+/K+-ATPase β subunits in invasion features and Na+/K+-ATPase α subunits in chemosensitisation by specific cardiotonic steroid-mediated apoptosis and anoïkis-sensitisation; the regulation of the expression of multidrug resistant-related genes; post-translational regulation, including glycosylation and ubiquitinylation of multidrug resistant-related proteins; c-Myc downregulation; hypoxia-inducible factor downregulation; NF-κB downregulation and deactivation; the inhibition of the glycolytic pathway with a reduction of intra-cellular ATP levels and an induction of non-apoptotic cell death. The aims of this review are to examine the various molecular pathways by which the NaK targeting can be more deleterious to biologically aggressive cancer cells than to normal cells. Georg Thieme Verlag KG Stuttgart · New York.

Antileishmanial and antitrypanosomal activity of bufadienolides isolated from the toad Rhinella jimi parotoid macrogland secretion.

PubMed

Tempone, André Gustavo; Pimenta, Daniel Carvalho; Lebrun, Ivo; Sartorelli, Patrícia; Taniwaki, Noemi N; de Andrade, Heitor Franco; Antoniazzi, Marta Maria; Jared, Carlos

2008-07-01

Amphibian skin secretions are considered a rich source of biologically active compounds and are known to be rich in peptides, bufadienolides and alkaloids. Bufadienolides are cardioactive steroids from animals and plants that have also been reported to possess antimicrobial activities. Leishmaniasis and American Trypanosomiasis are parasitic diseases found in tropical and subtropical regions. The efforts toward the discovery of new treatments for these diseases have been largely neglected, despite the fact that the only available treatments are highly toxic drugs. In this work, we have isolated, through bioguided assays, the major antileishmanial compounds of the toad Rhinella jimi parotoid macrogland secretion. Mass spectrometry and (1)H and (13)C NMR spectroscopic analyses were able to demonstrate that the active molecules are telocinobufagin and hellebrigenin. Both steroids demonstrated activity against Leishmania (L.) chagasi promastigotes, but only hellebrigenin was active against Trypanosoma cruzi trypomastigotes. These steroids were active against the intracellular amastigotes of Leishmania, with no activation of nitric oxide production by macrophages. Neither cytotoxicity against mouse macrophages nor hemolytic activities were observed. The ultrastructural studies with promastigotes revealed the induction of mitochondrial damage and plasma membrane disturbances by telocinobufagin, resulting in cellular death. This novel biological effect of R. jimi steroids could be used as a template for the design of new therapeutics against Leishmaniasis and American Trypanosomiasis.

Human Endometrial Adenocarcinoma Transplanted into Nude Mice: Growth Regulation by Estradiol

NASA Astrophysics Data System (ADS)

Satyaswaroop, P. G.; Zaino, R. J.; Mortel, R.

1983-01-01

A model for studying the growth of primary tumors of human endometrium and its regulation by 17β -estradiol has been developed in which ovariectomized nude mice are used as recipients. The receptors for sex steroids are maintained during serial transplantation of the tumor in this system. Although the rate of growth of receptor-negative endometrial tumors transplanted into ovariectomized nude mice is unaffected by the sustained presence or absence of estradiol, the growth of receptor-positive tumors is significantly increased by estradiol. Receptor-positive tumors treated with estradiol produced elevated concentrations of progesterone receptor. That the progesterone receptor is functional in this tumor is evident from the induction of estradiol 17β -dehydrogenase activity upon progestin administration. These findings are consistent with receptor-mediated regulation of growth of endometrial carcinoma.

A review of the evidence for use of thymoglobulin induction in renal transplantation.

PubMed

Gaber, A Osama; Knight, R J; Patel, S; Gaber, L W

2010-06-01

Depleting antilymphocyte, or antithymocyte antibodies, have long been an integral part of induction regimens and continue today to be used in the management of patients at risk of early rejection or those in whom the introduction of calcineurins or other immune suppressants must be delayed. Registry data demonstrate that the most commonly used depleting antibody, rabbit anti-human thymocyte globulin (rATG), is associated with improved outcomes following renal transplantation in high-risk patients, particularly in conjunction with steroid-avoidance regimens. Two prospective randomized trials in high-risk renal allograft patients have also demonstrated an advantage of r-ATG induction compared to the nondepleting interleukin receptor (IL2RA) antibodies. In low-immunologic-risk patients, however, r-ATG induction and IL2RA induction appear to be equivalent in terms of rejection prophylaxis and long-term function. Other studies have shown that sequential rATG-containing regimens were superior to no induction and allowed for successful late introduction of calcineurin inhibitors. The side effect profile of the depleting antibody included increased incidence of fever, hematologic abnormalities, cytomegalovirus infections when prophylaxis was not employed, and in some studies, increased incidence of posttransplant lymphoproliferative disease. This review describes the evidence supporting the use of depleting ATGs in kidney transplantation.

Dielectric screening of early differentiation patterns in mesenchymal stem cells induced by steroid hormones.

PubMed

Ron, Amit; Shur, Irena; Daniel, Ramiz; Singh, Ragini Raj; Fishelson, Nick; Croitoru, Nathan; Benayahu, Dafna; Shacham-Diamand, Yosi

2010-06-01

In the framework of this study, target identification and localization of differentiation patterns by means of dielectric spectroscopy is presented. Here, a primary pre-osteoblastic bone marrow-derived MBA-15 cellular system was used to study the variations in the dielectric properties of mesenchymal stem cells while exposed to differentiation regulators. Using the fundamentals of mixed dielectric theories combined with finite numerical tools, the permittivity spectra of MBA-15 cell suspensions have been uniquely analyzed after being activated by steroid hormones to express osteogenic phenotypes. Following the spectral analysis, significant variations were revealed in the dielectric properties of the activated cells in comparison to the untreated populations. Based on the differentiation patterns of MBA-15, the electrical modifications were found to be highly correlated with the activation of specific cellular mechanisms which directly react to the hormonal inductions. In addition, by describing the dielectric dispersion in terms of transfer functions, it is shown that the spectral perturbations are well adapted to variations in the electrical characteristics of the cells. The reported findings vastly emphasize the tight correlation between the cellular and electrical state of the differentiated cells. It therefore emphasizes the vast abilities of impedance-based techniques as potential screening tools for stem cell analysis. Copyright 2009 Elsevier B.V. All rights reserved.

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system...

Conserved steroid hormone homology converges on NFκB to modulate inflammation in asthma

PubMed Central

Payne, Asha S.; Freishtat, Robert J.

2012-01-01

Asthma is a complex, multifactorial disease comprising multiple different subtypes, rather than a single disease entity [1], yet has a consistent clinical phenotype: recurring episodes of chest tightness, wheezing, and difficulty breathing. Despite the complex pathogenesis of asthma, steroid hormones (e.g. glucocorticoids) are ubiquitous in the acute and chronic management of all types of asthma. Overall, steroid hormones are a class of widely-relevant, biologically-active compounds originating from cholesterol and altered in a stepwise fashion, but maintain a basic 17-carbon, 4-ring structure. Steroids are lipophilic molecules that diffuse readily through cell membranes to directly and/or indirectly affect gene transcription. In addition, they employ rapid, non-genomic actions to affect cellular products. Steroid hormones are comprised of several groups (including glucocorticoids, sex steroid hormones, and secosteroids) with critical divergent biological and physiological functions relevant to health and disease. However, the conserved homology of steroid hormone molecules, receptors, and signaling pathways suggest that each of these is part of dynamic system of hormone interaction, likely involving overlap of downstream signaling mechanisms. Therefore, we will review the similarities and differences of these three groups of steroid hormones (i.e. glucocorticoids, sex steroid hormones, and secosteroids), identifying NFκB as a common inflammatory mediator. Despite our understanding of the impact of individual steroids (e.g. glucocorticoids, sex steroids and secosteroids) on asthma, research has yet to explain the interplay of the dynamic system in which these hormones function. To do so, there needs to be better understanding of the interplay of classical, non-classical, and non-genomic steroid hormone function. However, clues from the conserved homology steroid hormone structure and function and signaling pathways, offer insight into a possible model of steroid hormone regulation of inflammation in asthma through common NFκB-mediated downstream events. PMID:22183120

What is the role of steroids in pneumonia therapy?

PubMed

Póvoa, Pedro; Salluh, Jorge I F

2012-04-01

This review evaluates the potential benefits as well as adverse effects from adjunctive therapy with systemic steroids in patients with pneumonia: either mild-to-moderate or severe, community-acquired or hospital-acquired, of bacterial or of viral origin (in particular H1N1 viral infection). Steroids potentially modulate the marked and persistent activation of the immune system in pneumonia. However, several recent randomized controlled trials and large prospective observational studies have repeatedly shown that steroids had no impact on survival, the clinical event of interest, but in severe pneumonia some studies pointed to potential harmful effect. In addition, adverse effects, namely hyperglycemia, superinfections, as well as increased length-of-stay, were frequent findings in the steroid-treated patients. According to the current evidence, there are no data to support the well tolerated use of systemic steroids as a standard of care in pneumonia, neither in mild-to-moderate and severe, nor in bacterial and viral infection. Clinical and basic research should work together to improve trial designs to identify reliable surrogate markers of outcome, in particular of mortality. This may improve the patient selection and facilitate the identification of subgroups that can benefit from adjunctive steroid therapy.

Neuroactive steroids and the peripheral nervous system: An update.

PubMed

Giatti, Silvia; Romano, Simone; Pesaresi, Marzia; Cermenati, Gaia; Mitro, Nico; Caruso, Donatella; Tetel, Marc J; Garcia-Segura, Luis Miguel; Melcangi, Roberto C

2015-11-01

In the present review we summarize observations to date supporting the concept that neuroactive steroids are synthesized in the peripheral nervous system, regulate the physiology of peripheral nerves and exert notable neuroprotective actions. Indeed, neuroactive steroids have been recently proposed as therapies for different types of peripheral neuropathy, like for instance those occurring during aging, chemotherapy, physical injury and diabetes. Moreover, pharmacological tools able to increase the synthesis of neuroactive steroids might represent new interesting therapeutic strategy to be applied in case of peripheral neuropathy. Copyright © 2015 Elsevier Inc. All rights reserved.

ent-Steroids: novel tools for studies of signaling pathways.

PubMed

Covey, Douglas F

2009-07-01

Membrane receptors are often modulated by steroids and it is necessary to distinguish the effects of steroids at these receptors from effects occurring at nuclear receptors. Additionally, it may also be mechanistically important to distinguish between direct effects caused by binding of steroids to membrane receptors and indirect effects on membrane receptor function caused by steroid perturbation of the membrane containing the receptor. In this regard, ent-steroids, the mirror images of naturally occurring steroids, are novel tools for distinguishing between these various actions of steroids. The review provides a background for understanding the different actions that can be expected of steroids and ent-steroids in biological systems, references for the preparation of ent-steroids, a short discussion about relevant forms of stereoisomerism and the requirements that need to be fulfilled for the interaction between two molecules to be enantioselective. The review then summarizes results of biophysical, biochemical and pharmacological studies published since 1992 in which ent-steroids have been used to investigate the actions of steroids in membranes and/or receptor-mediated signaling pathways.

ent-Steroids: Novel Tools for Studies of Signaling Pathways

PubMed Central

Covey, Douglas F.

2008-01-01

Membrane receptors are often modulated by steroids and it is necessary to distinguish the effects of steroids at these receptors from effects occurring at nuclear receptors. Additionally, it may also be mechanistically important to distinguish between direct effects caused by binding of steroids to membrane receptors and indirect effects on membrane receptor function caused by steroid perturbation of the membrane containing the receptor. In this regard, ent-steroids, the mirror images of naturally occurring steroids, are novel tools for distinguishing between these various actions of steroids. The review provides a background for understanding the different actions that can be expected of steroids and ent-steroids in biological systems, references for the preparation of ent-steroids, a short discussion about relevant forms of stereoisomerism and the requirements that need to be fulfilled for the interaction between two molecules to be enantioselective. The review then summarizes results of biophysical, biochemical and pharmacological studies published since 1992 in which ent-steroids have been used to investigate the actions of steroids in membranes and/or receptor-mediated signaling pathways. PMID:19103212

Treatment of Myasthenia Gravis Based on Its Immunopathogenesis

PubMed Central

Kim, Jee Young; Park, Kee Duk

2011-01-01

The prognosis of myasthenia gravis (MG) has improved dramatically due to advances in critical-care medicine and symptomatic treatments. Its immunopathogenesis is fundamentally a T-cell-dependent autoimmune process resulting from loss of tolerance toward self-antigens in the thymus. Thymectomy is based on this immunological background. For MG patients who are inadequately controlled with sufficient symptomatic treatment or fail to achieve remission after thymectomy, remission is usually achieved through the addition of other immunotherapies. These immunotherapies can be classified into two groups: rapid induction and long-term maintenance. Rapid induction therapy includes intravenous immunoglobulin (IVIg) and plasma exchange (PE). These produce improvement within a few days after initiation, and so are useful for acute exacerbation including myasthenic crisis or in the perioperative period. High-dose prednisone has been more universally preferred for remission induction, but it acts more slowly than IVIg and PE, commonly only after a delay of several weeks. Slow tapering of steroids after a high-dose pulse offers a method of maintaining the state of remission. However, because of significant side effects, other immunosuppressants (ISs) are frequently added as "steroid-sparing agents". The currently available ISs exert their immunosuppressive effects by three mechanisms: 1) blocking the synthesis of DNA and RNA, 2) inhibiting T-cell activation and 3) depleting the B-cell population. In addition, newer drugs including antisense molecule, tumor necrosis factor alpha receptor blocker and complement inhibitors are currently under investigation to confirm their effectiveness. Until now, the treatment of MG has been based primarily on experience rather than gold-standard evidence from randomized controlled trials. It is hoped that well-organized studies and newer experimental trials will lead to improved treatments. PMID:22259613

Org 214007-0: A Novel Non-Steroidal Selective Glucocorticoid Receptor Modulator with Full Anti-Inflammatory Properties and Improved Therapeutic Index

PubMed Central

Laskewitz, Anke J.; Dijkema, Rein; van der Maaden, Hans M.; Smit, Martin J.; Plate, Ralf; Conti, Paolo G. M.; Jans, Christan G. J. M.; Timmers, C. Marco; van Boeckel, Constant A. A.; Lusher, Scott J.; McGuire, Ross; van Schaik, Rene C.; de Vlieg, Jacob; Smeets, Ruben L.; Hofstra, Claudia L.; Boots, Annemieke M. H.; van Duin, Marcel; Ingelse, Benno A.; Schoonen, Willem G. E. J.; Grefhorst, Aldo; van Dijk, Theo H.; Kuipers, Folkert; Dokter, Wim H. A.

2012-01-01

Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects. PMID:23152771

Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index.

PubMed

van Lierop, Marie-José C; Alkema, Wynand; Laskewitz, Anke J; Dijkema, Rein; van der Maaden, Hans M; Smit, Martin J; Plate, Ralf; Conti, Paolo G M; Jans, Christan G J M; Timmers, C Marco; van Boeckel, Constant A A; Lusher, Scott J; McGuire, Ross; van Schaik, Rene C; de Vlieg, Jacob; Smeets, Ruben L; Hofstra, Claudia L; Boots, Annemieke M H; van Duin, Marcel; Ingelse, Benno A; Schoonen, Willem G E J; Grefhorst, Aldo; van Dijk, Theo H; Kuipers, Folkert; Dokter, Wim H A

2012-01-01

Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.

Steroid acne vs. Pityrosporum folliculitis: the incidence of Pityrosporum ovale and the effect of antifungal drugs in steroid acne.

PubMed

Yu, H J; Lee, S K; Son, S J; Kim, Y S; Yang, H Y; Kim, J H

1998-10-01

Steroid acne is a folliculitis that can result from systemic or topical administration of steroid, and has been described as showing a similar clinical picture to Pityrosporum folliculitis, but there have been few reports about the incidence of Pityrosporum ovale and the effect of antimycotic drugs in steroid acne and other acneiform eruptions. Our purpose was to describe the association between steroid acne and P. ovale, and to confirm the superior efficacy of oral antifungal drugs over anti-acne drugs in the treatment of steroid acne. The history, clinical features direct microscopy, histopathologic analysis, and therapeutic results of 125 cases with steroid acne or other acneiform eruptions were described and compared. Over 80% of patients with acneiform eruption receiving systemic steroid revealed significant numbers of P. ovale in the lesional follicle. Furthermore, oral antifungal drug (itraconazole) showed significantly better clinical and mycologic effects than any other group of medications used in this study. Steroid acne and other acneiform eruptions showing discrete follicular papules and/or pustules localized to the upper trunk and acneiform facial skin lesions associated with multiple acneiform lesions on the body in the summer period should be suspected as Pityrosporum folliculitis. In addition, oral antifungal drugs recommended for Pityrosporum folliculitis; however, it will require a larger case-control study to confirm the superiority of antifungal therapy over anti-acne treatment.

Steroids in teleost fishes: A functional point of view.

PubMed

Tokarz, Janina; Möller, Gabriele; Hrabě de Angelis, Martin; Adamski, Jerzy

2015-11-01

Steroid hormones are involved in the regulation of a variety of processes like embryonic development, sex differentiation, metabolism, immune responses, circadian rhythms, stress response, and reproduction in vertebrates. Teleost fishes and humans show a remarkable conservation in many developmental and physiological aspects, including the endocrine system in general and the steroid hormone related processes in particular. This review provides an overview of the current knowledge about steroid hormone biosynthesis and the steroid hormone receptors in teleost fishes and compares the findings to the human system. The impact of the duplicated genome in teleost fishes on steroid hormone biosynthesis and perception is addressed. Additionally, important processes in fish physiology regulated by steroid hormones, which are most dissimilar to humans, are described. We also give a short overview on the influence of anthropogenic endocrine disrupting compounds on steroid hormone signaling and the resulting adverse physiological effects for teleost fishes. By this approach, we show that the steroidogenesis, hormone receptors, and function of the steroid hormones are reasonably well understood when summarizing the available data of all teleost species analyzed to date. However, on the level of a single species or a certain fish-specific aspect of physiology, further research is needed. Copyright © 2015 Elsevier Inc. All rights reserved.

Astrocyte–endothelial interactions and blood–brain barrier permeability*

PubMed Central

Abbott, N Joan

2002-01-01

The blood–brain barrier (BBB) is formed by brain endothelial cells lining the cerebral microvasculature, and is an important mechanism for protecting the brain from fluctuations in plasma composition, and from circulating agents such as neurotransmitters and xenobiotics capable of disturbing neural function. The barrier also plays an important role in the homeostatic regulation of the brain microenvironment necessary for the stable and co-ordinated activity of neurones. The BBB phenotype develops under the influence of associated brain cells, especially astrocytic glia, and consists of more complex tight junctions than in other capillary endothelia, and a number of specific transport and enzyme systems which regulate molecular traffic across the endothelial cells. Transporters characteristic of the BBB phenotype include both uptake mechanisms (e.g. GLUT-1 glucose carrier, L1 amino acid transporter) and efflux transporters (e.g. P-glycoprotein). In addition to a role in long-term barrier induction and maintenance, astrocytes and other cells can release chemical factors that modulate endothelial permeability over a time-scale of seconds to minutes. Cell culture models, both primary and cell lines, have been used to investigate aspects of barrier induction and modulation. Conditioned medium taken from growing glial cells can reproduce some of the inductive effects, evidence for involvement of diffusible factors. However, for some features of endothelial differentiation and induction, the extracellular matrix plays an important role. Several candidate molecules have been identified, capable of mimicking aspects of glial-mediated barrier induction of brain endothelium; these include TGFβ, GDNF, bFGF, IL-6 and steroids. In addition, factors secreted by brain endothelial cells including leukaemia inhibitory factor (LIF) have been shown to induce astrocytic differentiation. Thus endothelium and astrocytes are involved in two-way induction. Short-term modulation of brain endothelial permeability has been shown for a number of small chemical mediators produced by astrocytes and other nearby cell types. It is clear that endothelial cells are involved in both long- and short-term chemical communication with neighbouring cells, with the perivascular end feet of astrocytes being of particular importance. The role of barrier induction and modulation in normal physiology and in pathology is discussed. PMID:12162730

Wegener's granulomatosis occurring de novo during pregnancy.

PubMed

Alfhaily, F; Watts, R; Leather, A

2009-01-01

Wegener's granulomatosis (WG) is rarely diagnosed during the reproductive years and uncommonly manifests for the first time during pregnancy. We report a case of de novo WG presenting at 30 weeks gestation with classical symptoms of WG (ENT, pulmonary). The diagnosis was confirmed by radiological, laboratory, and histological investigations. With a multidisciplinary approach, she had a successful vaginal delivery of a healthy baby. She was treated successfully by a combination of steroids, azathioprine and intravenous immunoglobulin in the active phase of disease for induction of remission and by azathioprine and steroids for maintenance of remission. The significant improvement in her symptoms allowed us to continue her pregnancy to 37 weeks when delivery was electively induced. Transplacental transmission of PR3-ANCA occurred but the neonate remained well. This case of de novo WG during pregnancy highlights the seriousness of this disease and the challenge in management of such patients.

Effects of Sex Steroids in the Human Brain.

PubMed

Nguyen, Tuong-Vi; Ducharme, Simon; Karama, Sherif

2017-11-01

Sex steroids are thought to play a critical developmental role in shaping both cortical and subcortical structures in the human brain. Periods of profound changes in sex steroids invariably coincide with the onset of sex differences in mental health vulnerability, highlighting the importance of sex steroids in determining sexual differentiation of the brain. Yet, most of the evidence for the central effects of sex steroids relies on non-human studies, as several challenges have limited our understanding of these effects in humans: the lack of systematic assessment of the human sex steroid metabolome, the different developmental trajectories of specific sex steroids, the impact of genetic variation and epigenetic changes, and the plethora of interactions between sex steroids, sex chromosomes, neurotransmitters, and other hormonal systems. Here we review how multimodal strategies may be employed to bridge the gap between the basic and clinical understanding of sex steroid-related changes in the human brain.

OKT3 treatment for steroid-resistant acute rejection in kidney transplantation.

PubMed

Sevmis, S; Emiroglu, R; Karakayali, F; Yagmurdur, M C; Dalgic, A; Moray, G; Haberal, M

2005-09-01

Orthoclone (OKT3, Ortho Biotech Inc, USA) monoclonal antilymphocyte antibody is a powerful T-cell-specific immunosuppressive agent. OKT3 has been used for induction therapy in kidney and liver transplantation, as well as to treat acute or steroid-resistant acute rejection episodes (ARE). This study was a retrospective analysis of 43 renal transplant recipients who developed steroid-resistant ARE and were treated with OKT3 between September 1994 and June 2004. The recipients were 36 men and 7 women of mean age 32.7 +/- 11.6 years (range, 19 to 48 years). The mean time from transplantation to OKT3 treatment was 7.2 +/- 6.7 months. Thirty-four episodes (79.1%) responded to OKT3 therapy with improved graft function, but the remaining 9 (20.9%) grafts did not respond. Among the 34 OKT3 responders, the mean serum creatinine decreased from 3.96 +/- 2.5 mg/dL to 2.45 +/- 1.77 mg/dL after treatment. Eleven (25.6%) of the 43 patients experienced minor side effects: fever, dyspnea, tachycardia, bradycardia. One patient (2.3%) developed acute pulmonary edema; one (2.3%), cytomegalovirus infection; and eight (18.6%), bacterial infections. The 1-, 3-, and 5-year graft survival rates for the 34 patients who responded to OKT3 therapy were 96%, 93%, and 85%, respectively. All patients are currently alive. The results indicate that OKT3 is a safe, effective treatment choice for steroid-resistant ARE in kidney transplantation.

Diabetes Insipidus

MedlinePlus

... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... an Endocrinologist Clinical Trials Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ...

Perioperative single high dose ATG-Fresenius S administration as induction immunosuppressive therapy in cadaveric renal transplantation--preliminary results.

PubMed

Samsel, R; Chmura, A; Włodarczyk, Z; Wyzgał, J; Cieciura, T; Lagiewska, B; Pliszczyński, J; Korczak, G; Lazowski, T; Paczek, L; Wałaszewski, J; Lao, M; Rowiński, W

1999-01-01

Monoclonal and polyclonal antilymphocyte antibodies have been used successfully in organ transplantation as induction therapy and in the treatment of acute graft rejection. Used for induction the medication is generally given for the first 7-10 days. The aim of this study was to assess the safety and efficacy of single high dose (9 mg/kg) ATG Fresenius S given perioperatively, before revascularization, to kidney allograft recipients. During last twelve months seventy six, first cadaveric kidney adult recipients were included into the study in two centers (center A-64, center B-12). All patients received triple drug immunosuppression (Neoral, steroids and Cellcept which was replaced by azathioprine after 4 months), and were randomized to receive ATG or not. The follow-up period ranged from 1 month up to 1 year. The preliminary results are very promising, the rejection rate in bolus group was significantly lower than in control. No significant side effects or serious adverse events in both groups were observed.

Dexamethasone Does Not Inhibit Sugammadex Reversal After Rocuronium-Induced Neuromuscular Block.

PubMed

Buonanno, Pasquale; Laiola, Anna; Palumbo, Chiara; Spinelli, Gianmario; Servillo, Giuseppe; Di Minno, Raffaele Maria; Cafiero, Tullio; Di Iorio, Carlo

2016-06-01

Sugammadex is a relatively new molecule that reverses neuromuscular block induced by rocuronium. The particular structure of sugammadex traps the cyclopentanoperhydrophenanthrene ring of rocuronium in its hydrophobic cavity. Dexamethasone shares the same steroidal structure with rocuronium. Studies in vitro have demonstrated that dexamethasone interacts with sugammadex, reducing its efficacy. In this study, we investigated the clinical relevance of this interaction and its influence on neuromuscular reversal. In this retrospective case-control study, we analyzed data from 45 patients divided into 3 groups: dexamethasone after induction group (15 patients) treated with 8 mg dexamethasone as an antiemetic drug shortly after induction of anesthesia; dexamethasone before reversal group (15 patients) treated with dexamethasone just before sugammadex injection; and control group (15 patients) treated with 8 mg ondansetron. All groups received 0.6 mg/kg rocuronium at induction, 0.15 mg/kg rocuronium at train-of-four ratio (TOF) 2 for neuromuscular relaxation, and 2 mg/kg sugammadex for reversal at the end of the procedure at TOF2. Neuromuscular relaxation was monitored with a TOF-Watch® system. The control group had a recovery time of 154 ± 54 seconds (mean ± SD), the dexamethasone after induction group 134 ± 55 seconds, and the dexamethasone before reversal group 131 ± 68 seconds. The differences among groups were not statistically significant (P = 0.5141). Our results show that the use of dexamethasone as an antiemetic drug for the prevention of postoperative nausea and vomiting does not interfere with reversal of neuromuscular blockade with sugammadex in patients undergoing elective surgery with general anesthesia in contrast to in vitro studies that support this hypothesis.

Adverse Effects of Nonsystemic Steroids (Inhaled, Intranasal, and Cutaneous): a Review of the Literature and Suggested Monitoring Tool.

PubMed

Gupta, Ratika; Fonacier, Luz S

2016-06-01

Inhaled, intranasal, and cutaneous steroids are prescribed by physicians for a plethora of disease processes including asthma and rhinitis. While the high efficacy of this class of medication is well known, the wide range of adverse effects, both local and systemic, is not well elucidated. It is imperative to monitor total steroid burden in its varied forms as well as tracking for possible side effects that may be caused by a high cumulative dose of steroids. This review article highlights the adverse effects of different steroid modalities as well as suggests a monitoring tool to determine steroid totality and side effects.

Steroid/Antiviral for the treatment of Bell's palsy: Double blind randomized clinical trial.

PubMed

Khedr, Eman Mohamed; Badry, Reda; Ali, Anwer Mohamed; Abo El-Fetoh, Noha; El-Hammady, Dina Hatem; Ghandour, Abeer Mohamed; Abdel-Haleem, Ahmed

2016-11-22

A large number of patients with Bell's palsy fail to recover facial function completely after steroid therapy. Only a few small trials have been conducted to test whether outcomes can be improved by the addition of antiviral therapy. To evaluate the efficacy of treatment with steroid alone versus steroid + antiviral in a group of patients with moderately severe to severe acute Bell's palsy. Fifty eligible patients out of a total of 65 with acute onset Bell's palsy were randomized to receive the two treatments. Evaluation was performed before starting treatment, after 2 weeks of treatment and 3 months after onset, using the House and Brackmann facial nerve grading system (HB) and the Sunnybrook grading system.This study was registered with ClinicalTrials.gov, number NCT02328079. Both treatments had comparable demographics and clinical scores at baseline. There was greater improvement in the mean HB and Sunnybrook scores of the steroid + antiviral group in comparison to steroid group at 3 months. At the end of the 3rd month, 17 patients (68%) had good recovery and 8 patients (32%) had poor recovery in the steroid group compared with 23 patients (92%) and 2 (8%) respectively in the steroid and antiviral group (p = 0.034). The combination of steroid and antiviral treatment increases the possibility of recovery in moderately severe to complete acute Bell's palsy.

Steroid receptors and their ligands: Effects on male gamete functions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aquila, Saveria; De Amicis, Francesca, E-mail: francesca.deamicis@unical.it

In recent years a new picture of human sperm biology is emerging. It is now widely recognized that sperm contain nuclear encoded mRNA, mitochondrial encoded RNA and different transcription factors including steroid receptors, while in the past sperm were considered incapable of transcription and translation. One of the main targets of steroid hormones and their receptors is reproductive function. Expression studies on Progesterone Receptor, estrogen receptor, androgen receptor and their specific ligands, demonstrate the presence of these systems in mature spermatozoa as surface but also as nuclear conventional receptors, suggesting that both systemic and local steroid hormones, through sperm receptors,more » may influence male reproduction. However, the relationship between the signaling events modulated by steroid hormones and sperm fertilization potential as well as the possible involvement of the specific receptors are still controversial issues. The main line of this review highlights the current research in human sperm biology examining new molecular systems of response to the hormones as well as specific regulatory pathways controlling sperm cell fate and biological functions. Most significant studies regarding the identification of steroid receptors are reported and the mechanistic insights relative to signaling pathways, together with the change in sperm metabolism energy influenced by steroid hormones are discussed.The reviewed evidences suggest important effects of Progesterone, Estrogen and Testosterone and their receptors on spermatozoa and implicate the involvement of both systemic and local steroid action in the regulation of male fertility potential. - Highlights: • One of the main targets of steroid hormones and their receptors is reproductive function. • Pg/PR co-work to stimulate enzymatic activities to sustain a capacitation process. • E2/ERs regulate sperm motility, capacitation and acrosome reaction and act as survival factors. • Androgens/AR mediate sperm death which is a novel field of investigation in sperm biology.« less

Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients.

PubMed

Hill, Penny; Cross, Nicholas B; Barnett, A Nicholas R; Palmer, Suetonia C; Webster, Angela C

2017-01-11

Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non-depleting interleukin-2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte-depleting antibodies but the relative benefits and harms of the available agents are uncertain. We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients). Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates.Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death-censored graft loss was uncertain at 1 to 2 years and 5 years. In non-CNI studies, ATG had uncertain effects on death but reduced death-censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non-CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all-cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death-censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post-transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT).Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death-censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD -13.35 mL/min, -23.91 to -2.80) and 2 years (2 studies: MD -12.86 mL/min, -23.73 to -2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all-cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance.Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all-cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD.Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo. ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non-CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection.In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG.Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient-centred outcomes (reduced death or lower toxicity) do not appear to be improved.

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis.

PubMed

Bebo, Bruce F; Dehghani, Babak; Foster, Scott; Kurniawan, Astrid; Lopez, Francisco J; Sherman, Larry S

2009-05-01

Steroidal estrogens can regulate inflammatory immune responses and may be involved in the suppression of multiple sclerosis (MS) during pregnancy. However, the risks and side effects associated with steroidal estrogens may limit their usefulness for long-term MS therapy. Selective estrogen receptor modulators (SERMs) could provide an alternative therapeutic strategy, because they behave as estrogen agonists in some tissues, but are either inert or behave like estrogen antagonists in other tissues. In this study, we investigated the ability of two commercially available SERMs (tamoxifen and raloxifene) to regulate myelin specific immunity and experimental autoimmune encephalomyelitis (EAE) in mice. Both tamoxifen and raloxifene suppressed myelin antigen specific T-cell proliferation. However, tamoxifen was more effective in this regard. Tamoxifen treatment reduced the induction of major histocompatibility complex II by lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific T-cells. At lower doses, tamoxifen was found to increase the levels of Th2 transcription factors and induce a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of demyelination were less severe in mice treated with tamoxifen than in control mice. These findings support the notion that tamoxifen or related SERMs are potential agents that could be used in the treatment of inflammatory autoimmune disorders that affect the central nervous system.

Effect of composting on the fate of steroids in beef cattle manure.

PubMed

Bartelt-Hunt, Shannon L; Devivo, Shannon; Johnson, Leslie; Snow, Daniel D; Kranz, William L; Mader, Terry L; Shapiro, Charles A; van Donk, Simon J; Shelton, David P; Tarkalson, David D; Zhang, Tian C

2013-07-01

In this study, the fate of steroid hormones in beef cattle manure composting is evaluated. The fate of 16 steroids and metabolites was evaluated in composted manure from beef cattle administered growth promotants and from beef cattle with no steroid hormone implants. The fate of estrogens (primary detected as estrone), androgens, progesterone, and the fusarium metabolite and implant α-zearalanol was monitored in manure compost piles. First-order decay rates were calculated for steroid half-lives in compost and ranged from 8 d for androsterone to 69 d for 4-androstenedione. Other steroid concentration data could not be fit to first-order decay models, which may indicate that microbial processes may result in steroid production or synthesis in composting systems. We demonstrate that composting is an effective strategy to remove steroid hormones from manure. Total steroid hormone removal in composted beef cattle manure ranged from 79 to 87%. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Neuroactive steroids and PTSD treatment.

PubMed

Rasmusson, Ann M; Marx, Christine E; Pineles, Suzanne L; Locci, Andrea; Scioli-Salter, Erica R; Nillni, Yael I; Liang, Jennifer J; Pinna, Graziano

2017-05-10

This review highlights early efforts to translate pre-clinical and clinical findings regarding the role of neuroactive steroids in stress adaptation and PTSD into new therapeutics for PTSD. Numerous studies have demonstrated PTSD-related alterations in resting levels or the reactivity of neuroactive steroids and their targets. These studies also have demonstrated substantial variability in the dysfunction of specific neuroactive steroid systems among PTSD subpopulations. These variabilities have been related to the developmental timing of trauma, severity and type of trauma, genetic background, sex, reproductive state, lifestyle influences such as substance use and exercise, and the presence of comorbid conditions such as depression and chronic pain. Nevertheless, large naturalistic studies and a small placebo-controlled interventional study have revealed generally positive effects of glucocorticoid administration in preventing PTSD after trauma, possibly mediated by glucocorticoid receptor-mediated effects on other targets that impact PTSD risk, including other neuroactive steroid systems. In addition, clinical and preclinical studies show that administration of glucocorticoids, 17β-estradiol, and GABAergic neuroactive steroids or agents that enhance their synthesis can facilitate extinction and extinction retention, depending on dose and timing of dose in relation to these complex PTSD-relevant recovery processes. This suggests that clinical trials designed to test neuroactive steroid therapeutics in PTSD may benefit from such considerations; typical continuous dosing regimens may not be optimal. In addition, validated and clinically accessible methods for identifying specific neuroactive steroid system abnormalities at the individual level are needed to optimize both clinical trial design and precision medicine based treatment targeting. Copyright © 2017. Published by Elsevier B.V.

A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes.

PubMed

Stevens, R Brian; Foster, Kirk W; Miles, Clifford D; Lane, James T; Kalil, Andre C; Florescu, Diana F; Sandoz, John P; Rigley, Theodore H; Nielsen, Kathleen J; Skorupa, Jill Y; Kellogg, Anna M; Malik, Tamer; Wrenshall, Lucile E

2015-01-01

We conducted a randomized and unblinded 2 × 2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor-withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose-rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.

A Randomized 2×2 Factorial Trial, Part 1: Single-Dose Rabbit Antithymocyte Globulin Induction May Improve Renal Transplantation Outcomes

PubMed Central

Stevens, R. Brian; Foster, Kirk W.; Miles, Clifford D.; Lane, James T.; Kalil, Andre C.; Florescu, Diana F.; Sandoz, John P.; Rigley, Theodore H.; Nielsen, Kathleen J.; Skorupa, Jill Y.; Kellogg, Anna M.; Malik, Tamer; Wrenshall, Lucile E.

2015-01-01

Background We conducted a randomized and unblinded 2×2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. Methods Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor–withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. Results Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose–rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. Conclusion The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety. PMID:25083614

The Fate and Transport of Reproductive Hormones and Their Conjugates in the Environment

USDA-ARS?s Scientific Manuscript database

Reproductive steroid hormones can disrupt the endocrine system of some species at ng/L concentrations. Sources of steroid hormones to the environment include human waste water effluents or manure produced at animal feeding operations (AFOs). Steroid hormones, such as 17ß-estradiol (E2) and estrone (...

Stereotypical architecture of the stem cell niche is spatiotemporally established by miR-125-dependent coordination of Notch and steroid signaling.

PubMed

Yatsenko, Andriy S; Shcherbata, Halyna R

2018-02-08

Stem cell niches act as signaling platforms that regulate stem cell self-renewal and sustain stem cells throughout life; however, the specific developmental events controlling their assembly are not well understood. Here, we show that during Drosophila ovarian germline stem cell niche formation, the status of Notch signaling in the cell can be reprogrammed. This is controlled via steroid-induced miR-125 , which targets a negative regulator of Notch signaling, Tom. Thus, miR-125 acts as a spatiotemporal coordinator between paracrine Notch and endocrine steroid signaling. Moreover, a dual security mechanism for Notch signaling activation exists to ensure the robustness of niche assembly. Particularly, stem cell niche cells can be specified either via lateral inhibition, in which a niche cell precursor acquires Notch signal-sending status randomly, or via peripheral induction, whereby Delta is produced by a specific cell. When one mechanism is perturbed due to mutations, developmental defects or environmental stress, the remaining mechanism ensures that the niche is formed, perhaps abnormally, but still functional. This guarantees that the germline stem cells will have their residence, thereby securing progressive oogenesis and, thus, organism reproduction. © 2018. Published by The Company of Biologists Ltd.

Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate the CYP3A23 Hormone Response Element

PubMed Central

SCHUETZ, ERIN G.; BRIMER, CYNTHIA; SCHUETZ, JOHN D.

2013-01-01

The pregnenolone X receptor (PXR), a new member of the nuclear hormone receptor superfamily, was recently demonstrated to mediate glucocorticoid agonist and antagonist activation of a hormone response element spaced by three nucleotides (DR-3) within the rat CYP3A23 promoter. Because many other steroids and xenobiotics can up-regulate CYP3A23 expression, we determined whether some of these other regulators used PXR to activate the CYP3A23 DR-3. Transient cotransfection of LLC-PK1 cells with (CYP3A23)2-tk-CAT and mouse PXR demonstrated that the organochlorine pesticides transnonachlor and chlordane and the nonplanar polychlorinated biphenyls (PCBs) each induced the CYP3A23 DR-3 element, and this activation required PXR. Additionally, this study found that PXR is activated to induce (CYP3A23)2-tk-CAT by antihormones of several steroid classes including the antimineralocorticoid spironolactone and the antiandrogen cyproterone acetate. These studies reveal that PXR is involved in the induction of CYP3A23 by pharmacologically and structurally distinct steroids and xenobiotics. Moreover, PXR-mediated PCB activation of the (CYP3A23)2-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs. PMID:9855641

Corticosteroids and Other Anti-Inflammatory Strategies in Pediatric Heart Surgery: A National Survey of Practice.

PubMed

Fudulu, Daniel P; Schadenberg, Alvin; Gibbison, Ben; Jenkins, Ian; Lightman, Stafford; Angelini, Gianni D; Stoica, Serban

2018-05-01

The role of steroids to mitigate the deleterious effects of pediatric cardiopulmonary bypass (CPB) remains a matter of debate; therefore, we aimed to assess preferences in administering corticosteroids (CSs) and the use of other anti-inflammatory strategies in pediatric cardiac surgery. A 19-question survey was distributed to consultants in pediatric cardiac anesthesia from 12 centers across the United Kingdom and Ireland. Of the 37 respondents (37/60, 62%), 24 (65%) use CSs, while 13 (35%) do not use steroids at all. We found variability within 5 (41%) of the 12 centers. Seven consultants (7/24, 29%) administer CSs in every case, while 17 administer CSs in selected cases only (17/24, 71%). There was variability in the dose of steroid administration. Almost all consultants (23/24, 96%) administer a single dose at induction, and one administers a two-dose regimen (1/24, 4%). There was variability in CS indications. Most consultants (24/37, 66%) use modified ultrafiltration at the conclusion of CPB. Fifteen consultants (15/32, 47%) report the use of aprotinin, while only 3 use heparin-coated circuits (3/24, 9%). We found wide variability in practice in the administration of CSs for pediatric cardiac surgery, both within and between units. While most anesthetists administer CSs in at least some cases, there is no consensus on the type of steroid, the dose, and at which patient groups this should be directed. Modified ultrafiltration is still used by most of the centers. Almost half of consultants use aprotinin, while heparin-coated circuits are infrequently used.

Production of malodorous steroids from androsta-5,16-dienes and androsta-4,16-dienes by Corynebacteria and other human axillary bacteria.

PubMed

Decréau, Richard A; Marson, Charles M; Smith, Kelvin E; Behan, John M

2003-12-01

The biotransformations of a number of steroids, chiefly 5,6,16,17-tetradehydro-androstanes, are reported. The strains investigated were Corynebacteria sp. G38, G40, G41, B, Brevis sp. CW5 and Micrococcus sp. M-DH2. Corynebacterium sp. G41 proved remarkably efficient in effecting oxidative isomerisation of 5-ene-3-sterols into the corresponding 4-en-3-ones. The main biochemical reactions involved were oxidation at C-3; no reduction processes were observed. Conversions of 3beta-sterols into the C-3 oxo-steroids were high, but were correspondingly low for the 3alpha-sterol epimers. Androsta-4,16-dien-3-one and 5beta-androsta-16-en-3-one are crucial to the formation of malodour. The rate of formation of these compounds was measured over 72 h incubation periods using three substrates: androsta-5,16-dien-3beta-ol, androsta-4,16-dien-3beta-ol and androsta-5,16-dien-3-one. Induction studies of the transformation of the androsta-5,16-dien-3beta-ol into the very odorous compound androsta-4,16-dien-3-one showed that cells incubated with a mixture of antibiotics displayed the same extent of biotransformation as normal cells if the concentration of antibiotic was low (1, 3, 5 and 7 microg/ml), although at concentrations higher than 10 microg/ml, biotransformation yields were reduced. Pre-incubation with a 3beta-fluoro-steroid inhibited the formation of the odorous androsta-4,16-dien-3-one.

Effect of immune stress on body weight regulation is altered by ovariectomy in female rats.

PubMed

Iwasa, Takeshi; Matsuzaki, Toshiya; Kinouchi, Riyo; Gereltsetseg, Ganbat; Murakami, Masahiro; Nakazawa, Hiroshi; Fujisawa, Shinobu; Yamamoto, Satoshi; Kuwahara, Akira; Yasui, Toshiyuki; Irahara, Minoru

2011-09-01

It has been suggested that obesity and loss of ovarian function alter the inflammatory response to immune stress. Ovariectomized (OVX) rats, which are used as a model of human menopause, exhibit both hyperphagia-induced obesity and gonadal steroid deficiency. To evaluate the effects of ovariectomy on inflammatory responses, we compared the anorectic response to LPS in OVX rats and gonad intact female rats. As leptin and hypothalamic interleukin-1β (IL1β) play pivotal roles in the anorectic response to immune stress, these factors were also measured. It was found that the OVX rats exhibited an increased anorectic response to LPS compared with the sham-operated rats. The OVX rats showed higher serum leptin concentrations and a greater increase in hypothalamic IL1β mRNA expression after LPS injection. In addition, in order to determine whether gonadal steroid deficiency contributes to the changes in the inflammatory responses of OVX rats, we compared responses between OVX rats treated with gonadal steroids and untreated OVX rats. There were no differences in appetite, the serum leptin level, and hypothalamic IL1β mRNA expression between the two groups after LPS injection. These findings suggest that the loss of ovarian function increases the induction of leptin and hypothalamic IL1β synthesis and consequently increases the anorectic response under immune stress conditions. It is possible that these alterations are caused by OVX-induced obesity rather than the direct effects of gonadal steroid deficiency. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Steroid Avoidance in Pediatric Heart Transplantation Results in Excellent Graft Survival

PubMed Central

Auerbach, Scott R.; Gralla, Jane; Campbell, David N.; Miyamoto, Shelley D.; Pietra, Biagio A.

2018-01-01

Background Maintenance steroid (MS) use in pediatric heart transplantation (HT) varies across centers. The purpose of this study was to evaluate the impact of steroid-free maintenance immunosuppression (SF) on graft outcomes in pediatric HT. Methods Patients younger than 18 years in the United States undergoing a first HT during 1990 to 2010 were analyzed for conditional 30-day graft loss (death or repeat HT) and death based on MS use by multivariable analysis. A propensity score was then given to each patient using a logistic model, and propensity matching was performed using pre-HT risk factors, induction therapy, and nonsteroid maintenance immunosuppression. Kaplan-Meier graft and patient survival probabilities by MS use were then calculated. Results Of 4894 patients, 3962 (81%) were taking MS and 932 (19%) SF. Of the 4530 alive at 30 days after HT, 3694 (82%) and 836 (18%) were in the MS and SF groups, respectively. Unmatched multivariable analysis showed no difference in 30-day conditional graft survival between MS and SF groups (hazard ratio=1.08, 95% confidence interval=0.93-1.24; P=0.33). Propensity matching resulted in 462 patients in each MS and SF group. Propensity-matched Kaplan-Meier survival analysis showed no difference in graft or patient survival between groups (P=0.3 and P=0.16, respectively). Conclusions We found no difference in graft survival between SF patients and those taking MS. An SF regimen in pediatric HT avoids potential complications of steroid use without compromising graft survival, even after accounting for pre-HT risk factors. PMID:24389908

Simultaneous determination of thirteen different steroid hormones using micro UHPLC-MS/MS with on-line SPE system.

PubMed

Márta, Zoltán; Bobály, Balázs; Fekete, Jenő; Magda, Balázs; Imre, Tímea; Mészáros, Katalin Viola; Bálint, Mária; Szabó, Pál Tamás

2018-02-20

Ultratrace analysis of sample components requires excellent analytical performance in terms of limits of quantitation (LOQ). Micro UHPLC coupled to sensitive tandem mass spectrometry provides state of the art solution for such analytical problems. Using on-line SPE with column switching on a micro UHPLC-MS/MS system allowed to decrease LOQ without any complex sample preparation protocol. The presented method is capable of reaching satisfactory low LOQ values for analysis of thirteen different steroid molecules from human plasma without the most commonly used off-line SPE or compound derivatization. Steroids were determined by using two simple sample preparation methods, based on lower and higher plasma steroid concentrations. In the first method, higher analyte concentrations were directly determined after protein precipitation with methanol. The organic phase obtained from the precipitation was diluted with water and directly injected into the LC-MS system. In the second method, low steroid levels were determined by concentrating the organic phase after steroid extraction. In this case, analytes were extracted with ethyl acetate and reconstituted in 90/10 water/acetonitrile following evaporation to dryness. This step provided much lower LOQs, outperforming previously published values. The method has been validated and subsequently applied to clinical laboratory measurement. Copyright © 2017 Elsevier B.V. All rights reserved.

Androgenic signaling systems and their role in behavioral evolution.

PubMed

Fuxjager, Matthew J; Schuppe, Eric R

2018-06-05

Sex steroids mediate the organization and activation of masculine reproductive phenotypes in diverse vertebrate taxa. However, the effects of sex steroid action in this context vary tremendously, in that steroid action influences reproductive physiology and behavior in markedly different ways (even among closely related species). This leads to the idea that the mechanisms underlying sex steroid action similarly differ across vertebrates in a manner that supports diversification of important sexual traits. Here, we highlight the Evolutionary Potential Hypothesis as a framework for understanding how androgen-dependent reproductive behavior evolves. This idea posits that the cellular mechanisms underlying androgenic action can independently evolve within a given target tissue to adjust the hormone's functional effects. The result is a seemingly endless number of permutations in androgenic signaling pathways that can be mapped onto the incredible diversity of reproductive phenotypes. One reason this hypothesis is important is because it shifts current thinking about the evolution of steroid-dependent traits away from an emphasis on circulating steroid levels and toward a focus on molecular mechanisms of hormone action. To this end, we also provide new empirical data suggesting that certain cellular modulators of androgen action-namely, the co-factors that dynamically adjust transcritpional effects of steroid action either up or down-are also substrates on which evolution can act. We then close the review with a detailed look at a case study in the golden-collared manakin (Manacus vitellinus). Work in this tropical bird shows how androgenic signaling systems are modified in specific parts of the skeletal muscle system to enhance motor performance necessary to produce acrobatic courtship displays. Altogether, this paper seeks to develop a platform to better understand how steroid action influences the evolution of complex animal behavior. Copyright © 2018 Elsevier Ltd. All rights reserved.

Selection and use of crystallization inhibitors for matrix-type transdermal drug-delivery systems containing sex steroids.

PubMed

Lipp, R

1998-12-01

The purpose of this study was to stabilize transdermal drug-delivery systems (TDDS) highly loaded with sex steroids against recrystallization of drugs during storage. To facilitate the selection of potential crystallization inhibitors a drug-excipient interaction test was also established. Analysis of the thermal behaviour of 1:1 steroid-excipient mixtures by differential scanning calorimetry (DSC) revealed that oestradiol and gestodene interact strongly with silicone dioxide and povidones, e.g. povidone K12. The addition of povidone K12 to polyacrylate-based matrix TDDS containing either 3% oestradiol or 2% gestodene resulted in stable systems which did not recrystallize during storage at 25 degrees C for more than 5 years. Significant recrystallization was, on the other hand, observed in non-stabilized reference patches even after 1 to 2 months storage. The DSC screening model proved very effective for selection of inhibitors of the crystallization of sex steroids in matrix TDDS. The crystallization inhibitor approach is a highly versatile stabilization tool for matrix patches containing high concentrations of sex steroids.

The Regulation of Steroid Action by Sulfation and Desulfation

PubMed Central

Mueller, Jonathan W.; Gilligan, Lorna C.; Idkowiak, Jan; Arlt, Wiebke

2015-01-01

Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined. PMID:26213785

Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland.

PubMed

Johnson, Michael D; Kenney, Nicholas; Stoica, Adriana; Hilakivi-Clarke, Leena; Singh, Baljit; Chepko, Gloria; Clarke, Robert; Sholler, Peter F; Lirio, Apolonio A; Foss, Colby; Reiter, Ronald; Trock, Bruce; Paik, Soonmyoung; Martin, Mary Beth

2003-08-01

It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

Update on the Systemic Risks of Superpotent Topical Steroids.

PubMed

Nakamura, Mio; Abrouk, Michael; Zhu, Henry; Farahnik, Benjamin; Koo, John; Bhutani, Tina

2017-07-01

INTRODUCTION: The potential for systemic effects due to percutaneous absorption of superpotent topical steroids has been a longstanding concern. The Food and Drug Administration currently recommends limiting the use of superpotent topical steroids to 50g per week for 2 or 4 consecutive weeks depending on the formulation, which is mostly based on the exact duration with which phase 3 clinical trials were allowed to be conducted per the FDA. This article reviews all published clinical incidence of adrenal adverse effects in the medical literature, specifically Cushing's syndrome (CS) and pathologic adrenal suppression (PAAS), to try to ascertain a more realistic limit for the safe use of superpotent topical steroids as it pertains to its potential systemic effects.

METHODS: Literature search was conducted using PubMed. Only cases of CS and PAAS secondary to the use of Class I superpotent topical steroids were included. Pediatric cases and full articles unavailable in English were excluded.

RESULTS: There were a total of 14 cases of CS and 5 cases of subsequent PAAS found in the current literature.

DISCUSSION: From our review of these cases, if the amount used per week is within FDA guidelines, it appears that patients needed to use superpotent topical steroids for far greater than 2 or 4 weeks to develop CS or PAAS. CS did not necessarily predict occurrence of PAAS, but in all cases CS appeared to be a prerequisite for developing PAAS. All cases of CS and all but one case of PAAS were reversible. If excessive amount of greater than 50g per week is avoided, it appears that superpotent topical steroids may be safe to use consecutively for months, perhaps even years, without causing systemic effects.

J Drugs Dermatol. 2017;16(7):643-648.

Activation of coagulation by a thalidomide-based regimen.

PubMed

Hoshi, Asuka; Matsumoto, Aya; Chung, Jihwa; Isozumi, Yu; Koyama, Takatoshi

2011-09-01

Combining thalidomide (Thal) with chemotherapeutic agents or steroid preparations led to improved response rates in the treatment of multiple myeloma. However, deep vein thrombosis (DVT) is one of the most serious side-effects noted with this regimen, and how a Thal-based regimen causes DVT is unclear. We investigated the procoagulant effects of Thal when combined with chemotherapeutic agents in vitro, focusing on tissue factor (TF) and phosphatidylserine. We examined the effects of the chemotherapeutic doxorubicin hydrochloride (Dox) and the steroid dexamethasone (Dex), with or without Thal. Our study used the human vascular endothelial, monocytic, and myeloma cell lines, EAhy926, THP-1, and RPMI8226, respectively. In EAhy926 and THP-1, Dex treatment increased expression of TF, which may induce procoagulant activity (PCA). Upregulation of TF mRNA correlated with activation of the Egr-1 pathway. In Thal and Dex treatments, the increase of PCA induction from phosphatidylserine exposure was modest. In contrast, Dox and Thal-Dox increased phosphatidylserine exposure in both cell types. In THP-1 cells, cell surface phosphatidylserine exposure correlated with increased PCA by Dox. Thal alone showed a modest increase in phosphatidylserine exposure in endothelial cells and monocytes. When Thal is given in combination with chemotherapies or Dex, endothelial cell and monocyte PCA may be induced through phosphatidylserine exposure, or TF expression. Induction may be protracted by Thal, which has an antiangiogenic activity. Therefore, prophylactic anticoagulant strategies should be considered in Thal-based combination regimens.

Endocrine modulation of the adolescent brain: a review.

PubMed

Vigil, Pilar; Orellana, Renán F; Cortés, Manuel E; Molina, Carmen T; Switzer, Barbara E; Klaus, Hanna

2011-12-01

Neurophysiological and behavioral development is particularly complex in adolescence. Youngsters experience strong emotions and impulsivity, reduced self-control, and preference for actions which offer immediate rewards, among other behavioral patterns. Given the growing interest in endocrine effects on adolescent central nervous system development and their implications on later stages of life, this article reviews the effects of gonadal steroid hormones on the adolescent brain. These effects are classified as organizational, the capacity of steroids to determine nervous system structure during development, and activational, the ability of steroids to modify nervous activity to promote certain behaviors. During transition from puberty to adolescence, steroid hormones trigger various organizational phenomena related to structural brain circuit remodelling, determining adult behavioral response to steroids or sensory stimuli. These changes account for most male-female sexual dimorphism. In this stage sex steroids are involved in the main functional mechanisms responsible for organizational changes, namely myelination, neural pruning, apoptosis, and dendritic spine remodelling, activated only during embryonic development and during the transition from puberty to adolescence. This stage becomes a critical organizational window when the appropriately and timely exerted functions of steroid hormones and their interaction with some neurotransmitters on adolescent brain development are fundamental. Thus, understanding the phenomena linking steroid hormones and adolescent brain organization is crucial in the study of teenage behavior and in later assessment and treatment of anxiety, mood disorders, and depression. Adolescent behavior clearly evidences a stage of brain development influenced for the most part by steroid hormones. Copyright © 2011 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Dose intraarticular steroid injection increase the rate of infection in subsequent arthroplasty: grading the evidence through a meta-analysis.

PubMed

Xing, Dan; Yang, Yang; Ma, Xinlong; Ma, Jianxiong; Ma, Baoyi; Chen, Yang

2014-11-13

Intraarticular steroid injections are widely used in joint arthritis. However, the data regarding an association between an increased risk for arthroplasty infection after an intraarticular steroid injection are still conflicting. We conducted a meta-analysis to evaluate the evidence from relevant studies that examine the relation between intraarticular steroid injections and infection rates in subsequent joint arthroplasty and to develop GRADE based recommendations for using the steroid before arthroplasty. A systematic search of all studies published through August 2014 was conducted using the MEDLINE, EMBASE, OVID, ScienceDirect and Cochrane CENTRAL databases. The relevant studies that examined the relation between intraarticular steroid injections and infection rates in subsequent joint arthroplasty were identified. Demographic characteristics, infection rates and clinical outcomes were manually extracted from all of the selected studies. The evidence quality levels and recommendations were assessed using the GRADE system. Eight studies looking at hip and knee arthroplasties were included. Meta-analysis showed that patients with steroid injection before arthroplasty had a higher deep infection rate than patients without steroid injection (OR = 2.13, 95% CI 1.02-4.45), but no significant effect on superficial infection rate (OR = 1.75, 95% CI 0.74-4.16). The overall GRADE system evidence quality was very low, which lowers our confidence in their recommendations. Intraarticular steroid injections may lead to increased deep infection rates of subsequent joint arthroplasty but not the superficial infection rates. Due to the poor quality of the evidence currently available, further studies are still required.

The effect of induction therapy on established CMV specific T cell immunity in living donor kidney transplantation.

PubMed

Stranavova, L; Hruba, P; Girmanova, E; Tycova, I; Slavcev, A; Fronek, J; Slatinska, J; Reinke, P; Volk, H-D; Viklicky, O

2018-05-04

Cytomegalovirus (CMV) infection influences both short and long term outcomes in immunosuppressed organ transplant recipients. The aim of this study was to evaluate the effect of different induction immunosuppression regimens on CMV specific T cell response in patients with already established CMV immunity. In 24 seropositive living donor kidney recipients, the frequency of CMV specific T cells was determined by ELISPOT (Enzyme-Linked ImmunoSpot) assay prior and 6 months after transplantation. Recipients' peripheral blood mononuclear cells were stimulated with immediate-early (IE1) and phosphoprotein 65 (pp65) CMV-derived peptide pools and the number of cells producing interferon gamma (IFN-gamma) was assessed. Patients received quadruple immunosuppression based either on depletive rabbit antithymocyte globulin (rATG) or non-depletive basiliximab induction and tacrolimus/mycophenolate mofetil/steroids. Patients with rATG induction received valgancyclovir prophylaxis. No effects of different induction agents on CMV specific T cell immunity were found at sixth month after kidney transplantation. There were no associations among dialysis vintage, pretransplant CMV specific T cell immunity, and later CMV DNAemia. Similarly, no effect of CMV prophylaxis on CMV specific T cell immunity was revealed. This study shows no effect of posttransplant immunosuppression on CMV specific T cell immunity in living donor kidney transplant recipients with CMV immunity already established, regardless of lymphocyte depletion and CMV prophylaxis.

Mycophenolate mofetil-related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs.

PubMed

Varnell, Charles D; Fukuda, Tsuyoshi; Kirby, Cassie L; Martin, Lisa J; Warshaw, Barry L; Patel, Hiren P; Chand, Deepa H; Barletta, Gina-Marie; Van Why, Scott K; VanDeVoorde, Rene G; Weaver, Donald J; Wilson, Amy; Verghese, Priya S; Vinks, Alexander A; Greenbaum, Larry A; Goebel, Jens; Hooper, David K

2017-11-01

MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The effect of different immunoprophylaxis regimens on post-transplant cytomegalovirus (CMV) infection in CMV-seropositive liver transplant recipients.

PubMed

Low, Chian Yong; Hosseini-Moghaddam, Seyed Mohammadmehdi; Rotstein, Coleman; Renner, Eberhard L; Husain, Shahid

2017-10-01

The effects of different immunoprophylaxis regimens on cytomegalovirus (CMV) infection in liver transplant recipients (LTRs) have not been compared. In a cohort, we studied 343 CMV-seropositive recipient (R+) and 83 seronegative donor/recipient (D-/R-) consecutive LTRs from 2004 to 2007. Immunoprophylaxis regimens included steroid-only, steroids plus rabbit anti-thymocyte globulin (rATG), and steroids plus basiliximab. Logistic regression analysis, Cox proportional hazards regression model, and log-rank test were performed for multivariate analysis as appropriate. In total, 164 (39%), 69 (16%), and 193 (45%) patients received steroid-only, basiliximab, and rATG immunoprophylaxis, respectively. CMV infection rates were 15.7% (54/343) in CMV R+ LTRs and 2.4% (2/83) in CMV R- LTRs. Among CMV R+ LTRs who received rATG, the use of at least 6 weeks of CMV prophylaxis reduced the rate of CMV infection from 24.4% (19/78) to 11.7% (9/77). In multivariate analysis, CMV R+ vs D-/R- (odds ratio [OR]=13.1, 95% confidence interval [CI]: 1.8-97.2), rATG >3 mg/kg vs steroid-only induction (OR=1.6, 95% CI: 1.1-2.3), and CMV prophylaxis <6 weeks vs ≥6 weeks (OR=2.7, 95% CI: 1.2-6.4) were independently associated with CMV infection. Subgroup analysis in CMV D-/R+ group who received rATG showed that ≥6 weeks of CMV prophylaxis significantly decreased the risk of CMV infection (OR=1.9, 95% CI: 1.1-3.9; P=.03). The use of rATG immunoprophylaxis increases the risk of CMV infection in CMV-seropositive LTRs, specifically in the CMV D-/R+ group. Prophylaxis with valganciclovir in this group for at least 6 weeks decreases the risk of CMV infection. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Regulatory T Cells in Chronic Graft-Versus-Host Disease After Extracorporeal Photopheresis: Correlation With Skin and Global Organ Responses, and Ability to Taper Steroids.

