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Sample records for clinical glucocorticoid responsiveness

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

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    Keith Bruce D

    2008-03-01

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

  2. Allelic polymorphism of glucocorticoid receptor NR3C1 (GR: from molecular biology to clinical implications

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    Orlovsky M. A.

    2012-09-01

    Full Text Available Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is focused on the molecular biology and clinical implications of glucocorticoid receptor gene polymorphism.

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

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    J.P. Herman

    2012-04-01

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

  4. Glucocorticoids boost stimulus-response memory formation in humans.

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    Guenzel, Friederike M; Wolf, Oliver T; Schwabe, Lars

    2014-07-01

    Stress affects memory beyond hippocampus-dependent spatial or episodic memory processes. In particular, stress may influence also striatum-dependent stimulus-response (S-R) memory processes. Rodent studies point to an important role of glucocorticoids in the modulation of S-R memory. However, whether glucocorticoids influence S-R memory processes in humans is still unknown. Therefore, we examined in the current experiment the impact of glucocorticoids on the formation of S-R memories in humans. For this purpose, healthy men and women received either hydrocortisone or a placebo 45 min before completing an S-R association learning task and an S-R navigation task. In addition, participants performed also a virtual spatial navigation task and a spatial navigation task in a real environment. Memory of all four learning tasks was tested one week later. Our data showed that hydrocortisone before learning enhanced memory of the S-R association learning task. Moreover, hydrocortisone enhanced the memory of the virtual spatial navigation task, mainly in women. Memory performance in the other tasks remained unaffected by hydrocortisone. These findings provide first evidence that glucocorticoids may facilitate S-R memory formation processes in humans.

  5. Disrupted glucocorticoid--Immune interactions during stress response in schizophrenia.

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    Chiappelli, Joshua; Shi, Qiaoyun; Kodi, Priyadurga; Savransky, Anya; Kochunov, Peter; Rowland, Laura M; Nugent, Katie L; Hong, L Elliot

    2016-01-01

    Glucocorticoid and immune pathways typically interact dynamically to optimize adaptation to stressful environmental challenges. We tested the hypothesis that a dysfunctional glucocorticoid-immune relationship contributes to abnormal stress response in schizophrenia. Saliva samples from 34 individuals with schizophrenia (20 male, 14 female) and 40 healthy controls (20 male, 20 female) were collected prior to and at 3 time points following completion of a computerized psychological challenge meant to be frustrating. Salivary concentrations of cortisol and interleukin-6 (IL-6) and their response to the challenge were examined. Both cortisol and IL-6 significantly increased in response to stress in the combined sample (both pschizophrenia patients (r=.379, p=.027). The trends were significantly different (Z=3.7, p=.0002). This stress paradigm induces a rise in both cortisol and IL-6. In healthy controls, a more robust acute cortisol response was associated with a steeper decline of IL-6 levels following stress, corresponding to the expected anti-inflammatory effects of cortisol. Patients exhibited the opposite relationship, suggesting an inability to down-regulate inflammatory responses to psychological stress in schizophrenia; or even a paradoxical increase of IL-6 response. This finding may partially underlie abnormalities in inflammatory and stress pathways previously found in the illness, implicating dysregulated stress response in the chronic inflammatory state in schizophrenia.

  6. Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses

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    André M. Xavier

    2016-04-01

    Full Text Available Glucocorticoids (GCs are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GCs effects on inflammation are generally mediated through GC receptors (GRs. Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors (TLRs pathway, or subject key transcription factors, such as NF-B and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins (APPs and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective glucocorticoid receptor modulators; SEGRMs, cell culture, animal treatment or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive.

  7. Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene.

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    Imai, E; Stromstedt, P E; Quinn, P G; Carlstedt-Duke, J; Gustafsson, J.A.; Granner, D K

    1990-01-01

    The minimal DNA sequence required for glucocorticoid induction of the phosphoenolpyruvate carboxykinase (PEPCK) gene in H4IIE rat hepatoma cells was defined. This novel glucocorticoid response unit (GRU) spans about 110 base pairs (bp) and includes two receptor-binding elements plus two accessory factor-binding elements. Purified glucocorticoid receptor bound to two regions (GR1 and GR2) between -395 and -349 bp relative to the transcription start site. Factors in crude rat liver nuclear extr...

  8. Clinical relevance of the glucocorticoid receptor gene polymorphisms in glucocorticoid-induced ocular hypertension and primary open angle glaucoma

    Institute of Scientific and Technical Information of China (English)

    Xiu-Qing; Wang; Zhao-Xia; Duan; Xiang-Ge; He; Xi-Yuan; Zhou

    2015-01-01

    AIM: To avoid the side effects of ocular hypertension of glucocorticoid(GC) usage in eye, we must identify susceptible individuals, which exists in about one-third of all population. Further, the majority of all primary open angle glaucoma(POAG) patients show this phenotype.Glucocorticoid receptor(GR) regulates C responsiveness in trabecular meshwork(TM) cells. In this study, single nucleotide polymorphism(SNP) genotyping was used to determine whether there are differences in the Bcl I(rs41423247) and N363S(rs6195) polymorphisms of the GR gene in healthy and POAG patients, and glucocorticoid-induced ocular hypertension(GIOH)populations.METHODS: Three hundred and twenty-seven unrelated Chinese adults, including 111 normal controls, 117 GIOH subjects and 99 POAG patients, were recruited. DNA samples were prepared and the Bcl I and N363 S polymorphisms were screened using real-time polymerase chain reaction(RT-PCR)-restriction fragment length polymorphism(RFLP) analysis. Frequencies of the Bcl I and N363 S polymorphisms were determined and compared using Fisher’s exact test and the Chi-squared test.RESULTS: Only the Bcl I polymorphism was identified in the Chinese Han population. The frequency of the G allele was 21.6 % in normal controls, 18.3% in GIOH patients, and 13.64% in the POAG patients. There was no significant difference in polymorphism or allele frequency in the 3 groups. Furthermore, no N363 S polymorphism was found in the study subjects.CONCLUSION: The Bcl I polymorphisms in GR gene had no association with GIOH and POAG patients, and N363 S polymorphism might not exist in the Chinese Han population. Therefore, the Bcl I polymorphism might not be responsible for the development of GC-induced ocular hypertension or POAG.

  9. Glucocorticoid receptors in the nucleus of the solitary tract (NTS) decrease endocrine and behavioral stress responses

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    Ghosal, Sriparna; Bundzikova-Osacka, Jana; Dolgas, C. Mark; Myers, Brent; Herman, James P.

    2014-01-01

    Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, leading to adrenocortical secretion of glucocorticoids. The magnitude and duration of the HPA axis response is mediated in large part by the glucocorticoid receptor (GR). The nucleus of the solitary tract (NTS) abundantly expresses the GR and is a key brain region for processing autonomic and endocrine stress responses. This study tests the hypothesis that GR within the NTS plays an important role in inhibiting stress-induced endo...

  10. Effects of a single glucocorticoid injection on propylene glycol-treated cows with clinical ketosis

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    van der Drift, Saskia G A; Houweling, Martin; Bouman, Marina; Koets, Ad P; Tielens, Aloysius G M; Nielen, Mirjam; Jorritsma, Ruurd

    2015-01-01

    This study investigated the metabolic effects of glucocorticoids when administered to propylene glycol-treated cows with clinical ketosis. Clinical ketosis was defined by depressed feed intake and milk production, and a maximal score for acetoacetate in urine. All cows received 250 mL oral propylene

  11. Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing.

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    Stavreva, Diana A; Coulon, Antoine; Baek, Songjoon; Sung, Myong-Hee; John, Sam; Stixova, Lenka; Tesikova, Martina; Hakim, Ofir; Miranda, Tina; Hawkins, Mary; Stamatoyannopoulos, John A; Chow, Carson C; Hager, Gordon L

    2015-06-01

    Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within ± 50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings. PMID:25677181

  12. The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test.

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    Solomon, Matia B; Wulsin, Aynara C; Rice, Taylor; Wick, Dayna; Myers, Brent; McKlveen, Jessica; Flak, Jonathan N; Ulrich-Lai, Yvonne; Herman, James P

    2014-04-01

    Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10mg/kg), CORT 108297 (30mg/kg and 60mg/kg), imipramine (10mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.

  13. Identification of plasma glucocorticoids in pallid sturgeon in response to stress

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    Webb, M.A.H.; Allert, J.A.; Kappenman, K.M.; Marcos, J.; Feist, G.W.; Schreck, C.B.; Shackleton, C.H.

    2007-01-01

    Compared to teleosts, little is known about the stress response in chondrosteans, and the glucocorticoid(s) most responsive to stress have never been definitively determined in sturgeon. In terms of cortisol production, pallid sturgeon (Scaphirhynchus albus) have a low physiological response to stress compared to other sturgeons (Acipenser sp.). Because of this, our null hypothesis was that cortisol is not the predominant glucocorticoid secreted in response to stress in pallid sturgeon. Our objective was to identify the putative glucocorticoids present in the plasma of pallid sturgeon during the stress response. Pallid sturgeon were subjected to a severe confinement stress (12 h) with an additional handling stressor for the first 6 h. Control fish were not subjected to confinement but were handled only to collect blood. Blood plasma was collected at time 0, 6, and 12 h. Gas chromatography/mass spectrometry was used to screen the plasma for the spectrum of glucocorticoids and determine the putative steroid secreted during the stress response. Cortisol was the primary glucocorticoid detected in stressed pallid sturgeon. In addition, the cortisol metabolites cortisone, alloTHE (5??-pregnane-3??,17??,21-triol-11,20-dione), allo-??-cortolone (3??,17??,20??,21-tetrahydro-5??-pregnan-11-one), and allo-??-cortolone (3??,17??,20??,21-tetrahydro-5??-pregnan-11-one) were detected. Plasma cortisol increased from a resting concentration of 0.67 ng/ml to 10.66 ng/ml at 6 h followed by a decrease to 6.78 ng/ml by 12 h. Plasma glucose increased significantly by time 6 and 12 h in both stressed and unstressed groups and remained elevated at time 12 h, while resting lactate concentrations were low to non-detectable and did not increase significantly with the stressor over time. Cortisol was the primary glucocorticoid synthesized and secreted in response to a stressor in pallid sturgeon. Though the proportional increase in plasma cortisol in stressed pallid sturgeon was lower than

  14. A zebrafish model of glucocorticoid resistance shows serotonergic modulation of the stress response

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    Brian eGriffiths

    2012-10-01

    Full Text Available One function of glucocorticoids is to restore homeostasis after an acute stress response by providing negative feedback to stress circuits in the brain. Loss of this negative feedback leads to elevated physiological stress and may contribute to depression, anxiety and post-traumatic stress disorder. We investigated the early, developmental effects of glucocorticoid signaling deficits on stress physiology and related behaviors using a mutant zebrafish, grs357, with non-functional glucocorticoid receptors. These mutants are morphologically inconspicuous and adult-viable. A previous study of adult grs357 mutants showed loss of glucocorticoid-mediated negative feedback and elevated physiological and behavioral stress markers. Already at five days post-fertilization, mutant larvae had elevated whole body cortisol, increased expression of pro-opiomelanocortin (POMC, the precursor of adrenocorticotropic hormone (ACTH, and failed to show normal suppression of stress markers after dexamethasone treatment. Mutant larvae had larger auditory-evoked startle responses compared to wildtype sibling controls (grwt, despite having lower spontaneous activity levels. Fluoxetine (Prozac treatment in mutants decreased startle responding and increased spontaneous activity, making them behaviorally similar to wildtype. This result mirrors known effects of selective serotonin reuptake inhibitors (SSRIs in modifying glucocorticoid signaling and alleviating stress disorders in human patients. Our results suggest that larval grs357 zebrafish can be used to study behavioral, physiological and molecular aspects of stress disorders. Most importantly, interactions between glucocorticoid and serotonin signaling appear to be highly conserved among vertebrates, suggesting deep homologies at the neural circuit level and opening up new avenues for research into psychiatric conditions.

  15. Endogenous glucocorticoid analysis by liquid chromatography-tandem mass spectrometry in routine clinical laboratories.

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    Hawley, James M; Keevil, Brian G

    2016-09-01

    Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful analytical technique that offers exceptional selectivity and sensitivity. Used optimally, LC-MS/MS provides accurate and precise results for a wide range of analytes at concentrations that are difficult to quantitate with other methodologies. Its implementation into routine clinical biochemistry laboratories has revolutionised our ability to analyse small molecules such as glucocorticoids. Whereas immunoassays can suffer from matrix effects and cross-reactivity due to interactions with structural analogues, the selectivity offered by LC-MS/MS has largely overcome these limitations. As many clinical guidelines are now beginning to acknowledge the importance of the methodology used to provide results, the advantages associated with LC-MS/MS are gaining wider recognition. With their integral role in both the diagnosis and management of hypo- and hyperadrenal disorders, coupled with their widespread pharmacological use, the accurate measurement of glucocorticoids is fundamental to effective patient care. Here, we provide an up-to-date review of the LC-MS/MS techniques used to successfully measure endogenous glucocorticoids, particular reference is made to serum, urine and salivary cortisol. PMID:27208627

  16. Ape conservation physiology: fecal glucocorticoid responses in wild Pongo pygmaeus morio following human visitation.

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    Michael P Muehlenbein

    Full Text Available Nature-based tourism can generate important revenue to support conservation of biodiversity. However, constant exposure to tourists and subsequent chronic activation of stress responses can produce pathological effects, including impaired cognition, growth, reproduction, and immunity in the same animals we are interested in protecting. Utilizing fecal samples (N = 53 from 2 wild habituated orangutans (Pongo pygmaeus morio (in addition to 26 fecal samples from 4 wild unhabituated orangutans in the Lower Kinabatangan Wildlife Sanctuary of Sabah, Malaysian Borneo, we predicted that i fecal glucocorticoid metabolite concentrations would be elevated on the day after tourist visitation (indicative of normal stress response to exposure to tourists on the previous day compared to samples taken before or during tourist visitation in wild, habituated orangutans, and ii that samples collected from habituated animals would have lower fecal glucocorticoid metabolites than unhabituated animals not used for tourism. Among the habituated animals used for tourism, fecal glucocorticoid metabolite levels were significantly elevated in samples collected the day after tourist visitation (indicative of elevated cortisol production on the previous day during tourist visitation. Fecal glucocorticoid metabolite levels were also lower in the habituated animals compared to their age-matched unhabituated counterparts. We conclude that the habituated animals used for this singular ecotourism project are not chronically stressed, unlike other species/populations with documented permanent alterations in stress responses. Animal temperament, species, the presence of coping/escape mechanisms, social confounders, and variation in amount of tourism may explain differences among previous experiments. Acute alterations in glucocorticoid measures in wildlife exposed to tourism must be interpreted conservatively. While permanently altered stress responses can be detrimental

  17. Ape conservation physiology: fecal glucocorticoid responses in wild Pongo pygmaeus morio following human visitation.

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    Muehlenbein, Michael P; Ancrenaz, Marc; Sakong, Rosman; Ambu, Laurentius; Prall, Sean; Fuller, Grace; Raghanti, Mary Ann

    2012-01-01

    Nature-based tourism can generate important revenue to support conservation of biodiversity. However, constant exposure to tourists and subsequent chronic activation of stress responses can produce pathological effects, including impaired cognition, growth, reproduction, and immunity in the same animals we are interested in protecting. Utilizing fecal samples (N = 53) from 2 wild habituated orangutans (Pongo pygmaeus morio) (in addition to 26 fecal samples from 4 wild unhabituated orangutans) in the Lower Kinabatangan Wildlife Sanctuary of Sabah, Malaysian Borneo, we predicted that i) fecal glucocorticoid metabolite concentrations would be elevated on the day after tourist visitation (indicative of normal stress response to exposure to tourists on the previous day) compared to samples taken before or during tourist visitation in wild, habituated orangutans, and ii) that samples collected from habituated animals would have lower fecal glucocorticoid metabolites than unhabituated animals not used for tourism. Among the habituated animals used for tourism, fecal glucocorticoid metabolite levels were significantly elevated in samples collected the day after tourist visitation (indicative of elevated cortisol production on the previous day during tourist visitation). Fecal glucocorticoid metabolite levels were also lower in the habituated animals compared to their age-matched unhabituated counterparts. We conclude that the habituated animals used for this singular ecotourism project are not chronically stressed, unlike other species/populations with documented permanent alterations in stress responses. Animal temperament, species, the presence of coping/escape mechanisms, social confounders, and variation in amount of tourism may explain differences among previous experiments. Acute alterations in glucocorticoid measures in wildlife exposed to tourism must be interpreted conservatively. While permanently altered stress responses can be detrimental, preliminary results

  18. Ape conservation physiology: fecal glucocorticoid responses in wild Pongo pygmaeus morio following human visitation.

    Science.gov (United States)

    Muehlenbein, Michael P; Ancrenaz, Marc; Sakong, Rosman; Ambu, Laurentius; Prall, Sean; Fuller, Grace; Raghanti, Mary Ann

    2012-01-01

    Nature-based tourism can generate important revenue to support conservation of biodiversity. However, constant exposure to tourists and subsequent chronic activation of stress responses can produce pathological effects, including impaired cognition, growth, reproduction, and immunity in the same animals we are interested in protecting. Utilizing fecal samples (N = 53) from 2 wild habituated orangutans (Pongo pygmaeus morio) (in addition to 26 fecal samples from 4 wild unhabituated orangutans) in the Lower Kinabatangan Wildlife Sanctuary of Sabah, Malaysian Borneo, we predicted that i) fecal glucocorticoid metabolite concentrations would be elevated on the day after tourist visitation (indicative of normal stress response to exposure to tourists on the previous day) compared to samples taken before or during tourist visitation in wild, habituated orangutans, and ii) that samples collected from habituated animals would have lower fecal glucocorticoid metabolites than unhabituated animals not used for tourism. Among the habituated animals used for tourism, fecal glucocorticoid metabolite levels were significantly elevated in samples collected the day after tourist visitation (indicative of elevated cortisol production on the previous day during tourist visitation). Fecal glucocorticoid metabolite levels were also lower in the habituated animals compared to their age-matched unhabituated counterparts. We conclude that the habituated animals used for this singular ecotourism project are not chronically stressed, unlike other species/populations with documented permanent alterations in stress responses. Animal temperament, species, the presence of coping/escape mechanisms, social confounders, and variation in amount of tourism may explain differences among previous experiments. Acute alterations in glucocorticoid measures in wildlife exposed to tourism must be interpreted conservatively. While permanently altered stress responses can be detrimental, preliminary results

  19. Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene

    NARCIS (Netherlands)

    N.A.T.M. Huizenga (Nannette); P. de Lange (Pieter); J.W. Koper (Jan); W.W. de Herder (Wouter); R. Abs; J.H. Kasteren; F.H. de Jong (Frank); S.W.J. Lamberts (Steven)

    2000-01-01

    textabstractCortisol resistance (CR) is a rare disease characterized by a generalized reduced sensitivity of end-organs to the actions of glucocorticoids (GCs). GC effects are mediated by the GC receptor (GR). The molecular alterations in CR described thus far were loca

  20. Low-stress and high-stress singing have contrasting effects on glucocorticoid response

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    Daisy eFancourt

    2015-09-01

    Full Text Available Performing music in public is widely recognised as a potentially stress-inducing activity. However, despite the interest in music performance as an acute psychosocial stressor, there has been relatively little research on the effects of public performance on the endocrine system. This study examined the impact of singing in a low-stress performance situation and a high-stress live concert on levels of glucocorticoids (cortisol and cortisone in 15 professional singers. The results showed a significant decrease in both cortisol and cortisone across the low-stress condition, suggesting that singing in itself is a stress-reducing (and possibly health-promoting activity, but significant increases across the high-stress condition. This is the first study to demonstrate that singing affects glucocorticoid responses and that these responses are modulated by the conditions of performance.

  1. Glucocorticoid receptors in the nucleus of the solitary tract (NTS) decrease endocrine and behavioral stress responses.

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    Ghosal, Sriparna; Bundzikova-Osacka, Jana; Dolgas, C Mark; Myers, Brent; Herman, James P

    2014-07-01

    Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, leading to adrenocortical secretion of glucocorticoids. The magnitude and duration of the HPA axis response is mediated in large part by the glucocorticoid receptor (GR). The nucleus of the solitary tract (NTS) abundantly expresses the GR and is a key brain region for processing autonomic and endocrine stress responses. This study tests the hypothesis that GR within the NTS plays an important role in inhibiting stress-induced endocrine and behavioral responses. Cohorts of rats received bilateral micropellet (30 μg) implantations of crystalline corticosterone, mifepristone (a GR antagonist) or cholesterol (control) directed into the region of the NTS, and were subsequently subjected to either acute psychogenic (restraint) stress or chronic variable stress (CVS). We found that NTS GR antagonism increased acute stress-induced corticosterone levels, whereas GR activation within the NTS attenuated this response. Following CVS, basal and 15 min post-restraint plasma corticosterone levels were increased by NTS GR antagonism, which was associated with an increase in Fos immunoreactivity within the PVN. Using the elevated plus maze (EPM) and forced swim test (FST), we assessed the effect of NTS GR inhibition on anxiety- and depression-like behaviors, respectively. GR inhibition within the NTS decreased open arm exploratory behavior in the EPM and increased immobility in the FST relative to controls. Together, the findings reveal a novel role of NTS GR signaling for inhibiting both endocrine and behavioral responses to stress.

  2. Treatment of Glucocorticoids Inhibited Early Immune Responses and Impaired Cardiac Repair in Adult Zebrafish.

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    Wei-Chang Huang

    Full Text Available Myocardial injury, such as myocardial infarction (MI, can lead to drastic heart damage. Zebrafish have the extraordinary ability to regenerate their heart after a severe injury. Upon ventricle resection, fibrin clots seal the wound and serve as a matrix for recruiting myeloid-derived phagocytes. Accumulated neutrophils and macrophages not only reduce the risk of infection but also secrete cytokines and growth factors to promote tissue repair. However, the underlying cellular and molecular mechanisms for how immune responses are regulated during the early stages of cardiac repair are still unclear. We investigated the role and programming of early immune responses during zebrafish heart regeneration. We found that zebrafish treated with an anti-inflammatory glucocorticoid had significantly reduced heart regenerative capacities, consistent with findings in other higher vertebrates. Moreover, inhibiting the inflammatory response led to excessive collagen deposition. A microarray approach was used to assess the differential expression profiles between zebrafish hearts with normal or impaired healing. Combining cytokine profiling and immune-staining, our data revealed that impaired heart regeneration could be due to reduced phagocyte recruitment, leading to diminished angiogenesis and cell proliferation post-cardiac injury. Despite their robust regenerative ability, our study revealed that glucocorticoid treatment could effectively hinder cardiac repair in adult zebrafish by interfering with the inflammatory response. Our findings may help to clarify the initiation of cardiac repair, which could be used to develop a therapeutic intervention that may enhance cardiac repair in humans to compensate for the loss of cardiomyocytes after an MI.

  3. Multiscale Evaluation of Thermal Dependence in the Glucocorticoid Response of Vertebrates.

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    Jessop, Tim S; Lane, Meagan L; Teasdale, Luisa; Stuart-Fox, Devi; Wilson, Robbie S; Careau, Vincent; Moore, Ignacio T

    2016-09-01

    Environmental temperature has profound effects on animal physiology, ecology, and evolution. Glucocorticoid (GC) hormones, through effects on phenotypic performance and life history, provide fundamental vertebrate physiological adaptations to environmental variation, yet we lack a comprehensive understanding of how temperature influences GC regulation in vertebrates. Using field studies and meta- and comparative phylogenetic analyses, we investigated how acute change and broadscale variation in temperature correlated with baseline and stress-induced GC levels. Glucocorticoid levels were found to be temperature and taxon dependent, but generally, vertebrates exhibited strong positive correlations with acute changes in temperature. Furthermore, reptile baseline, bird baseline, and capture stress-induced GC levels to some extent covaried with broadscale environmental temperature. Thus, vertebrate GC function appears clearly thermally influenced. However, we caution that lack of detailed knowledge of thermal plasticity, heritability, and the basis for strong phylogenetic signal in GC responses limits our current understanding of the role of GC hormones in species' responses to current and future climate variation. PMID:27501091

  4. Effects of glucocorticoids and tumor necrosis factor-alpha inhibitors on both clinical and molecular parameters in patients with Takayasu arteritis

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    Raffaele Serra

    2014-01-01

    Full Text Available Objective: To explore the effect of sequential treatment with glucocorticoid and tumor necrosis factor-alpha inhibitors in patients with Takayasu arteritis (TA. Materials and Methods: In five patients with TA, the effects of the sequential treatment with prednisone for 5-7 months and then with adalimumab (ADA + methotrexate (MTX or infliximab + MTX, or with ADA only, for 12 months on both clinical and laboratory findings were evaluated. Results: All treatments improved both symptoms and laboratory parameters without the development of side-effects. Conclusions: It was hypothesized that MMP-9 and neutrophil gelatinase-associated lipocalin could be markers of the response to the treatments.

  5. Impact of Glucocorticoid Excess on Glucose Tolerance: Clinical and Preclinical Evidence.

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    Pasieka, Aoibhe M; Rafacho, Alex

    2016-01-01

    Glucocorticoids (GCs) are steroid hormones that exert important physiological actions on metabolism. Given that GCs also exert potent immunosuppressive and anti-inflammatory actions, synthetic GCs such as prednisolone and dexamethasone were developed for the treatment of autoimmune- and inflammatory-related diseases. The synthetic GCs are undoubtedly efficient in terms of their therapeutic effects, but are accompanied by significant adverse effects on metabolism, specifically glucose metabolism. Glucose intolerance and reductions in insulin sensitivity are among the major concerns related to GC metabolic side effects, which may ultimately progress to type 2 diabetes mellitus. A number of pre-clinical and clinical studies have aimed to understand the repercussions of GCs on glucose metabolism and the possible mechanisms of GC action. This review intends to summarize the main alterations that occur in liver, skeletal muscle, adipose tissue, and pancreatic islets in the context of GC-induced glucose intolerance. For this, both experimental (animals) and clinical studies were selected and, whenever possible, the main cellular mechanisms involved in such GC-side effects were discussed. PMID:27527232

  6. Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine

    Directory of Open Access Journals (Sweden)

    Sebastien eParnaudeau

    2014-02-01

    Full Text Available The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs release. GCs bind the glucocorticoid receptor (GR a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While the GR within dopamine-innervated areas drives cocaine’s behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurones is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

  7. Viral infection increases glucocorticoid-induced interleukin-10 production through ERK-mediated phosphorylation of the glucocorticoid receptor in dendritic cells: potential clinical implications.

