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Glucocorticoids
Kinds of Glucocorticoids Terms modified by Glucocorticoids Selected AbstractsModulation of antigen expression in B-cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug-induced regulatory phenomenon.CYTOMETRY, Issue 3 2010Results of the AIEOP-BFM-ALL-FLOW-MRD-Study Group Abstract Background: Changes of antigen expression on residual blast cells of acute lymphoblastic leukemia (ALL) occur during induction treatment. Many markers used for phenotyping and minimal residual disease (MRD) monitoring are affected. Glucocorticoid (GC)-induced expression modulation has been causally suspected, however, subclone selection may also cause the phenomenon. Methods: We investigated this by following the phenotypic evolution of leukemic cells with flow cytometry from diagnosis to four time points during and after GC containing chemotherapy in the 20 (of 360 consecutive) B-cell precursor patients with ALL who had persistent MRD throughout. Results: The early expression changes of CD10 and CD34 were reversible after stop of GC containing chemotherapy. Modulation of CD20 and CD45 occurred mostly during the GC phase, whereas CD11a also changed later on. Blast cells at diagnosis falling into gates designed according to "shifted" phenotypes from follow-up did not form clusters and were frequently less numerous than later on. Conclusions: Our data support the idea that drug-induced modulation rather than selection causes the phenomenon. The good message for MRD assessment is that modulation is transient in at least two (CD10 and CD34) of the five prominent antigens investigated and reverts to initial aberrant patterns after stop of GC therapy, whereas CD20 expression gains new aberrations exploitable for MRD detection. © 2010 Clinical Cytometry Society [source] Predictors of persistence with 5-aminosalicylic acid therapy for ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2009S. V. KANE Summary Background, Individuals with ulcerative colitis (UC) are at risk for poor persistence with therapy. Aim, To identify factors predicting persistence with 5-aminosalicylic acid (5-ASA) therapy after 3 and 12 months in subjects with UC. Methods, In this retrospective cohort study, persistence with 5-ASA therapy was determined from prescription refill data from a commercial health insurance claims database. The analysis included subjects with UC who filled a prescription for any oral 5-ASA between October 2002 and September 2004. Persistence was defined as prescription refill at 3 and/or 12 months. Multivariate logistic regression modelling identified variables independently associated with persistence at 3 and 12 months. Results, In all, 3574 subjects were identified. Fifty-seven per cent (2044) were persistent at 3 months. Glucocorticoid use before the index prescription predicted improved persistence at 3 months. Psychiatric diagnosis, mail order of the index prescription, female gender and co-pay predicted decreased persistence. At 12 months, 1124 (55%) remained persistent. Rectal 5-ASA use, older age and switching to a different 5-ASA predicted improved persistence at 12 months. Hospitalization for a gastrointestinal condition, mail order of the 3-month prescription and number of co-morbid illnesses predicted lower persistence. Conclusion, Persistence with 5-ASA treatment in UC is complex and multifactorial, and differs by time period. [source] An In-Vivo Analysis of Capillary Stasis and Endothelial Apoptosis in a Model of HypertensionMICROCIRCULATION, Issue 8 2007Edward D. Tran ABSTRACT Objective: Recent evidence suggests endothelial apoptosis may be a mechanism for capillary rarefaction in hypertensives. The objective of this study was to examine the early phase of endothelial apoptosis and capillary blood flow in the spontaneously hypertensive rat (SHR) and the normotensive Wistar-Kyoto (WKY) rat. Methods: Since hypertension in SHR is dependent on glucocorticoids, the animals were treated with dexamethasone (DEX), by intraperitoneal injection and then by superfusion on exposed mesentery. Selected capillaries were continuously observed. Annexin V and propidium iodide were used to detect apoptosis. Results: Without central pressure reduction, permanent capillary stasis was initiated by the entrapment of leukocytes at the location of an endothelial cell that had platelets attached to it. Apoptosis of the endothelial cell was followed by apoptosis in other endothelial cells of the obstructed capillary. The incidence of stasis and total cell death in WKY+DEX were higher than WKY, whereas there were no differences between SHR+DEX and SHR. Blockade of the lectin domain of L-selectin or a platelet membrane adhesion molecule (glycoprotein IIb/IIIa) blocked the development of stasis. Conclusions: Glucocorticoid facilitates cell death and microvessel stasis. Immobilized platelets and leukocytes play a central role in capillary stasis, which leads to progression of endothelial apoptosis. [source] Methylprednisolone Exposure in Pediatric Renal Transplant PatientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2006P. Seikku Glucocorticoid (GC) dosing is commonly based on body mass or surface area in children, although the drug effects appear to correlate with steroid exposure, rather than dose. We compared the area under the serum concentration,time curve (AUC) of methylprednisolone (MP) with a recombinant cell bioassay measuring serum glucocorticoid bioactivity (GBA), in prediction of side effects in 16 pediatric patients (5.4,18.4 years of age) 2.0,14.9 years after renal transplantation (TX). They received 0.3 mg/kg of MP orally and timed blood samples were drawn up to 8 h postdose. Serum MP concentrations correlated moderately with GBA (r= 0.65, p < 0.0001) with best linear fit at 6 and 8 h (r= 0.72, 0.79, respectively, p < 0.001). MP-AUCt = 0,8 and GBAt = 6 were significantly greater in patients who gained excessive weight soon after TX. Change in growth after TX was inversely correlated with MP-AUC (r= 0.73, p < 0.05) and GBAt = 6 (r= 0.62, p < 0.05). No correlation of MP-AUC or GBA was found with blood glucose or serum lipid concentrations, glomerular filtration rate, bone mineral density or graft histology. In conclusion, GC exposure varies individually and dosing should be adjusted accordingly to control the adverse effects. GBA might provide a complementary tool for monitoring GC exposure but