PubMed

Denney, Helen A; Whittle, Robert J; Lai, Jennifer; Jacques, Richard M; Taylor, Peter C

2017-01-01

Induction of immune tolerance by an increase in regulatory T (Treg) cells after extracorporeal photopheresis (ECP) is thought to contribute to how ECP exerts its therapeutic effect in patients with chronic graft-versus-host disease (cGvHD). We investigated whether percentages and absolute counts of Treg cells changed post-ECP, and examined correlation with response. Absolute counts and % of CD4+ T cells and Treg cells (CD4 + CD25 + FOXP3 + CD127dim/-) were evaluated using flow cytometry in 32 patients with cGvHD treated by ECP for a minimum of 3 months, and up to 12 months. CD4+ or Treg cells at baseline to 12 months post-ECP were compared with changes in skin disease scores or global organ involvement, or the ability to taper steroids, at 14, 28, and 56 weeks. Regulatory T cells % increased significantly above any overall changes in CD4+ % at 6, 9, and 12 months post-ECP. There was no statistically significant association between Treg cells and skin or steroid response, whereas a larger increase in CD4+ count from baseline to 1 to 3 months corresponded to increased odds of being able to reduce steroid dose by 50% or greater at 14 weeks. Skin and global organ responders at 28 weeks had higher median Treg cell counts 3 months post-ECP than nonresponders, as did steroid responders at 56 weeks who were 12 months post-ECP. Regulatory T cell counts and % varied greatly among cGvHD patients, and the increase post-ECP was not significant until 6 months. No clear correlation was found between Treg cells and clinical improvement, suggesting that increases in Treg cell numbers and/or proportions are not driving the mechanism leading to a response after ECP.

The acute and temporary modulation of PERIOD genes by hydrocortisone in healthy subjects.

PubMed

Yurtsever, Türkan; Schilling, Thomas M; Kölsch, Monika; Turner, Jonathan D; Meyer, Jobst; Schächinger, Hartmut; Schote, Andrea B

2016-01-01

The physiological stress system and the circadian clock system communicate with each other at different signaling levels. The steroid hormone cortisol, the end-effector of the hypothalamus-pituitary-adrenal axis, is released in response to stress and acts as a mediator in circadian rhythms. We determined the effect of escalating cortisol doses on the expression of PERIOD genes (PER1, PER2 and PER3) in healthy subjects and analyzed whether the glucocorticoid receptor (GR) is involved in the cortisol-mediated PERIOD gene expression. Forty participants (50% males and 50% females) were randomly assigned to groups receiving a saline placebo solution or 3 mg, 6 mg, 12 mg and 24 mg of hydrocortisone. Blood was drawn every 15 min to measure quantitative gene expression of PER1, PER2 and PER3. A potential role of the GR was determined by an ex vivo study stimulating whole blood with hydrocortisone and RU486 (a GR antagonist). As a result, moderate doses of hydrocortisone produced an acute and temporary induction of PER1 and PER3 mRNA levels, whereas PER2 was not responsive to the hormone administration. The cortisol-dependent induction of PER1 was blocked by the GR antagonist in whole blood after treatment with hydrocortisone and RU486 ex vivo. In conclusion, acute pharmacological stress modulated the expression of PER1 and PER3 in whole blood temporarily in our short-term sampling design, suggesting that these circadian genes mediate stable molecular mechanisms in the periphery.

Transsynaptic trophic effects of steroid hormones in an avian model of adult brain plasticity

PubMed Central

Brenowitz, Eliot A.

2014-01-01

The avian song control system provides an excellent model for studying transsynaptic trophic effects of steroid sex hormones. Seasonal changes in systemic testosterone (T) and its metabolites regulate plasticity of this system. Steroids interact with the neurotrophin brain-derived neurotrophic factor (BDNF) to influence cellular processes of plasticity in nucleus HVC of adult birds, including the addition of newborn neurons. This interaction may also occur transsynpatically; T increases the synthesis of BDNF in HVC, and BDNF protein is then released by HVC neurons on to postsynaptic cells in nucleus RA where it has trophic effects on activity and morphology. Androgen action on RA neurons increases their activity and this has a retrograde trophic effect on the addition of new neurons to HVC. The functional linkage of sex steroids to BDNF may be of adaptive value in regulating the trophic effects of the neurotrophin and coordinating circuit function in reproductively relevant contexts. PMID:25285401

[A survey of perioperative asthmatic attack among patients with bronchial asthma underwent general anesthesia].

PubMed

Ie, Kenya; Yoshizawa, Atsuto; Hirano, Satoru; Izumi, Sinyuu; Hojo, Masaaki; Sugiyama, Haruhito; Kobayasi, Nobuyuki; Kudou, Kouichirou; Maehara, Yasuhiro; Kawachi, Masaharu; Miyakoshi, Kouichi

2010-07-01

We investigated the risk factor of perioperative asthmatic attack and effectiveness of preventing treatment for asthmatic attack before operation. We performed retrospective chart review of one hundred eleven patients with asthma underwent general anesthesia and surgical intervention from January 2006 to October 2007 in our hospital. The rate of perioperative asthmatic attack were as follows; 10.2% (5 in 49 cases) in no pretreatment group, 7.5% (3 in 40 cases) in any pretreatments except for systemic steroid, and 4.5% (1 in 22 cases) in systemic steroid pretreatment group. Neither preoperative asthma severity nor duration from the last attack had significant relevancy to perioperative attack rate. The otolaryngological surgery, especially those have nasal polyp and oral surgery had high perioperative asthma attack rate, although there was no significant difference. We recommend the systemic steroid pretreatment for asthmatic patients, especially when they have known risk factor such as administration of the systemic steroid within 6 months, or possibly new risk factor such as nasal polyp, otolaryngological and oral surgery.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Qun-Yi; Zhang, Meng; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai

Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids formore » the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.« less

SULT2B1b Sulfotransferase: Induction by Vitamin D Receptor and Reduced Expression in Prostate Cancer

PubMed Central

Seo, Young-Kyo; Mirkheshti, Nooshin; Song, Chung S.; Kim, Soyoung; Dodds, Sherry; Ahn, Soon C.; Christy, Barbara; Mendez-Meza, Rosario; Ittmann, Michael M.; Abboud-Werner, Sherry

2013-01-01

An elevated tumor tissue androgen level, which reactivates androgen receptor in recurrent prostate cancer, arises from the intratumor synthesis of 5α-dihydrotestosterone through use of the precursor steroid dehydroepiandrosterone (DHEA) and is fueled by the steroidogenic enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD1), aldoketoreductase (AKR1C3), and steroid 5-alpha reductase, type 1 (SRD5A1) present in cancer tissue. Sulfotransferase 2B1b (SULT2B1b) (in short, SULT2B) is a prostate-expressed hydroxysteroid SULT that converts cholesterol, oxysterols, and DHEA to 3β-sulfates. DHEA metabolism involving sulfonation by SULT2B can potentially interfere with intraprostate androgen synthesis due to reduction of free DHEA pool and, thus, conversion of DHEA to androstenedione. Here we report that in prostatectomy specimens from treatment-naive patients, SULT2B expression is markedly reduced in malignant tissue (P < .001, Mann-Whitney U test) compared with robust expression in adjacent nonmalignant glands. SULT2B was detected in formalin-fixed specimens by immunohistochemistry on individual sections and tissue array. Immunoblotting of protein lysates of frozen cancer and matched benign tissue confirmed immunohistochemistry results. An in-house–developed rabbit polyclonal antibody against full-length human SULT2B was validated for specificity and used in the analyses. Ligand-activated vitamin D receptor induced the SULT2B1 promoter in vivo in mouse prostate and increased SULT2B mRNA and protein levels in vitro in prostate cancer cells. A vitamin D receptor/retinoid X receptor-α–bound DNA element (with a DR7 motif) mediated induction of the transfected SULT2B1 promoter in calcitriol-treated cells. SULT2B knockdown caused an increased proliferation rate of prostate cancer cells upon stimulation by DHEA. These results suggest that the tumor tissue SULT2B level may partly control prostate cancer growth, and its induction in a therapeutic setting may inhibit disease progression. PMID:23579488

Bistability in cell signaling: How to make continuous processes discontinuous, and reversible processes irreversible

NASA Astrophysics Data System (ADS)

Ferrell, James E.; Xiong, Wen

2001-03-01

Xenopus oocyte maturation is an example of an all-or-none, irreversible cell fate induction process. In response to a submaximal concentration of the steroid hormone progesterone, a given oocyte may either mature or not mature, but it can exist in intermediate states only transiently. Moreover, once an oocyte has matured, it will remain arrested in the mature state even after the progesterone is removed. It has been hypothesized that the all-or-none character of oocyte maturation, and some aspects of the irreversibility of maturation, arise out of the bistability of the signal transduction system that triggers maturation. The bistability, in turn, is hypothesized to arise from the way the signal transducers are organized into a signaling circuit that includes positive feedback (which makes it so that the system cannot rest in intermediate states) and ultrasensitivity (which filters small stimuli out of the feedback loop, allowing the system to have a stable off-state). Here we review two simple graphical methods that are commonly used to analyze bistable systems, discuss the experimental evidence for bistability in oocyte maturation, and suggest that bistability may be a common means of producing all-or-none responses and a type of biochemical memory.

Effects of Sex Steroids on Fish Leukocytes

PubMed Central

Cabas, Isabel

2018-01-01

In vertebrates, in addition to their classically reproductive functions, steroids regulate the immune system. This action is possible mainly due to the presence of steroid receptors in the different immune cell types. Much evidence suggests that the immune system of fish is vulnerable to xenosteroids, which are ubiquitous in the aquatic environment. In vivo and in vitro assays have amply demonstrated that oestrogens interfere with both the innate and the adaptive immune system of fish by regulating the main leukocyte activities and transcriptional genes. They activate nuclear oestrogen receptors and/or G-protein coupled oestrogen receptor. Less understood is the role of androgens in the immune system, mainly due to the complexity of the transcriptional regulation of androgen receptors in fish. The aim of this manuscript is to review our present knowledge concerning the effect of sex steroid hormones and the presence of their receptors on fish leukocytes, taking into consideration that the studies performed vary as regard the fish species, doses, exposure protocols and hormones used. Moreover, we also include evidence of the probable role of progestins in the regulation of the immune system of fish. PMID:29315244

Epidural steroid injections: update on efficacy, safety, and newer medications for injection.

PubMed

Kozlov, N; Benzon, H T; Malik, K

2015-08-01

The best evidence for epidural injection appears to be in the setting of radicular pain with epidural steroid and non-steroid injections more efficacious than non-epidural injections. Studies showed the efficacy of non-particulate steroid to approach the efficacy of particulate steroid and very limited comparisons demonstrated no significant difference between epidural steroid and epidural non-steroid (local anesthetic) injection. Preliminary studies evaluating epidural injection of disease modifying anti-rheumatic drugs such etanercept and tocilizumab showed conflicting results and had significant limitations. Randomized studies support better efficacy of transforaminal injection due to greater incidence of ventral epidural spread of injectate when compared to interlaminar injection. Thus, the transforaminal approach is recommended when unilateral radicular pain is limited to one nerve root. However, the transforaminal approach is associated with greater incidence of central nervous system injury, including paraplegia, attributed to embolization of the particulate steroid. Recent studies showed that non-particulate steroids potentially last as long as particulate steroids. Therefore non-particulate steroid should be used in initial transforaminal epidural injection. Future studies should look into the role of adjunct diagnostic aids, including digital subtraction angiography, in detecting intravascular injection and the ideal site of needle placement, whether it is the safe triangle or the triangle of Kambin. Finally, the role of epidural disease -modifying antirheumatic drugs in the management of back pain needs to be better elucidated.

Hidden Danger of Irrational Abusing Illegal Androgenic-anabolic Steroids in Recreational Athletes Age Under 35 in Bosnia & Herzegovina.

PubMed

Solakovic, Sid; Totic, Dragan; Vukas, Haris; Djedovic, Muhamed

2015-06-01

Androgenic-anabolic steroids are rarely used by sportsmen who want to improve physical performance in competition sport. Despite that they are well aware of the side effects of anabolic steroids, many young athletes in Bosnia and Herzegovina without competition motivation come in temptation, trying to achieve better muscle proportion and physical performance unknowing consequence of side effects and what is hiding behind. Risk factors such as increasing of lipid levels and arterial hypertension are major factors which have important role in the Pathogenesis of atherosclerosis and are responsible for occurrence of cardiovascular disease even causing a sudden death in young athletes. The aim of the study was to estimate the frequency of misusing of androgenic anabolic steroid drugs in young recreational sportsmen without competition motivation. This study will try to estimate vascular and lipid status, analyzing the side effects of steroids in young recreational athletes under the age of 35, in Bosnia and Herzegovina. The study included 70 individuals in period of 2010 till 2015 on recreational exercising program; 35 individuals misusing androgenic anabolic steroids during the period of 5 years were compared with 35 individuals which do not use androgenic anabolic steroids. Non-invasive methods were used in all individual (clinical examination and vascular ultrasound examination of vein system). The routine of training units in both groups was approximately two hours 4-6 times per week. Final analysis has reveal that in androgenic anabolic steroids group in 18 individuals or 55.7% arterial hypertension with hyperlipidemia was more represented, compared with the group without using anabolic steroids, represented by 2 individuals or 5.7% and it was statistically considered significant by using p value less than 0.05. (p<0.05). Statistically dominant population using anabolic steroids drugs are males (100%) or 35 individuals; we did not find females using anabolic steroids and that is why our research was limited to male population. Recreational male sportsmen are dominant androgenic anabolic steroids misusers, trying to achieve better muscle proportion and physical performance, they neglect the anabolic steroids side effects which have devastating consequence on vascular system. Benefits of misusing drugs in recreational exercising program in young sportsmen are mostly connected with development of arterial hypertension and hyperlipidemia and the variety of serious health disorders, progressing the pathogenesis of cardiovascular disease.

Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp; Inajima, Jun; Kato, Sayaka

The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6more » but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR.« less

Effect of sex steroid hormones on the number of serotonergic neurons in rat dorsal raphe nucleus.

PubMed

Kunimura, Yuyu; Iwata, Kinuyo; Iijima, Norio; Kobayashi, Makito; Ozawa, Hitoshi

2015-05-06

Disorders caused by the malfunction of the serotonergic system in the central nervous system show sex-specific prevalence. Many studies have reported a relationship between sex steroid hormones and the brain serotonergic system; however, the interaction between sex steroid hormones and the number of brain neurons expressing serotonin has not yet been elucidated. In the present study, we determined whether sex steroid hormones altered the number of serotonergic neurons in the dorsal raphe nucleus (DR) of adult rat brains. Animals were divided into five groups: ovariectomized (OVX), OVX+low estradiol (E2), OVX+high E2, castrated males, and intact males. Antibodies against 5-hydroxytryptamine (5-HT, serotonin) and tryptophan hydroxylase (Tph), an enzyme for 5-HT synthesis, were used as markers of 5-HT neurons, and the number of 5-HT-immunoreactive (ir) or Tph-ir cells was counted. We detected no significant differences in the number of 5-HT-ir or Tph-ir cells in the DR among the five groups. By contrast, the intensity of 5-HT-ir showed significant sex differences in specific subregions of the DR independent of sex steroid levels, suggesting that the manipulation of sex steroid hormones after maturation does not affect the number and intensive immunostaining of serotonergic neurons in rat brain. Our results suggest that, the sexual dimorphism observed in the serotonergic system is due to factors such as 5-HT synthesis, transportation, and degradation but not to the number of serotonergic neurons. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Suppressive Antagonism Evidences Progesterone and Estrogen Receptor Pathway Interaction with Concomitant Regulation of Hand2, Bmp2 and ERK during Early Decidualization

PubMed Central

Mestre-Citrinovitz, Ana C.; Kleff, Veronika; Vallejo, Griselda

2015-01-01

Progesterone receptor and estrogen receptor participate in growth and differentiation of the different rat decidual regions. Steroid hormone receptor antagonists were used to study steroid regulation of decidualization. Here we describe a suppressive interaction between progesterone receptor (onapristone) and estrogen receptor (ICI182780) antagonists and their relation to a rescue phenomenon with concomitant regulation of Hand2, Bmp2 and p-ERK1/2 during the early decidualization steps. Phenotypes of decidua development produced by antagonist treatments were characterized by morphology, proliferation, differentiation, angiogenesis and expression of signaling molecules. We found that suppression of progesterone receptor activity by onapristone treatment resulted in resorption of the implantation sites with concomitant decrease in progesterone and estrogen receptors, PCNA, KI67 antigen, DESMIN, CCND3, CX43, Prl8a2, and signaling players such as transcription factor Hand2, Bmp2 mRNAs and p-ERK1/2. Moreover, FGF-2 and Vegfa increased as a consequence of onapristone treatment. Implantation sites from antagonist of estrogen receptor treated rats developed all decidual regions, but showed an anomalous blood vessel formation at the mesometrial part of the decidua. The deleterious effect of onapristone was partially counteracted by the impairment of estrogen receptor activity with rescue of expression levels of hormone steroid receptors, proliferation and differentiation markers, and the induction of a probably compensatory increase in signaling molecules Hand2, Bmp2 and ERK1/2 activation compared to oil treated controls. This novel drug interaction during decidualization could be applied to pathological endometrial cell proliferation processes to improve therapies using steroid hormone receptor targets. PMID:25897495

Regulation of Kiss1 Expression by Sex Steroids in the Amygdala of the Rat and Mouse

PubMed Central

Kim, Joshua; Semaan, Sheila J.; Clifton, Donald K.; Steiner, Robert A.; Dhamija, Sangeeta

2011-01-01

Kisspeptin (encoded by the Kiss1 gene) is an important regulator of reproduction. In rodents, Kiss1 is expressed in two hypothalamic regions, the arcuate nucleus and anteroventral periventricular/ periventricular continuum, where it is regulated by sex steroids. However, the distribution, regulation, and functional significance of neural kisspeptin outside of the hypothalamus have not been studied and are poorly understood. Here, we report the expression of Kiss1 in the amygdala, predominantly in the medial nucleus of the amygdala (MeA), a region implicated in social and emotional behaviors as well as various aspects of reproduction. In gonadally intact rats and mice, Kiss1-expressing neurons were identified in the MeA of both sexes, with higher Kiss1 expression levels in adult males than females in diestrus. In rats, Kiss1 expression in the MeA changed as a function of the estrous cycle, with highest levels at proestrus. Next, we tested whether Kiss1 in the MeA is regulated by the circulating sex steroid milieu. Kiss1 levels in the MeA were low in gonadectomized mice and rats of both sexes, and treatment with either testosterone or estradiol amplified Kiss1 expression in this region. Testosterone's inductive effect on Kiss1 expression in the MeA likely occurs via estrogen receptor-dependent pathways, not through the androgen receptor, because dihydrotestosterone (a nonaromatizable androgen) did not affect MeA Kiss1 levels. Thus, in rodents, Kiss1 is expressed and regulated by sex steroids in the MeA of both sexes and may play a role in modulating reproduction or brain functions that extend beyond reproduction. PMID:21363930

Effects of a protracted induction of parturition on the incidence of retained placenta and assessment of uterine artery blood flow as a measure of placental maturation in cattle.

PubMed

Hartmann, D; Honnens, A; Piechotta, M; Lüttgenau, J; Niemann, H; Rath, D; Bollwein, H

2013-08-01

The objectives of the present study were to compare the effects of a protracted and a conventional induction of parturition on the incidence of retained placenta, and to evaluate the suitability of transrectal Doppler sonography of the uterine arteries as a noninvasive method for the assessment of placental maturation. Protracted induction of labor (PIP) was precipitated in 13 cows by the administration of 1.3 mg dexamethasone im twice daily between Days 268 and 273 of gestation, and 40 mg dexamethasone im on Day 274 of gestation. For conventional induction of labor (SIP), 10 cows received 40 mg dexamethasone on Day 274 of gestation. A third group was not treated and served as control (SPON; N = 11). Blood flow volume (BFV) and resistance index in the uterine arteries were measured with Doppler sonography once a day from Day 268 of gestation until labor. After each ultrasonographic examination, blood samples for determination of steroid hormones were taken. Incidence of retained placenta was lower (P < 0.05) in group SPON (9%) compared with groups PIP (54%) and SIP (70%). In the last 7 days before parturition uterine BFV and resistance index did not change (P > 0.05) and did not differ between groups SPON, PIP, and SIP (P > 0.05). Resistance index was higher (P < 0.001) in cows with retained placenta compared with cows with released placenta, and BFV did not differ (P > 0.05) between them. Total estrogen concentrations increased by 283% (P < 0.001) in group PIP and by 60% (P < 0.05) in group SPON between Days -7 and -1 before parturition. They stayed constant (P > 0.05) until Day -2 in group SIP, but increased (P < 0.05) after the high dosage of dexamethasone within 1 day by 140%. Total estrogen levels were higher (P < 0.05) in cows with released placenta than in cows with retained placenta. In conclusion, a protracted compared with a short induction of labor results in higher estrogen levels before term, but does not affect incidence of placental retention. Neither alterations in placental maturation nor changes in steroid hormones influenced uterine blood supply. Therefore, Doppler sonography of uterine arteries is unsuitable to investigate the process of placental maturation induced by glucocorticoids in cows. Nevertheless, disturbances in the placental maturation process in cows with retained fetal membranes after parturition can be detected before parturition by a higher uterine blood flow resistance in the uterine arteries. Copyright © 2013 Elsevier Inc. All rights reserved.

Cationic lipid-conjugated hydrocortisone as selective antitumor agent.

PubMed

Rathore, Bhowmira; Chandra Sekhar Jaggarapu, Madhan Mohan; Ganguly, Anirban; Reddy Rachamalla, Hari Krishna; Banerjee, Rajkumar

2016-01-27

Hydrocortisone, the endogenously expressed steroidal, hormonal ligand for glucocorticoid receptor (GR), is body's natural anti-inflammatory and xenobiotic metabolizing agent. It has both palliative as well as adverse effects in different cancer patients. Herein, we show that conjugation product of C16-carbon chain-associated cationic lipid and hydrocortisone (namely, HYC16) induces selective toxicity in cancer (e.g. melanoma, breast cancer and lung adenocarcinoma) cells with least toxicity in normal cells, through induction of apoptosis and cell cycle arrest at G2/M phase. Further, significant tumor growth inhibition was observed in syngeneic melanoma tumor model with considerable induction of apoptosis in tumor-associated cells. In contrast to hydrocortisone, significantly higher anti-angiogenic behavior of HYC16 helped in effective tumor shrinkage. This is the first demonstration to convert natural hormone hydrocortisone into a selective bioactive entity possessing anti-tumor effect. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

RIP2: A novel player in the regulation of keratinocyte proliferation and cutaneous wound repair?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adams, Stephanie; Valchanova, Ralitsa S.; Munz, Barbara, E-mail: barbara.munz@charite.de

2010-03-10

We could recently demonstrate an important role of receptor interacting protein 4 (RIP4) in the regulation of keratinocyte differentiation. Now, we analyzed a potential role of the RIP4 homolog RIP2 in keratinocytes. Specifically, we demonstrate here that rip2 expression is induced by scratch-wounding and after the induction of differentiation in these cells. Furthermore, serum growth factors and cytokines can induce rip2, with TNF-{alpha}-dependent induction being dependent on p38 MAPK. In addition, we demonstrate that scratch-induced upregulation of rip2 expression is completely blocked by the steroid dexamethasone. Since we also show that RIP2 is an important player in the regulation ofmore » keratinocyte proliferation, these data suggest that inhibition of rip2 upregulation after wounding might contribute to the reduced and delayed wound re-epithelialization phenotype seen in glucocorticoid-treated patients.« less

Responses of Pathogenic and Nonpathogenic Yeast Species to Steroids Reveal the Functioning and Evolution of Multidrug Resistance Transcriptional Networks▿ †

PubMed Central

Banerjee, Dibyendu; Lelandais, Gaelle; Shukla, Sudhanshu; Mukhopadhyay, Gauranga; Jacq, Claude; Devaux, Frederic; Prasad, Rajendra

2008-01-01

Steroids are known to induce pleiotropic drug resistance states in hemiascomycetes, with tremendous potential consequences for human fungal infections. Our analysis of gene expression in Saccharomyces cerevisiae and Candida albicans cells subjected to three different concentrations of progesterone revealed that their pleiotropic drug resistance (PDR) networks were strikingly sensitive to steroids. In S. cerevisiae, 20 of the Pdr1p/Pdr3p target genes, including PDR3 itself, were rapidly induced by progesterone, which mimics the effects of PDR1 gain-of-function alleles. This unique property allowed us to decipher the respective roles of Pdr1p and Pdr3p in PDR induction and to define functional modules among their target genes. Although the expression profiles of the major PDR transporters encoding genes ScPDR5 and CaCDR1 were similar, the S. cerevisiae global PDR response to progesterone was only partly conserved in C. albicans. In particular, the role of Tac1p, the main C. albicans PDR regulator, in the progesterone response was apparently restricted to five genes. These results suggest that the C. albicans and S. cerevisiae PDR networks, although sharing a conserved core regarding the regulation of membrane properties, have different structures and properties. Additionally, our data indicate that other as yet undiscovered regulators may second Tac1p in the C. albicans drug response. PMID:17993571

Accurate and sensitive liquid chromatography/tandem mass spectrometry simultaneous assay of seven steroids in monkey brain.

PubMed

Bertin, Jonathan; Dury, Alain Y; Ke, Yuyong; Ouellet, Johanne; Labrie, Fernand

2015-06-01

Following its secretion mainly by the adrenal glands, dehydroepiandrosterone (DHEA) acts primarily in the cells/tissues which express the enzymes catalyzing its intracellular conversion into sex steroids by the mechanisms of intracrinology. Although reliable assays of endogenous serum steroids are now available using mass spectrometry (MS)-based technology, sample preparation from tissue matrices remains a challenge. This is especially the case with high lipid-containing tissues such as the brain. With the combination of a UPLC system with a sensitive tandem MS, it is now possible to measure endogenous unconjugated steroids in monkey brain tissue. A Shimadzu UPLC LC-30AD system coupled to a tandem MS AB Sciex Qtrap 6500 system was used. The lower limits of quantifications are achieved at 250 pg/mL for DHEA, 200 pg/mL for 5-androstenediol (5-diol), 12 pg/mL for androstenedione (4-dione), 50 pg/mL for testosterone (Testo), 10 pg/mL for dihydrotestosterone (DHT), 4 pg/mL for estrone (E1) and 1 pg/mL for estradiol (E2). The linearity and accuracy of quality controls (QCs) and endogenous quality controls (EndoQCs) are according to the guidelines of the regulatory agencies for all seven compounds. We describe a highly sensitive, specific and robust LC-MS/MS method for the simultaneous measurement of seven unconjugated steroids in monkey brain tissue. The single and small amount of sample required using a relatively simple preparation method should be useful for steroid assays in various peripheral tissues and thus help analysis of the role of locally-made sex steroids in the regulation of specific physiological functions. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of male and female sex steroids on the development of normal and the transient Froriep's dorsal root ganglia of the chick embryo.

PubMed

Liu, Jiali; Chen, Dawei; Goldstein, Ronald S; Cui, Sheng

2005-03-22

Sex steroids can influence developmental processes and support the survival of neurons in the embryonic central nervous system. Recent studies have shown that estrogen receptors are also expressed in the peripheral nervous system, in the dorsal root ganglia (DRG) of chick embryos. However, no studies have examined the effects of sex steroids on development of embryonic DRG. In the present study, 0.2 microg, 1.0 microg, 5.0 microg 10 microg, 20 microg, 25 microg, and 40 microg doses of testosterone or estradiol were delivered to chick embryos at Hamburger and Hamilton stage 18 (E3). The actions of these doses of sex steroids on the development of the C5DRG (fifth cervical ganglion, a "normal" DRG) and C2DRG (a transient ganglion known as a "Froriep's DRG") were then evaluated by quantifying ganglionic volumes, cell number, proliferation, and apoptosis after 1 day of growth to stage 23. We found that both testosterone and estradiol promoted proliferation of cells in both normal DRG and the Froriep's ganglia. By contrast, estradiol significantly increased the number of apoptotic cells, while testosterone strongly inhibited apoptosis. These actions of sex steroids on DRG development were dose-dependent, and C5DRG and C2DRG showed different sensitivities to the applied sex steroids. In addition, the present results demonstrated that specific ER and AR inhibitors (tamoxifen and flutamide) did not influence the effects of 5 microg E2 and 5 microg T on C2 and C5DRG significantly. These results demonstrate that male and female sex steroids can modulate DRG development through an epigenetic mechanism, as had been shown for the central nervous system.

Complexation of cytochrome P-450 isozymes in hepatic microsomes from SKF 525-A-induced rats.

PubMed

Murray, M

1988-05-01

Potassium ferricyanide-elicited reactivation of steroid hydroxylase activities, in hepatic microsomes from SKF 525-A-induced male rats, was used as an indicator of complex formation between individual cytochrome P-450 isozymes and the SKF 525-A metabolite. Induction of male rats with SKF 525-A (50 mg/kg for three days) led to apparent increases in androst-4-ene-3,17-dione 16 beta- and 6 beta-hydroxylation to 6.7- and 3-fold of control activities. Steroid 7 alpha-hydroxylase activity was decreased to 0.8-fold of control and 16 alpha-hydroxylation was unchanged. Ferricyanide-elicited dissociation of the SKF 525-A metabolite-P-450 complex revealed an even greater induction of 16 beta- and 6 beta-hydroxylase activities (to 1.8- and 1.6-fold of activities in the absence of ferricyanide). Androst-4-ene-3,17-dione 16 alpha-hydroxylase activity increased 2-fold after ferricyanide but 7 alpha-hydroxylase activity was unaltered. An antibody directed against the male-specific cytochrome P-450 UT-A decreased androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to 13% of control in hepatic microsomes from untreated rats. In contrast, 16 alpha-hydroxylase activity in microsomes from SKF 525-A-induced rats, before and after dissociation with ferricyanide, was reduced by anti UT-A IgG to 32 and 19% of the respective uninhibited controls. Considered together, these observations strongly suggest that the phenobarbital-inducible cytochrome P-450 isozymes PB-B and PCN-E are present in an inactive complexed state in microsomes from SKF 525-A-induced rat liver. Further, the increased susceptibility of androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to inhibition by an antibody to cytochrome P-450 UT-A, following ferricyanide treatment of microsomes, suggests that this male sexually differentiated enzyme is also complexed after in vivo SKF 525-A dosage. In contrast, the constitutive isozyme cytochrome P-450 UT-F, which is active in steroid 7 alpha-hydroxylation, does not appear to be complexed to any extent in microsomes from SKF 525-A-induced rats.

Occurrence, spatiotemporal distribution, and ecological risks of steroids in a large shallow Chinese lake, Lake Taihu.

PubMed

Zhou, Li-Jun; Zhang, Bei-Bei; Zhao, Yong-Gang; Wu, Qinglong L

2016-07-01

Steroids have been frequently detected in surface waters, and might pose adverse effects on aquatic organisms. However, little information is available regarding the occurrence and spatiotemporal distribution of steroids in lake environments. In addition to pollution sources, the occurrence and spatiotemporal distribution of steroids in lake environments might be related to lake types (shallow or deep), lake hydrodynamics, and sorption-desorption processes in the water-sediment systems. In this study, the occurrence, spatiotemporal distribution, and ecological risks of 36 steroids in a large shallow lake were evaluated by investigating surface water and sediment samples at 32 sites in Lake Taihu over two seasons. Twelve and 15 analytes were detected in aqueous and sedimentary phases, respectively, with total concentrations ranging from 0.86 to 116ng/L (water) and from 0.82 to 16.2ng/g (sediment, dry weight). Temporal variations of steroid concentrations in the water and sediments were statistically significant, with higher concentrations in winter. High concentrations of steroids were found in the seriously polluted bays rather than in the pelagic zone of the lake. Strong lake currents might mix pelagic waters, resulting in similar concentrations of steroids in the pelagic zone. Mass balance analysis showed that sediments in shallow lakes are in general an important sink for steroids. Steroids in the surface water and sediments of Lake Taihu might pose potential risks to aquatic organisms. Overall, our study indicated that the concentrations and spatiotemporal distribution of steroids in the large shallow lake are influenced simultaneously by pollution sources and lake hydrodynamics. Steroids in the large shallow Lake Taihu showed clear temporal and spatial variations and lake sediments may be a potential sink of steroids. Copyright © 2016 Elsevier B.V. All rights reserved.

Age Disparities in the Use of Steroid-sparing Therapy for Inflammatory Bowel Disease.

PubMed

Govani, Shail M; Wiitala, Wyndy L; Stidham, Ryan W; Saini, Sameer D; Hou, Jason K; Feagins, Linda A; Sussman, Jeremy B; Higgins, Peter D R; Waljee, Akbar K

2016-08-01

Corticosteroids are effective rescue therapies for patients with inflammatory bowel disease (IBD), but have significant side effects, which may be amplified in the growing population of elderly patients with IBD. We aimed to compare the use of steroids and steroid-sparing therapies (immunomodulators and biologics) and rates of complications among elderly (≥65) and younger patients in a national cohort of veterans with IBD. We used national Veterans Health Administrative data to conduct a retrospective study of veterans with IBD between 2002 and 2010. Medications and the incidence of complications were obtained from the Veterans Health Administrative Decision Support Systems. Multivariate logistic regression accounting for facility-level clustering was used to identify predictors of use of steroid-sparing medications. We identified 30,456 veterans with IBD. Of these, 94% were men and 40% were more than 65, and 32% were given steroids. Elderly veterans were less likely to receive steroids (23.8% versus 38.3%, P < 0.001) and were less likely to be prescribed steroid-sparing medications (25.5% versus 46.9%, respectively, P < 0.001). In multivariate analysis controlling for sex, age <65 (odds ratio, 2.19; 95% CI, 1.54-3.11) and gastroenterology care (odds ratio, 8.42; 95% CI, 6.18-11.47) were associated with initiation of steroid-sparing medications. After starting steroids, fracture rates increased in the elderly patients with IBD, whereas increases in venous thromboembolism and infections after starting steroids affected both age groups. Elderly veterans are less likely to receive steroids and steroid-sparing medications than younger veterans; elderly patients exposed to steroids were more likely to have fractures than the younger population.

Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives.

PubMed

Sahin, Zafer; Ertas, Merve; Berk, Barkın; Biltekin, Sevde Nur; Yurttas, Leyla; Demirayak, Seref

2018-05-01

Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC 50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC 50 :0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site. Copyright © 2018 Elsevier Ltd. All rights reserved.

Steroid intracochlear distribution differs by administration method: Systemic versus intratympanic injection.

PubMed

Lee, Jong Joo; Jang, Jeong Hun; Choo, Oak-Sung; Lim, Hye Jin; Choung, Yun-Hoon

2018-01-01

Steroids have been widely used to treat inner-ear diseases such as sudden sensorineural hearing loss, tinnitus, and Meniere's disease. They can be given via either systemic or intratympanic (IT) injection. The purpose of the present study was to explore differences in intracochlear steroid distribution by the administration method employed (systemic vs. IT injection). Animal study. Twenty-three Sprague-Dawley rats were given fluorescein isothiocyanate-labeled dexamethasone (FITC-DEX) three times (on successive days) via intraperitoneal (IP) or IT injection. Cochlear uptake of FITC-DEX was evaluated via immunohistochemistry and flow cytometry at 6 hours, and 3 and 7 days after the final injection. FITC-DEX uptake was evident in spiral ganglion cells (SGs), the organ of Corti (OC), and the lateral walls (LWs), the basal turns of which were stained relatively prominently in both groups. Animals receiving IP injections exhibited higher FITC-DEX uptakes by the SGs and OC, whereas IT injection triggered higher-level FITC-DEX accumulation by the OC and LWs. Flow cytometry revealed that intracochlear FITC-DEX uptake by IT-injected animals was higher and more prolonged than in animals subjected to IP injections. We thus describe differences in cochlear steroid distributions after systemic and IT injections. This finding could help our understanding of the pharmacokinetics of steroids in the cochlea. NA. Laryngoscope, 128:189-194, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

The role of steroids in the development of post-partum mental disorders.

PubMed

Paskova, Andrea; Jirak, Roman; Mikesova, Michaela; Adamcova, Karolina; Fartakova, Zdenka; Horakova, Vladimira; Koucky, Michal; Hill, Martin; Hruskovicova, Hana; Starka, Luboslav; Duskova, Michaela; Parizek, Antonin

2014-09-01

Unfavorable post-partum changes to mental well-being affect more than half of all women, and are a risk to the health of both mother and baby. Their effects place strains on health and social systems. Currently, no generally accepted theory exists of the causes and mechanisms of post-partum mental disorders. Literature search up to 2012, using PubMed and search words: neuroactive steroids, post-partum mental disorders, depression, corticotropin-releasing hormone and estrogens. There are several theories for post-partum depression. One is that autoimmune diseases are involved. Others revolve around genes responsible or that lead to increased disposition to the disorder. It is likely however that the process is associated with the separation of the placenta and the fetal zone of fetal adrenal gland, the main sources of corticotropin-releasing hormone and sexual and neuroactive steroids during pregnancy, and the ability of the receptor system to adapt to these changes. The central nervous system is able to produce neurosteroids, but the drop in levels of peripheral steroids likely leads to a sudden deficit in neuroinhibitory steroids modulating ionotropic receptors in the brain. Post-partum depression is a multifactorial disease with unknown etiology. It is probably associated with sudden changes in the production of hormones influencing the nervous system, and on the other hand the ability of the receptor system to adapt to these changes. When the relative changes in concentrations of hormones, rather than their absolute levels, is likely more important.

Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen.

PubMed

Desai, Pankaj B; Nallani, Srikanth C; Sane, Rucha S; Moore, Linda B; Goodwin, Bryan J; Buckley, Donna J; Buckley, Arthur R

2002-05-01

Tamoxifen is a widely utilized antiestrogen in the treatment and chemoprevention of breast cancer. Clinical studies document that tamoxifen administration markedly enhances the systemic elimination of other drugs. Additionally, tamoxifen enhances its own clearance following repeated dosing. The mechanisms that underlie these clinically important events remain unresolved. Here, we report that tamoxifen and its metabolite 4-hydroxytamoxifen markedly induce cytochrome P450 3A4, a drug-metabolizing enzyme of central importance, in primary cultures of human hepatocytes. Tamoxifen and 4-hydroxytamoxifen (1-10 microM) significantly increased the CYP3A4 expression and activity (measured as the rate of testosterone 6beta-hydroxylation). Maximal induction was achieved at the 5 microM level. At this level, tamoxifen and 4-hydroxytamoxifen caused a 1.5- to 3.3-fold (mean, 2.1-fold) and 3.4- to 17-fold (mean, 7.5-fold) increase in the CYP3A4 activity, respectively. In comparison, rifampicin treatment resulted in a 6- to 16-fold (mean, 10.5-fold) increase. We also observed corresponding increase in the CYP3A4 immunoreactive protein and mRNA levels. Furthermore, tamoxifen and 4-hydroxytamoxifen efficaciously activated the human pregnane X receptor (hPXR; also known as the steroid xenobiotic receptor), a key regulator of CYP3A4 expression. The efficacy of tamoxifen and 4-hydroxytamoxifen relative to rifampicin for hPXR activation was approximately 30 and 60%, respectively. Our results indicate that the mechanism of tamoxifen-mediated alteration in drug clearance pathways in humans may involve CYP3A4 induction by the parent drug and/or its metabolite. Furthermore, the CYP3A4 induction may be a result of hPXR activation. These findings have important implications for optimizing the use of tamoxifen and in the development of newer antiestrogens.

Reversible inhibition of the hydrocortisone induction of glycerol phosphate dehydrogenase by cytochalasin B in rat glial C6 cells. [Model for mechanisms of action of steroids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bennett, K.; de Vellis, J.

The hydrocortisone (HC) induction of glycerol phosphate dehydrogenase in rat glial C6 cells was inhibited reversibly and in a dose-dependent manner by cytochalasin B (CB). Addition of sodium pyruvate to the culture medium did not reverse the inhibitory effect of CB, suggesting that CB did not act by blocking glucose transport. CB had no effect on basal level GPDH, and total cellular RNA, DNA or protein content. Colcemid had no effect on the induction, suggesting that the integrity of microtubules is not necessary for the induction process. CB did not alter the rate of degradation of induced GPDH nor didmore » it act as an inhibitor of general protein synthesis. CB appears to specifically inhibit GPDH synthesis whether it was given before, simultaneously or after the addition of HC to the cultures. This effect of CB is correlated with a marked decrease, up to 60 percent, in specific nuclear binding of (/sup 3/H)-HC added to the culture media, even though total cell uptake of (/sup 3/H)-HC was unaffected. According to the current model of HC action, the nuclear effect of CB would result in reduced synthesis of mRNA for GPDH. Since CB dissociated microfilaments in C6 cells, we hypothesize that microfilaments may play a role in the hormonal induction process.« less

The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients

PubMed Central

O'Leary, Jacqueline G.; Samaniego, Millie; Barrio, Marta Crespo; Potena, Luciano; Zeevi, Adriana; Djamali, Arjang; Cozzi, Emanuele

2016-01-01

Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance. PMID:26680372

Using Digital Images of the Zebra Finch Song System as a Tool to Teach Organizational Effects of Steroid Hormones: A Free Downloadable Module

ERIC Educational Resources Information Center

Grisham, William; Schottler, Natalie A.; Beck McCauley, Lisa M.; Pham, Anh P.; Ruiz, Maureen L.; Fong, Michelle C.; Cui, Xinran

2011-01-01

Zebra finch song behavior is sexually dimorphic: males sing and females do not. The neural system underlying this behavior is sexually dimorphic, and this sex difference is easy to quantify. During development, the zebra finch song system can be altered by steroid hormones, specifically estradiol, which actually masculinizes it. Because of the…

Hepatic overexpression of steroid sulfatase ameliorates mouse models of obesity and type 2 diabetes through sex-specific mechanisms.

PubMed

Jiang, Mengxi; He, Jinhan; Kucera, Heidi; Gaikwad, Nilesh W; Zhang, Bin; Xu, Meishu; O'Doherty, Robert M; Selcer, Kyle W; Xie, Wen

2014-03-21

The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that overexpression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions, whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estrogen/estrogen sulfate delivery may represent a novel approach to manage metabolic syndrome.

Androgen Control of Cell Proliferation and Cytoskeletal Reorganization in Human Fibrosarcoma Cells

PubMed Central

Chauhan, Sanjay; Kunz, Susan; Davis, Kelli; Roberts, Jordan; Martin, Greg; Demetriou, Manolis C.; Sroka, Thomas C.; Cress, Anne E.; Miesfeld, Roger L.

2009-01-01

We recently generated an HT-1080-derived cell line called HT-AR1 that responds to dihydrotestosterone (DHT) treatment by undergoing cell growth arrest in association with cytoskeletal reorganization and induction of neuroendocrine-like cell differentiation. In this report, we show that DHT induces a dose-dependent increase in G0/G1 growth-arrested cells using physiological levels of hormone. The arrested cells increase in cell size and contain a dramatic redistribution of desmoplakin, keratin 5, and chromogranin A proteins. DHT-induced cytoskeletal changes were also apparent from time lapse video microscopy that showed that androgen treatment resulted in the rapid appearance of neuronal-like membrane extensions. Expression profiling analysis using RNA isolated from DHT-treated HT-AR1 cells revealed that androgen receptor activation leads to the coordinate expression of numerous cell signaling genes including RhoB, PTGF-β, caveolin-2, Egr-1, myosin 1B, and EHM2. Because RhoB has been shown to have a role in tumor suppression and neuronal differentiation in other cell types, we investigated RhoB signaling functions in the HT-AR1 steroid response. We found that steroid induction of RhoB was DHT-specific and that newly synthesized RhoB protein was post-translationally modified and localized to endocytic vesicles. Moreover, treatment with a farnesyl transferase inhibitor reduced DHT-dependent growth arrest, suggesting that prenylated RhoB might function to inhibit HT-AR1 cell proliferation. This was directly shown by transfecting HT-AR1 cells with RhoB coding sequences containing activating or dominant negative mutations. PMID:14576147

Reproductive Steroid Regulation of Mood and Behavior.

PubMed

Schiller, Crystal Edler; Johnson, Sarah L; Abate, Anna C; Schmidt, Peter J; Rubinow, David R

2016-06-13

In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135-1160, 2016e. Copyright © 2016 John Wiley & Sons, Inc.

Idiopathic Supraglottic Stenosis Refractory to Multiple Interventions Improved With Serial Office-based Steroid Injections.

PubMed

Hoffman, Matthew R; Mai, Johnny P; Dailey, Seth H

2017-10-30

The objective of this study was to describe a patient with idiopathic supraglottic stenosis who experienced persistent disease despite multiple office-based and operative interventions, whose disease is now better controlled with scheduled serial office-based steroid injections. This is a case report and literature review. A 42-year-old female was referred for worsening supraglottic stenosis despite systemic steroids. She underwent awake tracheotomy. A thorough historical, histologic, and laboratory workup did not reveal an etiology to her stenosis. She later underwent endoscopic partial laryngectomy and was able to be decannulated. She underwent a second endoscopic partial laryngectomy two years later for worsening disease and then was managed over the next seven years with intermittent systemic steroids. Over the last year, she has undergone eight office-based steroid injections with improvement in her degree of stenosis and symptom burden. There are only four prior reported cases of idiopathic supraglottic stenosis, none of which has been managed with serial office-based steroid injections. This case report adds to the small body of literature on the management of this rare disease and proposes a new office-based treatment pathway that may help induce regression of stenosis. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Combined treatment in punctate inner choroidopathy

PubMed Central

Terelak-Borys, Barbara; Zagajewska, Katarzyna; Jankowska-Lech, Irmina; Tesla, Piotr; Grabska-Liberek, Iwona

2016-01-01

Purpose The purpose of this study was to describe a combination treatment for choroidal neovascular (CNV) membrane, secondary to punctate inner choroidopathy (PIC). Patient and methods A 44-year-old female patient was diagnosed with PIC complicated by the development of recurrent juxtafoveal neovascular membrane. The treatment included a sequence of monotherapy regimens: systemic steroid therapy, photodynamic therapy, and intravitreal injections of vascular endothelial growth factor (VEGF) inhibitor (anti-VEGF). Owing to the CNV membrane resistance to various types of monotherapy, a combination treatment consisting of local injections of steroid underneath the Tenon’s capsule and intravitreal anti-VEGF injections was used. Results Systemic steroid therapy resulted in rapid local improvement with a very short remission period. No positive effects of photodynamic therapy were observed. Sequential anti-VEGF injections led to remission periods of several months. Permanent regression of CNV membrane was achieved following combined local application of steroid and intravitreal anti-VEGF injections. Conclusion A combination treatment including steroid and anti-VEGF medication characterized by anti-inflammatory and antiangiogenic effects may be a very beneficial option for the treatment of recurrent CNV membrane as a complication of PIC. PMID:27729795

Towards the emerging crosstalk: ERBB family and steroid hormones.

PubMed

D'Uva, Gabriele; Lauriola, Mattia

2016-02-01

Growth factors acting through receptor tyrosine kinases (RTKs) of ERBB family, along with steroid hormones (SH) acting through nuclear receptors (NRs), are critical signalling mediators of cellular processes. Deregulations of ERBB and steroid hormone receptors are responsible for several diseases, including cancer, thus demonstrating the central role played by both systems. This review will summarize and shed light on an emerging crosstalk between these two important receptor families. How this mutual crosstalk is attained, such as through extensive genomic and non-genomic interactions, will be addressed. In light of recent studies, we will describe how steroid hormones are able to fine-tune ERBB feedback loops, thus impacting on cellular output and providing a new key for understanding the complexity of biological processes in physiological or pathological conditions. In our understanding, the interactions between steroid hormones and RTKs deserve further attention. A system biology approach and advanced technologies for the analysis of RTK-SH crosstalk could lead to major advancements in molecular medicine, providing the basis for new routes of pharmacological intervention in several diseases, including cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunotherapeutics in Pediatric Autoimmune Central Nervous System Disease: Agents and Mechanisms.

PubMed

Nosadini, Margherita; Sartori, Stefano; Sharma, Suvasini; Dale, Russell C

2017-08-01

Beyond the major advances produced by careful clinical-radiological phenotyping and biomarker development in autoimmune central nervous system disorders, a comprehensive knowledge of the range of available immune therapies and a deeper understanding of their action should benefit therapeutic decision-making. This review discusses the agents used in neuroimmunology and their mechanisms of action. First-line treatments typically include corticosteroids, intravenous immunoglobulin, and plasmapheresis, while for severe disease second-line "induction" agents such as rituximab or cyclophosphamide are used. Steroid-sparing agents such as mycophenolate, azathioprine, or methotrexate are often used in potentially relapsing or corticosteroid-dependent diseases. Lessons from adult neuroimmunology and rheumatology could be translated into pediatric autoimmune central nervous system disease in the future, including the potential utility of monoclonal antibodies targeting lymphocytes, adhesion molecules for lymphocytic migration, cytokines or their receptors, or complement. Finally, many agents used in other fields have multiple mechanisms of action, including immunomodulation, with potential usefulness in neuroimmunology, such as antibiotics, psychotropic drugs, probiotics, gut health, and ketogenic diet. All currently accepted and future potential agents have adverse effects, which can be severe; therefore, a "risk-versus-benefit" determination should guide therapeutic decision-making. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of high-dose nandrolone aggravates septic shock in a mouse model.

PubMed

Lin, Che; Chen, Shou-Tung; Chien, Su-Yu; Kuo, Shou-Jen; Chen, Dar-Ren

2011-06-01

Nandrolone, an anabolic-androgenic steroid, is widely misused by athletes who wish to rapidly increase muscle mass and performance. An increasing number of reports have indicated that nandrolone may affect and modulate the immune system. This study aimed to investigate the effects of nandrolone on septic shock-caused immune responses and the cellular mechanism of action using a sepsis murine model. Before septic shock induction, BALB/c mice were given a high dose of nandrolone or peanut oil only. After septic shock induction, mice were sacrificed at different time points. Their blood and tissue specimens were analyzed. It was found that the high-dose nandrolone group had significantly increased mortality compared with the control group (p<0.001). The serum malondialdehyde level was significantly increased in the high-dose group compared with the control group. Animals administered a high dose of nandrolone had significantly increased hepatic tumor necrosis factor-α or splenic interferon-γ at 0 and 6 hours. In lung tissue, insulin-like growth factor-1, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor-1 receptor, and IGFBP1 and IGFBP2 mRNA expression were increased in the high-dose nandrolone group at 6 hours. Nandrolone abuse may hasten the death of patients with septic shock and may aggravate septic shock in mice. Copyright © 2011. Published by Elsevier B.V.

Symptomatic Spinal Epidural Lipomatosis After a Single Local Epidural Steroid Injection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tok, Chung Hong, E-mail: rogertok@gmail.com; Kaur, Shaleen; Gangi, Afshin

Spinal epidural lipomatosis is a rare disorder that can manifest with progressive neurological deficits. It is characterized by abnormal accumulation of unencapsulated epidural fat commonly associated with the administration of exogenous steroids associated with a variety of systemic diseases, endocrinopathies, and Cushing syndrome (Fogel et al. Spine J 5:202-211, 2005). Occasionally, spinal epidural lipomatosis may occur in patients not exposed to steroids or in patients with endocrinopathies, primarily in obese individuals (Fogel et al. Spine J 5:202-211, 2005). However, spinal lumbar epidural lipomatosis resulting from local steroid injection has rarely been reported. We report the case of a 45-year-old diabeticmore » man with claudication that was probably due to symptomatic lumbar spinal lipomatosis resulting from a single local epidural steroid injection.« less

LC-MS based analysis of endogenous steroid hormones in human hair.

PubMed

Gao, Wei; Kirschbaum, Clemens; Grass, Juliane; Stalder, Tobias

2016-09-01

The quantification of endogenous steroid hormone concentrations in hair is increasingly used as a method for obtaining retrospective information on long-term integrated hormone exposure. Several different analytical procedures have been employed for hair steroid analysis, with liquid chromatography-mass spectrometry (LC-MS) being recognized as a particularly powerful analytical tool. Several methodological aspects affect the performance of LC-MS systems for hair steroid analysis, including sample preparation and pretreatment, steroid extraction, post-incubation purification, LC methodology, ionization techniques and MS specifications. Here, we critically review the differential value of such protocol variants for hair steroid hormones analysis, focusing on both analytical quality and practical feasibility issues. Our results show that, when methodological challenges are adequately addressed, LC-MS protocols can not only yield excellent sensitivity and specificity but are also characterized by relatively simple sample processing and short run times. This makes LC-MS based hair steroid protocols particularly suitable as a high-quality option for routine application in research contexts requiring the processing of larger numbers of samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

Simultaneous determination of androgenic and estrogenic endpoints in the threespine stickleback (Gasterosteus aculeatus) using quantitative RT-PCR.

PubMed

Hogan, Natacha S; Wartman, Cheryl A; Finley, Megan A; van der Lee, Jennifer G; van den Heuvel, Michael R

2008-12-11

A method to evaluate the expression of three hormone responsive genes, vitellogenin (estrogens), spiggin (androgens), and an androgen receptor (ARbeta) using real-time PCR in threespine stickleback is presented. Primers were designed from previously characterised spiggin and ARbeta sequences, while a homology cloning strategy was used to isolate a partial gene sequence for stickleback vitellogenin (Vtg). Spiggin mRNA was significantly higher in kidneys of field-caught males compared to females by greater than five orders of magnitude while ARbeta levels were only 1.4-fold higher in males. Female fish had four order of magnitude higher liver Vtg expression than wild-captured males. To determine the sensitivity of these genes to induction by hormones, male and female sticklebacks were exposed to 1, 10 and 100 ng/L of methyltestosterone (MT) or estradiol (E2) in a flow-through exposure system for 7 days. Spiggin induction in females, and Vtg induction in males were both detectable at 10 ng/L of MT and E2, respectively. MT exposure did not induce ARbeta expression in the kidneys of female stickleback. In vitro gonadal steroid hormones production was measured in testes and ovaries of exposed stickleback to compare gene expression endpoints to an endpoint of hormonal reproductive alteration. Reduction in testosterone production in ovaries at all three MT exposure concentrations, and ovarian estradiol synthesis at the 100 ng/L exposure were the only effects observed in the in vitro steroidogenesis for either hormone exposure. Application of these methods to assess both androgenic, estrogenic, and anti-steroidogenic properties of environmental contaminants in a single fish species will be a valuable tool for identifying compounds causing reproductive dysfunction in fishes.

In vitro steroid profiling system for the evaluation of endocrine disruptors.

PubMed

Nakano, Yosuke; Yamashita, Toshiyuki; Okuno, Masashi; Fukusaki, Eiichiro; Bamba, Takeshi

2016-09-01

Endocrine disruptors (ED) are chemicals that affect various aspects of the endocrine system, often leading to the inhibition of steroidogenesis. Current chemical safety policies that restrict human exposure to such chemicals describe often time-consuming and costly methods for the evaluation of ED effects. We aimed to develop an effective tool for accurate phenotypic chemical toxicology studies. We developed an in vitro ED evaluation system using gas chromatography/mass spectrometry (GC/MS/MS) methods for metabolomic analysis of multi-marker profiles. Accounting for sample preparation and GC/MS/MS conditions, we established a screening method that allowed the simultaneous analysis of 17 steroids with good reproducibility and a linear calibration curve. Moreover, we applied the developed system to H295R human adrenocortical cells exposed to forskolin and prochloraz in accordance with the Organization for Economic Cooperation and Development (OECD) guidelines and observed dose-dependent variations in steroid profiles. While the OECD guidelines include only testosterone and 17β-estradiol, our system enabled a comprehensive and highly sensitive analysis of steroid profile alteration due to ED exposure. The application of our ED evaluation screen could be economical and provide novel insights into the hazards of ED exposure to the endocrine system. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Phenobarbital induction of cytochromes P-450. High-level long-term responsiveness of primary rat hepatocyte cultures to drug induction, and glucocorticoid dependence of the phenobarbital response.

PubMed Central

Waxman, D J; Morrissey, J J; Naik, S; Jauregui, H O

1990-01-01

The induction of hepatic cytochromes P-450 by phenobarbital (PB) was studied in rat hepatocytes cultured for up to 5 weeks on Vitrogen-coated plates in serum-free modified Chee's medium then exposed to PB (0.75 mM) for an additional 4 days. Immunoblotting analysis indicated that P-450 forms PB4 (IIB1) and PB5 (IIB2) were induced dramatically (greater than 50-fold increase), up to levels nearly as high as those achieved in PB-induced rat liver in vivo. The newly synthesized cytochrome P-450 was enzymically active, as shown by the major induction of the P-450 PB4-dependent steroid 16 beta-hydroxylase and pentoxyresorufin O-dealkylase activities in the PB-induced hepatocyte microsomes (up to 90-fold increase). PB induction of these P-450s was markedly enhanced by the presence of dexamethasone (50 nM-1 microM), which alone was not an affective inducing agent, and was inhibited by greater than 90% by 10% fetal bovine serum. The PB response was also inhibited (greater than 85%) by growth hormone (250 ng/ml), indicating that this hormone probably acts directly on the hepatocyte when it antagonizes the induction of P-450 PB4 in intact rats. In untreated hepatocytes, P-450 RLM2 (IIA2), P-450 3 (IIA1) and NADPH P-450 reductase levels were substantially maintained in the cultures for 10-20 days. The latter two enzymes were also inducible by PB to an extent (3-4 fold elevation) that is comparable with that observed in the liver in vivo. Moreover, P-450c (IA1) and P-450 3 (IIA1) were highly inducible by 3-methylcholanthrene (5 microM; 48 h exposure) even after 3 weeks in culture. In contrast, the male-specific pituitary-regulated P-450 form 2c (IIC11) was rapidly lost upon culturing the hepatocytes, suggesting that supplementation of appropriate hormonal factors may be necessary for its expression. The present hepatocyte culture system exhibits a responsiveness to drug inducers that is qualitatively and quantitatively comparable with that observed in vivo, and should prove valuable for more detailed investigations of the molecular and mechanistic basis of the response to PB and its modulation by endogenous hormones. Images Fig. 3. Fig. 5. PMID:2222405

Metabolite profiling of sex developmental steroid conjugates reveals an association between decreased levels of steroid sulfates and adiposity in obese girls.

PubMed

Lee, Su Hyeon; Kim, Shin Hye; Lee, Won-Yong; Chung, Bong Chul; Park, Mi Jung; Choi, Man Ho

2016-09-01

Free and conjugated steroids coexist in a dynamic equilibrium due to complex biosynthetic and metabolic processes. This may have clinical significance related to various physiological conditions, including sex development involving the reproductive system. Therefore, we performed quantitative profiling of 16 serum steroids conjugated with glucuronic and sulfuric acids using liquid chromatography-mass spectrometry (LC-MS). All steroid conjugates were purified by solid-phase extraction and then separated through a 3-μm particle size C18 column (150mm×2.1mm) at a flow rate of 0.3 mL/min in the negative ionization mode. The LC-MS-based analysis was found to be linear (r(2)>0.99), and all steroid conjugates had a limit-of-quantification (LOQ) of 10ng/mL, except for cholesterol sulfate and 17β-estradiol-3,17-disulfate (20ng/mL). The extraction recoveries of all steroid conjugates ranged from 97.9% to 110.7%, while the overall precision (% CV) and accuracy (% bias) ranged from 4.8% to 10.9% and from 94.4% to 112.9% at four different concentrations, respectively. Profiling of steroid conjugates corrected by adiposity revealed decreased levels of steroid sulfates (P<0.01) in overweight and obese girls compared to normal girls. The suggested technique can be used for evaluating metabolic changes in steroid conjugates and for understanding the pathophysiology and relative contributions of adiposity in childhood obesity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemiluminescence of the reaction system Ce(IV)-non-steroidal anti-inflammatory drugs containing europium(III) ions and its application to the determination of naproxen in pharmaceutical preparations and urine.

PubMed

Kaczmarek, Małgorzata

2011-11-01

The chemiluminescence (CL) of oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) by Ce(IV) ions, was recorded in the presence and absence europium(III) ions, in solution of pH ~ 4 of solution. Kinetic curves and CL emission spectra of the all studied systems were discussed. CL of measurable intensity was observed in the Ce(IV)-NP-Eu(III) reaction system only in acidic solutions. The CL spectrum rcegistered for this system shows emission bands, typical of Eu(III) ions, with maximum at λ ~ 600 nm. The chemiluminescent method, based on Eu(III) emission in reaction system of NP-Ce(IV)-Eu(III) in acid solution was therefore used for the determination of naproxen in mixture of non-steroidal anti-inflammatory drugs.

The Central Effects of Androgenic-anabolic Steroid Use.

PubMed

Mędraś, Marek; Brona, Anna; Jóźków, Paweł

: Millions of men use androgenic-anabolic steroids (AAS) to stimulate muscle growth and improve physical appearance. Although 1 out of 3 people who uses androgenic-anabolic steroids develops a steroid use disorder, the effects of the drugs on the central nervous system and the psyche are still not well understood. Although most addictive substances improve mood immediately after administration, AAS exert less pronounced euphoric effects. Instead, they are primarily taken for the delayed gratification of increased muscle mass. Withdrawal from AAS may lead to a range of somatic and psychiatric symptoms, and, in many cases, comprehensive treatment supervised by an endocrinologist and a psychiatrist is required.

Remission of type 1 diabetes mellitus recurrence 6 years after simultaneous pancreas and kidney transplantation.