    Directory of Open Access Journals (Sweden)

    Sinnie Sin Man Ng

    Full Text Available The hypothalamic-pituitary-adrenal axis plays a central role in the adaptive response to stress including infection of pathogens through glucocorticoids. Physical and/or mental stress alter susceptibility to viral infection possibly by affecting this regulatory system, thus we explored potential cellular targets and mechanisms that underlie this phenomenon in key immune components dendritic cells (DCs. Dexamethasone (DEX treatment and subsequent Newcastle disease virus (NDV infection most significantly and cooperatively stimulated mRNA expression of the interleukin (IL-10 in murine bone marrow-derived DCs among 89 genes involved in the Toll-like receptor signaling pathways. NDV increased DEX-induced IL-10 mRNA and protein expression by 7- and 3-fold, respectively, which was observed from 3 hours after infection. Conventional DCs (cDCs, but not plasmacytoid DCs (pDCs were major sources of IL-10 in bone marrow-derived DCs treated with DEX and/or infected with NDV. Murine cytomegalovirus and DEX increased serum IL-10 cooperatively in female mice. Pre-treatment of DCs with the extracellular signal-regulated kinase (ERK inhibitor U0126 abolished cooperative induction of IL-10 by DEX and NDV. Further, ERK overexpression increased IL-10 promoter activity stimulated by wild-type human GR but not by its mutant defective in serine 203, whereas ERK knockdown abolished NDV/DEX cooperation on IL-10 mRNA and phosphorylation of the mouse GR at serine 213. NDV also increased DEX-induced mRNA expression of three known glucocorticoid-responsive genes unrelated to the Toll-like receptor signaling pathways in DCs. These results indicate that virus and glucocorticoids cooperatively increase production of anti-inflammatory cytokine IL-10 by potentiating the transcriptional activity of GR in DCs, through which virus appears to facilitate its own propagation in infected hosts. The results may further underlie in part known exacerbation of IL-10/T helper-2-related

  8. Enhanced conditioned approach responses in transgenic mice with impaired glucocorticoid receptor function.

    Science.gov (United States)

    Steckler, T; Holsboer, F

    1999-07-01

    The long-term consequences of impaired glucocorticoid receptor (GR) function on reward-related learning were studied in transgenic mice with impaired GR function in a series of experiments taxing conditioned and unconditioned approach responses to stimuli predictive of food. There was a double-dissociation in that transgenic mice with impaired GR activity showed enhanced conditioned exploration in situations when stimuli predicted reward, while free-feeding food consumption over 24 h was reduced. Previous experiments have shown altered accumbens dopaminergic activity in these animals. In line with these findings, we observed an enhanced behavioural stimulation of transgenic mice following administration of d-amphetamine (2 mg/kg). This suggests that the increase in preparatory responses in transgenic mice may be mediated via an enhanced accumbens dopaminergic activity, possibly secondary to alterations in other brain systems. PMID:10403023

  9. Role of oxidative stress in disrupting the function of negative glucocorticoid response element in daily amphetamine-treated rats.

    Science.gov (United States)

    Chu, Shu-Chen; Yu, Ching-Han; Chen, Pei-Ni; Hsieh, Yih-Shou; Kuo, Dong-Yih

    2016-09-01

    Amphetamine (AMPH)-induced appetite suppression is associated with changes in hypothalamic reactive oxygen species (ROS), antioxidants, neuropeptides, and plasma glucocorticoid. This study explored whether ROS and glucocorticoid response element (GRE), which is the promoter site of corticotropin-releasing hormone (CRH) gene, participated in neuropeptides-mediated appetite control. Rats were treated daily with AMPH for four days, and changes in food intake, plasma glucocorticoid and expression levels of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), superoxide dismutase (SOD), CRH, and glucocorticoid receptor (GR) were examined and compared. Results showed that food intake decreased and NPY gene down-regulated, while POMC, SOD, and CRH gene up-regulated during AMPH treatment. GR and GRE-DNA bindings were disrupted on Day 1 and Day 2 when glucocorticoid levels were still high. Pretreatment with GR inhibitor or ROS scavenger modulated mRNA levels in NPY, POMC, SOD and CRH in AMPH-treated rats. We suggest that disruptions of negative GRE (nGRE) on Day 1 and Day 2 are associated with an increase in oxidative stress during the regulation of NPY/POMC-mediated appetite control in AMPH-treated rats. These results advance the understanding of molecular mechanism in regulating AMPH-mediated appetite suppression. PMID:27235634

  10. Fecal glucocorticoid metabolite responses to management stressors and social change in four species of callitrichine monkeys.

    Science.gov (United States)

    Wark, Jason D; Amendolagine, Laura; Lukas, Kristen E; Kuhar, Christopher W; Dennis, Patricia M; Snowdon, Charles T; Schoffner, Tad; Schook, Mandi W

    2016-04-01

    The use of enzyme immunoassays (EIA) for the non-invasive measurement of glucocorticoids provides a valuable tool for monitoring health and welfare in sensitive species. We validated methods for measuring fecal glucocorticoid metabolites (FGM) using the response to veterinary exams for four species of callitrichine monkeys: golden lion tamarin (Leontopithecus rosalia, n = 7), callimico (Callimico goeldii, n = 2), pied tamarin (Saguinus bicolor, n = 2), and white-fronted marmoset (Callithrix geoffroyi, n = 2). Routine veterinary exams were performed for the golden lion tamarins and callimicos, but exams for the pied tamarins and white-fronted marmosets were prompted by the death of a social partner. Prior to veterinary exams, fecal markers were evaluated to allow collection of individual samples and estimate approximate gut transit times. Based on this assessment, individual markers were fed in the afternoon, and fresh morning fecal samples were collected throughout this study. Following a veterinary exam, FGM increased roughly 3- to 28-fold above baseline in all species. Although FGM for most species returned to baseline concentrations within 24-48 h, the marmosets exhibited a progressive increase in FGM after an exam in response to the death of a breeding female and subsequent hand-rearing of a neonate. Individual differences were noted in the callimicos and tamarins, with higher baseline FGM levels in females vs. males, although small sample size precluded a clear determination of sex differences. To our knowledge, this is the first study to measure FGM in callimicos and white-fronted marmosets and the first to compare FGM across callitrichine species. These findings highlight the broad applicability of this EIA to measure the stress response of callitrichine monkeys. The progressive increase in FGM in the marmosets during hand-rearing of a neonate suggests that care should be taken to minimize this disturbance as much as possible. PMID:26831854

  11. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide.

    Science.gov (United States)

    Frank, Matthew G; Miguel, Zurine D; Watkins, Linda R; Maier, Steven F

    2010-01-01

    Acute and chronic stress has been found to sensitize or prime the neuroinflammatory response to both peripheral and central immunologic challenges. Several studies suggest that stress-induced sensitization of neuroinflammatory processes may be mediated by the glucocorticoid (GC) response to stress. GCs, under some conditions, exhibit pro-inflammatory properties, however whether GCs are sufficient to prime neuroinflammatory responses has not been systematically investigated. In the present investigation, we tested whether acute administration of exogenous GCs would be sufficient to reproduce the stress-induced sensitization of neuroinflammatory responses under a number of different timing relationships between GC administration and immune challenge (lipopolysaccharide; LPS). We demonstrate here that GCs potentiate both the peripheral (liver) and central (hippocampus) pro-inflammatory response (e.g. TNFalpha, IL-1beta, IL-6) to a peripheral immune challenge (LPS) if GCs are administered prior (2 and 24h) to challenge. Prior exposure (24h) to GCs also potentiated the pro-inflammatory response of hippocampal microglia to LPS ex vivo. In contrast, when GCs are administered after (1h) a peripheral immune challenge, GCs suppress the pro-inflammatory response to LPS in both liver and hippocampus. GCs also up-regulated microglial activation markers including Toll-like Receptor 2. The present data suggest that the temporal relationship between GC treatment and immune challenge may be an important factor determining whether GCs exhibit pro- or anti-inflammatory properties.

  12. Gender differences in response of hippocampus to chronic glucocorticoid stress: role of glutamate receptors.

    Science.gov (United States)

    Liu, Howard H; Payne, H Ross; Wang, Bin; Brady, Scott T

    2006-04-01

    Glucocorticoids (GC) play critical roles in the pathophysiological reactions to environmental stress. In brain, morphological changes were examined in hippocampal CA3 neurons with 2 weeks of chronic elevation of GC in male and female mice. Molecular correlates and underlying mechanisms paralleling these morphologic changes in hippocampus were investigated. Although the hippocampal neurons in the CA3 area in male mice atrophy with chronically elevated GC, female mice show minimal morphological changes with comparable GC regimens. These sexual morphological differences correlate with differences in the postsynaptic dense protein (PSD95) as well as the spectrum of glutamate receptors induced by GC treatment in male and female mice, including NMDA, AMPA, and KA receptors. These findings suggest that synaptic receptor composition is adapted to the unique physiological requirements of males and females and illuminate underlying mechanisms of GC/stress responses in the brain.

  13. Role of Glucocorticoids in the Response to Unloading of Muscle Protein and Amino Acid Metabolism

    Science.gov (United States)

    Tischler, M. E.; Jaspers, S. R.

    1985-01-01

    Intact control (weight bearing) and suspended rats gained weight at a similar rate during a 6 day period. Adrenaectomized (adx) weight bearing rats gained less weight during this period while adrenalectomized suspended rats showed no significant weight gain. Cortisol treatment of both of these groups of animals caused a loss of body weight. Results from these studies show several important findings: (1) Metabolic changes in the extensor digitorum longus muscle of suspended rats are due primarily to increased circulating gluccorticoids; (2) Metabolic changes in the soleus due to higher steroid levels are probably potentiated by greater numbers of receptors; and (3) Not all metabolic responses in the unloaded soleus muscle are due to direct action of elevated glucocorticoids or increased sensitivity to these hormones.

  14. The Regulation of Muscle Mass by Endogenous Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Daniel L Marks

    2015-02-01

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

  15. Importance of the glucocorticoid stress response in a changing world: theory, hypotheses and perspectives.

    Science.gov (United States)

    Angelier, Frédéric; Wingfield, John C

    2013-09-01

    In this perspective paper, we emphasize the importance that integrative mechanisms, and especially the GC (glucocorticoid) stress response, can play in the ability of vertebrates to cope with ongoing global change. The GC stress response is an essential mediator of allostasis (i.e., the responses of an organism to a perturbation) that aims at maintaining stability (homeostasis) despite changing conditions. The GC stress response is a complex mechanism that depends on several physiological components and aims at promoting immediate survival at the expense of other life-history components (e.g., reproduction) when a labile perturbation factor (LPF) occurs. Importantly, this mechanism is somewhat flexible and its degree of activation can be adjusted to the fitness costs and benefits that result from the GC stress response. Therefore, this GC stress response mediates life-history decisions and is involved in the regulation of important life-history trade-offs. By inducing abrupt and rapid changes in the regime of LPFs, we believe that global change can affect the efficiency of the GC stress response to maintain homeostasis and to appropriately regulate these trades-offs. This dysfunction may result in an important mismatch between new LPFs and the associated GC stress response and, thus, in the inability of vertebrates to cope with a changing world. In that context, it is essential to better understand how the GC stress response can be adjusted to new LPFs through micro-evolution, phenotypic plasticity and phenotypic flexibility (habituation and sensitization). This paper sets up a theoretical framework, hypotheses and new perspectives that will allow testing and better understanding how the GC stress response can help or constrain individuals, populations and species to adjust to ongoing global change.

  16. Enhancer Turnover Is Associated with a Divergent Transcriptional Response to Glucocorticoid in Mouse and Human Macrophages.

    Science.gov (United States)

    Jubb, Alasdair W; Young, Robert S; Hume, David A; Bickmore, Wendy A

    2016-01-15

    Phenotypic differences between individuals and species are controlled in part through differences in expression of a relatively conserved set of genes. Genes expressed in the immune system are subject to especially powerful selection. We have investigated the evolution of both gene expression and candidate enhancers in human and mouse macrophages exposed to glucocorticoid (GC), a regulator of innate immunity and an important therapeutic agent. Our analyses revealed a very limited overlap in the repertoire of genes responsive to GC in human and mouse macrophages. Peaks of inducible binding of the GC receptor (GR) detected by chromatin immunoprecipitation-Seq correlated with induction, but not repression, of target genes in both species, occurred at distal regulatory sites not promoters, and were strongly enriched for the consensus GR-binding motif. Turnover of GR binding between mice and humans was associated with gain and loss of the motif. There was no detectable signal of positive selection at species-specific GR binding sites, but clear evidence of purifying selection at the small number of conserved sites. We conclude that enhancer divergence underlies the difference in transcriptional activation after GC treatment between mouse and human macrophages. Only the shared inducible loci show evidence of selection, and therefore these loci may be important for the subset of responses to GC that is shared between species.

  17. The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling.

    Science.gov (United States)

    Kwan, Wanda; Cortes, Mauricio; Frost, Isaura; Esain, Virginie; Theodore, Lindsay N; Liu, Sarah Y; Budrow, Nadine; Goessling, Wolfram; North, Trista E

    2016-09-01

    Hematopoietic stem and progenitor cell (HSPC) specification is regulated by numerous defined factors acting locally within the hemogenic niche; however, it is unclear whether production can adapt to fluctuating systemic needs. Here we show that the CNS controls embryonic HSPC numbers via the hypothalamic-pituitary-adrenal/interrenal (HPA/I) stress response axis. Exposure to serotonin or the reuptake inhibitor fluoxetine increased runx1 expression and Flk1(+)/cMyb(+) HSPCs independent of peripheral innervation. Inhibition of neuronal, but not peripheral, tryptophan hydroxlyase (Tph) persistently reduced HSPC number. Consistent with central HPA/I axis induction and glucocorticoid receptor (GR) activation, GR agonists enhanced, whereas GR loss diminished, HSPC formation. Significantly, developmental hypoxia, as indicated by Hif1α function, induced the HPA/I axis and cortisol production. Furthermore, Hif1α-stimulated HSPC enhancement was attenuated by neuronal tph or GR loss. Our data establish that embryonic HSC production responds to physiologic stress via CNS-derived serotonin synthesis and central feedback regulation to control HSC numbers. PMID:27424782

  18. Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance.

    Science.gov (United States)

    Avitsur, Ronit; Grinshpahet, Rachel; Goren, Naama; Weinstein, Ido; Kirshenboim, Or; Chlebowski, Noa

    2016-08-01

    Life time prevalence of major depression disorder (MDD) is higher in women compared to men especially during the period surrounding childbirth. Women suffering from MDD during pregnancy use antidepressant medications, particularly Selective Serotonin Reuptake Inhibitors (SSRI). These drugs readily cross the placental barrier and impact the developing fetal brain. The present study assessed the effects of prenatal exposure to fluoxetine (FLX), an SSRI antidepressant drug, on corticosterone and behavioral responses to stress in female mice. In young females, prenatal FLX significantly elevated corticosterone response to continuous stress. In adults, prenatal FLX augmented corticosterone response to acute stress and suppressed the response to continuous stress. Additionally, prenatal FLX significantly augmented stress-induced increase in locomotion and reduced anxiety- and depressive-like behaviors in adult, but not young mice. The dexamethasone suppression test revealed that prenatal FLX induced a state of glucocorticoid resistance in adult females, indicating that the negative feedback control of the hypothalamic-pituitary-adrenal axis response to stress was disrupted. These findings provide the first indication of altered hormonal and behavioral responses to continuous stress and suggest a role for the development of glucocorticoid resistance in these effects. According to these findings, prenatal environment may have implications for stress sensitivity and responsiveness to life challenges. Furthermore, this study may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy. PMID:27283378

  19. The contents of glucocorticoid receptors in patients with nephritic syndrome and its clinical evaluation

    International Nuclear Information System (INIS)

    This paper reports the contents of lymphocyte glucocorticoid receptors (GCR) in 48 patients with nephritic syndrome, using radioligand binding assay of receptors. The contents of GCR in patients with nephritic syndrome was 18936 ± 10097 binding sites/cell in adult and 9274 ± 3847 binding sites/cell in children. There was significant difference between them (p 0.05). The contents of GCR in patients with nephritic syndrome was significantly increased. This result suggested that contents of GCR in lymphocytes are correlated with nephritic syndrome, and the treatment of nephritic syndrome may be effective by hormonal therapy

  20. Glucocorticoids modulate the response of ornithine decarboxylase to unilateral removal of the dorsal hippocampus

    NARCIS (Netherlands)

    De Kloet, E R; Cousin, M A; Veldhuis, H D; Voorhuis, T D; Lando, D

    1983-01-01

    The effect of unilateral removal of the dorsal hippocampus and of glucocorticoid administration was measured on the activity of ornithine decarboxylase (ODC) in the remaining contralateral hippocampus lobe. Unilateral hippocampectomy (Hx) resulted in a rapid rise of ODC activity in the contralateral

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

    Institute of Scientific and Technical Information of China (English)

    钟佰强

    2014-01-01

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

  2. Glucocorticoids modulate the NGF mRNA response in the rat hippocampus after traumatic brain injury.

    Science.gov (United States)

    Grundy, P L; Patel, N; Harbuz, M S; Lightman, S L; Sharples, P M

    2001-02-23

    Nerve growth factor (NGF) expression in the rat hippocampus is increased after experimental traumatic brain injury (TBI) and is neuroprotective. Glucocorticoids are regulators of brain neurotrophin levels and are often prescribed following TBI. The effect of adrenalectomy (ADX) and corticosterone (CORT) replacement on the expression of NGF mRNA in the hippocampus after TBI has not been investigated to date. We used fluid percussion injury and in situ hybridisation to evaluate the expression of NGF mRNA in the hippocampus 4 h after TBI in adrenal-intact or adrenalectomised rats (with or without CORT replacement). TBI increased expression of NGF mRNA in sham-ADX rats, but not in ADX rats. Furthermore, CORT replacement in ADX rats restored the increase in NGF mRNA induced by TBI. These findings suggest that glucocorticoids have an important role in the induction of hippocampal NGF mRNA after TBI.

  3. Serotonergic Mechanisms Influence the Response to Glucocorticoid Treatment in TMJ Arthritis

    Directory of Open Access Journals (Sweden)

    Lars Fredriksson

    2005-01-01

    Full Text Available The aims of this study were to investigate the influence of serotonin (5-HT on the effects of intra-articular injections of glucocorticoid on pain of the temporomandibular joint (TMJ in patients with inflammatory disorders of the TMJ. The pretreatment synovial fluid 5-HT was negatively, and plasma 5-HT positively, correlated to change in TMJ pain after treatment. The pretreatment plasma 5-HT was positively correlated to change in pressure-pain threshold after treatment. In conclusion, this study shows that local and systemic serotonergic mechanisms partly determine the effect of intra-articular glucocorticoid treatment on TMJ pain in patients with chronic TMJ arthritis of systemic nature, while change in pressure-pain threshold over the TMJ is influenced by systemic serotonergic mechanisms.

  4. Glucocorticoid Stress Responses of Reintroduced Tigers in Relation to Anthropogenic Disturbance in Sariska Tiger Reserve in India.

    Science.gov (United States)

    Bhattacharjee, Subhadeep; Kumar, Vinod; Chandrasekhar, Mithileshwari; Malviya, Manjari; Ganswindt, Andre; Ramesh, Krishnamurthy; Sankar, Kalyanasundaram; Umapathy, Govindhaswamy

    2015-01-01

    Tiger (Panthera tigris), an endangered species, is under severe threat from poaching, habitat loss, prey depletion and habitat disturbance. Such factors have been reported causing local extermination of tiger populations including in one of the most important reserves in India, namely Sariska Tiger Reserve (STR) in northwestern India. Consequently, tigers were reintroduced in STR between 2008 and 2010, but inadequate breeding success was observed over the years, thus invoking an investigation to ascertain physiological correlates. In the present study, we report glucocorticoid stress responses of the reintroduced tigers in relation to anthropogenic disturbance in the STR from 2011 to 2013. We found anthropogenic disturbance such as encounter rates of livestock and humans, distance to roads and efforts to kill domestic livestock associated with an elevation in fecal glucocorticoid metabolite (fGCM) concentrations in the monitored tigers. In this regard, female tigers seem more sensitive to such disturbance than males. It was possible to discern that tiger's fGCM levels were significantly positively related to the time spent in disturbed areas. Resulting management recommendations include relocation of villages from core areas and restriction of all anthropogenic activities in the entire STR.

  5. Development and validation of an immunohistochemistry assay to assess glucocorticoid receptor expression for clinical trials of mifepristone in breast cancer

    Directory of Open Access Journals (Sweden)

    Baker GM

    2015-12-01

    reproducible GR IHC assay was successfully developed for use in invasive breast carcinoma tissues. Differences in GR expression between larger single tissues and smaller TMA cores illustrate the heterogeneity of the disease, as well as potential intratumoral heterogeneity. This assay is currently being utilized in clinical trials of mifepristone, a GR antagonist, in patients with TNBC. Keywords: glucocorticoid receptor, immunohistochemistry, triple negative breast cancer, mifepristone 

  6. Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors.

    Science.gov (United States)

    Lehrner, Amy; Bierer, Linda M; Passarelli, Vincent; Pratchett, Laura C; Flory, Janine D; Bader, Heather N; Harris, Iris R; Bedi, Aarti; Daskalakis, Nikolaos P; Makotkine, Iouri; Yehuda, Rachel

    2014-02-01

    Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation. PMID:24485493

  7. Glucocorticoids for Management of Polymyalgia Rheumatica and Giant Cell Arteritis.

    Science.gov (United States)

    Matteson, Eric L; Buttgereit, Frank; Dejaco, Christian; Dasgupta, Bhaskar

    2016-02-01

    Diagnosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) is based on typical clinical, histologic, and laboratory features. Ultrasonographic imaging in PMR with assessment especially of subdeltoid bursitis can aid in diagnosis and in following response to treatment. In GCA, diagnosis and disease activity are supported with ultrasonographic, MRI, or [(18)F]fluorodeoxyglucose PET evaluation of large vessels. Glucocorticoids are the primary therapy for PMR and GCA. Methotrexate may be used in patients at high risk for glucocorticoid adverse effects and patients with frequent relapse or needing protracted therapy. Other therapeutic approaches including interleukin 6 antagonists are under evaluation. PMID:26611552

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

    NARCIS (Netherlands)

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

    2014-01-01

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  10. Amygdala kindling increases fear responses and decreases glucocorticoid receptor mRNA expression in hippocampal regions.

    Science.gov (United States)

    Kalynchuk, Lisa E; Meaney, Michael J

    2003-12-01

    Amygdala kindling dramatically increases fearful behavior in rats. Because kindling-induced fear increases in magnitude as rats receive more stimulations, kindling provides an excellent model for studying the nature and neural mechanisms of fear sensitization. In the present experiment, we studied whether the development of kindling-induced fear is related to changes in glucocorticoid receptor (GR) mRNA expression in various brain regions. Rats received 20, 60 or 100 amygdala kindling stimulations or 100 sham stimulations. One day after the final stimulation, their fearful behavior was assessed in an unfamiliar open field. Then, the rats were sacrificed and their brains were processed for in situ hybridization of GR mRNA expression. We found that compared with the sham-stimulated rats, the rats that received 60 or 100 kindling stimulations were significantly more fearful in the open field and also had significantly less GR mRNA expression in the dentate gyrus and CA1 subfield of the hippocampus. Importantly, the changes in fearful behavior were significantly correlated with the changes in GR mRNA expression. These results suggest that alterations in GR mRNA expression in hippocampal regions may play a role in the development of kindling-induced fear.

  11. The cardiovascular and hypothalamus-pituitary-adrenal axis response to stress is controlled by glucocorticoid receptor sequence variants and promoter methylation

    OpenAIRE

    Li-Tempel, Ting; Larra, Mauro F.; Sandt, Estelle; Mériaux, Sophie B.; Schote, Andrea B.; Schächinger, Hartmut; Claude P Muller; Turner, Jonathan D.

    2016-01-01

    Background Gender, genetic makeup, and prior experience interact to determine physiological responses to an external perceived stressor. Here, we investigated the contribution of both genetic variants and promoter methylation of the NR3C1 (glucocorticoid receptor) gene to the cardiovascular and hypothalamus-pituitary-adrenal (HPA) axis response to the socially evaluated cold pressor test (seCPT). Results Two hundred thirty-two healthy participants were recruited and underwent the experiment. ...

  12. The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

    Science.gov (United States)

    Videlock, Elizabeth J.; Shih, Wendy; Adeyemo, Mopelola; Mahurkar-Joshi, Swapna; Presson, Angela P.; Polytarchou, Christos; Alberto, Melissa; Iliopoulos, Dimitrios; Mayer, Emeran A.; Chang, Lin

    2016-01-01

    Background and aims Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis response has been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). Methods Rome III+ IBS patients and healthy controls underwent CRF (1 μg/kg ovine) and ACTH (250 μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n = 116). GR mRNA levels were measured using quantitative PCR (n = 143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. Results There were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p = 0.009), but in women AUC was blunted in IBS (p = 0.006). Men also had reduced GR mRNA expression (p = 0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. Conclusion This study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response. PMID:27038676

  13. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements

    DEFF Research Database (Denmark)

    Grøntved, Lars; John, Sam; Baek, Songjoon;

    2013-01-01

    Mechanisms regulating transcription factor interaction with chromatin in intact mammalian tissues are poorly understood. Exploiting an adrenalectomized mouse model with depleted endogenous glucocorticoids, we monitor changes of the chromatin landscape in intact liver tissue following glucocortico...