further studies are needed. [source] Actions of glucocorticoid and their regulatory mechanisms in the ovaryANIMAL SCIENCE JOURNAL, Issue 2 2007Masafumi TETSUKA ABSTRACT Glucocorticoid (G) directly modulates ovarian functions through binding to G receptor. The actions of G are both agonistic and antagonistic depending on the developmental stage of follicles and corpora lutea (CL). During follicular maturation, G suppresses follicular differentiation by downregulating expression of P450 aromatase and luteinizing hormone (LH) receptor in granulosa cells. During ovulation, G protects the ovulatory follicle from inflammatory damage and promotes luteinization, ensuring a smooth transition of the follicle to CL. Throughout life the ovary is exposed to periodic and sporadic waves of G. The Ovary appears to cope with this situation by locally modulating levels of active G. The primary regulatory mechanism consists of two isoforms of 11,-hydroxysteroid dehydrogenase (11,HSD) that catalyze conversion between active and inactive G. During follicular maturation the levels of active G are suppressed by the dehydrogenase activity of 11,HSD, whereas during the ovulatory process, levels of active G are further increased by the oxo-reductase activity of 11,HSD. The expression of these enzymes is under the control of gonadotrpins and local regulatory factors such as cytokines, allowing the mechanism to act in coordination with major reproductive events. Thus the G system is an integral part of ovarian physiology, which ensures that the ovary experiences only beneficial effects of G. [source] Glucocorticoid resistance in a multiple myeloma cell line is regulated by a transcription elongation block in the glucocorticoid receptor gene (NR3C1)BRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009Beatriz Sįnchez-Vega Summary Glucocorticoid (GC) effects are mediated by the glucocorticoid receptor (GR). Several studies have demonstrated that a lower number of receptors per cell were associated with poor GC response. The regulation of GR expression is complex; the levels of GR can be autologously regulated by its ligand and also by transcriptional, post-transcriptional and post-translational mechanisms. Using three human myeloma cell lines that parallel the development of GC resistance, this work describes the mechanism involved in the downregulation of GR expression. The decreased expression was neither due to mutations in the gene encoding GR, NR3C1, nor due to methylation of the promoters. A gradual decrease in NR3C1 transcripts was seen during the development of resistance, the level of expression of exon 1 to 2 RNA fragments remained the same in sensitive and resistant cell lines but a chromatin immunoprecipitation assay demonstrated that RNA polymerase II, detectable throughout exon 2 to 3 in the sensitive cells, was undetectable on exon 3 in the resistant variant, suggesting lower or no transcription at this site. These studies demonstrated that downregulation of NR3C1 mRNA in a resistant cell line involves a block to transcriptional elongation within intron B of NR3C1. This block may represent an important element in the regulation of GR expression. [source] Inflammatory pathways between placenta and foetusACTA PAEDIATRICA, Issue 1 2001Mikko Hallman Recent evidence indicates that intra-amniotic endotoxin (LPS) and interleukin-1 alpha (IL-1,) accelerate foetal lung maturity and protect from respiratory distress syndrome (RDS) more effectively than does antenatal glucocorticoid. Inflammatory cytokines promote development of chronic lung disease in the premature, acute RDS (ARDS) in children and adults. Systemic exposure to LPS or cytokines can result in generalized multiorgan damage. The abnormal host defence in the foetus and the premature newborn need to be considered in therapeutic interventions. [source] First-line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitroEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2010Thomas Lund Abstract Objectives:, The aim of the study was to investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix deposition for the first time in bisphosphonate-naļve, previously untreated patients with myeloma. Methods:, Twenty newly diagnosed patients received four cycles of bortezomib treatment, initially as monotherapy and then combined with a glucocorticoid from cycle two to four. Bone remodeling markers were monitored closely during treatment. Furthermore, the effects of bortezomib and a glucocorticoid on immature and mature osteoblasts were also studied in vitro. Results:, Treatment with bortezomib caused a significant increase in bone-specific alkaline phosphatase and pro-collagen type I N-terminal propeptide, a novel bone formation marker. The addition of a glucocorticoid resulted in a transient decrease in collagen deposition. In vitro bortezomib induced osteoblast proliferation and differentiation. Differentiation but not proliferation was inhibited by glucocorticoid treatment. Conclusions:, Bortezomib used as first-line treatment significantly increased collagen deposition in patients with multiple myeloma and osteolytic lesions, but the addition of a glucocorticoid to the treatment transiently inhibited the positive effect of bortezomib, suggesting that bortezomib may result in better healing of osteolytic lesions when used without glucocorticoids in patients that have obtained remission with a previous therapy. The potential bone-healing properties of single-agent bortezomib are currently being explored in a clinical study in patients who have undergone high-dose therapy and autologous stem cell transplantation. [source] Expression and regulation of alkaline phosphatases in human breast cancer MCF-7 cellsFEBS JOURNAL, Issue 5 2000Lai-Chen Tsai The effect of retinoic acid and dexamethasone on alkaline phosphatase (AP) expression was investigated in human breast cancer MCF-7 cells. Cellular AP activity was induced significantly by retinoic acid or dexamethasone in a time-dependent and dose-dependent fashion. A marked synergistic induction of AP activity was observed when the cells were incubated with both agents simultaneously. Two AP isozymes, tissue-nonspecific (TNAP) and intestinal (IAP), were shown to be expressed in MCF-7 cells as confirmed by the differential rate of thermal inactivation of these isozymes and RT-PCR. Based on the two-isozyme thermal-inactivation model, the specific activities for TNAP and IAP