PubMed

Kervella, Delphine; Scharbarg, Emeric; Mahot-Moreau, Pascale; Renaudin, Karine; Branchereau, Julien; Karam, Georges; Chaillous, Lucy; Bach, Kalyane; Cantarovich, Diego

2018-05-09

Recurrence of type 1 diabetes mellitus (T1DM) is not frequent following pancreas transplantation and is generally considered to cause irreversible allograft failure despite rescue traitement 1 .A 35-year-old woman experienced severe hyperglycaemia (>5 g/L) 6 years following a simultaneous pancreas and kidney (SPK) transplantation. Immunosuppressive treatment included induction with anti-thymocyte globuline (ATG) followed by a steroid-free regimen and a combination of tacrolimus and mycophenolate mofetil (MMF). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

[Anti-TNF-alpha therapy in ulcerative colitis].

PubMed

Lakatos, Péter László; Lakatos, László

2008-05-18

The most important factors that determine treatment strategy in ulcerative colitis (UC) are disease extent and severity. Orally-topically administered 5-aminosalicylates (5-ASA) remain the treatment of choice in mild-to-moderate UC. In contrast, the treatment of refractory (to steroids, azathioprine or 5-ASA) and fulminant cases is still demanding. New evidence supports a role for infliximab induction and/or maintenance therapy in these subgroup of patients leading to increased remission and decreased colectomy rates. The aim of this paper is to review the rationale for the use of TNF-alpha inhibitors in the treatment of UC.

Successful management of airway hemangioma with propranolol.

PubMed

Mendiratta, Vibhu; Varghese, Bincy; Chander, Ram; Parakh, Ankit; Solanki, Ravi S

2013-06-01

Airway hemangiomas can be difficult to manage and cause anxiety in both the parents and the treating physician. Propranolol, a nonselective beta-blocker, has recently been used for treating proliferating infantile hemangiomas. We report successful management of a proliferating, large, mixed infantile hemangioma with subglottic extension in an Indian infant using oral propranolol in a dose of 2mg/kg/day without any side effects. Induction of early involution and freedom from the side effects of steroid therapy seem encouraging for using propranolol as a first line treatment modality in the management of troublesome hemangiomas. © 2013 The International Society of Dermatology.

Inhibition of ultraviolet-B epidermal ornithine decarboxylase induction and skin carcinogenesis in hairless mice by topical indomethacin and triamcinolone acetonide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowe, N.J.; Connor, M.J.; Breeding, J.

1982-10-01

Modulation of ultraviolet-B (UVB) skin carcinogenesis by topical treatment with two antiinflammatory drugs expected to have different mechanisms of action has been studied in the hairless mouse. Indomethacin is a nonsteroidal antiinflammatory agent which may act by inhibiting prostaglandin biosynthesis. Triamcinolone acetonide is a steroidal antiinflammatory agent. Both of these drugs inhibited the induction of epidermal ornithine decarboxylase by UVB when applied topically in a acetone vehicle. A UVB skin tumor study was designed. Groups of mice were irradiated daily with UVB for 20 days, each mouse receiving a total of 17.1 kJ UVB per sq m. Group 1 wasmore » treated with acetone immediately after each irradiation; Group 2 received 700 nmol indomethacin in acetone immediately after each irradiation; Group 3 received 14.4 nmol triamcinolone acetonide in acetone immediately after each irradiation. Mice were killed after 52 weeks, and the tumors were excised and examined histologically. Both topical indomethacin and topical triamcinolone acetonide were effective in reducing the incidence and size of the skin tumors induced by UVB. This evidence supports the hypothesis that the induction of ornithine decarboxylase may be a critical component of UVB skin carcinogenesis and that inhibition of ornithine decarboxylase induction can be used as a screen for agents which will inhibit UVB skin carcinogenesis.« less

Current topics in membranes and transport

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kleinzeller, A.

1987-01-01

This book contains 10 chapters. Some of the chapter titles are: Expression of the Oxytocin and Vasopressin Genes; Steroid Effects on Excitable Membranes: The Secretory Vesicle in Processing and Secretion of Neuropeptides: and Steroid Hormone Influences on Cyclic AMP-Generating Systems.

Deducing the temporal order of cofactor function in ligand-regulated gene transcription: theory and experimental verification.

PubMed

Dougherty, Edward J; Guo, Chunhua; Simons, S Stoney; Chow, Carson C

2012-01-01

Cofactors are intimately involved in steroid-regulated gene expression. Two critical questions are (1) the steps at which cofactors exert their biological activities and (2) the nature of that activity. Here we show that a new mathematical theory of steroid hormone action can be used to deduce the kinetic properties and reaction sequence position for the functioning of any two cofactors relative to a concentration limiting step (CLS) and to each other. The predictions of the theory, which can be applied using graphical methods similar to those of enzyme kinetics, are validated by obtaining internally consistent data for pair-wise analyses of three cofactors (TIF2, sSMRT, and NCoR) in U2OS cells. The analysis of TIF2 and sSMRT actions on GR-induction of an endogenous gene gave results identical to those with an exogenous reporter. Thus new tools to determine previously unobtainable information about the nature and position of cofactor action in any process displaying first-order Hill plot kinetics are now available.

Deducing the Temporal Order of Cofactor Function in Ligand-Regulated Gene Transcription: Theory and Experimental Verification

PubMed Central

Dougherty, Edward J.; Guo, Chunhua; Simons, S. Stoney; Chow, Carson C.

2012-01-01

Cofactors are intimately involved in steroid-regulated gene expression. Two critical questions are (1) the steps at which cofactors exert their biological activities and (2) the nature of that activity. Here we show that a new mathematical theory of steroid hormone action can be used to deduce the kinetic properties and reaction sequence position for the functioning of any two cofactors relative to a concentration limiting step (CLS) and to each other. The predictions of the theory, which can be applied using graphical methods similar to those of enzyme kinetics, are validated by obtaining internally consistent data for pair-wise analyses of three cofactors (TIF2, sSMRT, and NCoR) in U2OS cells. The analysis of TIF2 and sSMRT actions on GR-induction of an endogenous gene gave results identical to those with an exogenous reporter. Thus new tools to determine previously unobtainable information about the nature and position of cofactor action in any process displaying first-order Hill plot kinetics are now available. PMID:22272313

Prevention effect of rare ginsenosides against stress-hormone induced MTOC amplification

PubMed Central

Lee, Jee-Hyun; Cheong, Kyu Jin; Jung, Youn-Sang; Woo, Tae-Gyun; Yoon, Min-Ho; Oh, Ah-Young; Kang, So-Mi; Lee, Chunghui; Sun, Hokeun; Hwang, Jihwan; Song, Gyu-Yong; Park, Bum-Joon

2016-01-01

Stress has been suggested as one of important cause of human cancer without molecular biological evidence. Thus, we test the effect of stress-related hormones on cell viability and mitotic fidelity. Similarly to estrogen, stress hormone cortisol and its relative cortisone increase microtubule organizing center (MTOC) number through elevated expression of γ-tubulin and provide the Taxol resistance to human cancer cell lines. However, these effects are achieved by glucocorticoid hormone receptor (GR) but not by estrogen receptor (ER). Since ginsenosides possess steroid-like structure, we hypothesized that it would block the stress or estrogen-induced MTOC amplification and Taxol resistance. Among tested chemicals, rare ginsenoside, CSH1 (Rg6) shows obvious effect on inhibition of MTOC amplification, γ-tubulin induction and Taxol resistance. Comparing to Fulvestant (FST), ER-α specific inhibitor, this chemical can block the cortisol/cortisone-induced MTOC deregulation as well as ER-α signaling. Our results suggest that stress hormone induced tumorigenesis would be achieved by MTOC amplification, and CSH1 would be useful for prevention of stress-hormone or steroid hormone-induced chromosomal instability. PMID:27147573

Rituximab Treatment for PR3-ANCA-Positive Membranoproliferative Glomerulonephritis Associated with Adult-Onset Periodic Fever Syndrome.

PubMed

Hamano, Yoshitomo; Yoshizawa, Hiromichi; Sugase, Taro; Miki, Takuya; Ohtani, Naoko; Hanawa, Shiho; Takeshima, Eri; Morishita, Yoshiyuki; Saito, Osamu; Takemoto, Fumi; Muto, Shigeaki; Yumura, Wako; Kusano, Eiji

2012-07-01

We report the case of a 36-year-old Japanese woman with nephrotic syndrome due to membranoproliferative glomerulonephritis (MPGN) Type I diagnosed after a 5-year history of periodic fever syndrome (PFS). Hypocomplementemia and elevation of anti-proteinase 3 anti-neutrophil cytoplasmic autoantibody (PR3-ANCA) were observed. HIV, and hepatitis B and C serology were negative. Nephrotic syndrome and periodic fever did not respond to oral steroid and intravenous steroid pulse therapies combined with cyclosporine, dipyridamole, warfarin and losartan. We tried immunotherapy using rituximab, a human-mouse chimeric monoclonal antibody directed against the CD20 antigen on mature B cells. This therapeutic approach led to improvement of renal function and remission of nephrotic syndrome and hypocomplementemia. However, it did not have a beneficial effect on periodic fever. Suspecting adult-onset hereditary PFS, we analyzed her genetic alteration of MEFV and TNFRSF1A genes. A rare genotype in intron 6 of TNFRSF1A was revealed. The etiological relationship between periodic fever and MPGN is discussed. Rituximab is a hopeful choice of induction therapy for refractory MPGN.

Factors impacting short and long-term kidney graft survival: modification by single intra-operative -high-dose induction with ATG-Fresenius.

PubMed

Kaden, Jürgen; May, Gottfried; Völp, Andreas; Wesslau, Claus

2011-01-01

A majority of recipients benefited from the intra-operative single high-dose induction (HDI) with ATG-Fresenius (ATG-F) still leaving a group of recipients who did not profit from this kind of induction. Therefore the aim of this retrospective analysis was 1st to identify the risk factors impacting short and long-term graft survival, and 2nd to assess the efficacy of this type of induction in kidney graft recipients with or without these risk factors. A total of 606 recipients receiving two different immunosuppressive treatment regimens (1st: Triple drug therapy [TDT, n=196] consisting mainly of steroids, azathioprine and cyclosporine; 2nd: TDT + 9 mg/kg ATG-F intra-operatively [HDI, n=410]) were included in this analysis and grouped according to their kidney graft survival time (short GST: ≤1 yr, n=100 and long GST: >5 yrs, n=506). The main risk factors associated with a shortened graft survival were pre-transplant sensitization, re-transplantation, rejections (in particular vascular or mixed ones) and the necessity of a long-term anti-rejection therapy. Adding ATG-F single high dose induction to TDT was more efficient in prolonging kidney graft survival than TDT alone not only in recipients without any risk factors (p<0.005) but also in recipients with at least one risk factor (p<0.021). Only in 4.6% of recipients having two or more risk factors this effect could not be demonstrated. The intra-operative single high-dose induction with ATG-F significantly improves the kidney graft survival in recipients with or without risk factors and can therefore be recommended.

Change of Oral to Topical Corticosteroid Therapy Exacerbated Glucose Tolerance in a Patient with Plaque Psoriasis.

PubMed

Hongo, Yui; Ashida, Kenji; Ohe, Kenji; Enjoji, Munechika; Yamaguchi, Miyuki; Kurata, Tsuyoshi; Emoto, Akiko; Yamanouchi, Hiroko; Takagi, Satoko; Mori, Hitoe; Kawata, Nozomi; Hisata, Yoshio; Sakanishi, Yuta; Izumi, Kenichi; Sugioka, Takashi; Anzai, Keizo

2017-11-13

BACKGROUND Psoriasis is known as the most frequent disease treated by long-term topical steroids. It is also known that patients with thick, chronic plaques require the highest potency topical steroids. However, the treatment is limited to up to four weeks due to risk of systemic absorption. CASE REPORT An 80-year-old man was diagnosed with type 2 diabetes 16 years before, and was being administered insulin combined with alpha glucosidase inhibitor. He was diagnosed with plaque psoriasis and his oral steroid treatment was switched to topical steroid treatment due to lack of improvement and poorly controlled blood glucose level. The hypoglycemic events improved after the psoriatic lesions improved. CONCLUSIONS Control of blood glucose level is difficult at the very beginning of topical steroid treatment for psoriasis especially if a patient is receiving insulin treatment. Intense monitoring of blood glucose level during initiation of topical steroid treatment is necessary to prevent unfavorable complications.

Risk of Osteoporotic Fracture After Steroid Injections in Patients With Medicare.

PubMed

Carreon, Leah Y; Ong, Kevin L; Lau, Edmund; Kurtz, Steven M; Glassman, Steven D

To further evaluate the relationship between steroid injections and osteoporotic fracture risk, we analyzed Medicare administrative claims data on both large-joint steroid injections (LJSIs) into knee and hip and transforaminal steroid injections (TSIs), as well as osteoporotic hip and wrist fractures. Our hypothesis was that a systemic effect of steroid injections would increase fracture risk in all skeletal locations regardless of injection site, whereas a local effect would produce a disproportionate increased risk of spine fracture with spine injection. Patients treated with an LJSI, a TSI, or an epidural steroid injection (ESI) were identified from 5% Medicare claims data. Patients under age 65 years and patients with prior osteoporotic fracture were excluded. Analyses were performed to determine fracture risk (adjusted hazard ratio) for each type of injection. Analysis of the Medicare data revealed that ESIs were associated with decreased osteoporotic spine fracture risk, but the effect was small and might not be clinically relevant. ESIs did not influence osteoporotic hip or wrist fracture risk, but LJSIs reduced the risk.

Mycobacterium intracellulare infection of the shoulder and spine in a patient with steroid-treated systemic Lupus erythematosus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zvetina, J.R.; Rubinstein, H.; Demos, T.C.

1982-05-01

Atypical mycobacterial infections of bone are rare. A patient with systemic lupus erythematosus treated with steroids developed an M. intracellulare infection of the shoulder and spine. These infections are insidious and diagnosis is difficult. Marked involvement of one joint, large effusion, or aspirated small synovial fragments suggest an atypical tuberculous joint infection.

Steroid hormone induction of temporal gene expression in Drosophila brain neuroblasts generates neuronal and glial diversity.

PubMed

Syed, Mubarak Hussain; Mark, Brandon; Doe, Chris Q

2017-04-10

An important question in neuroscience is how stem cells generate neuronal diversity. During Drosophila embryonic development, neural stem cells (neuroblasts) sequentially express transcription factors that generate neuronal diversity; regulation of the embryonic temporal transcription factor cascade is lineage-intrinsic. In contrast, larval neuroblasts generate longer ~50 division lineages, and currently only one mid-larval molecular transition is known: Chinmo/Imp/Lin-28+ neuroblasts transition to Syncrip+ neuroblasts. Here we show that the hormone ecdysone is required to down-regulate Chinmo/Imp and activate Syncrip, plus two late neuroblast factors, Broad and E93. We show that Seven-up triggers Chinmo/Imp to Syncrip/Broad/E93 transition by inducing expression of the Ecdysone receptor in mid-larval neuroblasts, rendering them competent to respond to the systemic hormone ecdysone. Importantly, late temporal gene expression is essential for proper neuronal and glial cell type specification. This is the first example of hormonal regulation of temporal factor expression in Drosophila embryonic or larval neural progenitors.

Sex Differences and Sex Steroids in Lung Health and Disease

PubMed Central

Townsend, Elizabeth A.; Miller, Virginia M.

2012-01-01

Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span. PMID:22240244

From molecule to market: steroid hormones and financial risk-taking.

PubMed

Coates, John M; Gurnell, Mark; Sarnyai, Zoltan

2010-01-27

Little is known about the role of the endocrine system in financial decision-making. Here, we survey research on steroid hormones and their cognitive effects, and examine potential links to trader performance in the financial markets. Preliminary findings suggest that cortisol codes for risk and testosterone for reward. A key finding of this endocrine research is the different cognitive effects of acute versus chronic exposure to hormones: acutely elevated steroids may optimize performance on a range of tasks; but chronically elevated steroids may promote irrational risk-reward choices. We present a hypothesis suggesting that the irrational exuberance and pessimism observed during market bubbles and crashes may be mediated by steroid hormones. If hormones can exaggerate market moves, then perhaps the age and sex composition among traders and asset managers may affect the level of instability witnessed in the financial markets.

Idiopathic granulomatous mastitis: a medical or surgical disease of the breast?

PubMed

Skandarajah, Anita; Marley, Leah

2015-12-01

Idiopathic granulomatous mastitis (IGM) is a rare benign breast disease, which can be protracted, disfiguring and may be linked to an underlying autoimmune disorder. The clinical presentation may mimic bacterial mastitis or carcinoma. To review the mode of presentation, diagnosis, management, resolution and incidence of IGM in three tertiary breast centres and propose guidelines for management. The breast and anatomical databases of three centres were reviewed from January 2000 to December 2013 to identify patients with histological diagnosis of IGM. Clinical and demographic characteristics were retrieved and treatment modalities and time to resolution were recorded. Seventeen patients were identified with a median age of 40. The majority of patients were premenopausal, multiparous and presented with a mass. All patients had initial treatment as infectious mastitis. The diagnosis was made by core biopsy in 71%. Eleven patients required immunosuppressive treatment with steroids and four of these patients required a steroid-sparing agent because of steroidal side effects, recurrence or persistence of symptoms. The median time to resolution was 3 months (0-24 months). One patient had subsequent systemic Wegener's granulomatosis diagnosed. Idiopathic granulomatosis mastitis requires histological confirmation, close monitoring, exclusion of underlying systemic autoimmune conditions and judicious use of steroids and steroid-sparing agents such as methotrexate. It has a protracted course with some patients relapsing quickly upon cessation of steroids. © 2014 Royal Australasian College of Surgeons.

Design of an Escherichia coli system for whole cell mediated steroid synthesis and molecular evolution of steroid hydroxylases.

PubMed

Hannemann, Frank; Virus, Cornelia; Bernhardt, Rita

2006-06-25

The 15beta-hydroxylase (CYP106A2) from Bacillus megaterium, one of the few bacterial steroid hydroxylases, which has been isolated and characterized so far, catalyses the 15beta-hydroxylation of a variety of steroids. The enzyme can be supported in its activity with adrenodoxin (Adx) and adrenodoxin reductase (AdR) from bovine adrenals, supplying this enzyme with the reducing equivalents necessary for steroid hydroxylation activity. This three-component electron transfer chain was implemented in Escherichia coli by coexpression of the corresponding coding sequences from two plasmids, containing different selection markers and compatible origins of replication. The cDNAs of AdR and Adx on the first plasmid were separated by a ribosome binding sequence, with the reductase preceding the ferredoxin. The second plasmid for CYP106A2 expression was constructed with all features necessary for a molecular evolution approach. The transformed bacteria show the inducible ability to efficiently convert 11-deoxycorticosterone (DOC) to 15beta-DOC at an average rate of 1 mM/d in culture volumes of 300 ml. The steroid conversion system was downscaled to the microtiter plate format and a robot set-up was developed for a fluorescence-based conversion assay as well as a CO difference spectroscopy assay, which enables the screening for enzyme variants with higher activity and stability.

A steroid-controlled global switch in sensitivity to apoptosis during Drosophila development.

PubMed

Kang, Yunsik; Bashirullah, Arash

2014-02-01

Precise control over activation of the apoptotic machinery is critical for development, tissue homeostasis and disease. In Drosophila, the decision to trigger apoptosis--whether in response to developmental cues or to DNA damage--converges on transcription of inhibitor of apoptosis protein (IAP) antagonists reaper, hid and grim. Here we describe a parallel process that regulates the sensitivity to, rather than the execution of, apoptosis. This process establishes developmental windows that are permissive or restrictive for triggering apoptosis, where the status of cells determines their capacity to die. We characterize one switch in the sensitivity to apoptotic triggers, from restrictive to permissive, that occurs during third-instar larval (L3) development. Early L3 animals are highly resistant to induction of apoptosis by expression of IAP-antagonists, DNA-damaging agents and even knockdown of the IAP diap1. This resistance to apoptosis, however, is lost in wandering L3 animals after acquiring a heightened sensitivity to apoptotic triggers. This switch in sensitivity to death activators is mediated by a change in mechanisms available for activating endogenous caspases, from an apoptosome-independent to an apoptosome-dependent pathway. This switch in apoptotic pathways is regulated in a cell-autonomous manner by the steroid hormone ecdysone, through changes in expression of critical pro-, but not anti-, apoptotic genes. This steroid-controlled switch defines a novel, physiologically-regulated, mechanism for controlling sensitivity to apoptosis and provides new insights into the control of apoptosis during development. © 2013 Published by Elsevier Inc.

Steroidal constituents from the edible sea urchin Diadema savignyi Michelin induce apoptosis in human cancer cells.

PubMed

Thao, Nguyen Phuong; Luyen, Bui Thi Thuy; Kim, Eun Ji; Kang, Jung Il; Kang, Hee Kyoung; Cuong, Nguyen Xuan; Nam, Nguyen Hoai; Kiem, Phan Van; Minh, Chau Van; Kim, Young Ho

2015-01-01

Bioassay-directed fractionation and purification were used to isolate 12 steroids (1-12) from a CH(2)Cl(2) extract of the edible Vietnamese sea urchin Diadema savignyi Michelin. The cytotoxic activity of the CH(2)Cl(2) extract and 12 steroids was evaluated in three human cancer cell lines (HL-60, PC-3, and SNU-C5). Relative to the effects of the positive control, mitoxantrone, the CH(2)Cl(2) extract (with an inhibitory concentration of 50% [IC(50)] values ranging from 1.37±0.15 to 3.11±0.15 μg/mL) and compounds 2 (with IC(50) values ranging from 5.29±0.11 to 6.80±0.67 μM) and 11 (with IC(50) values ranging from 4.95±0.07 to 6.99±0.28 μM) exhibited potent cytotoxic effects against all three tested human cancer cell lines. In addition, the CH(2)Cl(2) extract and compounds 2 and 11 were found to induce apoptosis. The induction of apoptosis was accompanied by alterations of the apoptosis-related protein expression, inactivation of ERK1/2 mitogen-activated protein kinase signaling, and decreased c-Myc expression. These data suggest that compounds 2 and 11 from the edible sea urchin D. savignyi may have potential for the treatment of colon cancer, leukemia, and prostate cancer as complementary cancer remedies.

The steroidal Na+/K+ ATPase inhibitor 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD) induces potent pro-apoptotic responses in colonic tumor cells.

PubMed

Alkahtani, Saad Hussin

2014-06-01

Recently, potent anticancer actions of the steroidal Na(+)/K(+) ATPase inhibitor 3-[(R)-3-pyrrolidinyl]oxime derivative 3 (3-R-POD) have been reported for multiple cell lines, including prostate and lung cancer cells. In the present study, the anticancer action of 3-R-POD was addressed in colonic tumor cells. Treatment of Caco2 colonic tumor cells with increasing concentrations of 3-R-POD induced potent, dose-dependent inhibition of cell growth as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the APOpercentage apoptosis assay revealed significant pro-apoptotic responses, suggesting that the anticancer activity of this steroidal Na(+)/K(+) ATPase inhibitor in colonic tumors takes places mainly through the induction of strong pro-apoptotic effects. Focussing on the molecular mechanism that may regulate these interactions, 3-R-POD was shown to induce significant early actin re-organization and late Protein Kinase B (AKT) de-phosphorylation. Finally, the 3-R-POD-induced inhibition of cell growth and early actin reorganization in colonic cancer cells remained unchanged when cells were pre-treated with pertussis toxin, thus excluding possible interactions of this inhibitor with G-coupled receptors. These results indicate that 3-R-POD induces potent pro-apoptotic responses in colonic tumor cells governed by actin re-organization and inhibition of AKT pro-survival signaling. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Steroid hormones, stress and the adolescent brain: a comparative perspective.

PubMed

Brown, G R; Spencer, K A

2013-09-26

Steroid hormones, including those produced by the gonads and the adrenal glands, are known to influence brain development during sensitive periods of life. Until recently, most brain organisation was assumed to take place during early stages of development, with relatively little neurogenesis or brain re-organisation during later stages. However, an increasing body of research has shown that the developing brain is also sensitive to steroid hormone exposure during adolescence (broadly defined as the period from nutritional independence to sexual maturity). In this review, we examine how steroid hormones that are produced by the gonads and adrenal glands vary across the lifespan in a range of mammalian and bird species, and we summarise the evidence that steroid hormone exposure influences behavioural and brain development during early stages of life and during adolescence in these two taxonomic groups. Taking a cross-species, comparative perspective reveals that the effects of early exposure to steroid hormones depend upon the stage of development at birth or hatching, as measured along the altricial-precocial dimension. We then review the evidence that exposure to stress during adolescence impacts upon the developing neuroendocrine systems, the brain and behaviour. Current research suggests that the effects of adolescent stress vary depending upon the sex of the individual and type of stressor, and the effects of stress could involve several neural systems, including the serotonergic and dopaminergic systems. Experience of stressors during adolescence could also influence brain development via the close interactions between the stress hormone and gonadal hormone axes. While sensitivity of the brain to steroid hormones during early life and adolescence potentially leaves the developing organism vulnerable to external adversities, developmental plasticity also provides an opportunity for the developing organism to respond to current circumstances and for behavioural responses to influence the future life history of the individual. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Regulation of TRP channels by steroids: Implications in physiology and diseases.

PubMed

Kumar, Ashutosh; Kumari, Shikha; Majhi, Rakesh Kumar; Swain, Nirlipta; Yadav, Manoj; Goswami, Chandan

2015-09-01

While effects of different steroids on the gene expression and regulation are well established, it is proven that steroids can also exert rapid non-genomic actions in several tissues and cells. In most cases, these non-genomic rapid effects of steroids are actually due to intracellular mobilization of Ca(2+)- and other ions suggesting that Ca(2+) channels are involved in such effects. Transient Receptor Potential (TRP) ion channels or TRPs are the largest group of non-selective and polymodal ion channels which cause Ca(2+)-influx in response to different physical and chemical stimuli. While non-genomic actions of different steroids on different ion channels have been established to some extent, involvement of TRPs in such functions is largely unexplored. In this review, we critically analyze the literature and summarize how different steroids as well as their metabolic precursors and derivatives can exert non-genomic effects by acting on different TRPs qualitatively and/or quantitatively. Such effects have physiological repercussion on systems such as in sperm cells, immune cells, bone cells, neuronal cells and many others. Different TRPs are also endogenously expressed in diverse steroid-producing tissues and thus may have importance in steroid synthesis as well, a process which is tightly controlled by the intracellular Ca(2+) concentrations. Tissue and cell-specific expression of TRP channels are also regulated by different steroids. Understanding of the crosstalk between TRP channels and different steroids may have strong significance in physiological, endocrinological and pharmacological context and in future these compounds can also be used as potential biomedicine. Copyright © 2014 Elsevier Inc. All rights reserved.

Steroids and endocrine disruptors--History, recent state of art and open questions.

PubMed

Hampl, Richard; Kubátová, Jana; Stárka, Luboslav

2016-01-01

This introductory chapter provides an overview of the levels and sites at which endocrine disruptors (EDs) affect steroid actions. In contrast to the special issue of Journal of Steroid Biochemistry and Molecular Biology published three years ago and devoted to EDs as such, this paper focuses on steroids. We tried to point to more recent findings and opened questions. EDs interfere with steroid biosynthesis and metabolism either as inhibitors of relevant enzymes, or at the level of their expression. Particular attention was paid to enzymes metabolizing steroid hormones to biologically active products in target cells, such as aromatase, 5α-reductase and 3β-, 11β- and 17β-hydroxysteroid dehydrogenases. An important target for EDs is also steroid acute regulatory protein (StAR), responsible for steroid precursor trafficking to mitochondria. EDs influence receptor-mediated steroid actions at both genomic and non-genomic levels. The remarkable differences in response to various steroid-receptor ligands led to a more detailed investigation of events following steroid/disruptor binding to the receptors and to the mapping of the signaling cascades and nuclear factors involved. A virtual screening of a large array of EDs with steroid receptors, known as in silico methods (≡computer simulation), is another promising approach for studying quantitative structure activity relationships and docking. New data may be expected on the effect of EDs on steroid hormone binding to selective plasma transport proteins, namely transcortin and sex hormone-binding globulin. Little information is available so far on the effects of EDs on the major hypothalamo-pituitary-adrenal/gonadal axes, of which the kisspeptin/GPR54 system is of particular importance. Kisspeptins act as stimulators for hormone-induced gonadotropin secretion and their expression is regulated by sex steroids via a feed-back mechanism. Kisspeptin is now believed to be one of the key factors triggering puberty in mammals, and various EDs affect its expression and function. Finally, advances in analytics of EDs, especially those persisting in the environment, in various body fluids (plasma, urine, seminal fluid, and follicular fluid) are mentioned. Surprisingly, relatively scarce information is available on the simultaneous determination of EDs and steroids in the same biological material. This article is part of a Special Issue entitled 'Endocrine disruptors & steroids'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Frequency of Anabolic Steroids Abuse in Bodybuilder Athletes in Kerman City†This article has been published in the Journal of Rafsanjan University of Medical Sciences in Persian language.

PubMed Central

Sepehri, Gholamreza; Mousavi Fard, Majid; Sepehri, Ehsan

2009-01-01

Background: Athletes, especially bodybuilders, abuse anabolic steroid drugs to improve their strength and enhance their muscle growth and appearance. This study was conducted to determine the type and frequency of anabolic steroids abuse in bodybuilder athletes in Kerman City. Methods: A confidential questionnaire which included demographic data (age, education), name of abused anabolic drug and duration of drug abuse was completed by 202 bodybuilder athletes, and the collected data were analyzed using Chi Square test. A value of p < 0.05 was considered significant. Findings: The frequency of anabolic steroid abuse was 18.8%. The mean period of bodybuilding activity was significantly higher in those used the anabolic drugs (38.8 months), comparing to those did not use any drugs (14.3 months). Oxymetholone was the most common drug used by athletes (42% merely used Oxymetholone). The frequency of anabolic steroids abuse was not related to education and age of the bodybuilder athletes. Conclusion: Bodybuilder athletes in Kerman city abuse anabolic steroids, and the health care system should plan to inform them about anabolic steroid adverse effects. PMID:24494079

Clinical management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult Asthma Registry.

PubMed

Sweeney, Joan; Brightling, Chris E; Menzies-Gow, Andrew; Niven, Robert; Patterson, Chris C; Heaney, Liam G

2012-08-01

Refractory asthma represents a significant unmet clinical need. Data from a national online registry audited clinical outcome in 349 adults with refractory asthma from four UK specialist centres in the British Thoracic Society Difficult Asthma Network. At follow-up, lung function improved, with a reduction in important healthcare outcomes, specifically hospital admission, unscheduled healthcare visits and rescue courses of oral steroids. The most frequent therapeutic intervention was maintenance oral corticosteroids and most steroid sparing agents (apart from omalizumab) demonstrated minimal steroid sparing benefit. A significant unmet clinical need remains in this group, specifically a requirement for therapies which reduce systemic steroid exposure.

A retrospective comparison of infliximab versus adalimumab as induction and maintenance therapy for Crohn disease.

PubMed

Varma, P; Paul, E; Huang, C; Headon, B; Sparrow, M P

2016-07-01

In Australia, infliximab (IFX) and adalimumab (ADA) are available for the treatment of moderate-severe Crohn disease (CD) refractory to conventional therapies, with minimal local data comparing their efficacy. The aim of this study was to compare clinical and biochemical outcomes at 3 and 12 months between patients receiving induction and maintenance therapy with IFX versus ADA. Retrospective single-centre audit of all patients commenced on IFX or ADA as their first anti-tumour necrosis factor agent between July 2007 and May 2012. Clinical and biochemical parameters were compared pre-commencement, 3 and 12 months post-commencement. A total of 81 patients was included in the study; 63 IFX-treated and 18 ADA-treated. Significant Crohn disease activity index (CDAI) reductions were noted within both groups at 3 months (P < 0.001) and 12 months (P < 0.001). Similarly, significant reductions were noted in steroid doses within groups at 3 months (P < 0.05) and 12 months (P < 0.05), with notable reductions in C-reactive protein (CRP) at 3 months within groups (P < 0.05). Adverse events occurred in 14.3% of IFX and 11.1% of ADA patients. Comparing IFX with ADA, no difference was shown between groups in CDAI reductions at 3 months (P = 0.94) and 12 months (P = 0.95), steroid dosing at 3 months (P = 0.23) and 12 months (P = 0.81), and CRP reduction at 3 months (P = 0.33) and 12 months (P = 0.62). Fistula-related admissions were significantly reduced in IFX patients (100% reduction post-IFX vs 66.7% post-ADA) (P = 0.01). Clinical and biochemical outcomes were similar in patients treated with IFX or ADA as induction and maintenance therapy for CD. However, significant reductions were noted in admissions relating to fistulising disease in IFX patients. © 2016 Royal Australasian College of Physicians.

Evaluation of boldenone formation and related steroids transformations in veal faeces by liquid chromatography/tandem mass spectrometry.

PubMed

Arioli, Francesco; Gavinelli, Matteo P; Fracchiolla, Maria L; Casati, Alessio; Fidani, Marco; Ferrer, Emilia; Pompa, Giuseppe

2008-01-01

It is established that bovine urine can result positive for boldenone and androstadienedione in consequence of faecal contamination. The simple transfer of steroids to urine is one minor aspect of faecal contamination. A high de novo production of steroids in faeces after deposition and in faeces-contaminated urine is almost certainly due to microbial activity, although the precursor compounds and transformations leading to the presence of these illegal steroids are unclear. We developed a simple in vitro method - incubation of faecal matter suspended in 0.9% saline - to induce steroid transformations in faeces, and analyzed the products by liquid chromatography/tandem mass spectrometry, without the need for prior extraction. Norethandrolone was the internal standard. The linearity (R(2): 0.987-0.999), sensitivity (LODs: 0.3 to 1.0 ng/mL; LOQs: 1.0 to 3.0 ng/mL), precision (intra-day CVs: 2.6-8.2; inter-day CVs: 4.5-11.5) and accuracy (percentage recovery: 89-120%) were calculated for the studied steroids. Androstenedione, androstadienedione, alpha- and beta-boldenone, testosterone and epitestosterone transformations were investigated. Mutual interconversion of steroids was observed, although 17beta-hydroxy steroids had low stability compared with 17alpha-hydroxy and 17-keto steroids. The results suggest that this simple in vitro system may be an effective way of studying hormone transformations in faeces and, after analogue studies, in faeces-contaminated urine. Copyright (c) 2007 John Wiley & Sons, Ltd.

Changes in the concentrations of four maternal steroids during embryonic development in the threespined stickleback (Gasterosteus aculeatus).

PubMed

Paitz, Ryan Thomas; Mommer, Brett Christian; Suhr, Elissa; Bell, Alison Marie

2015-08-01

Embryonic exposure to steroids often leads to long-term phenotypic effects. It has been hypothesized that mothers may be able to create a steroid environment that adjusts the phenotypes of offspring to current environmental conditions. Complicating this hypothesis is the potential for developing embryos to modulate their early endocrine environment. This study utilized the threespined stickleback (Gasterosteus aculeatus) to characterize the early endocrine environment within eggs by measuring four steroids (progesterone, testosterone, estradiol, and cortisol) of maternal origin. We then examined how the concentrations of these four steroids changed over the first 12 days post fertilization (dpf). Progesterone, testosterone, estradiol, and cortisol of maternal origin could be detected within unfertilized eggs and levels of all four steroids declined in the first 3 days following fertilization. While levels of progesterone, testosterone, and estradiol remained low after the initial decline, levels of cortisol rose again by 8 dpf. These results demonstrate that G. aculeatus embryos begin development in the presence of a number of maternal steroids but levels begin to change quickly following fertilization. This suggests that embryonic processes change the early endocrine environment and hence influence the ability of maternal steroids to affect development. With these findings, G. aculeatus becomes an intriguing system in which to study how selection may act on both maternal and embryonic processes to shape the evolutionary consequence of steroid-mediated maternal effects. © 2015 Wiley Periodicals, Inc.

Induction treatment with rabbit antithymocyte globulin versus basiliximab in renal transplant recipients with planned early steroid withdrawal.

PubMed

Martin, Spencer T; Roberts, Keri L; Malek, Sayeed K; Tullius, Stefan G; Vadivel, Nidyanandh; De Serres, Sacha; Grafals, Monica; Elsanjak, Abdelaziz; Filkins, Beth Anne; Chandraker, Anil; Gabardi, Steven

2011-06-01

To compare the safety and efficacy of rabbit antithymocyte globulin (r-ATG) with basiliximab in renal transplant recipients for whom an early steroid withdrawal (ESW) regimen was planned. Single-center, retrospective, cohort study. Tertiary care medical center, including inpatient hospital stays and outpatient nephrology clinics. Ninety-nine consecutive adult recipients of living- or deceased-donor renal transplants between January 1, 2004, and December 31, 2007, in whom ESW was planned and who received either r-ATG or basiliximab; patients receiving an extended-criteria kidney donation or a donation after cardiac death were excluded. All patients received mycophenolate mofetil and tacrolimus as maintenance therapy with planned ESW. Induction therapy was either r-ATG 1.5 mg/kg/day for 4 days (68 patients) or basiliximab 20 mg on postoperative days 0 and 4 (31 patients). The primary composite end point of biopsy-proven acute rejection (BPAR), graft loss, and death occurred in 6 patients (9%) and 9 patients (29%) in the r-ATG and basiliximab groups at 1 year after transplantation, respectively (p=0.01), with rates of 7% (5/68 patients) and 26% (8/31 patients) for BPAR (p=0.02), 0% and 3% (1/31 patients) for graft loss (p=0.31), and 2% (1/68 patients) and 0% for patient death (p>0.99). Average time to first BPAR was significantly longer in the r-ATG group (mean ± SD 151.4 ± 82.9 vs 53.6 ± 68.4 days, p<0.01). Kidney function at 12 months was similar between the two groups. Rabbit-ATG was associated with a lower frequency and delayed onset of BPAR compared with basiliximab in renal transplant recipients who received an ESW regimen.

The role of sex differences in the effect of anabolics on the liver.

PubMed

Kulcsár-Gergely, J; Kulcsár, A; Kiss, A

1975-03-01

The effect of two anabolic steroids, norandrostenolone-phenylpropionate (Nerobolil) and norandrostenolone-decanoate (Retabolil) on the liver was studied in rats. Body weight, wet liver weight and the protein content of the liver homogenisates were found to increase under the effect of anabolic treatment, the most explicitely in females treated with Nerobolil. The function of the liver to metabolize hexobarbital, measured in vivo, is increased by a single dose of anabolic. The prolongation of treatment keeps on shortening hexobarbital anaesthesia only in females. Even 8 weeks after the end of treatment the effect is invariably lasting in females, in males it is not. Studies of the vaginal cycle cannot prove a decline of ovarial function. In females the hepatotropic effect of anabolic treatment, performed simultaneously with the chronic carbon tetrachloride lesion can be demonstrated. The liver weight and protein content are maintained on the control level. Under the effect of anabolic treatment the function to metabolize the effect of anabolic treatment the function to metabolize hexobarbital, which has been impaired by the lesion, remains near the level of the untreated animals. Our experiments support the observations of the inductive property of the steroids being parallel to their anabolic characteristics. Their catatoxic effect is pronounced in females. Nerobolil was found to be more advantageous from the point of view of both anabolic and hepatotropic effect. Our experiments do not suggest the possibility of liver damage during the administration of these two anabolics. The effect of the anabolics on the enzymatic induction may be of therapeutic value when adequate preparations are selected and sex differences as well as the character of the liver damage are taken into consideration.

Identification of Location and Kinetically Defined Mechanism of Cofactors and Reporter Genes in the Cascade of Steroid-regulated Transactivation*

PubMed Central

Blackford, John A.; Guo, Chunhua; Zhu, Rong; Dougherty, Edward J.; Chow, Carson C.; Simons, S. Stoney

2012-01-01

A currently obscure area of steroid hormone action is where the component factors, including receptor and reporter gene, act. The DNA binding of factors can be precisely defined, but the location and timing of factor binding and action are usually not equivalent. These questions are addressed for several factors (e.g. glucocorticoid receptor (GR), reporter, TIF2, NCoR, NELF-A, sSMRT, and STAMP) using our recently developed competition assay. This assay reveals both the kinetically defined mechanism of factor action and where the above factors act relative to both each other and the equilibrium equivalent to the rate-limiting step, which we call the concentration limiting step (CLS). The utility of this competition assay would be greatly increased if the position of the CLS is invariant and if the factor acting at the CLS is known. Here we report that the exogenous GREtkLUC reporter acts at the CLS as an accelerator for gene induction by GRs in U2OS cells. This mechanism of reporter function at the CLS persists with different reporters, factors, receptors, and cell types. We, therefore, propose that the reporter gene always acts at the CLS during gene induction and constitutes a landmark around which one can order the actions of all other factors. Current data suggest that how and where GR and the short form of SMRT act is also constant. These results validate a novel and rational methodology for identifying distally acting factors that would be attractive targets for pharmaceutical intervention in the treatment of diseases involving GR-regulated genes. PMID:23055525

Novel orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium

PubMed Central

Catherino, William H.; Malik, Minnie; Driggers, Paul; Chappel, Scott; Segars, James; Davis, Joseph

2012-01-01

Context Uterine leiomyomas are highly prevalent and often symptomatic. Current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. Objective and Methods To determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947 in human immortalized leiomyoma and patient-matched myometrial cells. Receptor binding in vitro was assessed using LNCaP, Ishikawa, T-47D, and HeLa cell extracts for AR, ER-α, PR, and GR, respectively. Progestational activity assessed by alkaline phosphatase assay in T47D cells and ER-α expression in human leiomyoma and myometrial cells. In vivo progestational activity assayed by the McPhail assay. Proliferation and gene expression studies (q RT-PCR and western blot) were performed in immortalized leiomyoma and myometrial cells. Results Both CP8863 and CP8947 is highly selective for PR but not for ER-α, AR, and GR. Both induced alkaline phosphatase comparably to progesterone, while CP8947 induced ER-α in leiomyoma cells but not myometrial cells. CP8947 was progestational in rabbit endometrium. Nanomolar CP8947 treatment inhibited human leiomyoma but not myometrial cell proliferation. The decreased proliferation correlated with increased TRAIL and caspase -7, suggesting induction of apoptosis in leiomyoma cells. ECM components were decreased in leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations. Conclusions CP8947 was a potent novel non-steroidal SPRM that was selective for PR, showed progestational activity in endometrium, inhibited leiomyoma cell proliferation (potentially via induction of apoptosis), and decreased ECM component production, without disrupting myometrial cell proliferation. PMID:20493256

Concurrent Etoposide, Steroid, High-dose Ara-C and Platinum chemotherapy with radiation therapy in localised extranodal natural killer (NK)/T-cell lymphoma, nasal type.

PubMed

Michot, Jean-Marie; Mazeron, Renaud; Danu, Alina; Lazarovici, Julien; Ghez, David; Antosikova, Anna; Willekens, Christophe; Chamseddine, Ali N; Minard, Veronique; Dartigues, Peggy; Bosq, Jacques; Carde, Patrice; Koscielny, Serge; De Botton, Stéphane; Ferme, Christophe; Girinsky, Theodore; Ribrag, Vincent

2015-11-01

Radiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen. An induction phase with two upfront courses of CCRT delivering a 40Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2-3 cycles of ESHAP chemotherapy alone. Thirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3-4 haematological toxicity. The main non-haematological grade 3-4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%. With optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type. Copyright © 2015 Elsevier Ltd. All rights reserved.

From molecule to market: steroid hormones and financial risk-taking

PubMed Central

Coates, John M.; Gurnell, Mark; Sarnyai, Zoltan

2010-01-01

Little is known about the role of the endocrine system in financial decision-making. Here, we survey research on steroid hormones and their cognitive effects, and examine potential links to trader performance in the financial markets. Preliminary findings suggest that cortisol codes for risk and testosterone for reward. A key finding of this endocrine research is the different cognitive effects of acute versus chronic exposure to hormones: acutely elevated steroids may optimize performance on a range of tasks; but chronically elevated steroids may promote irrational risk-reward choices. We present a hypothesis suggesting that the irrational exuberance and pessimism observed during market bubbles and crashes may be mediated by steroid hormones. If hormones can exaggerate market moves, then perhaps the age and sex composition among traders and asset managers may affect the level of instability witnessed in the financial markets. PMID:20026470

Steroid dysregulation and stomatodynia (burning mouth syndrome).

PubMed

Woda, Alain; Dao, Thuan; Gremeau-Richard, Christelle

2009-01-01

Stomatodynia ( burning mouth syndrome) is characterized by a spontaneous, continuous burning pain felt in the oral mucosa typically of anxiodepressive menopausal women. Because there is no obvious organic cause, it is considered a nonspecific pain. This Focus Article proposes a hypothesis based on the following pathophysiological cascade: chronic anxiety or post traumatic stress leads to a dysregulation of the adrenal production of steroids. One consequence is a decreased or modified production of some major precursors for the neuroactive steroid synthesis occurring in the skin, mucosa, and nervous system. At menopause, the drastic fall of the other main precursor supply , the gonadal steroids, leads to a brisk alteration of the production of neuroactive steroids. This results in neurodegenerative alterations of small nerves fibers of the oral mucosa and /or some brain areas involved in oral somatic sensations. These neuropathic changes become irreversible and precipitate the burning pain, dysgeusia, and xerostomia associated with stomatodynia, which all involve thin nerve fibers.

Steroids reduce the periapical inflammatory and neural changes after pulpectomy.

PubMed

Holland, G R

1996-09-01

Root canal treatment, including obturation with gutta-percha and a zinc oxide and eugenol sealer, was conducted, under general anesthesia, on the canine teeth of 12 young ferrets. Six of the ferrets were given 0.5 mg/kg dexamethasone daily. Three months after the root canal treatment, under general anesthesia, the animals were perfused with fixative and the canine periapical tissues prepared for histological examination. The extent of periapical inflammation was measured and the degree of neural sprouting in the periodontal and subapical regions estimated. Periapical lesions in steroid-treated animals were 30% of the size of those in untreated animals. Innervation density in the subapical region of the steroid-treated animals was lower than that in the animals who did not receive steroids and not significantly different from controls. Reduction in periapical inflammation induced by systemic steroids is accompanied by a reduction in neural sprouting.

Ovulation induction and artificial insemination of a captive polar bear (Ursus maritimus) using fresh semen.

PubMed

Curry, Erin; Wyatt, Jeff; Sorel, Lawrence J; MacKinnon, Katherine M; Roth, Terri L

2014-09-01

In 2008, polar bears were listed as a species threatened with extinction by the U.S. Endangered Species Act. Unfortunately, reproductive success has been poor despite breeding recommendations for almost every reproductively viable bear by the Species Survival Plan. Assisted reproductive technologies could complement breeding efforts by overcoming the challenges of behavioral incompatibilities and deficiencies, facilitating genetic management and increasing cub production. The goal of this study was to artificially inseminate a female polar bear after inducing ovarian activity and ovulation with exogenous hormones (equine chorionic gonadotropin and porcine luteinizing hormone). Fresh semen collected from an adult male via electroejaculation/urethral catheterization was used for the insemination. Fecal steroid monitoring indicated that the female ovulated following the exogenous hormone treatment. Progestin concentrations increased in late summer, at the time implantation was expected to occur; however, no cubs were produced. To the authors' knowledge, this is the first report of ovulation induction and artificial insemination in a polar bear.

Anti-inflammatory lipocortin 1 production by peripheral blood leucocytes in response to hydrocortisone.

PubMed

Goulding, N J; Godolphin, J L; Sharland, P R; Peers, S H; Sampson, M; Maddison, P J; Flower, R J

1990-06-16

The presence and amount of the anti-inflammatory protein lipocortin 1 was determined in plasma and peripheral blood leucocytes by a highly specific, enzyme-linked immunosorbent assay. Within 120 min of a single intravenous dose of 100 mg hydrocortisone, the intracellular concentrations of lipocortin 1 in peripheral monocytes in 7 of 8 healthy men increased by a median of 225% (range 129-507%) compared with pretreatment levels, and mononuclear cell-surface lipocortin increased by a median of 224% (range 76-483%). Placebo injections had no effect. There was no increase at any time in free plasma or polymorph-associated lipocortin. In 3 of 4 subjects, induction of lipocortin was also observed when whole unseparated blood was incubated in vitro after steroid administration, but cells which had first been isolated and purified were refractory to such induction. Thus rapid changes in the concentration of an active anti-inflammatory protein can occur in man after normal therapeutic doses of hydrocortisone.

Age-related cochlear cytokine gene expression in the BALB/cJ mouse with systemic versus intratympanic dosing of steroid drugs.

PubMed

Tokarz, Sara A; Pang, Jiaqing; Grosz, Anna; Kempton, J Beth; Trune, Dennis R; Pillers, De-Ann M

2013-07-01

Age-related differences in the expression of inflammatory cytokines in the inner ear may contribute to the development of age-related hearing loss (ARHL). ARHL is characterized by tissue remodeling, ischemia, ion homeostasis, and inflammation. Steroid therapy is an otoprotective strategy that likely acts by reducing inflammation. We examined age-related changes in cytokine gene expression in the cochlea of the BALB/cJ mouse model of premature ARHL after systemic or intratympanic steroid delivery. 'Young' (2.5-3 months) and 'Old' (5-9 months) mice were treated with dexamethasone or fludrocortisone administered either orally or intratympanically. Cytokine gene expression in cochlear RNA was analyzed using prefabricated cDNA arrays. Old groups were compared to Young groups to identify age-related changes. Down-regulation of a cytokine associated with bone remodeling (SPP1) was observed in the untreated Old group. Numerous genes were up- or down-regulated by more than twofold by steroid treatment, including proinflammatory interleukins (IL-16) and anti-inflammatory cytokines.

Biocatalyst mediated production of 6β,11α-dihydroxy derivatives of 4-ene-3-one steroids.

PubMed

Kolet, Swati P; Niloferjahan, Siddiqui; Haldar, Saikat; Gonnade, Rajesh; Thulasiram, Hirekodathakallu V

2013-11-01

Biotransformation of steroids with 4-ene-3-one functionality such as progesterone (I), testosterone (II), 17α-methyltestosterone (III), 4-androstene-3,17-dione (IV) and 19-nortestosterone (V) were studied by using a fungal system belonging to the genera of Mucor (M881). The fungal system efficiently and quantitatively converted these steroids in regio- and stereo-selective manner into corresponding 6β,11α-dihydroxy compounds. Time course experiments suggested that the transformation was initiated by hydroxylation at 6β- or 11α-(10β-hydroxy in case of V) to form monohydroxy derivatives which upon prolonged incubation were converted into corresponding 6β,11α-dihydroxy derivatives. The fermentation studies carried out using 5L table-top fermentor with substrates (I and II) clearly indicates that 6β,11α-dihydroxy derivatives of steroids with 4-ene-3-one functionality can be produced in large scale by using M881. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Detection of clobetasol propionate in a cream advertised to be effective against atopic dermatitis].

PubMed

Ikarashi, Yoshiaki; Takita, Yoko; Uchino, Tadashi; Nishimura, Tetsuji

2009-01-01

Addition of medical ingredients to cosmetics is prohibited. However, last year some cases of illegal cosmetics containing steroids were successfully identified. We have already reported an analytical method to detect steroids in cosmetics [Bull. Natl. Inst. Health Sci, 126, 51-56 (2008)]. In this study, we initially examined whether this method could be applied for the detection of some new steroids as target chemicals. We then used this developed method to detect steroids in cosmetics obtained from manufacturers by spot checks. These manufacturers have been advertising the effectiveness of a steroid-free cream against atopic dermatitis. The results revealed that clobetasol propionate (CP) was present in this facial moisturizing cream, which was available in the market. The steroid was extracted with methanol. After ultrasonication and centrifugation, the resulting supernatant was injected into the high-performance liquid chromatography system equipped with an ODS column. The separation was achieved using a mixture of acetonitrile and water as the mobile phase. The retention times of the observed peaks were in accordance with those of some preservatives and CP. The presence of CP was also confirmed by thin-layer chromatography. The concentration of CP in the cream was approximately 0.039%. CP is a steroid that has the strongest effect as compared to those of other steroids. The cream was therefore recalled for safety reasons.

In vivo detection of fluctuating brain steroid levels SHORT

PubMed Central

Ikeda, Maaya; Rensel, Michelle A.; Schlinger, Barney A.; Remage-Healey, Luke

2015-01-01

This protocol describes a method for in vivo measurement of steroid hormones in brain circuits of the zebra finch. In vivo microdialysis has been used successfully to detect fluctuating neurosteroids in the auditory forebrain (Remage-Healey et al., 2008; 2012; Ikeda et al., 2012) and in the hippocampus (Rensel et al., 2012; 2013) of behaving adult zebra finches. In some cases, the steroids measured are derived locally (e.g., ‘neurosteroids’ like estrogens in males) whereas in other cases the steroids measured reflect systemic circulating levels and/or central conversion (e.g., the primary androgen testosterone and the primary glucocorticoid corticosterone). We also describe the method of reverse-microdialysis (‘retrodialysis’) of compounds that can influence local steroid neurochemistry as well as behavior. In vivo microdialysis can now be used to study steroid signaling in the brain for a variety of experimental purposes. Furthermore, similar methods have been developed to examine changing levels of catecholamines in behaving zebra finches (e.g., Sasaki et al., 2006). Thus, the combined study of neurochemistry and behavior in a vocal learning species now has a new set of powerful tools. PMID:25342066

Steroid and sterol 7-hydroxylation: ancient pathways.

PubMed

Lathe, Richard

2002-11-01

B-ring hydroxylation is a major metabolic pathway for cholesterols and some steroids. In liver, 7 alpha-hydroxylation of cholesterols, mediated by CYP7A and CYP39A1, is the rate-limiting step of bile acid synthesis and metabolic elimination. In brain and other tissues, both sterols and some steroids including dehydroepiandrosterone (DHEA) are prominently 7 alpha-hydroxylated by CYP7B. The function of extra-hepatic steroid and sterol 7-hydroxylation is unknown. Nevertheless, 7-oxygenated cholesterols are potent regulators of cell proliferation and apoptosis; 7-oxygenated derivatives of DHEA, pregnenolone, and androstenediol can have major effects in the brain and in the immune system. The receptor targets involved remain obscure. It is argued that B-ring modification predated steroid evolution: non-enzymatic oxidation of membrane sterols primarily results in 7-oxygenation. Such molecules may have provided early growth and stress signals; a relic may be found in hydroxylation at the symmetrical 11-position of glucocorticoids. Early receptor targets probably included intracellular sterol sites, some modern steroids may continue to act at these targets. 7-Hydroxylation of DHEA may reflect conservation of an early signaling pathway.

Development of Focal Segmental Glomerulosclerosis after Anabolic Steroid Abuse

PubMed Central

Herlitz, Leal C.; Markowitz, Glen S.; Farris, Alton B.; Schwimmer, Joshua A.; Stokes, Michael B.; Kunis, Cheryl; Colvin, Robert B.

2010-01-01

Anabolic steroid abuse adversely affects the endocrine system, blood lipids, and the liver, but renal injury has not been described. We identified an association of focal segmental glomerulosclerosis (FSGS) and proteinuria in a cohort of 10 bodybuilders (six white and four Hispanic; mean body mass index 34.7) after long-term abuse of anabolic steroids. The clinical presentation included proteinuria (mean 10.1 g/d; range 1.3 to 26.3 g/d) and renal insufficiency (mean serum creatinine 3.0 mg/dl; range 1.3 to 7.8 mg/dl); three (30%) patients presented with nephrotic syndrome. Renal biopsy revealed FSGS in nine patients, four of whom also had glomerulomegaly, and glomerulomegaly alone in one patient. Three biopsies revealed collapsing lesions of FSGS, four had perihilar lesions, and seven showed ≥40% tubular atrophy and interstitial fibrosis. Among eight patients with mean follow-up of 2.2 yr, one progressed to ESRD, the other seven received renin-angiotensin system blockade, and one also received corticosteroids. All seven patients discontinued anabolic steroids, leading to weight loss, stabilization or improvement in serum creatinine, and a reduction in proteinuria. One patient resumed anabolic steroid abuse and suffered relapse of proteinuria and renal insufficiency. We hypothesize that secondary FSGS results from a combination of postadaptive glomerular changes driven by increased lean body mass and potential direct nephrotoxic effects of anabolic steroids. Because of the expected rise in serum creatinine as a result of increased muscle mass in bodybuilders, this complication is likely underrecognized. PMID:19917783

A liposomal steroid nano-drug for treating systemic lupus erythematosus.

PubMed

Moallem, E; Koren, E; Ulmansky, R; Pizov, G; Barlev, M; Barenholz, Y; Naparstek, Y

2016-10-01

Glucocorticoids have been known for years to be the most effective therapy in systemic lupus erythematosus. Their use, however, is limited by the need for high doses due to their unfavorable pharmacokinetics and biodistribution. We have previously developed a novel liposome-based steroidal (methylprednisolone hemisuccinate (MPS)) nano-drug and demonstrated its specific accumulation in inflamed tissues, as well as its superior therapeutic efficacy over that of free glucocorticoids (non-liposomal) in the autoimmune diseases, including the adjuvant arthritis rat model and the experimental autoimmune encephalomyelitis mouse model. In the present work we have evaluated the therapeutic effect of the above liposome-based steroidal (MPS) nano-drug in the MRL-lpr/lpr murine model of SLE and compared it with similar doses of the free MPS. MRL-lpr/lpr mice were treated with daily injections of free MPS or weekly injections of 10% dextrose, empty nano-liposomes or the steroidal nano-drug and the course of their disease was followed up to the age of 24 weeks. Treatment with the steroidal nano-drug was found to be significantly superior to the free MPS in suppressing anti-dsDNA antibody levels, proliferation of lymphoid tissue and renal damage, and in prolonging survival of animals. This significant superiority of our liposome based steroidal nano-drug administered weekly compared with daily injections of free methylprednisolone hemisuccinate in suppressing murine lupus indicates this glucocorticoid nano-drug formulation may be a good candidate for the treatment of human SLE. © The Author(s) 2016.

Transport of Steroid Hormones, Phytoestrogens, and Estrogenic Activity across a Swine Lagoon/Sprayfield System

PubMed Central

Yost, Erin E.; Meyer, Michael T.; Dietze, Julie E.; Williams, C. Michael; Worley-Davis, Lynn; Lee, Boknam; Kullman, Seth W.

2017-01-01

The inflow, transformation, and attenuation of natural steroid hormones, phytoestrogens, and estrogenic activity was assessed across the lagoon/sprayfield system of a prototypical commercial swine sow operation. Free and conjugated steroid hormones (estrogens, androgens, and progesterone) were detected in urine and feces of sows across reproductive stages, with progesterone being the most abundant steroid hormone. Excreta also contained phytoestrogens indicative of a soy-based diet; particularly daidzein, genistein, and equol. During storage in barn pits and the anaerobic lagoon, conjugated hormones dissipated, and androgens and progesterone were attenuated. Estrone and equol persisted along the waste disposal route. Following application of lagoon slurry to agricultural soils, all analytes exhibited attenuation within 2 days. However, analytes including estrone, androstenedione, progesterone, and equol remained detectable in soil at two months post-application. Estrogenic activity in the yeast estrogen screen and T47D-KBluc in vitro bioassays generally tracked well with analyte concentrations. Estrone found to be the greatest contributor to estrogenic activity across all sample types. This investigation encompasses the most comprehensive suite of natural hormone and phytoestrogen analytes examined to date across a lagoon/sprayfield system, and provides global insight into the fate of these analytes in this widely used waste management system. PMID:25148584

Exposure to p,p′-DDE or dieldrin during the reproductive season alters hepatic CYP expression in largemouth bass (Micropterus salmoides)

PubMed Central

Barber, David S.; McNally, Alex J.; Garcia-Reyero, Natàlia; Denslow, Nancy D.

2007-01-01

Largemouth bass (LMB) in Central Florida living on sites with high levels of organochlorine pesticides (OCPs) have exhibited poor reproductive success and altered steroid profiles. The mechanism underlying these changes is unknown, however changes in the rate of steroid metabolism could alter steroid homeostasis. Members of the CYP2 and CYP3A families play a significant role in the metabolism of many xenobiotics and endogenous compounds, including sex steroids. Therefore, the goal of this study was to identify members of the CYP2 and CYP3A families in LMB and characterize the effects of OCP exposure on their expression. Full-length clones of two CYP3A isoforms were obtained from LMB liver, CYP3A68 and 3A69, which exhibited significant sequence divergence. Full-length clones for CYP2N14 and CYP2P11 were also obtained from LMB liver. Steady-state mRNA levels of each of these CYPs increased in both sexes between early reproductive phase (December) and peak reproductive phase (March). Expression of CYP3A68 and CYP2P11 was sexually dimorphic during peak reproductive phase with 2-fold higher expression in females and males, respectively. Foodborne exposure to 46 ppm p,p′-DDE or 0.8 ppm dieldrin for 30 days did not have a significant effect on expression of CYPs. However, 4 months exposure to p,p′-DDE induced CYP3A68 and 3A69 expression in both sexes, while dieldrin produced weak induction of CYP3A68 and suppressed CYP3A69 expression in females, but had no effect on males. Neither p,p′-DDE nor dieldrin significantly altered the expression of CYP2P11 or CYP2N14. This work demonstrates that there are significant changes in CYP expression that occur during LMB reproduction which can be modified by exposure to OCPs. PMID:17145087

Oestradiol and prostaglandin F2α regulate sexual displays in females of a sex-role reversed fish

PubMed Central

Gonçalves, David; Costa, Silvia Santos; Teles, Magda C.; Silva, Helena; Inglês, Mafalda; Oliveira, Rui F.