  14. Glucocorticoid pulsatility : implications for brain functioning

    NARCIS (Netherlands)

    Sarabdjitsingh, Ratna Angela

    2010-01-01

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

  15. Perinatal glucocorticoid treatment and perspectives for antioxidat therapy

    NARCIS (Netherlands)

    Tijsseling, D.

    2014-01-01

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

  16. Glucocorticoids inhibit lipopolysaccharide-mediated inflammatory response by downregulating microRNA-155: a novel anti-inflammation mechanism.

    Science.gov (United States)

    Zheng, Yijie; Xiong, Shudao; Jiang, Pei; Liu, Ronghua; Liu, Xiaoming; Qian, Jing; Zheng, Xiujuan; Chu, Yiwei

    2012-04-15

    Glucocorticoids (GCs) are among the most widely used and effective therapies for many chronic inflammatory diseases. Although attempts have been made to identify important protein-coding genes and pathways involved in the anti-inflammatory effect of GCs, knowledge of genomic aberrations associated with noncoding genes, such as micro-RNAs (miRNAs), and their contributions is relatively limited. In this study, a systematic screening of the miRNA expression profile by microarray showed that GCs inhibited the expression of miR-155 in lipopolysaccharide (LPS)-induced macrophage inflammatory responses. Overexpression of miR-155 markedly reversed the suppressive action of GCs, whereas inhibition of miR-155 exhibited an effect similar to that of GCs on LPS-treated RAW264.7 cells, indicating miR-155 to be a functional regulator in the anti-inflammatory effect of GCs. Furthermore, GCs inhibited miR-155 expression in a GC receptor- and NF-κB-dependent manner. Bioinformatics analysis and luciferase assay revealed that the NF-κB binding site located in the promoter region of the B-cell integration cluster was important in mediating the GC-driven suppression of miR-155 in response to LPS stimulation. In addition, the combination of treatment with GCs and inhibition of miR-155 enhanced the anti-inflammatory effect of GCs on LPS-stimulated RAW264.7 cells. Therefore, we identify miR-155 to be a novel target through which GCs exert their anti-inflammatory effect on the LPS-induced macrophage inflammatory response. These findings may provide a basic rationale for new approaches in the effort to develop anti-inflammatory therapeutics. PMID:22326887

  17. Responsibility of the clinical physicist

    International Nuclear Information System (INIS)

    The author discusses the various aspects of the responsibilities of physicians and clinical physicists with regard to radiation protection in medical applications of ionizing radiation. He annotates that in the Netherlands only 4 registered clinical physicists find a full-time task in x-ray diagnostics. Much more often it concerns a part-time task. the Dutch Society for Nuclear Medicine therefore recommends a legal basis for responsibilities of the clinical physicists and for taking up the appropriate discipline in the BIG-law. Also in this respect the society pleads for bringing into level of the number of qualified clinical physicists needed. The institutes involved should be obliged legally to acquire the necessary experts and should therefore dispose of the proper financial resources. (author)

  18. Occurrence of glucocorticoids discharged from a sewage treatment plant in Japan and the effects of clobetasol propionate exposure on the immune responses of common carp (Cyprinus carpio) to bacterial infection.

    Science.gov (United States)

    Nakayama, Kei; Sato, Kentaro; Shibano, Takazumi; Isobe, Tomohiko; Suzuki, Go; Kitamura, Shin-Ichi

    2016-04-01

    The present study evaluated the environmental risks to common carp (Cyprinus carpio) posed by glucocorticoids present in sewage treatment plant (STP) effluent. To gather information on the seasonal variations in glucocorticoid concentration, the authors sampled the effluent of a Japanese STP every other week for 12 mo. Six of 9 selected glucocorticoids were detected in the effluent, with clobetasol propionate and betamethasone 17-valerate detected at the highest concentrations and frequencies. The present study's results indicated that effluent glucocorticoid concentration may depend on water temperature, which is closely related to the removal efficiency of the STP or to seasonal variations in the public's use of glucocorticoids. In a separate experiment, to clarify whether glucocorticoids in environmental water increase susceptibility to bacterial infection in fish, the authors examined the responses to bacterial infection (Aeromonas veronii) of common carp exposed to clobetasol propionate. Clobetasol propionate exposure did not affect bacterial infection-associated mortality. In fish infected with A. veronii but not exposed to clobetasol propionate, head kidney weight and number of leukocytes in the head kidney were significantly increased (p < 0.05), whereas these effects were not observed in infected fish exposed to clobetasol. This suggests that clobetasol propionate alleviated bacterial infection-associated inflammation. Together, these results indicate that susceptibility to bacterial infection in common carp is not affected by exposure to glucocorticoids at environmentally relevant concentrations.

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

    Science.gov (United States)

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

    2015-01-01

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

  20. Glucocorticoids and nervous system plasticity

    Institute of Scientific and Technical Information of China (English)

    Kathryn M Madalena; Jessica K Lerch

    2016-01-01

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

  1. Glucocorticoids and nervous system plasticity

    Directory of Open Access Journals (Sweden)

    Kathryn M Madalena

    2016-01-01

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

  2. The acute glucocorticoid stress response does not differentiate between rewarding and aversive social stimuli in rats.

    Science.gov (United States)

    Buwalda, Bauke; Scholte, Jan; de Boer, Sietse F; Coppens, Caroline M; Koolhaas, Jaap M

    2012-02-01

    The mere presence of elevated plasma levels of corticosterone is generally regarded as evidence of compromised well-being. However, environmental stimuli do not necessarily need to be of a noxious or adverse nature to elicit activation of the stress response systems. In the present study, the physiological and neuroendocrine responses to repeated social stimuli that can be regarded as emotional opposites, i.e. social defeat and sexual behavior, were compared. Similar corticosterone responses were observed in animals confronted for the first time with either a highly aggressive male intruder or a receptive female, but a decrease was noticed in defeated rats tested during a third interaction. Only if animals are being physically attacked does the corticosterone response remain similar to the one observed during sexual behavior. In addition, the number of activated cells in the parvocellular hypothalamic paraventricular nucleus, as visualized by c-Fos immunocytochemistry, shows no difference between rats 1h after the third exposure to defeat or sex. Finally, biotelemetric recordings of heart rate, body temperature and locomotor activity show a robust response to both social stimuli that is generally, however, higher in animals being confronted with a receptive female. The data clearly indicate that acute plasma corticosterone levels are not reflecting the emotional valence of a salient stimulus. The magnitude of the response seems to be a direct reflection of the behavioral activity and hence of the metabolic requirements of activated tissues. Next to its direct metabolic role, acute increases in plasma corticosterone will have neurobiological and behavioral effects that largely depend on the neural circuitry that is activated by the stimulus that triggered its release. PMID:22210197

  3. Fecal glucocorticoid response to environmental stressors in green iguanas (Iguana iguana)

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Timm, Jeanette; Ibsen, Ida;

    2012-01-01

    study, fecal corticosterone metabolite (FCM) levels in green iguanas (Iguana iguana) were quantified during periods of rest and exposure to hypothesized stressors. FCM quantification was combined with behavioral analysis to further contextualize the measured increases. It was shown that both daily 5......-minute handling/restraint, as well as housing devoid of climbing opportunity, resulted in increased FCM excretion. Behavioral analysis suggested that the iguanas were chronically stressed by the lack of climbing opportunity, whereas handling may have induced only a transient stress response....... The experimental design, using repeated periods of stressor-exposure, also revealed a facilitating effect, where the two stressors potentiated one another. Furthermore, the order of the two stressors was found to be important. The study provides insight into the functioning of the hormonal stress response in green...

  4. Ape Conservation Physiology: Fecal Glucocorticoid Responses in Wild Pongo pygmaeus morio following Human Visitation

    OpenAIRE

    Michael P Muehlenbein; Marc Ancrenaz; Rosman Sakong; Laurentius Ambu; Sean Prall; Grace Fuller; Mary Ann Raghanti

    2012-01-01

    Nature-based tourism can generate important revenue to support conservation of biodiversity. However, constant exposure to tourists and subsequent chronic activation of stress responses can produce pathological effects, including impaired cognition, growth, reproduction, and immunity in the same animals we are interested in protecting. Utilizing fecal samples (N = 53) from 2 wild habituated orangutans (Pongo pygmaeus morio) (in addition to 26 fecal samples from 4 wild unhabituated orangutans)...

  5. Glucocorticoids in early rheumatoid arthritis

    NARCIS (Netherlands)

    Everdingen, Amalia A. van

    2002-01-01

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

  6. Assessment of Flooring Renovations on African Elephant (Loxodonta africana Behavior and Glucocorticoid Response.

    Directory of Open Access Journals (Sweden)

    Sarah A Boyle

    Full Text Available Captive African (Loxodonta africana and Asian (Elephas maximus elephants can experience foot pathologies and arthritis. As a preventative measure against these pathologies and to alleviate the potential discomfort due to concrete substrates, some zoological institutions have renovated elephant housing to increase the amount of natural or shock-absorbent substrates. The objective of this study was to compare behavioral (diurnal and nocturnal and glucorticoid (e.g., serum cortisol responses of three female African elephants before, during, and after renovation to their indoor housing floor to assess whether renovations had short-term effects on the elephants' behavior and stress physiology. Behavioral data were collected using scan-sampling methods, and activity budgets were constructed for each of the three elephants. In addition, the duration of all lying rest activities were recorded. Weekly serum cortisol concentrations were determined with enzyme immunoassay (EIA. Overall, eating was the most prevalent behavior exhibited outdoors during the day, while resting (either in a lying or standing position were most common during the indoor, nocturnal periods. Although variation existed among the three elephants, all three females spent significantly more time walking and less time eating during the day after the completion of the renovations. The extent to which the three elephants exhibited nocturnal lying rest behavior varied among the elephants, with the oldest elephant exhibiting the least amount (an average of 13.2 ± 2.8% of the nightly behavioral scans compared to the two younger elephants (an average of 34.5 ± 2.1% and 56.6 ± 2.8% of the nightly behavioral scans. There was a significant increase in lying rest behavior for one elephant and standing rest for a second elephant following renovations. Baseline cortisol concentrations prior to renovations were 3.0 ± 0.4 ng/ml, 4.5 ± 0.5 ng/ml, and 4.9 ± 0.5 ng/ml for the three elephants

  7. Assessment of Flooring Renovations on African Elephant (Loxodonta africana) Behavior and Glucocorticoid Response.

    Science.gov (United States)

    Boyle, Sarah A; Roberts, Beth; Pope, Brittany M; Blake, Margaret R; Leavelle, Stephen E; Marshall, Jennifer J; Smith, Andrew; Hadicke, Amanda; Falcone, Josephine F; Knott, Katrina; Kouba, Andrew J

    2015-01-01

    Captive African (Loxodonta africana) and Asian (Elephas maximus) elephants can experience foot pathologies and arthritis. As a preventative measure against these pathologies and to alleviate the potential discomfort due to concrete substrates, some zoological institutions have renovated elephant housing to increase the amount of natural or shock-absorbent substrates. The objective of this study was to compare behavioral (diurnal and nocturnal) and glucorticoid (e.g., serum cortisol) responses of three female African elephants before, during, and after renovation to their indoor housing floor to assess whether renovations had short-term effects on the elephants' behavior and stress physiology. Behavioral data were collected using scan-sampling methods, and activity budgets were constructed for each of the three elephants. In addition, the duration of all lying rest activities were recorded. Weekly serum cortisol concentrations were determined with enzyme immunoassay (EIA). Overall, eating was the most prevalent behavior exhibited outdoors during the day, while resting (either in a lying or standing position) were most common during the indoor, nocturnal periods. Although variation existed among the three elephants, all three females spent significantly more time walking and less time eating during the day after the completion of the renovations. The extent to which the three elephants exhibited nocturnal lying rest behavior varied among the elephants, with the oldest elephant exhibiting the least amount (an average of 13.2 ± 2.8% of the nightly behavioral scans) compared to the two younger elephants (an average of 34.5 ± 2.1% and 56.6 ± 2.8% of the nightly behavioral scans). There was a significant increase in lying rest behavior for one elephant and standing rest for a second elephant following renovations. Baseline cortisol concentrations prior to renovations were 3.0 ± 0.4 ng/ml, 4.5 ± 0.5 ng/ml, and 4.9 ± 0.5 ng/ml for the three elephants. Cortisol

  8. Glucocorticoids are ineffective in alcoholic hepatitis

    DEFF Research Database (Denmark)

    Christensen, E; Gluud, C

    1995-01-01

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

  9. Environmental conditions experienced during the tadpole stage alter post-metamorphic glucocorticoid response to stress in an amphibian.

    Science.gov (United States)

    Crespi, Erica J; Warne, Robin W

    2013-12-01

    Exposure to adverse environmental conditions during early development can shape life-history traits and have lasting effects on physiological function in later life. Although findings within the biomedical literature have shown that environmentally induced elevations in glucocorticoids (GCs) during critical developmental windows can cause persistent carry-over effects (i.e., developmental programming), little is known about whether such effects of GCs can be generalized to wildlife species. Using wood frogs as a study species, we conducted an experiment with a split-plot design to assess the short-term and the long-term physiological consequences of availability of food, hydroperiod length (i.e., pond drying), and the interaction between these two environmental conditions. In outdoor experimental ponds, we reared tadpoles in chronically high or low-food conditions, and tadpoles from each pond experienced either high water until metamorphosis or a reduction in water volume during late developmental stages (after Gosner stage 38). After metamorphosis, animals were housed individually and fed ad libitum for 10 weeks, and growth rate, fat content, and resting and acute stress-induced GC levels were measured. We found that tadpoles experiencing low availability of food and reduced water volume had elevated GC levels, reduced mass, and body condition as they approached metamorphosis. At 10 weeks after metamorphosis, we found that these two conditions also had persistent interactive effects on post-metamorphic allocation of resources to growth, energy storage, and responsiveness of GCs to a novel stressor. Of individuals that experienced reduced water volume, only those that experienced high food as tadpoles were able to catch up to individuals that did not experience reduced water volume in terms of body mass, femur length, and body condition, and they allocated more resources to fat storage. By contrast, 10-week old frogs with low-food and that experienced low water

  10. Previous history of chronic stress changes the transcriptional response to glucocorticoid challenge in the dentate gyrus region of the male rat hippocampus.

    Science.gov (United States)

    Datson, Nicole A; van den Oever, Jessica M E; Korobko, Oksana B; Magarinos, Ana Maria; de Kloet, E Ronald; McEwen, Bruce S

    2013-09-01

    Chronic stress is a risk factor for several neuropsychiatric diseases, such as depression and psychosis. In response to stress glucocorticoids (GCs) are secreted that bind to mineralocorticoid and glucocorticoid receptors, ligand-activated transcription factors that regulate the transcription of gene networks in the brain necessary for coping with stress, recovery, and adaptation. Chronic stress particularly affects the dentate gyrus (DG) subregion of the hippocampus, causing several functional and morphological changes with consequences for learning and memory, which are likely adaptive but at the same time make DG neurons more vulnerable to subsequent challenges. The aim of this study was to investigate the transcriptional response of DG neurons to a GC challenge in male rats previously exposed to chronic restraint stress (CRS). An intriguing finding of the current study was that having a history of CRS had profound consequences for the subsequent response to acute GC challenge, differentially affecting the expression of several hundreds of genes in the DG compared with challenged nonstressed control animals. This enduring effect of previous stress exposure suggests that epigenetic processes may be involved. In line with this, CRS indeed affected the expression of several genes involved in chromatin structure and epigenetic processes, including Asf1, Ash1l, Hist1h3f, and Tp63. The data presented here indicate that CRS alters the transcriptional response to a subsequent GC injection. We propose that this altered transcriptional potential forms part of the molecular mechanism underlying the enhanced vulnerability for stress-related disorders like depression caused by chronic stress.

  11. Molecular mechanisms of glucocorticoid receptor signaling

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

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

  12. Responsiveness of Clinical Outcome Measures

    DEFF Research Database (Denmark)

    Lauridsen, Henrik Hein

    Rating Scale is recommended. The MCID was more or less stable across subgroups for most instruments and increased monotonously with baseline condition severity in PrS and LBP patients only. The clinical question: “how are you now compared to when you started the treatment” seems to be most sensitive......Background The Oswestry Disability Index (ODI) is one of two standardised functional health measurement scales (HMS) recommended. Despite extensive psychometric testing, little is known about HMS behaviour and the minimal clinically important difference (MCID) in subgroups of LBP patients. Moreover...... subgroups of patients with LBP. In addition, we explored whether low back pain patients were able to determine an acceptable treatment outcome before it began. Methods The responsiveness in subgroups study. An extensive cross-cultural adaptation and validation of the ODI was carried out on patients seen...

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

    Science.gov (United States)

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

    2016-02-01

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

  14. Clinical analysis of glucocorticoid in the treatment of endocrine disorders%糖皮质激素治疗内分泌疾病的临床分析

    Institute of Scientific and Technical Information of China (English)

    葛军

    2015-01-01

    Objective:To explore the clinical effect of glucocorticoid in the treatment of endocrine disorders.Methods:106 patients with endocrine diseases were selected.They were randomly divided into the experimental group and the control group with 54 cases in each.The control group were given conventional treatment,and the experimental group were given glucocorticoids on the basis of the control group,then we observed the therapeutic effect in the two groups.Results:In the experimental group,the total efficiency(98.1%) was significantly higher than that of the control group(79.6%);the satisfaction(98.1%) was significantly higher than that of the control group(79.6%);the adverse reaction rate(3.7%) was significantly lower than that of the control group(14.8%), P<0.05.Conclusion:Glucocorticoid treatment of endocrine disorders can significantly improve the patient's symptoms and improve patient satisfaction,and the safety was good.%目的:探讨糖皮质激素治疗内分泌疾病的临床效果。方法:收治内分泌疾病患者106例,随机分为试验组和对照组各54例,对照组采用常规方法治疗,试验组在对照组的基础上加入糖皮质激素治疗,观察两组的治疗效果。结果:在试验组总有效率(98.1%)明显高于对照组(79.6%),满意度(98.1%)明显高于对照组(79.6%),不良反应率(3.7%)明显低于对照组(14.8%),P<0.05。结论:采用糖皮质激素治疗内分泌疾病可以明显改善患者的症状,提高患者的满意度,安全性好。

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Glucocorticoidinduced osteoporosis (GIOP) is a widespread clinical complication following glucocorticoid therapy. This irreversible damage to boneforming and resorbing cells is essential in the pathogenesis of osteoporosis. Autophagy is a physiological process involved in the regulation of cells...... and their responses to diverse stimuli, however, the role of autophagy in glucocorticoidinduced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy......, immunohistochemistry and western blot analysis detected autophagy in vitro and in GIOP model rats (in vivo). With the addition of the autophagy inhibitor 3methyladenine, the proliferative ability of BMSCs was further reduced, while the number of apoptotic BMSCs was significantly increased. The data suggests...

  16. Single nucleotide polymorphisms in non-coding region of the glucocorticoid receptor gene and prednisone response in childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Xue, Lu; Li, Chunhuai; Wang, Yue; Sun, Wei; Ma, Cui; He, Yongyan; Yu, Yongli; Cai, Lu; Wang, Liying

    2015-06-01

    Poor prednisone response predicts an inferior outcome in pediatric acute lymphoblastic leukemia (ALL) in Berlin-Frankfurt-Münster (BFM) treatment protocols. Here, we investigated five single nucleotide polymorphisms (SNPs) in both the coding and non-coding regions of the glucocorticoid receptor (GR) gene, and analyzed their association with prednisone responsiveness in vivo in 63 pediatric patients with ALL in China. Of the five SNPs, the rs41423247 and rs7701443 polymorphisms were significantly associated with prednisone response at the allelic level (rs41423247 odds ratio [OR] = 9.58; 95% confidence interval [CI]: 1.23-74.21; p = 0.01; rs7701443 OR = 3.12; 95% CI: 1.08-9; p = 0.02). Two polymorphisms (rs6189/6190 and rs6198) were not observed in the study cohort. Haplotypes composed of CCC alleles and TCG alleles at three loci (rs7701443, Tth111I and BclI) were both associated with prednisone response (p = 0.013; p = 0.028). Our results suggested that polymorphisms in the non-coding region of the GR gene were associated with prednisone response in vivo in pediatric ALL in Han Chinese. PMID:25644744

  17. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    NARCIS (Netherlands)

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T.; Van Der Horst, Geertje; Lemhemmer, Daniël; Marijt, Koen A.; Hwang, Ming S.; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M.; Meijer, Onno C.; Culig, Zoran; Van Der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCA). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. I

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  19. Relationship between the induction of heat shock proteins and the decrease in glucocorticoid receptor during heat shock response in human osteosarcoma cells

    Institute of Scientific and Technical Information of China (English)

    宋亮年

    1995-01-01

    Previously,it has been found that glucocorticoid receptor(GR)binding activity decreasedrapidly during heat shock response in HOS-8603,a human osteosarcorna cell line.In this study,Therelationship between the induction of heat shock proteins(HSPs)and the decrease in GR was furtherstudied in the same cell line.It was found that even though quercetin could specifically inhibit the ex-pression of hsp90α and hsp70 mRNA,it could not prevent GR from the decrease in response to the heatshock treatment.This represents the first reported evidence that the induction of HSPs and the decrease inGR during heat shock response were 2 independent biological events.The results of the present study furthershowed that although the heat shock treatment alone had no effects on alkaline phosphatase(AKP)activity,itcould completely block the induction of AKP activity in HOS-8603 cells by dexamethasone(Dex),a syntheticglucocorticoid.These results demonstrate that the heat shock-induced alteration in GR was accompanied by adecrease in GR functional activity.Furthermore,when the induction of HSPs was inhibited by the treatmentof cells with quercetin,the stimulatory effects of Dex on AKP activity could still be inhibited completely bythe heat shock treatment.The results of this part,on the basis of GR functional activity,further demonstratethat quercetin could not inhibit the heat shock-induced decrease in GR,even though it could inhibit the induc-tion of HSPs.To clarify further the effects of quercetin alone on GR binding activity in HOS-8603 cells,theregulation of GR by quercetin was also studied.It was found for the first time that quercetin coulddown-regulate GR in a time-dependent manner significantly,and that the down-regulation of GR by quercetinin HOS-8603 cells paralelled with a decrease in glucocorticoid-mediated functional responses,suggesting thatthe down-regulation of GR by quercetin is of biological significance.

  20. Biological significance of glucocorticoid receptor beta

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

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

  1. Cardiac atrial circadian rhythms in PERIOD2::LUCIFERASE and per1:luc mice: amplitude and phase responses to glucocorticoid signaling and medium treatment.

    Directory of Open Access Journals (Sweden)

    Daan R van der Veen

    Full Text Available Circadian rhythms in cardiac function are apparent in e.g., blood pressure, heart rate, and acute adverse cardiac events. A circadian clock in heart tissue has been identified, but entrainment pathways of this clock are still unclear. We cultured tissues of mice carrying bioluminescence reporters of the core clock genes, period 1 or 2 (per1(luc or PER2(LUC and compared in vitro responses of atrium to treatment with medium and a synthetic glucocorticoid (dexamethasone [DEX] to that of the suprachiasmatic nucleus (SCN and liver. We observed that PER2(LUC, but not per1(luc is rhythmic in atrial tissue, while both per1(luc and PER2(LUC exhibit rhythmicity in other cultured tissues. In contrast to the SCN and liver, both per1(luc and PER2(LUC bioluminescence amplitudes were increased in response to DEX treatment, and the PER2(LUC amplitude response was dependent on the time of treatment. Large phase-shift responses to both medium and DEX treatments were observed in the atrium, and phase responses to medium treatment were not attributed to serum content but the treatment procedure itself. The phase-response curves of atrium to both DEX and medium treatments were found to be different to the liver. Moreover, the time of day of the culturing procedure itself influenced the phase of the circadian clock in each of the cultured tissues, but the magnitude of this response was uniquely large in atrial tissue. The current data describe novel entrainment signals for the atrial circadian clock and specifically highlight entrainment by mechanical treatment, an intriguing observation considering the mechanical nature of cardiac tissue.

  2. Cardiac Atrial Circadian Rhythms in PERIOD2::LUCIFERASE and per1:luc Mice: Amplitude and Phase Responses to Glucocorticoid Signaling and Medium Treatment

    Science.gov (United States)

    Xi, Yang; Li, Lei; Duffield, Giles E.

    2012-01-01

    Circadian rhythms in cardiac function are apparent in e.g., blood pressure, heart rate, and acute adverse cardiac events. A circadian clock in heart tissue has been identified, but entrainment pathways of this clock are still unclear. We cultured tissues of mice carrying bioluminescence reporters of the core clock genes, period 1 or 2 (per1luc or PER2LUC) and compared in vitro responses of atrium to treatment with medium and a synthetic glucocorticoid (dexamethasone [DEX]) to that of the suprachiasmatic nucleus (SCN) and liver. We observed that PER2LUC, but not per1luc is rhythmic in atrial tissue, while both per1luc and PER2LUC exhibit rhythmicity in other cultured tissues. In contrast to the SCN and liver, both per1luc and PER2LUC bioluminescence amplitudes were increased in response to DEX treatment, and the PER2LUC amplitude response was dependent on the time of treatment. Large phase-shift responses to both medium and DEX treatments were observed in the atrium, and phase responses to medium treatment were not attributed to serum content but the treatment procedure itself. The phase-response curves of atrium to both DEX and medium treatments were found to be different to the liver. Moreover, the time of day of the culturing procedure itself influenced the phase of the circadian clock in each of the cultured tissues, but the magnitude of this response was uniquely large in atrial tissue. The current data describe novel entrainment signals for the atrial circadian clock and specifically highlight entrainment by mechanical treatment, an intriguing observation considering the mechanical nature of cardiac tissue. PMID:23110090

  3. Analyses of the role of the glucocorticoid receptor gene polymorphism (rs41423247) as a potential moderator in the association between childhood overweight, psychopathology, and clinical outcomes in Eating Disorders patients: A 6 years follow up study.