in each sample were analyzed. TNAP activity was induced only by retinoic acid and IAP activity was induced only by dexamethasone. Whereas dexamethasone conferred no significant effect on TNAP activity, retinoic acid was shown to inhibit IAP activity by , 50%. Interestingly, TNAP was found to be the only isozyme activity superinduced when the cells were costimulated with retinoic acid and dexamethasone. Northern blot and RT-PCR analysis were then used to demonstrate that the steady-state TNAP mRNA level was also superinduced, which indicates that the superinduction is regulated at the transcriptional or post-transcriptional levels. In the presence of the glucocorticoid receptor antagonist RU486, the dexamethasone-mediated induction of IAP activity was blocked completely as expected. However, the ability of RU486 to antagonize the action of glucocorticoid was greatly compromised in dexamethasone-mediated superinduction of TNAP activity. Furthermore, in the presence of retinoic acid, RU486 behaved as an agonist, and conferred superinduction of TNAP gene expression in the same way as dexamethasone. Taken together, these observations suggest that the induction of IAP activity by dexamethasone and the superinduction of TNAP by dexamethasone were mediated through distinct regulatory pathways. In addition, retinoic acid plays an essential role in the superinduction of TNAP gene expression by enabling dexamethasone to exert its agonist activity, which otherwise has no effect. [source] Methylprednisolone inhibits the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans in reactivated astrocytesGLIA, Issue 13 2008Wei-Lin Liu Abstract Reactive gliosis caused by post-traumatic injury often results in marked expression of chondroitin sulfate proteoglycan (CSPG), which inhibits neurite outgrowth and regeneration. Methylprednisolone (MP), a synthetic glucocorticoid, has been shown to have neuroprotective and anti-inflammatory effects for the treatment of acute spinal cord injury (SCI). However, the effect of MP on CSPG expression in reactive glial cells remains unclear. In our study, we induced astrocyte reactivation using ,-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and cyclothiazide to mimic the excitotoxic stimuli of SCI. The expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivation, and CSPG neurocan and phosphacan were significantly elevated by AMPA treatment. The conditioned media from AMPA-treated astrocytes strongly inhibited neurite outgrowth of rat dorsal root ganglion neurons, and this effect was reversed by pretreatment with MP. Furthermore, MP downregulated GFAP and CSPG expression in adult rats with SCI. Additionally, both the glucocorticoid receptor (GR) antagonist RU486 and GR siRNA reversed the inhibitory effects of MP on GFAP and neurocan expression. Taken together, these results suggest that MP may improve neuronal repair and promote neurite outgrowth after excitotoxic insult via GR-mediated downregulation of astrocyte reactivation and inhibition of CSPG expression. © 2008 Wiley-Liss, Inc. [source] Relevance between lipid metabolism-associated genes and rat liver regenerationHEPATOLOGY RESEARCH, Issue 8 2008Cunshuan Xu Aim:, Lipids are important in constituting cell structure and participating in many biological processes, particularly in energy supplementation to cells. The aim of the present study is to elucidate the action of lipid metabolism-associated genes on rat liver regeneration (LR). Methods:, Lipid metabolism-associated genes were obtained by collecting website data and retrieving related articles, and their expression changes in the regenerating rat liver were checked by the Rat Genome 230 2.0 array. Results:, In total, 280 genes involved in lipid metabolism were proven to be LR-associated by comparing the gene expression discrepancy between the partial-hepatectomy and sham-operation groups. The initial and total expression numbers of these genes occurring in the initial phase, G0/G1 transition, cell proliferation, cell differentiation, and structure,functional rebuilding of LR were 128, 33, 135, 6, and 267, 147, 1026, 306, respectively, illustrating that these genes were initially expressed mainly in the initiation stage and functioned in different phases. Upregulation (850 times) and downregulation (749 times), as well as 25 types of expression patterns, showed that the physiological and biochemical activities were diverse and complicated in LR. Conclusion:, According to the results of the chip detection, it was presumed that fatty acid synthesis at 24,66 h, leukotriene and androgen synthesis at 16,168 h, prostaglandin synthesis at 2,96 h, triglyceride synthesis at 18,24 h, glycosphingolipid synthesis at 0.5,66 h, metabolism of phosphatidyl inositol and sphingomyelin at 2,16 h, and cholesterol catabolism at 30,168 h were enhanced. Throughout almost the whole LR, the genes participating in estrogen, glucocorticoid, and progesterone synthesis, and triglyceride catabolism were upregulated, while phospholipid and glycosphingolipid catabolism were downregulated. [source] Does prolonged systemic glucocorticoid use increase risk of tophus formation among gouty arthritis patients?INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 3 2009Anne-Annette P. RASO Abstract Aim:, To determine the relationship of steroid use with tophus formation and other comorbid conditions among male gout patients. Methods:, Review of medical records of Filipino gout patients under the care of rheumatologists was conducted. Univariate analysis (chi-square, Student's t -test) and multiple logistic regression analysis were performed to establish the risk for tophus formation among glucocorticoid users. Bivariate analysis was separately done to determine the confounding effect of steroid use in the association of comorbidities and tophi formation. Results:, There were 295 Filipino men with a mean age of 56 years and a mean duration of 12 years of gouty arthritis who were included in the study. Multivariate analysis showed a five times higher likelihood (OR 4.81 95% CI 1.92,12.04, P < 0.001) for tophus formation among prolonged steroid users. Confounders identified were disease duration of gout (, 10 years), presence of chronic kidney disease (CKD) and elevated serum creatinine level (SCr). Bivariate analysis of comorbidities showed that steroid use introduced a considerable bias in the relationship of hypertension, elevated SCr, CKD and