2014-01-01

The mechanisms regulating sexual behaviours in female vertebrates are still poorly understood, mainly because in most species sexual displays in females are more subtle and less frequent than displays in males. In a sex-role reversed population of a teleost fish, the peacock blenny Salaria pavo, an external fertilizer, females are the courting sex and their sexual displays are conspicuous and unambiguous. We took advantage of this to investigate the role of ovarian-synthesized hormones in the induction of sexual displays in females. In particular, the effects of the sex steroids oestradiol (E2) and testosterone (T) and of the prostaglandin F2α (PGF2α) were tested. Females were ovariectomized and their sexual behaviour tested 7 days (sex steroids and PGF2α) and 14 days (sex steroids) after ovariectomy by presenting females to an established nesting male. Ovariectomy reduced the expression of sexual behaviours, although a significant proportion of females still courted the male 14 days after the ovary removal. Administration of PGF2α to ovariectomized females recovered the frequency of approaches to the male's nest and of courtship displays towards the nesting male. However, E2 also had a positive effect on sexual behaviour, particularly on the frequency of approaches to the male's nest. T administration failed to recover sexual behaviours in ovariectomized females. These results suggest that the increase in E2 levels postulated to occur during the breeding season facilitates female mate-searching and assessment behaviours, whereas PGF2α acts as a short-latency endogenous signal informing the brain that oocytes are mature and ready to be spawned. In the light of these results, the classical view for female fishes, that sex steroids maintain sexual behaviour in internal fertilizers and that prostaglandins activate spawning behaviours in external fertilizers, needs to be reviewed. PMID:24452030

Safety and Efficacy of Combination Treatment With Calcineurin Inhibitors and Vedolizumab in Patients With Refractory Inflammatory Bowel Disease.

PubMed

Christensen, Britt; Gibson, Peter; Micic, Dejan; Colman, Ruben J; Goeppinger, Sarah R; Kassim, Olufemmi; Yarur, Andres; Weber, Christopher R; Cohen, Russell D; Rubin, David T

2018-05-08

Little is known about the efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab for patients with Crohn's disease (CD) or ulcerative colitis (UC). We analyzed the outcomes of patients receiving vedolizumab along with calcineurin inhibitors METHODS: We collected data on patients with CD (n=9) or UC (n=11) who began treatment with vedolizumab from May 20, 2014 through March 30, 2015 and received calcineurin inhibitors (tacrolimus or cyclosporin) during the first 12 months of vedolizumab therapy. Clinical activity scores and inflammatory markers were measured at baseline and at weeks 14, 30, and 52 of vedolizumab treatment. Clinical remission was defined as a Harvey Bradshaw index score ≤4 or short clinical colitis activity index score ≤2; steroid-free clinical remission was defined as clinical remission without corticosteroids. By week 14 of treatment, 44% of the patients with CD and 55% of the patients with UC achieved steroid-free clinical remission; after 52 weeks of treatment, 33% of the patients with CD and 45% of the patients with UC were in steroid-free clinical remission. Seven patients received salvage therapy with a calcineurin inhibitor after primary non-response to vedolizumab-1 of the 2 patients with UC and 2 of 5 patients with CD stopped taking the calcineurin inhibitors and achieved steroid-free remission at week 52. In total, 16 patients (59%) received 52 weeks of treatment with vedolizumab. Three serious adverse events were associated with calcineurin inhibitors. Combination therapy of vedolizumab with either cyclosporin or tacrolimus is effective and safe at inducing and maintaining clinical remission in patients with CD and UC with up to 52 weeks of follow-up. Larger studies of the ability of calcineurin inhibitors to induce remission in patients on vedolizumab are warranted. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Exposure to p,p'-DDE or dieldrin during the reproductive season alters hepatic CYP expression in largemouth bass (Micropterus salmoides).

PubMed

Barber, David S; McNally, Alex J; Garcia-Reyero, Natàlia; Denslow, Nancy D

2007-02-15

Largemouth bass (LMB) in Central Florida living on sites with high levels of organochlorine pesticides (OCPs) have exhibited poor reproductive success and altered steroid profiles. The mechanism underlying these changes is unknown, however changes in the rate of steroid metabolism could alter steroid homeostasis. Members of the CYP2 and CYP3A families play a significant role in the metabolism of many xenobiotics and endogenous compounds, including sex steroids. Therefore, the goal of this study was to identify members of the CYP2 and CYP3A families in LMB and characterize the effects of OCP exposure on their expression. Full-length clones of two CYP3A isoforms were obtained from LMB liver, CYP3A68 and 3A69, which exhibited significant sequence divergence. Full-length clones for CYP2N14 and CYP2P11 were also obtained from LMB liver. Steady-state mRNA levels of each of these CYPs increased in both sexes between early reproductive phase (December) and peak reproductive phase (March). Expression of CYP3A68 and CYP2P11 was sexually dimorphic during peak reproductive phase with 2-fold higher expression in females and males, respectively. Foodborne exposure to 46 ppm p,p'-DDE or 0.8 ppm dieldrin for 30 days did not have a significant effect on expression of CYPs. However, 4 months exposure to p,p'-DDE induced CYP3A68 and 3A69 expression in both sexes, while dieldrin produced weak induction of CYP3A68 and suppressed CYP3A69 expression in females, but had no effect on males. Neither p,p'-DDE nor dieldrin significantly altered the expression of CYP2P11 or CYP2N14. This work demonstrates that there are significant changes in CYP expression that occur during LMB reproduction which can be modified by exposure to OCPs.

Acute scrotum caused by Henoch-Schönlein purpura, with immediate response to short-term steroid therapy.

PubMed

Ben-Chaim, J; Korat, E; Shenfeld, O; Shelhav, A; Jonas, P; Goldwasser, B

1995-10-01

The authors report a case of acute scrotum caused by Henoch-Schönlein purpura. It involved bilateral swelling of the epididymis and testes, which was documented by scrotal ultrasonography and which responded immediately to systemic steroid treatment.

Simultaneous profiling of 17 steroid hormones for the evaluation of endocrine-disrupting chemicals in H295R cells.

PubMed

Jumhawan, Udi; Yamashita, Toshiyuki; Ishida, Kazuya; Fukusaki, Eiichiro; Bamba, Takeshi

2017-01-01

There is urgent need to develop a new protocol for the evaluation of chemical substances to potentially interact with the endocrine system and induce numerous pathological issues. The recently validated in vitro screening assay is limited on monitoring two steroid hormones. Methodology & results: The H295R model cell was exposed to seven endocrine disrupting chemicals (EDCs). The levels of 17 steroid hormones in cell extracts were subsequently determined by a quantitative targeted GC/MS/MS method. Through wide coverage, this system managed to capture the effects of exposure to increasing EDCs concentrations in the entire steroidogenic pathways. The developed approach could be beneficial for the mechanistic investigation of EDCs.

Fluorescence anisotropy microplate assay to investigate the interaction of full-length steroid receptor coactivator-1a with steroid receptors

PubMed Central

Zhang, Chen; Nordeen, Steven K.; Shapiro, David J.

2013-01-01

Estrogens, acting via estrogen receptor (ER) play key roles in growth, differentiation and gene regulation in the reproductive, central nervous and skeletal systems. ER-mediated gene transcription contributes to the development and spread of breast, uterine, and liver cancer. Steroid receptor coactivator-1a (SRC1a) belongs to the P160 family of coactivators, which is the best known of the many coactivators implicated in ER-mediated transactivation. Binding of full-length P160 coactivators to steroid receptors has been difficult to investigate in vitro. This chapter details how to investigate the interaction of SRC1a with ER using the fluorescence anisotropy/polarization microplate assay (FAMA). PMID:23436375

The Sturm und Drang of anabolic steroid use: angst, anxiety, and aggression

PubMed Central

Oberlander, Joseph G.; Henderson, Leslie P.

2014-01-01

Anabolic androgenic steroids (AAS) are illicitly administered to enhance athletic performance and body image. Although conferring positive actions on performance, steroid abuse is associated with changes in anxiety and aggression. AAS users are often keenly invested in understanding the biological actions of these drugs. Thus, mechanistic information on AAS actions is important not only for the biomedical community, but also for steroid users. Here we review findings from animal studies on the impact of AAS exposure on neural systems that are crucial for the production of anxiety and aggression, and compare the effects of the different classes of AAS and their potential signaling mechanisms, as well as context-, age- and sex-dependent aspects of their actions. PMID:22516619

Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity.

PubMed

Rus, Florentina; Flatt, Thomas; Tong, Mei; Aggarwal, Kamna; Okuda, Kendi; Kleino, Anni; Yates, Elisabeth; Tatar, Marc; Silverman, Neal

2013-05-29

Throughout the animal kingdom, steroid hormones have been implicated in the defense against microbial infection, but how these systemic signals control immunity is unclear. Here, we show that the steroid hormone ecdysone controls the expression of the pattern recognition receptor PGRP-LC in Drosophila, thereby tightly regulating innate immune recognition and defense against bacterial infection. We identify a group of steroid-regulated transcription factors as well as two GATA transcription factors that act as repressors and activators of the immune response and are required for the proper hormonal control of PGRP-LC expression. Together, our results demonstrate that Drosophila use complex mechanisms to modulate innate immune responses, and identify a transcriptional hierarchy that integrates steroid signalling and immunity in animals.

 Albumin dialysis with MARS for the treatment of anabolic steroid-induced cholestasis.

PubMed

Díaz, Francia C; Sáez-González, Esteban; Benlloch, Salvador; Álvarez-Sotomayor, Diego; Conde, Isabel; Polo, Begoña; García, María; Rodríguez, María; Prieto, Martín

 Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support. We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-). A minimum of two MARS sessions were performed. After MARS® procedure, patients' symptoms improved, as well as liver function tests, thus avoiding liver transplantation. Albumin dialysis appears as a valuable therapeutic option for the management of anabolic steroid-induced cholestasis in patients that are unresponsive to SMT.

The formation and transformation of hormones in maternal, placental and fetal compartments: biological implications.

PubMed

Pasqualini, Jorge R; Chetrite, Gérard S

2016-07-01

The fetal endocrine system constitutes the earliest system developing in fetal life and operates during all the steps of gestation. Its regulation is in part dependent on the secretion of placental and/or maternal precursors emanating across the feto-maternal interface. Human fetal and placental compartments possess all the enzymatic systems necessary to produce steroid hormones. However, their activities are different and complementary: the fetus is very active in converting acetate into cholesterol, in transforming pregnanes to androstanes, various hydroxylases, sulfotransferases, while all these transformations are absent or very limited in the placenta. This compartment can transform cholesterol to C21-steroids, convert 5-ene to 4-ene steroids, and has a high capacity to aromatize C19 precursors and to hydrolyze sulfates. Steroid hormone receptors are present at an early stage of gestation and are functional for important physiological activities. The production rate of some steroids greatly increases with fetal evolution (e.g. estriol increases 500-1000 times in relation to non-pregnant women). Other hormones, such as glucocorticoids, in particular the stress hormone cortisol, adipokines (e.g. leptin, adiponectin), insulin-like growth factors, are also a key factor for regulating reproduction, metabolism, appetite and may be significant in programming the fetus and its growth. We can hypothesize that the fetal and placental factors controlling hormonal levels in the fetal compartment can be of capital importance in the normal development of extra-uterine life.

Severe Vaso-Occlusive Episodes Associated with Use of Systemic Corticosteroids in Patients with Sickle Cell Disease

PubMed Central

Darbari, Deepika S.; Castro, Oswaldo; Taylor, James G.; Fasano, Ross; Rehm, Jeffrey; Gordeuk, Victor R.; Minniti, Caterina P.

2017-01-01

Patients with sickle cell disease (SCD) are occasionally prescribed systemic corticosteroids to treat steroid-responsive conditions. Additionally, use of systemic corticosteroids for sickle cell pain episodes and acute chest syndrome is under investigation. We report 4 patients with SCD who developed severe vaso-occlusive events following the administration of systemic steroids. We also review similar cases from the literature and suggest measures for reducing the potential risk associated with use of systemic corticosteroids in this group of patients. We conclude that corticosteroids should be used with caution in patients with SCD. PMID:28643632

Rapid and sensitive analysis of phthalate metabolites, bisphenol A, and endogenous steroid hormones in human urine by mixed-mode solid-phase extraction, dansylation, and ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry.

PubMed

Wang, He-xing; Wang, Bin; Zhou, Ying; Jiang, Qing-wu

2013-05-01

Steroid hormone levels in human urine are convenient and sensitive indicators for the impact of phthalates and/or bisphenol A (BPA) exposure on the human steroid hormone endocrine system. In this study, a rapid and sensitive method for determination of 14 phthalate metabolites, BPA, and ten endogenous steroid hormones in urine was developed and validated on the basis of ultra-performance liquid chromatography coupled with electrospray ionization triple quadrupole mass spectrometry. The optimized mixed-mode solid phase-extraction separated the weakly acidic or neutral BPA and steroid hormones from acidic phthalate metabolites in urine: the former were determined in positive ion mode with a methanol/water mobile phase containing 10 mM ammonium formate; the latter were determined in negative ion mode with a acetonitrile/water mobile phase containing 0.1 % acetic acid, which significantly alleviated matrix effects for the analysis of BPA and steroid hormones. Dansylation of estrogens and BPA realized simultaneous and sensitive analysis of the endogenous steroid hormones and BPA in a single chromatographic run. The limits of detection were less than 0.84 ng/mL for phthalate metabolites and less than 0.22 ng/mL for endogenous steroid hormones and BPA. This proposed method had satisfactory precision and accuracy, and was successfully applied to the analyses of human urine samples. This method could be valuable when investigating the associations among endocrine-disrupting chemicals, endogenous steroid hormones, and relevant adverse outcomes in epidemiological studies.

T cell-replacing factor for glucocorticosteroid-induced immunoglobulin production. A unique steroid-dependent cytokine

PubMed Central

1983-01-01

Glucocorticosteroids (GCS) added to otherwise unstimulated cultures of human peripheral blood mononuclear cells (PBMC) induce the synthesis and secretion of all classes of immunoglobulin. The magnitude of this response is similar to that seen with other polyclonal B cell activators such as pokeweed mitogen (PWM), and like that of PWM, the steroid effect is dependent on both T cells and monocytes. To determine the cellular target for GCS in these cultures, separated populations of T cells and non-T cells were preincubated with steroids and then recombined. No immunoglobulin was produced in any of these preincubation experiments. As a different approach to this question, supernatants were collected from various cell populations following stimulation with PWM, concanavalin A (Con A), phytohemagglutinin (PHA), alloantigens, or GCS. These supernatants were tested for their effects on GCS-induced Ig production by B cells. Supernatants from 3-d cultures of unstimulated, as well as GCS-treated, PBMC contained a T cell- replacing factor that permitted T-depleted PBMC to produce Ig upon steroid stimulation. This supernatant factor (TRF-S) could be produced in the absence of steroid stimulation, but both the factor and GCS were necessary for the induction of Ig synthesis. Production of the TRF-S required the presence of both T cells and adherent cells in culture and was found in the highest concentrations at 3-4 d of culture. Supernatants from cultures stimulated with PWM, PHA, Con A, and alloantigens did not contain detectable TRF-S activity, and TRF-S was unable to replace helper T cells for PWM-induced Ig production. TRF-S required the presence of adherent cells in the T cell-depleted responder population for its action. Further, it was effective in inducing Ig production along with GCS in the presence of a sufficient concentration of cyclosporin A to block all T cell helper activity for primary responses of PBMC to PWM or GCS. TRF-S was inactivated by trypsin treatment, heating to 56 degrees C, freezing, lyophilization, and storage at 4 degrees C for greater than 3 wk. Its molecular weight is probably 10,000 daltons or more, since TRF-S activity is not rapidly dialyzable. These experiments indicate that GCS-induced Ig production by human B cells does not require the presence of intact T cells in the cultures and therefore the steroids are not exerting their influence directly on T suppressor or T helper cells. Furthermore, they demonstrate a previously unrecognized cytokine that induces the differentiation of human B cells to Ig production in the presence of GCS. PMID:6605406

Sex Steroids, Adult Neurogenesis, and Inflammation in CNS Homeostasis, Degeneration, and Repair

PubMed Central

Larson, Tracy A.

2018-01-01

Sex steroidal hormones coordinate the development and maintenance of tissue architecture in many organs, including the central nervous systems (CNS). Within the CNS, sex steroids regulate the morphology, physiology, and behavior of a wide variety of neural cells including, but not limited to, neurons, glia, endothelial cells, and immune cells. Sex steroids spatially and temporally control distinct molecular networks, that, in turn modulate neural activity, synaptic plasticity, growth factor expression and function, nutrient exchange, cellular proliferation, and apoptosis. Over the last several decades, it has become increasingly evident that sex steroids, often in conjunction with neuroinflammation, have profound impact on the occurrence and severity of neuropsychiatric and neurodegenerative disorders. Here, I review the foundational discoveries that established the regulatory role of sex steroids in the CNS and highlight recent advances toward elucidating the complex interaction between sex steroids, neuroinflammation, and CNS regeneration through adult neurogenesis. The majority of recent work has focused on neuroinflammatory responses following acute physical damage, chronic degeneration, or pharmacological insult. Few studies directly assess the role of immune cells in regulating adult neurogenesis under healthy, homeostatic conditions. As such, I also introduce tractable, non-traditional models for examining the role of neuroimmune cells in natural neuronal turnover, seasonal plasticity of neural circuits, and extreme CNS regeneration. PMID:29760681

Polyoxygenated steroids from the gorgonian Menella woodin with capabilities to modulate ROS levels in macrophages at response to LPS.

PubMed

Tu, Vu A; Lyakhova, Ekaterina G; Diep, Chau N; Kalinovsky, Anatoly I; Dmitrenok, Pavel S; Cuong, Nguyen X; Thanh, Nguyen V; Menchinskaya, Ekaterina S; Pislyagin, Evgeny A; Nam, Nguyen H; Kiem, Phan V; Stonik, Valentin A; Minh, Chau V

2015-12-01

Four new polyoxygenated sterol derivatives (1-4) along with the compounds (5-7) previously known from other biological sources were isolated from the gorgonian Menella woodin, collected from the Vietnamese waters. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses as well as comparison with those reported in literature data. Compounds 1, 4, and 6 decrease the production of reactive oxygen species (ROS) by the murine macrophages of RAW 264.7 line at induction by endotoxic lipopolysaccharide (LPS) from Escherichia coli. Copyright © 2015 Elsevier Inc. All rights reserved.

Symptomatic severe hypertriglyceridaemia with asparaginase therapy in acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma: is rechallenging safe?

PubMed

Lashkari, Harsha Prasada; Lancaster, Donna; Atra, Ayad; Champion, Michael P; Taj, Mary M

2011-12-01

Severe hyperlipidaemia with asparaginase therapy is rare. We report six cases, four of which developed significant problems with severe hyperlipidaemia during induction therapy for ALL and lymphoblastic lymphoma. The median triglyceride level was 22.3 mmol/L and the median cholesterol level was 12.3 mmol/L. None of the patients showed signs or symptoms of pancreatitis. Three children were re-exposed with Peg asparaginase, and one with Erwinia asparaginase, without recurrence of hyperlipidaemia or other symptoms. These cases highlight the dilemma in managing such rare cases of symptomatic hypertriglyceridaemia secondary to asparaginase and steroid therapy.

Comparative Effectiveness of Tacrolimus-Based Steroid Sparing versus Steroid Maintenance Regimens in Kidney Transplantation: Results from Discrete Event Simulation.

PubMed

Desai, Vibha C A; Ferrand, Yann; Cavanaugh, Teresa M; Kelton, Christina M L; Caro, J Jaime; Goebel, Jens; Heaton, Pamela C

2017-10-01

Corticosteroids used as immunosuppressants to prevent acute rejection (AR) and graft loss (GL) following kidney transplantation are associated with serious cardiovascular and other adverse events. Evidence from short-term randomized controlled trials suggests that many patients on a tacrolimus-based immunosuppressant regimen can withdraw from steroids without increased AR or GL risk. To measure the long-term tradeoff between GL and adverse events for a heterogeneous-risk population and determine the optimal timing of steroid withdrawal. A discrete event simulation was developed including, as events, AR, GL, myocardial infarction (MI), stroke, cytomegalovirus, and new onset diabetes mellitus (NODM), among others. Data from the United States Renal Data System were used to estimate event-specific parametric regressions, which accounted for steroid-sparing regimen (avoidance, early 7-d withdrawal, 6-mo withdrawal, 12-mo withdrawal, and maintenance) as well as patients' demographics, immunologic risks, and comorbidities. Regression-equation results were used to derive individual time-to-event Weibull distributions, used, in turn, to simulate the course of patients over 20 y. Patients on steroid avoidance or an early-withdrawal regimen were more likely to experience AR (45.9% to 55.0% v. 33.6%, P < 0.05) and GL (51.5% to 68.8% v. 37.8%, P < 0.05) compared to patients on steroid maintenance. Patients in 6-mo and 12-mo steroid withdrawal groups were less likely to experience MI (11.1% v. 13.3%, P < 0.05), NODM (30.7% to 34.4% v. 37.7%, P < 0.05), and cardiac death (29.9% to 30.5% v. 32.4%, P < 0.05), compared to steroid maintenance. Strategies of 6- and 12-mo steroid withdrawal post-kidney transplantation are expected to reduce the rates of adverse cardiovascular events and other outcomes with no worsening of AR or GL rates compared with steroid maintenance.

Simultaneous analysis of fourteen endogenous steroid hormones by liquid chromatography tandem mass spectrometry with atmospheric pressure photoionization

EPA Science Inventory

Product Description: To understand how some chemicals affect the endocrine system, controlled lab experiments often monitor how chemicals impact natural steroid hormones in fish. Current methods can target only one or two hormones in a single sample, limiting the information that...

Drug-induced psoriasis: clinical perspectives.

PubMed

Balak, Deepak Mw; Hajdarbegovic, Enes

2017-01-01

Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta-blockers, lithium, antimalarial drugs such as (hydroxy)chloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of "classical" nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments.

Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age.

PubMed

Rigaud, Charlotte; Barkaoui, Mohamed A; Thomas, Caroline; Bertrand, Yves; Lambilliotte, Anne; Miron, Jean; Aladjidi, Nathalie; Plat, Geneviève; Jeziorski, Eric; Galambrun, Claire; Mansuy, Ludovic; Lutz, Patrick; Deville, Anne; Armari-Alla, Corinne; Reguerre, Yves; Fraitag, Sylvie; Coulomb, Aurore; Gandemer, Virginie; Leboulanger, Nicolas; Moshous, Despina; Hoang-Xuan, Khe; Tazi, Abdellatif; Heritier, Sébastien; Emile, Jean-François; Donadieu, Jean

2016-09-01

The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4-97·5%) overall, improving from 92% pre-1998 to 99% post-1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent. © 2016 John Wiley & Sons Ltd.

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute Lymphoblastic leukaemia, 1980–2001

PubMed Central

Mitchell, Christopher; Richards, Sue; Harrison, Christine J; Eden, Tim

2009-01-01

Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party has conducted 4 clinical trial in acute lymphoblastic leukemia, which have recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of CNS-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL X D template (two intensification phases), examined the role of different steroids in induction and different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared to other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. Additionally, ALL97 and 97/99 demonstrated a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials there has been a major improvement in both event-free and overall survival for children in the UK with ALL. PMID:20010621

Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock.

PubMed

Hebbar, Kiran B; Stockwell, Jana A; Leong, Traci; Fortenberry, James D

2011-05-01

Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion. We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need. Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids. Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 μg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 μg/kg/min to 0.05 μg/kg/min at 4 hrs (p = .039). Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.

Sexual differentiation of the copulatory neuromuscular system in green anoles (Anolis carolinensis): normal ontogeny and manipulation of steroid hormones.

PubMed

Holmes, Melissa M; Wade, Juli

2005-09-05

The copulatory neuromuscular system of green anoles is sexually dimorphic and differentiates during embryonic development, although details of the process were unknown. In Experiment 1, we determined the time course of normal ontogeny. Both male and female embryos possessed bilateral copulatory organs (hemipenes) and associated muscles until incubation day 13; the structures completely regressed in female embryos by incubation day 19 (total incubation 34 days). In Experiment 2, we treated eggs with testosterone, dihydrotestosterone, estradiol, or vehicle on both incubation days 10 and 13 to determine whether these steroid hormones mediate sexual differentiation. These time points fall between gonadal differentiation, which was determined in Experiment 1 to complete before day 10, and regression of the peripheral copulatory system in females. Tissue was collected on the day of hatching. Gonads were classified as testes or ovaries; presence versus absence of hemipenes and muscles, and the number and size of copulatory motoneurons were determined. Copulatory system morphology of vehicle-treated animals matched their gonadal sex. Hemipenes and muscles were absent in estradiol-treated animals, and androgens rescued the hemipenes and muscles in most females. Both testosterone and dihydrotestosterone treatment also caused hypertrophy of the hemipenes, which were everted in animals treated with these steroids. Copulatory motoneurons, assessed on the day of hatching in both experiments, were not dimorphic in size or number. Steroid treatment significantly increased motoneuron size and number overall, but no significant differences were detected in pairwise comparisons. These data demonstrate that differentiation of peripheral copulatory neuromuscular structures occurs during embryonic development and is influenced by gonadal steroids (regression by estradiol and enhancement by androgens), but associated motoneurons do not differentiate until later in life.

Epidemiological investigation of the UGT2B17 polymorphism in doping control urine samples and its correlation to T/E ratios.

PubMed

Anielski, Patricia; Simmchen, Juliane; Wassill, Lars; Ganghofner, Dirk; Thieme, Detlef

2011-10-01

The deletion polymorphism of the enzyme UGT2B17 is known to correlate with the level of the testosterone to epitestosterone (T/E) ratio in urine specimen. Due to the importance of the T/E ratio to detect testosterone abuse in doping analysis, a PCR-ELISA system (Genotype® UGT test, AmplexDiagnostics) was established to identify the UGT2B17 phenotype in urine samples. Epidemiological investigations in a set of 674 routine doping controls (in- and out-of-competition) resulted in 22.8% homozygote gene-deleted and 74.5% UGT2B17-positive athletes. The validated test system has shown to be robust and sensitive: in only 18 cases (2.7%) isolation of cell material from urine failed. Following hydrolysis of glucuronidated conjugates, steroids were analyzed as bis-TMS derivatives by gas chromatography-mass spectrometry (GC-MS), for example, testosterone (T) and epitestosterone (E). Additionally, isotope ration mass spectrometry (IRMS) analysis and luteinizing hormone (LH) measurement were applied. Mean T/E ratios significantly correlated with the UGT2B17 phenotype (del: T/E 0.9; pos: 1.7), however the values did not differ as distinctive as reported in previous studies. Additionally, the T/E ratios in the gene-deleted group did not show a normal curve of distribution (median of T/E 0.5). Obviously, beside the UGT2B17 deletion further influences have to be taken into account, for example, polymorphisms or induction of other metabolizing enzymes. Our results indicate that the UGT2B17 polymorphism might be insufficient when utilized solely as a crucial parameter for individual interpretation of T/E in urine. Nevertheless, the detection of the UGT2B17-gene deletion in urine samples would provide additional information important for gathering evidence in analysis of steroids in doping control. Copyright © 2011 John Wiley & Sons, Ltd.

Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

PubMed

Jedeon, Katia; Loiodice, Sophia; Salhi, Khaled; Le Normand, Manon; Houari, Sophia; Chaloyard, Jessica; Berdal, Ariane; Babajko, Sylvie

2016-11-01

Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

Current Knowledge on the Acute Regulation of Steroidogenesis.

PubMed

Selvaraj, Vimal; Stocco, Douglas M; Clark, Barbara J

2018-04-27

How rapid induction of steroid hormone biosynthesis occurs in response to trophic hormone stimulation of steroidogenic cells has been a subject of intensive investigation for approximately six decades. A key observation made very early was that acute regulation of steroid biosynthesis required swift and timely synthesis of a new protein whose role appeared to be involved in the delivery of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane where the process of steroidogenesis begins. It was quickly learned that this transfer of cholesterol to the inner mitochondrial membrane was the regulated and rate limiting step in steroidogenesis. Following this observation, the quest for this putative regulator protein(s) began in earnest in the late 1950s. This review provides a history of this quest, the candidate proteins that arose over the years, and facts surrounding their rise or decline. Only two have persisted-Translocator Protein (TSPO) and the Steroidogenic Acute Regulatory Protein (StAR). We present a detailed summary of the work that has been published for each of these two proteins, the specific data that has appeared in support of their role in cholesterol transport and steroidogenesis, and the ensuing observations that have arisen in recent years that have refuted the role of TSPO in this process. We believe that the only viable candidate that has been shown to be indispensable is the StAR protein. Lastly, we provide our view on what may be the most important questions concerning the acute regulation of steroidogenesis that need to be asked in future.

Management of a rare presentation of Vogt-Koyanagi-Harada disease in human immunodeficiency virus/acquired immunodeficiency disease syndrome patient.

PubMed

Priya, D; Sudharshan, S; Biswas, Jyotirmay

2017-05-01

Vogt-Koyanagi-Harada (VKH), a multisystem autoimmune bilateral panuveitis with systemic manifestations, is uncommon in immunocompromised patients such as human immunodeficiency virus (HIV)/acquired immunodeficiency disease syndrome (AIDS). We report a rare presentation of VKH in a 45-year-old HIV-positive female on highly active antiretroviral therapy (HAART) who presented with a history of recurrent panuveitis. A diagnosis of probable VKH was made based on ocular and systemic signs and symptoms. She was treated with topical and systemic steroids with close monitoring of CD4 counts and viral loads. After inflammation control, complicated cataract was managed surgically under perioperative steroid cover. VKH in HIV/AIDS has not been reported earlier. This case shows that significant inflammation can be seen even in HIV/AIDS patients on HAART with VKH in spite of moderate CD4 counts. Management is a challenge considering the systemic risks with long-term use of steroids.

The benefits of steroids versus steroids plus antivirals for treatment of Bell's palsy: a meta-analysis.

PubMed

Quant, Eudocia C; Jeste, Shafali S; Muni, Rajeev H; Cape, Alison V; Bhussar, Manveen K; Peleg, Anton Y

2009-09-07

To determine whether steroids plus antivirals provide a better degree of facial muscle recovery in patients with Bell's palsy than steroids alone. Meta-analysis. PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies published in all languages from 1984 to January 2009. Additional studies were identified from cited references. Selection criteria Randomised controlled trials that compared steroids with the combination of steroids and antivirals for the treatment of Bell's palsy were included in this study. At least one month of follow-up and a primary end point of at least partial facial muscle recovery, as defined by a House-Brackmann grade of at least 2 (complete palsy is designated a grade of 6) or an equivalent score on an alternative recognised scoring system, were required. Review methods Two authors independently reviewed studies for methodological quality, treatment regimens, duration of symptoms before treatment, length of follow-up, and outcomes. Odds ratios with 95% confidence intervals were calculated and pooled using a random effects model. Six trials were included, a total of 1145 patients; 574 patients received steroids alone and 571 patients received steroids and antivirals. The pooled odds ratio for facial muscle recovery showed no benefit of steroids plus antivirals compared with steroids alone (odds ratio 1.50, 95% confidence interval 0.83 to 2.69; P=0.18). A one study removed analysis showed that the highest quality studies had the greatest effect on the lack of difference between study arms shown by the odds ratio. Subgroup analyses assessing causes of heterogeneity defined a priori (time from symptom onset to treatment, length of follow-up, and type of antiviral studied) showed no benefit of antivirals in addition to that provided by steroids. Antivirals did not provide an added benefit in achieving at least partial facial muscle recovery compared with steroids alone in patients with Bell's palsy. This study does not, therefore, support the routine use of antivirals in Bell's palsy. Future studies should use improved herpes virus diagnostics and newer antivirals to assess whether combination therapy benefits patients with more severe facial paralysis at study entry.

Alemtuzumab induction with tacrolimus monotherapy in de novo renal transplantation.

PubMed

Villanueva, M E; Muñoz, A S; Casasola, C C; Africa, J B; Danguilan, R A; Ona, E T

2008-09-01

Alemtuzumab is increasingly being used as induction therapy for kidney transplantation, allowing immunosuppression minimization. This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients. This retrospective cohort of primary standard risk renal transplant recipients were given alemtuzumab induction and low-dose tacrolimus maintenance immunosuppression (target trough 7 to 10 ng/mL for the first 6 months and 5 to 7 ng/mL thereafter). Serum creatinine values, acute rejection episodes, and graft survival were noted at week 1 as well as months 3, 6, 12, and 18. At the time of analysis, 47 patients were at 6 months, 28 at 12 months, and 6 patients at 18 months from transplant. Mean follow-up was 12.53 months (range, 6 to 23). Mean serum creatinine was 1.47 +/- 0.65 mg/dL at 3 months, 1.56 +/- 0.84 at 6 months, 1.45 +/- 0.37 at 12 months, and 1.74 +/- 0.35 at 18 months. The 1-year clinical acute rejection rate was 21% (6/28), occurring at 0 to 3 months in 2 (33%), 4 to 6 months in 1 (17%), and >6 months in 3 patients (50%). Biopsy-proven acute rejection was 14% (4/28). The episodes were classified as borderline in one, Banff 2A in two, and Banff 3 in one patients. One patient had both acute cellular and acute humoral rejection; half responded to steroid pulse therapy. The 1-year patient survival rate was 90%. The 1-year death-censored graft survival rate was 98%. Alemtuzumab induction with tacrolimus monotherapy is an acceptable option in standard risk patients. BPAR was 14%, but renal function remained satisfactory at 18 months posttransplant.

Comparative Effectiveness of Mesalamine, Sulfasalazine, Corticosteroids, and Budesonide for the Induction of Remission in Crohn's Disease: A Bayesian Network Meta-analysis.

PubMed

Coward, Stephanie; Kuenzig, M Ellen; Hazlewood, Glen; Clement, Fiona; McBrien, Kerry; Holmes, Rebecca; Panaccione, Remo; Ghosh, Subrata; Seow, Cynthia H; Rezaie, Ali; Kaplan, Gilaad G

2017-03-01

Induction treatment of mild-to-moderate Crohn's disease is controversial. To compare the induction of remission between different doses of mesalamine, sulfasalazine, corticosteroids, and budesonide for active Crohn's disease. We identified randomized controlled trials from existing Cochrane reviews and an updated literature search in Medline, EMBASE, and CENTRAL to November 2015. We included randomized controlled trials (n = 22) in adult patients with Crohn's disease that compared budesonide, sulfasalazine, mesalamine, or corticosteroids with placebo or each other, for the induction of remission (8-17 wks). Mesalamine (above and below 2.4 g/d) and budesonide (above and below 6 mg/d) were stratified into low and high doses. Our primary outcome was remission, defined as a Crohn's Disease Activity Index score <150. A Bayesian random-effects network meta-analysis was performed on the proportion in remission. Corticosteroids (odds ratio [OR] = 3.80; 95% credible interval [CrI]: 2.48-5.66), high-dose budesonide (OR = 2.96; 95% CrI: 2.06-4.30), and high-dose mesalamine (OR = 2.29; 95% CrI: 1.58-3.33) were superior to placebo. Corticosteroids were similar to high-dose budesonide (OR = 1.21; 95% CrI: 0.84-1.76), but more effective than high-dose mesalamine (OR = 1.83; 95% CrI: 1.16-2.88). Sulfasalazine was not significantly superior to any therapy including placebo. Randomized controlled trials that use a strict definition of induction of remission and disease severity at enrollment to assess effectiveness in treating mild-to-moderate Crohn's disease are limited. Corticosteroids and high-dose budesonide were effective treatments for inducing remission in mild-to-moderate Crohn's disease. High-dose mesalamine is an option among patients preferring to avoid steroids.

Bamboo Nodes of Vocal Folds: A Description of 10 Cases and Review of the Literature.

PubMed

Todic, Jelena; Schweizer, Valérie; Leuchter, Igor

2018-05-30

Bamboo nodes are vocal fold lesions, mostly associated with autoimmune diseases. This is a retrospective clinical study including 10 patients with bamboo nodes. Data were collected regarding associated autoimmune disorder and type of treatment. A systematic review of the literature was conducted. All patients were women, with hoarseness as the most frequent symptom. There was in most cases an associated autoimmune disease: 3 patients with systemic lupus erythematosus; 3 with rheumatoid arthritis; 1 with Sjögren syndrome; 1 with Hashimoto disease; and 1 with mixed connective tissue disease. Four patients were treated with speech therapy, 3 with oral steroids, 1 with speech therapy and oral steroids combined, 1 with oral steroids and laryngeal steroid injections, and 1 had oral steroids, surgery, and speech therapy. Speech therapy was the first-line treatment. Bamboo nodes should be looked for in every patient with a diagnosis of autoimmune disease complaining of dysphonia. © 2018 S. Karger AG, Basel.

Management of pemphigus vulgaris: challenges and solutions

PubMed Central

Gregoriou, Stamatis; Efthymiou, Ourania; Stefanaki, Christina; Rigopoulos, Dimitris

2015-01-01

The main objective in the treatment of pemphigus vulgaris is to control the disease, prevent relapses, and avoid adverse events associated with the prolonged use of steroids and immunosuppressive agents. Systemic corticosteroids remain the gold standard treatment for pemphigus vulgaris. Azathioprine and mycophenolate mofetil are the first line of steroid-sparing treatment. Rituximab is extremely effective in recalcitrant pemphigus, when other treatments fail to control the disease. The European Dermatology Forum recommends tapering prednisolone by 25% every 2 weeks after the consolidation phase, and a 5 mg reduction every 4 weeks when the dose is reduced to <20 mg. If the patient relapses, options include increasing steroids back to the previous dose, adding an immunosuppressant if using steroid monotherapy, or replacing a first-line immunosuppressant by another if already on combination therapy. PMID:26543381

Modulation of the phenotype and function of Mycobacterium tuberculosis-stimulated dendritic cells by adrenal steroids.

PubMed

Angerami, Matias; Suarez, Guadalupe; Pascutti, Maria Fernanda; Salomon, Horacio; Bottasso, Oscar; Quiroga, Maria Florencia

2013-07-01

Cell-mediated immunity, cytokines induced during the specific immune response and T-cell populations are crucial factors for containing Mycobacterium tuberculosis infection. Recent reports suggest a cross-regulation between adrenal steroids (glucocorticoids and dehydroepiandrosterone, DHEA) and the function of antigen-presenting cells (APCs). Therefore, we investigated the role of adrenal hormones on the functional capacity of M. tuberculosis-induced dendritic cells (DCs). Cortisol significantly inhibited the functions of M. tuberculosis-induced DCs. Interestingly, the presence of DHEA enhanced the M. tuberculosis-induced expression of MHC I, MHC II and CD86 and also increased ERK1/2 phosphorylation. Moreover, DHEA improved the production of IL-12 in response to M. tuberculosis stimulation, diminished IL-10 secretion and could not modify TNF-α synthesis. Importantly, we observed that DHEA enhanced the antigen-specific T-cell proliferation and IFN-γ production induced by M. tuberculosis-stimulated DC. These data show for the first time the relevance of the adrenal axis (especially of DHEA) in the modulation of DC function in the context of tuberculosis, a disease where the induction of a Th1 environment by APCs is crucial for the development of an effective immune response to the mycobacteria.

Non-reproductive effects of sex steroids: their immunoregulatory role.

PubMed

Arroyo, Ignácio Camacho; Montor, Jorge Morales

2011-01-01

In this special issue of Current Topics in Medicinal Chemistry, the reader will find reviewed some of the hottest topics in the field of the non-reproductive effects of sex steroids. Cabrera-Muñoz et al., show that progesterone participates in the regulation of human brain tumors growth. The contribution of Martocchia suggests that sex steroid receptor modulating drugs provide new therapeutic approaches to autoimmune diseases. The role of sex steroid participation in the differentiation of stem cells to neurones is discussed by I. Velasco. Pérez-Torres and collaborators demonstrate that sex steroids play an important role in the appearance and development of renal diseases and the metabolic syndrome, the new epidemics of our century. Paris and Frye hypthetize that gestational stress, have effects on cognitive performance and/or neuronal integrity in the fetus, and that exposure to variable stress during gestation can perturb cognitive performance, concomitant with dendrite development in hippocampus and diencephalon. Muñoz-Cruz et al. thoroughly review the growing body of evidence that shows reciprocal relationship between sex steroids and the immune system, and conclude that understanding the mechanisms of action of sex steroids on immune cells is important for further progress in the development of novel therapies for chronic diseases associated to immune dysregulation. Besides, the effects of sexual steroids on pancreatic function and diabetes are reviewed by Morimoto et al. Yanes et al. review some of the contradictions raised in the context of the recently proposed critical period hypothesis, which takes into account the frame-time after cessation of ovarian function. Finally, another vey intetresting aspect of the non-reproductive effects of sex-steroids, is the related to some cognition-related aspects, which is reviewed by Picazo et al.

The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: Implications for diagnosis and treatment

PubMed Central

Guille, Constance; Spencer, Susan; Cavus, Idil; Epperson, C. Neill

2014-01-01

Despite our understanding of hormonal influences on central nervous system (CNS) function, there is still much to learn about the pathogenesis of menstrual cycle-linked disorders. A growing literature suggests that the influence of sex steroids on neurological and psychiatric disorders is in part mediated by an aberrant CNS response to neuroactive steroids. Although sex steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO) influence numerous neurotransmitter systems, it is their potent effect on the brain's primary inhibitory and excitatory neurotransmitters γ aminobutyric acid (GABA) and glutamate that links the study of premenstrual dysphoric disorder (PMDD) and catamenial epilepsy (CE). After providing an overview of these menstrual cycle-linked disorders, this article focuses on the preclinical and clinical research investigating the role of estradiol and progesterone (via ALLO) in the etiology of PMDD and CE. Through exploration of the phenomenological and neurobiological overlap between CE and PMDD, we aim to highlight areas for future research and development of treatments for menstrual cycle-linked neuropsychiatric disorders. PMID:18346939

Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding

PubMed Central

Purushotham, Aparna; Xu, Qing; Li, Xiaoling

2012-01-01

SIRT1 is a highly-conserved NAD+-dependent protein deacetylase that plays essential roles in the regulation of energy metabolism, genomic stability, and stress response. Although the functions of SIRT1 in many organs have been extensively studied in tissue-specific knockout mouse models, the systemic role of SIRT1 is still largely unknown as a result of severe developmental defects that result from whole-body knockout in mice. Here, we investigated the systemic functions of SIRT1 in metabolic homeostasis by utilizing a whole-body SIRT1 heterozygous mouse model. These mice are phenotypically normal under standard feeding conditions. However, when chronically challenged with a 40% fat diet, they become obese and insulin resistant, display increased serum cytokine levels, and develop hepatomegaly. Hepatic metabolomic analyses revealed that SIRT1 heterozygous mice have elevated gluconeogenesis and oxidative stress. Surprisingly, they are depleted of glycerolipid metabolites and free fatty acids, yet accumulate lysolipids. Moreover, high-fat feeding induces elevation of serum testosterone levels and enlargement of seminal vesicles in SIRT1 heterozygous males. Microarray analysis of liver mRNA indicates that they have altered expression of genes involved in steroid metabolism and glycerolipid metabolism. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of systemic energy and steroid hormone homeostasis.—Purushotham, A., Xu, Q., Li, X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. PMID:22006157

Steroid conversion with CYP106A2 – production of pharmaceutically interesting DHEA metabolites

PubMed Central

2014-01-01

Background Steroids are lipophilic compounds with a gonane skeleton and play an important role in higher organisms. Due to different functionalizations - mainly hydroxylations - at the steroid molecule, they vary highly in their mode of action. The pharmaceutical industry is, therefore, interested in hydroxysteroids as therapeutic agents. The insertion of hydroxyl groups into a steroid core, however, is hardly accomplishable by classical chemical means; that is because microbial steroid hydroxylations are investigated and applied since decades. CYP106A2 is a cytochrome P450 monooxygenase from Bacillus megaterium ATCC 13368, which was first described in the late 1970s and which is capable to hydroxylate a variety of 3-oxo-delta4 steroids at position 15beta. CYP106A2 is a soluble protein, easy to express and to purify in high amounts, which makes this enzyme an interesting target for biotechnological purposes. Results In this work a focused steroid library was screened in vitro for new CYP106A2 substrates using a reconstituted enzyme assay. Five new substrates were identified, including dehydroepiandrosterone and pregnenolone. NMR-spectroscopy revealed that both steroids are mainly hydroxylated at position 7beta. In order to establish a biotechnological system for the preparative scale production of 7beta-hydroxylated dehydroepiandrosterone, whole-cell conversions with growing and resting cells of B. megaterium ATCC1336 the native host of CYP1062 and also with resting cells of a recombinant B. megaterium MS941 strain overexpressing CYP106A2 have been conducted and conversion rates of 400 muM/h (115 mg/l/h) were obtained. Using the B. megaterium MS941 overexpression strain, the selectivity of the reaction was improved from 0.7 to 0.9 for 7beta-OH-DHEA. Conclusions In this work we describe CYP106A2 for the first time as a regio-selective hydroxylase for 3-hydroxy-delta5 steroids. DHEA was shown to be converted to 7beta-OH-DHEA which is a highly interesting human metabolite, supposed to act as neuroprotective, anti-inflammatory and immune-modulatory agent. Optimization of the whole-cell system using different B. megaterium strains lead to a conversion of DHEA with B. megaterium showing high selectivity and conversion rates and displaying a volumetric yield of 103 mg/l/h 7beta-OH-DHEA. PMID:24903845

Steroid conversion with CYP106A2 - production of pharmaceutically interesting DHEA metabolites.

PubMed

Schmitz, Daniela; Zapp, Josef; Bernhardt, Rita

2014-06-05

Steroids are lipophilic compounds with a gonane skeleton and play an important role in higher organisms. Due to different functionalizations - mainly hydroxylations - at the steroid molecule, they vary highly in their mode of action. The pharmaceutical industry is, therefore, interested in hydroxysteroids as therapeutic agents. The insertion of hydroxyl groups into a steroid core, however, is hardly accomplishable by classical chemical means; that is because microbial steroid hydroxylations are investigated and applied since decades. CYP106A2 is a cytochrome P450 monooxygenase from Bacillus megaterium ATCC 13368, which was first described in the late 1970s and which is capable to hydroxylate a variety of 3-oxo-delta4 steroids at position 15beta. CYP106A2 is a soluble protein, easy to express and to purify in high amounts, which makes this enzyme an interesting target for biotechnological purposes. In this work a focused steroid library was screened in vitro for new CYP106A2 substrates using a reconstituted enzyme assay. Five new substrates were identified, including dehydroepiandrosterone and pregnenolone. NMR-spectroscopy revealed that both steroids are mainly hydroxylated at position 7beta. In order to establish a biotechnological system for the preparative scale production of 7beta-hydroxylated dehydroepiandrosterone, whole-cell conversions with growing and resting cells of B. megaterium ATCC1336 the native host of CYP1062 and also with resting cells of a recombinant B. megaterium MS941 strain overexpressing CYP106A2 have been conducted and conversion rates of 400 muM/h (115 mg/l/h) were obtained. Using the B. megaterium MS941 overexpression strain, the selectivity of the reaction was improved from 0.7 to 0.9 for 7beta-OH-DHEA. In this work we describe CYP106A2 for the first time as a regio-selective hydroxylase for 3-hydroxy-delta5 steroids. DHEA was shown to be converted to 7beta-OH-DHEA which is a highly interesting human metabolite, supposed to act as neuroprotective, anti-inflammatory and immune-modulatory agent. Optimization of the whole-cell system using different B. megaterium strains lead to a conversion of DHEA with B. megaterium showing high selectivity and conversion rates and displaying a volumetric yield of 103 mg/l/h 7beta-OH-DHEA.

Molecular characterization of kiss2 and differential regulation of reproduction-related genes by sex steroids in the hypothalamus of half-smooth tongue sole (Cynoglossus semilaevis).

PubMed

Wang, Bin; Liu, Quan; Liu, Xuezhou; Xu, Yongjiang; Song, Xuesong; Shi, Bao

2017-11-01

Kisspeptin (Kiss) plays a critical role in mediating gonadal steroid feedback to the gonadotropin-releasing hormone (GnRH) neurons in mammals. However, little information regarding the regulation of kisspeptin gene by sex steroids is available in teleosts. In this study, we examined the direct actions of estradiol (E2) and testosterone (T) on hypothalamic expression of kisspeptin and other key factors involved in reproductive function of half-smooth tongue sole. As a first step, a partial-length cDNA of kiss2 was identified from the brain of tongue sole and kiss2 transcript levels were shown to be widely expressed in various tissues, notably in the ovary. Then, the actions of sex steroids on kiss2 and other reproduction-related genes were evaluated using a primary hypothalamus culture system. Our results showed that neither kiss2 nor its receptor kiss2r mRNA levels were significantly altered by sex steroids. Moreover, sex steroids did not modify hypothalamic expression of gonadotropin-inhibitory hormone (gnih) and its receptor gnihr mRNAs, either. However, E2 markedly stimulated both gnrh2 and gnrh3 mRNAs levels. Overall, this study provides insights into the role of sex steroids in the reproductive function of Pleuronectiform teleosts. Copyright © 2017 Elsevier Inc. All rights reserved.

Preliminary study of a traditional Chinese medicine formula in systemic lupus erythematosus patients to taper steroid dose and prevent disease flare-up.

PubMed

Liao, Yen-Nung; Liu, Ching-Shen; Tsai, Tong-Rong; Hung, Yu-Chiang; Chang, Shun-Jen; Lin, Hong-Long; Chen, Ying-Chou; Lai, Han-Ming; Yu, Shan-Fu; Chen, Chung-Jen

2011-07-01

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. Prolonged complete remission is rare. Most patients with SLE need long-term treatment with glucocorticoid and immunomodulators. However, side effects because of the above medications are common. We evaluated the effect of adding-on Dan-Chi-Liu-Wei combination (DCLWC) on SLE patients with conventional therapy in tapering steroid and preventing disease flare-up. This was a double-blind and randomized controlled trial. Sixty-six SLE patients were recruited into this study and 53 patients who fulfilled the 1997 revised criteria for the classification of SLE with an SLE disease activity index (SLEDAI) score of 2-12 and a steroid (measured with prednisolone) daily dose of less than 20mg/d were enrolled. The patients were randomized into either an experimental or control group. We checked the urine analysis, hemogram, liver function, renal function, C3, C4, erythrocyte sedimentation rate, and anti-dsDNA, evaluated the SLEDAI score, and recorded the steroid dose at 0 months, 3 months, and 6 months, respectively. After 6 months of study, the C4 and blood urea nitrogen level revealed a statistically significant difference in either group. There was a tendency toward a decreased SLEDAI score in the experimental group (p=0.083) but not in the control group (p=0.867). The steroid dose was not statistically significant in either group. Renal function and liver function revealed no statistically significant statistics changes in either group. Adding-on DCLWC to conventional therapy for the treatment of SLE was safe and might have a borderline effect in decreasing disease activity, but it was not possible to taper the dosage of steroid after 6 months of clinical trial. Therefore, a long-term follow-up and a large-scale study are necessary to confirm the effect of DCLWC. Copyright © 2011 Elsevier Taiwan LLC. All rights reserved.

Transport of steroid hormones, phytoestrogens, and estrogenic activity across a swine lagoon/sprayfield system.

PubMed

Yost, Erin E; Meyer, Michael T; Dietze, Julie E; Williams, C Michael; Worley-Davis, Lynn; Lee, Boknam; Kullman, Seth W

2014-10-07

The inflow, transformation, and attenuation of natural steroid hormones and phytoestrogens and estrogenic activity were assessed across the lagoon/sprayfield system of a prototypical commercial swine sow operation. Free and conjugated steroid hormones (estrogens, androgens, and progesterone) were detected in urine and feces of sows across reproductive stages, with progesterone being the most abundant steroid hormone. Excreta also contained phytoestrogens indicative of a soy-based diet, particularly, daidzein, genistein, and equol. During storage in barn pits and the anaerobic lagoon, conjugated hormones dissipated, and androgens and progesterone were attenuated. Estrone and equol persisted along the waste disposal route. Following application of lagoon slurry to agricultural soils, all analytes exhibited attenuation within 2 days. However, analytes including estrone, androstenedione, progesterone, and equol remained detectable in soil at 2 months postapplication. Estrogenic activity in the yeast estrogen screen and T47D-KBluc in vitro bioassays generally tracked well with analyte concentrations. Estrone was found to be the greatest contributor to estrogenic activity across all sample types. This investigation encompasses the most comprehensive suite of natural hormone and phytoestrogen analytes examined to date across a livestock lagoon/sprayfield and provides global insight into the fate of these analytes in this widely used waste management system.

Quantification of three steroid hormone receptors of the leopard gecko (Eublepharis macularius), a lizard with temperature-dependent sex determination: their tissue distributions and the effect of environmental change on their expressions.

PubMed

Endo, Daisuke; Park, Min Kyun

2003-12-01

Sex steroid hormones play a central role in the reproduction of all vertebrates. These hormones function through their specific receptors, so the expression levels of the receptors may reflect the responsibility of target organs. However, there was no effective method to quantify the expression levels of these receptors in reptilian species. In this study, we established the competitive-PCR assay systems for the quantification of the mRNA expression levels of three sex steroid hormone receptors in the leopard gecko. These assay systems were successfully able to detect the mRNA expression level of each receptor in various organs of male adult leopard geckoes. The expression levels of mRNA of these receptors were highly various depending on the organs assayed. This is the first report regarding the tissue distributions of sex steroid hormone receptor expressions in reptile. The effects of environmental conditions on these hormone receptor expressions were also examined. After the low temperature and short photoperiod treatment for 6 weeks, only the androgen receptor expression was significantly increased in the testes. The competitive-PCR assay systems established in this report should be applicable for various studies of the molecular mechanism underlying the reproductive activity of the leopard gecko.

Steroids and Autoimmunity.

PubMed

Trombetta, Amelia Chiara; Meroni, Marianna; Cutolo, Maurizio

2017-01-01

From the middle of the 19th century, it is known that endocrine and immune systems interact bi-directionally in different processes that ensure organism homeostasis. Endocrine and nervous systems have a pivotal role in the balancing of pro- and anti-inflammatory functions of immune system, and constitute a complex circadian neuroendocrine network. Autoimmune diseases have in fact a complex pathogenic origin in which the importance of endocrine system was demonstrated. In this chapter, we will mention the structure and function of steroidal hormones involved in the neuroendocrine immune network and we will address the ways in which endocrine and immune systems influence each other, in a bi-directional fashion. Adrenal hormones, sex hormones, vitamin D, and melatonin and prolactin importantly all contribute to the homeostasis of the immune system. Indeed, some of the steroidal hormone activities determine inhibition or stimulation of immune system components, in both physiological (i.e. suppression of an unwanted response in pregnancy, or stimulation of a protective response in infections) and pathological conditions. We will finally mention the rationale for optimization of exogenous administration of glucocorticoids in chronic autoimmune diseases, and the latest developments concerning these drugs. © 2017 S. Karger AG, Basel.

Emerging roles for neurosteroids in sexual behavior and function.

PubMed

King, Steven R

2008-01-01

Although gonadal and adrenal steroids heavily impact sexual function at the level of the brain, the nervous system also produces its own steroids de novo that may regulate sexual behavior and reproduction. Current evidence points to important roles for neurosteroids in sexual and gender-typical behaviors, control of ovulation, and behaviors that strongly influence sexual interest and motivation like aggression, anxiety and depression. At the cellular level, neurosteroids act through stimulating rapid changes in excitability and direct activation of membrane receptors in neurons. Thus, unlike peripheral steroids, neurosteroids can have immediate and specific effects on select neuronal pathways to regulate sexual function.

A review of designer anabolic steroids in equine sports.

PubMed

Waller, Christopher C; McLeod, Malcolm D

2017-09-01

In recent years, the potential for anabolic steroid abuse in equine sports has increased due to the growing availability of designer steroids. These compounds are readily accessible online in 'dietary' or 'nutritional' supplements and contain steroidal compounds which have never been tested or approved as veterinary agents. They typically have unusual structures or substitution and as a result may pass undetected through current anti-doping screening protocols, making them a significant concern for the integrity of the industry. Despite considerable focus in human sports, until recently there has been limited investigation into these compounds in equine systems. To effectively respond to the threat of designer steroids, a detailed understanding of their metabolism is needed to identify markers and metabolites arising from their misuse. A summary of the literature detailing the metabolism of these compounds in equine systems is presented with an aim to identify metabolites suitable for incorporation into screening protocols by anti-doping laboratories. The future of equine anti-doping research is likely to be guided by the incorporation of alternate testing matrices into routine screening, the improvement of in vitro technologies that can mimic in vivo equine metabolism, and the improvement of instrumentation or analytical methods that allow for the development of untargeted screening, and metabolomics approaches for use in anti-doping screening protocols. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Actions of Steroids: New Neurotransmitters

PubMed Central

Cornil, Charlotte A.; Mittelman-Smith, Melinda A.; Rainville, Jennifer R.; Remage-Healey, Luke; Sinchak, Kevin; Micevych, Paul E.

2016-01-01

Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain. PMID:27911748

High-dose nebulized budesonide is effective for mild asthma exacerbations in children under 3 years of age.

PubMed

Saito, M; Kikuchi, Y; Kawarai Lefor, A; Hoshina, M

2017-01-01

Background. High-dose inhaled steroid therapy has been shown to be effective in children and adults with asthma exacerbations. However, few reports are available regarding its efficacy for asthma exacerbations in younger children. Objective. In this study, we administered high-dose nebulized budesonide therapy for mild asthma exacerbations in children < 3 years of age and compared its efficacy and safety with systemic steroid therapy. Methods. This study included children < 3 years old with mild asthma exacerbations. Patients were randomly assigned to two groups: the BIS group was given 1 mg of nebulized budesonide twice daily, and the PSL group received prednisolone 0.5 mg/kg iv three times daily. Days to disappearance of wheezing, days of steroid use, days of oxygen use, serum cortisol level, and incidence of adverse events during treatment were compared between the groups. Result. Wheezing disappeared after an average of five days, and steroids were administered for an average of five days in both groups, with no significant difference in days of oxygen use. Serum cortisol levels at initiation and during the course of treatment remained unchanged in the BIS group, and were decreased in the PSL group; however, the decrease in the latter group was not pathologic. Conclusion. For children < 3 years old with mild asthma exacerbations, high-dose nebulized budesonide therapy is equally as effective as systemic steroid therapy.

Preoperative steroid administration: effect on morbidity among patients undergoing intestinal bowel resection for Crohńs disease.

PubMed

Bruewer, Matthias; Utech, Markus; Rijcken, Emile J M; Anthoni, Christoph; Laukoetter, Mike G; Kersting, Sabine; Senninger, Norbert; Krieglstein, Christian F

2003-12-01

Long-term steroid therapy may predispose to increased perioperative morbidity in patients undergoing surgery with bowel anastomoses. The aim of our study was to review our data to determine if the steroid dosage is associated with the incidence of early complications after bowel resection in patients with prolonged steroid therapy for Crohńs disease (CD). Altogether, 397 patients underwent bowel resection with primary intestinal anastomoses for CD between 1982 and 2000 in our institution. The mortality and morbidity rates, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and length of postoperative hospitalization in patients who were having high-dose (>/= 20 mg of prednisolone per day, n = 73) and low-dose (< 20 mg prednisolone per day, n = 146) steroid therapy for more than 1 month before surgery were compared with those of patients ( n = 177) who were not receiving steroids. Statistical analysis was performed using Fisher's exact test and Student's t-test, with p < 0.05 considered significant. The three groups were similar in terms of gender, duration since first diagnosis, American Society of Anesthesiologists classification, and obesity. Mortality, morbidity, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and average postoperative stay were not statistically different in patients with high-dose, low-dose, or no steroid therapy. The only factor associated with increased morbidity was a low preoperative hemoglobin level. Our results demonstrate that, in patients who are undergoing bowel resection for CD, even high-dose prolonged preoperative systemic steroid therapy is not associated with increased postoperative complications.

Antifungal activity and fungal metabolism of steroidal glycosides of Easter lily (Lilium longiflorum Thunb.) by the plant pathogenic fungus, Botrytis cinerea.

PubMed

Munafo, John P; Gianfagna, Thomas J

2011-06-08

Botrytis cinerea Pers. Fr. is a plant pathogenic fungus and the causal organism of blossom blight of Easter lily (Lilium longiflorum Thunb.). Easter lily is a rich source of steroidal glycosides, compounds which may play a role in the plant-pathogen interaction of Easter lily. Five steroidal glycosides, including two steroidal glycoalkaloids and three furostanol saponins, were isolated from L. longiflorum and evaluated for fungal growth inhibition activity against B. cinerea, using an in vitro plate assay. All of the compounds showed fungal growth inhibition activity; however, the natural acetylation of C-6''' of the terminal glucose in the steroidal glycoalkaloid, (22R,25R)-spirosol-5-en-3β-yl O-α-L-rhamnopyranosyl-(1→2)-[6-O-acetyl-β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside (2), increased antifungal activity by inhibiting the rate of metabolism of the compound by B. cinerea. Acetylation of the glycoalkaloid may be a plant defense response to the evolution of detoxifying mechanisms by the pathogen. The biotransformation of the steroidal glycoalkaloids by B. cinerea led to the isolation and characterization of several fungal metabolites. The fungal metabolites that were generated in the model system were also identified in Easter lily tissues infected with the fungus by LC-MS. In addition, a steroidal glycoalkaloid, (22R,25R)-spirosol-5-en-3β-yl O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside (6), was identified as both a fungal metabolite of the steroidal glycoalkaloids and as a natural product in L. longiflorum for the first time.

Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts.