    Science.gov (United States)

    Castellini, Giovanni; Lelli, Lorenzo; Tedde, Andrea; Piaceri, Irene; Bagnoli, Silvia; Lucenteforte, Ersilia; Sorbi, Sandro; Monteleone, Alessio Maria; Hudziak, James J; Nacmias, Benedetta; Ricca, Valdo

    2016-09-30

    Childhood overweight and the SNP rs41423247 of the glucocorticoid receptor gene (GR) were reported to represent predisposing factors for Eating Disorders (EDs). The distribution of the polymorphism was evaluated in 202 EDs patients, and in 116 healthy subjects. The Structured Clinical Interview for the DSM-IV and self-reported questionnaires were administered at the admission to the clinic and at 3 time points (end of a cognitive behavioral therapy, 3 and 6 years follow up). G-allele was associated with childhood overweight, depressive disorder comorbidity, and diagnostic instability. G-allele carriers reporting childhood overweight showed greater frequency of subjective binge eating and emotional eating.

  4. Ethical responsibilities of the clinical engineer.

    Science.gov (United States)

    Saha, P; Saha, S

    1986-01-01

    Because of the growth of medical technology, Clinical Engineers have increased responsibilities in respect to this new technology and so to modern medicine itself. This results in a need to ensure that an ethical consciousness of responsibilities to patients, physicians, and institutions grows within Clinical Engineers as they move into evermore important roles within the health care system. Clinical Engineers must have clearly defined roles, as well as authority acknowledged and supported by other health care professionals. Most importantly, Clinical Engineers themselves must recognize the seriousness of their professional responsibilities as they contribute to the maintenance of equipment, use and design instrumentation, and fulfill roles in administration, management, and research. As members of the health care team, Clinical Engineers must be prepared to face ethical issues arising from defective or inadequate equipment, hazards and incidents, scarcity and resources, conflict of interest, confidentiality, clinical research, "truth-telling," and care of the terminally ill. PMID:10275911

  5. Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress

    OpenAIRE

    Myers, Brent; McKlveen, Jessica M.; Herman, James P.

    2013-01-01

    Environmental stimuli that signal real or potential threats to homeostasis lead to glucocorticoid secretion by the hypothalamic-pituitary-adrenocortical (HPA) axis. Glucocorticoids promote energy redistribution and are critical for survival and adaptation. This adaptation requires the integration of multiple systems and engages key limbic-neuroendocrine circuits. Consequently, glucocorticoids have profound effects on synaptic physiology, circuit regulation of stress responsiveness, and, ultim...

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

    DEFF Research Database (Denmark)

    Lunn, T H; Kehlet, H

    2013-01-01

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

  7. Improved human islet preparations using glucocorticoid and exendin-4

    OpenAIRE

    Miki, A.; Ricordi, C; Yamamoto, T.; Sakuma, Y; Misawa, R.; Mita, A; Inverardi, L; Alejandro, R; Ichii, H.

    2014-01-01

    Copyright © 2014 by Lippincott Williams & Wilkins. Objectives: The effects of glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of glucocorticoids and EX on human islet cells during pretransplant culture. Methods: Methylprednisolone (MP) and/or EX were added to the standard culture medium for clinical islet c...

  8. Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome.

    Science.gov (United States)

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

    2015-01-01

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

  9. [Personnel reduction in clinics and legal responsibility].

    Science.gov (United States)

    Schelling, P

    2011-06-01

    Executive clinical physicians are increasingly being made jointly responsible for the economic success of clinics and it is to be expected that this joint responsibility will result in measures to reduce personnel. In this article it will be explained to which limits a reduction in medical personnel can be justified with respect to liability and from what level a reduction in staff can result in forensic risks. Furthermore, it will be discussed which liability or even penal responsibility in this connection affects the physicians, the hospital and especially the senior medical personnel.

  10. Panthenol and glucocorticoids.

    Science.gov (United States)

    Fidanaza, A; Floridi, S; Lenti, L

    1981-09-30

    Urinary metabolites of glucocorticoids have been measured in man before and after administration of panthenol in high doses. The quantitative assay was performed according to the technique of Porter and Silber which measures only cortisol and some of its metabolites. In all panthenol treated subjects a significant increase in the urinary excretion of 17-alpha-21-dihydroxy-20-keto steroids has been observed and it appeared to be higher in male ageing between 18 and 25. The results obtained confirm that a statistically significant increase in glucocorticoid production after panthenol administration in high doses is present also in man. PMID:7317179

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

    Science.gov (United States)

    Conrad, Cheryl D

    2008-01-01

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

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

    Science.gov (United States)

    Suri, D; Vaidya, V A

    2013-06-01

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

  13. Glucocorticoid Regulation of the Vitamin D Receptor

    Science.gov (United States)

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

    2010-01-01

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

  14. Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.

    LENUS (Irish Health Repository)

    Frodl, T

    2012-01-01

    Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and\\/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.

  15. Responsiveness and minimal clinically important change

    DEFF Research Database (Denmark)

    Christiansen, David Høyrup; Frost, Poul; Falla, Deborah;

    2015-01-01

    Study Design A prospective cohort study nested in a randomized controlled trial. Objectives To determine and compare responsiveness and minimal clinically important change of the modified Constant score (CS) and the Oxford Shoulder Score (OSS). Background The OSS and the CS are commonly used to a...

  16. Manipulation of the metabolic response in clinical practice

    DEFF Research Database (Denmark)

    Kehlet, H

    2000-01-01

    Surgical injury is followed by profound changes in endocrine metabolic function and various host defense mechanisms leading to catabolism, immunosuppression, ileus, impaired pulmonary function, and hypoxemia. These physiologic changes are supposed to be involved in the pathogenesis of postoperative...... morbidity. Effective afferent neural blockade with continuous epidural local anesthetic techniques inhibits a major part of the endocrine metabolic response, leading to improved protein economy but without important effects on inflammatory or immunologic responses. In contrast, pain treatment with other...... modalities such as nonsteroidal antiinflammatory drugs (NSAIDs) and opioids has only a small inhibitory effect on endocrine metabolic responses. Preoperative high-dose glucocorticoid therapy provides additional pain relief and improves pulmonary function, but it reduces the inflammatory response (acute...

  17. Clinical predictive factors of pathologic tumor response

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Chi Hwan; Kim, Won Dong; Lee, Sang Jeon; Park, Woo Yoon [Chungbuk National University College of Medicine, Cheongju (Korea, Republic of)

    2012-09-15

    The aim of this study was to identify clinical predictive factors for tumor response after preoperative chemoradiotherapy (CRT) in rectal cancer. The study involved 51 patients who underwent preoperative CRT followed by surgery between January 2005 and February 2012. Radiotherapy was delivered to the whole pelvis at a dose of 45 Gy in 25 fractions, followed by a boost of 5.4 Gy in 3 fractions to the primary tumor with 5 fractions per week. Three different chemotherapy regimens were used. Tumor responses to preoperative CRT were assessed in terms of tumor downstaging and pathologic complete response (ypCR). Statistical analyses were performed to identify clinical factors associated with pathologic tumor response. Tumor downstaging was observed in 28 patients (54.9%), whereas ypCR was observed in 6 patients (11.8%). Multivariate analysis found that predictors of downstaging was pretreatment relative lymphocyte count (p = 0.023) and that none of clinical factors was significantly associated with ypCR. Pretreatment relative lymphocyte count (%) has a significant impact on the pathologic tumor response (tumor downstaging) after preoperative CRT for locally advanced rectal cancer. Enhancement of lymphocyte-mediated immune reactions may improve the effect of preoperative CRT for rectal cancer.

  18. Effect of Calpain inhibitor I on glucocorticoid receptor-dependent degradation and its transactivation ability

    Institute of Scientific and Technical Information of China (English)

    程晓刚; 粟永萍; 罗成基; 刘晓宏

    2004-01-01

    Objective: To investigate the effect of Calpain inhibitor I on glucocorticoid receptor-dependent proteasomal degradation and its transcriptional activity. Methods: After Raw-264.7 cells were treated with Calpain inhibitor I, dexamethasone, or both for about 12 h, the change of glucocorticoid receptor was detected by western blot analysis. COS-7 cells were transfected with PRsh-GRα expression vector and glucocorticoid-responsive receptor pMAMneo-CAT, then the effect of Calpain inhibitor I on glucocorticoid receptor transcriptional activation ability was determined by CAT activity. Results: The glucocorticoid receptor levels decreased after RAW-264.7 cells were treated with dexamethasone for 12 hours, which effect can be inhibited by Calpain inhibitor I to some extent. CAT activity assay showed that Calpain inhibitor I enhance glucocorticoid receptor transcriptional activity. Conclusion: Calpain inhibitor I can inhibit the down-regulation of dexamethasone on glucocoaicoid receptor, and enhances glucocorticoid receptor transactivation ability.

  19. Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: a prospective clinical trial

    Directory of Open Access Journals (Sweden)

    Teramukai Satoshi

    2010-11-01

    Full Text Available Abstract Background Sudden sensorineural hearing loss (SSHL is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1 application using gelatin hydrogels as a treatment for SSHL. Methods Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy. Results In total, 25 patients received the test treatment at a median of 23 days (range 15-32 after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086 of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; P = 0.015 at 24 weeks. No serious adverse events were observed. Conclusions Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids.

  20. Patients newly diagnosed with clinical type 2 diabetes during oral glucocorticoid treatment and observed for 14 years: all-cause mortality and clinical developments

    DEFF Research Database (Denmark)

    Olivarius, Niels de Fine; Siersma, Volkert Dirk; Dyring-Andersen, B.;

    2011-01-01

    patients not being treated with GCs. In a univariate Cox regression model, GC treatment at diagnosis increased all-cause mortality with a hazard ratio (95% confidence interval) of 2.01 (1.39-2.89, p = 0.0002, n = 1369), while this decreased to 1.41 (0.98-2.04, p = 0.065, n = 1369) when adjusted for age...... and sex and to 1.39 (0.92-2.11, p = 0.12, n = 1086) when risk factors, complications and cancer were added to the model. Apart from differences in age and overweight, patients in this relatively small sample of those diagnosed with clinical type 2 diabetes during GC treatment were comparable at diagnosis...

  1. Patients Newly Diagnosed with Clinical Type 2 Diabetes during Oral Glucocorticoid Treatment and Observed for 14 Years: All-Cause Mortality and Clinical Developments

    DEFF Research Database (Denmark)

    Olivarius, Niels de Fine; Siersma, Volkert; Dyring-Andersen, Beatrice;

    2010-01-01

    patients not being treated with GCs. In a univariate Cox regression model, GC treatment at diagnosis increased all-cause mortality with a hazard ratio (95% confidence interval) of 2.01 (1.39-2.89, p = 0.0002, n = 1369), while this decreased to 1.41 (0.98-2.04, p = 0.065, n = 1369) when adjusted for age...... and sex and to 1.39 (0.92-2.11, p = 0.12, n = 1086) when risk factors, complications and cancer were added to the model. Apart from differences in age and overweight, patients in this relatively small sample of those diagnosed with clinical type 2 diabetes during GC treatment were comparable at diagnosis...

  2. Clinical Asthma Phenotypes and Therapeutic Responses

    OpenAIRE

    Zedan, M.; Attia, G.; Zedan, M. M.; Osman, A; Abo-Elkheir, N.; Maysara, N.; Barakat, T.; Gamil, N.

    2013-01-01

    Asthma is a heterogeneous disease that means not all asthmatics respond to the same treatment. We hypothesize an approach to characterize asthma phenotypes based on symptomatology (shortness of breath (SOB), cough, and wheezy phenotypes) in correlation with airway inflammatory biomarkers and FEV1. We aimed to detect whether those clinical phenotypes have an impact on the response to asthma medications. Two hundred three asthmatic children were allocated randomly to receive either montelukast ...

  3. Noise trauma and systemic application of the selective glucocorticoid receptor modulator compound A

    OpenAIRE

    Landegger, Lukas D.; Honeder, Clemens; Zhu, Chengjing; Schöpper, Hanna; Engleder, Elisabeth; Gabor, Franz; Gstoettner, Wolfgang; ARNOLDNER, CHRISTOPH

    2016-01-01

    Background Selective glucocorticoid receptor modulators (SEGRMs) comprise a novel class of drugs promising both reduced side effects and similar pharmacological potency relative to glucocorticoids, which presently serve as the only clinical treatment for many otologic disorders. In the first otologic SEGRM experiment in an animal model of noise trauma, we compare the effects of Compound A (a SEGRM) and dexamethasone (potent glucocorticoid). Methods Forty adult guinea pigs received experimenta...

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

    Directory of Open Access Journals (Sweden)

    Christel Gumy

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

  5. Physiology and molecular mechanism of glucocorticoid action

    OpenAIRE

    Andrzej Nagalski; Anna Kiersztan

    2010-01-01

    Endogenous glucocorticoids (GCs) are secreted into the systemic circulation from the adrenal cortex. This release is under the control of the circadian clock and can be enhanced at any time in response to a stressor. The levels of circulating GC are regulated systemically by the hypothalamo-pituitary-adrenal axis and locally by access to target cells and pre-receptor metabolism by 11β-hydroxysteroids dehydrogenase enzymes. GCs mediate their genomic action by binding to two different ligand-in...

  6. [Psychiatric manifestations due to abnormal glucocorticoid levels].

    Science.gov (United States)

    Lommerse, K M; Dijkstra, F N; Boeke, A J P; Eekhoff, E M W; Jacobs, G E

    2016-01-01

    This clinical case presentation describes the disease trajectory in two patients who presented with psychiatric symptoms as a result of abnormal serum glucocorticoid levels. One case involves a 58-year-old man with hypercortisolism, the other case concerns a 55-year-old woman with hypocortisolism. In both cases there was a considerable diagnostic delay in recognizing the underlying adrenal gland pathology. Abnormal glucocorticoid levels, caused by endocrine disorders, often results in psychiatric symptoms. Delay in diagnosis may have adverse consequences. Hyper- or hypocortisolism should be considered in patients who present with an atypical presentation of psychiatric symptoms. Moreover, the absence of specific physical signs or symptoms at first presentation in such patients does not exclude an underlying endocrinological cause. Therefore, physical and psychiatric reassessment of such patients should be considered at regular intervals. PMID:27507414

  7. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

    NARCIS (Netherlands)

    S.W.J. Lamberts (Steven); E.F.C. van Rossum (Liesbeth)

    2004-01-01

    textabstractMost actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding f

  8. Clinical and radiographic outcome of a treat-to-target strategy using methotrexate and intra-articular glucocorticoids with or without adalimumab induction

    DEFF Research Database (Denmark)

    Hørslev-Petersen, K; Hetland, M L; Ørnbjerg, L M;

    2016-01-01

    OBJECTIVES: To study clinical and radiographic outcomes after withdrawing 1 year's adalimumab induction therapy for early rheumatoid arthritis (eRA) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy (NCT00660647). METHODS: Disease-modifying antirheuma......OBJECTIVES: To study clinical and radiographic outcomes after withdrawing 1 year's adalimumab induction therapy for early rheumatoid arthritis (eRA) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy (NCT00660647). METHODS: Disease......-modifying antirheumatic drug (DMARD)-naive patients with eRA started methotrexate (20 mg/week) and intra-articular triamcinolone (20 mg/ml) for 2 years. In addition, they were randomised to receive placebo adalimumab (DMARD group, n=91) or adalimumab (40 mg/every other week) (DMARD+adalimumab group, n=89) during....... RESULTS: One year after adalimumab withdrawal, treatment profiles and clinical responses did not differ between groups. In the DMARD/DMARD+adalimumab groups, the median 2-year methotrexate dose was 20/20 mg/week (p=0.45), triple DMARD therapy had been initiated in 33/27 patients (p=0.49), adalimumab...

  9. The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids.

    OpenAIRE

    Hall, R K; Sladek, F M; Granner, D K

    1995-01-01

    Glucocorticoids stimulate hepatic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) gene expression, thereby increasing the rate of gluconeogenesis. The effect of glucocorticoids on PEPCK gene expression is mediated by a set of promoter elements collectively referred to as the glucocorticoid response unit. The response unit spans a 100-bp segment and includes two glucocorticoid receptor binding sites (GR1 and GR2) and two accessory factor binding sites (AF1 and AF2), all of which are req...

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  11. Biochemical endpoints of glucocorticoid hormone action

    Energy Technology Data Exchange (ETDEWEB)

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

    1978-01-01

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

  12. Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma

    OpenAIRE

    Bossley, C.J.; Saglani, S; Kavanagh, C.; Payne, D.N.R.; Wilson, N; Tsartsali, L.; Rosenthal, M; Balfour-Lynn, I M; Nicholson, A.G.; Bush, A

    2009-01-01

    This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction (FeNO) and no bronchodilator responsiveness (BDR

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

    Science.gov (United States)

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

    2008-08-15

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

  14. Generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene

    Institute of Scientific and Technical Information of China (English)

    ZHU Hui-juan; GONG Feng-ying; DAI Yu-fei; WANG Ou; LI Mei; LU Lin; ZHAO Wei-gang; XING Xiao-ping; PAN Hui; LI Nai-shi

    2011-01-01

    Background Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. This syndrome is partially caused by mutations in human glucocorticoid receptor (hGR) gene. The clinical spectrum of generalized glucocorticoid resistance is broad, ranging from fatigue or no symptoms to severe hypertension with hypokalemic alkalosis. The purpose of this study was to explore the genetic disorder of glucocorticoid resistance syndrome.Methods We identified a 56-year-old male patient diagnosed with generalized glucocorticoid resistance syndrome accompanied with an adrenocortical adenoma. This asymptomatic patient referred to Peking Union Medical College Hospital for treatment of his adrenal incidentaloma. Endocrinological evaluation consistently revealed his elevated serum cortisol level. Total RNA was extracted from the patient's peripheral blood mononuclear leukocytes (PBMLs) and entire coding region of hGR alpha was amplified by reverse transcription (RT)-PCR. To confirm the possible mutation identified by sequencing RT-PCR products, genomic DNA sequence of hGR gene from the patient and 50 healthy controls was analyzed by PCR and directly sequencing.Results A heterozygotic (C→T) substitution at nucleotide position of 1667 (exon 5) in GR alpha gene was found in this patient by sequencing of RT-PCR products of hGR gene. This substitution was also identified at genomic DNA level and it was absent in 100 chromosomes from 50 unrelated health controls. This substitution resulted in a threonine to isoleucine substitution (ACT→ATT) at amino acid 556 in the ligand-binding domain of GR alpha. Conclusion Generalized glucocorticoid resistance in this patient might be caused by a novel heterozygotic mutation in the ligand-binding domain of the GR alpha.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1993-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Eduardo Amaro Bogaz

    2014-06-01

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

  17. Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

    Science.gov (United States)

    Sundahl, Nora; Clarisse, Dorien; Bracke, Marc; Offner, Fritz; Berghe, Wim Vanden; Beck, Ilse M.

    2016-01-01

    Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting.

  18. Glucocorticoid Receptor Variants Modulate the Sensitivity to Cortisol

    NARCIS (Netherlands)

    H. Russcher (Henk)

    2006-01-01

    textabstractSynthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this mo

  19. Glucocorticoid Treatment in Childhood Nephrotic Syndrome : weighting the cornerstone

    NARCIS (Netherlands)

    N. Teeninga (Nynke)

    2013-01-01

    textabstractUnderstanding which factors influence relapse patterns in childhood nephrotic syndrome is clinically very relevant and could aid in developing new treatment strategies. Clinicians are continuously challenged to reduce relapse rates and at the same time to avoid glucocorticoid toxicity. B

  20. Tolloid-like 1 is negatively regulated by stress and glucocorticoids.

    Science.gov (United States)

    Tamura, Goichiro; Olson, Dawne; Miron, Joel; Clark, Timothy G

    2005-12-14

    Glucocorticoids affect a variety of tissues to enable the organism to adapt to the stress. Hippocampal neurons contain glucocorticoid receptors and respond to elevated glucocorticoid levels by down-regulating the HPA axis. Chronically, however, stress is deleterious to hippocampal neurons. Chronically elevated levels of glucocorticoids result in a decrease in the number of dendritic spines, reduced axonal growth and synaptogenesis, and decreased neurogenesis in the hippocampus. Tolloid-like 1 (Tll-1) is a metalloprotease that potentiates the activity of the bone morphogenetic proteins (BMPs). Neurogenesis in the hippocampus of both developing and adult mammals requires BMPs. In this study, we demonstrate that Tll-1 expression is increased in mice that have increased neurogenesis. The Tll-1 promoter contains glucocorticoid response elements which are capable of binding to purified glucocorticoid receptor. Glucocorticoids decrease Tll-1 expression in vitro. Finally, prenatal stress leads to a decrease in Tll-1 mRNA expression in the hippocampus of adult female mice that is not observed in adult male mice indicating that Tll-1 expression is differentially regulated in males and females. The results of this study indicate that Tll-1 is responsive to glucocorticoids and this mechanism might influence neurogenesis in the hippocampus.

  1. Glucocorticoid dose determines osteocyte cell fate

    OpenAIRE

    Jia, Junjing; Yao, Wei; Guan, Min; Dai, WeiWei; Shahnazari, Mohammad; Kar, Rekha; Bonewald, Lynda; Jiang, Jean X.; Lane, Nancy E.

    2011-01-01

    In response to cellular insult, several pathways can be activated, including necrosis, apoptosis, and autophagy. Because glucocorticoids (GCs) have been shown to induce both osteocyte apoptosis and autophagy, we sought to determine whether osteocyte cell fate in the presence of GCs was dose dependent by performing in vivo and in vitro studies. Male Swiss-Webster mice were treated with slow-release prednisolone pellets at 1.4, 2.8, and 5.6 mg/kg/d for 28 d. An osteocyte cell line, MLO-Y4 cells...

  2. Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Pedro Escoll

    2015-01-01

    Full Text Available Clinical treatment with glucocorticoids (GC can be complicated by cytokine-induced glucocorticoid low-responsiveness (GC-resistance, GCR, a condition associated with a homogeneous reduction in the expression of GC-receptor- (GR- driven anti-inflammatory genes. However, GR level and phosphorylation changes modify the expression of individual GR-responsive genes differently. As sustained IL-1β exposure is key in the pathogenesis of several major diseases with prevalent GCR, we examined GR signaling and the mRNA expression of six GR-driven genes in cells cultured in IL-1β and afterwards challenged with GC. After a GC challenge, sustained IL-1β exposure reduced the cytoplasmic GR level, GRSer203 and GRSer211 phosphorylation, and GR nuclear translocation and led to selective GCR in the expression of the studied genes. Compared to GC alone, in a broad range of GC doses plus sustained IL-1β, FKBP51 mRNA expression was reduced by 1/3, TTP by 2/3, and IRF8 was completely knocked down. In contrast, high GC doses did not change the expression of GILZ and DUSP1, while IGFBP1 was increased by 5-fold. These effects were cytokine-selective, IL-1β dose- and IL-1R1-dependent. The integrated gain and loss of gene functions in the “split GCR” model may provide target cells with a survival advantage by conferring resistance to apoptosis, chemotherapy, and GC.

  3. Recommendations for Responsible Monitoring and Regulation of Clinical Software Systems

    OpenAIRE

    Miller, Randolph A; Gardner, Reed M.

    1997-01-01

    In mid-1996, the FDA called for discussions on regulation of clinical software programs as medical devices. In response, a consortium of organizations dedicated to improving health care through information technology has developed recommendations for the responsible regulation and monitoring of clinical software systems by users, vendors, and regulatory agencies. Organizations assisting in development of recommendations, or endorsing the consortium position include the...

  4. Molecular mechanisms of glucocorticoid receptor signaling Mecanismos moleculares de señalización del receptor de glucocorticoides

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR. Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.Esta revisión destaca los más recientes hallazgos sobre los mecanismos moleculares del receptor de glucocorticoides (GR. La mayoría de los efectos de los glucocorticoides son mediados por los GR intracelulares presentes en casi todos los tejidos y controlan la activación transcripcional por mecanismos directos e indirectos. Las respuestas a los glucocorticoides son específicas para cada gen y tejido. Los GR se asocian en forma selectiva con ligandos producidos en la glándula adrenal, corticosteroides, en respuesta a cambios neuroendocrinos. La interacción del ligando con el GR promueve: a la unión del GR a elementos genómicos de respuesta a glucocorticoides, modulando la transcripción; b la interacción de monómeros del GR con otros factores de transcripción activados por otras vías, llevando a la transrepresión. El GR regula un amplio espectro de funciones fisiológicas, incluyendo la

  5. The selective glucocorticoid receptor antagonist ORG 34116 decreases immobility time in the forced swim test and affects cAMP-responsive element-binding protein phosphorylation in rat brain.

    Science.gov (United States)

    Bachmann, Cornelius G; Bilang-Bleuel, Alicia; De Carli, Sonja; Linthorst, Astrid C E; Reul, Johannes M H M

    2005-01-01

    Glucocorticoid receptor (GR) antagonists can block the retention of the immobility response in the forced swimming test. Recently, we showed that forced swimming evokes a distinct spatiotemporal pattern of cAMP-responsive element-binding protein (CREB) phosphorylation in the dentate gyrus (DG) and neocortex. In the present study, we found that chronic treatment of rats with the selective GR antagonist ORG 34116 decreased the immobility time in the forced swim test, increased baseline levels of phosphorylated CREB (P-CREB) in the DG and neocortex and affected the forced swimming-induced changes in P-CREB levels in a time- and site-specific manner. Overall, we observed that, in control rats, forced swimming evoked increases in P-CREB levels in the DG and neocortex, whereas in ORG 34116-treated animals a major dephosphorylation of P-CREB was observed. These observations underscore an important role of GRs in the control of the phosphorylation state of CREB which seems to be of significance for the immobility response in the forced swim test and extend the molecular mechanism of action of GRs in the brain.

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

    Science.gov (United States)

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

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3’-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death. PMID:26715915

  7. Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Sara De Iudicibus; Raffaella Franca; Stefano Martelossi; Alessandro Ventura; Giuliana Decorti

    2011-01-01

    Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn’s disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, consider-able clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear re-ceptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in ad-dition, several polymorphisms of this gene have been described and associated with GC response and toxicity. However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large coopera-tive hetero-oligomeric complex that binds the hormone-free GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a com-prehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been

  8. Global and Targeted Metabolomics Evidence of the Protective Effect of Chinese Patent Medicine Jinkui Shenqi Pill on Adrenal Insufficiency after Acute Glucocorticoid Withdrawal in Rats.