dyslipidemia. Conclusion:, Patients with equivalent prednisone intake of at least 15 mg/week for , 3 months is associated with tophi formation. In the presence of hypertension, renal impairment, and elevated serum creatinine level, use of steroids confounds the individual risk that each factor carries. [source] Adrenarche and Bone Modeling and Remodeling at the Proximal Radius: Weak Androgens Make Stronger Cortical Bone in Healthy Children,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2003Thomas Remer Abstract Adrenarche, the physiological increase in adrenal androgen secretion, may contribute to better bone status. Proximal radial bone and 24-h urinary steroid hormones were analyzed cross-sectionally in 205 healthy children and adolescents. Positive adrenarchal effects on radial diaphyseal bone were observed. Obviously, adrenarche is one determinant of bone mineral status in children. Introduction: Increased bone mass has been reported in several conditions with supraphysiological adrenal androgen secretion during growth. However, no data are available for normal children. Therefore, our aim was to examine whether adrenal androgens within their physiological ranges may be involved in the strengthening of diaphyseal bone during growth. Methods: Periosteal circumference (PC), cortical density, cortical area, bone mineral content, bone strength strain index (SSI), and forearm cross-sectional muscle area were determined with peripheral quantitative computed tomography (pQCT) at the proximal radial diaphysis in healthy children and adolescents. All subjects, aged 6,18 years, who collected a 24-h urine sample around the time of their pQCT analysis (100 boys, 105 girls), were included in the present study, and major urinary glucocorticoid (C21) and androgen (C19) metabolites were quantified using gas chromatography-mass spectrometry. Results and Conclusions: We found a significant influence of muscularity, but not of hormones, on periosteal modeling (PC) before the appearance of pubic hair (prepubarche). Similarly, no influence of total cortisol secretion (C21) was seen on the other bone variables. However, positive effects of C19 on cortical density (p < 0.01), cortical area (p < 0.001), bone mineral content (p < 0.001), and SSI (p < 0.001),reflecting, at least in part, reduction in intracortical remodeling,were observed in prepubarchal children after muscularity or age had been adjusted for. This early adrenarchal contribution to proximal radial diaphyseal bone strength was further confirmed for all cortical variables (except PC) when, instead of C19 and C21, specific dehydroepiandrosterone metabolites were included as independent variables in the multiple regression model. During development of pubic hair (pubarche), muscularity and pubertal stage rather than adrenarchal hormones seemed to influence bone variables. Our study shows that especially the prepubarchal increase in adrenal androgen secretion plays an independent role in the accretion of proximal radial diaphyseal bone strength in healthy children. [source] Large-scale analysis of glucocorticoid target genes in rat hypothalamusJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Hirohito Sato Abstract Insufficient glucocorticoid (GC) signaling is frequently observed in major depressive disorder (MDD). Since emotional and behavioral symptoms are often accompanied by disturbances in hypothalamic systems, GC insufficiency in this region is regarded as important in the pathogenesis of MDD. In this study, 22 early GC-responsive genes comprising 15 up-regulated and 7 down-regulated genes in rat hypothalamus were identified as being regulated at least two-fold by dexamethasone using microarray with 22 599 unique transcripts. Among these 22 genes, five of which are novel GC-responsive genes, the expression patterns of sgk, bcl6, pdk4, and plekhf1 were examined in vitro in detail, and GC-responsive regions were identified only within the promoter of sgk. This suggests that glucocorticoid response element-independent pathways also play a critical role in early GC-response in hypothalamus. Considering that a number of these GC-responsive genes are candidate neuronal regulators, this gene list should be useful in clarifying the relationship between GC insufficiency and the pathogenesis of MDD. [source] Blunted Pituitary-Adrenocortical Stress Response in Adult Rats Following Neonatal Dexamethasone TreatmentJOURNAL OF NEUROENDOCRINOLOGY, Issue 10 2000K. Felszeghy Abstract Glucocorticoids have a prominent impact on the maturation of the stress-related neuroendocrine system and on the postnatal establishment of adaptive behaviour. The present study aimed at investigating the stress responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis in young and adult rats after neonatal treatment with the synthetic glucocorticoid agonist, dexamethasone. Newborn male Wistar rats were injected s.c. with 1 µg/g dexamethasone on postnatal days 1, 3 and 5. Circulating adrenocorticotropic hormone (ACTH) and corticosterone concentrations were measured in the resting state and following a 30-min cold stress at the age of 10 days, as well as after a 30-min restraint stress at the age of 14 weeks. Also in adults, pituitary and adrenocortical hormone responsiveness was evaluated after i.v. administration of 2 µg/kg corticotropin releasing hormone (CRH). In addition, glucocorticoid (GR) and mineralocorticoid receptor (MR) binding capacities were assessed in the pituitaries of adult rats. The results showed that at day 10 basal ACTH concentration was elevated while the cold stress-evoked ACTH response was attenuated in the dexamethasone-treated rats. As adults, treated rats showed a suppressed elevation of both ACTH and corticosterone plasma cncentrations in response to restraint, while basal hormonal concentrations were not altered. There was no difference in the magnitude of the CRH-induced elevation of ACTH and corticosterone concentrations initially; however, the dexamethasone-treated animals showed a prolonged secretion of both hormones. These animals also showed a selective decrease in pituitary GR binding capacity. Neonatal dexamethasone treatment strongly suppressed body weight gain, and adrenal and thymus weights in the early phase of postnatal development. By adulthood, the body and adrenal weights were normalized while thymus weight was greater than in controls. These findings indicate that neonatal