PubMed

Pomari, Elena; Dalla Valle, Luisa; Pertile, Paolo; Colombo, Lorenzo; Thornton, M Julie

2015-02-01

Peripheral intracrine sex steroid synthesis from adrenal precursors dehydroepiandrosterone (DHEA) and DHEA-sulfate has evolved in humans. We sought to establish if there are differences in intracrine, paracrine, and endocrine regulation of sex steroids by primary cultures of human skin epidermal keratinocytes and dermal fibroblasts. Microarray analysis identified multifunctional genes modulated by steroids, quantitative RT-PCR (qRT-PCR) mRNA expression, enzymatic assay aromatase activity, scratch assay cell migration, immunocytochemistry α-smooth muscle actin (α-SMA), and collagen gel fibroblast contraction. All steroidogenic components were present, although only keratinocytes expressed the organic anion organic anion transporter protein (OATP) 2B1 transporter. Both expressed the G-protein-coupled estrogen receptor (GPER1). Steroids modulated multifunctional genes, up-regulating genes important in repair and aging [angiopoietin-like 4 (ANGPTL4), chemokine (C-X-C motif) ligand 1 (CXCL1), lamin B1 (LMNB1), and thioredoxin interacting protein (TXNIP)]. DHEA-sulfate (DHEA-S), DHEA, and 17β-estradiol stimulated keratinocyte and fibroblast migration at early (4 h) and late (24-48 h) time points, suggesting involvement of genomic and nongenomic signaling. Migration was blocked by aromatase and steroid sulfatase (STS) inhibitors confirming intracrine synthesis to estrogen. Testosterone had little effect, implying it is not an intermediate. Steroids stimulated fibroblast contraction but not α-SMA expression. Mechanical wounding reduced fibroblast aromatase activity but increased keratinocyte activity, amplifying the bioavailability of intracellular estrogen. Cultured fibroblasts and keratinocytes provide a biologically relevant model system to investigate the complex pathways of sex steroid intracrinology in human skin. © FASEB.

Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice.

PubMed

Gaignard, Pauline; Savouroux, Stéphane; Liere, Philippe; Pianos, Antoine; Thérond, Patrice; Schumacher, Michael; Slama, Abdelhamid; Guennoun, Rachida

2015-08-01

Sex steroids regulate brain function in both normal and pathological states. Mitochondria are an essential target of steroids, as demonstrated by the experimental administration of 17β-estradiol or progesterone (PROG) to ovariectomized female rodents, but the influence of endogenous sex steroids remains understudied. To address this issue, mitochondrial oxidative stress, the oxidative phosphorylation system, and brain steroid levels were analyzed under 3 different experimental sets of endocrine conditions. The first set was designed to study steroid-mediated sex differences in young male and female mice, intact and after gonadectomy. The second set concerned young female mice at 3 time points of the estrous cycle in order to analyze the influence of transient variations in steroid levels. The third set involved the evaluation of the effects of a permanent decrease in gonadal steroids in aged male and female mice. Our results show that young adult females have lower oxidative stress and a higher reduced nicotinamide adenine dinucleotide (NADH)-linked respiration rate, which is related to a higher pyruvate dehydrogenase complex activity as compared with young adult males. This sex difference did not depend on phases of the estrous cycle, was suppressed by ovariectomy but not by orchidectomy, and no longer existed in aged mice. Concomitant analysis of brain steroids showed that pregnenolone and PROG brain levels were higher in females during the reproductive period than in males and decreased with aging in females. These findings suggest that the major male/female differences in brain pregnenolone and PROG levels may contribute to the sex differences observed in brain mitochondrial function.

Moderator's view: Treatment of IgA nephropathy-getting comfortable with uncertainty.

PubMed

Glassock, Richard J

2016-11-01

A Polar Views discussion by Pozzi and Rauen et al. on the interpretation and clinical application of the recently published Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) trial has elucidated important points concerning potential strengths and weaknesses of this landmark randomized trial. This critical examination of the impact of steroid monotherapy or steroid plus an immunosuppressive (IS) agent compared with 'supportive' therapy with inhibitors of the renin-angiotensin system (RAS) has enhanced our appreciation of the importance of rigorous application of titrated RAS inhibition in high-risk patients with persistent proteinuria >0.75 g/day. At the same time, it brings a new level of uncertainty concerning the overall value and risk of steroid or steroid plus IS therapy in patients failing such 'supportive' therapy. Some of these uncertainties revolve on issues of study design, such as the duration of follow-up, participant stratification (particularly underlying pathology) and dosing regimens. It is hoped that additional trials, better methods of patient selection, improved surrogate end points and safer regimens will lead to less uncertainty over the best treatment practices. On balance, the STOP-IgAN trial raises some key concerns about the merits of steroid alone or steroid plus IS therapy for selected subjects with IgAN, but it does not by itself close the door on the utility of steroid monotherapy in subjects with high-risk IgAN, even as it further degrades the value of steroid plus IS, at least with sequential cyclophosphamide and azathioprine. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Interactions between hormones and epilepsy.

PubMed

Taubøll, Erik; Sveberg, Line; Svalheim, Sigrid

2015-05-01

There is a complex, bidirectional interdependence between sex steroid hormones and epilepsy; hormones affect seizures, while seizures affect hormones thereby disturbing reproductive endocrine function. Both female and male sex steroid hormones influence brain excitability. For the female sex steroid hormones, progesterone and its metabolites are anticonvulsant, while estrogens are mainly proconvulsant. The monthly fluctuations in hormone levels of estrogen and progesterone are the basis for catamenial epilepsy described elsewhere in this issue. Androgens are mainly anticonvulsant, but the effects are more varied, probably because of its metabolism to, among others, estradiol. The mechanisms for the effects of sex steroid hormones on brain excitability are related to both classical, intracellularly mediated effects, and non-classical membrane effects due to binding to membrane receptors. The latter are considered the most important in relation to epilepsy. The different sex steroids can also be further metabolized within the brain to different neurosteroids, which are even more potent with regard to their effect on excitability. Estrogens potentiate glutamate responses, primarily by potentiating NMDA receptor activity, but also by affecting GABA-ergic mechanisms and altering brain morphology by increasing dendritic spine density. Progesterone and its main metabolite 5α-pregnan-3α-ol-20-one (3α-5α-THP) act mainly to enhance postsynaptic GABA-ergic activity, while androgens enhance GABA-activated currents. Seizures and epileptic discharges also affect sex steroid hormones. There are close anatomical connections between the temporolimbic system and the hypothalamus controlling the endocrine system. Several studies have shown that epileptic activity, especially mediated through the amygdala, alters reproductive function, including reduced ovarian cyclicity in females and altered sex steroid hormone levels in both genders. Furthermore, there is an asymmetric activation of the hypothalamus with unilateral amygdala seizures. This may, again, be the basis for the occurrence of different reproductive endocrine disorders described for patients with left-sided or right-sided temporal lobe epilepsy. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Up-regulation of the alligator CYP3A77 gene by toxaphene and dexamethasone and its short term effect on plasma testosterone concentrations.

PubMed

Gunderson, M P; Kohno, S; Blumberg, B; Iguchi, T; Guillette, L J

2006-06-30

In this study we describe an alligator hepatic CYP3A gene, CYP3A77, which is inducible by dexamethasone and toxaphene. CYP3A plays a broad role in biotransforming both exogenous compounds and endogenous hormones such as testosterone and estradiol. Alligators collected from sites in Florida that are contaminated with organochlorine compounds exhibit differences in sex steroid concentrations. Many organochlorine compounds induce CYP3A expression in other vertebrates; hence, CYP3A induction by organochlorine contaminants could increase biotransformation and clearance of sex steroids by CYP3A and provide a plausible mechanism for the lowering of endogenous sex steroid concentrations in alligator plasma. We used real time PCR to examine whether known and suspected CYP3A inducers (dexamethasone, metyrapone, rifampicin, and toxaphene) up-regulate steady state levels of hepatic CYP3A77 transcript to determine if induction patterns in female juvenile alligators are similar to those reported in other vertebrates and whether toxaphene, an organochlorine compound found in high concentrations in Lake Apopka alligators, induces this gene. Estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), and steroid-xenobiotic receptor (SXR) transcripts were also measured to determine whether any of these nuclear receptors are also regulated by these compounds in alligators. Dexamethasone (4.2-fold) and toxaphene (3.5-fold) significantly induced CYP3A77 gene transcript, whereas rifampicin (2.8-fold) and metyrapone (2.1-fold) up-regulated ERbeta after 24h. None of the compounds significantly up-regulated AR, ERalpha, GR, PR, or SXR over this time period. Plasma testosterone (T) did not change significantly after 24h in alligators from any of the treatment groups. Dexamethasone treated animals exhibited a strong relationship between the 24h plasma T concentrations and CYP3A77 (R(2)=0.9, positive) and SXR (R(2)=0.77, negative) transcripts, which suggests that the expression of these genes is related to plasma T in alligators. In light of our findings, we hypothesized that higher steady state CYP3A77 (and possibly SXR) gene expression would be observed in alligators collected from Lake Apopka, a polluted lake containing organochlorine compounds known to induce CYP3A isoforms in other taxa. Therefore, we measured basal levels of CYP3A77 and SXR gene transcripts in wild juvenile alligators collected from Orange Lake (reference lake), Lake Woodruff (reference lake), and Lake Apopka (contaminated lake). We found that no differences existed in CYP3A77 or SXR gene expression among animals from the lakes sampled suggesting that exposure to organochlorine compounds at concentrations present in Lake Apopka does not lead to variation in the expression of these genes, although capture stress could be interfering with these results since the glucocorticoid dexamethasone induces CYP3A77 transcript in alligators.

Vitamin-C, steroid and environmental carcinogenesis (review).

PubMed

Kodama, M; Kodama, T

1995-04-01

An attempt was made to investigate the relation between oxidative metabolism of neoplastic tissues and carcinogenesis from the point of view of the vitaminology/endocrinology fusion science. Our discussion was developed on the basis of maximum information available in- and outside our laboratory. We present 3 suggestions to throw new light on the phenomenon of eternal enigma - carcinogenesis. They are given as follows: i) the emergence of the oxidant criminal theory motivated us to refresh our old memory surrounding the metabolic characteristics of cancer cells with increased aerobic glycolysis. Evidence was presented to suggest that a neoplastic cell in its behavior can be classified as a facultative anaerobe, whereas a non-neoplastic cell belongs to the family of obligate aerobes. Information is also available to indicate that both glucocorticoid and vitamin C are working together to maintain concerted relationship between mitochondria and cytoplasm. On the basis of the information in paleontology, we propose to assume the metabolic characteristics of a neoplastic cell as an example of failed symbiosis between oxidant-intoxicated host cell (an anaerobe) and rebelling mitochondria (aerobes). ii) In view of the complexity of relation between the ever-changing environment and the humans as regards the cancer risk variations in time and space, we propose to assume the presence of a signal translation system as the intermediator between the outer environment and the target tissue. The steroid generating system, of which the implication to carcinogenesis is suggested in both human and non-human systems, may take over that role maintaining a cross talk with the hypothalamus-pituitary complex. One finds a good model of carcinogenesis in polymorphism of insects in which tranposon may well play important role in the induction of genetic transformation. iii) We should make further effort to explore the usefulness of vitamin C in cancer prevention. Worth consideration in this respect is our clinical experience that autoimmune disease and allergy are controlled through vitamin C infusion treatment by way of ACTH-linked stimulation of adrenocortical function - a modification of the hormonal milieu by use of vitamin C.

An overview of estrogen-associated endocrine disruption in fishes: evidence of effects on reproductive and immune physiology

USGS Publications Warehouse

Iwanowicz, L.R.; Blazer, V.S.

2011-01-01

Simply and perhaps intuitively defined, endocrine disruption is the abnormal modulation of normal hormonal physiology by exogenous chemicals. In fish, endocrine disruption of the reproductive system has been observed worldwide in numerous species and is known to affect both males and females. Observations of biologically relevant endocrine disruption most commonly occurs near waste water treatment plant outfalls, pulp and paper mills, and areas of high organic loading sometimes associated with agricultural practices. Estrogenic endocrine disrupting chemicals (EEDCs) have received an overwhelmingly disproportionate amount of scientific attention compared to other EDCs in recent years. In male fishes, exposure to EEDCs can lead to the induction of testicular oocytes (intersex), measurable plasma vitellogenin protein, altered sex steroid profiles, abnormal spawning behavior, skewed population sex ratios, and lessened reproductive success. Interestingly, contemporary research purports that EDCs modulate aspects of non-reproductive physiology including immune function. Here we present an overview of endocrine disruption in fishes associated with estrogenic compounds, implications of this phenomenon, and examples of EDC related research findings by our group in the Potomac River Watershed, USA.

Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber officinale (ginger) rhizomes in rat adjuvant-induced arthritis.

PubMed

Ramadan, Gamal; Al-Kahtani, Mohammed Ali; El-Sayed, Wael Mohamed

2011-08-01

Turmeric (rich in curcuminoids) and ginger (rich in gingerols and shogaols) rhizomes have been widely used as dietary spices and to treat different diseases in Ayurveda/Chinese medicine since antiquity. Here, we compared the anti-inflammatory/anti-oxidant activity of these two plants in rat adjuvant-induced arthritis (AIA). Both plants (at dose 200 mg/kg body weight) significantly suppressed (but with different degrees) the incidence and severity of arthritis by increasing/decreasing the production of anti-inflammatory/pro-inflammatory cytokines, respectively, and activating the anti-oxidant defence system. The anti-arthritic activity of turmeric exceeded that of ginger and indomethacin (a non-steroidal anti-inflammatory drug), especially when the treatment started from the day of arthritis induction. The percentage of disease recovery was 4.6-8.3% and 10.2% more in turmeric compared with ginger and indomethacin (P < 0.05), respectively. The present study proves the anti-inflammatory/anti-oxidant activity of turmeric over ginger and indomethacin, which may have beneficial effects against rheumatoid arthritis onset/progression as shown in AIA rat model.

Steroid hormone induction of temporal gene expression in Drosophila brain neuroblasts generates neuronal and glial diversity

PubMed Central

Syed, Mubarak Hussain; Mark, Brandon; Doe, Chris Q

2017-01-01

An important question in neuroscience is how stem cells generate neuronal diversity. During Drosophila embryonic development, neural stem cells (neuroblasts) sequentially express transcription factors that generate neuronal diversity; regulation of the embryonic temporal transcription factor cascade is lineage-intrinsic. In contrast, larval neuroblasts generate longer ~50 division lineages, and currently only one mid-larval molecular transition is known: Chinmo/Imp/Lin-28+ neuroblasts transition to Syncrip+ neuroblasts. Here we show that the hormone ecdysone is required to down-regulate Chinmo/Imp and activate Syncrip, plus two late neuroblast factors, Broad and E93. We show that Seven-up triggers Chinmo/Imp to Syncrip/Broad/E93 transition by inducing expression of the Ecdysone receptor in mid-larval neuroblasts, rendering them competent to respond to the systemic hormone ecdysone. Importantly, late temporal gene expression is essential for proper neuronal and glial cell type specification. This is the first example of hormonal regulation of temporal factor expression in Drosophila embryonic or larval neural progenitors. DOI: http://dx.doi.org/10.7554/eLife.26287.001 PMID:28394252

Computational analysis of liquid chromatography-tandem mass spectrometric steroid profiling in NCI H295R cells following angiotensin II, forskolin and abiraterone treatment.

PubMed

Mangelis, Anastasios; Dieterich, Peter; Peitzsch, Mirko; Richter, Susan; Jühlen, Ramona; Hübner, Angela; Willenberg, Holger S; Deussen, Andreas; Lenders, Jacques W M; Eisenhofer, Graeme

2016-01-01

Adrenal steroid hormones, which regulate a plethora of physiological functions, are produced via tightly controlled pathways. Investigations of these pathways, based on experimental data, can be facilitated by computational modeling for calculations of metabolic rate alterations. We therefore used a model system, based on mass balance and mass reaction equations, to kinetically evaluate adrenal steroidogenesis in human adrenal cortex-derived NCI H295R cells. For this purpose a panel of 10 steroids was measured by liquid chromatographic-tandem mass spectrometry. Time-dependent changes in cell incubate concentrations of steroids - including cortisol, aldosterone, dehydroepiandrosterone and their precursors - were measured after incubation with angiotensin II, forskolin and abiraterone. Model parameters were estimated based on experimental data using weighted least square fitting. Time-dependent angiotensin II- and forskolin-induced changes were observed for incubate concentrations of precursor steroids with peaks that preceded maximal increases in aldosterone and cortisol. Inhibition of 17-alpha-hydroxylase/17,20-lyase with abiraterone resulted in increases in upstream precursor steroids and decreases in downstream products. Derived model parameters, including rate constants of enzymatic processes, appropriately quantified observed and expected changes in metabolic pathways at multiple conversion steps. Our data demonstrate limitations of single time point measurements and the importance of assessing pathway dynamics in studies of adrenal cortical cell line steroidogenesis. Our analysis provides a framework for evaluation of steroidogenesis in adrenal cortical cell culture systems and demonstrates that computational modeling-derived estimates of kinetic parameters are an effective tool for describing perturbations in associated metabolic pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

The benefits of steroids versus steroids plus antivirals for treatment of Bell’s palsy: a meta-analysis

PubMed Central

Quant, Eudocia C; Jeste, Shafali S; Muni, Rajeev H; Cape, Alison V; Bhussar, Manveen K

2009-01-01

Objective To determine whether steroids plus antivirals provide a better degree of facial muscle recovery in patients with Bell’s palsy than steroids alone. Design Meta-analysis. Data sources PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies published in all languages from 1984 to January 2009. Additional studies were identified from cited references. Selection criteria Randomised controlled trials that compared steroids with the combination of steroids and antivirals for the treatment of Bell’s palsy were included in this study. At least one month of follow-up and a primary end point of at least partial facial muscle recovery, as defined by a House-Brackmann grade of at least 2 (complete palsy is designated a grade of 6) or an equivalent score on an alternative recognised scoring system, were required. Review methods Two authors independently reviewed studies for methodological quality, treatment regimens, duration of symptoms before treatment, length of follow-up, and outcomes. Odds ratios with 95% confidence intervals were calculated and pooled using a random effects model. Results Six trials were included, a total of 1145 patients; 574 patients received steroids alone and 571 patients received steroids and antivirals. The pooled odds ratio for facial muscle recovery showed no benefit of steroids plus antivirals compared with steroids alone (odds ratio 1.50, 95% confidence interval 0.83 to 2.69; P=0.18). A one study removed analysis showed that the highest quality studies had the greatest effect on the lack of difference between study arms shown by the odds ratio. Subgroup analyses assessing causes of heterogeneity defined a priori (time from symptom onset to treatment, length of follow-up, and type of antiviral studied) showed no benefit of antivirals in addition to that provided by steroids. Conclusions Antivirals did not provide an added benefit in achieving at least partial facial muscle recovery compared with steroids alone in patients with Bell’s palsy. This study does not, therefore, support the routine use of antivirals in Bell’s palsy. Future studies should use improved herpes virus diagnostics and newer antivirals to assess whether combination therapy benefits patients with more severe facial paralysis at study entry. PMID:19736282

Mammalian follicular development and atresia: role of apoptosis.

PubMed

Asselin, E; Xiao, C W; Wang, Y F; Tsang, B K

2000-01-01

The regulation of follicular development and atresia is a complex process and involves interactions between endocrine factors (gonadotropins) and intraovarian regulators (sex steroids, growth factors and cytokines) in the control of follicular cell fate (i.e. proliferation, differentiation and programmed cell death). Granulosa and theca cells are key players in this fascinating process. As atresia is the fate of most follicles, understanding of how these physiological regulators participate in determining the destiny of the follicle (to degenerate or to ovulate) at cellular and subcellular levels is fundamental. This short review summarizes the role of intraovarian modulators of programmed cell death in the induction of atresia during follicular development. Copyright 2000 S. Karger AG, Basel

Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme.

PubMed Central

Masferrer, J L; Seibert, K; Zweifel, B; Needleman, P

1992-01-01

The effect of endogenous glucocorticoids on the expression of the cyclooxygenase enzyme was studied by contrasting cyclooxygenase expression and prostanoid synthesis in adrenalectomized and sham-adrenalectomized mice with or without the concurrent administration of endotoxin. Peritoneal macrophages obtained from adrenalectomized mice showed a 2- to 3-fold induction in cyclooxygenase synthesis and activity when compared to sham controls. Intravenous injection of a sublethal dose of endotoxin (5 micrograms/kg) further stimulated cyclooxygenase synthesis, resulting in a 4-fold increase in prostaglandin production. Similar cyclooxygenase induction can be achieved in macrophages obtained from normal mice but only after high doses of endotoxin (2.5 mg/kg) that are 100% lethal to adrenalectomized mice. Restoration of glucocorticoids in adrenalectomized animals with dexamethasone completely inhibited the elevated cyclooxygenase and protected these animals from endotoxin-induced death. In contrast, no signs of cyclooxygenase induction were observed in the kidneys of the adrenalectomized mice, even when treated with endotoxin. Dexamethasone did not affect the constitutive cyclooxygenase activity and prostaglandin production present in normal and adrenalectomized kidneys. These data indicate the existence of a constitutive cyclooxygenase that is normally present in most cells and tissues and is unaffected by steroids and of an inducible cyclooxygenase that is expressed only in the context of inflammation by proinflammatory cells, like macrophages, and that is under glucocorticoid regulation. Under normal physiological conditions glucocorticoids maintain tonic inhibition of inducible cyclooxygenase expression. Depletion of glucocorticoids or the presence of an inflammatory stimulus such as endotoxin causes rapid induction of this enzyme, resulting in an exacerbated inflammatory response that is often lethal. Images PMID:1570314

Epigenetic control of vasopressin expression is maintained by steroid hormones in the adult male rat brain

PubMed Central

Auger, Catherine J.; Coss, Dylan; Auger, Anthony P.; Forbes-Lorman, Robin M.

2011-01-01

Although some DNA methylation patterns are altered by steroid hormone exposure in the developing brain, less is known about how changes in steroid hormone levels influence DNA methylation patterns in the adult brain. Steroid hormones act in the adult brain to regulate gene expression. Specifically, the expression of the socially relevant peptide vasopressin (AVP) within the bed nucleus of the stria terminalis (BST) of adult brain is dependent upon testosterone exposure. Castration dramatically reduces and testosterone replacement restores AVP expression within the BST. As decreases in mRNA expression are associated with increases in DNA promoter methylation, we explored the hypothesis that AVP expression in the adult brain is maintained through sustained epigenetic modifications of the AVP gene promoter. We find that castration of adult male rats resulted in decreased AVP mRNA expression and increased methylation of specific CpG sites within the AVP promoter in the BST. Similarly, castration significantly increased estrogen receptor α (ERα) mRNA expression and decreased ERα promoter methylation within the BST. These changes were prevented by testosterone replacement. This suggests that the DNA promoter methylation status of some steroid responsive genes in the adult brain is actively maintained by the presence of circulating steroid hormones. The maintenance of methylated or demethylated states of some genes in the adult brain by the presence of steroid hormones may play a role in the homeostatic regulation of behaviorally relevant systems. PMID:21368111

Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension

PubMed Central

Roghair, Robert D.; Segar, Jeffrey L.; Sharma, Ram V.; Zimmerman, Matthew C.; Jagadeesha, D. K.; Segar, Emily M.; Scholz, Thomas D.; Lamb, Fred S.

2009-01-01

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces organ-specific alterations in postnatal cardiovascular physiology. To determine whether early gestation corticosteroid exposure alters coronary reactivity before the development of systemic hypertension, dexamethasone (0.28 mg·kg−1 · day−1) was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term, 145 days). Vascular responsiveness was assessed in endothelium-intact coronary arteries isolated from 1-wk-old steroid-exposed and age-matched control lambs (N = 6). Calcium imaging was performed in fura 2-loaded primary cultures of vascular smooth muscle cells (VSMC) from the harvested coronary arteries. Early gestation steroid exposure did not significantly alter mean arterial blood pressure or coronary reactivity to KCl, thromboxane A2 mimetic U-46619, or ANG II. Steroid exposure significantly increased coronary artery vasoconstriction to acetylcholine and endothelin-1. Vasodilatation to adenosine, but not nitroprusside or forskolin, was significantly attenuated following early gestation steroid exposure. Endothelin-1 or U-46619 stimulation resulted in a comparable increase in intracellular calcium concentration ([Ca2+]i) in coronary VSMC isolated from either dexamethasone-treated or control animals. However, the ANG II- or KCl-mediated increase in [Ca2+]i in control VSMC was significantly attenuated in VSMC harvested from dexamethasone-treated lambs. Coronary expression of muscle voltage-gated l-type calcium channel α-1 subunit protein was not significantly altered by steroid exposure, whereas endothelial nitric oxide synthase expression was attenuated. These findings demonstrate that early gestation glucocorticoid exposure elicits primary alterations in coronary responsiveness before the development of systemic hypertension. Glucocorticoid-induced alterations in coronary physiology may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease. PMID:15961529

Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications

PubMed Central

Moravek, Molly B.; Yin, Ping; Ono, Masanori; Coon V, John S.; Dyson, Matthew T.; Navarro, Antonia; Marsh, Erica E.; Chakravarti, Debabrata; Kim, J. Julie; Wei, Jian-Jun; Bulun, Serdar E.

2015-01-01

BACKGROUND Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention. METHODS A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript. RESULTS Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem-progenitor cell properties, and was found to be essential for ovarian steroid-dependent growth of leiomyomas. Interestingly, these stem-progenitor cells were deficient in ERα and PR and instead relied on the strikingly higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone action via paracrine signaling. CONCLUSIONS It has been well established that estrogen and progesterone are involved in the proliferation and maintenance of uterine leiomyoma, and the majority of medical treatments currently available for leiomyoma work by inhibiting steroid hormone production or action. A pitfall of these therapeutics is that they decrease leiomyoma size, but do not completely eradicate them, and tumors tend to regrow once treatment is stopped. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma has the potential to provide the missing link between developing therapeutics that temper leiomyoma growth and those that eradicate them. PMID:25205766

The endocrine system controlling sexual reproduction in animals: Part of the evolutionary ancient but well conserved immune system?

PubMed

De Loof, Arnold; Schoofs, Liliane; Huybrechts, Roger

2016-01-15

Drastic changes in hormone titers, in particular of steroid hormones, are intuitively interpreted as necessary and beneficial for optimal functioning of animals. Peaks in progesterone- and estradiol titers that accompany the estrus cycle in female vertebrates as well as in ecdysteroids at each molt and during metamorphosis of holometabolous insects are prominent examples. A recent analysis of insect metamorphosis yielded the view that, in general, a sharp rise in sex steroid hormone titer signals that somewhere in the body some tissue(s) is undergoing programmed cell death/apoptosis. Increased steroid production is part of this process. Typical examples are ovarian follicle cells in female vertebrates and invertebrates and the prothoracic gland cells, the main production site of ecdysteroids in larval insects. A duality emerges: programmed cell death-apoptosis is deleterious at the cellular level, but it may yield beneficial effects at the organismal level. Reconciling both opposites requires reevaluating the probable evolutionary origin and role of peptidic brain hormones that direct steroid hormone synthesis. Do e.g. Luteinizing Hormone in vertebrates and Prothoracicotropic Hormone (PTTH: acting through the Torso receptor) in insects still retain an ancient role as toxins in the early immune system? Does the functional link of some neuropeptides with Ca(2+)-induced apoptosis make sense in endocrine archeology? The endocrine system as a remnant of the ancient immune system is undoubtedly counterintuitive. Yet, we will argue that such paradigm enables the logical framing of many aspects, the endocrine one inclusive of both male and female reproductive physiology. Copyright © 2015 Elsevier Inc. All rights reserved.

A thermographic and clinical comparison of three intra-articular steroid preparations in rheumatoid arthritis.

PubMed Central

Bird, H A; Ring, E F; Bacon, P A

1979-01-01

We have compared three intra-articular steroid preparations in a double blind study on 30 patients with rheumatoid arthritis and bilateral synovitis of the knees. One knee was injected with 1.0 ml of either prednisolone t-butyl acetate, methyl prednisolone acetate, or triamcinolone hexacetonide, and the patients were followed up for 6 weeks with regular clinical and thermographic assessments. Thermographic improvement was seen with all 3 drugs but was greatest initially and longest lasting with triamcinolone. No significant systemic improvement was seen with any drug after a single injection, though all 3 steroid preparations suppressed endogenous cortisol. PMID:373651

Underutilization of gastroprotective drugs in patients receiving non-steroidal anti-inflammatory drugs.

PubMed

Thiéfin, Gérard; Schwalm, Marie-Sophie

2011-03-01

To assess the prevalence of gastroprotective agent prescription in patients treated with non-steroidal anti-inflammatory drugs in France and to analyze the determinants of this prescription. A cross-sectional observational study was performed in 2576 patients treated with non-steroidal anti-inflammatory drugs recruited prospectively in the French primary care system. Thirty-nine percent of the patients (n=1002) received gastroprotective agents, mostly proton pump inhibitors (99.5%). In patients with a single risk factor, the gastroprotection rates were: 50% for age>65, 67% for concurrent use of corticosteroids or antithrombotics, and 87% and 100% for history of uncomplicated and complicated gastroduodenal ulcers. In patients without risk factors, gastroprotective agents were prescribed in 31.8%. Among them, two thirds had symptoms of gastro-oesophageal reflux or history of non-steroidal anti-inflammatory drug intolerance or dyspepsia. Conversely, 40% (n=256) of at-risk non-steroidal anti-inflammatory drug users did not receive gastroprotective agents. Gastroprotection was significantly associated with history of gastroduodenal ulcer (OR: 8.2; 95%CI: 4.3-15.6) or history of non-steroidal anti-inflammatory drug intolerance (OR: 6; 95%CI: 4.5-8.1), gastro-oesophageal reflux (OR: 6; 95%CI: 4.4-8.2), dyspepsia (OR: 5.2; 95%CI: 3.7-7.5), concurrent gastrotoxic treatment (OR: 3.3; 95%CI: 1.9-5.6) and age>65 (OR: 3; 95%CI: 2.3-4.1). Despite widespread recommendations, gastroprotection is still largely underprescribed in patients at risk of gastrointestinal non-steroidal anti-inflammatory drug complications in France. Only half of non-steroidal anti-inflammatory drug users above 65 years are prescribed gastroprotective agents. Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Use of a Risk-Stratification Tool in Identification of Potential Adrenal Suppression Preceding Steroid Injection Therapy in Chronic Pain Patients.

PubMed

Goel, Aneesh Paul; Nguyen, Vu Huy; Hamill-Ruth, Robin

2015-12-01

Patients who present for steroid injections are not routinely screened for potential hypothalamic-pituitary-adrenal (HPA) axis suppression from previous steroid exposure. Patients often receive various steroid therapies that are not reported by the patient or recorded in available medical records. Yet, HPA axis suppression has been reported with a single intra-articular injection. An IRB-approved quality improvement questionnaire was implemented to comprehensively screen patients for risk of HPA axis suppression secondary to prior and/or concurrent corticosteroid use. This questionnaire was given to adult patients seen in a University Pain Management Clinic, who were being considered for a steroid injection, to define the extent of exposure to corticosteroids either by mouth, topically, inhaled, or systemic/local injection within the past 6 months. Two hundred patients completed the questionnaire. Eighty-nine patients (44.5%) screened positive for significant steroid exposure with a screen score of three or above. The average score for the screen positive group was 6.31 ± 3.47 (range 3-22). Women were 1.9 times more likely to screen positive than men (53.4% vs 27.5%, P < 0.0004). Otherwise, the screen positive and screen negative groups were similar in demographic characteristics (age, BMI, and diabetes status). Our results suggest that patients receive steroids from many sources and may be at risk for HPA axis suppression. Further testing is necessary to determine if these patients indeed have biochemical evidence of adrenal suppression. Utilization of a screening questionnaire might help identify patients who should be considered for HPA axis testing prior to steroid injections. Wiley Periodicals, Inc.

Wired on steroids: sexual differentiation of the brain and its role in the expression of sexual partner preferences.

PubMed

Alexander, Brenda M; Skinner, Donal C; Roselli, Charles E

2011-01-01

The preference to seek out a sexual partner of the opposite sex is robust and ensures reproduction and survival of the species. Development of female-directed partner preference in the male is dependent on exposure of the developing brain to gonadal steroids synthesized during critical periods of sexual differentiation of the central nervous system. In the absence of androgen exposure, a male-directed partner preference develops. The development and expression of sexual partner preference has been extensively studied in rat, ferret, and sheep model systems. From these models it is clear that gonadal testosterone, often through estrogenic metabolites, cause both masculinization and defeminization of behavior during critical periods of brain development. Changes in the steroid environment during these critical periods result in atypical sexual partner preference. In this manuscript, we review the major findings which support the hypothesis that the organizational actions of sex steroids are responsible for sexual differentiation of sexual partner preferences in select non-human species. We also explore how this information has helped to frame our understanding of the biological influences on human sexual orientation and gender identity.

Wired on Steroids: Sexual Differentiation of the Brain and Its Role in the Expression of Sexual Partner Preferences

PubMed Central

Alexander, Brenda M.; Skinner, Donal C.; Roselli, Charles E.

2011-01-01

The preference to seek out a sexual partner of the opposite sex is robust and ensures reproduction and survival of the species. Development of female-directed partner preference in the male is dependent on exposure of the developing brain to gonadal steroids synthesized during critical periods of sexual differentiation of the central nervous system. In the absence of androgen exposure, a male-directed partner preference develops. The development and expression of sexual partner preference has been extensively studied in rat, ferret, and sheep model systems. From these models it is clear that gonadal testosterone, often through estrogenic metabolites, cause both masculinization and defeminization of behavior during critical periods of brain development. Changes in the steroid environment during these critical periods result in atypical sexual partner preference. In this manuscript, we review the major findings which support the hypothesis that the organizational actions of sex steroids are responsible for sexual differentiation of sexual partner preferences in select non-human species. We also explore how this information has helped to frame our understanding of the biological influences on human sexual orientation and gender identity. PMID:22654808

Inhibition of phorbol ester-induced tumor promotion in mice by vitamin A analog and anti-inflammatory steroid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weeks, C.E.; Slaga, T.J.; Hennings, H.

1979-08-01

The effects of a vitamin A analog, TMMP ethyl retinoate (abbreviated Ro 10-9359), and an anti-inflammatory steroid, fluocinoione acetonide (abbreviated FA), given alone or together were studied in a two-stage carcinogenesis system. the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used as the tumor promoter in a DMBA-initiated mouse skin system. Two stocks of female mice, which differ in their degrees of sensitivity to skin carcinogenesis, were used. A dose-dependent inhibition of carcinogenic expression, as determined by a decreased number of papillomas per animal, was observed in each mouse stock with the use of both FA and Ro 10-9359 were given alone.more » When FA and RO 10-9359 were given together, an enhanced effect on the lowering of tumor incidence was noted. FA effectively inhibited tumor formation in the sensitive mouse stock even when the steroid was given 1 day prior to TPA treatment under conditions of unusually high doses of initiator (DMBA) and/or promoter (TPA). These results suggest that both anti-inflammatory steroids and retinoids inhibit tumor promotion and can be effectively used as a combination regimen for increased chemopreventive response.« less

Induction of human macrophage vascular endothelial growth factor and intercellular adhesion molecule-1 by Ureaplasma urealyticum and downregulation by steroids.

PubMed

Li, Ying-Hua; Brauner, Annelie; Jensen, Jørgen Skov; Tullus, Kjell

2002-01-01

Chronic lung disease (CLD) remains a major cause of morbidity for the prematurely born infant. The pathogenesis of CLD is complex and has not been defined entirely. Infection and lung inflammatory events have been thought to play a key role in the development of CLD. However, the contribution of Ureaplasma urealyticum to the development of CLD is debated and steroids produce some improvement in neonates with this disease. The aim of this study was to investigate if U. urealyticum could stimulate macrophages to produce vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) in vitro, which are potentially associated with both early and later pathological changes in the lung during the development of CLD. In addition, the impact of dexamethasone and budesonide on these processes was examined. We found that U. urealyticum antigen (>/=4 x 10(7) color-changing units/ml) stimulated human macrophages (phorbol 12-myristate 13-acetate-differentiated THP-1 cell line) to produce VEGF and soluble ICAM-1 in a dose-dependent manner (p < 0.05) measured by ELISA. Likewise, cell surface ICAM-1 (CD54) measured by flow cytometry was increased after stimulation with U. urealyticum. This effect was attenuated by budesonide and dexamethasone (p < 0.05). The mRNA expressions of VEGF and ICAM-1 detected by a semi-quantitative reverse transcriptase polymerase chain reaction were also induced in response to U. urealyticum and inhibited by the steroids (p < 0.05). The expression of ICAM-1 was reduced by 85.5% when the TNF-alpha production was neutralized with an anti-TNF-alpha antibody. Our findings imply that U. urealyticum might be involved in the development of CLD of prematurity. Copyright 2002 S. Karger AG, Basel

Enhanced glucocorticoid-induced leucine zipper in dendritic cells induces allergen-specific regulatory CD4(+) T-cells in respiratory allergies.

PubMed

Karaki, S; Garcia, G; Tcherakian, C; Capel, F; Tran, T; Pallardy, M; Humbert, M; Emilie, D; Godot, V

2014-05-01

Respiratory allergies rely on a defect of IL-10-secreting regulatory CD4(+) T-cells (IL-10-Tregs ) leading to excessive Th2-biased immune responses to allergens. According to clinical data, the restoration of allergen-specific IL-10-Tregs is required to control respiratory allergies and cure patients. The discovery of mechanisms involved in the generation of IL-10-Tregs will thus help to provide effective treatments. We previously demonstrated that dendritic cells (DCs) expressing high levels of the glucocorticoid-induced leucine zipper protein (GILZ) generate antigen-specific IL-10-Tregs . We suspect a defective expression of GILZ in the DCs of respiratory allergic patients and speculate that increasing its expression might restore immune tolerance against allergens through the induction of IL-10-Tregs . We assessed GILZ expression in blood DCs of patients and healthy nonallergic donors by qPCR. We compared the ability of patients' DCs to induce allergen-specific IL-10-Tregs before and after an in vivo up-regulation of GILZ expression by steroid administration, steroids being inducers of GILZ. We report lower levels of GILZ in DCs of respiratory allergic patients that return to normal levels after steroid administration. We show that patients' DCs with increased levels of GILZ generate allergen-specific IL-10-Tregs again. We further confirm unequivocally that GILZ is required in patients' DCs to activate these IL-10-Tregs . This proof of concept study shows that the re-establishment of GILZ expression in patients' DCs to normal levels restores their capacity to activate allergen-specific IL-10-Tregs . We thus highlight the up-regulation of GILZ in DCs as a new interventional approach to restore the immune tolerance to allergens. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The effect of sugammadex on steroid hormones: A randomized clinical study.

PubMed

Gunduz Gul, Gulay; Ozer, Ayse B; Demirel, Ismail; Aksu, Ahmet; Erhan, Omer L

2016-11-01

Sugammadex is an alternative drug to traditional decurarization by cholinesterase inhibitors. It has been examined the effect of sugammadex on steroid hormones in this study. Randomized clinical trial. The study was conducted in a University Teaching Hospital from January 2013 to May 2014. Fifty male patients between 18 and 45years of age with an American Society of Anesthesiology (ASA) class I or II undergoing elective lower extremity surgery were included in this study. Patients were categorized into two groups (neostigmin group, Group N; and sugammadex group, Group S). In addition to standard monitorization, train-of-four (TOF) was also used to monitorize the level of neuromuscular blockade. Standard induction and maintenance of anesthesia were performed. At the termination of surgery, neuromuscular blockade was antagonized using 0.05mg/kg of neostigmine and 0.01mg/kg of atropin when spontaneous recovery of neuromuscular blockade occurred with the reappearance of T2 in Group N and using 4mg/kg sugammadex in Group S. The primary outcome in this study was to determine serum aldosterone, cortisol, progesterone, and free testosterone levels. Three blood samples were obtained in each patient just before and 15minutes and 4hours after antagonism, No significant differences were found in demographic characteristics between the groups. While there were no differences in serum progesterone levels, patients in neostigmin group had significantly higher cortisol levels at 15minutes as compared to baseline. Also, patients in sugammadex group had significantly higher serum aldosterone and testosterone levels 15minutes after antagonism as compared to those in the neostigmine group. Our findings suggest that sugammadex is not associated with adverse effects on steroid hormones progesterone and cortisol, while it may lead to a temporary increase in aldosterone and testosterone. Copyright © 2016 Elsevier Inc. All rights reserved.

Ouabain interactions with the α4 isoform of the sodium pump trigger non-classical steroid hormone signaling and integrin expression in spermatogenic cells.

PubMed

Upmanyu, Neha; Dietze, Raimund; Kirch, Ulrike; Scheiner-Bobis, Georgios

2016-11-01

In addition to the ubiquitous α1 isoform of the sodium pump, sperm cells also express a male-specific α4 isoform whose function has been associated with sperm motility, fertility, and capacitation. Here we investigate in the murine spermatogenic cell line GC-2 interactions of the α4 isoform with the cardiotonic steroid ouabain in signaling cascades involved in the non-classical action of steroid hormones. Exposure of GC-2 cells to low concentrations of ouabain stimulates the phosphorylation of Erk1/2 and of the transcription factors CREB and ATF-1. As a consequence of this signaling cascade, ouabain stimulates on the mRNA level the expression of integrins αv, β3 and α5, whose expression is also modulated by the cAMP response element. Increased expression of integrins αv and β3 is also seen in cultures of seminiferous tubules exposed to 10nM ouabain. At the protein level we observed a significant stimulation of β3 integrin expression by ouabain. Abrogation of α4 isoform expression by siRNA leads to the complete suppression of all ouabain-induced signaling mentioned above, including its stimulatory effect on the expression of β3 integrin. The results presented here demonstrate for the first time the induction of signaling cascades through the interaction of ouabain with the α4 isoform in a germ-cell derived cell line. The novel finding that these interactions lead to increased expression of integrins in GC-2 cells and the confirmation of these results in the ex vivo experiments indicate that hormone/receptor-like interactions of ouabain with the α4 isoform might be of significance for male physiology. Copyright © 2016 Elsevier B.V. All rights reserved.

Is there a benefit from the concomitant use of immunosupression with anti-TNF in Crohn's disease; heads or tails?

PubMed

Lakatos, Peter Laszlo

2009-09-01

Over the last some years the increasing knowledge on the pathogenesis of Crohn's disease led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, first of all TNF-alpha and its receptors. Infliximab, adalimumab and certolizumab have been successful in inducing and maintaining remission in Crohn's disease at both short and long term. This was recently confirmed by a Cochrane meta-analysis and also open label extension follow-up and cohort studies. Emerging new data however indicate that combination therapy with infliximab-azathioprine appears to have added benefit in inducing steroid-free remission and mucosal healing than either infliximab or azathioprine alone in azathioprine-naïve patients with early disease. Similarly the combination of steroids induction and infliximab was efficacious in luminal Crohn's disease. In contrast, there seems to be no synergism between methotrexate and infliximab. It is also less clear whether it is beneficial to use short or long-term infliximab-azathioprine combination in patients who previously failed therapy with azathioprine. In contrast, combination may potentially be associated with increased risk for infection and cancer. In case control-studies, especially the combination of steroids and anti-TNF and older age increased the risk for infectious complications, while scattered case reports point to the potentially increased risk of a rare form of non-Hodgkin's lymphoma (Hepatosplenic T cell lymphoma) with the use of azathioprine-anti-TNF combination. The aim of this review is to summarize the benefits and risks for the use combination therapy with TNF-alpha inhibitors in the treatment of Crohn's disease.

Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice*

PubMed Central

Lei, Wei; Feng, Xu-Hui; Deng, Wen-Bo; Ni, Hua; Zhang, Zhi-Rong; Jia, Bo; Yang, Xin-Ling; Wang, Tong-Song; Liu, Ji-Long; Su, Ren-Wei; Liang, Xiao-Huan; Qi, Qian-Rong; Yang, Zeng-Ming

2012-01-01

Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus. PMID:22403396

Steroids induce acetylcholine receptors on cultured human muscle: Implications for myasthenia gravis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaplan, I.; Blakely, B.T.; Pavlath, G.K.

1990-10-01

Antibodies to the acetylcholine receptor (AChR), which are diagnostic of the human autoimmune disease myasthenia gravis, block AChR function and increase the rate of AChR degradation leading to impaired neuromuscular transmission. Steroids are frequently used to alleviate symptoms of muscle fatigue and weakness in patients with myasthenia gravis because of their well-documented immunosuppressive effects. The authors show here that the steroid dexamethasone significantly increases total surface AChRs on cultured human muscle exposed to myasthenia gravis sera. The results suggest that the clinical improvement observed in myasthenic patients treated with steroids is due not only to an effect on the immunemore » system but also a direct effect on muscle. They propose that the identification and development of pharmacologic agents that augment receptors and other proteins that are reduced by human genetic or autoimmune disease will have broad therapeutic applications.« less

Sex steroids, immune system, and parasitic infections: facts and hypotheses.

PubMed

Nava-Castro, Karen; Hernández-Bello, Romel; Muñiz-Hernández, Saé; Camacho-Arroyo, Ignacio; Morales-Montor, Jorge

2012-07-01

It has been widely reported that the incidence and the severity of natural parasitic infections are different between males and females of several species, including humans. This sexual dimorphism involves a distinct exposure of males and females to various parasite infective stages, differential effects of sex steroids on immune cells, and direct effects of these steroids on parasites, among others. Typically, for a large number of parasitic diseases, the prevalence and intensity is higher in males than females; however, in several parasitic infections, males are more resistant than females. In the present work, we review the effects of sex hormones on immunity to protozoa and helminth parasites, which are the causal agents of several diseases in humans, and discuss the most recent research related to the role of sex steroids in the complex host-parasite relationship. © 2012 New York Academy of Sciences.

Frequency, predictors, and consequences of maintenance infliximab therapy intensification in ulcerative colitis.

PubMed

Fernández-Salazar, Luis; Barrio, Jesús; Muñoz, Fernando; Muñoz, Concepción; Pajares, Ramón; Rivero, Montserrat; Prieto, Vanesa; Legido, Jesús; Bouhmidi, Abdel; Herranz, Maite; González-Redondo, Guillermo; Fernández, Nereida; Santos, Fernando; Sánchez-Ocaña, Ramón; Joao, Diana

2015-09-01

Infliximab (IFX) therapy intensification in ulcerative colitis (UC) is more common than established in pivotal studies. To establish the frequency and form of intensification for UC in clinical practice, as well as predictors, and to compare outcomes between intensified and non-intensified treatment. A retrospective study of 10 hospitals and 144 patients with response to infliximab (IFX) induction. Predictive variables for intensification were analyzed using a Cox regression analysis. Outcome, loss of response to IFX, and colectomy were compared between intensified and non-intensified therapy. Follow-up time from induction to data collection: 38 months [interquartile range (IQR), 20-62]. Time on IFX therapy: 24 months (IQR, 10-44). In all, 37% of patients required intensification. Interval was shortened for 36 patients, dose was increased for 7, and 10 subjects received both. Concurrent thiopurine immunosuppressants (IMM) and IFX initiation was an independent predictor of intensification [Hazard ratio, 0.034; p, 0.006; CI, 0.003-0.371]. In patients on intensified therapy IFX discontinuation for loss of response (30.4% vs. 10.2%; p, 0.002), steroid reintroduction (35% vs. 18%; p, 0.018), and colectomy (22% vs. 6.4%; p, 0.011) were more common. Of patients on intensification, 17% returned to receiving 5 mg/kg every 8 weeks. Intensification is common and occasionally reversible. IMM initiation at the time of induction with IFX predictsnon-intensification. Intensification, while effective, is associated with poorer outcome.

Retropharyngeal Steroids and Dysphagia Following Multilevel Anterior Cervical Surgery.

PubMed

Koreckij, Theodore D; Davidson, Abigail A; Baker, Kevin C; Park, Daniel K

2016-05-01

A retrospective case-control study. The aim of this study was to determine the effect of retropharyngeal steroids on postoperative dysphagia scores and clinical outcomes following multilevel anterior cervical discectomy and fusion (ACDF). Dysphagia is a well-known complication following ACDF surgery and increased rates of dysphagia are seen with increased levels of surgery. Retropharyngeal steroids have been shown to decrease painful swallowing and prevertebral soft tissue (PSTS) swelling in 1- and 2-level anterior cervical surgery. A retrospective review of 44 patients undergoing multilevel (2-, 3-, 4-level) ACDF. Twenty-two patients who received retropharyngeal steroids (methylprednisone) placed on a collagen sponge at the time of surgery were compared with a matched cohort of controls who did not receive local steroids. Postoperative day 1 and 6-week radiographs were analyzed for differences in PSTS. Clinical outcomes were measured pre-operatively, 6 weeks, and 3 months postoperatively utilizing the Neck Disability Index (NDI), the Bazaz-Yoo Dysphagia Scoring System, and Eat Assessment Tool (EAT-10). Significant improvement in dysphagia scores were seen utilizing both outcome measures. Bazaz-Yoo scores were significantly better at both 6 weeks and 3 months in patients receiving local steroids compared with controls (P = 0.008 and P = 0.022, respectively). EAT-10 showed similar improvement of the steroid group versus control at 6 weeks and 3 months (P = 0.067 and P = 0.012, respectively). A trend toward decreased PSTS was found with locally delivered steroids on initial postoperative radiographs (P = 0.07), but was no longer evident at 6 weeks. NDI, although improved from pre-operative scores, failed to demonstrate significant differences between groups. No differences in length of stay or complications were observed between the groups. The use of retropharyngeal steroids resulted in decreased rates of dysphagia following multilevel ACDF. Locally delivered methylprednisone did not result in increased rates of short-term postoperative complications. 4.

Steroids in house sparrows (Passer domesticus): Effects of POPs and male quality signalling.

PubMed

Nossen, Ida; Ciesielski, Tomasz M; Dimmen, Malene V; Jensen, Henrik; Ringsby, Thor Harald; Polder, Anuschka; Rønning, Bernt; Jenssen, Bjørn M; Styrishave, Bjarne

2016-03-15

At high trophic levels, environmental contaminants have been found to affect endocrinological processes. Less attention has been paid to species at lower trophic levels. The house sparrow (Passer domesticus) may be a useful model for investigating effects of POPs in mid-range trophic level species. In male house sparrows, ornamental traits involved in male quality signalling are important for female selection. These traits are governed by endocrinological systems, and POPs may therefore interfere with male quality signalling. The aim of the present study was to use the house sparrow as a mid-range trophic level model species to study the effects of environmental contaminants on endocrinology and male quality signalling. We analysed the levels of selected PCBs, PBDEs and OCPs and investigated the possible effects of these contaminants on circulating levels of steroid hormones (4 progestagens, 4 androgens and 3 estrogens) in male and female adult house sparrows from a population on the island Leka, Norway. Plasma samples were analysed for steroid hormones by GC-MS and liver samples were analysed for environmental contaminants by GC-ECD and GC-MS. In males, we also quantified ornament traits. It was hypothesised that POPs may have endocrine disrupting effects on the local house sparrow population and can thus interfere with the steroid hormone homeostasis. Among female house sparrows, bivariate correlations revealed negative relationships between POPs and estrogens. Among male sparrows, positive relationships between dihydrotestosterone levels and PCBs were observed. In males, positive relationships were also found between steroids and beak length, and between steroids and ornamental traits such as total badge size. This was confirmed by a significant OPLS model between beak length and steroids. Although sparrows are in the mid-range trophic levels, the present study indicates that POPs may affect steroid homeostasis in house sparrows, in particular for females. For males, circulating steroid levels appears to be more associated with biometric parameters related to ornamental traits. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficacy and safety of certolizumab pegol induction therapy in an unselected Crohn's disease population: results of the FACTS survey.

PubMed

Schoepfer, Alain M; Vavricka, Stephan R; Binek, Janek; Felley, Christian; Geyer, Martin; Manz, Michael; Rogler, Gerhard; de Saussure, Philippe; Sauter, Bernhard; Seibold, Frank; Straumann, Alex; Michetti, Pierre

2010-06-01

Switzerland was the first country to approve certolizumab pegol (Cimzia, CZP) for the treatment of patients with moderate to severe Crohn's disease (CD) in September 2007. This phase IV study aimed to evaluate the efficacy and safety of CZP in a Swiss multicenter cohort of practice-based patients. Baseline and Week 6 evaluation questionnaires were sent to all Swiss gastroenterologists in hospitals and private practices. Disease activity was assessed with the Harvey-Bradshaw Index (HBI) and adverse events were evaluated according to WHO guidelines. Fifty patients (31 women, 19 men) were included; 56% had complicated disease (stricture or fistula) and 52% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 78% to infliximab, and 50% to adalimumab. A significant decrease in HBI was observed at Week 6 (versus Week 0) following induction therapy with CZP 400 mg subcutaneously at Weeks 0, 2, and 4 (12.6 +/- 4.7 Week 0 versus 6.2 +/- 4.4 Week 6, P < 0.001). Response and remission rates at Week 6 were 54% and 40%, respectively. We identified 8/11 CD patients undergoing a 50% fistula response (P = 0.021). The frequency of adverse drug reactions attributed to CZP was 6%. CZP was continued in 80% of patients beyond Week 6. In a population of CD patients with complicated disease behavior, CZP induced a response and remission in 54% and 40% of patients, respectively. This series provides the first evidence of the effectiveness of CZP in perianal fistulizing CD.

Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K/Akt/Nrf2-dependent pathway in human dopaminergic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, Yong Pil; College of Pharmacy, Chosun University, Gwangju; Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.k

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a popular traditional herbal medicine. Ginsenoside Rb1 (Rb1), an active component commonly found in ginseng root, is a phytoestrogen that exerts estrogen-like activity. In this study, we demonstrate that the phytoestrogen Rb1 inhibits 6-hydroxydopamine (6-OHDA)-induced oxidative injury via an ER-dependent Gbeta1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of SH-SY5Y cells with Rb1 significantly reduced 6-OHDA-induced caspase-3 activation and subsequent cell death. Rb1 also up-regulated HO-1 expression, which conferred cytoprotection against 6-OHDA-induced oxidative injury. Moreover, Rb1 induced both Nrf2 nuclear translocation,more » which is upstream of HO-1 expression and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Also, Rb1-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that Rb1 augments the cellular antioxidant defenses through ER-dependent HO-1 induction via the Gbeta1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress. Thus our study indicates that Rb1 has a partial cytoprotective role in dopaminergic cell culture systems.« less

Steroid Hormone Signaling Is Essential to Regulate Innate Immune Cells and Fight Bacterial Infection in Drosophila

PubMed Central

Regan, Jennifer C.; Brandão, Ana S.; Leitão, Alexandre B.; Mantas Dias, Ângela Raquel; Sucena, Élio; Jacinto, António; Zaidman-Rémy, Anna

2013-01-01

Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. Drosophila metamorphosis represents a striking example of drastic and systemic physiological changes that need to be integrated with the innate immune system. However, nothing is known about the mechanisms that coordinate development and immune cell activity in the transition from larva to adult. Here, we reveal that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. Although it is generally accepted that steroid hormones impact immunity in mammals, their action on monocytes (e.g. macrophages and neutrophils) is still not well understood. Here in a simpler model system, we used an approach that allows in vivo, cell autonomous analysis of hormonal regulation of innate immune cells, by combining genetic manipulation with flow cytometry, high-resolution time-lapse imaging and tissue-specific transcriptomic analysis. We show that in response to ecdysone, hemocytes rapidly upregulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic and local production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential for hemocyte immune functions and survival after infection. Microarray analysis of hemocytes revealed a large set of genes regulated at metamorphosis by EcR signaling, among which many are known to function in cell motility, cell shape or phagocytosis. This study demonstrates an important role for steroid hormone regulation of immunity in vivo in Drosophila, and paves the way for genetic dissection of the mechanisms at work behind steroid regulation of innate immune cells. PMID:24204269

The utility of ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) for clinically relevant steroid analysis.

PubMed

Storbeck, Karl-Heinz; Gilligan, Lorna; Jenkinson, Carl; Baranowski, Elizabeth S; Quanson, Jonathan L; Arlt, Wiebke; Taylor, Angela E

2018-05-15

Liquid chromatography tandem mass spectrometry (LC-MS/MS) assays are considered the reference standard for serum steroid hormone analyses, while full urinary steroid profiles are only achievable by gas chromatography (GC-MS). Both LC-MS/MS and GC-MS have well documented strengths and limitations. Recently, commercial ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) systems have been developed. These systems combine the resolution of GC with the high-throughput capabilities of UHPLC. Uptake of this new technology into research and clinical labs has been slow, possibly due to the perceived increase in complexity. Here we therefore present fundamental principles of UHPSFC-MS/MS and the likely applications for this technology in the clinical research setting, while commenting on potential hurdles based on our experience to date. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Reducing inappropriate non-steroidal anti-inflammatory prescription in primary care patients with chronic kidney disease.

PubMed

Keohane, David M; Dennehy, Thomas; Keohane, Kenneth P; Shanahan, Eamonn

2017-08-14

Purpose The purpose of this paper is to reduce inappropriate non-steroidal anti-inflammatory prescribing in primary care patients with chronic kidney disease (CKD). Once diagnosed, CKD management involves delaying progression to end stage renal failure and preventing complications. It is well established that non-steroidal anti-inflammatories have a negative effect on kidney function and consequently, all nephrology consensus groups suggest avoiding this drug class in CKD. Design/methodology/approach The sampling criteria included all practice patients with a known CKD risk factor. This group was refined to include those with an estimated glomerular filtration rate (eGFR)<60 ml/min per 1.73m2 (stage 3 CKD or greater). Phase one analysed how many prescriptions had occurred in this group over the preceding three months. The intervention involved creating an automated alert on at risk patient records if non-steroidal anti-inflammatories were prescribed and discussing the rationale with practice staff. The re-audit phase occurred three months' post intervention. Findings The study revealed 728/7,500 (9.7 per cent) patients at risk from CKD and 158 (2.1 per cent) who were subsequently found to have an eGFR<60 ml/min, indicating=stage 3 CKD. In phase one, 10.2 per cent of at risk patients had received a non-steroidal anti-inflammatory prescription in the preceding three months. Additionally, 6.2 per cent had received non-steroidal anti-inflammatories on repeat prescription. Phase two post intervention revealed a significant 75 per cent reduction in the total non-steroidal anti-inflammatories prescribed and a 90 per cent reduction in repeat non-steroidal anti-inflammatory prescriptions in those with CKD. Originality/value The study significantly reduced non-steroidal anti-inflammatory prescription in those with CKD in primary care settings. It also created a CKD register within the practice and an enduring medication alert system for individuals that risk nephrotoxic non-steroidal anti-inflammatory prescription. It established a safe, reliable and efficient process for reducing morbidity and mortality, improving quality of life and limiting the CKD associated health burden.

Spliceosome Protein (SRp) Regulation of Glucocorticoid Receptor Isoforms and Glucocorticoid Response in Human Trabecular Meshwork Cells

PubMed Central

Jain, Ankur; Wordinger, Robert J.; Yorio, Thomas; Clark, Abbot F.

2012-01-01

Purpose. Glaucoma is a leading cause of visual impairment and blindness, with elevated intraocular pressure (IOP) as a major causative risk factor. Glucocorticoid (GC) therapy causes morphologic and biochemical changes in the trabecular meshwork (TM), an ocular tissue involved in regulating IOP, which can lead to the development of glaucoma in susceptible individuals (steroid responders). Steroid responders comprise 40% of the general population and are at higher risk of developing glaucoma. In addition, a majority of glaucoma patients are steroid responders. Differential distribution of various isoforms of GC receptor (GR) may be responsible for this heterogeneity in the steroid response. The alternatively spliced GRβ isoform acts as dominant negative regulator of classical GRα transcriptional activity. mRNA splicing is mediated by spliceosomes, which include serine-arginine rich proteins (SRps). The purpose of this study was to determine whether specific SRps regulate levels of these isoforms and thereby GC response in TM cells. Methods. Quantitative RT-PCR, Western blot analysis, and immunocytochemistry were used to determine the differential expression of different SRps (SRp20, 30c, and 40) in human normal and glaucomatous TM cell strains. Bioinformatics was used to find putative binding sites for SRp20 and SRp40 on exon 9 of the GR gene. A peptide modulator of splicing (bombesin) and SRp expression vectors were used to modulate SRp levels and determine their effects on GRα/GRβ ratios as well as dexamethasone (DEX) responsiveness via GRE- luciferase reporter activity, fibronectin, and myocilin induction in TM cells. Results. SRp20, SRp30c, and SRp40 regulate GR splicing and the GC response in TM cells. Modulation of SRp levels altered the GRβ/α ratio that correlated with DEX responsiveness. Bombesin decreased SRp20; increased SRp30c, SRp40 levels, and GRβ/α ratio, and suppressed DEX response in TM cells. Conclusions. Relative levels of SRp20, SRp30c, and SRp40 in TM cells control differential expression of the two alternatively spliced isoforms of the GR and thereby regulate GC responsiveness. Different levels and/or activities of these SRps may account for differential GC sensitivity among the normal and glaucoma populations. PMID:22205602

Decreased Serum Vitamin D Levels in Children with Asthma are Associated with Increased Corticosteroid Usage

PubMed Central

Searing, Daniel A.; Zhang, Yong; Murphy, James R.; Hauk, Pia J.; Goleva, Elena; Leung, Donald Y. M.