    Science.gov (United States)

    Zhao, Linjing; Zhao, Aihua; Chen, Tianlu; Chen, Wenlian; Liu, Jiajian; Wei, Runmin; Su, Jing; Tang, Xuelan; Liu, Keyi; Zhang, Ran; Xie, Guoxiang; Panee, Jun; Qiu, Mingfeng; Jia, Wei

    2016-07-01

    Glucocorticoids are commonly used in anti-inflammatory and immunomodulatory therapies, but glucocorticoid withdrawal can result in life-threatening risk of adrenal insufficiency. Chinese patented pharmaceutical product Jinkui Shenqi pill (JKSQ) has potent efficacy on clinical adrenal insufficiency resulting from glucocorticoid withdrawal. However, the underlying molecular mechanism remains unclear. We used an animal model to study JKSQ-induced metabolic changes under adrenal insufficiency and healthy conditions. Sprague-Dawley rats were treated with hydrocortisone for 7 days with or without 15 days of JKSQ pretreatment. Sera were collected after 72 h hydrocortisone withdrawal and used for global and free fatty acids (FFAs)-targeted metabolomics analyses using gas chromatography/time-of-flight mass spectrometry and ultraperformance liquid chromatography/quadruple time-of-flight mass spectrometry. Rats without hydrocortisone treatment were used as controls. JKSQ pretreatment normalized the significant changes of 13 serum metabolites in hydrocortisone-withdrawal rats, involving carbohydrates, lipids, and amino acids. The most prominent effect of JKSQ was on the changes of FFAs and some [product FFA]/[precursor FFA] ratios, which represent estimated desaturase and elongase activities. The opposite metabolic responses of JKSQ in adrenal insufficiency rats and normal rats highlighted the "Bian Zheng Lun Zhi" (treatment based on ZHENG differentiation) guideline of TCM and suggested that altered fatty acid metabolism was associated with adrenal insufficiency after glucocorticoid withdrawal and the protective effects of JKSQ. PMID:27267777

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  10. Glucocorticoid programming of intrauterine development.

    Science.gov (United States)

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

    2016-07-01

    Glucocorticoids (GCs) are important environmental and maturational signals during intrauterine development. Toward term, the maturational rise in fetal glucocorticoid receptor concentrations decreases fetal growth and induces differentiation of key tissues essential for neonatal survival. When cortisol levels rise earlier in gestation as a result of suboptimal conditions for fetal growth, the switch from tissue accretion to differentiation is initiated prematurely, which alters the phenotype that develops from the genotype inherited at conception. Although this improves the chances of survival should delivery occur, it also has functional consequences for the offspring long after birth. Glucocorticoids are, therefore, also programming signals that permanently alter tissue structure and function during intrauterine development to optimize offspring fitness. However, if the postnatal environmental conditions differ from those signaled in utero, the phenotypical outcome of early-life glucocorticoid receptor overexposure may become maladaptive and lead to physiological dysfunction in the adult. This review focuses on the role of GCs in developmental programming, primarily in farm species. It examines the factors influencing GC bioavailability in utero and the effects that GCs have on the development of fetal tissues and organ systems, both at term and earlier in gestation. It also discusses the windows of susceptibility to GC overexposure in early life together with the molecular mechanisms and long-term consequences of GC programming with particular emphasis on the cardiovascular, metabolic, and endocrine phenotype of the offspring. PMID:27345310

  11. Glucocorticoid programming of intrauterine development.

    Science.gov (United States)

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

    2016-07-01

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

  12. Clinical errors as a lack of context responsiveness.

    Science.gov (United States)

    Bugatti, Matteo; Boswell, James F

    2016-09-01

    Although standardized treatments have the potential to decrease clinical errors, within-session responsiveness is complicated and complementary frameworks may be needed to foster enhanced responsiveness in the context of evidence-based treatments. Recent efforts have targeted the enhancement of flexibility and responsiveness in the delivery of manualized treatments, including the development of transdiagnostic treatments (i.e., protocols that are designed to be used across different diagnoses) intended to tailor intervention principles to the needs of individual patients. Context-Responsive Psychotherapy Integration (Constantino, Boswell, Bernecker, & Castonguay, 2013) offers an framework that supports the utilization of evidence-based clinical strategies in response to the identification of specific process markers. Failure to identify or appropriately respond to such markers may result in negative therapeutic process as well as outcomes. This case study uses the context-response psychotherapy integration framework to understand critical moments of clinical decision-making through examining an individual treatment case that unilaterally terminated after seven sessions of transdiagnostic treatment. This illustrative empirical case analysis focuses on three potential clinical errors, as indicated by a lack of responsiveness to three candidate process markers: (a) low outcome expectations, (b) self-strivings, and (c) outcome monitoring. For each clinical error, alternative clinical strategies are discussed. (PsycINFO Database Record PMID:27631853

  13. Clinical errors as a lack of context responsiveness.

    Science.gov (United States)

    Bugatti, Matteo; Boswell, James F

    2016-09-01

    Although standardized treatments have the potential to decrease clinical errors, within-session responsiveness is complicated and complementary frameworks may be needed to foster enhanced responsiveness in the context of evidence-based treatments. Recent efforts have targeted the enhancement of flexibility and responsiveness in the delivery of manualized treatments, including the development of transdiagnostic treatments (i.e., protocols that are designed to be used across different diagnoses) intended to tailor intervention principles to the needs of individual patients. Context-Responsive Psychotherapy Integration (Constantino, Boswell, Bernecker, & Castonguay, 2013) offers an framework that supports the utilization of evidence-based clinical strategies in response to the identification of specific process markers. Failure to identify or appropriately respond to such markers may result in negative therapeutic process as well as outcomes. This case study uses the context-response psychotherapy integration framework to understand critical moments of clinical decision-making through examining an individual treatment case that unilaterally terminated after seven sessions of transdiagnostic treatment. This illustrative empirical case analysis focuses on three potential clinical errors, as indicated by a lack of responsiveness to three candidate process markers: (a) low outcome expectations, (b) self-strivings, and (c) outcome monitoring. For each clinical error, alternative clinical strategies are discussed. (PsycINFO Database Record

  14. Mode of Glucocorticoid Actions in Airway Disease

    Directory of Open Access Journals (Sweden)

    Kazuhiro Ito

    2006-01-01

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

  15. Aggressive combination therapy with intraarticular glucocorticoid injections and conventional DMARDs in early rheumatoid arthritis Two Year Clinical and Radiographic Results From The CIMESTRA Study

    DEFF Research Database (Denmark)

    Hetland, Merete; Stengaard-Pedersen, Kristian; Junker, Peter;

    2008-01-01

    -cyclosporine (monotherapy) or methotrexate plus cyclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76-104 cyclosporine/placebo-cyclosporine was tapered to zero. RESULTS: ACR20, ACR50 and ACR70 were achieved in 88%, 79% and 59% of patients...... years, and the radiographic erosive progression was minimal. Addition of cyclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome....

  16. 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes.

    Science.gov (United States)

    Nasiri, Maryam; Nikolaou, Nikolaos; Parajes, Silvia; Krone, Nils P; Valsamakis, George; Mastorakos, George; Hughes, Beverly; Taylor, Angela; Bujalska, Iwona J; Gathercole, Laura L; Tomlinson, Jeremy W

    2015-08-01

    Glucocorticoids and androgens have both been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females, and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a prereceptor level by the enzyme 5α-reductase type 2 (SRD5A2), which inactivates glucocorticoids to their dihydrometabolites and converts T to DHT. We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whereas androgen treatment (T and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 overexpression reduced the effects of cortisol to suppress lipogenesis and this effect was lost following transfection with an inactive mutant construct. Conversely, pharmacological inhibition using the 5α-reductase inhibitors finasteride and dutasteride augmented cortisol action. We have demonstrated that manipulation of SRD5A2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux. PMID:25974403

  17. The distorting effect of varying diets on fecal glucocorticoid measurements as indicators of stress

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Teilmann, A. Charlotte; Abelson, Klas S. P.;

    2015-01-01

    The physiological stress response is frequently gauged in animals, non-invasively, through measuring glucocorticoids in excreta. A concern with this method is, however, the unknown effect of variations in diets on the measurements. With an energy dense diet, leading to reduced defecation, will low...... concentrations of glucocorticoids be artificially inflated? Can this effect be overcome by measuring the total output of glucocorticoids in excreta? In a controlled laboratory setting we explored the effect in mice. When standard mouse chow – high in dietary fiber – was replaced with a 17% more energy-dense diet...

  18. Glucocorticoid programming of the mesopontine cholinergic system

    Directory of Open Access Journals (Sweden)

    Sónia eBorges

    2013-12-01

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

  19. Stress Exacerbates Neuropathic Pain via Glucocorticoid and NMDA Receptor Activation

    OpenAIRE

    Alexander, Jessica K.; DeVries, A Courtney; KIGERL, KRISTINA A.; Dahlman, Jason M.; G.Popovich, Phillip

    2009-01-01

    There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g. corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, ...

  20. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens : current questions and tentative answers in rheumatology

    NARCIS (Netherlands)

    Buttgereit, F; da Silva, JAP; Burmester, GR; Cutolo, M; Jacobs, J; Kirwan, J; Kohler, L; van Riel, P; Vischer, T; Bijlsma, JWJ

    2002-01-01

    In rheumatology and other medical specialties there is a discrepancy between the widespread use and the imprecise designation of glucocorticoid treatment regimens. Verbal descriptions of glucocorticoid treatment regimens used in various phases of diseases vary between countries and institutions. Giv

  1. Thai clinical laboratory responsible to economic crisis.

    Science.gov (United States)

    Sirisali, K; Vattanaviboon, P; Manochiopinij, S; Ananskulwat, W

    1999-01-01

    Nowadays, Thailand encounters a serious economic crisis. A clear consensus has been made that a cost-saving system must be the important tool. Both private and government organizations are engaged in this situation. We studied the cost-saving in the clinical laboratory. A questionnaire was distributed to 45 hospital laboratories located in Bangkok. Results showed that efforts to control the cost are the essential policy. There was a variety of factors contributing to the cost-saving process. The usage of public utility, non-recycle material and unnecessary utility were reconsidered. Besides, capital cost (wages and salary) personnel incentive are assessed. Forty three of the 45 respondents had attempted to reduce the cost via curtailing the unnecessary electricity. Eliminating the needless usage of telephone-call. water and unnecessary material was also an effective strategy. A reduction of 86.9%, 80 % and 80.0% of the mentioned factors respectively, was reported. An inventory system of the reagent, chemical and supplies was focused. Most of the laboratories have a policy on cost-saving by decreased the storage. Twenty eight of the 45 laboratories considered to purchase the cheaper with similar quality reagents instead. And some one would purchase a bulky pack when it is the best bargain. A specific system "contact reagent with a free rent instrument" has been used widely (33.3%). Finally, a new personnel management system has been chosen. Workload has rearranged and unnecessary extra-hour work was abandoned.

  2. A Historical Cohort Study on the Efficacy of Glucocorticoids and Riboflavin Among Patients with Late-onset Multiple Acyl-CoA Dehydrogenase Deficiency

    Institute of Scientific and Technical Information of China (English)

    Xin-Yi Liu; Zhi-Qiang Wang; Dan-Ni Wang; Min-Ting Lin; Ning Wang

    2016-01-01

    Background:Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common type of lipid storage myopathies in China.Most patients with late-onset MADD are well responsive to riboflavin.Up to now,these patients are often treated with glucocorticoids as the first-line drug because they are misdiagnosed as polymyositis without muscle biopsy or gene analysis.Although glucocorticoids seem to improve the fatty acid metabolism of late-onset MADD,the objective evaluation of their rationalization on this disorder and comparison with riboflavin treatment are unknown.Methods:We performed a historical cohort study on the efficacy of the two drugs among 45 patients with late-onset MADD,who were divided into glucocorticoids group and riboflavin group.Detailed clinical information of baseline and 1-month follow-up were collected.Results:After 1-month treatment,a dramatic improvement of muscle strength was found in riboflavin group (P < 0.05).There was no significant difference in muscle enzymes between the two groups.Significantly,the number of patients with full recovery in glucocorticoids group was less than the number in riboflavin group (P < 0.05).On the other hand,almost half of the patients in riboflavin group still presented high-level muscle enzymes and weak muscle strength after 1-month riboflavin treatment,meaning that 1-month treatment duration maybe insufficient and patients should keep on riboflavin supplement for a longer time.Conclusions:Our results provide credible evidences that the overall efficacy of riboflavin is superior to glucocorticoids,and a longer duration of riboflavin treatment is necessary for patients with late-onset MADD.

  3. Physiology and molecular mechanism of glucocorticoid action

    Directory of Open Access Journals (Sweden)

    Andrzej Nagalski

    2010-03-01

    Full Text Available Endogenous glucocorticoids (GCs are secreted into the systemic circulation from the adrenal cortex. This release is under the control of the circadian clock and can be enhanced at any time in response to a stressor. The levels of circulating GC are regulated systemically by the hypothalamo-pituitary-adrenal axis and locally by access to target cells and pre-receptor metabolism by 11β-hydroxysteroids dehydrogenase enzymes. GCs mediate their genomic action by binding to two different ligand-inducible transcription factors: high-affinity mineralocorticoid receptor (MR and 10-fold lower affinity glucocorticoid receptors (GRs. Responses to GCs vary among individuals, cells, and tissues. The diversity and specificity in the steroid hormone’s response in the cell is controlled at different levels, including receptor translocation, interaction with specific transcription factors and coregulators, and the regulation of receptor protein levels by microRNA. Moreover, multiple GR isoforms are generated from one single GR gene by alternative splicing and alternative translation initiation. These isoforms all have unique tissue distribution patterns and transcriptional regulatory profiles. Furthermore, each is subjected to various post-translational modifications that affect receptor function. Deciphering the molecular mechanisms of GC action is further complicated by the realization that GCs can induce rapid, non-genomic effects within the cytoplasm. A tight regulation of GC secretion and their cell-specific activity is essential for proper organism function. This is particularly seen under conditions of GC deficiency or excess, as in Addison’s disease and Cushing’s syndrome, respectively.

  4. Glucocorticoids induce transactivation of tight junction genes occludin and claudin-5 in retinal endothelial cells via a novel cis-element.

    Science.gov (United States)

    Felinski, Edward A; Cox, Amy E; Phillips, Brett E; Antonetti, David A

    2008-06-01

    Tight junctions between vascular endothelial cells help to create the blood-brain and blood-retinal barriers. Breakdown of the retinal tight junction complex is problematic in several disease states including diabetic retinopathy. Glucocorticoids can restore and/or preserve the endothelial barrier to paracellular permeability, although the mechanism remains unclear. We show that glucocorticoid treatment of primary retinal endothelial cells increases content of the tight junction proteins occludin and claudin-5, co-incident with an increase in barrier properties of endothelial monolayers. The glucocorticoid receptor antagonist RU486 reverses both the glucocorticoid-stimulated increase in occludin content and the increase in barrier properties. Transcriptional activity from the human occludin and claudin-5 promoters increases in retinal endothelial cells upon glucocorticoid treatment, and is dependent on the glucocorticoid receptor (GR) as demonstrated by siRNA. Deletion analysis of the occludin promoter reveals a 205bp sequence responsible for the glucocorticoid response. However, this region does not possess a canonical glucocorticoid response element and does not bind to the GR in a chromatin immunoprecipitation (ChIP) assay. Mutational analysis of this region revealed a novel 40bp occludin enhancer element (OEE), containing two highly conserved regions of 10 and 13 base pairs, that is both necessary and sufficient for glucocorticoid-induced gene expression in retinal endothelial cells. These data suggest a novel mechanism for glucocorticoid induction of vascular endothelial barrier properties through increased occludin and claudin-5 gene expression. PMID:18501346

  5. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

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

    2011-01-01

    of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids...

  6. The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Shoko, E-mail: satosho@rs.tus.ac.jp [Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan); Shirakawa, Hitoshi, E-mail: shirakah@m.tohoku.ac.jp [Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan); Tomita, Shuhei, E-mail: tomita@med.tottori-u.ac.jp [Division of Molecular Pharmacology, Department of Pathophysiological and Therapeutic Science, Yonago 683-8503 (Japan); Tohkin, Masahiro, E-mail: tohkin@phar.nagoya-cu.ac.jp [Department of Medical Safety Science, Graduate School of Pharmaceutical Science, Nagoya City University, Nagoya 267-8603 (Japan); Gonzalez, Frank J., E-mail: gonzalef@mail.nih.gov [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Komai, Michio, E-mail: mkomai@m.tohoku.ac.jp [Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan)

    2013-11-15

    Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHR or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein–protein interactions with GR. - Highlights: • Aryl hydrocarbon receptor forms a complex with glucocorticoid receptor in cells. • Human metallothionein gene is regulated by the AHR and GR interaction. • AHR–GR complex binds to glucocorticoid response element in metallothionein gene. • We demonstrated a novel transcriptional mechanism via AHR and GR interaction.

  7. Do the interactions between glucocorticoids and sex hormones regulate the development of the Metabolic Syndrome?

    Directory of Open Access Journals (Sweden)

    Marià eAlemany

    2012-02-01

    Full Text Available The metabolic syndrome is basically a maturity-onset disease. Typically, its manifestations begin to flourish years after the initial dietary or environmental aggression began. Since most hormonal, metabolic or defense responses are practically immediate, the procrastinated response don't seem justified. Only in childhood, the damages of the metabolic syndrome appear with minimal delay. Sex affects the incidence of the metabolic syndrome, but this is more an effect of timing than absolute gender differences, females holding better than males up to menopause, when the differences between sexes tend to disappear. The metabolic syndrome is related to an immune response, countered by a permanent increase in glucocorticoids, which keep the immune system at bay but also induce insulin resistance, alter the lipid metabolism, favor fat deposition, mobilize protein and decrease androgen synthesis. Androgens limit the operation of glucocorticoids, which is also partly blocked by estrogens, since they decrease inflammation (which enhances glucocorticoid release. These facts suggest that the appearance of the metabolic syndrome symptoms depends on the strength (i.e. levels of androgens and estrogens. The predominance of glucocorticoids and the full manifestation of the syndrome in men are favored by decreased androgen activity. Low androgens can be found in infancy, maturity, advanced age, or because of their inhibition by glucocorticoids (inflammation, stress, medical treatment. Estrogens decrease inflammation and reduce the glucocorticoid response. Low estrogen (infancy, menopause again allow the predominance of glucocorticoids and the manifestation of the metabolic syndrome. It is postulated that the equilibrium between sex hormones and glucocorticoids may be a critical element in the timing of the manifestation of metabolic syndrome-related pathologies.

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  9. Glucocorticoid Signaling: An Update from a Genomic Perspective.

    Science.gov (United States)

    Sacta, Maria A; Chinenov, Yurii; Rogatsky, Inez

    2016-01-01

    Glucocorticoid hormones (GC) regulate essential physiological functions including energy homeostasis, embryonic and postembryonic development, and the stress response. From the biomedical perspective, GC have garnered a tremendous amount of attention as highly potent anti-inflammatory and immunosuppressive medications indispensable in the clinic. GC signal through the GC receptor (GR), a ligand-dependent transcription factor whose structure, DNA binding, and the molecular partners that it employs to regulate transcription have been under intense investigation for decades. In particular, next-generation sequencing-based approaches have revolutionized the field by introducing a unified platform for a simultaneous genome-wide analysis of cellular activities at the level of RNA production, binding of transcription factors to DNA and RNA, and chromatin landscape and topology. Here we describe fundamental concepts of GC/GR function as established through traditional molecular and in vivo approaches and focus on the novel insights of GC biology that have emerged over the last 10 years from the rapidly expanding arsenal of system-wide genomic methodologies. PMID:26667074

  10. Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials

    Science.gov (United States)

    Tétreault, Pascal; Mansour, Ali; Vachon-Presseau, Etienne; Schnitzer, Thomas J.; Apkarian, A. Vania

    2016-01-01

    Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active

  11. A pilot study exploring the role of glucocorticoid receptor variants in primary biliary cirrhosis and primary sclerosing cholangitis

    NARCIS (Netherlands)

    A. Hagendorf; H.R. van Buuren (Henk); J.W. Koper (Jan); S.W.J. Lamberts (Steven); P.C.J. ter Borg (Pieter)

    2004-01-01

    textabstractBACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) significant therapeutic effects of glucocorticoids have not been documented. The most important clinical problem in patients with these diseases is fatigue, which is occasionally inv

  12. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man.

    Directory of Open Access Journals (Sweden)

    Evangelia Charmandari

    Full Text Available CONTEXT AND OBJECTIVE: Circulating cortisol fluctuates diurnally under the control of the "master" circadian CLOCK, while the peripheral "slave" counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans. DESIGN AND PARTICIPANTS: We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs as non-synchronized controls. RESULTS: GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. CONCLUSIONS: Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night.

  13. Psychosocial stress, glucocorticoids, and structural alterations in the tree shrew hippocampus.

    Science.gov (United States)

    Fuchs, E; Flügge, G; Ohl, F; Lucassen, P; Vollmann-Honsdorf, G K; Michaelis, T

    2001-06-01

    Animal models for chronic stress represent an indispensable preclinical approach to human pathology since clinical data point to a major role of psychological stress experiences, acute and/or chronic, to the development of behavioral and physiological disturbances. Chronic emotional arousal is a consequence of various types of social interactions, and one major neurohumoral accompaniment is the activation of the classic stress circuit, the limbic--hypothalamic--pituitary--adrenocortical (LHPA) axis. The adrenocortical glucocorticoid hormones cortisol and corticosterone are principal effectors within this circuit since they affect neurotransmission and neuroendocrine control, thus having profound effects on mood and behavior. Using the experimental paradigm of chronic psychosocial stress in tree shrews, we investigated the impact of aversive chronic social encounters on hippocampal structure and function. In chronically stressed animals, we observed dendritic atrophy of hippocampal pyramidal neurons and an impairment of neurogenesis in the dentate gyrus. However, a stress-induced loss of hippocampal neurons was not observed in this animal model. This review summarizes our recent results on structural changes occurring during chronic stress in neurons of the hippocampus and their potential influence on learning and memory. We discuss whether these changes are reversible and to what extent glucocorticoids might be responsible for the stress-induced effects.

  14. The transcriptomics of glucocorticoid receptor signaling in developing zebrafish.

    Directory of Open Access Journals (Sweden)

    Dinushan Nesan

    Full Text Available Cortisol is the primary corticosteroid in teleosts that is released in response to stressor activation of the hypothalamus-pituitary-interrenal axis. The target tissue action of this hormone is primarily mediated by the intracellular glucocorticoid receptor (GR, a ligand-bound transcription factor. In developing zebrafish (Danio rerio embryos, GR transcripts and cortisol are maternally deposited into the oocyte prior to fertilization and influence early embryogenesis. To better understand of the molecular mechanisms involved, we investigated changes in the developmental transcriptome prior to hatch, in response to morpholino oligonucleotide knockdown of GR using the Agilent zebrafish microarray platform. A total of 1313 and 836 mRNA transcripts were significantly changed at 24 and 36 hours post fertilization (hpf, respectively. Functional analysis revealed numerous developmental processes under GR regulation, including neurogenesis, eye development, skeletal and cardiac muscle formation. Together, this study underscores a critical role for glucocorticoid signaling in programming molecular events essential for zebrafish development.

  15. Ectopic microRNA-150-5p transcription sensitizes glucocorticoid therapy response in MM1S multiple myeloma cells but fails to overcome hormone therapy resistance in MM1R cells

    OpenAIRE

    Palagani, Ajay; Op de Beeck, Ken; Naulaerts, Stefan; Diddens, Jolien; Chirumamilla, Chandra Sekhar; Camp, Guy; Laukens, Kris; Heyninck, Karen; Gerlo, Sarah; Mestdagh, Pieter; Vandesompele, Jo; Vanden Berghe, Wim

    2014-01-01

    Glucocorticoids (GCs) selectively trigger cell death in the multiple myeloma cell line MM1S which express NR3C1/Glucocorticoid Receptor (GR) protein, but fail to kill MM1R cells which lack GR protein. Given recent demonstrations of altered microRNA profiles in a diverse range of haematological malignancies and drug resistance, we characterized GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that...

  16. Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans

    OpenAIRE

    Cao, Yun; Bender, Ingrid K.; Konstantinidis, Athanasios K.; Shin, Soon Cheon; Jewell, Christine M.; Cidlowski, John A; Schleimer, Robert P.; Lu, Nick Z.

    2013-01-01

    Mature, but not immature, dendritic cells are sensitive to glucocorticoid-induced apoptosis.Mature, but not immature, dendritic cells express proapoptotic glucocorticoid receptor translational isoforms.

  17. Liposomal glucocorticoids: pharmaceutical, preclinical and clinical aspects

    NARCIS (Netherlands)

    Hoven, J.M. van den

    2012-01-01

    Liposomes have proven to be well tolerated drug delivery vehicles that offer the possibility of drug delivery for a wide range of therapeutic agents, for instance for the treatment of rheumatoid arthritis. Optimal liposomal physicochemical properties depend on the administration route: large-sized l

  18. Caldesmon, an actin-linked regulatory protein, comes across glucocorticoids

    OpenAIRE

    Sobue, Kenji; Fukumoto, Kentaro

    2010-01-01

    The glucocorticoids (GCs), the most downstream effectors of the hypothalamic-pituitary-adrenal (HPA) axis, are the main mediators of stress response. Stress-triggered GCs as well as acute and chronic GC treatment can impair the structural plasticity and function of the brain. The exposure of perinatal animals and humans to excess stress or GCs can affect the brain development, resulting in altered behaviors in the adult offspring of animals and an increased risk of psychiatric disorders in hu...