dexamethasone treatment permanently alters HPA axis activity by reducing stress responses to cold and restraint probably through supra-pituitary actions, and by decreasing the effectiveness of feedback through a diminished GR binding in the pituitary. [source] Zinc signaling through glucocorticoid and glutamate signaling in stressful circumstancesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2010Atsushi Takeda Abstract Humans and animals are constantly exposed to environmental stress. The hypothalamic-pituitary-adrenal (HPA) axis responds to stress, followed by glucocorticoid secretion from the adrenal glands. This response serves to maintain homeostasis in the living body through energy mobilization or to restore it. The brain is an important target for glucocorticoids. The hippocampus participates in the regulation of the HPA axis. Stress activates glutamatergic neurons in the hippocampus, and serious stress induces dyshomeostasis of extracellular glutamate. This dyshomeostasis, which is potentiated by glucocorticoids, modifies cognitive and emotional behavior. On the other hand, zinc is necessary for glucocorticoid signaling and is released from glutamatergic (zincergic) neurons to modulate synaptic glutamate signaling. Stress also induces dyshomeostasis of extracellular zinc, which may be linked to dyshomeostasis of extracellular glutamate. Thus, glucocorticoid signaling might also contribute to dyshomeostasis of extracellular zinc. It is likely that zinc signaling participates in cognitive and emotional behavior through glucocorticoid and glutamate signaling under stressful circumstances. This Mini-Review analyzes the relationship among signals of glucocorticoid, glutamate, and zinc under stressful circumstances to elucidate the significance of the zinc signaling in response to stress. © 2010 Wiley-Liss, Inc. [source] In vitro study comparing two collageneous membranes in view of their clinical application for rotator cuff tendon regenerationJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 1 2007Milena Fini Abstract Tenocytes were isolated from the rotator cuff tendons of healthy (HT) and glucocorticoid (GC)-treated rats (GCT) and were cultured on polystyrene wells (TCP) as control, and on 2 de-cellularized collagen matrices: porcine small intestinal submucosa (SIS), and human dermal matrix (Graftjacket®, GJ). At 3 and 7 days cell proliferation and synthesis were evaluated. Proliferation of HT tenocytes increased between experimental times for both tested membranes, but already at 3 days, HT tenocytes cultured on GJ showed the highest WST-1 value. The collagen-I (CICP) synthesis on GJ membrane did not change between experimental times and was significantly higher than TCP and SIS at 7 days. Proteoglycans (PG), and fibronectin (FBN) synthesis increased when HT were cultured on GJ, between experimental times, and both PG and FBN synthesis on GJ membrane were higher than TCP and SIS at 7 days. GC determined decreases in cell proliferation, CICP and PG syntheses at 3 days of culture on TCP when compared to HT tenocytes while a decrease in WST-1 was maintained at 7 days. CICP, PG and FBN (only at 3 days) syntheses were significantly higher in GCT tenocytes cultured on GJ. The negative effects on GC on GCT tenocytes cultured on membrane were particularly evident on SIS for CICP (,18%) and FBN (,67%) synthesis. The obtained results support the conclusion that GJ is more suitable than SIS as a scaffold for in situ tissue engineering and for the in vitro bioengineering of tendons to heal massive tears of the rotator cuff tendon. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:98,107, 2007 [source] Human receptor kinetics, tissue binding affinity, and stability of mometasone furoateJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2004Anagnostis Valotis Abstract Mometasone furoate (MF) is a topically used glucocorticoid with high anti-inflammatory potency. In contrast to the wealth of data derived from clinical studies, information about the molecular pharmacology of the compound is lacking or contradictory. Thus, we elucidated the characteristics of receptor binding kinetics and receptor affinity in a bioassay. Metabolite formation was determined in human plasma and lung tissue as well as binding affinity to human lung tissue. Fast and extensive association of MF to the human glucocorticoid receptor was observed while the dissociation of the MF,receptor complex was faster compared to fluticasone propionate (FP). The relative receptor affinity of MF was calculated as 2200 (dexamethasone,=,100, FP,=,1800) and confirmed in a bioassay measuring the induction of the glucocorticoid regulated protein CD163 in human monocytes. In plasma and human lung tissue MF formed a 9,11-epoxy degradation product. The binding affinity of MF to human lung tissue was low compared to FP due to fast redistribution from tissue into plasma. These molecular pharmacological properties are in accordance with clinical data. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1337,1350, 2004 [source] A02 Effects of housing and short term transportation on hormonal levels and on lymphocyte glucocorticoid and ,-adrenergic receptor concentrations in beef calvesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2006R. ODORE No abstract is available for this article. [source] Regular vs prn nebulized treatment in wheeze preschool childrenALLERGY, Issue 10 2009A. Papi Background:, International guidelines recommend regular treatment with inhaled glucocorticoids for children with frequent wheezing; however, prn inhaled bronchodilator alone or in combination with glucocorticoid is also often used in practice. We aimed to evaluate whether regular nebulized glucocorticoid plus a prn bronchodilator or a prn nebulized bronchodilator/glucocorticoid combination is more effective than prn bronchodilator alone in preschool children with frequent wheeze. Methods:, Double-blind, double-dummy, randomized, parallel-group trial. After a 2-week run-in period, 276 symptomatic children with frequent wheeze, aged 1,4 years, were randomly assigned to three groups for a 3-month nebulized treatment: (1) 400 ,g beclomethasone bid plus 2500 ,g salbutamol prn; (2) placebo bid plus 800 ,g beclomethasone/1600 ,g salbutamol combination prn; (3) placebo bid plus 2500 ,g salbutamol prn. The percentage of symptom-free days was the primary outcome measure. Secondary outcomes included symptom