2010-01-01

Background There is little knowledge about clinical variables associated with vitamin D (vitD) insufficiency in asthmatic children. Objective To investigate disease variables associated with vitD insufficiency in childhood asthma and interaction of vitD with corticosteroid-mediated anti-inflammatory responses. Methods We analyzed 25-hydroxyvitamin D serum levels in 100 asthmatic children to investigate relationships between 25-hydroxyvitamin D levels and patient characteristics. We determined vitD effects on dexamethasone (DEX) induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) and IL-10 in peripheral blood mononuclear cells (PBMC). Results The median 25-hydroxyvitamin D serum level was 31 ng/mL. 47% of subjects had vitD levels in the insufficient range (<30 ng/mL), while 17% were vitD deficient (<20 ng/mL). Log10 IgE (p=0.01, ρ=−0.25) and the number of positive aeroallergen skin prick tests (p=0.02, ρ=−0.23) showed a significant inverse correlation with vitD, whereas FEV1% predicted (p =0.004, ρ=0.34) and FEV1/FVC ratio (p=0.01, ρ=0.30) showed a significant positive correlation with vitD. The use of inhaled steroids (p=0.0475), oral steroids (p=0.02), and total steroid dose (p=0.001), all showed significant inverse correlations with vitD. The amount of MKP-1 and IL-10 mRNA induced by vitD plus DEX was significantly greater than that induced by DEX alone (p<0.01). In an experimental model of steroid resistance where DEX alone did not inhibit T cell proliferation, addition of vitD to DEX resulted in significant dose dependent suppression of cell proliferation. Conclusions Corticosteroid use and worsening airflow limitation is associated with lower vitD serum levels in asthmatics. VitD enhances glucocorticoid action in asthmatic PBMC and enhances the immunosuppressive function of DEX in vitro. Clinical Implications Our study suggests that vitD supplementation may potentiate anti-inflammatory function of corticosteroids in asthmatics and thereby improve asthma control. PMID:20381849

Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use.

PubMed

Searing, Daniel A; Zhang, Yong; Murphy, James R; Hauk, Pia J; Goleva, Elena; Leung, Donald Y M

2010-05-01

There is little knowledge about clinical variables associated with vitamin D (VitD) insufficiency in asthmatic children. We sought to investigate disease variables associated with VitD insufficiency in patients with childhood asthma and interaction of VitD with corticosteroid-mediated anti-inflammatory responses. We analyzed 25-hydroxyvitamin D serum levels in 100 asthmatic children to investigate relationships between 25-hydroxyvitamin D levels and patients' characteristics. We determined VitD's effects on dexamethasone (DEX) induction of mitogen-activated protein kinase phosphatase 1 and IL-10 in PBMCs. The median 25-hydroxyvitamin D serum level was 31 ng/mL. Forty-seven percent of subjects had VitD levels in the insufficient range (<30 ng/mL), whereas 17% were VitD deficient (<20 ng/mL). Log(10) IgE (P = .01, rho = -0.25) and the number of positive aeroallergen skin prick test responses (P = .02, rho = -0.23) showed a significant inverse correlation with VitD levels, whereas FEV(1) percent predicted (P = .004, rho = 0.34) and FEV(1)/forced vital capacity ratio (P = .01, rho = 0.30) showed a significant positive correlation with VitD levels. The use of inhaled steroids (P = .0475), use of oral steroids (P = .02), and total steroid dose (P = .001) all showed significant inverse correlations with VitD levels. The amount of mitogen-activated protein kinase phosphatase 1 and IL10 mRNA induced by VitD plus DEX was significantly greater than that induced by DEX alone (P < .01). In an experimental model of steroid resistance in which DEX alone did not inhibit T-cell proliferation, addition of VitD to DEX resulted in significant dose-dependent suppression of cell proliferation. Corticosteroid use and worsening airflow limitation are associated with lower VitD serum levels in asthmatic patients. VitD enhances glucocorticoid action in PBMCs from asthmatic patients and enhances the immunosuppressive function of DEX in vitro. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

EGR-1 and DUSP-1 are important negative regulators of pro-allergic responses in airway epithelium.

PubMed

Golebski, Korneliusz; van Egmond, Danielle; de Groot, Esther J; Roschmann, Kristina I L; Fokkens, Wytske J; van Drunen, Cornelis M

2015-05-01

Primary nasal epithelium of house dust mite allergic individuals is in a permanently activated inflammatory transcriptional state. To investigate whether a deregulated expression of EGR-1 and/or DUSP-1, two potential negative regulators of pro-inflammatory responses, could contribute to the activation of the inflammatory state. We silenced the expression of EGR-1 or DUSP-1 in the airway epithelial cell line NCI-H292. The cell lines were stimulated in a 24-h time course with the house dust mite allergen or poly(I:C). RNA expression profiles of cytokines were established using q-PCR and protein levels were determined in supernatants with ELISA. The shRNA-mediated gene silencing reduced expression levels of EGR-1 by 92% (p<0.0001) and of DUSP-1 by 76% (p<0.0001). Both mutant cells lines showed an increased and prolonged response to the HDM allergen. The mRNA induction of IL-6 was 4.6 fold (p=0.02) and 2.4 fold higher (p=0.01) in the EGR-1 and DUSP-1 knock-down, respectively when compared to the induced levels in the control cell line. For IL-8, the induction levels were 4.6 fold (p=0.01) and 13.0 (p=0.001) fold higher. The outcome was largely similar, yet not identical at the secreted protein levels. Furthermore, steroids were able to suppress the poly(I:C) induced cytokine levels by 70-95%. Deregulation of EGR-1 and/or DUSP-1 in nasal epithelium could be responsible for the prolonged activated transcriptional state observed in vivo in allergic disease. This could have clinical consequences as cytokine levels after the steroid treatment in EGR-1 or DUSP-1 knock-down remained higher than in the control cell line. Copyright © 2015 Elsevier Ltd. All rights reserved.

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response?

PubMed

D'Haens, Geert R; Panaccione, Remo; Higgins, Peter D R; Vermeire, Severine; Gassull, Miquel; Chowers, Yehuda; Hanauer, Stephen B; Herfarth, Hans; Hommes, Daan W; Kamm, Michael; Löfberg, Robert; Quary, A; Sands, Bruce; Sood, A; Watermeyer, G; Watermayer, G; Lashner, Bret; Lémann, Marc; Plevy, Scott; Reinisch, Walter; Schreiber, Stefan; Siegel, Corey; Targan, Stephen; Watanabe, M; Feagan, Brian; Sandborn, William J; Colombel, Jean Frédéric; Travis, Simon

2011-02-01

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

A PROSPECTIVE TRIAL OF TACROLIMUS (FK 506) IN CLINICAL HEART TRANSPLANTATION: INTERMEDIATE-TERM RESULTS

PubMed Central

Pham, Si M.; Kormos, Robert L.; Hattler, Brack G.; Kawai, Akihiko; Tsamandas, Athanassios C.; Demetris, Anthony J.; Murali, Srinivas; Fricker, Frederick J.; Chang, Huang C.; Jain, Ashosk B.; Starzl, Thomas E.; Hardesty, Robert L.; Griffith, Bartley P.

2010-01-01

Between January 1, 1989, and December 31, 1994, we have treated 122 primary heart recipients with FK 506 (group I) and 121 with cyclosporine (group II). Fifty patients in the cyclosporine (CyA) group received no lympholytic induction (CyA alone) and 71 others received lympholytic induction with either rabbit antithymocyte globulin or OKT3 (CyA + LI). The mean follow-up was longer in the FK 506 group than in the CyA groups (3.2 ± 1.3 vs 2.3 ± 1.8 years; p < 0.01). Patient survival did not differ on the basis of the type of immunosuppression used. At 3 months after transplantation, the freedom from rejection in the FK 506 group was higher than that of the CyA-alone group (47% vs 22%, p < 0.01) but similar to that of the CyA + LI group (47% vs 53%). The linearized rejection rate (episodes/100 patient-days) of the FK 506 group (0.09 episodes) was lower (p < 0.05) than that of the CyA-alone group (0.26) and the CyA + LI group (0.13). The requirement for pulsed steroids to treat rejection was less in common in the FK 506 group than in either CyA group. Eighteen patients in the CyA group had refractory rejections; all resolved with FK 506 rescue. Two patients in the FK 506 group had refractory rejection that resolved with total lymphoid irradiation (n = 1) and methotrexate therapy (n = 1). Patients receiving FK 506 had a lower risk of hypertension and required a lower dose of steroids. Although the mean serum creatinine concentration at 1 year was higher in the FK 506 group, this difference disappeared after 2 years. No patients required discontinuation of FK 506 because of its side effects. Our intermediate-term results indicate that FK 506 compares favorably with CyA as a primary immunosuppressant in heart transplantation. PMID:8614136

Progesterone protects normative anxiety-like responding among ovariectomized female mice that conditionally express the HIV-1 regulatory protein, Tat, in the CNS.

PubMed

Paris, Jason J; Fenwick, Jason; McLaughlin, Jay P

2014-05-01

Increased anxiety is co-morbid with human immunodeficiency virus (HIV) infection. Actions of the neurotoxic HIV-1 regulatory protein, Tat, may contribute to affective dysfunction. We hypothesized that Tat expression would increase anxiety-like behavior of female GT-tg bigenic mice that express HIV-1 Tat protein in the brain in a doxycycline-dependent manner. Furthermore, given reports that HIV-induced anxiety may occur at lower rates among women, and that the neurotoxic effects of Tat are ameliorated by sex steroids in vitro, we hypothesized that 17β-estradiol and/or progesterone would ameliorate Tat-induced anxiety-like effects. Among naturally-cycling proestrous and diestrous mice, Tat-induction via 7days of doxycycline treatment significantly increased anxiety-like responding in an open field, elevated plus maze and a marble-burying task, compared to treatment with saline. Proestrous mice demonstrated less anxiety-like behavior than diestrous mice in the open field and elevated plus maze, but these effects did not significantly interact with Tat-induction. Among ovariectomized mice, doxycycline-induced Tat protein significantly increased anxiety-like behavior in an elevated plus maze and a marble burying task compared to saline-treated mice, but not an open field (where anxiety-like responding was already maximal). Co-administration of progesterone (4mg/kg), but not 17β-estradiol (0.09mg/kg), with doxycycline significantly ameliorated anxiety-like responding in the elevated plus maze and marble burying tasks. When administered together, 17β-estradiol partially antagonized the protective effects of progesterone on Tat-induced anxiety-like behavior. These findings support evidence of steroid-protection over HIV-1 proteins, and extend them by demonstrating the protective capacity of progesterone on Tat-induced anxiety-like behavior of ovariectomized female mice. Copyright © 2014 Elsevier Inc. All rights reserved.

Progesterone treatment modulates mRNA OF neurosteroidogenic enzymes in a murine model of multiple sclerosis.

PubMed

Garay, Laura; Gonzalez Giqueaux, Paula; Guennoun, Rachida; Schumacher, Michael; Gonzalez Deniselle, Maria Claudia; De Nicola, Alejandro F

2017-01-01

Previous studies of experimental autoimmune encephalomyelitis (EAE) have shown that progesterone decreases inflammatory cell infiltration and proinflammatory factors, increases myelination and attenuates clinical grade of EAE mice. To elucidate potential mediators of these effects, we analyzed the mRNA expression of neurosteroidogenic enzymes in the spinal cord, in view of the protective role of steroids in EAE. We also analyzed mitochondrial morphology and dynamics (fusion and fission proteins), considering the role of mitochondria in neurosteroidogenesis. EAE was induced in C57Bl6 mice using MOG 40-54 and killed on day 16 after induction. Using qPCR, we found in steroid-untreated EAE mice decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), P450scc (cholesterol side-chain cleavage), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSD) and aromatase, whereas levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) showed a large intra-group variance. We also found increased mRNA expression of 18Kd translocator protein (TSPO), which likely resulted from the reactive microgliosis in this model. EAE mice also showed pathological mitochondrial morphology and reduced expression of fission and fusion protein mRNAs. Most importantly, pretreatment with progesterone a week before EAE induction increased Star,VDAC, P450scc, 5α-reductase type I, 3α-HSD and aromatase mRNAs and did not modify 3β-HSD. TSPO mRNA was decreased, consequent with the inhibition of microgliosis. Mitochondrial morphology was improved and fission/fusion protein mRNAs were enhanced by progesterone treatment. Furthermore, progesterone protective effects on mitochondrial and endoplasmic reticulum may allow the recovery of neurosteroidogenesis. In this way, endogenously synthesized neurosteroids may reinforce the beneficial effects of exogenous progesterone previously shown in MS mice. Copyright © 2016 Elsevier Ltd. All rights reserved.

Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.

PubMed

Giacobini, Paolo; Parkash, Jyoti; Campagne, Céline; Messina, Andrea; Casoni, Filippo; Vanacker, Charlotte; Langlet, Fanny; Hobo, Barbara; Cagnoni, Gabriella; Gallet, Sarah; Hanchate, Naresh Kumar; Mazur, Danièle; Taniguchi, Masahiko; Mazzone, Massimiliano; Verhaagen, Joost; Ciofi, Philippe; Bouret, Sébastien G; Tamagnone, Luca; Prevot, Vincent

2014-03-01

Neuropilin-1 (Nrp1) guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH), the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3aloxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction.

Music increase altruism through regulating the secretion of steroid hormones and peptides.

PubMed

Fukui, Hajime; Toyoshima, Kumiko

2014-12-01

Music is well known for its effect on human behavior especially of their bonding and empathy towards others. Music provokes one's emotion and activates mirror neurons and reward system. It also regulates social hormones such as steroid hormones or peptides, and increases empathy, pro-sociality and altruism. As a result, it improves one's reproductive success. Copyright © 2014 Elsevier Ltd. All rights reserved.

Immune mediated neuropathy following checkpoint immunotherapy.

PubMed

Gu, Yufan; Menzies, Alexander M; Long, Georgina V; Fernando, S L; Herkes, G

2017-11-01

Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy - induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Steroidal saponins from Tribulus terrestris.

PubMed

Kang, Li-Ping; Wu, Ke-Lei; Yu, He-Shui; Pang, Xu; Liu, Jie; Han, Li-Feng; Zhang, Jie; Zhao, Yang; Xiong, Cheng-Qi; Song, Xin-Bo; Liu, Chao; Cong, Yu-Wen; Ma, Bai-Ping

2014-11-01

Sixteen steroidal saponins, including seven previously unreported compounds, were isolated from Tribulus terrestris. The structures of the saponins were established using 1D and 2D NMR spectroscopy, mass spectrometry, and chemical methods. They were identified as: 26-O-β-d-glucopyranosyl-(25R)-furost-4-en-2α,3β,22α,26-tetrol-12-one (terrestrinin C), 26-O-β-d-glucopyranosyl-(25R)-furost-4-en-22α,26-diol-3,12-dione (terrestrinin D), 26-O-β-d-glucopyranosyl-(25S)-furost-4-en-22α,26-diol-3,6,12-trione (terrestrinin E), 26-O-β-d-glucopyranosyl-(25R)-5α-furostan-3β,22α,26-triol-12-one (terrestrinin F), 26-O-β-d-glucopyranosyl-(25R)-furost-4-en-12β,22α,26-triol-3-one (terrestrinin G), 26-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranosyl-(25R)-furost-4-en-22α,26-diol-3,12-dione (terrestrinin H), and 24-O-β-d-glucopyranosyl-(25S)-5α-spirostan-3β,24β-diol-12-one-3-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside (terrestrinin I). The isolated compounds were evaluated for their platelet aggregation activities. Three of the known saponins exhibited strong effects on the induction of platelet aggregation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Changes in serum sex steroid levels throughout the reproductive cycle of Bufo arenarum females.

PubMed

Medina, Marcela F; Ramos, Inés; Crespo, Claudia A; González-Calvar, Silvia; Fernández, Silvia N

2004-04-01

The changes in the serum levels of the sexual steroids estradiol-17beta (E(2)), testosterone (T), dihydrotestosterone (DHT), and progesterone (P) in Bufo arenarum females were determined by radioimmunoassay (RIA) during 3 consecutive cycles (1999-2001). The serum concentrations of T and DHT, which showed a close parallelism during the annual reproductive cycle, exhibited the highest levels during the preovulatory period, when oogenesis is advanced, while lowest serum levels of these hormones were found during the ovulatory period. The data obtained for E(2) showed a pattern contrary to that determined for androgens. The maximum E(2) concentrations detected in the early postovulatory period might be associated with vitellogenesis and follicular growth. Lowest E(2) concentrations were reached during the period in which B. arenarum undergoes its final hibernation stage. Serum P showed a peak during the preovulatoy period, related to the induction of nuclear maturation in full grown oocytes. A strong decrease in the levels of the circulating hormones was observed after ovariectomy. Our results showed that, out of the four hormones examined, T and DHT were the best indicators of ovarian and oviductal stage, as shown by the strong positive correlation found between androgen levels and organ weight, while E(2) showed a weak negative correlation with ovarian and oviductal weight.

Characterization of rat model of acute anterior uveitis using optical coherence tomography angiography

NASA Astrophysics Data System (ADS)

Choi, Woo June; Pepple, Kathryn L.; Zhi, Zhongwei; Wang, Ruikang K.

2015-03-01

Uveitis, or ocular inflammation, is a cause of severe visual impairment. Rodent models of uveitis are powerful tools used to investigate the pathological mechanisms of ocular inflammation and to study the efficacy of new therapies prior to human testing. In this paper, we report the utility of spectral-domain optical coherence tomography (SD-OCT) angiography in characterizing the inflammatory changes induced in the anterior segment of a rat model of uveitis. Acute anterior uveitis (AAU) was induced in two rats by intravitreal injection of a killed mycobacterial extract. One of them received a concurrent periocular injection of steroids to model a treatment effect. OCT imaging was performed prior to inflammation induction on day 0 (baseline), and 2 days post-injection (peak inflammation). Baseline and inflamed images were compared. OCT angiography identified swelling of the cornea, inflammatory cells in the anterior and posterior chambers, a fibrinous papillary membrane, and dilation of iris vessels in the inflamed eyes when compared to baseline images. Steroid treatment was shown to prevent the changes associated with inflammation. This is a novel application of anterior OCT imaging in animal models of uveitis, and provides a high resolution, in vivo assay for detecting and quantifying ocular inflammation and the response to new therapies.

Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

PubMed

Brattsand, R; Linden, M

1996-01-01

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in cascades, this means that steroid treatment can block expression of the subsequent cytokines. The blocked cytokine activity does not depend on a reduced cytokine receptor expression; in fact available in vitro investigations show that while the cytokine expression is blunted, its receptor is upregulated. The cellular studies presented here may represent the maximum potential of steroids to modulate cytokine expression in human mononuclear cells. It remains to be determined by clinical-experimental studies how effective cytokine modulation can be achieved in situ in inflamed bowel by systemic or by topical steroid therapy. Such studies may also answer whether a blocked cytokine production/action is the key or just a secondary mechanism behind the unique efficacy of steroids in active inflammatory bowel disease.

Strategies for the Assessment of Metabolic Profiles of Steroid Hormones in View of Diagnostics and Drug Monitoring: Analytical Problems and Challenges.

PubMed

Plenis, Alina; Oledzka, Ilona; Kowalski, Piotr; Baczek, Tomasz

2016-01-01

During the last few years there has been a growing interest in research focused on the metabolism of steroid hormones despite that the study of metabolic hormone pathways is still a difficult and demanding task because of low steroid concentrations and a complexity of the analysed matrices. Thus, there has been an increasing interest in the development of new, more selective and sensitive methods for monitoring these compounds in biological samples. A lot of bibliographic databases for world research literature were structurally searched using selected review question and inclusion/exclusion criteria. Next, the reports of the highest quality were selected using standard tools (181) and they were described to evaluate the advantages and limitations of different approaches in the measurements of the steroids and their metabolites. The overview of the analytical challenges, development of methods used in the assessment of the metabolic pathways of steroid hormones, and the priorities for future research with a special consideration for liquid chromatography (LC) and capillary electrophoresis (CE) techniques have been presented. Moreover, many LC and CE applications in pharmacological and psychological studies as well as endocrinology and sports medicine, taking into account the recent progress in the area of the metabolic profiling of steroids, have been critically discussed. The latest reports show that LC systems coupled with mass spectrometry have the predominant position in the research of steroid profiles. Moreover, CE techniques are going to gain a prominent position in the diagnosis of hormone levels in the near future.

Sex steroids, the insulin-like growth factor regulatory system, and aging: implications for the management of older postmenopausal women.

PubMed

Rosen, C J; Glowacki, J; Craig, W

1998-01-01

Aging is associated with profound changes in the growth hormone/insulin-like growth factor (IGF) regulatory system. These include reductions in growth hormone, IGF-I, IGFBP3, and IGFBP-5 and an increase in IGFBP-4. These changes, coupled with rather marked declines in sex steroid production from both the ovary and adrenals may combine to have very deleterious effects on several organ systems in the postmenopausal woman. In particular, the prevalence of two very common diseases, osteoporosis and coronary artery disease, increase dramatically after the cessation of gonadal steroid production. The complex interrelationship between the IGF regulatory system and estrogens/androgens in the postmenopausal period may provide important clues as to the pathophysiology of both these disorders. In this paper, we begin to define the role of IGF-I (and its constituent IGF binding proteins) in skeletal and vascular tissue. Recent experimental data show the effects of estrogen on circulating and tissue IGFs in older individuals. Finally, estrogen replacement therapy affects the IGF regulatory system in postmenopausal women. Although conclusions from early studies remain somewhat preliminary, it is likely that the IGF regulatory system will be a prime target for future studies into the pathogenesis of several age and sex hormone related degenerative disorders.

Use of estetrol with other steroids for attenuation of neonatal hypoxic-ischemic brain injury: to combine or not to combine?

PubMed

Tskitishvili, Ekaterine; Pequeux, Christel; Munaut, Carine; Viellevoye, Renaud; Nisolle, Michelle; Noël, Agnes; Foidart, Jean-Michel

2016-06-07

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated.The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival.In vivopretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4.

14 CFR 29.1103 - Induction systems ducts and air duct systems.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Induction systems ducts and air duct systems. 29.1103 Section 29.1103 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1103 Induction systems ducts and air duct...

14 CFR 25.1103 - Induction system ducts and air duct systems.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Induction system ducts and air duct systems. 25.1103 Section 25.1103 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY AIRPLANES Powerplant Induction System § 25.1103 Induction system ducts and air duct...

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): A lymphocytic reactive response of the central nervous system? A case report.

PubMed

Wang, Xiaolin; Huang, Dehui; Huang, Xusheng; Zhang, Jiatang; Ran, Ye; Lou, Xin; Gui, Qiuping; Yu, Shengyuan

2017-04-15

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroid (CLIPPERS) was first described in 2010. The characteristic clinical picture, radiological distribution and steroid response have been well-described in previous reports. However, the underlying pathogenesis and nosological position of CLIPPERS in the CNS require further investigation for the primary CNS lymphoma have been identified by autopsy subsequently. Here, we report a 51-year-old woman who was diagnosed with CLIPPERS but progressed to primary CNS lymphomatoid granulomatosis, which supports that CLIPPERS is not just an inflammatory CNS disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

Biotransformation of cholesterol and 16,17-alpha epoxypregnenolone by novel Cladosporium sp. strain IS547.

PubMed

Pang, Cuiping; Cao, Yuting; Zhu, Xiangdong

2017-01-01

Nowadays, there are a few steroid drugs or intermediates that have been obtained via the transformation of microorganisms, and many strains of transformed steroids have not been found yet. Therefore, it is very significant to screen for the strains that have the abilities to transform steroids to produce valuable products. This study has focused on the screen and identification of strains, the structural identification of converted products, and the optimization of transformation conditions, as well as the establishment of transformation systems. A soil microbiota was screened for strain involved in the biotransformation of steroids. A new isolate IS547 is capable of converting a variety of steroids (such as cholesterol, ergosterol, hydrocortisone, progesterone, pregnenolone, and 16,17-alpha-epoxypregnenolone). Based on the 18S rDNA gene sequence comparison, the isolate IS547 has been demonstrated to be very closely related to Cladosporium sp. genus. Present paper is the first report regarding the microbial transformation by Cladosporium sp. to produce active intermediates, which include 7-hydroxy cholesterol, 20-droxyl-16α,17α-epoxypregna-4-dien-3-one, 7-ketocholesterol, and 7-droxyl-16α,17α-epoxypregna-4-dien-3,20-dione. Under the optimum conditions, the yields of product 3 and product 4 were 20.58 and 17.42%, respectively, higher than that prior to the optimization. The transformation rate increased significantly under the optimum fermentation conditions. This study describes an efficient, rapid, and inexpensive biotransformation system for the production of active pharmaceutical intermediates. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Regulation of bone sialoprotein mRNA by steroid hormones

PubMed Central

1989-01-01

In this report we demonstrate an increase in the steady-state level of bone sialoprotein (BSP) mRNA in rat calvaria and a rat osteosarcoma cell line (ROS 17/2.8) after treatment with the synthetic glucocorticoid, dexamethasone. In contrast, 1.25-dihydroxyvitamin D3 reduced the amount of BSP mRNA in calvaria and inhibited the dexamethasone induction in ROS 17/2.8 cells. The increase in BSP mRNA is most likely due to an increase in the transcriptional rate. The stability of mRNA was unchanged after dexamethasone treatment with a half-life of approximately 5 h. Nuclear transcription experiments with nuclei isolated from ROS 17/2.8 cells showed an increased BSP mRNA synthesis in cells treated with dexamethasone. PMID:2592421

The antiprogesterone steroid RU 486: a short pharmacological and clinical review, with emphasis on the interruption of pregnancy.

PubMed

Garfield, R E; Baulieu, E E

1987-02-01

In this review we have briefly outlined the clinical applications and mechanism of action of the progesterone antagonist RU 486. RU 486 has been successfully used in a variety of conditions to regulate the reproductive cycle and to control fertility in women. We suggest that the mechanism by which RU 486 acts during the cycle and early pregnancy is probably by affecting mainly the endometrium. During late pregnancy, the compound has significant effects on the myometrium including the induction of gap junctions between myometrium cells, which is required for muscle contractility during labour. The use of RU 486 has helped to demonstrate that progesterone is required for maintenance of the late stages of pregnancy in women.

Aspergillus osteomyelitis of the lumbar spine complicated with orbital apex syndrome: A potential role of the Batson's plexus in disease propagation.

PubMed

Camargo, Jose F; Seriburi, Vimon; Tenner, Michael; El Khoury, Marc Y

2012-01-01

We report a rare case of orbital apex syndrome following epidural steroid injections of the lumbar spine in an immunocompetent individual with osteomyelitis and discitis caused by Aspergillus fumigatus. We suspect that the craniospinal venous system, also known as the Batson's plexus, was the main route for steroid-facilitated disease propagation from the spine to intracranial structures.

Autoimmune Disease with Cardiac Valves Involvement: Libman-Sacks Endocarditis.

PubMed

Ginanjar, Eka; Yulianto, Yulianto

2017-04-01

This case study aim to evaluate the response of steroid treatment for autoimmune endocarditis. Valvular heart disease is relatively rising in both congenital and acquired cases, but the autoimmune endocarditis remains rare. In this case, a 34 year old woman with clinical manifestation resembling systemic lupus erythematosus (SLE) is diagnosed with Libman-sacks Endocarditis. After six months of steroid treatment, her clinical manifestations and heart structure improved.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): An Uncommon Manifestation of Systemic Lupus Erythematosus (SLE).

PubMed

Abraham, Hrudya; Kuzhively, Jose; Rizvi, Syed W

2017-09-12

BACKGROUND Chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon manifestation of systemic lupus erythematosus (SLE). We report a case of SLE presenting as CIDP and discuss the diagnosis, management, and prognosis of CIDP. CASE REPORT A 40-year-old woman with a past medical history of SLE treated with hydroxychloroquine presented with bilateral, progressive, ascending, sensory and motor neuropathy. Physical examination showed weakness and reduced temperature of all extremities, reduced pinprick and vibration sense of the distal extremities, loss of reflexes, and walking with a wide-based unsteady gait. Laboratory investigations showed positive antinuclear antibodies (ANA), anti-(smooth muscle (SM) antibody, anti-RNP antibody, anti-SSA antibody, anti-ds-DNA antibody, and an erythrocyte sedimentation rate (ESR) of 75 mm/hr, low C4, leukopenia, and anemia. Electromyography (EMG) confirmed the diagnosis of CIDP. The patient's neuropathy and muscle weakness improved on treatment with intravenous immunoglobulin (IVIG) and high-dose steroids. CONCLUSIONS The early clinical diagnosis of CIDP, supported by serological autoantibody profiles associated with SLE, can predict a good response to steroids. Most patients with CIDP are treated successfully with steroids if the diagnosis is made early. IVIG, plasmapheresis, or immunosuppressive therapy should be considered if there is no response to steroids.

Anabolic androgenic steroid nandrolone decanoate reduces hypothalamic proopiomelanocortin mRNA levels.

PubMed

Lindblom, Jonas; Kindlundh, Anna M S; Nyberg, Fred; Bergström, Lena; Wikberg, Jarl E S

2003-10-03

Supratherapeutical doses of anabolic androgenic steroids (AASs) have dramatic effects on metabolism in humans, and also inhibit feeding and reduce the rate of body weight gain in rats. In order to test the hypothesis that the AAS metabolic syndrome is accompanied by alterations in the central melanocortin system, we evaluated body weight, food intake and hypothalamic agouti-related protein (AgRP) and proopiomelanocortin (POMC) mRNA levels following administration of different doses of the anabolic androgenic steroid nandrolone decanoate. In order to distinguish changes induced by the steroid treatment per se from those resulting from the reduced food intake and growth rate, we also compared the effect of nandrolone decanoate on AgRP and POMC mRNA expression with both normally fed, and food restricted control groups. We here report that administration of nandrolone specifically reduces arcuate nucleus POMC mRNA levels while not affecting the expression level of AgRP. The effect on POMC expression was not observed in the food restricted controls, excluding the possibility that the observed effect was a mere response to the reduced food intake and body weight. These results raise the possibility that some of the metabolic and behavioural consequences of AAS abuse may be the result of alterations in the melanocortin system.

Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients.

PubMed

Calmus, Yvon; Kamar, Nassim; Gugenheim, Jean; Duvoux, Christophe; Ducerf, Christian; Wolf, Philippe; Samuel, Didier; Vanlemmens, Claire; Neau-Cransac, Martine; Salamé, Ephrem; Chazouillères, Olivier; Declerck, Nicole; Pageaux, Georges-Philippe; Dubel, Laurence; Rostaing, Lionel

2010-06-27

Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection. This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months. The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time. Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.

Role of human pregnane X receptor in tamoxifen- and 4-hydroxytamoxifen-mediated CYP3A4 induction in primary human hepatocytes and LS174T cells.

PubMed

Sane, Rucha S; Buckley, Donna J; Buckley, Arthur R; Nallani, Srikanth C; Desai, Pankaj B

2008-05-01

Previously we observed that the antiestrogens tamoxifen and 4-hydroxytamoxifen (4OHT) induce CYP3A4 in primary human hepatocytes and activate human pregnane X receptor (PXR) in cell-based reporter assays. Given the complex cross-talk between nuclear receptors, tissue-specific expression of CYP3A4, and the potential for tamoxifen and 4OHT to interact with a myriad of receptors, this study was undertaken to gain mechanistic insights into the inductive effects of tamoxifen and 4OHT. First, we observed that transfection of the primary cultures of human hepatocytes with PXR-specific small interfering RNA reduced the PXR mRNA expression and the extent of CYP3A4 induction by tamoxifen and 4OHT by 50%. Second, in LS174T colon carcinoma cells, which were observed to have significantly lower PXR expression relative to human hepatocytes, neither tamoxifen nor 4OHT induced CYP3A4. Third, N-desmethyltamoxifen, which did not induce CYP3A4 in human hepatocytes, also did not activate PXR in LS174T cells. We then used cell-based reporter assay to evaluate the effects of other receptors such as glucocorticoid receptor GR alpha and estrogen receptor ER alpha on the transcriptional activation of PXR. The cotransfection of GR alpha in LS174T cells augmented PXR activation by tamoxifen and 4OHT. On the other hand, the presence of ER alpha inhibited PXR-mediated basal activation of CYP3A4 promoter, possibly via competing for common cofactors such as steroid receptor coactivator 1 and glucocorticoid receptor interacting protein 1. Collectively, our findings suggest that the CYP3A4 induction by tamoxifen and 4OHT is primarily mediated by PXR but the overall stoichiometry of other nuclear receptors and transcription cofactors also contributes to the extent of the inductive effect.

14 CFR 125.181 - Induction system ice prevention.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Induction system ice prevention. 125.181... Requirements § 125.181 Induction system ice prevention. A means for preventing the malfunctioning of each engine due to ice accumulation in the engine air induction system must be provided for each airplane. ...

14 CFR 125.181 - Induction system ice prevention.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Induction system ice prevention. 125.181... Requirements § 125.181 Induction system ice prevention. A means for preventing the malfunctioning of each engine due to ice accumulation in the engine air induction system must be provided for each airplane. ...

14 CFR 125.181 - Induction system ice prevention.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Induction system ice prevention. 125.181... Requirements § 125.181 Induction system ice prevention. A means for preventing the malfunctioning of each engine due to ice accumulation in the engine air induction system must be provided for each airplane. ...

14 CFR 125.181 - Induction system ice prevention.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Induction system ice prevention. 125.181... Requirements § 125.181 Induction system ice prevention. A means for preventing the malfunctioning of each engine due to ice accumulation in the engine air induction system must be provided for each airplane. ...

14 CFR 125.181 - Induction system ice prevention.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Induction system ice prevention. 125.181... Requirements § 125.181 Induction system ice prevention. A means for preventing the malfunctioning of each engine due to ice accumulation in the engine air induction system must be provided for each airplane. ...

Idiopathic Granulomatous Mastitis: Comparison of Wide Local Excision with or without Corticosteroid Therapy

PubMed Central

Akcan, Alper; Öz, A. Bahadir; Dogan, Serap; Akgün, Hülya; Akyüz, Muhammet; Ok, Engin; Gök, Mustafa; Talih, Tutkun

2014-01-01

Summary Background Idiopathic granulomatous mastitis (IGM) is an uncommon chronic inflammatory disease of the breast with uncertain optimal treatment regimen. In this study, our purpose was to report our clinical experience with 74 IGM patients who were treated wide local excision with or without steroid therapy. Patients and Method 74 cases diagnosed histologically as IGM were identified from surgical and pathological records between January 1995 and January 2012. Group 1 (surgery-only group) comprised 53 patients, and the 21 patients in group 2 were treated with corticosteroids prior to surgical treatment (steroid-and-surgery group). Results Follow-up data were complete for 67 (91.7%) of the 73 patients. Recurrence developed in 4 (7.5%) patients in the surgery-only group, while there was no recurrence in the steroid-and-surgery group; the difference was not statistically significant (p = 0.19). Conclusion Systemic steroid therapy with surgical resection is the recommended first-line treatment strategy for IGM. PMID:24944554

Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Talamo, J.H.; Gollamudi, S.; Green, W.R.

1991-08-01

A 193-nm excimer laser system was used to create deep stromal ablations in seven New Zealand white rabbits and shallow ablations in three. Eyes were randomized for treatment with topical mitomycin C, steroids, and erythromycin; topical steroids and erythromycin; or topical erythromycin only. All treatment regimens were instituted twice daily for 14 days. All eyes reepithelialized normally within 3 to 5 days. During 10 weeks of follow-up, all eyes developed moderate reticular subepithelial haze without significant differences among treatment groups. Results of light, fluorescence, and electron microscopic examination showed anterior stromal scarring and markedly reduced new subepithelial collagen formation inmore » the group treated with mitomycin C, corticosteroids, and erythromycin. Focal abnormalities of Descemet's membrane and endothelial abnormalities were present in all treatment groups. Combination therapy with topical steroids, mitomycin C, and erythromycin to control the corneal wound healing response after refractive laser surgery appears promising and warrants further study.« less

Neurosteroid production in the songbird brain: a re-evaluation of core principles

PubMed Central

London, Sarah E.; Remage-Healey, Luke; Schlinger, Barney A.

2009-01-01

Concepts of brain-steroid signaling have traditionally placed emphasis on the gonads and adrenals as the source of steroids, the strict dichotomy of early developmental (“organizational”) and mature (“activational”) effects, and a relatively slow mechanism of signaling through intranuclear receptors. Continuing research shows that these concepts are not inaccurate, but they are certainly incomplete. In this review, we focus on the song control circuit of songbird species to demonstrate how each of these concepts is limited. We discuss the solid evidence for steroid synthesis within the brain (“neurosteroidogenesis”), the role of neurosteroids in organizational events that occur both early in development and later in life, and how neurosteroids can act in acute and non-traditional ways. The songbird model therefore illustrates how neurosteroids can dramatically increase the diversity of steroid-sensitive brain functions in a behaviorally-relevant system. We hope this inspires further research and thought into neurosteroid signaling in songbirds and other animals. PMID:19442685

Circulating neuroactive C21- and C19-steroids in young men before and after ejaculation.

PubMed

Stárka, L; Hill, M; Havlíková, H; Kancheva, L; Sobotka, V

2006-01-01

Twelve neuroactive and neuroprotective steroids, androgens and androgen precursors i.e. 3alpha,17beta-dihydroxy-5alpha-androstane, 3alpha-hydroxy-5alpha-androstan-17-one, 3alpha-hydroxy-5beta-androstan-17-one, androst-5-ene-3beta,17beta-diol, 3beta,17alpha-dihydroxy-pregn-5-en-20-one (17alpha-hydroxy-pregnenolone), 3beta-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA), testosterone, androst-4-ene-3,17-dione (androstenedione), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), 3beta-hydroxy-pregn-5-en-20-one (pregnenolone), 7alpha-hydroxy-DHEA, and 7beta-hydroxy-DHEA were measured using the GC-MS system in young men before and after ejaculation provoked by masturbation. The circulating level of 17alpha-hydroxypregnenolone increased significantly, whereas the other circulating steroids were not changed at all. This fact speaks against the hypothesis that a drop in the level of neuroactive steroids, e.g. allopregnanolone may trigger the orgasm-related increase of oxytocin, reported by other authors.

Systemic Epstein-Barr Virus-positive T-Cell Lymphoproliferative Disease of Childhood With Good Response to Steroid Therapy.

PubMed

Kim, Do-Hoon; Kim, Myungshin; Kim, Yonggoo; Han, Kyungja; Han, Eunhee; Lee, Jae Wook; Chung, Nack-Gyun; Cho, Bin

2017-11-01

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood is a rare disease and has a very fulminant clinical course with high mortality. A 21-month-old female patient was referred to our hospital with a 1 week history of fever and was subsequently diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood. After starting treatment with dexamethasone, she showed early defervescence and improvement of laboratory parameters, and has remained disease-free after stopping steroid treatment, although longer follow-up is necessary. Our report underscores the possibility that this disease entity may be heterogenous in terms of prognosis.

Effects of centrifugation on gonadal and adrenocortical steroids in rats

NASA Technical Reports Server (NTRS)

Kakihana, R.; Butte, J. C.

1980-01-01

Many endocrine systems are sensitive to external changes in the environment. Both the pituitary adrenal and pituitary gonadal systems are affected by stress including centrifugation stress. The effect of centrifugation on the pituitary gonadal and pituitary adrenocortical systems was examined by measuring the gonadal and adrenal steroids in the plasma and brain following different duration and intensity of centrifugation stress in rats. Two studies were completed and the results are presented. The second study was carried out to describe the developmental changes of brain, plasma and testicular testosterone and dihydrotestosterone in Sprague Dawley rats so that the effect of centrifugation stress on the pituitary gonadal syatem could be better evaluated in future studies.

Hypereosinophilic Syndrome (HES)

MedlinePlus

... 5 (IL-5) monocolonal antibodies (mepolizumab and reslizumab). Systemic steroids are often needed to treat HES with organ involvement or with systemic symptoms, like severe rash, fluid retention, and similar. ...

Neuroactive steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients.

PubMed

Caruso, Donatella; Melis, Marta; Fenu, Giuseppe; Giatti, Silvia; Romano, Simone; Grimoldi, Maria; Crippa, Donatella; Marrosu, Maria Giovanna; Cavaletti, Guido; Melcangi, Roberto Cosimo

2014-08-01

Neuroactive steroid family includes molecules synthesized in peripheral glands (i.e., hormonal steroids) and directly in the nervous system (i.e., neurosteroids) which are key regulators of the nervous function. As already reported in clinical and experimental studies, neurodegenerative diseases affect the levels of neuroactive steroids. However, a careful analysis comparing the levels of these molecules in cerebrospinal fluid (CSF) and in plasma of multiple sclerosis (MS) patients is still missing. To this aim, the levels of neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in CSF and plasma of male adults affected by Relapsing-Remitting MS and compared with those collected in control patients. An increase in pregnenolone and isopregnanolone levels associated with a decrease in progesterone metabolites, dihydroprogesterone, and tetrahydroprogesterone was observed in CSF of MS patients. Moreover, an increase of 5α-androstane-3α,17β-diol and of 17β-estradiol levels associated with a decrease of dihydrotestosterone also occurred. In plasma, an increase in pregnenolone, progesterone, and dihydrotestosterone and a decrease in dihydroprogesterone and tetrahydroprogesterone levels were reported. This study shows for the first time that the levels of several neuroactive steroids, and particularly those of progesterone and testosterone metabolites, are deeply affected in CSF of relapsing-remitting MS male patients. We here demonstrated that, the cerebrospinal fluid and plasma levels of several neuroactive steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis. © 2014 International Society for Neurochemistry.

Closely Related Antibody Receptors Exploit Fundamentally Different Strategies for Steroid Recognition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verdino, P.; Aldag, C.; Hilvert, D.

2009-05-26

Molecular recognition by the adaptive immune system relies on specific high-affinity antibody receptors that are generated from a restricted set of starting sequences through homologous recombination and somatic mutation. The steroid binding antibody DB3 and the catalytic Diels-Alderase antibody 1E9 derive from the same germ line sequences but exhibit very distinct specificities and functions. However, mutation of only two of the 36 sequence differences in the variable domains, Leu{sup H47}Trp and Arg{sup H100}Trp, converts 1E9 into a high-affinity steroid receptor with a ligand recognition profile similar to DB3. To understand how these changes switch binding specificity and function, we determinedmore » the crystal structures of the 1E9 Leu{sup H47}Trp/Arg{sup H100}Trp double mutant (1E9dm) as an unliganded Fab at 2.05 {angstrom} resolution and in complex with two configurationally distinct steroids at 2.40 and 2.85 {angstrom}. Surprisingly, despite the functional mimicry of DB3, 1E9dm employs a distinct steroid binding mechanism. Extensive structural rearrangements occur in the combining site, where residue H47 acts as a specificity switch and H100 adapts to different ligands. Unlike DB3, 1E9dm does not use alternative binding pockets or different sets of hydrogen-bonding interactions to bind configurationally distinct steroids. Rather, the different steroids are inserted more deeply into the 1E9dm combining site, creating more hydrophobic contacts that energetically compensate for the lack of hydrogen bonds. These findings demonstrate how subtle mutations within an existing molecular scaffold can dramatically modulate the function of immune receptors by inducing unanticipated, but compensating, mechanisms of ligand interaction.« less

Endogenous steroid profiling in the athlete biological passport.

PubMed

Sottas, Pierre-Edouard; Saugy, Martial; Saudan, Christophe

2010-03-01

The Athlete Biological Passport (ABP) is an individual electronic document that collects data regarding a specific athlete that is useful in differentiating between natural physiologic variations of selected biomarkers and deviations caused by artificial manipulations. A subsidiary of the endocrine module of the ABP, that which here is called Athlete Steroidal Passport (ASP), collects data on markers of an altered metabolism of endogenous steroidal hormones measured in urine samples. The ASP aims to identify not only doping with anabolic-androgenic steroids, but also most indirect steroid doping strategies such as doping with estrogen receptor antagonists and aromatase inhibitors. Development of specific markers of steroid doping, use of the athlete's previous measurements to define individual limits, with the athlete becoming his or her own reference, the inclusion of heterogeneous factors such as the UDPglucuronosyltransferase B17 genotype of the athlete, the knowledge of potentially confounding effects such as heavy alcohol consumption, the development of an external quality control system to control analytical uncertainty, and finally the use of Bayesian inferential methods to evaluate the value of indirect evidence have made the ASP a valuable alternative to deter steroid doping in elite sports. The ASP can be used to target athletes for gas chromatography/combustion/ isotope ratio mass spectrometry (GC/C/IRMS) testing, to withdraw temporarily the athlete from competing when an abnormality has been detected, and ultimately to lead to an antidoping infraction if that abnormality cannot be explained by a medical condition. Although the ASP has been developed primarily to ensure fairness in elite sports, its application in endocrinology for clinical purposes is straightforward in an evidence-based medicine paradigm. Copyright 2010 Elsevier Inc. All rights reserved.

Effects of sex steroids on expression of genes regulating growth-related mechanisms in rainbow trout (Oncorhynchus mykiss).

PubMed

Cleveland, Beth M; Weber, Gregory M

2015-05-15

Effects of a single injection of 17β-estradiol (E2), testosterone (T), or 5β-dihydrotestosterone (DHT) on expression of genes central to the growth hormone (GH)/insulin-like growth factor (IGF) axis, muscle-regulatory factors, transforming growth factor-beta (TGFβ) superfamily signaling cascade, and estrogen receptors were determined in rainbow trout (Oncorhynchus mykiss) liver and white muscle tissue. In liver in addition to regulating GH sensitivity and IGF production, sex steroids also affected expression of IGF binding proteins, as E2, T, and DHT increased expression of igfbp2b and E2 also increased expression of igfbp2 and igfbp4. Regulation of this system also occurred in white muscle in which E2 increased expression of igf1, igf2, and igfbp5b1, suggesting anabolic capacity may be maintained in white muscle in the presence of E2. In contrast, DHT decreased expression of igfbp5b1. DHT and T decreased expression of myogenin, while other muscle regulatory factors were either not affected or responded similarly for all steroid treatments. Genes within the TGFβ superfamily signaling cascade responded to steroid treatment in both liver and muscle, suggesting a regulatory role for sex steroids in the ability to transmit signals initiated by TGFβ superfamily ligands, with a greater number of genes responding in liver than in muscle. Estrogen receptors were also regulated by sex steroids, with era1 expression increasing for all treatments in muscle, but only E2- and T-treatment in liver. E2 reduced expression of erb2 in liver. Collectively, these data identify how physiological mechanisms are regulated by sex steroids in a manner that promotes the disparate effects of androgens and estrogens on growth in salmonids. Published by Elsevier Inc.

Cogan syndrome: Characteristics, outcome and treatment in a French nationwide retrospective study and literature review.

PubMed

Durtette, Charlotte; Hachulla, Eric; Resche-Rigon, Matthieu; Papo, Thomas; Zénone, Thierry; Lioger, Bertrand; Deligny, Christophe; Lambert, Marc; Landron, Cédric; Pouchot, Jacques; Kahn, Jean Emmanuel; Lavigne, Christian; De Wazieres, Benoit; Dhote, Robin; Gondran, Guillaume; Pertuiset, Edouard; Quemeneur, Thomas; Hamidou, Mohamed; Sève, Pascal; Le Gallou, Thomas; Grasland, Anne; Hatron, Pierre-Yves; Fain, Olivier; Mekinian, Arsène

2017-12-01

Cogan syndrome is mainly treated with steroids. We aimed to determine the place of DMARDs and biologic-targeted treatments. We conducted a French nationwide retrospective study of patients with Cogan syndrome (n=40) and a literature review of cases (n=22) and analyzed the efficacy of disease-modifying anti-rheumatic drugs (DMARDs) and tumor necrosis factor α (TNF-α) antagonists. We included 62 patients (31 females) (median age 37years [range 2-76]. At diagnosis, 61 patients (98%) had vestibulo-auditory symptoms, particularly bilateral hearing loss in 41% and deafness in 31%. Ocular signs were present in 57 patients (92%), with interstitial keratitis in 31 (51%). The first-line treatment consisted of steroids alone (n=43; 70%) or associated with other immunosuppressive drugs (n=18; 30%). Overall, 13/43 (30%) and 4/18 (22%) patients with steroids alone and with associated immunosuppressive drugs, respectively (p=0.8), showed vestibulo-auditory response; 32/39 (82%) and 15/19 (79%) ocular response; and 23/28 (82%) and 10/14 (71%) general response. Overall 61 patients had used a total of 126 lines of treatment, consisting of steroids alone (n=51 lines), steroids with DMARDs (n=65) and infliximab (n=10). Vestibulo-auditory response was significantly more frequent with infliximab than DMARDs or steroids alone (80% vs 39% and 35%, respectively), whereas ocular, systemic and acute-phase reactant response rates were similar. Infliximab was the only significant predictor of vestibulo-auditory improvement (odds ratio 20.7 [95% confidence interval 1.65; 260], p=0.019). Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome, but prospective studies are necessary. Copyright © 2017 Elsevier B.V. All rights reserved.

Long-term use of steroids protects from the development of symptomatic diverticulitis requiring hospitalization in the Asian population.

PubMed

Chang, Shen-Shong; Hu, Hsiao-Yun

2015-01-01

The pathophysiology of diverticulitis is poorly understood. Factors such as physical inactivity, constipation, obesity, smoking, and the use of nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with an increased risk of diverticular disease. To evaluate whether patients exhibiting long-term steroid use are at increased risk of colonic diverticulitis. We conducted a population-based, nested case-control study. Data were retrospectively collected from the National Health Insurance Research Database. The study cohort comprised patients diagnosed with diverticulitis, identified using inpatient discharge records using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (562.11 and 562.13), and those who were administered one or more prescriptions for corticosteroids for systemic use. Control patients were matched to cases by age, sex, NSAID use, laxative drug use, and index date. We enrolled 690 patients with colonic diverticulitis and 2760 in the control group. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Compared with steroid nonusers, the adjusted ORs were 0.60 (95% CI = 0.35-1.06) and 0.80 (95% CI = 0.64-1.008) in current steroid users and previous steroid users, respectively. In addition, the adjusted ORs were 0.55 (95% CI = 0.31-0.98), 0.57 (95% CI = 0.31-0.98), and 0.44 (95% CI = 0.22-0.86) for steroid use duration more than half time by an exposure period of 90 days, 180 days, and 365 days before the claim date of colonic diverticulitis, respectively. The results indicated that long-term steroid use within one year is associated with lower risk of colonic diverticulitis.

Anabolic Steroids...What's the Hype?...

ERIC Educational Resources Information Center

Landry, Gregory L.; Wagner, Lauris L.

This pamphlet uses a question-and-answer format to examine the use and abuse of anabolic steroids. It begins by explaining that all steroids are not anabolic steroids and that anabolic steroids are those used specifically to build muscles quickly. Medical uses of anabolic steroids are reviewed; how people get steroids, how they take them, and…

Per- and polyfluoroalkyl substances (PFASs) - New endocrine disruptors in polar bears (Ursus maritimus)?

PubMed

Pedersen, Kathrine Eggers; Letcher, Robert J; Sonne, Christian; Dietz, Rune; Styrishave, Bjarne

2016-11-01

Per- and polyfluoroalkyl substances (PFASs) are emerging in the Arctic and accumulate in brain tissues of East Greenland (EG) polar bears. In vitro studies have shown that PFASs might possess endocrine disrupting abilities and therefore the present study was conducted to investigate potential PFAS induced alterations in brain steroid concentrations. The concentrations of eleven steroid hormones were determined in eight brain regions from ten EG polar bears. Pregnenolone (PRE), the dominant progestagen, was found in mean concentrations of 5-47ng/g (ww) depending on brain region. PRE showed significantly (p<0.01) higher concentrations in female compared to male bears. Dehydroepiandrosterone (DHEA) found in mean concentrations 0.67-4.58ng/g (ww) was the androgen found in highest concentrations. Among the estrogens estrone (E1) showed mean concentrations of 0.90-2.21ng/g (ww) and was the most abundant. Remaining steroid hormones were generally present in concentrations below 2ng/g (ww). Steroid levels in brain tissue could not be explained by steroid levels in plasma. There was however a trend towards increasing estrogen levels in plasma resulting in increasing levels of androgens in brain tissue. Correlative analyses showed positive associations between PFASs and 17α-hydroxypregnenolone (OH-PRE) (e.g. perflouroalkyl sulfonates (∑PFSA): p<0.01, r=0.39; perfluoroalkyl carboxylates (∑PFCA): p<0.01, r=0.61) and PFCA and testosterone (TS) (∑PFCA: p=0.03, r=0.30) across brain regions. Further when investigating correlative associations in specific brain regions significant positive correlations were found between ∑PFCA and several steroid hormones in the occipital lobe. Correlative positive associations between PFCAs and steroids were especially observed for PRE, progesterone (PRO), OH-PRE, DHEA, androstenedione (AN) and testosterone (TS) (all p≤0.01, r≥0.7). The results from the present study generally indicate that an increase in PFASs concentration seems to concur with an increase in steroid hormones of EG polar bears. It is, however, not possible to determine whether alterations in brain steroid concentrations arise from interference with de novo steroid synthesis or via disruption of peripheral steroidogenic tissues mainly in gonads and feedback mechanisms. Steroids are important for brain plasticity and gender specific behavior as well as postnatal development and sexually dimorph brain function. The present work indicates an urgent need for a better mechanistic understanding of how PFASs may affect the endocrine system of polar bears and potentially other mammal species. Copyright © 2016 Elsevier Ltd. All rights reserved.

14 CFR 29.1105 - Induction system screens.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1105 Induction system... screen may be in any part of the induction system that is the only passage through which air can reach the engine, unless it can be deiced by heated air; (c) No screen may be deiced by alcohol alone; and...

14 CFR 25.1105 - Induction system screens.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY AIRPLANES Powerplant Induction System § 25.1105 Induction system... screen may be in any part of the induction system that is the only passage through which air can reach the engine, unless it can be deiced by heated air; (c) No screen may be deiced by alcohol alone; and...

Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications.

PubMed

Moravek, Molly B; Yin, Ping; Ono, Masanori; Coon, John S; Dyson, Matthew T; Navarro, Antonia; Marsh, Erica E; Chakravarti, Debabrata; Kim, J Julie; Wei, Jian-Jun; Bulun, Serdar E

2015-01-01

Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention. A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript. Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem-progenitor cell properties, and was found to be essential for ovarian steroid-dependent growth of leiomyomas. Interestingly, these stem-progenitor cells were deficient in ERα and PR and instead relied on the strikingly higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone action via paracrine signaling. It has been well established that estrogen and progesterone are involved in the proliferation and maintenance of uterine leiomyoma, and the majority of medical treatments currently available for leiomyoma work by inhibiting steroid hormone production or action. A pitfall of these therapeutics is that they decrease leiomyoma size, but do not completely eradicate them, and tumors tend to regrow once treatment is stopped. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma has the potential to provide the missing link between developing therapeutics that temper leiomyoma growth and those that eradicate them. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The efficacy and safety of systemic injection of Ginkgo biloba extract, EGb761, in idiopathic sudden sensorineural hearing loss: a randomized placebo-controlled clinical trial.

PubMed

Koo, Ja-Won; Chang, Mun Young; Yun, Sung-Cheol; Kim, Tae Su; Kong, Soo-Keun; Chung, Jong Woo; Goh, Eui-Kyung

2016-09-01

Steroids are currently the most frequently accepted agents for idiopathic sudden sensorineural hearing loss (ISSNHL). However, the therapeutic effect of steroids is not always satisfactory. In this pilot study, we evaluated whether systemic treatment with Ginkgo biloba extract (EGb761) has an additive therapeutic effect in patients receiving a systemic steroid due to ISSNHL. A multicenter, randomized, double-blind clinical trial was performed. Fifty-six patients with ISSNHL were allocated to either EGb761 or placebo. In both groups, methylprednisolone was administered for 14 days. EGb761 was infused intravenously for 5 days in the EGb761 group, while the same amount of normal saline was infused in the placebo group. For the efficacy evaluation, pure-tone audiometry, speech audiometry, tinnitus handicap inventory (THI) and short form-36 health (SF-36) survey outcomes were obtained before administration and on days 3, 5, 14 and 28 of administration. Twenty-four patients in each group completed the study protocol. There was no difference in hearing loss between the two groups before treatment. At day 28, air conduction threshold values in the placebo and EGb761 groups were 34.63 ± 28.90 and 23.84 ± 25.42 dB, respectively (p = 0.082). Speech discrimination scores in the placebo and EGb761 groups were 69.17 ± 40.89 and 87.48 ± 28.65 %, respectively (p = 0.050). THI and SF-36 scores in the placebo and EGb761 groups were similar. Although a combination of steroid and EGb761 for initial treatment did not show better pure tone threshold, compared with steroid alone, speech discrimination was significantly improved in combination therapy. Further studies will be needed to know if addition of EGb761 actually improves the outcome of ISSNHL treatment.

Monanchosterols A and B, bioactive bicyclo[4.3.1]steroids from a Korean sponge Monanchora sp.

PubMed

Wang, Weihong; Lee, Tae Gu; Patil, Rahul S; Mun, Bora; Yang, Inho; Kim, Hiyoung; Hahn, Dongyup; Won, Dong Hwan; Lee, Jihye; Lee, Yehee; Choi, Hyukjae; Nam, Sang-Jip; Kang, Heonjoong

2015-03-27

Chemical investigation of a Korean marine sponge, Monanchora sp., led to the isolation of three new steroids (1-3). Compounds 1 and 2, designated as monanchosterols A and B, respectively, represent the first examples of steroids possessing the bicyclo[4.3.1] A/B ring system from a natural source. Compounds 1-3 were investigated for their anti-inflammatory activity by evaluating their inhibitory effects on the mRNA expression of IL-6, TNF-α, and COX-2 in the LPS-stimulated murine RAW264.7 macrophage cells. Compounds 2 and 3 exhibited significant inhibitory effects on the mRNA expression of IL-6 without notable cytotoxicity to the cells in a dose-dependent manner.

Platelet-rich plasma versus steroid injection for subacromial impingement syndrome.

PubMed

Say, F; Gurler, D; Bulbul, M

2016-04-01

To compare the 6-week and 6-month outcome in 60 patients who received a single-dose injection of platelet-rich plasma (PRP) or steroid for subacromial impingement syndrome (SIS). 22 men and 38 women (mean age, 49.7 years) opted to receive a single-dose injection of PRP (n=30) or steroid (n=30) for SIS that had not responded to conservative treatment for >3 months. The PRP or a mixture of 1 ml 40 mg methylprednisolone and 8 ml prilocaine was administered via a dorsolateral approach through the interval just beneath the dorsal acromial edge. Both groups were instructed to perform standard rotator cuff stretching and strengthening exercises for 6 weeks. The use of non-steroid anti-inflammatory drugs was prohibited. Patients were evaluated before and 6 weeks and 6 months after treatment using the Constant score, visual analogue scale (VAS) for pain, and range of motion (ROM) of the shoulder. No local or systemic complication occurred. Improvement in the Constant score and VAS for pain at week 6 and month 6 was significantly better following steroid than PRP injection. The difference in the Constant score was greater than the mean clinically important difference of 10.4. Nonetheless, the 2 groups were comparable for improvement in ROM of the shoulder. Steroid injection was more effective than PRP injection for treatment of SIS in terms of the Constant score and VAS for pain at 6 weeks and 6 months.

Aspergillus osteomyelitis of the lumbar spine complicated with orbital apex syndrome: A potential role of the Batson's plexus in disease propagation

PubMed Central

Camargo, Jose F.; Seriburi, Vimon; Tenner, Michael; El Khoury, Marc Y.

2012-01-01

We report a rare case of orbital apex syndrome following epidural steroid injections of the lumbar spine in an immunocompetent individual with osteomyelitis and discitis caused by Aspergillus fumigatus. We suspect that the craniospinal venous system, also known as the Batson's plexus, was the main route for steroid-facilitated disease propagation from the spine to intracranial structures. PMID:24371725

Reference ranges for urinary concentrations and ratios of endogenous steroids, which can be used as markers for steroid misuse, in a Caucasian population of athletes.

PubMed

Van Renterghem, Pieter; Van Eenoo, Peter; Geyer, Hans; Schänzer, Wilhelm; Delbeke, Frans T

2010-02-01

The detection of misuse with naturally occurring steroids is a great challenge for doping control laboratories. Intake of natural anabolic steroids alters the steroid profile. Thus, screening for exogenous use of these steroids can be established by monitoring a range of endogenous steroids, which constitute the steroid profile, and evaluate their concentrations and ratios against reference ranges. Elevated values of the steroid profile constitute an atypical finding after which a confirmatory IRMS procedure is needed to unequivocally establish the exogenous origin of a natural steroid. However, the large inter-individual differences in urinary steroid concentrations and the recent availability of a whole range of natural steroids (e.g. dehydroepiandrosterone and androstenedione) which each exert a different effect on the monitored parameters in doping control complicate the interpretation of the current steroid profile. The screening of an extended steroid profile can provide additional parameters to support the atypical findings and can give specific information upon the steroids which have been administered. The natural concentrations of 29 endogenous steroids and 11 ratios in a predominantly Caucasian population of athletes were determined. The upper reference values at 97.5%, 99% and 99.9% levels were assessed for male (n=2027) and female (n=1004) populations. Monitoring minor metabolites and evaluation of concentration ratios with respect to their natural abundances could improve the interpretation of the steroid profile in doping analysis. Copyright 2009 Elsevier Inc. All rights reserved.

Determination of a cost-effective air pollution control technology for the control of VOC and HAP emissions from a steroids processing plant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamel, T.M.