  19. Glucocorticoid Hyper- and Hypofunction: Stress Effects on Cognition and Aggression

    OpenAIRE

    Kim, Jeansok J.; Haller, József

    2007-01-01

    It is now well documented that both increased and decreased stress responses can profoundly affect cognition and behavior. This mini review presents possible neural mechanisms subserving stress effects on memory and aggression, particularly focusing on glucocorticoid (GC) hyper- and hypofunction. First, uncontrollable stress impedes hippocampal memory and long-term potentiation (LTP). Because the hippocampus is important for the stability of long-term memory and because LTP has qualities desi...

  20. Physicians' Professionally Responsible Power: A Core Concept of Clinical Ethics.

    Science.gov (United States)

    McCullough, Laurence B

    2016-02-01

    The gathering of power unto themselves by physicians, a process supported by evidence-based practice, clinical guidelines, licensure, organizational culture, and other social factors, makes the ethics of power--the legitimation of physicians' power--a core concept of clinical ethics. In the absence of legitimation, the physician's power over patients becomes problematic, even predatory. As has occurred in previous issues of the Journal, the papers in the 2016 clinical ethics issue bear on the professionally responsible deployment of power by physicians. This introduction explores themes of physicians' power in papers from an international group of authors who address autonomy and trust, the virtues of perinatal hospice, conjoined twins in ethics and law, addiction and autonomy in clinical research on addicting substances, euthanasia of patients with dementia in Belgium, and a pragmatic approach to clinical futility.

  1. Physicians' Professionally Responsible Power: A Core Concept of Clinical Ethics.

    Science.gov (United States)

    McCullough, Laurence B

    2016-02-01

    The gathering of power unto themselves by physicians, a process supported by evidence-based practice, clinical guidelines, licensure, organizational culture, and other social factors, makes the ethics of power--the legitimation of physicians' power--a core concept of clinical ethics. In the absence of legitimation, the physician's power over patients becomes problematic, even predatory. As has occurred in previous issues of the Journal, the papers in the 2016 clinical ethics issue bear on the professionally responsible deployment of power by physicians. This introduction explores themes of physicians' power in papers from an international group of authors who address autonomy and trust, the virtues of perinatal hospice, conjoined twins in ethics and law, addiction and autonomy in clinical research on addicting substances, euthanasia of patients with dementia in Belgium, and a pragmatic approach to clinical futility. PMID:26671961

  2. Dendritic Cell Responses to Surface Properties of Clinical Titanium Surfaces

    OpenAIRE

    Kou, Peng Meng; Schwartz, Zvi; Boyan, Barbara D; Babensee, Julia E.

    2010-01-01

    Dendritic cells (DCs) play pivotal roles in responding to foreign entities during an innate immune response and initiating effective adaptive immunity as well as maintaining immune tolerance. The sensitivity of DCs to foreign stimuli also makes them useful cells to assess the inflammatory response to biomaterials. Elucidating the material property-DC phenotype relationships using a well-defined biomaterial system is expected to provide criteria for immuno-modulatory biomaterial design. Clinic...

  3. Synergistic action of interleukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat alpha 2 macroglobulin gene.

    OpenAIRE

    Hocke, G M; Barry, D.; Fey, G H

    1992-01-01

    One class of genes coding for the acute-phase proteins (acute-phase genes) is induced by interleukin 6 (IL-6) through the human transcription factor NF-IL-6 and its rat homolog IL-6-DBP/LAP. A second class, represented by the rat alpha 2 macroglobulin gene, utilizes a different IL-6 response element (IL-6-RE) and different DNA-binding proteins interacting with this element, the so-called IL-6-RE binding proteins (IL-6 RE-BPs). Human Hep3B and HepG2 hepatoma, U266 myeloma, and CESS lymphoblast...

  4. Clinical predictors of response to immunomodulators for multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Guilherme Sciascia do Olival

    2012-01-01

    Full Text Available OBJECTIVES: To determine, based on clinical criteria, the proportion of multiple sclerosis (MS patients responsive to immunomodulators (RI and nonresponsive to immunomodulators (NRI, and to ascertain whether clinical and epidemiological data differs between RI and NRI patient groups. METHODS: Patients were assessed on rate of exarcerbations per year, for the period before and after commencement of treatment. The RI and NRI groups were compared for several clinical and epidemiological characteristics. DISCUSSION AND CONCLUSION: A total of 31.4% of the patients were nonresponders to the immunomodulatory treatment. The main predictors of immunomodulatory response were early diagnostic and commencement of therapy and high rate of annual exacerbations prior to treatment. Given the arsenal of medication options available for MS management, screening potential candidates for different therapeutic approaches are critical to optimize evolution of patients with the disease.

  5. Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting β(2-adrenoceptor [corrected] agonist and glucocorticoid receptor ligands.

    Directory of Open Access Journals (Sweden)

    Christopher F Rider

    Full Text Available Acting on the glucocorticoid receptor (NR3C1, glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2 × glucocorticoid response element (GRE reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-α (TNF or interleukin-1β inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3

  6. Antenatal glucocorticoid treatment and polymorphisms of the glucocorticoid and mineralocorticoid receptors are associated with IQ and behavior in young adults born very preterm

    NARCIS (Netherlands)

    Voorn, B. van der; Pal, S.M. van der; Rotteveel, J.; Finken, M.J.

    2015-01-01

    Context: Preterm survivors exhibit neurodevelopmental impairments. Whether this association is influenced by antenatal glucocorticoid treatment and glucocorticoid sensitivity is unknown. Objectives: To study the effects of antenatal glucocorticoid treatment and glucocorticoid receptor (GR) and miner

  7. Admission Privileges and Clinical Responsibilities for Interventional Radiologists

    Energy Technology Data Exchange (ETDEWEB)

    Al-Kutoubi, Aghiad, E-mail: mk00@aub.edu.lb [The American University of Beirut Medical Center, IR Division, The Department of Diagnostic Radiology (Lebanon)

    2015-04-15

    Although clinical involvement by interventional radiologists in the care of their patients was advocated at the inception of the specialty, the change into the clinical paradigm has been slow and patchy for reasons related to pattern of practice, financial remuneration or absence of training. The case for the value of clinical responsibilities has been made in a number of publications and the consequences of not doing so have been manifest in the erosion of the role of the interventional radiologists particularly in the fields of peripheral vascular and neuro intervention. With the recent recognition of interventional radiology (IR) as a primary specialty in the USA and the formation of IR division in the Union of European Medical Specialists and subsequent recognition of the subspecialty in many European countries, it is appropriate to relook at the issue and emphasize the need for measures to promote the clinical role of the interventional radiologist.

  8. Admission Privileges and Clinical Responsibilities for Interventional Radiologists

    International Nuclear Information System (INIS)

    Although clinical involvement by interventional radiologists in the care of their patients was advocated at the inception of the specialty, the change into the clinical paradigm has been slow and patchy for reasons related to pattern of practice, financial remuneration or absence of training. The case for the value of clinical responsibilities has been made in a number of publications and the consequences of not doing so have been manifest in the erosion of the role of the interventional radiologists particularly in the fields of peripheral vascular and neuro intervention. With the recent recognition of interventional radiology (IR) as a primary specialty in the USA and the formation of IR division in the Union of European Medical Specialists and subsequent recognition of the subspecialty in many European countries, it is appropriate to relook at the issue and emphasize the need for measures to promote the clinical role of the interventional radiologist

  9. Clinical spectrum of dopa-responsive dystonia and related disorders.

    Science.gov (United States)

    Lee, Woong-Woo; Jeon, Beom Seok

    2014-07-01

    Dopa-responsive dystonia (DRD) has a classic presentation of childhood or adolescent-onset dystonia, mild parkinsonism, marked diurnal fluctuations, improvement with sleep or rest, and a dramatic and sustained response to low doses of L-dopa without motor fluctuations or dyskinesias. However, there have been many papers on patients with a wide range of features, which report them as DRD mainly because they had dystonic syndromes with L-dopa responsiveness. Many mutations in the dopaminergic system have been found as molecular genetic defects. Therefore, the clinical and genetic spectra of DRD are unclear, which lead to difficulties in diagnostic work-ups and planning treatments. We propose the concept of DRD and DRD-plus to clarify the confusion in this area and to help understand the pathophysiology and clinical features, which will help in guiding diagnostic investigations and planning treatments. We critically reviewed the literature on atypical cases and discussed the limitations of the gene study. PMID:24844652

  10. Proposed glucocorticoid-mediated zinc signaling in the hippocampus.

    Science.gov (United States)

    Takeda, Atsushi; Tamano, Haruna

    2012-07-01

    Corticosteroid hormones are secreted from the adrenal glands in hourly pulses and signal the hippocampus for the development and function. In contrast, the stress-induced rise in corticosteroid concentrations has a profound effect on emotional arousal, motivational processes and cognitive performance. This rise is required as the stress response to maintain homeostasis in the living body or restore it. However, abnormal rise in corticosteroid concentrations is a disadvantage to the hippocampus. Corticosteroid-glutamatergic interactions during information processing are proposed as a potential model to explain many of the diverse actions of corticosteroids in synaptic plasticity such as long-term potentiation and cognition. Because zincergic neurons are a subtype of glutamatergic neurons and release Zn(2+) and glutamate into the synaptic cleft, it is possible that homeostasis of synaptic Zn(2+), in addition to homeostasis of glutamate, is modified by glucocorticoids, followed by the changes in cognitive function and stress response. Zn(2+) signal participates in cognitive and emotional behavior in cooperation with signaling of glucocorticoids and glutamate, while can disadvantageously act on the hippocampus under sever stress circumstances. This paper analyzes the actions of glucocorticoid-mediated Zn(2+) signal in the hippocampus under stressful circumstances and its significance in both hippocampal function and dysfunction.

  11. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

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

    2011-01-01

    reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported......Glucocorticoids are commonly used in treatment of paediatric diseases, but evidence of associated adverse cerebral effects is accumulating. The various pharmacokinetic profiles of the exogenous glucocorticoids and the changes in pharmacodynamics during childhood, result in different exposure...... of nervous tissue to exogenous glucocorticoids. Glucocorticoids activate two types of intracellular receptors, the mineralocorticoid receptor and the glucocorticoid receptor. The two receptors differ in cerebral distribution, affinity and effects. Exogenous glucocorticoids favor activation...

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

    Directory of Open Access Journals (Sweden)

    Burnsides C

    2012-08-01

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

  13. Lipopolysaccharide induces intestinal glucocorticoid synthesis in a TNFalpha-dependent manner.

    Science.gov (United States)

    Noti, Mario; Corazza, Nadia; Tuffin, Gérald; Schoonjans, Kristina; Brunner, Thomas

    2010-05-01

    Stringent control of immune responses in the intestinal mucosa is critical for the maintenance of immune homeostasis and prevention of tissue damage, such as observed during inflammatory bowel disease. Intestinal epithelial cells, primarily thought to form a simple physical barrier, critically regulate intestinal immune cell functions by producing immunoregulatory glucocorticoids on T-cell activation. In this study we investigated whether stimulation of cells of the innate immune system results in the induction of intestinal glucocorticoids synthesis and what role TNF-alpha plays in this process. Stimulation of the innate immune system with lipopolysaccharide (LPS) led to an up-regulation of colonic steroidogenic enzymes and the induction of intestinal glucocorticoid synthesis. The observed induction was dependent on macrophage effector functions, as depletion of macrophages using clodronate-containing liposomes, but not absence of T and B cells, inhibited intestinal glucocorticoid synthesis. LPS-induced glucocorticoid synthesis was critically dependent on TNF-alpha as it was significantly decreased in TNF-alpha-deficient animals. Both TNF receptor-1 and -2 were found to be equally involved in LPS- and T-cell-induced intestinal GC synthesis. These results describe a novel and critical role of TNF-alpha in immune cell-induced intestinal glucocorticoid synthesis. PMID:20056718

  14. Fibrinogen synthesis in serum-free hepatocyte cultures: stimulation by glucocorticoids.

    Science.gov (United States)

    Grieninger, G; Hertzberg, K M; Pindyck, J

    1978-11-01

    Fibrinogen synthesis was investigated in cultures of chicken embryo hepatocytes initiated and maintained in chemically defined, serum-free medium. 11-Hydroxy glucocorticoids caused a 3-fold stimulation of fibrinogen synthesis. Half-maximal stimulation was achieved with 1 nM corticosterone or hydrocortisone, as compared with only 0.1 nM dexamethasone. Increased fibrinogen production in the presence of these glucocorticoids was characterized by a 4-hr delay in onset, a sensitivity to actinomycin D, and a requirement for the continuous presence of the steroid. Crossed immunoelectrophoresis permitted analysis of the simultaneous effects of glucocorticoids on the synthesis of more than 20 plasma proteins secreted in culture. The absence of an effect on the synthesis of most of these proteins was in sharp contrast to the 3-fold increase in fibrinogen production. Sera from a variety of animals also stimulated an increase in fibrinogen synthesis that was similar in degree but less specific than that due to glucocorticoids and that partially masked the response of the cells to the steroid hormones. The presence of an anticoagulant in the medium was found to be necessary for detection of the fibrinogen secreted in culture. Although insulin was routinely included in the chemically defined medium, the cells synthesized fibrinogen and responded to glucocorticoids in the absence of hormonal supplementation of the medium. These findings are consistent with the thesis that variations in glucocorticoid levels contribute to the regulation of fibrinogen production in the intact animal. PMID:281699

  15. [Glucocorticoids and... infections, doping, surgery, sexuality].

    Science.gov (United States)

    Grossi, O; Généreau, T

    2013-05-01

    The risk of infection is increased in patients treated with glucocorticoids, especially in those taking long-term and high dosage treatment. However, there is little valid practice for the prevention of infections in this patient population. The risk of reactivation or worsening of a latent infection (e.g., hepatitis B, tuberculosis, strongyloidiasis) is proved and individual reflection should be conducted in at-risk patients. Preventions of Pneumocystis jiroveci or upper urinary tract infections are considered differently according to practitioners' habits and their specialties. Adequate prevention should be prescribed in glucocorticoid-treated patients who have been in contact with varicella zoster or measles virus. Many vaccines could be prescribed in those people but live vaccines should be avoided. A consultation of travel medicine should be systematically proposed before a travel in intertropical zone. Anti-inflammatory and stimulant properties of glucocorticoids are frequently misused in order to improve sport performances. All glucocorticoids are considered as performance-enhancing drugs. Their prescription should therefore be adapted to the laws in force in the sport. By reducing vomiting and pain, glucocorticoids may be beneficial in patients undergoing surgery. However, in people prescribed long-term glucocorticoid therapy, the risk of postoperative adrenal insufficiency has to be considered, even though very few data are available on this topic. Oral contraceptives or intra-uterine devices are effective contraceptives methods in patients treated with systemic glucocorticoids. PMID:23415059

  16. Blood flow in histamine- and allergen-induced weal and flare responses, effects of an H1 antagonist, alpha-adrenoceptor agonist and a topical glucocorticoid.

    Science.gov (United States)

    Hammarlund, A; Olsson, P; Pipkorn, U

    1990-01-01

    Allergen has previously been shown to induce a continuous increase in local dermal blood flow after a prick test in allergic subjects, whereas histamine induced, initially, similar peak increases in blood flow of much shorter duration. Blood flow changes induced by histamine and allergen have now been evaluated (i) after pretreatment with a local corticosteroid cream, clobetasole-17-propionate; (ii) after oral administration of the H1-antihistamine loratadine; and (iii) after oral pretreatment with the alpha 1-adrenoceptor agonist pseudoephedrine. Blinded placebo-controlled designs were used in the substudies. Laser doppler flowmetry was used for non-invasive recording of changes in local blood flow intermittently for 24 h after the topical corticosteroid, 6 h for the substudies on loratadine and pseudoephedrine. The size of the immediate weal and flare reactions, as well as late phase reactions, were also determined. Pretreatment with clobetasole-17-propionate cream on the skin for 1 week prior to prick tests did not affect the blood flow response elicited by histamine or allergen, in either the initial part (up to 1 h) or the protracted 24 h determinations. The size of the weal and flare reactions decreased. Loratadine and pseudoephedrine did not reduce the initial allergen-induced increase in blood flow, while lower blood flow compared with placebo pretreatment was noted for the protracted (1-6 h) determinations. Blood flow changes after histamine were unaffected. The histamine-induced weal and flare was inhibited by loratadine more effectively than the corresponding allergen-induced reaction. The weal and flare reactions after histamine and allergen were not changed after pseudoephedrine.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Using biological markers to inform a clinically meaningful treatment response.

    Science.gov (United States)

    Yehuda, Rachel; Bierer, Linda M; Pratchett, Laura C; Pelcovitz, Michelle

    2010-10-01

    Combat veterans with posttraumatic stress disorder (PTSD) demonstrate less robust improvement following treatments than do civilians with PTSD. This paper discusses a theoretical model for evaluating treatment response based on the extent of change in biological markers of symptom severity or resilience between treatment initiation and termination. Such analysis permits a determination of biological change associated with the liberal criteria commonly used to determine treatment response in combat PTSD, and a comparison of this to the biological change associated with clinical response determined according to the conservative definition more appropriate to civilian PTSD. Interim data supporting the utility of this approach is presented based on preliminary analyses from our work in progress. We propose that future studies consider the unique consequences of combat trauma and develop treatments that incorporate the complex nature of the exposure and response characteristic of a veteran population. PMID:20955338

  18. Sequential monitoring of response-adaptive randomized clinical trials

    CERN Document Server

    Zhu, Hongjian; 10.1214/10-AOS796

    2010-01-01

    Clinical trials are complex and usually involve multiple objectives such as controlling type I error rate, increasing power to detect treatment difference, assigning more patients to better treatment, and more. In literature, both response-adaptive randomization (RAR) procedures (by changing randomization procedure sequentially) and sequential monitoring (by changing analysis procedure sequentially) have been proposed to achieve these objectives to some degree. In this paper, we propose to sequentially monitor response-adaptive randomized clinical trial and study it's properties. We prove that the sequential test statistics of the new procedure converge to a Brownian motion in distribution. Further, we show that the sequential test statistics asymptotically satisfy the canonical joint distribution defined in Jennison and Turnbull (\\citeyearJT00). Therefore, type I error and other objectives can be achieved theoretically by selecting appropriate boundaries. These results open a door to sequentially monitor res...

  19. Eosinophilic Esophagitis: Clinical Features, Endoscopic Findings and Response to Treatment

    OpenAIRE

    Enns, Robert; Kazemi, Pooya; Chung, Wiley; Lee, Mitchell

    2010-01-01

    Eosinophilic esophagitis (EE) is a motility disorder of the esophagus that typically presents with dysphagia. The objective of the present study was to explore patient characteristics, clinical and endoscopic features, and response to treatment of patients with EE. Patients were selected retrospectively based on a review of biopsy results from previous endoscopies performed between 2004 and 2008. A total of 54 patients (41 men and 13 women) with biopsy-proven EE were included in the study. Fu...

  20. Genetics Home Reference: familial glucocorticoid deficiency

    Science.gov (United States)

    ... Clark AJ, Metherell LA. ACTH resistance: genes and mechanisms. Endocr Dev. 2013;24:57-66. doi: 10. ... Metherell LA. Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013 May 22;371(1- ...

  1. Glucocorticoid Regulation of Human Pulmonary Surfactant Protein-B mRNA Stability Involves the 3′-Untranslated Region

    OpenAIRE

    Huang, Helen W.; Bi, Weizhen; Jenkins, Gaye N.; Alcorn, Joseph L.

    2007-01-01

    Expression of pulmonary surfactant, a complex mixture of lipids and proteins that acts to reduce alveolar surface tension, is developmentally regulated and restricted to lung alveolar type II cells. The hydrophobic protein surfactant protein-B (SP-B) is essential in surfactant function, and insufficient levels of SP-B result in severe respiratory dysfunction. Glucocorticoids accelerate fetal lung maturity and surfactant synthesis both experimentally and clinically. Glucocorticoids act transcr...

  2. Glucocorticoids enhance stability of human growth hormone mRNA.

    OpenAIRE

    Paek, I; Axel, R.

    1987-01-01

    We have studied the control of expression of the human growth hormone (hGH) gene introduced into the chromosomes of mouse fibroblasts. Cell lines transformed with the hGH gene expressed low levels of intact hGH mRNA and secreted hGH protein into the medium. Although the level of expression of hGH mRNA was low, the gene remained responsive to induction by glucocorticoid hormones. To localize the sequences responsible for induction and to determine the mechanism by which these cis-acting sequen...

  3. Glucocorticoid Regulation of the Vitamin D Receptor

    OpenAIRE

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

    2010-01-01

    Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and...

  4. Biochemical characterization of nuclear receptors for vitamin D{sub 3} and glucocorticoids in prostate stroma cell microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Hidalgo, Alejandro A. [Laboratory of Molecular Endocrinology, Department of Physiopathology, University of Concepcion, Concepcion (Chile); Department of Molecular Pharmacology and Therapeutics, NY (United States); Montecinos, Viviana P.; Paredes, Roberto; Godoy, Alejandro S.; McNerney, Eileen M.; Tovar, Heribelt; Pantoja, Diego [Laboratory of Molecular Endocrinology, Department of Physiopathology, University of Concepcion, Concepcion (Chile); Johnson, Candace [Department of Molecular Pharmacology and Therapeutics, NY (United States); Trump, Donald [Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (United States); Onate, Sergio A., E-mail: sergio.onate@udec.cl [Laboratory of Molecular Endocrinology, Department of Physiopathology, University of Concepcion, Concepcion (Chile); Department of Urology, State University of New York at Buffalo, NY (United States)

    2011-08-19

    Highlights: {yields} Fibroblasts from benign and carcinoma-associated stroma were biochemically characterized for VDR and GR function as transcription factors in prostate stroma cell microenvironment. {yields} Decreased SRC-1/CBP coactivators recruitment to VDR and GR may result in hormone resistance to 1,25D{sub 3} in stromal cell microenvironment prostate cancer. {yields} 1a,25-Dyhidroxyvitamin D{sub 3} (1,25D{sub 3}) and glucocorticoids, either alone or in combination, may not be an alternative for 'some' advanced prostate cancers that fails androgen therapies. -- Abstract: The disruption of stromal cell signals in prostate tissue microenvironment influences the development of prostate cancer to androgen independence. 1{alpha},25-Dihydroxyvitamin D{sub 3} (1,25D{sub 3}) and glucocorticoids, either alone or in combination, have been investigated as alternatives for the treatment of advanced prostate cancers that fails androgen therapies. The effects of glucocorticoids are mediated by the intracellular glucocorticoid receptor (GR). Similarly, the effect of 1,25D{sub 3} is mediated by the 1,25D{sub 3} nuclear receptor (VDR). In this study, fibroblasts from benign- (BAS) and carcinoma-associated stroma (CAS) were isolated from human prostates to characterize VDR and GR function as transcription factors in prostate stroma. The VDR-mediated transcriptional activity assessed using the CYP24-luciferase reporter was limited to 3-fold induction by 1,25D{sub 3} in 9 out of 13 CAS (70%), as compared to >10-fold induction in the BAS clinical sample pair. Expression of His-tagged VDR (Ad-his-VDR) failed to recover the low transcriptional activity of the luciferase reporter in 7 out of 9 CAS. Interestingly, expression of Ad-his-VDR successfully recovered receptor-mediated induction in 2 out of the 9 CAS analyzed, suggesting that changes in the receptor protein itself was responsible for decreased response and resistance to 1,25D{sub 3} action. Conversely, VDR

  5. Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid.

    Science.gov (United States)

    Chen, Jiao; Wang, Zhen-zhen; Zuo, Wei; Zhang, Shuai; Chu, Shi-feng; Chen, Nai-hong

    2016-02-01

    Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus-pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors. PMID:26592454

  6. Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid.

    Science.gov (United States)

    Chen, Jiao; Wang, Zhen-zhen; Zuo, Wei; Zhang, Shuai; Chu, Shi-feng; Chen, Nai-hong

    2016-02-01

    Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus-pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors.

  7. Differential effect of glucocorticoid receptor antagonists on glucocorticoid receptor nuclear translocation and DNA binding

    Science.gov (United States)

    Spiga, Francesca; Knight, David M; Droste, Susanne K; Conway-Campbell, Becky; Kershaw, Yvonne; MacSweeney, Cliona P; Thomson, Fiona J; Craighead, Mark; Peeters, Bernard WMM; Lightman, Stafford L

    2016-01-01

    The effects of RU486 and S-P, a more selective glucocorticoid receptor antagonist from Schering-Plough, were investigated on glucocorticoid receptor nuclear translocation and DNA binding. In the in vitro study, AtT20 cells were treated with vehicle or with RU486, S-P or corticosterone (3–300 nM) or co-treated with vehicle or glucocorticoid receptor antagonists (3–300 nM) and 30 nM corticosterone. Both glucocorticoid receptor antagonists induced glucocorticoid receptor nuclear translocation but only RU486 induced DNA binding. RU486 potentiated the effect of corticosterone on glucocorticoid receptor nuclear translocation and DNA binding, S-P inhibited corticosterone-induced glucocorticoid receptor nuclear translocation, but not glucocorticoid receptor-DNA binding. In the in vivo study, adrenalectomized rats were treated with vehicle, RU486 (20 mg/kg) and S-P (50 mg/kg) alone or in combination with corticosterone (3 mg/kg). RU486 induced glucocorticoid receptor nuclear translocation in the pituitary, hippocampus and prefrontal cortex and glucocorticoid receptor-DNA binding in the hippocampus, whereas no effect of S-P on glucocorticoid receptor nuclear translocation or DNA binding was observed in any of the areas analysed. These findings reveal differential effects of RU486 and S-P on areas involved in regulation of hypothalamic–pituitary–adrenal axis activity in vivo and they are important in light of the potential use of this class of compounds in the treatment of disorders associated with hyperactivity of the hypothalamic–pituitary–adrenal axis. PMID:20093322

  8. Modeling clinical radiation responses in the IMRT era

    International Nuclear Information System (INIS)

    The purpose of this review is to highlight the critical issues of radiobiological models, particularly as they apply to clinical radiation therapy. Developing models of radiation responses has a long history that continues to the present time. Many different models have been proposed, but in the field of radiation oncology, the linear-quadratic (LQ) model has had the most impact on the design of treatment protocols. Questions have been raised as to the value of the LQ model given that the biological assumption underlying it has been challenged by molecular analyses of cell and tissue responses to radiation. There are also questions as to use of the LQ model for hypofractionation, especially for high dose treatments using a single fraction. While the LQ model might over-estimate the effects of large radiation dose fractions, there is insufficient information to fully justify the adoption of alternative models. However, there is increasing evidence in the literature that non-targeted and other indirect effects of radiation sometimes produce substantial deviations from LQ-like dose-response curves. As preclinical and clinical hypofractionation studies accumulate, new or refined dose-response models that incorporate high-dose/fraction non-targeted and indirect effects may be required, but for now the LQ model remains a simple, useful tool to guide the design of treatment protocols.