scores, use of relief medication and exacerbation frequency. Results:, As compared with prn salbutamol (61.0 ± 24.83 [SD]), the percentage of symptom-free days was higher with regular beclomethasone (69.6%, SD 20.89; P = 0.034) but not with prn combination (64.9%, SD 24.74). Results were no different in children with or without risk factors for developing persistent asthma. The effect of prn combination was no different from that of regular beclomethasone on the primary and on several important secondary outcomes. Conclusions:, Regular inhaled glucocorticoid is the most effective treatment for frequent wheezing in preschool children. However, prn bronchodilator/glucocorticoid combination might be an alternative option, but it requires further study. [source] Arginase activity in a murine macrophage cell line (RAW264.7) stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitansMOLECULAR ORAL MICROBIOLOGY, Issue 3 2006W. Sosroseno Aims:, The aim of the present study was to determine whether or not lipopolysaccharide from Actinobacillus actinomycetemcomitans could stimulate arginase activity in a murine macrophage cell line (RAW264.7 cells). Methods:, RAW264.7 cells were treated with A. actinomycetemcomitans- lipopolysaccharide or lipopolysaccharide from Escherichia coli for 24 h. The effect of polymyxin B, l -norvaline, dl -norvaline, dexamethasone and cytokines (interferon-, and interleukin-4) on arginase activity in A. actinomycetemcomitans- lipopolysaccharide-stimulated cells was also determined. The cells were pretreated with anti-CD14, anti -toll-like receptor 2, or anti-toll-like receptor 4 antibody prior to stimulation with A. actinomycetemcomitans- lipopolysaccharide. Arginase activity was determined by a colorimetric assay. Results:,A. actinomycetemcomitans- lipopolysaccharide stimulated arginase activity in RAW264.7 cells in a dose-dependent manner, but was less potent than E. coli- lipopolysaccharide. Polymyxin B and l -norvaline, but not dl -norvaline, blocked the arginase activity in A. actinomycetemcomitans- lipopolysaccharide-stimulated cells. Dexamethasone and interleukin-4 but not interferon-, augmented arginase activity in A. actinomycetemcomitans- lipopolysaccharide-stimulated cells. Treatment of the cells with anti-CD14 and anti-toll-like receptor 4 but not anti-toll-like receptor 2 antibody decreased arginase activity in A. actinomycetemcomitans- lipopolysaccharide-stimulated cells. Conclusion:, The results of the present study suggest that lipopolysaccharide from A. actinomycetemcomitans via CD14/toll-like receptor 4 complex molecules and the regulatory control of glucocorticoid and cytokines may stimulate arginase activity in RAW264.7 cells. [source] Sex differences in response to steroids in preterm sheep lungs are not explained by glucocorticoid receptor number or binding affinity,PEDIATRIC PULMONOLOGY, Issue 1 2001Jana Kovar BScHons Abstract We recently reported that prenatal glucocorticoid therapy is less effective at promoting an improvement in lung function in male than in female sheep. This observation, and the higher incidence of respiratory distress syndrome in human males, suggests that the male fetal lung may be less responsive to glucocorticoids than is the female fetal lung. Since glucocorticoids are known to exert their effects via specific cytoplasmic glucocorticoid receptors (GR), we hypothesized that there may be sexual dimorphism in either the number or binding affinity of lung GR. To test the hypothesis, binding of dexamethasone (a synthetic glucocorticoid, 0.5,40 nM) by cytosolic fractions of male (n,=,16) and female (n,=,16) fetal sheep lung was measured at 125 days gestation (term,=,148 days). Scatchard analysis of dexamethasone binding showed that the total number of GR (Bmax) did not significantly differ between male (346,±,42 fmol/mg protein) and female (277,±,23 fmol/mg protein) fetuses. The measured binding affinity (Kd) in male fetal lungs (6.85,±,0.43 nM) was not significantly different from that in females (8.46,±,1.02 nM). In conclusion, this study suggests that sex differences in fetal sheep lung responses to glucocorticoid therapy are not due to differences in the number or binding affinity of lung GR. Pediatr Pulmonol. 2001; 32:8,13. © 2001 Wiley-Liss, Inc. [source] Mechanical ventilation in children with severe asthmaPEDIATRIC PULMONOLOGY, Issue 6 2001DMSc, Kristiina Malmström MD Abstract Hospital admissions for childhood asthma have increased during the past few decades. The aim of this study was to describe the need for mechanical ventilation for severe asthma exacerbation in children in Finland from 1976 to 1995. We reviewed medical records and collected data retrospectively from all 5 university hospitals in Finland, thus covering the entire population of about 5 million. The endpoints selected were the number of admissions and readmissions leading to mechanical ventilation, duration of stay in the hospital, and mortality. Moreover, asthma medications prescribed prior to admission and administered in the intensive care unit (ICU), as well as the etiology of the exacerbation associated with mechanical ventilation were examined. Mechanical ventilation was required in 66 ICU admissions (59 patients). This constituted approximately 10% of all 632 admissions for acute asthma to an ICU. The number of admissions decreased from 1976 to 1995: 41 admissions between 1976 and 1985 vs. 25 admissions during the next 10-year period. The mean age at admission to the ICU was 3.6 years, and 46% of the patients were boys. Prior to the index admission, 70% of the patients had used asthma medication such as oral bronchodilator (50%), inhaled bronchodilator (20%), theophylline (38%), inhaled glucocorticoid (18%), oral glucocorticoid (5%), and cromoglycate (7%). Respiratory infection was by far the most common cause of all the exacerbations (61%), followed by food allergy (8%) and gastroesophageal reflux (3%). In 28% of cases the cause of the severe asthma exacerbation could not be identified. In the mechanically ventilated patients readmissions occurred 38 times between 1976 and 1985 vs. 5 times between 1986 and 1995. Five of the patients who received mechanical ventilation died, and in 3 of these patients asthma was the event causing death. In conclusion, there has been decrease in the number of first and repeat ICU admission for asthma requiring mechanical ventilation between 1970 and 1995. This trend occurred despite a simultaneous 5% yearly increase in hospital admissions for childhood asthma during these 2 decades. Pediatr Pulmonol. 