1997-12-31

A steroids processing plant located in northeastern Puerto Rico emits a combined average of 342 lb/hr of hazardous air pollutants (HAPs) and volatile organic compounds (VOCs) from various process operations. The approach that this facility used to implement maximum achievable control technology (MACT) may assist others who must contend with MACT for pharmaceutical or related manufacturing facilities. Federal air regulations define MACT standards for stationary sources emitting any of 189 HAPs. The MACT standards detailed in the NESHAPs are characterized by industry and type of emission control system or technology. It is anticipated that the standard will require HAP reductionsmore » of approximately 95%. The steroid plant`s emissions include the following pollutant loadings: VOC/HAP Emission Rate (lb/hr): Methanol 92.0; Acetone 35.0; Methylene chloride 126.0; Chloroform 25.0; Ethyl acetate 56.0; Tetrahydrofuran 5.00; and 1,4-Dioxane 3.00. The facility`s existing carbon adsorption control system was nearing the end of its useful life, and the operators sought to install an air pollution control system capable of meeting MACT requirements for the pharmaceutical industry. Several stand-alone and hybrid control technologies were considered for replacement of the carbon adsorption system at the facility. This paper examines the following technologies: carbon adsorption, membrane separation, thermal oxidation, membrane separation-carbon adsorption, and condensation-carbon adsorption. Each control technology is described; the advantages and disadvantages of utilizing each technology for the steroid processing plant are examined; and capital and operating costs associated with the implementation of each technology are presented. The rationale for the technology ultimately chosen to control VOC and HAP emissions is presented.« less

A retrospective study demonstrating properties of nonvariceal upper gastrointestinal bleeding in Turkey.

PubMed

Bor, Serhat; Dağli, Ulkü; Sarer, Banu; Gürel, Selim; Tözün, Nurdan; Sıvrı, Bülent; Akbaş, Türkay; Sahın, Burhan; Memık, Faruk; Batur, Yücel

2011-06-01

Helicobacter pylori infection, non-steroidal anti-inflammatory drugs and peptic ulcer are considered as the major factors for upper gastrointestinal system bleeding. The objective of the study was to determine the sociodemographic and etiologic factors, management and outcome of patients with non-variceal upper gastrointestinal system bleeding in Turkey. Patients who admitted to hospitals with upper gastrointestinal system bleeding and in whom upper gastrointestinal endoscopy was performed were enrolled in this retrospective study. The detailed data of medical history, comorbid diseases, medications, admission to intensive care units, Helicobacter pylori infection, blood transfusion, upper gastrointestinal endoscopy, and treatment outcome were documented. The most frequent causes of bleeding (%) were duodenal ulcer (49.4), gastric ulcer (22.8), erosion (9.6), and cancer (2.2) among 1,711 lesions in endoscopic appearances of 1,339 patients from six centers. Seven hundred and four patients were evaluated for Helicobacter pylori infection and the test was positive in 45.6% of those patients. Comorbid diseases were present in 59.2% of the patients. The percentage of patients using acetylsalicylic acid and/or other non-steroidal anti-inflammatory drug was 54.3%. Bleeding was stopped with medical therapy in 66.9%. Only 3.7% of the patients underwent emergency surgery, and a 1.1% mortality rate was determined. Patients with upper gastrointestinal system bleeding were significantly older, more likely to be male, and more likely to use non-steroidal anti-inflammatory drugs. Though most of the patients were using gastro-protective agents, duodenal and gastric ulcers were the contributing factors in more than 70% of the upper gastrointestinal bleeding. The extensive use of non-steroidal anti-inflammatory drug is a hazardous health issue considering the use of these drugs in half of the patients.

Hydrocortisone Stimulation of RNA Synthesis in Induction of Hepatic Enzymes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kenney, Francis T.; Wicks, Wesley D.; Greenman, David L.

Increased synthesis of hepatic enzymes due to hydrocortisone is preceded by an increase in the rate of synthesis of nuclear RNA. Pulse-labeled RNA from liver nuclei was fractionated by a differential thermal phenol procedures, and the labeled RNA of each fraction was characterized by sucrose gradient centrifugation and base composition analysis. Hormone treatment increases the rate of synthesis of three types of RNA: (1) the nuclear precursor to ribosomal RNA, (2) a rapid turnover component with base composition similar to the tissue DNA, and (3) transfer RNA. Much of the total isotope incorporation into transfer RNA can be traced tomore » turnover of the terminal adenylate residue, but this type of labeling is insensitive to the hormone. The steroid also stimulates isotope incorporation into tissue precursor pools. The effect is abolished by actinomycin and thus is secondary to the hormonal stimulation of RNA synthesis. Growth hormone stimulates RNA synthesis in both intact and adrenalectomized rats, but induces the rapid turnover enzymes (tyrosine transaminase and tryptophan pyrrolase) only in the presence of functional adrenals. It therefore seems that glucocorticoids initiate both a generalized increase in synthesis of RNA and a selective induction of specific enzymes.« less

Impact of Intraoperative Steroids on Postoperative Infection Rates and Length of Hospital Stay: A Study of 1200 Spine Surgery Patients.

PubMed

Elsamadicy, Aladine A; Wang, Timothy Y; Back, Adam G; Sergesketter, Amanda; Warwick, Hunter; Karikari, Isaac O; Gottfried, Oren N

2016-12-01

The use of intraoperative steroids and their effects are relatively unknown and remain controversial. The aim of this study was to determine the effects of intraoperative steroid use on postoperative complications and length of hospital stay after spine surgery. Medical records of 1200 adult patients undergoing spine surgery at Duke University Medical Center during the period 2008-2010 were retrospectively reviewed; 495 (41.25%) patients were administered intraoperative steroids, and 705 (58.75%) patients were not administered intraoperative steroids. Patient demographics, comorbidities, and postoperative complication rates were collected. The primary outcomes investigated were postoperative complications, specifically length of hospital stay and infection rates. Patient demographics were similar between both cohorts. Comorbidities were also similar, with the intraoperative steroid use cohort having a higher number of patients with long-term steroid use than the no intraoperative steroid use cohort (6.95% [no steroids] vs. 13.74% [steroid use], P < 0.001). Operative variables, including length of operation and median number of fusion levels operated, were also similar between the 2 groups. Lumbar spine was the most common surgical location. Patients who were administered intraoperative steroids had a shorter length of hospital stay by an average of 1 day (6.06 days ± 6.76 [no steroids] vs. 5.04 days ± 4.86 [steroid use], P = 0.0025), lower rates of urinary tract infections (10.37% [no steroids] vs. 6.88% [steroid use], P = 0.040), and lower rates of other infections that were not deep or superficial surgical site infections (9.22% [no steroids] vs. 6.06% [steroid use], P = 0.0460). Patients who receive intraoperative steroids have shorter hospital stays and lower infection rates after spine surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Rapid test by liquid chromatography/tandem mass spectrometry to evaluate equine urine reactivity towards 17beta-OH steroids.

PubMed

Fidani, Marco; Casagni, Eleonora; Montana, Marco; Pasello, Emanuela; Pecoraro, Chiara; Gambaro, Veniero

2006-01-01

Bacteria frequently found in equine urine samples may cause degradation of 17beta-OH steroids. A simple liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed to evaluate the microbiological contamination of equine urine as a marker of poor storage conditions. Norethandrolone was used as the internal standard, and the linearity, sensitivity, precision and accuracy of the method were evaluated. 17beta-OH oxidation was demonstrated for testosterone, nandrolone, trenbolone and boldenone, but did not occur in alpha-epimers such as alpha-boldenone and epitestosterone, demonstrating the stereoselectivity of the reaction. A rapid test was performed by spiking one of the four 17beta-OH steroids in samples of diluted equine urine. The steroids were transformed into their respective ketones in the presence of bacterial activity. The test allows direct injection of diluted samples into the LC/MS system, without the need for prior extraction. Results show that the best method of storage is freezing at -18 degrees C. Urine specimens should be analyzed as soon as possible after thawing. This allows bacterial degradation of equine urine to be arrested temporarily, so that the urine can be used for qualitative or quantitative analysis of 17beta-OH steroids.

Androgens and estrogens in skeletal sexual dimorphism

PubMed Central

Laurent, Michaël; Antonio, Leen; Sinnesael, Mieke; Dubois, Vanessa; Gielen, Evelien; Classens, Frank; Vanderschueren, Dirk

2014-01-01

Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis. PMID:24385015

The islet estrogen receptor-α is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes.

PubMed

Kilic, Gamze; Alvarez-Mercado, Ana I; Zarrouki, Bader; Opland, Darren; Liew, Chong Wee; Alonso, Laura C; Myers, Martin G; Jonas, Jean-Christophe; Poitout, Vincent; Kulkarni, Rohit N; Mauvais-Jarvis, Franck

2014-01-01

The female steroid, 17β-estradiol (E2), is important for pancreatic β-cell function and acts via at least three estrogen receptors (ER), ERα, ERβ, and the G-protein coupled ER (GPER). Using a pancreas-specific ERα knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERαKO ⁻/⁻), we previously reported that islet ERα suppresses islet glucolipotoxicity and prevents β-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERα to prevent β-cell apoptosis in vivo. However, the contribution of the islet ERα to β-cell survival in vivo, without the contribution of ERα in other tissues is still unclear. Using the PERαKO ⁻/⁻ mouse, we show that ERα mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERα elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERαKO ⁻/⁻ mice exhibited a predisposition to β-cell destruction and insulin deficient diabetes. In male PERαKO ⁻/⁻ mice, exposure to E2 partially prevented alloxan-induced β-cell destruction and diabetes. ERα mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERα mRNA by hyperglycemia was retained in insulin receptor-deficient β-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERα expression acts to naturally protect β-cells against oxidative injury.

Regulation of schistosome egg production by HMG CoA reductase

DOE Office of Scientific and Technical Information (OSTI.GOV)

VandeWaa, E.A.; Bennett, J.L.

1986-03-05

Hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase) catalyzes the conversion of HMG CoA to mevalonate in the synthesis of steroids, isoprenoids and terpenes. Mevinolin, an inhibitor of this enzyme, decreased egg production in Schistosoma mansoni during in vitro incubations. This was associated with a reduction in the incorporation of /sup 14/C-acetate into polyisoprenoids and a reduction in the formation of a lipid-linked oligosaccharide. In vivo, mevinolin in daily doses of 50 mg/kg (p.o., from days 30-48 post-infection) caused no change in gross liver pathology in S. mansoni infected mice. However, when parasites exposed to mevinolin or its vehicle in vivomore » were cultured in vitro, worms from mevinolin-treated mice produced six times more eggs than control parasites. When infected mice were dosed with 250 mg/kg mevinolin daily (p.o., from days 35-45 post-infection), liver pathology was reduced in comparison to control mice. Thus, during in vivo exposure to a high dose of the drug egg production is decreased, while at a lower dose it appears unaffected until the parasites are cultured in a drug-free in vitro system wherein egg production is stimulated to extraordinarily high levels. It may be that at low doses mevinolin, by inhibiting the enzyme, is blocking the formation of a product (such as an isoprenoid) which normally acts to down-regulate enzyme synthesis, resulting in enzyme induction. Induction of HMG CoA reductase is then expressed as increased egg production when the worms are removed from the drug. These data suggest that HMG CoA reductase plays a role in schistosome egg production.« less

The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

PubMed Central

Selvaraj, Saravanakumar; Oh, Jung-Hwa; Spanel, Reinhard; Länger, Florian; Han, Hyoung-Yun; Lee, Eun-Hee; Yoon, Seokjoo; Borlak, Jürgen

2017-01-01

Hypersensitivity to non-steroidal anti-inflammatory drugs is a common adverse drug reaction and may result in serious inflammatory reactions of the liver. To investigate mechanism of immunoallergic hepatitis beagle dogs were given 1 or 3 mg/kg/day (HD) oral diclofenac for 28 days. HD diclofenac treatment caused liver function test abnormalities, reduced haematocrit and haemoglobin but induced reticulocyte, WBC, platelet, neutrophil and eosinophil counts. Histopathology evidenced hepatic steatosis and glycogen depletion, apoptosis, acute lobular hepatitis, granulomas and mastocytosis. Whole genome scans revealed 663 significantly regulated genes of which 82, 47 and 25 code for stress, immune response and inflammation. Immunopathology confirmed strong induction of IgM, the complement factors C3&B, SAA, SERPING1 and others of the classical and alternate pathway. Alike, marked expression of CD205 and CD74 in Kupffer cells and lymphocytes facilitate antigen presentation and B-cell differentiation. The highly induced HIF1A and KLF6 protein expression in mast cells and macrophages sustain inflammation. Furthermore, immunogenomics discovered 24, 17, 6 and 11 significantly regulated marker genes to hallmark M1/M2 polarized macrophages, lymphocytic and granulocytic infiltrates; note, the latter was confirmed by CAE staining. Other highly regulated genes included alpha-2-macroglobulin, CRP, hepcidin, IL1R1, S100A8 and CCL20. Diclofenac treatment caused unprecedented induction of myeloperoxidase in macrophages and oxidative stress as shown by SOD1/SOD2 immunohistochemistry. Lastly, bioinformatics defined molecular circuits of inflammation and consisted of 161 regulated genes. Altogether, the mechanism of diclofenac induced liver hypersensitivity reactions involved oxidative stress, macrophage polarization, mastocytosis, complement activation and an erroneous programming of the innate and adaptive immune system. PMID:29296203

Detection of potential (anti)progestagenic endocrine disruptors using a recombinant human progesterone receptor binding and transactivation assay.

PubMed

Viswanath, Gunda; Halder, Sujata; Divya, Gunda; Majumder, Chandrajeet B; Roy, Partha

2008-11-25

The present work describes the identification of (anti)progestin endocrine disrupting chemicals (EDC) using a two step screening system. In the first step a competitive binding assay was developed using recombinant human progesterone receptor (hPR). The tested chemicals were of various classes like insecticides, their metabolites, industrial chemicals and waste water treatment plant (WWTP) effluents. All the tested chemicals demonstrated a high affinity binding for hPR. The average IC50 values of the test chemicals were within the range of 1-25microM. In the second step of screening, a mammalian cell-based hPR transactivation assay was developed where HEK 293 cells were co-transfected with hPR and luciferase reporter gene under the control of progesterone-response element. Stimulation of the cells with progesterone resulted in about 25-fold up regulation of luciferase activity, with EC50 value of 4nM. Potent anti-progesterone, RU486, significantly inhibited progesterone-induced transactivation and non-progestagenic steroids failed to transactivate hPR till 1microM concentrations. The chemicals showing high binding affinities in competitive binding assays were then tested in transactivation assay and all of them were found to be anti-progestative except WWTP effluents. Transactivation assays using extracted water samples from five different WWTP effluents showed that it was rich in progestative compounds. The levels of induction caused by these effluents were in the range of 15-25% of induction by progesterone and they represented about 6ng/l equivalent progesterone activities. In conclusion, we demonstrated that this two step assay provides an efficient screening tool for the detection of (anti)progestative EDC in various samples.

14 CFR 29.1091 - Air induction.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Air induction. 29.1091 Section 29.1091... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1091 Air induction. (a) The air induction system for each engine and auxiliary power unit must supply the air required by that engine and...

14 CFR 29.1091 - Air induction.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Air induction. 29.1091 Section 29.1091... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1091 Air induction. (a) The air induction system for each engine and auxiliary power unit must supply the air required by that engine and...

14 CFR 29.1091 - Air induction.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Air induction. 29.1091 Section 29.1091... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1091 Air induction. (a) The air induction system for each engine and auxiliary power unit must supply the air required by that engine and...

14 CFR 27.1091 - Air induction.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Air induction. 27.1091 Section 27.1091... STANDARDS: NORMAL CATEGORY ROTORCRAFT Powerplant Induction System § 27.1091 Air induction. (a) The air induction system for each engine must supply the air required by that engine under the operating conditions...

14 CFR 27.1091 - Air induction.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Air induction. 27.1091 Section 27.1091... STANDARDS: NORMAL CATEGORY ROTORCRAFT Powerplant Induction System § 27.1091 Air induction. (a) The air induction system for each engine must supply the air required by that engine under the operating conditions...

14 CFR 27.1091 - Air induction.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Air induction. 27.1091 Section 27.1091... STANDARDS: NORMAL CATEGORY ROTORCRAFT Powerplant Induction System § 27.1091 Air induction. (a) The air induction system for each engine must supply the air required by that engine under the operating conditions...

14 CFR 27.1091 - Air induction.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Air induction. 27.1091 Section 27.1091... STANDARDS: NORMAL CATEGORY ROTORCRAFT Powerplant Induction System § 27.1091 Air induction. (a) The air induction system for each engine must supply the air required by that engine under the operating conditions...

14 CFR 27.1091 - Air induction.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Air induction. 27.1091 Section 27.1091... STANDARDS: NORMAL CATEGORY ROTORCRAFT Powerplant Induction System § 27.1091 Air induction. (a) The air induction system for each engine must supply the air required by that engine under the operating conditions...

14 CFR 29.1091 - Air induction.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Air induction. 29.1091 Section 29.1091... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1091 Air induction. (a) The air induction system for each engine and auxiliary power unit must supply the air required by that engine and...

14 CFR 29.1091 - Air induction.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Air induction. 29.1091 Section 29.1091... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1091 Air induction. (a) The air induction system for each engine and auxiliary power unit must supply the air required by that engine and...

Engineering Design Handbook. Helicopter Engineering. Part One. Preliminary Design

DTIC Science & Technology

1974-08-30

1.3 ENGINE REPLACEMENT .............. ......................... 8-1 8-1.4 ENGINE AIR INDUCTION SYSTEM .............................. 8-2 8-1.5 ENGINE ...8-5 8-2.2 ENGINE AIR INDUCTION SYSTEM .............................. 8-5 8-2.2.1 G eneral Design...8-5 8-2.2.2 Air Induction System Inlet Location ............................... 8-6 8-2.2.3 Engine Air Induction System Pressure Losses

Outcomes Associated with Steroid Avoidance and Alemtuzumab among Kidney Transplant Recipients.

PubMed

Serrano, Oscar K; Friedmann, Patricia; Ahsanuddin, Sayeeda; Millan, Carlos; Ben-Yaacov, Almog; Kayler, Liise K

2015-11-06

Alemtuzumab is a humanized anti-CD52 monoclonal antibody used as induction in kidney transplantation (KTX) since 2003. Few studies have evaluated long-term outcomes of this agent or changes in outcomes over time. A retrospective cohort study was performed examining United States registry data from 2003 to 2014 of primary KTX recipients receiving induction with alemtuzumab (AZ; n=5521) or antithymocyte globulin (ATG; n=8504) and maintenance immunosuppression with tacrolimus and mycophenolate mofetil and early withdrawal of steroids. The primary outcome was overall death-censored graft survival (DCGS), and secondary outcomes were overall patient survival and 1-year acute rejection. Multivariate models were fit with donor, recipient, and transplant covariates. Because poorer outcomes with AZ may occur from a learning curve impact with the use of a new medication, transplant year was categorized into three time periods to evaluate outcomes over time (2003-2005, 2006-2008, ≥2009), and an interaction term of induction type with transplant year category was included in all models to test for era impacts. On multivariate analysis of DCGS there was a significant interaction between AZ and era (P<0.001). AZ was significantly associated with inferior DCGS in the earliest 2003-2005 era (adjusted hazard ratio [aHR], 2.21; 95% confidence interval [95% CI], 1.72 to 2.84) but not in the middle 2006-2008 era (aHR, 1.14; 95% CI, 0.96 to 1.36) or the most recent 2009-2014 era (aHR, 1.08; 95% CI, 0.90 to 1.29) compared with ATG. Risk-adjusted patient survival (aHR, 1.32; 95% CI, 1.08 to 1.61; aHR, 1.26; 95% CI, 1.09 to 1.46; and aHR, 1.10; 95% CI, 0.93 to 1.29 by era, respectively) and acute rejection (adjusted odds ratio [aOR], 1.17; 95% CI, 0.96 to 1.42; aOR, 0.94; 95% CI, 0.82 to 1.07; aOR, 0.89; 95% CI, 0.81 to 0.98 by era, respectively) with AZ was comparable with ATG in the most recent era; however, there was no significant interaction with time (P=0.13 and P=0.06, respectively). Current alemtuzumab utilization is associated with comparable graft and patient survival and acute rejection compared with ATG. Graft survival with alemtuzumab has improved over time. Copyright © 2015 by the American Society of Nephrology.

Outcomes Associated with Steroid Avoidance and Alemtuzumab among Kidney Transplant Recipients

PubMed Central

Serrano, Oscar K.; Friedmann, Patricia; Ahsanuddin, Sayeeda; Millan, Carlos; Ben-Yaacov, Almog

2015-01-01

Background and objectives Alemtuzumab is a humanized anti-CD52 monoclonal antibody used as induction in kidney transplantation (KTX) since 2003. Few studies have evaluated long-term outcomes of this agent or changes in outcomes over time. Design, setting, participants, & measurements A retrospective cohort study was performed examining United States registry data from 2003 to 2014 of primary KTX recipients receiving induction with alemtuzumab (AZ; n=5521) or antithymocyte globulin (ATG; n=8504) and maintenance immunosuppression with tacrolimus and mycophenolate mofetil and early withdrawal of steroids. The primary outcome was overall death-censored graft survival (DCGS), and secondary outcomes were overall patient survival and 1-year acute rejection. Multivariate models were fit with donor, recipient, and transplant covariates. Because poorer outcomes with AZ may occur from a learning curve impact with the use of a new medication, transplant year was categorized into three time periods to evaluate outcomes over time (2003–2005, 2006–2008, ≥2009), and an interaction term of induction type with transplant year category was included in all models to test for era impacts. Results On multivariate analysis of DCGS there was a significant interaction between AZ and era (P<0.001). AZ was significantly associated with inferior DCGS in the earliest 2003–2005 era (adjusted hazard ratio [aHR], 2.21; 95% confidence interval [95% CI], 1.72 to 2.84) but not in the middle 2006–2008 era (aHR, 1.14; 95% CI, 0.96 to 1.36) or the most recent 2009–2014 era (aHR, 1.08; 95% CI, 0.90 to 1.29) compared with ATG. Risk-adjusted patient survival (aHR, 1.32; 95% CI, 1.08 to 1.61; aHR, 1.26; 95% CI, 1.09 to 1.46; and aHR, 1.10; 95% CI, 0.93 to 1.29 by era, respectively) and acute rejection (adjusted odds ratio [aOR], 1.17; 95% CI, 0.96 to 1.42; aOR, 0.94; 95% CI, 0.82 to 1.07; aOR, 0.89; 95% CI, 0.81 to 0.98 by era, respectively) with AZ was comparable with ATG in the most recent era; however, there was no significant interaction with time (P=0.13 and P=0.06, respectively). Conclusions Current alemtuzumab utilization is associated with comparable graft and patient survival and acute rejection compared with ATG. Graft survival with alemtuzumab has improved over time. PMID:26342042

Steroid profiling reveals widespread local regulation of glucocorticoid levels during mouse development.

PubMed

Taves, Matthew D; Plumb, Adam W; Sandkam, Benjamin A; Ma, Chunqi; Van Der Gugten, Jessica Grace; Holmes, Daniel T; Close, David A; Abraham, Ninan; Soma, Kiran K

2015-02-01

Glucocorticoids (GCs) are produced by the adrenal glands and circulate in the blood to coordinate organismal physiology. In addition, different tissues may independently regulate their local GC levels via local GC synthesis. Here, we find that in the mouse, endogenous GCs show tissue-specific developmental patterns, rather than mirroring GCs in the blood. Using solid-phase extraction, HPLC, and specific immunoassays, we quantified endogenous steroids and found that in tissues of female and male mice, (1) local GC levels can be much higher than systemic GC levels, (2) local GCs follow age-related patterns different from those of systemic GCs, and (3) local GCs have identities different from those of systemic GCs. For example, whereas corticosterone is the predominant circulating adrenal GC in mice, high concentrations of cortisol were measured in neonatal thymus, bone marrow, and heart. The presence of cortisol was confirmed with liquid chromatography-tandem mass spectrometry. In addition, gene expression of steroidogenic enzymes was detected across multiple tissues, consistent with local GC production. Our results demonstrate that local GCs can differ from GCs in circulating blood. This finding suggests that steroids are widely used as local (paracrine or autocrine) signals, in addition to their classic role as systemic (endocrine) signals. Local GC regulation may even be the norm, rather than the exception, especially during development.

[Steroid hormones and pancreas: a new paradigm].

PubMed

Morales-Miranda, Angélica; Robles-Díaz, Guillermo; Díaz-Sánchez, Vicente

2007-01-01

The relation between steroid hormones and pancreatic function has been poorly discussed and not very well understood. In general, there is a lack of recognition among the scientific community about the importance of steroids in pancreatic function (current paradigm). In the present article we present basic, as well as clinic and epidemiologic data that demonstrate steroid synthesis and steroid biotransformation by pancreatic tissue, how exocrine and endocrine functions are modulated by steroids, the gender specific frequency and behavior of some tumors and the use of synthetic steroids and steroid action antagonists as therapeutic agents. With the available information it is possible to establish that: 1. Pancreatic tissue synthesize and transform steroid hormones. 2. Pancreatic tissue respond to steroid hormones and express steroid specific receptor molecules. 3. Some endocrine functions such as insulin synthesis and release are modulated by steroids. 4. Tumor growth is modulated by steroids and anti-steroid drugs. This set of data creates a new paradigm for the holistic study of pancreas and opens new research fields. The application of this new paradigm might result in an increase in the knowledge of pancreatic physiology, in the design of new and better diagnostic methods and eventually in the design of more effective medical treatments for the pancreatic cancers.

Food allergy and asthma morbidity in children.

PubMed

Simpson, Alyson B; Glutting, Joe; Yousef, Ejaz

2007-06-01

Coexisting food allergy and asthma is a significant problem in the pediatric population. Studies have looked at the association between food sensitization and asthma severity. It is unknown whether specific food allergies are associated with increased asthma morbidity. We studied the independent effect that allergy to egg, milk, fish, and peanut has on the number of hospitalizations and courses of systemic steroids in children with asthma. We performed a medical record review to evaluate the effect food allergy to egg, fish, peanut, and milk has on asthma morbidity. We reviewed the records of 201 children aged 3 months to 14 years with the diagnosis of asthma (ICD-9 codes 493.90, 493.91, and 493.92), of which 88 had coexistent food allergy. All children in the food allergy group had food-specific IgE concentrations greater than the 95% positive predictive value. We compared the rate of hospitalizations and use of systemic steroids between children with asthma and food allergies and those without coexisting food allergy using direct-entry, multiple regression analysis. Patients were adjusted for the severity of their asthma based on symptoms documented at their first visit to the allergist according to the National Asthma Education and Prevention Program guidelines and presence of environmental allergy, eczema, smoke exposure, and gastroesophageal reflux. Peanut and milk allergies were both associated with increased number of hospitalizations (P=0.009, 0.016), and milk allergy was associated with increased use of systemic steroids (P=0.001). Peanut and milk allergies were associated with increased hospitalization and steroid use and may serve as early markers for increased asthma morbidity. (c) 2007 Wiley-Liss, Inc.

Lactobacillus plantarum Strains Can Enhance Human Mucosal and Systemic Immunity and Prevent Non-steroidal Anti-inflammatory Drug Induced Reduction in T Regulatory Cells

PubMed Central

de Vos, Paul; Mujagic, Zlatan; de Haan, Bart J.; Siezen, Roland J.; Bron, Peter A.; Meijerink, Marjolein; Wells, Jerry M.; Masclee, Ad A. M.; Boekschoten, Mark V.; Faas, Marijke M.; Troost, Freddy J.

2017-01-01

Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or WCFS1) or placebo for 7 days. To determine whether L. plantarum can enhance immune response, we compared the effects of three stains on systemic and gut mucosal immunity, by among others assessing memory responses against tetanus toxoid (TT)-antigen, and mucosal gene transcription, in human volunteers during induction of mild immune stressor in the intestine, by giving a commonly used enteropathic drug, indomethacin [non-steroidal anti-inflammatory drug (NSAID)]. Systemic effects of the interventions were studies in peripheral blood samples. NSAID was found to induce a reduction in serum CD4+/Foxp3 regulatory cells, which was prevented by L. plantarum TIFN101. T-cell polarization experiments showed L. plantarum TIFN101 to enhance responses against TT-antigen, which indicates stimulation of memory responses by this strain. Cell extracts of the specific L. plantarum strains provoked responses after WCFS1 and TIFN101 consumption, indicating stimulation of immune responses against the specific bacteria. Mucosal immunomodulatory effects were studied in duodenal biopsies. In small intestinal mucosa, TIFN101 upregulated genes associated with maintenance of T- and B-cell function and antigen presentation. Furthermore, L. plantarum TIFN101 and WCFS1 downregulated immunological pathways involved in antigen presentation and shared downregulation of snoRNAs, which may suggest cellular destabilization, but may also be an indicator of tissue repair. Full sequencing of the L. plantarum strains revealed possible gene clusters that might be responsible for the differential biological effects of the bacteria on host immunity. In conclusion, the impact of oral consumption L. plantarum on host immunity is strain dependent and involves responses against bacterial cell components. Some strains may enhance specific responses against pathogens by enhancing antigen presentation and leukocyte maintenance in mucosa. In future studies and clinical settings, caution should be taken in selecting beneficial bacteria as closely related strains can have different effects. Our data show that specific bacterial strains can prevent immune stress induced by commonly consumed painkillers such as NSAID and can have enhancing beneficial effects on immunity of consumers by stimulating antigen presentation and memory responses. PMID:28878772

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): An Uncommon Manifestation of Systemic Lupus Erythematosus (SLE)

PubMed Central

Abraham, Hrudya; Kuzhively, Jose; Rizvi, Syed W.

2017-01-01

Patient: Female, 40 Final Diagnosis: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Symptoms: Gait disorder Medication: — Clinical Procedure: — Specialty: Rheumatology Objective: Rare disease Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon manifestation of systemic lupus erythematosus (SLE). We report a case of SLE presenting as CIDP and discuss the diagnosis, management, and prognosis of CIDP. Case Report: A 40-year-old woman with a past medical history of SLE treated with hydroxychloroquine presented with bilateral, progressive, ascending, sensory and motor neuropathy. Physical examination showed weakness and reduced temperature of all extremities, reduced pinprick and vibration sense of the distal extremities, loss of reflexes, and walking with a wide-based unsteady gait. Laboratory investigations showed positive antinuclear antibodies (ANA), anti-(smooth muscle (SM) antibody, anti-RNP antibody, anti-SSA antibody, anti-ds-DNA antibody, and an erythrocyte sedimentation rate (ESR) of 75 mm/hr, low C4, leukopenia, and anemia. Electromyography (EMG) confirmed the diagnosis of CIDP. The patient’s neuropathy and muscle weakness improved on treatment with intravenous immunoglobulin (IVIG) and high-dose steroids. Conclusions: The early clinical diagnosis of CIDP, supported by serological autoantibody profiles associated with SLE, can predict a good response to steroids. Most patients with CIDP are treated successfully with steroids if the diagnosis is made early. IVIG, plasmapheresis, or immunosuppressive therapy should be considered if there is no response to steroids. PMID:28894082

Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation.

PubMed

Ertas, Merve; Sahin, Zafer; Berk, Barkin; Yurttas, Leyla; Biltekin, Sevde N; Demirayak, Seref

2018-04-01

Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine-substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC 50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules. © 2018 Deutsche Pharmazeutische Gesellschaft.

Updates in Reproduction Coming from the Endocannabinoid System

PubMed Central

Bradshaw, Heather B.

2014-01-01

The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility. PMID:24550985

Steroids

MedlinePlus

... Staying Safe Videos for Educators Search English Español Steroids KidsHealth / For Kids / Steroids What's in this article? ... a good idea to avoid them. What Are Steroids? "Steroids" has more than one meaning. Your body ...

Induction generators for Wind Energy Conversion Systems. Part I: review of induction generator with squirrel cage rotor. Part II: the Double Output Induction Generator (DOIG). Progress report, July-December 1975

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jayadev, T.S.

1976-02-01

The application of induction generators in Wind Energy Conversion Systems (WECS) is described. The conventional induction generator, which is an induction machine with a squirrel cage rotor, had been used in large wind power plants in Europe, but has not caught much attention until now by designers of large systems in this country. The induction generator with a squirrel cage rotor is described and useful design techniques to build induction generators for wind energy application are outlined. The Double Output Induction Generator (DOIG) - so called because power is fed into the grid from the stator, as well as themore » rotor is described. It is a wound rotor induction machine with power electronics to convert rotor slip frequency power to that of line frequency.« less

Modeling induction heater temperature distribution in polymeric material

NASA Astrophysics Data System (ADS)

Sorokin, A. G.; Filimonova, O. V.

2017-10-01

An induction heating system has a number of inherent benefits compared to traditional heating systems due to a non-contact heating process. The main interesting area of the induction heating process is the efficiency of the usage of energy, choice of the plate material and different coil configurations based on application. Correctly designed, manufactured and maintained induction coils are critical to the overall efficiency of induction heating solutions. The paper describes how the induction heating system in plastic injection molding is designed. The use of numerical simulation in order to get the optimum design of the induction coil is shown. The purpose of this work is to consider various coil configurations used in the induction heating process, which is widely used in plastic molding. Correctly designed, manufactured and maintained induction coils are critical to the overall efficiency of induction heating solutions. The results of calculation are in the numerical model.

Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions

PubMed Central

Shu, H-J; Zeng, C-M; Wang, C; Covey, D F; Zorumski, C F; Mennerick, S

2006-01-01

Background and purpose: Neuroactive steroids are potent modulators of GABAA receptors and are thus of interest for their sedative, anxiolytic, anticonvulsant and anaesthetic properties. Cyclodextrins may be useful tools to manipulate neuroactive effects of steroids on GABAA receptors because cyclodextrins form inclusion complexes with at least some steroids that are active at the GABAA receptor, such as (3α,5α)-3-hydroxypregnan-20-one (3α5αP, allopregnanolone). Experimental approach: To assess the versatility of cyclodextrins as steroid modulators, we investigated interactions between γ-cyclodextrin and neuroactive steroids of different structural classes. Key results: Both a bioassay based on electrophysiological assessment of GABAA receptor function and optical measurements of cellular accumulation of a fluorescent steroid analogue suggest that γ-cyclodextrin sequesters steroids rather than directly influencing GABAA receptor function. Neither a 5β-reduced A/B ring fusion nor a sulphate group at carbon 3 affected the presumed inclusion complex formation between steroid and γ-cyclodextrin. Apparent dissociation constants for interactions between natural steroids and γ-cyclodexrin ranged from 10-60 μM. Although γ-cyclodextrin accommodates a range of natural and synthetic steroids, C11 substitutions reduced inclusion complex formation. Using γ-cyclodextrin to remove steroid not directly bound to GABAA receptors, we found that cellular retention of receptor-unbound steroid rate limits potentiation by 3α- hydroxysteroids but not inhibition by sulphated steroids. Conclusions and implications: We conclude that γ-cyclodextrins can be useful, albeit non-specific, tools for terminating the actions of multiple classes of naturally occurring neuroactive steroids. PMID:17160009

14 CFR 23.1107 - Induction system filters.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Induction system filters. 23.1107 Section... § 23.1107 Induction system filters. If an air filter is used to protect the engine against foreign material particles in the induction air supply— (a) Each air filter must be capable of withstanding the...

14 CFR 23.1107 - Induction system filters.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Induction system filters. 23.1107 Section... § 23.1107 Induction system filters. If an air filter is used to protect the engine against foreign material particles in the induction air supply— (a) Each air filter must be capable of withstanding the...

14 CFR 23.1107 - Induction system filters.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Induction system filters. 23.1107 Section... § 23.1107 Induction system filters. If an air filter is used to protect the engine against foreign material particles in the induction air supply— (a) Each air filter must be capable of withstanding the...

14 CFR 23.1107 - Induction system filters.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Induction system filters. 23.1107 Section... § 23.1107 Induction system filters. If an air filter is used to protect the engine against foreign material particles in the induction air supply— (a) Each air filter must be capable of withstanding the...

14 CFR 23.1107 - Induction system filters.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Induction system filters. 23.1107 Section... § 23.1107 Induction system filters. If an air filter is used to protect the engine against foreign material particles in the induction air supply— (a) Each air filter must be capable of withstanding the...

Intralesional steroid therapy of pyoderma gangrenosum.

PubMed

Goldstein, F; Krain, R; Thornton, J J

1985-12-01

Treatment of pyoderma gangrenosum complicating ulcerative colitis has in the past been frustrating and usually unsuccessful, frequently resulting in colectomy. Intralesional steroid therapy has been used off and on in a few patients, but the treatment is not widely known to gastroenterologists. We report two patients successfully treated for early pyoderma gangrenosum by intralesional injection of triamcinolone acetonide (Kenalog, 40 mg injection) together with conventional doses of systemic steroids. A single series of injections was sufficient to bring about healing of the lesions in both patients. The treatment permitted early discharge of patients from the hospital, and the skin lesions were completely healed within 2 months. The lesions have not recurred in follow-up examinations of 11/2 and 21/2 years, respectively. We hope that other physicians will find this approach equally effective.

Disordered follicle development

PubMed Central

Chang, R. Jeffrey; Cook-Andersen, Heidi

2013-01-01

Alterations of ovarian follicle morphology and function have been well documented in women with PCOS. These include increased numbers of growing preantral follicles, failure of follicle growth beyond the mid-antral stage, evidence of granulosa call degeneration, and theca cell hyperplasia. Functional abnormalities include paradoxical granulosa cell hyperresponsiveness to FSH which is clinically linked to ovarian hyperstimulation during ovulation induction. In addition, there is likely a primary theca cell defect that accounts for the majority of excess androgen production in this disorder. The precise mechanisms responsible for altered follicle function are not completely clear. However, several factors appear to influence normal advancement of follicle development as well as impair ovarian steroidogenesis. These include intra- as well as extraovarian influences that distort normal ovarian growth and disrupt steroid production by follicle cells. PMID:22874072

Lithocholic acid is an endogenous inhibitor of MDM4 and MDM2

PubMed Central

Vogel, Simon M.; Bauer, Matthias R.; Joerger, Andreas C.; Wilcken, Rainer; Brandt, Tobias; Veprintsev, Dmitry B.; Rutherford, Trevor J.; Fersht, Alan R.; Boeckler, Frank M.

2012-01-01

The proteins MDM2 and MDM4 are key negative regulators of the tumor suppressor protein p53, which are frequently upregulated in cancer cells. They inhibit the transactivation activity of p53 by binding separately or in concert to its transactivation domain. MDM2 is also a ubiquitin ligase that leads to the degradation of p53. Accordingly, MDM2 and MDM4 are important targets for drugs to inhibit their binding to p53. We found from in silico screening and confirmed by experiment that lithocholic acid (LCA) binds to the p53 binding sites of both MDM2 and MDM4 with a fivefold preference for MDM4. LCA is an endogenous steroidal bile acid, variously reported to have both carcinogenic and apoptotic activities. The comparison of LCA effects on apoptosis in HCT116 p53+/+ vs. p53-/- cells shows a predominantly p53-mediated induction of caspase-3/7. The dissociation constants are in the μM region, but only modest inhibition of binding of MDM2 and MDM4 is required to negate their upregulation because they have to compete with transcriptional coactivator p300 for binding to p53. Binding was weakened by structural changes in LCA, and so it may be a natural ligand of MDM2 and MDM4, raising the possibility that MDM proteins may be sensors for specific steroids. PMID:23035244

Highly sensitive and selective analysis of urinary steroids by comprehensive two-dimensional gas chromatography combined with positive chemical ionization quadrupole mass spectrometry

PubMed Central

Zhang, Ying; Tobias, Herbert J.; Brenna, J. Thomas

2014-01-01

Comprehensive two dimensional gas chromatography (GC×GC) provides greater separation space than conventional GC. Because of fast peak elution, a time of flight mass spectrometer (TOFMS) is the usual structure-specific detector of choice. The quantitative capabilities of a novel GC×GC fast quadrupole MS were investigated with electron ionization (EI), and CH4 or NH3 positive chemical ionization (PCI) for analysis of endogenous urinary steroids targeted in anti-doping tests. Average precisions for steroid quantitative analysis from replicate urine extractions were 6% (RSD) for EI and 8% for PCI-NH3. The average limits of detection (LOD) calculated by quantification ions for 12 target steroids spiked into steroid-free urine matrix (SFUM) were 2.6 ng mL−1 for EI, 1.3 ng mL−1 for PCI-CH4, and 0.3 ng mL−1 for PCI-NH3, all in mass scanning mode. The measured limits of quantification (LOQ) with full mass scan GC×GC-qMS were comparable with the LOQ values measured by one-dimensional GC-MS in single ion monitoring (SIM) mode. PCI-NH3 yields fewer fragments and greater (pseudo)molecular ion abundances than EI or PCI-CH4. These data show a benchtop GC×GC-qMS system has the sensitivity, specificity, and resolution to analyze urinary steroids at normal urine concentrations, and that PCI-NH3, not currently available on most GC×GC-TOFMS instruments, is of particular value for generation of structure-specific ions. PMID:22606686

Synthesis of 19-nor-aldosterone, 18-hydroxy-19-nor-corticosterone and 18,19-dihydroxycorticosterone in the human aldosterone-producing adenoma.

PubMed

Takeda, Y; Lewicka, S; Koch, S; Bige, K; Vecsei, P; Abdelhamid, S; Cojocaru, M; Harnik, M

1990-11-30

The recently synthesized 18-C-steroid derivative, 19-nor-aldosterone(19-nor- aldo) and 18-hydroxy-19-nor-corticosterone(18-OH-19-nor-corticosterone) possess mineralocoroticoid and hypertensinogenic activity. They and an additional newly synthesized steriod, 18,19-dihydroxycorticosterone[18,19(OH)2-corticosterone], may play a role in the etiology and pathogenesis of disorders thought to be caused by steroids with mineralocorticoid and hypertensionogenic properties. In this study we provide evidence that 19-nor-aldo, 18-OH-19-nor-corticosterone and 18,19(OH)2-corticosterone are produced in vitro by aldosterone-producing adrenal adenomas and adenomas and adenoma of Cushing's syndrome. "silent" adrenal adenomas and the adjacent adrenal tissue. Measurable amounts of these steroids were found in the incubation fluids of adrenal tissues using specific RIAs performed after a sequence of HPLC systems. The rates of production of the three steroids were high in the aldosterone-producing adrenal adenomas and in adrenal hyperplasia compared with in either Cushing's adenoma or "silent" adenoma.

Effect of sexual steroids on boar kinematic sperm subpopulations.

PubMed

Ayala, E M E; Aragón, M A

2017-11-01

Here, we show the effects of sexual steroids, progesterone, testosterone, or estradiol on motility parameters of boar sperm. Sixteen commercial seminal doses, four each of four adult boars, were analyzed using computer assisted sperm analysis (CASA). Mean values of motility parameters were analyzed by bivariate and multivariate statistics. Principal component analysis (PCA), followed by hierarchical clustering, was applied on data of motility parameters, provided automatically as intervals by the CASA system. Effects of sexual steroids were described in the kinematic subpopulations identified from multivariate statistics. Mean values of motility parameters were not significantly changed after addition of sexual steroids. Multivariate graphics showed that sperm subpopulations were not sensitive to the addition of either testosterone or estradiol, but sperm subpopulations responsive to progesterone were found. Distribution of motility parameters were wide in controls but sharpened at distinct concentrations of progesterone. We conclude that kinematic sperm subpopulations responsive to progesterone are present in boar semen, and these subpopulations are masked in evaluations of mean values of motility parameters. © 2017 International Society for Advancement of Cytometry. © 2017 International Society for Advancement of Cytometry.

Protective effect of rimexolone on cartilage damage in arthritic mice: a comparative study with triamcinolone hexacetonide.

PubMed

Joosten, L A; Helsen, M M; van den Berg, W B

1990-08-01

We studied the effect of the local steroid preparation rimexolone on cartilage metabolism in arthritis and normal joints. Prolonged anti-inflammatory action was evident after intraarticular injection of a single dose of 450 micrograms into mice with monoarticular antigen-induced arthritis. Suppression of inflammation lasted for at least 21 days. A single dose of 25 micrograms of the anti-inflammatory steroid triamcinolone hexacetonide (THA) induced comparable suppression in the initial stage of the arthritis, but the suppressive action was of shorter duration. Both drugs significantly prevented osteophyte formation, which is a characteristic feature of this type of experimental arthritis. Although chondrocyte proteoglycan (PG) synthesis in patellar cartilage was significantly suppressed upon injection in normal joints, both steroids counteracted the severe suppression of PG synthesis in arthritic joints. These data indicate that although steroids may have significant side effects on chondrocytes, the overall effect on arthritic chondrocytes is beneficial. An advantage of rimexolone over THA is its prolonged retention, which may explain its sustained anti-inflammatory action, and the lack of systemic effects.

Optimised deconjugation of androgenic steroid conjugates in bovine urine.

PubMed

Pedersen, Mikael; Frandsen, Henrik L; Andersen, Jens H

2017-04-01

After administration of steroids to animals the steroids are partially metabolised in the liver and kidney to phase 2 metabolites, i.e., glucuronic acid or sulphate conjugates. During analysis these conjugated metabolites are normally deconjugated enzymatically with aryl sulphatase and glucuronidase resulting in free steroids in the extract. It is well known that some sulphates are not deconjugated using aryl sulphatase; instead, for example, solvolysis can be used for deconjugation of these aliphatic sulphates. The effectiveness of solvolysis on androgenic steroid sulphates was tested with selected aliphatic steroid sulphates (boldenone sulphate, nortestosteron sulphate and testosterone sulphate), and the method was validated for analysis of androgenic steroids in bovine urine using free steroids, steroid sulphates and steroid glucuronides as standards. Glucuronidase and sulphuric acid in ethyl acetate were used for deconjugation and the extract was purified by solid-phase extraction. The final extract was evaporated to dryness, re-dissolved and analysed by LC-MS/MS.

Effects of selective type I and II adrenal steroid agonists on immune cell distribution.

PubMed

Miller, A H; Spencer, R L; hassett, J; Kim, C; Rhee, R; Ciurea, D; Dhabhar, F; McEwen, B; Stein, M

1994-11-01

Adrenal steroids exert their effects through two distinct adrenal steroid receptor subtypes; the high affinity type I, or mineralocorticoid, receptor and the lower affinity type II, or glucocorticoid, receptor. Adrenal steroids have well known effects on immune cell distribution, and although both type I and II receptors are expressed in immune cells and tissues, few data exist on the relative effects mediated through these two receptor subtypes. Accordingly, we administered selective type I and II adrenal steroid receptor agonists to young adult male Sprague-Dawley rats for 7 days and then measured immune cell distribution in the peripheral blood and spleen. Results were compared with those of similar studies using the naturally occurring glucocorticoid of the rat, corticosterone, which binds both type I and II receptors. The majority of the well characterized effects of adrenal steroids on peripheral blood immune cells (increased neutrophils and decreased lymphocytes and monocytes) were reproduced by the type II receptor agonist, RU28362. RU28362 decreased the numbers of all lymphocyte subsets [T-cells, B-cells, and natural killer (NK) cells] to very low absolute levels. The largest relative decrease (i.e. in percentage) was seen in B-cells, whereas NK cells exhibited the least relative decrease and actually showed a 2-fold increase in relative percentage during RU28362 treatment. Similar to RU28362, the type I receptor agonist, aldosterone, significantly reduced the number of lymphocytes and monocytes. In contrast to RU28362, however, aldosterone significantly decreased the number of neutrophils. Moreover, aldosterone decreased the number of T-helper cells and NK cells, while having no effect on the number of B-cells or T-suppressor/cytotoxic cells. Corticosterone at physiologically relevant concentrations had potent effects on immune cell distribution, which were indistinguishable from those of the type II receptor agonist, RU28362. Taken together, these results indicate that effects of adrenal steroids on immune cell distribution are dependent on the receptor subtype involved as well as the specific cell type targeted. These factors allow for varied and complex effects of adrenal steroids on the immune system under physiological conditions.

Detection of Synthetic Testosterone Use by Novel Comprehensive Two-Dimensional Gas Chromatography Combustion Isotope Ratio Mass Spectrometry (GC×GCC-IRMS)

PubMed Central

Tobias, Herbert J.; Zhang, Ying; Auchus, Richard J.; Brenna, J. Thomas

2011-01-01

We report the first demonstration of Comprehensive Two-dimensional Gas Chromatography Combustion Isotope Ratio Mass Spectrometry (GC×GCC-IRMS) for the analysis of urinary steroids to detect illicit synthetic testosterone use, of interest in sport doping. GC coupled to IRMS (GCC-IRMS) is currently used to measure the carbon isotope ratios (CIR, δ13C) of urinary steroids in anti-doping efforts; however, extensive cleanup of urine extracts is required prior to analysis to enable baseline separation of target steroids. With its greater separation capabilities, GC×GC has the potential to reduce sample preparation requirements and enable CIR analysis of minimally processed urine extracts. Challenges addressed include on-line reactors with minimized dimensions to retain narrow peaks shapes, baseline separation of peaks in some cases, and reconstruction of isotopic information from sliced steroid chromatographic peaks. Difficulties remaining include long-term robustness of on-line reactors and urine matrix effects that preclude baseline separation and isotopic analysis of low concentration and trace components. In this work, steroids were extracted, acetylated, and analyzed using a refined, home-built GC×GCC-IRMS system. 11-hydroxy-androsterone (11OHA) and 11-ketoetiocolanolone (11KE) were chosen as endogenous reference compounds (ERC) because of their satisfactory signal intensity, and their CIR was compared to target compounds (TC) androsterone (A) and etiocholanolone (E). Separately, a GC×GC-qMS system was used to measure testosterone (T)/EpiT concentration ratios. Urinary extracts of urine pooled from professional athletes, and urine from one individual that received testosterone gel (T-gel) and one individual that received testosterone injections (T-shot) were analyzed. The average precisions of δ13C and Δδ13C measurements were SD(δ13C) approximately ± 1‰ (n=11). The T-shot sample resulted in a positive for T use with a T/EpiT ratio of > 9 and CIR measurements of Δδ13C > 5‰, both fulfilling World Anti-Doping Agency criteria. These data show for the first time that synthetic steroid use is detectable by GC×GCC-IRMS without need for extensive urine cleanup. PMID:21846122

Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jacobs, Miriam N.; Nolan, Gail T.; Hood, Steven R.

2005-12-01

The pregnane X receptor (PXR) mediates the induction of enzymes involved in steroid metabolism and xenobiotic detoxification. The receptor is expressed in liver and intestinal tissues and is activated by a wide range of compounds. The ability of a diverse range of dietary compounds to activate PXR-mediated transcription was assayed in HuH7 cells following transient transfection with human PXR (hPXR). The compounds investigated included phytochemicals such as lignans and phytoestrogens, organochlorine dietary contaminants such as polychlorinated biphenyls (PCBs) and triclosan and selected steroid, drug and herbal compounds. The hPXR activation at the top concentrations tested (10 {mu}M) relative to themore » positive control 10 {mu}M rifampicin ranged from 1.3% (trans-resveratrol) to 152% (ICI 182780). Hydroxylated compounds were marginally more potent than the parent compounds (tamoxifen activation was 74.6% whereas 4 hydroxytamoxifen activation was 84.2%) or significantly greater (vitamin D{sub 3} activation was 1.6%, while hydroxylated vitamin D{sub 3} activation was 55.6%). Enterolactone, the metabolite of common dietary lignans, was a medium activator of PXR (35.6%), compared to the lower activation of a parent lignan, secoisolariciresinol (20%). Two non-hydroxylated PCB congeners (PCB 118 and 153), which present a larger fraction of the PCB contamination of fatty foods, activated hPXR by 26.6% and 17%, respectively. The pesticide trans-nonachlor activation was 53.8%, while the widely used bacteriocide triclosan was a medium activator of hPXR at 46.2%. The responsiveness of PXR to activation by lignan metabolites suggests that dietary intake of these compounds may affect the metabolism of drugs that are CYP3A substrates. Additionally, the evidence that organochlorine chemicals, particularly the ubiquitous triclosan, activate hPXR suggests that these environmental chemicals may, in part, exhibit their endocrine disruptor activities by altering PXR-regulated steroid hormone metabolism with potential adverse health effects in exposed individuals.« less

Rituximab in highly sensitized kidney transplant recipients.

PubMed

Munoz, A S; Rioveros, A A; Cabanayan-Casasola, C B; Danguilan, R A; Ona, E T

2008-09-01

Rituximab, an anti-CD20 monoclonal antibody therapy, depletes B cells and suppresses antibody production. This study sought to describe the efficacy and safety of rituximab among seven highly sensitized kidney transplant patients. A highly sensitized patient was defined as panel-reactive antibody (PRA) >30%, more than three pregnancies, or history of positive tissue crossmatch. Demographics, immunological risk profile, and immunosuppression were collected on all highly sensitized patients transplanted from March to July 2007 and given rituximab. We noted graft function as well as clinical events posttransplantation. The seven patients included in the study showed a mean age of 39 years (range = 17-60) and a mean follow-up of 3 months (range = 1.5-5). Their average PRA was 62% with mean HLA mismatches of three. Five patients (71%) were retransplantations; one had a history of a positive crossmatch, and two had multiple pregnancies. Two had donor-specific antibody, but negative tissue crossmatches. All had living donors. Six patients received a single dose of rituximab (375 mg/m2) 1 day prior to transplantation and one received two doses after 19 sessions of plasmapheresis. All were given tacrolimus, mycophenolate, and steroids combined with induction therapy using 30 mg alemtuzumab in 33%; two doses of 20 mg basiliximab in 33%; and seven doses of 1 mg/kg/dose of daclizumab in 14%. Mean shown creatinine levels were 1.1 and 1.2 mg/dL at 1 and 6 months posttransplantation. Two recipients experienced acute humoral rejections within 1 month after transplantation. Both were given steroid pulsing, one of whom was steroid-resistant necessitating alemtuzumab therapy and plasmapheresis. Graft function of both improved with creatinine values of 1.3 mg/dL on discharge. No episodes of infection were noted. Rituximab can be safely administered and may be effective to improve outcomes among highly sensitized kidney transplant patients.

Inductive Communication System Design Summary

DOT National Transportation Integrated Search

1978-09-01

The report documents the experience obtained during the design and development of the Inductive Communications System used in the Morgantown People Mover. The Inductive Communications System is used to provide wayside-to-vehicle and vehicle-to-waysid...

Neuroendocrine control of seasonal plasticity in the auditory and vocal systems of fish

PubMed Central

Forlano, Paul M.; Sisneros, Joseph A.; Rohmann, Kevin N.; Bass, Andrew H.

2014-01-01

Seasonal changes in reproductive-related vocal behavior are widespread among fishes. This review highlights recent studies of the vocal plainfin midshipman fish, Porichthys notatus, a neuroethological model system used for the past two decades to explore neural and endocrine mechanisms of vocal-acoustic social behaviors shared with tetrapods. Integrative approaches combining behavior, neurophysiology, neuropharmacology, neuroanatomy, and gene expression methodologies have taken advantage of simple, stereotyped and easily quantifiable behaviors controlled by discrete neural networks in this model system to enable discoveries such as the first demonstration of adaptive seasonal plasticity in the auditory periphery of a vertebrate as well as rapid steroid and neuropeptide effects on vocal physiology and behavior. This simple model system has now revealed cellular and molecular mechanisms underlying seasonal and steroid-driven auditory and vocal plasticity in the vertebrate brain. PMID:25168757

Towards Coleoptera-specific high-throughput screening systems for compounds with ecdysone activity: development of EcR reporter assays using weevil (Anthonomus grandis)-derived cell lines and in silico analysis of ligand binding to A. grandis EcR ligand-binding pocket.

PubMed

Soin, Thomas; Iga, Masatoshi; Swevers, Luc; Rougé, Pierre; Janssen, Colin R; Smagghe, Guy

2009-08-01

Molting in insects is regulated by ecdysteroids and juvenile hormones. Several synthetic non-steroidal ecdysone agonists are on the market as insecticides. These ecdysone agonists are dibenzoylhydrazine (DBH) analogue compounds that manifest their toxicity via interaction with the ecdysone receptor (EcR). Of the four commercial available ecdysone agonists, three (tebufenozide, methoxyfenozide and chromafenozide) are highly lepidopteran specific, one (halofenozide) is used to control coleopteran and lepidopteran insects in turf and ornamentals. However, compared to the very high binding affinity of these DBH analogues to lepidopteran EcRs, halofenozide has a low binding affinity for coleopteran EcRs. For the discovery of ecdysone agonists that target non-lepidopteran insect groups, efficient screening systems that are based on the activation of the EcR are needed. We report here the development and evaluation of two coleopteran-specific reporter-based screening systems to discover and evaluate ecdysone agonists. The screening systems are based on the cell lines BRL-AG-3A and BRL-AG-3C that are derived from the weevil Anthonomus grandis, which can be efficiently transduced with an EcR reporter cassette for evaluation of induction of reporter activity by ecdysone agonists. We also cloned the almost full length coding sequence of EcR expressed in the cell line BRL-AG-3C and used it to make an initial in silico 3D-model of its ligand-binding pocket docked with ponasterone A and tebufenozide.

Interactions between opioids and anabolic androgenic steroids: implications for the development of addictive behavior.

PubMed

Nyberg, Fred; Hallberg, Mathias

2012-01-01

Over the past decades, research on doping agents, such as anabolic androgenic steroids (AAS), has revealed that these compounds are often used in combination with other drugs of abuse. It seems that misuse of AAS probably involves more than a desire to enhance appearance or sports performance and studies have revealed that steroids are commonly connected with alcohol, opioids, tobacco, and psychotropic drugs. We have observed that AAS may interact with the endogenous opioids, excitatory amino acids, and dopaminergic pathways involved in the brain reward system. Furthermore, our studies provide evidence that AAS may induce an imbalance in these signal systems leading to an increased sensitivity toward opioid narcotics and central stimulants. In fact, studies performed in various clinics have shown that individuals taking AAS are likely to get addicted to opioids like heroin. This chapter reviews current knowledge on interactions between AAS and endogenous as well as exogenous opioids based not only on research in our laboratory but also on research carried out by several other clinical and preclinical investigators. Copyright © 2012 Elsevier Inc. All rights reserved.

The Neumann Type of Pemphigus Vegetans Treated with Combination of Dapsone and Steroid

PubMed Central

Son, Young-Min; Kang, Hong-Kyu; Yun, Jeong-Hwan; Roh, Joo-Young

2011-01-01

Pemphigus vegetans is a rare variant of pemphigus vulgaris and is characterized by vegetating lesions in the inguinal folds and mouth and by the presence of autoantibodies against desmoglein 3. Two clinical subtypes of pemphigus vegetans exist, which are initially characterized by flaccid bullae and erosions (the Neumann subtype) or pustules (the Hallopeau subtype). Both subtypes subsequently develop into hyperpigmented vegetative plaques with pustules and hypertrophic granulation tissue at the periphery of the lesions. Oral administration of corticosteroids alone does not always induce disease remission in patients with pemphigus vegetans. We report here on a 63-year-old woman with pemphigs vegetans. She had a 2-year history of vegetating, papillomatous plaques on the inguinal folds and erosions of the oral mucosa. The enzyme-linked immunosorbent assay was positive for anti-desmoglein 3, but it was negative for anti-desmoglein 1. She was initially treated with systemic steroid, but no improvement was observed. The patient was then successfully treated with a combination of systemic steroid and dapsone with a good clinical response. PMID:22346265

Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata.

PubMed

Kaur, Satwant; Baynes, Alice; Lockyer, Anne E; Routledge, Edwin J; Jones, Catherine S; Noble, Leslie R; Jobling, Susan

2016-01-01

Gastropod mollusks have been proposed as alternative models for male reproductive toxicity testing, due to similarities in their reproductive anatomy compared to mammals, together with evidence that endocrine disrupting chemicals can cause effects in some mollusks analogous to those seen in mammals. To test this hypothesis, we used the freshwater pulmonate snail, Biomphalaria glabrata, for which various genetic tools and a draft genome have recently become available, to investigate the effects of two steroid androgens on the development of mollusk secondary sexual organs. Here we present the results of exposures to two potent androgens, the vertebrate steroid; 5α-dihydrotestosterone (DHT) and the pharmaceutical anabolic steroid; 17α-methyltestosterone (MT), under continuous flow-through conditions throughout embryonic development and up to sexual maturity. Secondary sexual gland morphology, histopathology and differential gene expression analysis were used to determine whether steroid androgens stimulated or inhibited organ development. No significant differences between tissues from control and exposed snails were identified, suggesting that these androgens elicited no biologically detectable response normally associated with exposure to androgens in vertebrate model systems. Identifying no effect of androgens in this mollusk is significant, not only in the context of the suitability of mollusks as alternative model organisms for testing vertebrate androgen receptor agonists but also, if applicable to other similar mollusks, in terms of the likely impacts of androgens and anti-androgenic pollutants present in the aquatic environment.

[Neurological and psychiatric aspects of some endocrine diseases. The role of neurosteroids and neuroactive steroids].

PubMed

Aszalós, Zsuzsa

2007-10-14

Regardless of their origin, neuroactive steroids are capable of modifying neural activities by modulating different types of membrane receptors. Neurosteroids are synthesized de novo in neurones and glia. Steroidogenic enzymes are found in the central nervous system. Classical steroid receptors are localized in the cytoplasm, they exert regulatory actions on the genome, and their activation causes medium- and long-term effects. Non-classical receptors are located within the membrane and act as mediators of short-term effects. Other important players are co-repressors and co-activators that can interfere with or enhance the activity of steroid receptors. Beyond their function in stress, corticosteroids play a very important role in fear, anxiety, and memory functions. Patients with Cushing's syndrome frequently develop mood disorder, reversible brain atrophy with transient memory loss, rarely delirium or psychosis. Well-known peripheral symptom is steroidal myopathy. In patients with Addison's disease the main signs are weakness of muscles, lack of energy, decreased mental functions and reduced quality of life. Estrogen and progesterone have their own respective hormone receptors, whereas allopregnanolone acts via the GABA receptors. These hormones have significant role in the development of brain, the architecture of neural circuits and dendrites, density of axonal connections, and the number of neurons. They influence maturation, neuroprotection, seizures, cognitive functions, mood, anxiety, pain, and restitution of peripheral nerves. Androgens also affect cognitive functions, pain, anxiety, mood, and additionally aggression.

Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata

PubMed Central

Lockyer, Anne E.; Routledge, Edwin J.; Jones, Catherine S.; Noble, Leslie R.; Jobling, Susan

2016-01-01

Gastropod mollusks have been proposed as alternative models for male reproductive toxicity testing, due to similarities in their reproductive anatomy compared to mammals, together with evidence that endocrine disrupting chemicals can cause effects in some mollusks analogous to those seen in mammals. To test this hypothesis, we used the freshwater pulmonate snail, Biomphalaria glabrata, for which various genetic tools and a draft genome have recently become available, to investigate the effects of two steroid androgens on the development of mollusk secondary sexual organs. Here we present the results of exposures to two potent androgens, the vertebrate steroid; 5α-dihydrotestosterone (DHT) and the pharmaceutical anabolic steroid; 17α-methyltestosterone (MT), under continuous flow-through conditions throughout embryonic development and up to sexual maturity. Secondary sexual gland morphology, histopathology and differential gene expression analysis were used to determine whether steroid androgens stimulated or inhibited organ development. No significant differences between tissues from control and exposed snails were identified, suggesting that these androgens elicited no biologically detectable response normally associated with exposure to androgens in vertebrate model systems. Identifying no effect of androgens in this mollusk is significant, not only in the context of the suitability of mollusks as alternative model organisms for testing vertebrate androgen receptor agonists but also, if applicable to other similar mollusks, in terms of the likely impacts of androgens and anti-androgenic pollutants present in the aquatic environment. PMID:27448327

5Alpha-Reduced Steroids Are Major Metabolites in the Early Equine Embryo Proper and Its Membranes.

PubMed

Raeside, James I; Christie, Heather L; Betteridge, Keith J

2015-09-01

Steroid production and metabolism by early conceptuses are very important for the establishment and maintenance of pregnancy in horses. Our earlier work suggested the possible formation of 5alpha-reduced steroids in equine conceptuses. We have now demonstrated the formation of 5alpha-reduced metabolites of androstenedione, testosterone, and progesterone by the embryo and its membranes. A total of 44 conceptuses were collected from 26 mares between 20 and 31 days of pregnancy. Tissues from the embryo proper and from the separated components of the conceptus (bilaminar and trilaminar trophoblast, allantois) were incubated with tritium-labeled substrates. 5Alpha-reduced metabolites (5alpha-dihydro- and 3beta,5alpha-tetrahydro- steroids) as radiolabeled products were identified from a series of chromatographic steps using four solvent systems for high-performance liquid chromatography. Use of a 5alpha-reductase inhibitor confirmed the metabolites were indeed 5alpha-reduced steroids. For the embryo, the only products from androstenedione were 5alpha-dihydroandrostenedione and 3beta,5alpha-tetrahydroandrostenedione, with no evidence of more polar metabolites; there was some 3beta,5alpha-tetrahydrotestosterone but no 5alpha-dihydrotestosterone from testosterone, and formation of androstenedione was followed by the production of 5alpha-dihydroandrostenedione and 3beta,5alpha-tetrahydroandrostenedione. The major 5alpha-reduced product from progesterone was 3beta,5alpha-tetrahydroprogesterone, with lesser amounts of 5alpha-dihydroprogesterone. For the membranes, reductions to tetrahydro, 5alpha-reduced steroids were prominent in most instances, but also present were considerable amounts of products more polar than the substrates. The well-recognized activity of some 5alpha-reduced steroids--for example, 5alpha-dihydrotestosterone in male sexual differentiation--provokes interest in their even earlier appearance, as seen in this study, and suggests a possible role for them in early embryonic development in horses and, more generally, in other species. © 2015 by the Society for the Study of Reproduction, Inc.

Marine steroids as potential anticancer drug candidates: In silico investigation in search of inhibitors of Bcl-2 and CDK-4/Cyclin D1.

PubMed

Saikia, Surovi; Kolita, Bhaskor; Dutta, Partha P; Dutta, Deep J; Neipihoi; Nath, Shyamalendu; Bordoloi, Manobjyoti; Quan, Pham Minh; Thuy, Tran Thu; Phuong, Doan Lan; Long, Pham Quoc

2015-10-01

Star fishes (Asteroidea) are rich in polar steroids with diverse structural characteristics. The structural modifications of star fish steroids occur at 3β, 4β, 5α, 6α (or β), 7α (or β), 8, 15α (or β) and 16β positions of the steroidal nucleus and in the side chain. Widely found polar steroids in starfishes include polyhydroxysteroids, steroidal sulfates, glycosides, steroid oligoglycosides etc. Bioactivity of these steroids is less studied; only a few reports like antibacterial, cytotoxic activity etc. are available. In continuation of our search for bioactive molecules from natural sources, we undertook in silico screening of steroids from star fishes against Bcl-2 and CDK-4/Cyclin D1 - two important targets of progression and proliferation of cancer cells. We have screened 182 natural steroids from star fishes occurring in different parts of the world and their 282 soft-derivatives by in silico methods. Their physico-chemical properties, drug-likeliness, binding potential with the selected targets, ADMET (absorption, distribution, metabolism, toxicity) were predicted. Further, the results were compared with those of existing steroidal and non steroidal drugs and inhibitors of Bcl-2 and CDK-4/Cyclin D1. The results are promising and unveil that some of these steroids can be potent leads for cancer treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis

PubMed Central

Iizuka, Masahiro; Etou, Takeshi; Kumagai, Makoto; Matsuoka, Atsushi; Numata, Yuka; Sagara, Shiho

2017-01-01

Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed “long-interval cytapheresis (LI-CAP)”, in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (p<0.0001). The rate of clinical remission after LI-CAP was 80%. The rate of steroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC. PMID:28924114

Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis.

PubMed

Iizuka, Masahiro; Etou, Takeshi; Kumagai, Makoto; Matsuoka, Atsushi; Numata, Yuka; Sagara, Shiho

2017-10-15

Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed "long-interval cytapheresis (LI-CAP)", in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (p<0.0001). The rate of clinical remission after LI-CAP was 80%. The rate of steroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC.

Rapid Improvement of thyroid storm-related hemodynamic collapse by aggressive anti-thyroid therapy including steroid pulse: A case report.

PubMed

Kiriyama, Hiroyuki; Amiya, Eisuke; Hatano, Masaru; Hosoya, Yumiko; Maki, Hisataka; Nitta, Daisuke; Saito, Akihito; Shiraishi, Yasuyuki; Minatsuki, Shun; Sato, Tatsuyuki; Murakami, Haruka; Uehara, Masae; Manaka, Katsunori; Makita, Noriko; Watanabe, Masafumi; Komuro, Issei

2017-06-01

Heart failure is relatively common in patients with hyperthyroidism, but thyrotoxic cardiomyopathy with poor left ventricular (LV) systolic function is very rare. We experienced a representative case of a patient who presented with severe LV dysfunction related to thyroid storm and needed extracorporeal membrane oxygenation (ECMO) temporally. Thyrotoxic cardiomyopathy. Aggressive antithyroid therapy, including steroid pulse to hyperthyroidism, leads to the dramatic improvement of cardiac function and she was successfully weaned from ECMO. The most outstanding feature of the current case was the rapid decrease of cardiac injury and improvement of cardiac function by strengthening antithyroid therapy, including steroid pulse, without thyroid hormone level normalization. In thyroid storm, various systemic inflammatory reactions have different time courses and among them, the cardiac phenotype emerges in most striking and critical ways.

Human parvovirus B19 infection during the inactive stage of systemic lupus erythematosus.

PubMed

Suzuki, Takashiro; Saito, Shinichiro; Hirabayashi, Yasuhiko; Harigae, Hideo; Ishii, Tomonori; Kodera, Takao; Fujii, Hiroshi; Munakata, Yasuhiko; Sasaki, Takeshi

2003-06-01

A 42-year-old woman with systemic lupus erythematosus (SLE) had an episode of fever, arthralgia and anemia. In order to treat the suspected activation of SLE, the daily dose of steroid was increased, however, the anemia progressed and pancytopenia developed. Both IgM anti-B19 antibodies to human parvovirus B19 (B19) and B19 DNA were positive, and bone marrow analysis revealed pure red cell aplasia with giant proerythroblasts. High dose gamma globulin was administered and the daily dose of steroid was tapered, resulting in the improvement of her condition. B19 infection should be ruled out in cases with reactivation of autoimmune diseases.

Systemic Lupus Erythematosus Pancreatitis: An Uncommon Presentation of a Common Disease

PubMed Central

Rodriguez, Eduardo A.; Sussman, Daniel A.; Rodriguez, Vanessa R.

2014-01-01

Patient: Female, 21 Final Diagnosis: Systemic lupus erythematosus pancreatitis Symptoms: Abdominal pain Medication: — Clinical Procedure: — Specialty: Gastroenterology and Hepatology Objective: Challenging differential diagnosis Background: Acute pancreatitis is uncommon in systemic lupus erythematosus (SLE). When recognized early and properly treated with IV steroids and hydration, the course may be benign, as exemplified in the following report. Case Report: A 21-year-old woman with history of SLE and stage IV lupus nephritis, was admitted to the Sergio Bernales Hospital ICU (Lima, Peru), complaining of worsening epigastric pain radiating to the back, and nausea and vomiting for 1 week. She denied prior cholelithiasis, alcohol use, or recent medication changes. On examination, she was tachycardic and normotensive, with a slightly distended abdomen and epigastric tenderness on deep palpation, without signs of peritoneal irritation. Laboratory results demonstrated leukocytosis without left shift, creatinine of 2.26 mg/dL, amylase of 750 U/L, and lipase of 1038 U/L. Liver chemistries, calcium, lactic acid, triglycerides, and IgG4 were normal and alcohol level was undetectable. Ultrasound did not show cholelithiasis, biliary sludge, or common bile duct dilation. CT of the abdomen showed pancreas head (parenchyma) stranding with uniform enhancement consistent with interstitial pancreatitis. Despite receiving IV fluids, opiates, anti-emetics, and nothing by mouth, her clinical condition deteriorated, prompting the use of IV methylprednisolone. After completing 1 week of IV steroids, she was transferred to the medical floor clinically improved. The patient was discharged with an oral steroid taper and complete resolution of symptoms. Conclusions: After ruling out common causes, such as hepatobiliary pathology or toxin-related insults like alcohol, hypercalcemia, hypertriglyceridemia or medications, steroids may be used in SLE pancreatitis because they might improve the overall prognosis. PMID:25399483

Steroid-antivirals treatment versus steroids alone for the treatment of Bell's palsy: a meta-analysis.

PubMed

Dong, Yabing; Zhu, Yong; Ma, Chuan; Zhao, Huaqiang

2015-01-01

To illustrate whether the steroid-antivirals treatment could acquire a better recovery in patients with Bell's palsy than the steroids alone treatment. We conducted an exhaustive search over Pub med/Medline, Ovid, Elsevier search engines and the Cochrane library thereby collecting the randomized controlled trials in the treatment of patients with Bell's palsy with steroid-antivirals and steroids. The qualities of relevant articles were assessed by GRADE, which was used to present the overall quality of evidence as recommended by the Cochrane Handbook for Systematic Reviews of Interventions. Two investigators evaluated these papers independently, and resolved the disagreements by discussion. At last 8 eligible papers (1816 patients included: 896 treated with steroid-antivirals and 920 treated with steroids alone) match the criteria. Owing to the result (chi(2) = 12.57, P = 0.08, I(2) = 44%) presented by the formal test for heterogeneity, the fixed effect meta-analysis model was chosen. The facial muscle recovery between the steroids-antivirals group and the steroids alone group show significant differences (OR = 1.52, 95% CI: 1.20-1.94), while the statistical outcome of adverse effect shows no statistical significance (OR = 1.28, 95% CI: 0.71-2.31). The present meta-analysis indicates that the steroid-antivirals treatment could improve the recovery rate in patients with Bell's palsy when comparing with the steroid alone treatment. This meta-analysis showed that the steroid-antivirals treatment achieved the better outcomes in patients with Bell's palsy. Clinicians should consider that steroid-antivirals therapy is an alternative choice for the patients with Bell's palsy.

Profiling intact steroid sulfates and unconjugated steroids in biological fluids by liquid chromatography-tandem mass spectrometry (LC-MS-MS).

PubMed

Galuska, Christina E; Hartmann, Michaela F; Sánchez-Guijo, Alberto; Bakhaus, Katharina; Geyer, Joachim; Schuler, Gerhard; Zimmer, Klaus-Peter; Wudy, Stefan A

2013-07-07

Within the combined DFG research project "Sulfated Steroids in Reproduction" an analytical method was needed for determining sulfated and unconjugated steroids with highest specificity out of different biological matrices such as aqueous solution, cell lysate and serum. With regard to this analytical challenge, LC-MS-MS presents the technique of choice because it permits (1) analysis of the intact steroid conjugate, (2) allows for simultaneous determination of multiple analytes (profiling, targeted metabolomics approach) and (3) is independent of phenomena such as cross-reactivity. Sample work up consisted of incubation of sample with internal standards (deuterium labeled steroids) followed by solid phase extraction. Only serum samples required a protein precipitation step prior to solid phase extraction. The extract was divided in two parts: six steroid sulfates (E1S, E2S, AS, 16-OH-DHEAS, PREGS, DHEAS) were analyzed by C18aQ-ESI-MS-MS in negative ion mode and eleven unconjugated steroids (E3, 16-OH-DHEA, E1, E2, (4)A, DHEA, T, 17-OH-PREG, Prog, An, PREG) were analyzed by C18-APCI-MS-MS in positive ion mode. For steroid sulfates, we found high sensitivities with LoQ values ranging from 0.08 to 1 ng mL(-1). Unconjugated steroids showed LoQ values between 0.5 and 10 ng mL(-1). Calibration plots showed excellent linearity. Mean intra- and inter-assay CVs were 2.4% for steroid sulfates and 6.4% for unconjugated steroids. Accuracy - determined in a two-level spike experiment - showed mean relative errors of 5.9% for steroid sulfates and 6.1% for unconjugated steroids. In summary, we describe a novel LC-MS-MS procedure capable of profiling six steroid sulfates and eleven unconjugated steroids from various biological matrices.

A high-throughput UPC2-MS/MS method for the separation and quantification of C19 and C21 steroids and their C11-oxy steroid metabolites in the classical, alternative, backdoor and 11OHA4 steroid pathways.

PubMed

du Toit, Therina; Stander, Maria A; Swart, Amanda C

2018-03-30

In the present study an ultra-performance convergence chromatography tandem mass spectrometry (UPC 2 -MS/MS) analytical method was developed and validated for the determination of 17 C 19 and 14 C 21 steroids, including C11-oxy C 19 and C11-oxy C 21 steroids. The limit of detection and limit of quantification ranged from 0.01 to 10 ng/mL and from 0.01 to 20 ng/mL, respectively, and the method shows the recovery, matrix effect and process efficiency of steroids isolated from a serum matrix to be within acceptable limits. Good accuracy, repeatability and reproducibility were also shown and the method provided excellent sensitivity and selectivity as stereoisomers and regioisomers were also resolved and quantified accurately. Clinical conditions such as congenital adrenal hyperplasia, polycystic ovary syndrome in females and disorders of sex development in neonates and in children, amongst others, are characterized by abnormal steroid levels. Steroid profiling is essential to accurately diagnose steroid levels in the above settings as well as in androgen excess or deficiency in adrenal-linked endocrine diseases. Our method, separating C 19 and C 21 steroids in a single chromatographic step, offers a reduced sample turnover rate in the clinical setting, while providing comprehensive steroid profiles of in vivo steroids in the nmol/L range. This is, to our knowledge, the first method reported to simultaneously separate C 19 and C 21 steroids, together with their C11-hydroxy and C11-keto metabolites -one which may hold promise in the identification of new steroid markers in steroid-linked endocrine diseases, in addition to profiling steroid metabolism and abnormal enzyme activity in patients. Copyright © 2018 Elsevier B.V. All rights reserved.

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat.

PubMed

Delgado, Silvia Marcela; Casais, Marilina; Sosa, Zulema; Rastrilla, Ana María

2006-08-01

Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of alpha and beta adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a "per se" effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia.

PubMed

Giordano, Paola; Molinari, Angelo Claudio; Del Vecchio, Giovanni Carlo; Saracco, Paola; Russo, Giovanna; Altomare, Maria; Perutelli, Paolo; Crescenzio, Nicoletta; Santoro, Nicola; Marchetti, Marina; De Mattia, Domenico; Falanga, Anna

2010-05-01

In a group of newly diagnosed acute lymphocytic leukemia (ALL) children we evaluated a number of hemostatic and inflammatory markers at diagnosis and at different time points during chemotherapy for the remission induction to identify alterations in the plasma levels of prothrombotic markers before and during the course of chemotherapy. The following plasma markers were evaluated: thrombin-antithrombin complex (TAT), D-Dimer, plasminogen activator inhibitor 1 (PAI-1), antithrombin, fibrinogen, von Willebrand factor (VWF) antigen and high molecular weight VWF (HMW-VWF) multimers, P-selectin, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6). Plasma samples were collected at the following time points: at T0 (baseline) and T1 (+24 days of therapy), T2 (+36 days therapy), and T3 (+64 days therapy). The results show that, at diagnosis, ALL children presented with laboratory signs of increased thrombin generation and fibrin formation (i.e. high TAT and D-dimer levels), fibrinolysis inhibition (i.e. high PAI-1 level), endothelial activation (i.e., high HMW-VWF and soluble P-selectin levels) and inflammation (i.e. high TNF-alpha and IL-6 levels). After starting induction therapy, the thrombin generation markers and inflammatory cytokines significantly decreased. To the opposite, PAI-1 and P-selectin significantly increased, suggesting an insult by chemotherapy on the vascular endothelium. These effects were more evident during steroid administration. Symptomatic venous thromboembolism (VTE) episodes developed in two cases during induction therapy, which did not allow the evaluation of the predictive value for VTE of laboratory markers. (c) 2010 Wiley-Liss, Inc.

Azathioprine as a treatment option for uveitis in patients with juvenile idiopathic arthritis.

PubMed

Goebel, J C; Roesel, M; Heinz, C; Michels, H; Ganser, G; Heiligenhaus, A

2011-02-01

To investigate the therapeutic value of azathioprine as monotherapy or combined with other immunosuppressive drugs for uveitis in patients with juvenile idiopathic arthritis (JIA). A retrospective multicentre study including 41 children with JIA (28 (68.2%) female) with unilateral or bilateral (n=28) chronic anterior uveitis. Azathioprine was used to treat uveitis that was active in patients receiving topical or systemic corticosteroids, methotrexate or other immunosuppressive drugs. The primary end point was assessment of uveitis inactivity. Secondary end points comprised dose sparing of topical steroids and systemic corticosteroids, and immunosuppression. At 1 year, uveitis inactivity was achieved in 13/17 (76.5%) patients by using azathioprine as systemic monotherapy and in 5/9 (56.6%) as combination therapy. During the entire azathioprine treatment period (mean 26 months), inactivity was obtained in 16/26 patients (61.5%) with monotherapy and in 10/15 (66.7%) when combined with other immunosuppressives (p=1.0). With azathioprine, dosages of systemic immunosuppression and steroids could be reduced by ≥ 50% (n=12) or topical steroids reduced to ≤ 2 drops/eye/day in six patients. In three patients (7.3%), azathioprine was discontinued because of nausea and stomach pain. Conclusions Azathioprine may be reconsidered in the stepladder approach for the treatment of JIA-associated uveitis. The addition of azathioprine may also be beneficial for patients not responding properly to methotrexate.

TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease. Association of -1082 AA low producer IL-10 genotype with steroid dependency.

PubMed

Castro-Santos, Patricia; Suarez, Ana; López-Rivas, Laureano; Mozo, Lourdes; Gutierrez, Carmen

2006-05-01

An altered production of cytokines underlies inflammatory bowel disease (IBD) susceptibility. Various polymorphisms at the IL-10 and TNFalpha gene promoters control cytokine production levels. The influence of these polymorphisms on susceptibility to ulcerative colitis (UC) and Crohn's disease (CD) and their association with clinical features were analyzed. Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A, -812 C/T, and -592 C/A) were determined using the LightCycler system with hybridization probes matched with one sequence variant. The study population included 99 UC patients, 146 CD patients, and 343 matched controls. We did not find association between TNFalpha or IL-10 gene polymorphisms and UC or CD susceptibility, though a slight influence of -1082*G allele in UC appearance was observed. In a stratified analysis, a highly significant association between the -1082 AA IL-10 genotype and the steroid dependency was observed in IBD (p < 0.0001), contributing both UC (p = 0.004) and CD (p = 0.003) to this association. In contrast, TNFalpha genotypes did not influence steroid dependency in IBD. Further, the contribution of cytokine genotypes and of clinical features to the appearance of steroid-dependent status (dependent variable) was studied by multivariate analysis. The steroid-dependent phenotype correlated in UC with extensive disease (p = 0.010) and with the low producer -1082 AA IL-10 genotype (p = 0.002) and in CD with penetrating disease (p = 0.010), arthritis (p = 0.011), and the -1082 AA IL-10 genotype (p = 0.006). The main conclusion is that carriage of the -1082 AA IL-10 genotype (low producer) is a relevant risk factor for developing steroid-dependent IBD.

Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators

PubMed Central

Padmanabhan, Vasantha; Sarma, Hiren N.; Savabieasfahani, Mozhgan; Steckler, Teresa L.; Veiga-Lopez, Almudena

2014-01-01

The inappropriate programming of developing organ systems by exposure to excess native or environmental steroids, particularly the contamination of our environment and our food sources with synthetic endocrine disrupting chemicals that can interact with steroid receptors, is a major concern. Studies with native steroids have found that in utero exposure of sheep to excess testosterone, an estrogen precursor, results in low birth weight offspring and leads to an array of adult reproductive / metabolic deficits manifested as cycle defects, functional hyperandrogenism, neuroendocrine / ovarian defects, insulin resistance, and hypertension. Furthermore, the severity of reproductive dysfunction is amplified by excess postnatal weight gain. The constellation of adult reproductive and metabolic dysfunction in prenatal testosterone-treated sheep is similar to features seen in women with polycystic ovary syndrome. Prenatal dihydrotestosterone treatment failed to result in similar phenotype suggesting that many effects of prenatal testosterone excess are likely facilitated via aromatization to estradiol. Similarly, exposure to environmental steroid imposters such as bisphenol A (BPA) and methoxychlor (MXC) from days 30-90 of gestation had long-term but differential effects. Exposure of sheep to BPA, which resulted in maternal levels of 30-50 ng/ml BPA, culminated in low birth-weight offspring. These female offspring were hypergonadotropic during early postnatal life and characterized by severely dampened preovulatory LH surges. Prenatal MXC-treated females had normal birth weight and manifested delayed but normal amplitude LH surges. Importantly, the effects of BPA were evident at levels, which approximated twice the highest levels found in human maternal circulation of industrialized nations. These findings provide evidence in support of developmental origin of adult reproductive and metabolic diseases and highlight the risk posed by exposure to environmental endocrine disrupting chemicals. PMID:20070410

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

Steroids in Athletics: One University's Experience.

ERIC Educational Resources Information Center

Lopez, Mike

1990-01-01

Presents an account of one university's experience in conducting an investigation into possible steroid use by student athletes and the development of a program to deal with the problem. Discusses why athletes use steroids and how steroids are taken. Concludes it is likely many steroid-related deaths of athletes go undetected. (Author/ABL)

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

Adolescent Steroid Use.

ERIC Educational Resources Information Center

Office of Inspector General (DHHS), Washington, DC.

The study focused on non-medical steroid use by adolescents according to data obtained from the National Institute on Drug Abuse, professional literature, 30 key informants knowledgeable in steroid issues, and 72 current or former steroid users. The findings indicated: (1) over 250,000 adolescents, primarily males, used or have used steroids, and…

Quest for steroidomimetics: Amino acids derived steroidal and nonsteroidal architectures.

PubMed

Shagufta; Ahmad, Irshad; Panda, Gautam

2017-06-16

The chiral pool amino acids have been utilized for the construction of steroidal and non-steroidal architectures in the quest for steroidomimetics. Chirality derived from amino acid-based architectures provides new and easy to incorporate chiral chemical space, which is otherwise very difficult to introduce and comprised of several synthetic steps for asymmetric steroids. The different and exciting ligand-receptor interactions may arise from the use of each amino acid enantiomer that was introduced into the chiral steroidal backbone. The A and D rings of steroidal architectures can be mimicked by the phenyl group of the amino acid tyrosine. The Mitsunobu reaction, nucleophilic substitution and elimination, etc. were utilized for constructing diverse tri- and tetracyclic steroidal skeletons as well as benzofused seco-steroids from amino acids. These benzofused, amino acid-derived steroidal and nonsteroidal molecules had promising biological activity in hormonal related disorders. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Characterizing the distribution of steroid sulfatase during embryonic development: when and where might metabolites of maternal steroids be reactivated?

PubMed

Paitz, Ryan T; Duffield, Kristin R; Bowden, Rachel M

2017-12-15

All vertebrate embryos are exposed to maternally derived steroids during development. In placental vertebrates, metabolism of maternal steroids by the placenta modulates embryonic exposure, but how exposure is regulated in oviparous vertebrates is less clear. Recent work in oviparous vertebrates has demonstrated that steroids are not static molecules, as they can be converted to more polar steroid sulfates by sulfotransferase enzymes. Importantly, these steroid sulfates can be converted back to the parent compound by the enzyme steroid sulfatase (STS). We investigated when and where STS was present during embryonic development in the red-eared slider turtle, Trachemys scripta We report that STS is present during all stages of development and in all tissues we examined. We conclude that STS activity may be particularly important for regulating maternal steroid exposure in oviparous vertebrates. © 2017. Published by The Company of Biologists Ltd.

Effect of oxidizing adulterants on human urinary steroid profiles.

PubMed

Kuzhiumparambil, Unnikrishnan; Fu, Shanlin

2013-02-01

Steroid profiling is the most versatile and informative technique adapted by doping control laboratories for detection of steroid abuse. The absolute concentrations and ratios of endogenous steroids including testosterone, epitestosterone, androsterone, etiocholanolone, 5α-androstane-3α,17β-diol and 5β-androstane-3α,17β-diol constitute the significant characteristics of a steroid profile. In the present study we report the influence of various oxidizing adulterants on the steroid profile of human urine. Gas chromatography-mass spectrometry analysis was carried out to develop the steroid profile of human male and female urine. Oxidants potassium nitrite, sodium hypochlorite, potassium permanganate, cerium ammonium nitrate, sodium metaperiodate, pyridinium chlorochromate, potassium dichromate and potassium perchlorate were reacted with urine at various concentrations and conditions and the effect of these oxidants on the steroid profile were analyzed. Most of the oxidizing chemicals led to significant changes in endogenous steroid profile parameters which were considered stable under normal conditions. These oxidizing chemicals can cause serious problems regarding the interpretation of steroid profiles and have the potential to act as masking agents that can complicate or prevent the detection of the steroid abuse. Copyright © 2012 Elsevier Inc. All rights reserved.

What goes on behind closed doors: physiological vs. pharmacological steroid hormone actions

PubMed Central

Simons, S. Stoney

2009-01-01

Summary Steroid hormone-activated receptor proteins are among the best understood class of factors for altering gene transcription in cells. Steroid receptors are of major importance in maintaining normal human physiology by responding to circulating concentrations of steroid in the nM range. Nonetheless, most studies of steroid receptor action have been conducted using the supra-physiological conditions of saturating concentrations (≥100 nM) of potent synthetic steroid agonists. Here we summarize the recent developments arising from experiments using two clinically relevant conditions: subsaturating concentrations of agonist (to mimic the circulating concentrations in mammals) and saturating concentrations of antagonists (which are employed in endocrine therapies to block the actions of endogenous steroids). These studies have revealed new facets of steroid hormone action that could not be uncovered by conventional experiments with saturating concentrations of agonist steroids, such as a plethora of factors/conditions for the differential control of gene expression by physiological levels of steroid, a rational approach for examining the gene-specific variations in partial agonist activity of antisteroids, and a dissociation of steroid potency and efficacy that implies the existence of separate, and possibly novel, mechanistic steps and cofactors. PMID:18623071

Pan-brachial plexus neuropraxia following lightning: A rare case report.

PubMed

Patnaik, Ashis; Mahapatra, Ashok Kumar; Jha, Menka

2015-01-01

Neurological complications following lightning are rare and occur in form of temporary neurological deficits of central origin. Involvement of peripheral nervous system is extremely rare and only a few cases have been described in the literature. Isolated unilateral pan-brachial plexus neuropraxia has never been reported in the literature. Steroids have long been used for treatment of neuropraxia. However, their use in lightning neural injury is unique and requires special mention. We report a rare case of lightning-induced unilateral complete flaccid paralysis along with sensory loss in a young patient. Lightning typically causes central nervous involvement in various types of motor and sensory deficit. Surprisingly, the nerve conduction study showed the involvement of peripheral nervous system involvement. Steroids were administered and there was significant improvement in neurological functions within a short span of days. Patients' functions in the affected limb were normal in one month. Our case was interesting since it is the first such case in the literature where lightning has caused such a rare instance of unilateral pan-brachial plexus lesion. Such cases when seen, raises the possibility of more common central nervous system pathology rather than peripheral involvement. However, such lesions can be purely benign forms of peripheral nerve neuropraxia, which can be managed by steroid treatment without leaving any long-term neurological deficits.

Effects of anabolic-androgens on brain reward function

PubMed Central

Mhillaj, Emanuela; Morgese, Maria G.; Tucci, Paolo; Bove, Maria; Schiavone, Stefania; Trabace, Luigia

2015-01-01

Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming androgen anabolic steroids (AAS). These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, their off-label utilization is very wide. Furthermore, combinations of different steroids and doses generally higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. The frequency of side effects is higher among AAS abusers, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because data collection is very difficult due to the subjects' reticence and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in the reward process, leading to increased sensitivity toward opioid narcotics and central stimulants. The goal of this article is to review the literature on steroid abuse and changes to the reward system in preclinical and clinical studies. PMID:26379484

Effects of anabolic-androgens on brain reward function.

PubMed

Mhillaj, Emanuela; Morgese, Maria G; Tucci, Paolo; Bove, Maria; Schiavone, Stefania; Trabace, Luigia

2015-01-01

Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming androgen anabolic steroids (AAS). These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, their off-label utilization is very wide. Furthermore, combinations of different steroids and doses generally higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. The frequency of side effects is higher among AAS abusers, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because data collection is very difficult due to the subjects' reticence and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in the reward process, leading to increased sensitivity toward opioid narcotics and central stimulants. The goal of this article is to review the literature on steroid abuse and changes to the reward system in preclinical and clinical studies.

Surface design with self-heating smart polymers for on-off switchable traps

NASA Astrophysics Data System (ADS)

Techawanitchai, Prapatsorn; Yamamoto, Kazuya; Ebara, Mitsuhiro; Aoyagi, Takao

2011-08-01

We have developed a novel self-heating, temperature-responsive chromatography system for the effective separation of biomolecules. Temperature-responsive poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide), poly(NIPAAm-co-HMAAm), was covalently grafted onto the surface of magnetite/silica composites as 'on-off' switchable surface traps. The lower critical solution temperature (LCST) of the poly(NIPAAm-co-HMAAm)s was controlled from 35 to 55 °C by varying the HMAAm content. Using the heat generated by magnetic particles in an alternating magnetic field (AMF) we were able to induce the hydrophilic to hydrophobic phase separation of the grafted temperature-responsive polymers. To assess the feasibility of the poly(NIPAAm-co-HMAAm)-grafted magnetite/silica particles as the stationary phase for chromatography, we packed the particles into the glass column of a liquid chromatography system and analyzed the elusion profiles for steroids. The retention time for hydrophobic steroids markedly increased in the AMF, because the hydrophobic interaction was enhanced via self-heating of the grafted magnetite/silica particles, and this effect could be controlled by changing the AMF irradiation time. Turning off the AMF shortened the total analysis time for steroids. The proposed system is useful for separating bioactive compounds because their elution profiles can be easily controlled by an AMF.

Out come of induction of remission in undernourished children with acute lymphoblastic leukaemia.

PubMed

Begum, M; Jahan, S; Tawfique, M; Mannan, M A

2012-10-01

Acute lymphoblastic leukaemia (ALL) is the most common childhood leukaemia. On the other hand under-nutrition is a common problem in our country. This prospective study was conducted to see the outcome of induction of remission in undernourished children with acute lymphoblastic leukaemia. This study was carried out in the department of Paediatric hematology and oncology of Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period from November 2002 to October 2004. A total of sixty (60) children who were diagnosed as acute lymphoblastic leukaemia in 1 to 15 years of age were included in this study. But the children with previous history of congenital disease and that of chemotherapy or steroid were excluded from this study. Patients were divided into two groups on the basis of Z score of weight for age. Thirty (30) children those with Z score- 2 or less were classified as undernourished and was labeled as Group A and another thirty (30) patient those Z score above-2 were classified as well nourished and was placed in Group B, After inclusion into the study, completion of induction of remission was monitored by physical examination and laboratory investigations. The result showed that mean age in Group A was 77.16 ± 7.07 months and that in Group B was 74.13 ± 5.09 months with male preponderance in both the groups. Mean body weight in Group A was 14.55 ± 0.76 Kg and that in Group B was 21.40 ± 1.05 kg (p<0.001). Children in Group A required 39.06 ± 0.72 days to complete induction but in Group B it required 31.63 ± 0.17 days (p<0.04). Hospital stay in Group A children was 52.10 ± 1.08 days and in Group B 42.37 ± 0.50 (p<0.002). The result suggested that under nutrition has an influence on the out come of induction of remission in undernourished children with acute lymphoblastic leukaemia. So appropriate measures are essential to improve nutritional status of children for successful management of ALL in children.

Outcomes in African-Americans vs. Caucasians using thymoglobulin or interleukin-2 receptor inhibitor induction: analysis of USRDS database.

PubMed

Jindal, Rahul M; Das, Neal P; Neff, Robert T; Hurst, Frank P; Falta, Edward M; Elster, Eric A; Abbott, Kevin C

2009-01-01

We used the USRDS database to test the hypothesis that graft survival was similar using either rabbit antithymocyte globulin (rATG) vs. interleukin-2 receptor inhibitor (IL2i) in the Prograf era. We further explored the variable of race in the two groups of patients. We conducted a retrospective cohort study of kidney transplant patients in the USRDS from 2000 through 2005 to compare graft survival (including death) using rATG vs. IL2i with particular reference to outcomes between African-Americans vs. Caucasians. Kaplan-Meier analysis was performed to assess patient and graft survival after transplantation, stratified by recipient induction with rATG versus IL2i. Cox regression analysis was performed to assess adjusted survival after transplantation, assessing whether induction rATG (vs. IL2i) was significant as an interaction term (i.e. an effect modifier) with black race for graft survival. Propensity score analysis was used to address potential confounding by indication. In stratified Cox Regression analysis limited to IL2i, black race was significantly associated with graft loss (adjusted hazard ratio (AHR) 1.17, 95% CI, 1.09-1.26). In analysis limited to rATG induction, black race was not significant (AHR 1.00, 95% CI, 0.92-1.10). We detected a significant interaction between rATG and black race (in comparison with non-black race) for the development of graft loss (AHR, 0.86, 95% CI, 0.76-0.97). Analysis limited to black recipients showed that while use of rATG was not significantly different from IL2i (AHR 0.95, 95% CI 0.87-1.04), the direction of this association was in the opposite direction of non-blacks. Patient and graft survival were similar in African-American and Caucasian recipients of kidney transplantation using either rATG or IL2i. Limitations of the study are the retrospective nature of USRDS data, center-bias in using rATG vs. IL2i and lack of data on steroid dosage. Results of the present study call for a critical review of induction practices. (c) 2008 S. Karger AG, Basel.

The place of hyperbaric oxygen therapy and ozone therapy in sudden hearing loss.

PubMed

Ergun Taşdöven, Gülin; Derin, Alper Tunga; Yaprak, Neslihan; Özçağlar, Hasan Ümit

It is difficult to evaluate the effect of drugs clinically used for idiopathic sudden sensorineural hearing loss, mainly because its underlying mechanism remains unknown. This study assessed the efficacy of hyperbaric oxygen therapy or ozone therapy in the treatment of idiopathic sudden sensorineural hearing loss, when either therapy was included with steroid treatment. A retrospective analysis examined 106 patients with idiopathic sudden sensorineural hearing loss seen between January 2010 and June 2012. Those with an identified etiology were excluded. The patients were divided into three treatment groups: oral steroid only (n=65), oral steroid+hyperbaric oxygen (n=26), and oral steroid+ozone (n=17). Treatment success was assessed using Siegel criteria and mean gains using pre- and post-treatment audiograms. The highest response rate to treatment was observed in the oral steroid+ozone therapy group (82.4%), followed by the oral steroid+hyperbaric oxygen (61.5%), and oral steroid groups (50.8%). There were no significant differences in the response to treatment between the oral steroid and oral steroid+hyperbaric oxygen groups (p<0.355). The oral steroid+ozone group showed a significantly higher response rate to treatment than the oral steroid group (p=0.019). There were no significant differences between the oral steroid+hyperbaric oxygen and oral steroid+ozone groups (p=0.146). The efficiency of steroid treatment in patients with severe hearing loss was low. It was statistically ascertained that adding hyperbaric oxygen or ozone therapy to the treatment contributed significantly to treatment success. Copyright © 2016 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Steroid-antivirals treatment versus steroids alone for the treatment of Bell’s palsy: a meta-analysis

PubMed Central

Dong, Yabing; Zhu, Yong; Ma, Chuan; Zhao, Huaqiang

2015-01-01

Background: To illustrate whether the steroid-antivirals treatment could acquire a better recovery in patients with Bell’s palsy than the steroids alone treatment. Materials and methods: We conducted an exhaustive search over Pub med/Medline, Ovid, Elsevier search engines and the Cochrane library thereby collecting the randomized controlled trials in the treatment of patients with Bell’s palsy with steroid-antivirals and steroids. The qualities of relevant articles were assessed by GRADE, which was used to present the overall quality of evidence as recommended by the Cochrane Handbook for Systematic Reviews of Interventions. Results: Two investigators evaluated these papers independently, and resolved the disagreements by discussion. At last 8 eligible papers (1816 patients included: 896 treated with steroid-antivirals and 920 treated with steroids alone) match the criteria. Owing to the result (chi2 = 12.57, P = 0.08, I2 = 44%) presented by the formal test for heterogeneity, the fixed effect meta-analysis model was chosen. The facial muscle recovery between the steroids-antivirals group and the steroids alone group show significant differences (OR = 1.52, 95% CI: 1.20-1.94), while the statistical outcome of adverse effect shows no statistical significance (OR = 1.28, 95% CI: 0.71-2.31). Conclusions: The present meta-analysis indicates that the steroid-antivirals treatment could improve the recovery rate in patients with Bell’s palsy when comparing with the steroid alone treatment. Clinical significance: This meta-analysis showed that the steroid-antivirals treatment achieved the better outcomes in patients with Bell’s palsy. Clinicians should consider that steroid-antivirals therapy is an alternative choice for the patients with Bell’s palsy. PMID:25785012

Characteristics of Steroid Users in an Adolescent School Population.

ERIC Educational Resources Information Center

Adlaf, Edward M.; Smart, Reginald G.

1992-01-01

Examined rates of steroid use among Ontario adolescent students. Findings from 3,892 students revealed that 1.1 percent reported using steroids over past year. Steroid users were significantly more likely to use stimulants, caffeine, and relaxants than were nonsteroid users. Demographically, steroid users were significantly more likely to be male…

Inductance and resistance measurement method for vessel detection and coil powering in all-surface inductive heating systems composed of outer squircle coils

NASA Astrophysics Data System (ADS)

Kilic, Veli Tayfun; Unal, Emre; Demir, Hilmi Volkan

2017-05-01

In this work, we investigate a method proposed for vessel detection and coil powering in an all-surface inductive heating system composed of outer squircle coils. Besides conventional circular coils, coils with different shapes such as outer squircle coils are used for and enable efficient all-surface inductive heating. Validity of the method, which relies on measuring inductance and resistance values of a loaded coil at different frequencies, is experimentally demonstrated for a coil with shape different from conventional circular coil. Simple setup was constructed with a small coil to model an all-surface inductive heating system. Inductance and resistance maps were generated by measuring coil's inductance and resistance values at different frequencies loaded by a plate made of different materials and located at various positions. Results show that in an induction hob for various coil geometries it is possible to detect a vessel's presence, to identify its material type and to specify its position on the hob surface by considering inductance and resistance of the coil measured on at least two different frequencies. The studied method is important in terms of enabling safe, efficient and user flexible heating in an all-surface inductive heating system by automatically detecting the vessel's presence and powering on only the coils that are loaded by the vessel with predetermined current levels.

[Efficacy of systemic glucocorticoids combined with inhaled steroid on children with acute laryngitis].

PubMed

Chen, Q P; Zhou, R F; Zhang, Y M; Yang, L

2018-01-07

Objective: To evaluate the efficacy of systemic glucocorticoid (steroid) combined with high dose inhaled steroid in the treatment of children with acute laryngitis. Methods: A total of 78 children with acute laryngitis were randomly divided into study group( n =40) and control group( n =38) between November 2016 and April 2017. In addition to routine treatment of anti infection and symptomatic treatment, Dexamethasone injection(0.3-0.5 mg/kg, 1-3 d, according to the patient's condition) was provided to each group. In addition to the treatment mentioned above, the study group were assigned to receive 1.0 mg Budesonide suspension for inhalation, oxygen-driven atomizing inhalation, every/30 minutes, 2 times in a row, after that every 12 hours. The improvement of inspiratory dyspnea, hoarseness, barking cough and wheezing of both groups was evaluated at 30 min, 1 h, 2 h, 6 h, 12 h, 24 h and 72 h after treatment.Sigmaplot 11.5 software was used to analyze the data. Results: No significant difference was detected in terms of inspiratory dyspnea, hoarseness, barking cough or stridor score before treatment between the two groups( P >0.05). Compared with those before treatment, symptoms of inspiratory dyspnea, hoarseness, barking cough and stridor score of both groups improved markedly at 12 h and 24 h after treatment( P <0.05). While there was no significant difference regarding inspiratory dyspnea, hoarseness, barking cough or stridor score at each time point after treatment between the two groups( P >0.05). The effective rate was 92.50% and 92.11% in study group and control group, respectively, and no significant difference was noted ( P >0.05). Conclusion: Compared with single systemic glucocorticoid, systemic glucocorticoids combined with inhaled steroid possessed similar efficacy in treating acute laryngitis and relieving laryngeal obstruction of children.

Sudden sensorineural hearing loss: results of intratympanic steroids as salvage treatment.

PubMed

Dispenza, Francesco; De Stefano, Alessandro; Costantino, Claudio; Marchese, Donatella; Riggio, Francesco

2013-01-01

The aim of the present study was to verify the efficacy and the safety of intratympanic dexamethasone to treat sudden sensorineural hearing loss as salvage therapy. A prospective study was conducted on patients affected by idiopathic sudden hearing loss who were treated before with some systemic therapy, but without recovery of the hearing The patients able to undergo the study, but who refused salvage treatment were considered as control group. A solution of Dexamethasone 4 mg/ml was then injected through the posterior-inferior quadrant filling completely the middle ear. The follow-up in the following 6 months included an audiogram every month. The number of patients treated with salvage therapy was 36. The patients who refused treatment were further 10. The salvage treatment was done with a mean delay of 24.3 days from the onset of symptoms. Mean hearing threshold after the onset of sudden hearing loss at PTA was 66.5 dB. After the failed treatment the mean PTA was 59.6 dB. The mean PTA after the intratympanic steroid administration was 46.8 dB, with a mean improvement of 12.8 dB. No hearing change was noted in the 10 patients who refused salvage therapy. The patients that assumed systemic steroid as first therapy showed a better PTA threshold after the salvage intratympanic treatment (p<0.01). A significant difference (p<0.05) of hearing recovery was evidenced between non-smoker patients and those with smoking habit. Our data showed that a salvage treatment with intratympanic dexamethasone should be suggested to all patients who failed the first systemic treatment. The systemic steroid therapy done before the salvage treatment seems to exert a protective role for the inner ear, as shown by our series. On the contrary the smoke habit is a negative prognostic factor in the hearing recovery. Copyright © 2013 Elsevier Inc. All rights reserved.

14 CFR 33.35 - Fuel and induction system.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Fuel and induction system. 33.35 Section 33... AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Design and Construction; Reciprocating Aircraft Engines § 33.35 Fuel and induction system. (a) The fuel system of the engine must be designed and constructed to supply an...

14 CFR 33.35 - Fuel and induction system.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Fuel and induction system. 33.35 Section 33... AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Design and Construction; Reciprocating Aircraft Engines § 33.35 Fuel and induction system. (a) The fuel system of the engine must be designed and constructed to supply an...

14 CFR 33.35 - Fuel and induction system.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Fuel and induction system. 33.35 Section 33... AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Design and Construction; Reciprocating Aircraft Engines § 33.35 Fuel and induction system. (a) The fuel system of the engine must be designed and constructed to supply an...

14 CFR 33.35 - Fuel and induction system.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Fuel and induction system. 33.35 Section 33... AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Design and Construction; Reciprocating Aircraft Engines § 33.35 Fuel and induction system. (a) The fuel system of the engine must be designed and constructed to supply an...

Steroid avoidance or withdrawal for kidney transplant recipients.

PubMed

Haller, Maria C; Royuela, Ana; Nagler, Evi V; Pascual, Julio; Webster, Angela C

2016-08-22

Steroid-sparing strategies have been attempted in recent decades to avoid morbidity from long-term steroid intake among kidney transplant recipients. Previous systematic reviews of steroid withdrawal after kidney transplantation have shown a significant increase in acute rejection. There are various protocols to withdraw steroids after kidney transplantation and their possible benefits or harms are subject to systematic review. This is an update of a review first published in 2009. To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. We searched the Cochrane Kidney and Transplant Specialised Register to 15 February 2016 through contact with the Information Specialist using search terms relevant to this review. All randomised and quasi-randomised controlled trials (RCTs) in which steroids were avoided or withdrawn at any time point after kidney transplantation were included. Assessment of risk of bias and data extraction was performed by two authors independently and disagreement resolved by discussion. Statistical analyses were performed using the random-effects model and dichotomous outcomes were reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals. We included 48 studies (224 reports) that involved 7803 randomised participants. Of these, three studies were conducted in children (346 participants). The 2009 review included 30 studies (94 reports, 5949 participants). Risk of bias was assessed as low for sequence generation in 19 studies and allocation concealment in 14 studies. Incomplete outcome data were adequately addressed in 22 studies and 37 were free of selective reporting.The 48 included studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance, and steroid avoidance compared with steroid withdrawal. For the adult studies there was no significant difference in patient mortality either in studies comparing steroid withdrawal versus steroid maintenance (10 studies, 1913 participants, death at one year post transplantation: RR 0.68, 95% CI 0.36 to 1.30) or in studies comparing steroid avoidance versus steroid maintenance (10 studies, 1462 participants, death at one year after transplantation: RR 0.96, 95% CI 0.52 to 1.80). Similarly no significant difference in graft loss was found comparing steroid withdrawal versus steroid maintenance (8 studies, 1817 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.17, 95% CI 0.72 to 1.92) and comparing steroid avoidance versus steroid maintenance (7 studies, 1211 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.09, 95% CI 0.64 to 1.86). The risk of acute rejection significantly increased in patients treated with steroids for less than 14 days after transplantation (7 studies, 835 participants: RR 1.58, 95% CI 1.08 to 2.30) and in patients who were withdrawn from steroids at a later time point after transplantation (10 studies, 1913 participants, RR 1.77, 95% CI 1.20 to 2.61). There was no evidence to suggest a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients. The effect of steroid withdrawal in children is unclear. This updated review increases the evidence that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but long-term consequences of steroid avoidance and withdrawal remain unclear until today, because prospective long-term studies have not been conducted.

Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.

PubMed

Warejko, Jillian K; Tan, Weizhen; Daga, Ankana; Schapiro, David; Lawson, Jennifer A; Shril, Shirlee; Lovric, Svjetlana; Ashraf, Shazia; Rao, Jia; Hermle, Tobias; Jobst-Schwan, Tilman; Widmeier, Eugen; Majmundar, Amar J; Schneider, Ronen; Gee, Heon Yung; Schmidt, J Magdalena; Vivante, Asaf; van der Ven, Amelie T; Ityel, Hadas; Chen, Jing; Sadowski, Carolin E; Kohl, Stefan; Pabst, Werner L; Nakayama, Makiko; Somers, Michael J G; Rodig, Nancy M; Daouk, Ghaleb; Baum, Michelle; Stein, Deborah R; Ferguson, Michael A; Traum, Avram Z; Soliman, Neveen A; Kari, Jameela A; El Desoky, Sherif; Fathy, Hanan; Zenker, Martin; Bakkaloglu, Sevcan A; Müller, Dominik; Noyan, Aytul; Ozaltin, Fatih; Cadnapaphornchai, Melissa A; Hashmi, Seema; Hopcian, Jeffrey; Kopp, Jeffrey B; Benador, Nadine; Bockenhauer, Detlef; Bogdanovic, Radovan; Stajić, Nataša; Chernin, Gil; Ettenger, Robert; Fehrenbach, Henry; Kemper, Markus; Munarriz, Reyner Loza; Podracka, Ludmila; Büscher, Rainer; Serdaroglu, Erkin; Tasic, Velibor; Mane, Shrikant; Lifton, Richard P; Braun, Daniela A; Hildebrandt, Friedhelm

2018-01-06

Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1 , PLCE1 , NPHS2 , and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome. Copyright © 2018 by the American Society of Nephrology.

14 CFR 23.1103 - Induction system ducts.

Code of Federal Regulations, 2013 CFR

2013-01-01

... withstanding the effects of temperature extremes, fuel, oil, water, and solvents to which it is expected to be exposed in service and maintenance without hazardous deterioration or delamination. (d) For reciprocating engine installations, each induction system duct must be— (1) Strong enough to prevent induction system...

14 CFR 23.1103 - Induction system ducts.

Code of Federal Regulations, 2010 CFR

2010-01-01

... withstanding the effects of temperature extremes, fuel, oil, water, and solvents to which it is expected to be exposed in service and maintenance without hazardous deterioration or delamination. (d) For reciprocating engine installations, each induction system duct must be— (1) Strong enough to prevent induction system...

14 CFR 23.1103 - Induction system ducts.

Code of Federal Regulations, 2012 CFR

2012-01-01

... withstanding the effects of temperature extremes, fuel, oil, water, and solvents to which it is expected to be exposed in service and maintenance without hazardous deterioration or delamination. (d) For reciprocating engine installations, each induction system duct must be— (1) Strong enough to prevent induction system...

14 CFR 23.1103 - Induction system ducts.

Code of Federal Regulations, 2014 CFR

2014-01-01

... withstanding the effects of temperature extremes, fuel, oil, water, and solvents to which it is expected to be exposed in service and maintenance without hazardous deterioration or delamination. (d) For reciprocating engine installations, each induction system duct must be— (1) Strong enough to prevent induction system...

14 CFR 23.1103 - Induction system ducts.

Code of Federal Regulations, 2011 CFR

2011-01-01

... withstanding the effects of temperature extremes, fuel, oil, water, and solvents to which it is expected to be exposed in service and maintenance without hazardous deterioration or delamination. (d) For reciprocating engine installations, each induction system duct must be— (1) Strong enough to prevent induction system...

Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways

PubMed Central

Grogan, Patrick T.; Sleder, Kristina D.; Samadi, Abbas K.; Timmermann, Barbara N.; Cohen, Mark S.

2012-01-01

Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was found to inhibit proliferation by inducing a dose-dependent G2/M cell cycle arrest and promoting cell death through both intrinsic and extrinsic apoptotic pathways. This was accompanied by an inhibitory shift in the Akt/mTOR signaling pathway which included diminished expression and/or phosphorylation of Akt, mTOR, p70 S6K, and p85 S6K with increased activation of AMPKα and the tumor suppressor tuberin/TSC2. Alterations in proteins of the MAPK pathway and cell surface receptors like EGFR, Her2/ErbB2, and c-Met were also observed. WA induced an N-acetyl-L-cysteinerepressible enhancement in cellular oxidative potential/stress with subsequent induction of a heat shock stress response primarily through HSP70, HSP32, and HSP27 upregulation and HSF1 downregulation. Taken together, we suggest that WA may represent a promising chemotherapeutic candidate in glioblastoma therapy warranting further translational evaluation. PMID:23129310

Identification of natural products with neuronal and metabolic benefits through autophagy induction.

PubMed

Fan, Yuying; Wang, Nan; Rocchi, Altea; Zhang, Weiran; Vassar, Robert; Zhou, Yifa; He, Congcong

2017-01-02

Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies. From this pilot plant metabolite library, we identified several novel autophagy-inducing phytochemicals, including Rg2. Rg2 is a steroid glycoside chemical that activates autophagy in an AMPK-ULK1-dependent and MTOR-independent manner. Induction of autophagy by Rg2 enhances the clearance of protein aggregates in a cell-based model, improves cognitive behaviors in a mouse model of Alzheimer disease, and prevents high-fat diet-induced insulin resistance. Thus, we discovered a series of autophagy-inducing phytochemicals from medicinal plants, and found that one of the compounds Rg2 mediates metabolic and neurotrophic effects dependent on activation of the autophagy pathway. These findings may help explain how medicinal plants exert the therapeutic functions against metabolic diseases.

The incidence of malignancy in heart transplant recipients.

PubMed

Garlicki, M; Wierzbicki, K; Przybyłowski, P; Drop, D; Biernat, M; Rudziński, P; Olszewska, B; Dziatkowiak, A

1998-01-01

219 heart transplant recipients with survival over 3 months were retro- and prospectively analysed for the incidence of primary neoplasms. Patients received immunosuppressive drugs (cyclosporine A, azathioprine, steroids) with a 4-5 days induction course of Rabbit Anti-Thymocyte Immunoglobulin (RATG) or monoclonal antibodies induction /OKT3/ in some cases. Anti-rejection treatment consisted of pulse doses of methyloprednisolon or RATG. 9 cases of malignancy (4.1%) with one case of pre-malignant liver condition (dysplasia gigantocellulare, 0.45%) were found (8M; 1F; age: 45-67 y.o., x57.7). Symptoms of neoplasms occurred 7-79 months (x31.4) postoperatively. Skin carcinomas: planoepitheliale, spinocellulare, soft tissue neoplasms/mesenchymal sarcoma, larynx Ca planoepitheliale, lung: adenocarcinoma and Ca microcellulare, kidney Ca clarocellulare and post transplant non-Hodgkin lymphoma were diagnosed. Chemo- and radiotherapy, surgery and reduction of immunosuppression did not change the outcome of malignancy in 6 pts.; (regression-1 pt was., remission-2 pts). Patients died 7-86 months after Htx (x41), 4-25 mos. (x12.5) after suffering from first symptoms and 0-10 months (x4.9) after pathology-based diagnosis of neoplasm. Heart transplant recipients have an increased risk of carcinogenesis. The incidence of malignancies in the studied group is similar or even lower than in other reports.

Steroids

MedlinePlus

... or sometimes with chemotherapy. Steroids are used for short-term symptom control although they may occasionally be continued ... even in lymphoma steroids are not typically a long-term cure for this tumor. HOW ARE STEROIDS TAKEN? ...

Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems.

PubMed

Frye, C A; Bo, E; Calamandrei, G; Calzà, L; Dessì-Fulgheri, F; Fernández, M; Fusani, L; Kah, O; Kajta, M; Le Page, Y; Patisaul, H B; Venerosi, A; Wojtowicz, A K; Panzica, G C

2012-01-01

Some environmental contaminants interact with hormones and may exert adverse consequences as a result of their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically a result of contamination of the food chain, inhalation of contaminated house dust or occupational exposure. EDCs include pesticides and herbicides (such as dichlorodiphenyl trichloroethane or its metabolites), methoxychlor, biocides, heat stabilisers and chemical catalysts (such as tributyltin), plastic contaminants (e.g. bisphenol A), pharmaceuticals (i.e. diethylstilbestrol; 17α-ethinylestradiol) or dietary components (such as phytoestrogens). The goal of this review is to address the sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or nonreproductive, sexually-dimorphic behaviours. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing the morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific 'critical periods' of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, compared to other periods. However, exposure to EDCs in adulthood can also alter physiology. Several EDCs are xenoestrogens, which can alter serum lipid concentrations or metabolism enzymes that are necessary for converting cholesterol to steroid hormones. This can ultimately alter the production of oestradiol and/or other steroids. Finally, many EDCs may have actions via (or independent of) classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor, the peroxisome proliferator-activated receptor and the retinoid X receptor, signal transduction pathways, calcium influx and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organisational effects during development and/or activational effects in adulthood that influence sexually-dimorphic, reproductively-relevant processes or other functions, by mimicking, antagonising or altering steroidal actions. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

ENDOCRINE DISRUPTERS: A REVIEW OF SOME SOURCES, EFFECTS, AND MECHANISMS OF ACTIONS ON BEHAVIOR AND NEUROENDOCRINE SYSTEMS

PubMed Central

Frye, C.; Bo, E.; Calamandrei, G.; Calzà, L.; Dessì-Fulgheri, F.; Fernández, M.; Fusani, L.; Kah, O.; Kajta, M.; Le Page, Y.; Patisaul, H.B.; Venerosi, A.; Wojtowicz, A.K.; Panzica, G.C.

2011-01-01

Some environmental contaminants interact with hormones and may exert adverse consequences due to their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically due to contamination of the food chain, inhalation of contaminated house dust, or occupational exposure. EDCs include pesticides and herbicides (such as diphenyl-dichloro-trichloroethane, DDT, or its metabolites), methoxychlor, biocides, heat stabilizers and chemical catalysts (such as tributyltin, TBT), plastic contaminants (e.g. bisphenol A, BPA), pharmaceuticals (i.e. diethylstilbestrol, DES; 17alpha-ethynilestradiol, EE2), or dietary components (such as phytoestrogens). The goal of this review is to address sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or non-reproductive, sexually-dimorphic behaviors. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific “critical periods” of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, than in other periods. However, exposure to EDCs in adulthood also can alter physiology. Several EDCs are xenoestrogens, may alter serum lipid concentrations, or metabolism enzymes that are necessary for converting cholesterol to steroid hormones, ultimately altering production of E2 and/or other steroids. Finally, many EDCs may have actions via, or independent of, classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor (AhR), the peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR), signal transduction pathways, calcium influx, and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organizational effects during development, and/or activational effects in adulthood, that influence sexually-dimorphic, reproductively-relevant processes or other functions, by mimicking, antagonizing, or altering steroidal actions. PMID:21951193

[A Case of a Multidisciplinary Team Approach to Serious Hand-Foot Syndrome Induced by High-Dose Cytarabine Therapy].

PubMed

Sakurada, Hiroaki; Aoi, Miki; Yuge, Masaaki; Sugimura, Yuriko; Kitamura, Kunio; Yamamura, Masumi; Tachi, Tomoya; Teramachi, Hitomi

2016-07-01

A 40's year-old female patient with acute myeloblastic leukemia received high-dose cytarabine(HD-Ara-C)as her third induction therapy. Because the pharmacist in charge noticed on a prior interview that she had experienced a mild skin eruption similar to hand-foot syndrome(HFS)in the previous round oftherapy(idarubicin and cytarabine), heparinoid lotion and hypoallergenic soap were used to prevent HFS. However, HFS occurred on day 3, and further developed on day 6 to grade 3 with painful erythema, swelling, and paresthesia affecting the entire surface of both hands. We cared for her with moisturization, lifestyle guidance, rotation of steroid ointment, and occlusive dressing techniques according to a multidisciplinary team approach composed ofa hematologist, dermatologist, pharmacist, and nurse. Her symptoms resolved on day 40.

Comparative study on cytogenetic damage induced by homo-aza-steroidal esters in human lymphocytes.

PubMed

Mourelatos, D; Papageorgiou, A; Boutis, L; Catsoulacos, P

1995-02-01

The effect of P[N,N-bis(2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-N-methyl-17 alpha-aza-D-homo-5 alpha-androstan-17-one (compound 3) and 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstane (compound 2) on sister-chromatid exchange (SCE) frequencies and on human lymphocytes proliferation kinetics was studied. The results are compared with those of the P[N,N-bis(2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstan-17-one (compound 1). All compounds were found to be active in inducing markedly increased SCE rates and cell division delays. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumour activity of these compounds was observed.

Comparative study of the efficacy of topical steroid and antibiotic combination therapy versus oral antibiotic alone when treating acute rhinosinusitis.

PubMed

El-Hennawi, D M; Ahmed, M R; Farid, A M; Al Murtadah, A M

2015-05-01

Acute rhinosinusitis arises as a consequence of viral rhinitis, and bacterial infection can subsequently occur. Intranasal antibiotics as an adjunct to corticosteroids usually demonstrate the greatest symptom relief. We wanted to clinically evaluate the effects of a topical antibiotic and steroid combination administered intranasally, versus an oral antibiotic alone when treating acute rhinosinusitis. Forty patients with acute bacterial rhinosinusitis were divided into two groups. Group A received an antibiotic and steroid combination (ofloxacin 0.26 per cent and dexamethasone 0.053 per cent nasal drops) for 10 days, administered intranasally (5 drops in each nostril/8 hours). Group B, the control group, received an oral antibiotic alone (amoxicillin 90 mg/kg). Eight hours after commencing treatment, facial pain was more severe in group B and nasal obstruction was reduced in both groups. Ten days after commencing treatment, anterior nasal discharge was 0.15 per cent in group A and absent in group B. The application of a topical antibiotic and steroid combination into the nasal cavity is an effective way of treating uncomplicated, acute bacterial rhinosinusitis with the theoretical advantages of easy administration, high local drug concentration and minimal systemic adverse effects.