  9. Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression.

    Science.gov (United States)

    Nikkheslat, Naghmeh; Zunszain, Patricia A; Horowitz, Mark A; Barbosa, Izabela G; Parker, Jennie A; Myint, Aye-Mu; Schwarz, Markus J; Tylee, Andre T; Carvalho, Livia A; Pariante, Carmine M

    2015-08-01

    Coronary heart disease (CHD) and depression are very common and often co-existing disorders. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients. Inflammation has been proposed as one of the mechanisms involved in the association between these two debilitating diseases. Therefore, the present study aimed to evaluate inflammatory responses as well as to investigate the pathophysiological mechanisms underlying the putative inflammatory activation in CHD patients with and without depression, by assessing the function of two important biological factors regulating inflammation, the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid receptor (GR). Eighty-three CHD patients with (n=28) and without (n=55) comorbid depression were recruited from primary care services in South London. Depression status was assessed by means of Clinical Interview Schedule Revised for diagnosis of depression, and Beck Depression Inventory for the presence of depressive symptoms. Serum C-reactive protein (CRP), plasma vascular endothelial growth factor (VEGF), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and interleukin-6 (IL-6) were conducted via qPCR. GR sensitivity was evaluated in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Serum levels of kynurenine pathway metabolites were measured using high performance liquid chromatography. Our results show that CHD patients with depression had higher levels of CRP, IL-6 gene expression, and VEGF compared with CHD non-depressed, as well as lower plasma and saliva cortisol levels. The CHD depressed group also exhibited a reduction in GR expression and sensitivity. Finally, tryptophan levels were significantly lower in patients with depression, who also showed an increased kynurenine/tryptophan ratio. In conclusion, CHD

  10. Dopa-responsive dystonia--clinical and genetic heterogeneity.

    Science.gov (United States)

    Wijemanne, Subhashie; Jankovic, Joseph

    2015-07-01

    Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment. PMID:26100751

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

    Science.gov (United States)

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

    2012-01-01

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

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

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    Leonardo Rizzo

    2007-06-01

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

  13. 慢性心力衰竭急性加重伴2型糖尿病肾功能不全患者应用糖皮质激素的临床分析%THE CLINICAL ANALYSIS OF GLUCOCORTICOID ON PATIENTS WITH ACUTE EXACERBATION OF CONGESTIVE HEART FAILURE,TYPE 2 DIABETES AND RENAL INSUFFICIENCY

    Institute of Scientific and Technical Information of China (English)

    甄宇治; 高延秋; 刘超; 刘刚; 籍振国; 刘坤申

    2011-01-01

    Objective To determine the clinical efficacy of glucocorticoid on patients with acute exacerbation of congestive heart failure, type 2 diabetes and renal insufficiency. Methods Prednisone was used in addition to traditional treatment in 13 patients with acute exacerbation of congestive heart failure,type 2 diabetes and renal insufficiency. Results Prednisone dramatically improved patients ' symptoms, clinical status, heart function and renal function ( i. e. the glomerular filtration rate ).Conclusion In patients with acute exacerbation of congestive heart failure, type 2 diabetes and renal insufficiency , glucocorticoid treatment could remarkably improve the renal function.%目的 探讨糖皮质激素对于慢性充血性心力衰竭急性加重伴2型糖尿病肾功能不全患者的治疗效果.方法 慢性心力衰竭急性加重伴2型糖尿病肾功能不全患者13例在常规治疗基础上加用糖皮质激素治疗.结果 加用糖皮质激素治疗后,13例患者临床症状均好转,心功能改善,肾功能改善,血肌酐下降,肾小球滤过率升高.结论 慢性心力衰竭急性加重伴2型糖尿病肾功能不全患者在常规治疗基础上加用糖皮质激素治疗,肾功能可得到明显改善.

  14. Effects of antenatal glucocorticoid therapy on hippocampal histology of preterm infants.

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    Deodata Tijsseling

    Full Text Available OBJECTIVE: To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn. PATIENTS AND METHODS: Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids. The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage. RESULTS: The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01 and neurons irrespective of size (p = 0.02 as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage. CONCLUSION: We found a significantly lower density of neurons in the hippocampus of neonates after antenatal glucocorticoid treatment. Although the pathophysiological and clinical interpretations of these findings are not clear, they are consistent with those from experiments in mice and rhesus monkeys.

  15. 糖皮质激素治疗多发性硬化不同方案的临床应用%Clinical application of different protocols of glucocorticoids on treating multiple sclerosis

    Institute of Scientific and Technical Information of China (English)

    董艳玲; 李吕力; 李瑶宣; 梁浩; 滕晓茗; 肖继东; 张德敏

    2012-01-01

    Objective To evaluate the curative effects, the expenses and time of hospitalization, the condition of recurrence and the adverse reactions of different protocols of glucocorticoids on treating multiple sclerosis (MS). Methods Ninty-seven MS patients at acute stage were randomly divided into melhylprednisolone (MPS) intrathecal injection group (30 cases) , MPS pulse therapy group (36 cases) and dexamethasone ( DXM ) therapy group (31 cases). The decrease of Kurtzke expanded disability status scale(EDSS) at different time after treatmentand, the expenses and time of hospitalization, the proportion of drugs in hospitalization expenses, the condition of recurrence and the adverse reactions among all the groups were compared with each other. Results The decrease of EDSS in MPS intrathecal injection group scince 5 d after treatment and in MPS pulse therapy group scince 10 d after treatment were significantly higher than that in DXM therapy group (all P<0. 05). The decrease of EDSS in MPS intrathecal injection group at 5 d after treatment was significantly higher than that in MPS pulse therapy group (P < 0.05). Among the three groups, the total expense of hospitalization and the proportion of drugs in hospitalization expenses were the least in MPS intrathecal injection group, and the daily mean expense of hospitalization was little, ihe hospitalization time was short (all P<0.05). The daily mean expense of hospitalization was the most in MPS pulse therapy group, and the hospitalization time was the longest in DXM therapy group (all P<0.05). The recurrence rate was the highest and the recurrence time was the shortest in MPS pulse therapy group (all P < 0. 05). The difference of recurrence rate and time was no statistical significance between MPS intrathecal injection group and DXM therapy group. There was no severe adverse reaction in all the groups. Conclusions The curative effect of MPS intrathecal injection on treating MS is fast and significant in short-term with

  16. Efficacy of Puls-therapy with Glucocorticoids in Patients with Autoimmune Ophtalmopatay

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    E V Bogomazova

    2008-09-01

    Full Text Available The article is presents the results of estimation efficiency of various schemes pathogenetic glucocorticoids treatment of autoimmune ophthalmopathy. Research of clinical parameters dynamics including subjective and objective attributes, proptosis, dynamics of the soluble form of intercellular molecule adhesion-1 levels was made before treatment and at the end of research (in 6 month follow up after complete course of pathogenetic treatment. The study has demonstrated that combination of glucocorticoids pulse-therapy and mean volume plasmapheresis is the most effective pathogenetic method of autoimmune ophthalmopathy treatment; absence of advantages of the used schemes of treatment for reduction proptosis. Advantages of use of the combined therapy are marked in comparison with monotherapy by glucocorticoids at estimation of subjective attributes.

  17. Clinical significance of scoring system for systemic inflammatory response syndrome

    Institute of Scientific and Technical Information of China (English)

    HAN Jian; LIANG Hua-ping

    2006-01-01

    The concepts of systemic inflammatory response syndrome (SIRS) and scoring system were defined by the journal of Bone in 1992. SIRS was described as occurrence of two or more clinical criteria in four ones (fever or hypothermia, tachypnea, tachycardia, and leukocytosis).An early diagnosis and estimation of systemic inflammation in patients is helpful for treatment selection. This paper reviews the application of SIRS scoring system, which has been extensively validated for large groups of critical care patients with severe injury and critical surgical diseases.Recent studies have documented SIRS score as a significant predictive parameter of adverse outcome in critical care patients. Furthermore, some studies also give us a suggestion on how to reduce the overload systemic response.

  18. Bone loss during simulated weightlessness - Is it glucocorticoid mediated?

    Science.gov (United States)

    Bikle, D. D.; Halloran, B. P.; Cone, C. M.; Morey-Holton, E.

    1985-01-01

    Elevating the hindquarters of a rat by the tail unweights the hind limbs but maintains normal weight-bearing by the forelimbs. This maneuver leads to a decrease in bone mass and calcium content in the unweighted bones (e.g., tibia and L1 vertebra), but not in the normally weighted bones (e.g., humerus and mandible). Potentially, the stress of the maneuver, mediated by increased glucocorticoid production and secretion, could explain the decreased bone formation, rather than the skeletal unweighting per se. To test this possibility, the effects of adrenalectomy on the response of bone to the unweighting of the hind limbs of normal rats were evaluated.

  19. Impact of genetic polymorphisms on clinical response to antithrombotics

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    Kena J Lanham

    2010-06-01

    Full Text Available Kena J Lanham1,2, Julie H Oestreich3, Steven P Dunn1,2, Steven R Steinhubl41Pharmacy Services, UK HealthCare, University of Kentucky, Lexington, Kentucky, USA; 2Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA; 3Department of Pharmacy Practice, College of Pharmacy, University of Nebraska, Omaha, Nebraska, USA; 4The Medicines Company, Zurich, Switzerland and The Geisinger Clinic, Danville, Pennsylvania, USAAbstract: Antithrombotic therapy, including anticoagulants as well as antiplatelet drugs, is an important component in the treatment of cardiovascular disease. Variability in response to such medications, of which pharmacogenetic response is a major source, can decrease or enhance the benefits expected. This review is a comprehensive assessment of the literature published to date on the effects of genetic polymorphisms on the actions of a variety of antithrombotic medications, including warfarin, clopidogrel, prasugrel, and aspirin. Literature evaluating surrogate markers in addition to the impact of pharmacogenetics on clinical outcomes has been reviewed. The results of the studies are conflicting as to what degree pharmacogenetics will affect medication management in cardiovascular disease. Additional research is necessary to discover, characterize, and prospectively evaluate genetic and non-genetic factors that impact antithrombotic treatment in order to maximize the effectiveness and limit the harmful effects of these valuable agents.Keywords: aspirin, warfarin, clopidogrel, prasugrel, pharmacogenetic, antithrombotic, antiplatelet

  20. A facile, branched DNA assay to quantitatively measure glucocorticoid receptor auto-regulation in T-cell acute lymphoblastic leukemia

    Institute of Scientific and Technical Information of China (English)

    Jason R. Schwartz; Purvaba J. Sarvaiya; Lily E. Leiva; Maria C. Velez; Tammuella C. Singleton; Lolie C. Yu; Wayne V. Vedeckis

    2012-01-01

    Glucocorticoid (GC) steroid hormones are used to treat acute lymphoblastic leukemia (ALL) because of their pro-apoptotic effects in hematopoietic cells.However,not all leukemia cells are sensitive to GC,and no assay to stratify patients is available.In the GC-sensitive T-cell ALL cell line CEM-C7,auto-up-regulation of RNA transcripts for the glucocorticoid receptor (GR) correlates with increased apoptotic response.This study aimed to determine if a facile assay of GR transcript levels might be promising for stratifying ALL patients into hormone-sensitive and hormone-resistant populations.The GR transcript profiles of various lymphoid cell lines and 4 bone marrow samples from patients with T-cell ALL were analyzed using both an optimized branched DNA (bDNA) assay and a real-time quantitative reverse transcription-polymerase chain reaction assay.There were significant correlations between both assay platforms when measuring total GR (exon 5/6) transcripts in various cell lines and patient samples,but not for a probe set that detects a specific,low abundance GR transcript (exon 1A3).Our results suggest that the bDNA platform is reproducible and precise when measuring total GR transcripts and,with further development,may ultimately offer a simple clinical assay to aid in the prediction of GC-sensitivity in ALL patients.

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

    NARCIS (Netherlands)

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

    2009-01-01

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

  2. Genetics of glucocorticoid regulation and posttraumatic stress disorder--What do we know?

    Science.gov (United States)

    Castro-Vale, Ivone; van Rossum, Elisabeth F C; Machado, José Carlos; Mota-Cardoso, Rui; Carvalho, Davide

    2016-04-01

    CASTRO-VALE, I., E.F.C. van Rossum, J.C. Machado, R. Mota-Cardoso and D. Carvalho. Genetics of glucocorticoid regulation and posttraumatic stress disorder-What do we know? NEUROSCI. BIOBEHAV. REV. 43 (1) XXX-XXX, 2014 - Posttraumatic stress disorder (PTSD) develops in a small proportion of those who have been exposed to a traumatic event. Genetic factors are estimated to be responsible for 30% of the variance in PTSD risk. Dysfunction of the hypothalamic-pituitary-adrenal (HPA)-axis in PTSD has been found, particularly hypersensitivity of the glucocorticoid receptor (GR). In this review we aim to understand the genetic factors that influence glucocorticoid function in PTSD. Glucocorticoid action is regulated by a corticotrophin-releasing hormone, arginine vasopressin (AVP)/oxytocin pathway, GR, and regulators such as co-chaperone FKBP5. Single nucleotide polymorphisms (SNPs) in the GR gene, CRHR1 gene and FKBP5 gene affect HPA-axis sensitivity. The GR gene SNP BclI has been associated with hypersensitivity to glucocorticoids and PTSD symptoms. FKBP5 gene SNPs interacted with childhood adversity to moderate PTSD risk and in particular, the rs9470080 SNP was independently associated with lifetime PTSD. SNPs in the CRHR1 gene were also associated with PTSD risk. Gene-environment interaction studies have highlighted the importance of multifactorial vulnerability in PTSD, with epigenetic mechanisms contributing to the equation. PMID:26872620

  3. Eosinophilic Esophagitis: Clinical Features, Endoscopic Findings and Response to Treatment

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    Robert Enns

    2010-01-01

    Full Text Available Eosinophilic esophagitis (EE is a motility disorder of the esophagus that typically presents with dysphagia. The objective of the present study was to explore patient characteristics, clinical and endoscopic features, and response to treatment of patients with EE. Patients were selected retrospectively based on a review of biopsy results from previous endoscopies performed between 2004 and 2008. A total of 54 patients (41 men and 13 women with biopsy-proven EE were included in the study. Further information regarding the patients’ clinical and endoscopic features, and response to treatment were obtained through chart reviews and patient telephone interviews. The mean age of the patients at symptom onset was 30 years. All patients complained of dysphagia, 81% had a history of bolus obstruction, 43% had a history of asthma and 70% had a history of environmental allergies. Thirty-three per cent had a family history of asthma, while 52% had a family history of food or seasonal allergies. The most common endoscopic findings were rings and/or corrugations, which were found in 63% of patients. Swallowed fluticasone therapy resulted in symptom resolution in 74% of patients; however, 79% of these patients relapsed after discontinuing fluticasone therapy and required repeat treatments. Esophageal dilation was complication free and resulted in improvement in 80% of patients. However, 83% of those reporting improvement relapsed within one year. The clinical and endoscopic findings were similar to those found in the literature, with most patients requiring ongoing, repeated therapies. Further studies are needed to assess the safety and efficacy of treatment modalities ideally suited to patients with EE.

  4. Glucocorticoid effects on hippocampal protein synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Schlatter, L.K.

    1988-01-01

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

  5. Glucocorticoid interaction with aggression in non-mammalian vertebrates: reciprocal action.

    Science.gov (United States)

    Summers, Cliff H; Watt, Michael J; Ling, Travis L; Forster, Gina L; Carpenter, Russ E; Korzan, Wayne J; Lukkes, Jodi L; Overli, Oyvind

    2005-12-01

    Socially aggressive interaction is stressful, and as such, glucocorticoids are typically secreted during aggressive interaction in a variety of vertebrates, which may both potentiate and inhibit aggression. The behavioral relationship between corticosterone and/or cortisol in non-mammalian (as well as mammalian) vertebrates is dependent on timing, magnitude, context, and coordination of physiological and behavioral responses. Chronically elevated plasma glucocorticoids reliably inhibit aggressive behavior, consistent with an evolutionarily adaptive behavioral strategy among subordinate and submissive individuals. Acute elevation of plasma glucocorticoids may either promote an actively aggressive response via action in specialized local regions of the brain such as the anterior hypothalamus, or is permissive to escalated aggression and/or activity. Although the permissive effect of glucocorticoids on aggression does not suggest an active role for the hormone, the corticosteroids may be necessary for full expression of aggressive behavior, as in the lizard Anolis carolinensis. These effects suggest that short-term stress may generally be best counteracted by an actively aggressive response, at least for socially dominant proactive individuals. An acute and active response may be evolutionarily maladaptive under chronic, uncontrollable and unpredictable circumstances. It appears that subordinate reactive individuals often produce compulsorily chronic responses that inhibit aggression and promote submissive behavior. PMID:16298361

  6. Network analysis of quantitative proteomics on asthmatic bronchi: effects of inhaled glucocorticoid treatment

    Directory of Open Access Journals (Sweden)

    Sihlbom Carina

    2011-09-01

    Full Text Available Abstract Background Proteomic studies of respiratory disorders have the potential to identify protein biomarkers for diagnosis and disease monitoring. Utilisation of sensitive quantitative proteomic methods creates opportunities to determine individual patient proteomes. The aim of the current study was to determine if quantitative proteomics of bronchial biopsies from asthmatics can distinguish relevant biological functions and whether inhaled glucocorticoid treatment affects these functions. Methods Endobronchial biopsies were taken from untreated asthmatic patients (n = 12 and healthy controls (n = 3. Asthmatic patients were randomised to double blind treatment with either placebo or budesonide (800 μg daily for 3 months and new biopsies were obtained. Proteins extracted from the biopsies were digested and analysed using isobaric tags for relative and absolute quantitation combined with a nanoLC-LTQ Orbitrap mass spectrometer. Spectra obtained were used to identify and quantify proteins. Pathways analysis was performed using Ingenuity Pathway Analysis to identify significant biological pathways in asthma and determine how the expression of these pathways was changed by treatment. Results More than 1800 proteins were identified and quantified in the bronchial biopsies of subjects. The pathway analysis revealed acute phase response signalling, cell-to-cell signalling and tissue development associations with proteins expressed in asthmatics compared to controls. The functions and pathways associated with placebo and budesonide treatment showed distinct differences, including the decreased association with acute phase proteins as a result of budesonide treatment compared to placebo. Conclusions Proteomic analysis of bronchial biopsy material can be used to identify and quantify proteins using highly sensitive technologies, without the need for pooling of samples from several patients. Distinct pathophysiological features of asthma can be

  7. A new function of glucocorticoid receptor: regulation of mRNA stability

    OpenAIRE

    Park, Ok Hyun; Do, Eunjin; Kim, Yoon Ki

    2015-01-01

    It has long been thought that glucocorticoid receptor (GR) functions as a DNA-binding transcription factor in response to its ligand (a glucocorticoid) and thus regulates various cellular and physiological processes. It is also known that GR can bind not only to DNA but also to mRNA; this observation points to the possible role of GR in mRNA metabolism. Recent data revealed a molecular mechanism by which binding of GR to target mRNA elicits rapid mRNA degradation. GR binds to specific RNA seq...

  8. Environmental Enrichment Effect on Fecal Glucocorticoid Metabolites and Captive Maned Wolf (Chrysocyon brachyurus) Behavior.

    Science.gov (United States)

    Coelho, Carlyle Mendes; de Azevedo, Cristiano Schetini; Guimarães, Marcelo Alcino de Barros Vaz; Young, Robert John

    2016-01-01

    Environmental enrichment is a technique that may reduce the stress of nonhuman animals in captivity. Stress may interfere with normal behavioral expression and affect cognitive decision making. Noninvasive hormonal studies can provide important information about the stress statuses of animals. This study evaluated the effectiveness of different environmental enrichment treatments in the diminution of fecal glucocorticoid metabolites (stress indicators) of three captive maned wolves (Chrysocyon brachyurus). Correlations of the fecal glucocorticoid metabolite levels with expressed behaviors were also determined. Results showed that environmental enrichment reduced fecal glucocorticoid metabolite levels. Furthermore, interspecific and foraging enrichment items were most effective in reducing stress in two of the three wolves. No definite pattern was found between behavioral and physiological responses to stress. In conclusion, these behavioral and physiological data showed that maned wolves responded positively from an animal well being perspective to the enrichment items presented. PMID:27057585

  9. [Annexin-1: 2nd messanger of the anti-inflammatory actions of glucocorticoids].

    Science.gov (United States)

    Castro-Caldas, Margarida

    2006-01-01

    Glucocorticoids have important immunosupressive properties, being used as anti-inflammatory therapeutic agents in a wide range of inflammatory and auto-immune pathologies. One of the best studied mechanisms by which glucocorticoids exert most of their anti-inflammatory actions involves the induction of the synthesis and the secretion of the mediator and effector protein annexin 1 (ANXA1). Here we review the molecular and cellular pathways involved on the glucocorticoid-induced synthesis and secretion of ANXA1 in a variety of cell types. Since its discovery as an anti-phospholipase A2 protein, ANXA1 has come a long way to encompass a wide range of cellular effects, the most relevant ones being those that directly modulate the inflammatory response. The results presented in this review open the way to further pharmacological studies which will allow the identification of the role of ANXA1 in inflamatory pathologies, namely rheumatoid arthritis.

  10. Behavioral Neuroadaptation to Alcohol: From Glucocorticoids to Histone Acetylation

    Science.gov (United States)

    Mons, Nicole; Beracochea, Daniel

    2016-01-01

    A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic–pituitary–adrenal axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents) from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit, including the prefrontal cortex (PFC), the hippocampus (HPC), and the amygdala (AMG). These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally AMG hyperactivity coupled with a hypofunction of the PFC and the HPC. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcohol-induced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as [cAMP response element-binding protein (CREB)] and chromatin remodeling due to posttranslational modifications of histone proteins. We describe the role of prefrontal–HPC–AMG circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region-specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes how persistently increased glucocorticoid levels in PFC may be involved in mediating working memory impairments and

  11. GLUCOCORTICOID RECEPTOR IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

    Institute of Scientific and Technical Information of China (English)

    YANG Ping; LIAO Qing-kui; LUO Chun-hua

    1999-01-01

    Objective: To investigate the relationship among glucocorticoid receptor (GCR) level, immunological classification and clinical efficacy of chemotherapy in acute lymphoblastic leukemia (ALL) children. Methods: The GCR level of venous blood lymphocytes was measured by receptor radioligand binding assay in 50 cases with childhood ALL and 41 normal children. The immunological classification of 32 children with ALL was analyzed by ABC immunoenzymatic method. Results: The GCR number in venous blood lymphocytes of normal children was 4651±1617 binding sites/cell. The normal range (95%) was 1482-7800 binding sites/cell. The GCR level of 50 cases with ALL (6695±5256 binding sites/cell) was significantly higher than that of the normal ones (t=2.50, P<0.05). The GCR level of the ALL children with good prognosis was significantly higher than that of bad prognosis (t=4.39,P<0.001). The relationship between immunological classification and GCR level of 32 cases with children ALL was as follows: GCR level of T-ALL and B-ALL were significantly lower than AUL, C-ALL and pre-B-ALL; the prognosis of T-ALL and B-ALL was also bad; the GCR level of the group with good prognosis was significantly higher than that with bad prognosis in all immunological types. Conclusion: The GCR level of the peripheral venous blood lymphocytes in children ALL may be an important biochemistry indicator and used to predict prognosis and guide combination chemotherapy. The relationship between GCR and immunological classification can be useful to the expectation of prognosis.