2001; 31:405,411. © 2001 Wiley-Liss, Inc. [source] Host intrinsic determinants and potential consequences of parasite infection in free-ranging red-fronted lemurs (Eulemur fulvus rufus)AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 3 2010Dagmar Clough Abstract Parasites and infectious diseases represent ecological forces shaping animal social evolution. Although empirical studies supporting this link abound in various vertebrate orders, both the study of the dynamics and impact of parasite infections and infectious diseases in strepsirrhine primates have received little empirical attention. We conducted a longitudinal parasitological study on four groups of wild red-fronted lemurs (Eulemur fulvus rufus) at Kirindy Forest, Madagascar, during two field seasons in consecutive years to investigate i) the degree of gastrointestinal parasite infection on population and individual levels and ii) factors potentially determining individual infection risk. Using a comprehensive dataset with multiple individually assignable parasite samples as well as information on age, sex, group size, social rank, and endocrine status (fecal androgen and glucocorticoid), we examined parasite infection patterns and host traits that may affect individual infection risk. In addition, we examined whether parasite infection affects mating and reproductive success. Our results indicated high variability in parasite infection on individual and population levels. Time of year and group size was important determinants of variability in parasite infection. Variation in hormone levels was also associated with parasite species richness and parasite infection intensity. Differences in parasite infection between years indicate a potential immune-enhancing function of steroid hormones on nematode infections, which has not been reported before from other vertebrates studied under natural conditions. Male mating and reproductive success were not correlated to any measure of parasite infection, which suggests a nonfunctional role of the parasites we examined in primate sexual selection. Am J Phys Anthropol, 2010. © 2010 Wiley-Liss, Inc. [source] Testing extraction and storage parameters for a fecal hormone methodAMERICAN JOURNAL OF PRIMATOLOGY, Issue 11 2010David J. Pappano Abstract Four experiments were conducted to test different aspects of a "field-friendly" fecal hormone extraction method that utilizes methanol extraction in the field followed by storage on C18 solid-phase extraction cartridges. Fecal samples were collected from geladas (Theropithecus gelada) housed at the Bronx Zoo, and the experiments were conducted in a laboratory setting to ensure maximum control. The experiments were designed to either simulate the conditions to which fecal samples are subjected during fieldwork or improve on an existing protocol. The experiments tested the relationship between fecal hormone metabolite preservation/recovery and: (1) the amount of time a sample is stored at ambient temperature; (2) the number of freeze/thaw cycles a sample undergoes; (3) the effectiveness of different extraction solutions; and (4) the effectiveness of different cartridge washes. For each experiment, samples were assayed by radioimmunoassay for fecal glucocorticoid (GC) and testosterone (T) metabolites. Results for each of the experiments were as follows. First, storage at ambient temperature did not affect hormone levels until 4 weeks of storage, with significant increases for both GC and T metabolites at 4 weeks. Second, hormone levels significantly decreased in samples after two freeze/thaw cycles for GCs and six freeze/thaws cycles for T. Third, for both GCs and T, hormone extraction using various methanol solutions was significantly higher than using 100% ethanol. Finally, using a 20% methanol solution to wash cartridges significantly increased GC levels but had no effect on T levels. These results suggest that, when utilizing C18 cartridges for fecal steroid storage, researchers should consider several methodological options to optimize hormone preservation and recovery from fecal samples. Am. J. Primatol. 72:934,941, 2010. © 2010 Wiley-Liss, Inc. [source] Effects of a multilamellar emulsion on glucocorticoid-induced epidermal atrophy and barrier impairmentTHE JOURNAL OF DERMATOLOGY, Issue 2 2006Sung K. AHN ABSTRACT Skin atrophy is one of the most frequent side-effects of the topical glucocorticoid. Skin barrier impairment has also been reported as a steroid-induced side effect. Although there have been various studies on preventing or minimizing this atrophogenic effect, little has been reported about preventing barrier impairment. This study was performed to determine the effects of a multilamellar emulsion (MLE) that had a well-ordered lamellar structure on the steroid-induced barrier impairment and epidermal atrophy. To confirm these effects of MLE, 0.05% clobetasol-17-propionate (CP) and 0.05% clobetasol-17-propionate in MLE (MLE/CP) were topically applied to both flanks of hairless mice for 9 days. The topically applied CP induced a significant impairment of the epidermal permeability barrier, and MLE/CP also did not have a preventive effect on this change. However, skinfold thickness studies and histological studies showed that MLE/CP significantly reduced the steroid-induced atrophy. The topical application of MLE/CP was also shown to have a preventive effect on the steroid-induced increase of the stratum corneum (SC) surface pH. In addition, the electron microscopic findings showed relatively well-conserved lamellar bilayers in the skin treated with MLE, as compared to CP only. The results showed that the topical application of MLE immediately after CP treatment prevented the glucocorticoid-induced transepidermal water loss values increase. Light microscopy measurements showed that the skin treated with MLE immediately after CP treatment for 1 week had a slightly lower decline of skin thickness than did the CP-treated skin. These results suggest that MLE should be effective for preventing glucocorticoid-induced epidermal atrophy and for repairing the barrier impairment. [source] New pOp/LhG4 vectors for stringent glucocorticoid-dependent transgene expression in ArabidopsisTHE PLANT JOURNAL, Issue 6 2005Judith Craft Summary To facilitate glucocorticoid-inducible transgene expression from the pOp promoter in Arabidopsis the ligand-binding domain of a rat glucocorticoid receptor (GR LBD) was fused to the amino terminus of the synthetic transcription factor LhG4 to generate LhGR-N. Fusions bearing the GR LBD at other positions in LhG4 exhibited incomplete repression or inefficient induction. LhGR-N was stringently repressed in the absence of exogenous glucocorticoid but was fully activated by addition of 2 ,m dexamethasone which resulted in 1000-fold increase in GUS reporter activity. Half maximal induction was achieved with 0.2 ,m dexamethasone. Reporter transcripts were detectable within 2 h of dexamethasone application and peaked 4,10 h later. Neither LhGR-N nor dexamethasone affected seedling development although ethanol retarded development when used as a solvent for dexamethasone. The efficiency of the pOp target promoter was improved 10- to 20-fold by incorporating six copies of the ideal lac operator with sufficient inter-operator spacing to allow simultaneous occupancy. Introduction of the TMV , sequence into the 5,UTR resulted in a further 10-fold increase in dexamethasone-inducible reporter activity and an increase in the induction factor to 104. Although promoters containing the TMV , sequence exhibited slightly increased basal expression levels in the absence of dexamethasone, stringent regulation of the cytokinin biosynthetic gene ipt was achieved with all promoters. Despite the severity of the induced ipt phenotypes, transcripts for the KNOX homoeodomain transcription factors BREVIPEDICELLUS and SHOOTMERISTEMLESS were not significantly increased within 48 h of dexamethasone application to seedlings. [source] Actions of glucocorticoid and their regulatory mechanisms in the ovaryANIMAL SCIENCE JOURNAL, Issue 2 2007Masafumi TETSUKA ABSTRACT Glucocorticoid (G) directly modulates ovarian functions through binding to G receptor. The actions of G are both agonistic and antagonistic depending on the developmental stage of follicles and corpora lutea (CL). During follicular maturation, G suppresses follicular differentiation by downregulating expression of P450 aromatase and luteinizing hormone (LH) receptor in granulosa cells. During ovulation, G protects the ovulatory follicle from inflammatory damage and promotes luteinization, ensuring a smooth transition of the follicle to CL. Throughout life the ovary is exposed to periodic and sporadic waves of G. The Ovary appears to cope with this situation by locally modulating levels of active G. The primary regulatory mechanism consists of two isoforms of 11,-hydroxysteroid dehydrogenase (11,HSD) that catalyze conversion between active and inactive G. During follicular maturation the levels of active G are suppressed by the dehydrogenase activity of 11,HSD, whereas during the ovulatory process, levels of active G are further increased by the oxo-reductase activity of 11,HSD. The expression of these enzymes is under the control of gonadotrpins and local regulatory factors such as cytokines, allowing the mechanism to act in coordination with major reproductive events. Thus the G system is an integral part of ovarian physiology, which ensures that the ovary experiences only beneficial effects of G. [source] Glucocorticoid-induced differentiation of primary cultured bone marrow mesenchymal cells into adipocytes is antagonized by exogenous Runx2APMIS, Issue 8 2010LE LIN Lin L, Dai S-Dong, Fan G-Yu. Glucocorticoid-induced differentiation of primary cultured bone marrow mesenchymal cells into adipocytes is antagonized by exogenous Runx2. APMIS 2010; 118: 595,605. Long-term clinical use of glucocorticoids often causes the serious side effect of non-traumatic avascular osteonecrosis. The aim of this study was to examine the effects and mechanisms of a glucocorticoid, dexamethasone (Dex), on differentiation of primary cultured rat bone marrow mesenchymal cells (BMCs). We also tried to block the inhibitory effects of Dex on osteoblast differentiation. Adipocyte markers (peroxisome proliferator-activated receptor,-2 and aP2) were increased in response to Dex treatment in a dose- and time-dependent manner, while osteoblastic markers [Runx2, COL 1, osterix, alkaline phosphatase (ALP) and OC] were down-regulated, consistent with ALP and osteocalcin promoter activity. To validate the effects of Runx2 on the expression of osteogenesis and adipocyte genes, pCMV/Flag-Runx2 was transfected into BMCs, and relevant markers were detected after 10,7 M Dex treatment for 48 h. The results indicated that Dex treatment induced adipogenic differentiation and suppressed proliferation. No significant difference was detected in expressions of these genes between Runx2-transfected cells and Dex-treated BMCs. These data suggest that Dex primarily induced adipocyte differentiation of BMCs. Exogenous Runx2 can antagonize the effect of Dex on osteoblast differentiation. [source] Validation of enzyme-linked immunosorbent assay for measurement of faecal cortisol in fishAQUACULTURE RESEARCH, Issue 4 2009Samuel J Lupica Abstract Quantification of glucocorticoid (GC) levels in faeces has become an established method for the non-invasive assessment of adrenocortical activity. These hormones are frequently determined in plasma samples as parameters of adrenal activity and response to stress. Because GCs are metabolized and excreted with both intact hormone and their metabolites present in faeces, the concentration of GCs can be measured in excreta. Faecal samples present the advantages of easy collection, no stress to the animal and elimination of the issue of potentially misleading acute GC spikes. The aim of this study was to determine if an enzyme-linked immunosorbent assay (ELISA) for cortisol was appropriate for monitoring adrenocortical activity in faecal casts of fishes. Performance of the cortisol ELISA was validated by comparison to high-performance liquid chromatography, which is an established method for measuring free GCs and GC metabolites in faeces. Parallelism and sample extraction efficiency were compared for the two methods. Pearson's correlation across samples for these methods was 0.996. Results demonstrated that the ELISA was an efficient, sensitive and reliable method for cortisol measurement in faecal extracts, which should permit integration of non-invasive stress monitoring into studies of fish behaviour and physiology. [source] | |||||||||||||||||||||||||||||||||||||