  12. Clinical effects of prenatal glucocorticoid by intramuscular injection on preterm infants%糖皮质激素产前肌注用于早产儿效果探讨

    Institute of Scientific and Technical Information of China (English)

    黄平

    2016-01-01

    Objective To investigate the effects of prenatal glucocorticoid by intramuscular injection on postpartum complications and long -term growth and mental development of preterm infants .Methods From July 2012 to July 2014 totally 120 patients with premature delivery admitted in department of obstetrics and gynecology in People ’ s Hospital of Leshan City were selected as research objects , and 64 cases in control group with prenatal magnesium sulfate by intravenous infusion and 56 cases in observation group with prenatal glucocorticoid by intramuscular injection additionally .Apgar score, incidence of respiratory distress syndrome , mortality, growth development indicators and mental development indicators in 1 year of follow-up were compared between groups .Results There was no significant difference in 1min Apgar score between two groups (t=1.34, P>0.05).The 5 min Apgar score of the observation group was higher than the control group , and the differences was statistically significant (t=2.04, P0.05).Conclusion Prenatal glucocorticoid by intramuscular injection on premature infant can efficiently reduce the risk of respiratory distress syndrome and death and has no adverse effect on long-term growth and intellectual development .%目的:探讨糖皮质激素产前肌注对早产儿产后并发症、远期生长及智力发育水平的影响。方法研究对象选取四川乐山市人民医院妇产科2012年7月至2014年7月收治早产分娩产妇共120例,其中64例仅行硫酸镁产前静脉滴注,设为对照组,56例则在此基础上加用糖皮质激素产前肌注,设为观察组;比较两组早产儿Apgar评分、呼吸窘迫综合征发生率、死亡率、随访1年生长发育指标及智力发育指标水平等。结果两组早产儿产后1min Apgar评分比较无显著性差异(t=1.34,P>0.05),观察组早产儿产后5min Apgar评分显著高于对照组,差异具有统计学意义(t=2.04,P<0.05)。观

  13. Glucocorticoid control of gene transcription in neural tissue

    NARCIS (Netherlands)

    Morsink, Maarten Christian

    2007-01-01

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

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

    OpenAIRE

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

    2015-01-01

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

  15. Detecting qualitative interactions in clinical trials with binary responses.

    Science.gov (United States)

    Kitsche, Andreas

    2014-01-01

    This study considers the detection of treatment-by-subset interactions in a stratified, randomised clinical trial with a binary-response variable. The focus lies on the detection of qualitative interactions. In addition, the presented method is useful more generally, as it can assess the inconsistency of the treatment effects among strata by using an a priori-defined inconsistency margin. The methodology presented is based on the construction of ratios of treatment effects. In addition to multiplicity-adjusted p-values, simultaneous confidence intervals are recommended to use in detecting the source and the amount of a potential qualitative interaction. The proposed method is demonstrated on a multi-regional trial using the open-source statistical software R. PMID:25049176

  16. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance

    Science.gov (United States)

    Bonapace, Laura; Bornhauser, Beat C.; Schmitz, Maike; Cario, Gunnar; Ziegler, Urs; Niggli, Felix K.; Schäfer, Beat W.; Schrappe, Martin; Stanulla, Martin; Bourquin, Jean-Pierre

    2010-01-01

    In vivo resistance to first-line chemotherapy, including to glucocorticoids, is a strong predictor of poor outcome in children with acute lymphoblastic leukemia (ALL). Modulation of cell death regulators represents an attractive strategy for subverting such drug resistance. Here we report complete resensitization of multidrug-resistant childhood ALL cells to glucocorticoids and other cytotoxic agents with subcytotoxic concentrations of obatoclax, a putative antagonist of BCL-2 family members. The reversal of glucocorticoid resistance occurred through rapid activation of autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis. This effect was associated with dissociation of the autophagy inducer beclin-1 from the antiapoptotic BCL-2 family member myeloid cell leukemia sequence 1 (MCL-1) and with a marked decrease in mammalian target of rapamycin (mTOR) activity. Consistent with a protective role for mTOR in glucocorticoid resistance in childhood ALL, combination of rapamycin with the glucocorticoid dexamethasone triggered autophagy-dependent cell death, with characteristic features of necroptosis. Execution of cell death, but not induction of autophagy, was strictly dependent on expression of receptor-interacting protein (RIP-1) kinase and cylindromatosis (turban tumor syndrome) (CYLD), two key regulators of necroptosis. Accordingly, both inhibition of RIP-1 and interference with CYLD restored glucocorticoid resistance completely. Together with evidence for a chemosensitizing activity of obatoclax in vivo, our data provide a compelling rationale for clinical translation of this pharmacological approach into treatments for patients with refractory ALL. PMID:20200450

  17. Comparing the effects of two inhaled glucocorticoids on allergen-induced bronchoconstriction and markers of systemic effects, a randomised cross-over double-blind study

    Directory of Open Access Journals (Sweden)

    Lötvall Jan

    2011-10-01

    Full Text Available Abstract Background Inhaled glucocorticoids are efficient in protecting against asthma exacerbations, but methods to compare their efficacy vs systemic effects have only been attempted in larger multi-centre studies. The aim of the current study was therefore to directly compare the effects of two separate inhaled glucocorticoids, mometasone and budesonide, to compare the effects on the early and late asthmatic responses to inhaled allergen in patients with mild allergic asthma, and sputum eosinophils, and to relate the clinical positive effects to any systemic effects observed. Methods Twelve patients with documented early and late asthmatic responses (EAR and LAR to inhaled allergen at a screening visit were randomized in a double-blind fashion to treatment with mometasone (200 μg × 2 or 400 μg × 2, budesonide (400 μg × 2 or placebo in a double-blind crossover fashion for a period of seven days. Challenge with the total allergen dose causing both an EAR and LAR was given on the last day of treatment taken in the morning. Lung function was assessed using FEV1, and systemic glucocorticoid activity was quantified using 24 h urinary cortisol. Results Mometasone and budesonide attenuate both EAR and LAR to allergen to a similar degree. No significant dose-related effects on the lung function parameters were observed. Both treatments reduced the relative amount of sputum eosinophils (% after allergen. At the dose of 800 μg daily, mometasone reduced 24 h urinary cortisol by approximately 35%. Both drugs were well tolerated. Conclusions Mometasone and budesonide are equieffective in reducing early and late asthmatic responses induced by inhaled allergen challenge. Mometasone 800 μg given for seven days partially affects the HPA axis.

  18. Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression: complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain.

    Science.gov (United States)

    Bodwell, Jack E; Kingsley, Lauren A; Hamilton, Joshua W

    2004-08-01

    Arsenic (As) contamination of drinking water is considered a principal environmental health threat throughout the world. Chronic intake is associated with an increased risk of cancer, diabetes, and cardiovascular disease, and recent studies suggest increased health risks at levels as low as 5-10 ppb. We report here that 0.05-1 microM (6-120 ppb) As showed stimulatory effects on glucocorticoid receptor (GR)-mediated gene activation in rat EDR3 hepatoma cells of both the endogenous tyrosine aminotransferase (TAT) gene and the reporter genes containing TAT glucocorticoid response elements. At slightly higher concentrations (1-3 microM), the effects of As became inhibitory. Thus, over this narrow concentration range, the effects of As changed from a 2- to 4-fold stimulation to a greater than 2-fold suppression in activity. Interestingly, the inhibitory effect of GR on both AP1- and NF-kappa B-mediated gene activation was not affected by As. The magnitude of GR stimulation and inhibition by As was highly dependent on the cellular level of hormone-activated GR. Mutational deletion studies indicated that the central DNA binding domain (DBD) of GR is the minimal region required for the As effect and does not require free sulfhydryls. Point mutations located within the DBD that have known structural consequences significantly altered the GR response to As. In particular, point mutations in the DBD that confer a DNA-bound GR confirmation abolished the low dose As stimulatory effect but enhanced the inhibitory response, further indicating that the DBD is important for mediating these As effects. PMID:15310238

  19. The HPA – immune axis and the immunomodulatory actions of glucocorticoids in the brain

    Directory of Open Access Journals (Sweden)

    Marc-Andre eBellavance

    2014-03-01

    Full Text Available In response to physiological and psychogenic stressors, the hypothalamic-pituitary adrenal (HPA axis orchestrates the systemic release of glucocorticoids (GCs. By virtue of nearly ubiquitous expression of the GC receptor (GR and the multifaceted metabolic, cardiovascular, cognitive and immunologic functions of GCs, this system plays an essential role in the response to stress and restoration of an homeostatic state. GCs act on almost all types of immune cells and were long recognized to perform salient immunosuppressive and anti-inflammatory functions through various genomic and non-genomic mechanisms. These renowned effects of the steroid hormone have been exploited in the clinic for the past 70 years and synthetic GC derivatives are commonly used for the therapy of various allergic, autoimmune, inflammatory and haematological disorders. The role of the HPA axis and GCs in restraining immune responses across the organism is however still debated in light of accumulating evidence suggesting that GCs can also have both permissive and stimulatory effects on the immune system under specific conditions. Such paradoxical actions of GCs are particularly evident in the brain, where substantial data support either a beneficial or detrimental role of the steroid hormone. In this review, we examine the roles of GCs on the innate immune system with a particular focus on the CNS compartment. We also dissect the numerous molecular mechanisms through which GCs exert their effects and discuss the various parameters influencing the paradoxical immunomodulatory functions of GCs in the brain.

  20. Sex Offender Populations and Clinical Efficacy: A Response to Rosky.

    Science.gov (United States)

    Jensen, Todd M; Shafer, Kevin; Roby, C Y; Roby, Jini L

    2016-06-01

    We provide a brief response to a commentary submitted by Rosky in which he questions the rationale and methodological merits of our original study about full-disclosure polygraph outcome differences between juvenile and adult sex offenders. At the heart of Rosky's substantive concerns is the premise that only research tying polygraphy outcomes to actual recidivism is useful or worthwhile. He also questions the overall utility and validity of polygraphy. We acknowledge and challenge these two points. Furthermore, many of the methodological concerns expressed by Rosky represent either a misunderstanding of our research question, study design, and sample, or a disregard for the explicit declarations we made with respect to our study limitations. Overall, it appears Rosky has accused us of not answering well a question we were not trying to ask. Our response addresses the key substantive and methodological concerns extended by Rosky and clarifies the actual aims and scope of our original study. We also argue that a calm, rational, and scientific discussion is the best approach to understanding how to improve clinical methods used in sex offender treatment. PMID:25670743

  1. Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes

    OpenAIRE

    Wu, I; Shin, S. C.; Cao, Y; Bender, I K; N Jafari; Feng, G.; Lin, S.; Cidlowski, J. A.; Schleimer, R. P.; Lu, N Z

    2013-01-01

    Induction of T-cell apoptosis contributes to the anti-inflammatory and antineoplastic benefits of glucocorticoids. The glucocorticoid receptor (GR) translational isoforms have distinct proapoptotic activities in osteosarcoma cells. Here we determined whether GR isoforms selectively induce apoptosis in Jurkat T lymphoblastic leukemia cells. Jurkat cells stably expressing individual GR isoforms were generated and treated with vehicle or dexamethasone (DEX). DEX induced apoptosis in cells expres...

  2. The glucocorticoid properties of the synthetic steroid pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) are not entirely correlated with the steroid binding to the glucocorticoid receptor.

    Science.gov (United States)

    Vicent, G P; Pecci, A; Ghini, A A; Piwien-Pilipuk, G; Veleiro, A S; Burton, G; Lantos, C P; Galigniana, M D

    1999-03-25

    -acetyl transferase activity in cells transfected with a plasmid that possesses two canonical glucocorticoid-responsive elements. Unlike most glucocorticoids, deltaHOP does not induce the fragmentation of DNA in a regular pattern characteristic of apoptosis and it does not reduce thymus weight. This unusual dissociation of glucocorticoid parameters makes deltaHOP a useful tool to discriminate between mechanisms of action by which steroids can exert their biological effects.

  3. Glucocorticoid-induced osteoporosis in growing rats.

    Science.gov (United States)

    Lin, Sien; Huang, Jianping; Zheng, Liang; Liu, Yanzhi; Liu, Guihua; Li, Nan; Wang, Kuixing; Zou, Liyi; Wu, Tie; Qin, Ling; Cui, Liao; Li, Gang

    2014-10-01

    This study evaluated whether growing rats were appropriate animal models of glucocorticoid-induced osteoporosis. The 3-month-old male rats were treated with either vehicle or prednisone acetate at 1.5, 3.0, and 6.0 mg/kg/day by oral gavage, respectively. All rats were injected with tetracycline and calcein before sacrificed for the purpose of double in vivo labeling. Biochemistry, histomorphometry, mechanical test, densitometry, micro-CT, histology, and component analysis were performed. We found that prednisone treatments dose dependently decreased body weight, serum biomarkers, biomechanical markers, bone formation, and bone resorption parameters in both tibial and femoral trabecular bone without trabecular bone loss. We also found that significant bone loss happened in femoral cortical bone in the glucocorticoid-treated rats. The results suggested that prednisone not only inhibited bone formation, but also inhibited bone resorption which resulted in poor bone strength but with no cancellous bone loss in growing rats. These data also suggested that the effects of glucocorticoid on bone metabolism were different between cortical bone and trabecular bone, and different between tibia and femur. Growing rats may be a glucocorticoid-induced osteoporosis animal model when evaluated the effects of drugs upon juvenile patients exposed to GC for a long time. PMID:25086673

  4. Glucocorticoid receptor knockdown and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Hooijdonk, Leonarda Wilhelmina Antonia van

    2010-01-01

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

  5. Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes.

    Science.gov (United States)

    Wu, I; Shin, S C; Cao, Y; Bender, I K; Jafari, N; Feng, G; Lin, S; Cidlowski, J A; Schleimer, R P; Lu, N Z

    2013-01-01

    Induction of T-cell apoptosis contributes to the anti-inflammatory and antineoplastic benefits of glucocorticoids. The glucocorticoid receptor (GR) translational isoforms have distinct proapoptotic activities in osteosarcoma cells. Here we determined whether GR isoforms selectively induce apoptosis in Jurkat T lymphoblastic leukemia cells. Jurkat cells stably expressing individual GR isoforms were generated and treated with vehicle or dexamethasone (DEX). DEX induced apoptosis in cells expressing the GR-A, -B, or -C, but not the GR-D, isoform. cDNA microarray analyses of cells sensitive (GR-C3) and insensitive (GR-D3) to DEX revealed glucocorticoid-induced proapoptotic transcriptomes. Genes that were regulated by the proapoptotic GR-C3, but not by the GR-D3, isoform likely contributed to glucocorticoid-induced apoptosis. The identified genes include those that are directly involved in apoptosis and those that facilitate cell killing. Chromatin immunoprecipitation assays demonstrated that distinct chromatin modification abilities may underlie the distinct functions of GR isoforms. Interestingly, all GR isoforms, including the GR-D3 isoform, suppressed mitogen-stimulated cytokines. Furthermore, the GR-C isoforms were selectively upregulated in mitogen-activated primary T cells and DEX treatment induced GR-C target genes in activated T cells. Cell-specific expressions and functions of GR isoforms may help to explain the tissue- and individual-selective actions of glucocorticoids and may provide a basis for developing improved glucocorticoids. PMID:23303127

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

    Institute of Scientific and Technical Information of China (English)

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

    2010-01-01

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

  7. CB1 receptor mediates the effects of glucocorticoids on AMPK activity in the hypothalamus.

    Science.gov (United States)

    Scerif, Miski; Füzesi, Tamás; Thomas, Julia D; Kola, Blerina; Grossman, Ashley B; Fekete, Csaba; Korbonits, Márta

    2013-10-01

    AMP-activated protein kinase (AMPK), a regulator of cellular and systemic energy homeostasis, can be influenced by several hormones. Tissue-specific alteration of AMPK activity by glucocorticoids may explain the increase in appetite, the accumulation of lipids in adipose tissues, and the detrimental cardiac effects of Cushing's syndrome. Endocannabinoids are known to mediate the effects of various hormones and to influence AMPK activity. Cannabinoids have central orexigenic and direct peripheral metabolic effects via the cannabinoid receptor type 1 (CB1). In our preliminary experiments, WT mice received implants of a corticosterone-containing pellet to establish a mouse model of Cushing's syndrome. Subsequently, WT and Cb1 (Cnr1)-knockout (CB1-KO) littermates were treated with corticosterone and AMPK activity in the hypothalamus, various adipose tissues, liver and cardiac tissue was measured. Corticosterone-treated CB1-KO mice showed a lack of weight gain and of increase in hypothalamic and hepatic AMPK activity. In adipose tissues, baseline AMPK activity was higher in CB1-KO mice, but a glucocorticoid-induced drop was observed, similar to that observed in WT mice. Cardiac AMPK levels were reduced in CB1-KO mice, but while WT mice showed significantly reduced AMPK activity following glucocorticoid treatment, CB1-KO mice showed a paradoxical increase. Our findings indicate the importance of the CB1 receptor in the central orexigenic effect of glucocorticoid-induced activation of hypothalamic AMPK activity. In the periphery adipose tissues, changes may occur independently of the CB1 receptor, but the receptor appears to alter the responsiveness of the liver and myocardial tissues to glucocorticoids. In conclusion, our data suggest that an intact cannabinoid pathway is required for the full metabolic effects of chronic glucocorticoid excess.

  8. VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Jesse M Damsker

    Full Text Available Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.

  9. VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice.

    Science.gov (United States)

    Damsker, Jesse M; Dillingham, Blythe C; Rose, Mary C; Balsley, Molly A; Heier, Christopher R; Watson, Alan M; Stemmy, Erik J; Jurjus, Roslyn A; Huynh, Tony; Tatem, Kathleen; Uaesoontrachoon, Kitipong; Berry, Dana M; Benton, Angela S; Freishtat, Robert J; Hoffman, Eric P; McCall, John M; Gordish-Dressman, Heather; Constant, Stephanie L; Reeves, Erica K M; Nagaraju, Kanneboyina

    2013-01-01

    Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases. PMID:23667681

  10. Glucocorticoid augmentation of prolonged exposure therapy: rationale and case report

    Directory of Open Access Journals (Sweden)

    Laura Pratchett

    2010-12-01

    Full Text Available Rationale: Prolonged exposure (PE therapy has been found to reduce symptoms of posttraumatic stress disorder (PTSD; however, it is difficult for many patients to engage fully in the obligatory retelling of their traumatic experiences. This problem is compounded by the fact that habituation and cognitive restructuring – the main mechanisms through which PE is hypothesized to work – are not instantaneous processes, and often require several weeks before the distress associated with imaginal exposure abates. Case reports: Two cases are described that respectively illustrate the use of hydrocortisone and placebo, in combination with PE, for the treatment of combat-related PTSD. Based on known effects of glucocorticoids on learning and memory performance, we hypothesized that augmentation with hydrocortisone would improve the therapeutic effects of PE by hastening “new” learning and facilitating decreases in the emotional impact of fear memories during the course of treatment. The veteran receiving hydrocortisone augmentation of PE displayed an accelerated and ultimately greater decline in PTSD symptoms than the veteran receiving placebo. Conclusions: While no general conclusion can be derived from comparison of two patients, the findings are consistent with the rationale for augmentation. These case reports support the potential for an appropriately designed and powered clinical trial to examine the efficacy of glucocorticoids in augmenting the effects of psychotherapy for PTSD.

  11. X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

    Science.gov (United States)

    Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

    2015-06-01

    X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Stress, Glucocorticoid Hormones and Hippocampal Neural Progenitor Cells: Implications to Mood Disorders

    Directory of Open Access Journals (Sweden)

    Tomoshige eKino

    2015-08-01

    Full Text Available The hypothalamic-pituitary-adrenal (HPA axis and its end-effectors glucocorticoid hormones play central roles in the adaptive response to numerous stressors that can be either internal or external. Thus, this system has a strong impact on the brain hippocampus and its major functions, such as cognition, memory as well as behavior and mood. The hippocampal area of the adult brain contains neural stem cells or more committed neural progenitor cells, which retain throughout the human life the ability of self-renewal and to differentiate into multiple neural cell lineages, such as neurons, astrocytes and oligodendrocytes. Importantly, these characteristic cells contribute significantly to the above-indicated functions of the hippocampus, while various stressors and glucocorticoids influence proliferation, differentiation and fate of these cells. This review offers an overview of the current understanding on the interactions between the HPA axis/glucocorticoid stress-responsive system and hippocampal neural progenitor cells by focusing on the actions of glucocorticoids. Also addressed is a further discussion on the implications of such interactions to the pathophysiology of mood disorders.

  14. Concanavalin a increases beta-adrenergic and glucocorticoid receptors in porcine splenocytes

    International Nuclear Information System (INIS)

    We identified specific glucocorticoid and beta-adrenergic receptors on porcine splenocytes. There are 2000 to 4000 glucocorticoid receptors per cell with a K /SUB D/ of 2 to 4 nM and 1000 beta-adrenergic receptors with a K /SUB D/ of 0.3 to 0.6 nM. When splenocytes were incubated with concanavalin A (Con A), there was an approximate 2-fold increase in both gluococorticoid and beta-adrenergic receptors with no change in binding affinity. Incubation of splenocytes with cortisol as low as 40 nM (13 ng/ml) inhibited proliferation in response to Con A. This inhibitory effect of cortisol was not due to cytotoxic effects of glucocorticoids. At maximal physiologic concentrations (400 nM; 135 ng/ml), cortisol caused reductions in Con A activation of thymocytes and peripheral blood mononuclear cells. When eight wk old pigs were restrained, there was an increase in plasma cortisol, atrophy of thymus and reduction in skin test responses to phytohemagglutinin. On the basis of the data, we suggest that physiologic concentrations of stress asociated hormones affect functional activities of porcine lymphoid cells. Since activated splenocytes display increased numbers of receptors for these hormones, perhaps glucocorticoids or catecholamines normally function in vivo to suppress clonal expansion of antigen activated and autoreactive T lymphocytes

  15. Selective modulation through the glucocorticoid receptor ameliorates muscle pathology in mdx mice.

    Science.gov (United States)

    Huynh, Tony; Uaesoontrachoon, Kitipong; Quinn, James L; Tatem, Kathleen S; Heier, Christopher R; Van Der Meulen, Jack H; Yu, Qing; Harris, Mark; Nolan, Christopher J; Haegeman, Guy; Grounds, Miranda D; Nagaraju, Kanneboyina

    2013-10-01

    The over-expression of NF-κB signalling in both muscle and immune cells contribute to the pathology in dystrophic muscle. The anti-inflammatory properties of glucocorticoids, mediated predominantly through monomeric glucocorticoid receptor inhibition of transcription factors such as NF-κB (transrepression), are postulated to be an important mechanism for their beneficial effects in Duchenne muscular dystrophy. Chronic glucocorticoid therapy is associated with adverse effects on metabolism, growth, bone mineral density and the maintenance of muscle mass. These detrimental effects result from direct glucocorticoid receptor homodimer interactions with glucocorticoid response elements of the relevant genes. Compound A, a non-steroidal selective glucocorticoid receptor modulator, is capable of transrepression without transactivation. We confirm the in vitro NF-κB inhibitory activity of compound A in H-2K(b) -tsA58 mdx myoblasts and myotubes, and demonstrate improvements in disease phenotype of dystrophin deficient mdx mice. Compound A treatment in mdx mice from 18 days of post-natal age to 8 weeks of age increased the absolute and normalized forelimb and hindlimb grip strength, attenuated cathepsin-B enzyme activity (a surrogate marker for inflammation) in forelimb and hindlimb muscles, decreased serum creatine kinase levels and reduced IL-6, CCL2, IFNγ, TNF and IL-12p70 cytokine levels in gastrocnemius (GA) muscles. Compared with compound A, treatment with prednisolone, a classical glucocorticoid, in both wild-type and mdx mice was associated with reduced body weight, reduced GA, tibialis anterior and extensor digitorum longus muscle mass and shorter tibial lengths. Prednisolone increased osteopontin (Spp1) gene expression and osteopontin protein levels in the GA muscles of mdx mice and had less favourable effects on the expression of Foxo1, Foxo3, Fbxo32, Trim63, Mstn and Igf1 in GA muscles, as well as hepatic Igf1 in wild-type mice. In conclusion, selective

  16. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    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 for 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.

  17. Autophagy in the immune response to tuberculosis: clinical perspectives.

    LENUS (Irish Health Repository)

    Ní Cheallaigh, C

    2011-06-01

    A growing body of evidence points to autophagy as an essential component in the immune response to tuberculosis. Autophagy is a direct mechanism of killing intracellular Mycobacterium tuberculosis and also acts as a modulator of proinflammatory cytokine secretion. In addition, autophagy plays a key role in antigen processing and presentation. Autophagy is modulated by cytokines; it is stimulated by T helper type 1 (Th1) cytokines such as tumour necrosis factor (TNF)-α and interferon (IFN)-γ, and is inhibited by the Th2 cytokines interleukin (IL)-4 and IL-13 and the anti-inflammatory cytokine IL-10. Vitamin D, via cathelicidin, can also induce autophagy, as can Toll-like receptor (TLR)-mediated signals. Autophagy-promoting agents, administered either locally to the lungs or systemically, could have a clinical application as adjunctive treatment of drug-resistant and drug-sensitive tuberculosis. Moreover, vaccines which effectively induce autophagy could be more successful in preventing acquisition or reactivation of latent tuberculosis.

  18. The efficacy of statins in preventing glucocorticoid-related osteonecrosis in animal models

    Science.gov (United States)

    Yang, Z.; Liu, H.; Li, D.; Xie, X.; Qin, T.; Ma, J.

    2016-01-01

    Objectives The primary purpose of this meta-analysis was to determine whether statin usage could reduce the risk of glucocorticoid-related osteonecrosis in animal models. Methods A systematic literature search up to May 2015 was carried out using the PubMed, Ovid, EBM reviews, ISI Web of Science, EBSCO, CBM, CNKI databases with the term and boolean operators: statins and osteonecrosis in all fields. Risk ratio (RR), as the risk estimate of specific outcome, was calculated along with 95% confidence intervals (CI). The methodological quality of individual studies was assessed using a quantitative tool based on the updated Stroke Therapy Academic Industry Roundtable (STAIR) recommendations. Results A total of 11 eligible studies were included according to predetermined criteria. The pooled data demonstrated that animals with statin usage, either alone or combined with other treatments, were at a decreased risk of developing glucocorticoid-related osteonecrosis (RR = 2.06, 95% confidence interval (CI) 1.71 to 2.50). Moreover, subgroup analysis revealed that compared with statins alone, statins combined with other treatments significantly decreased the risk of osteonecrosis (RR = 1.23, 95% CI 1.02 to 1.47). However, we could find no significant risk difference for different gender, or for different time points. Conclusions The present study suggests that statins combined with other treatments are efficient in preventing the development of glucocorticoid-related osteonecrosis in animals. These results might shed light on clinical practice when glucocorticoids are prescribed, and could be further investigated in high-quality clinical trials. Cite this article: Z. Yang, H. Liu, D. Li, X. Xie, T. Qin, J. Ma, P. Kang. The efficacy of statins in preventing glucocorticoid-related osteonecrosis in animal models: A meta-analysis. Bone Joint Res 2016;5:393–402. DOI: 10.1302/2046-3758.59.2000500. PMID:27660333

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

    Science.gov (United States)

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

    1992-01-01

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

  20. A combined clinical and biomarker approach to predict diuretic response in acute heart failure

    NARCIS (Netherlands)

    Ter Maaten, Jozine M; Valente, Mattia A E; Metra, Marco; Bruno, Noemi; O'Connor, Christopher M; Ponikowski, Piotr; Teerlink, John R; Cotter, Gad; Davison, Beth; Cleland, John G; Givertz, Michael M; Bloomfield, Daniel M; Dittrich, Howard C; van Veldhuisen, Dirk J; Hillege, Hans L; Damman, Kevin; Voors, Adriaan A

    2015-01-01

    BACKGROUND: Poor diuretic response in acute heart failure is related to poor clinical outcome. The underlying mechanisms and pathophysiology behind diuretic resistance are incompletely understood. We evaluated a combined approach using clinical characteristics and biomarkers to predict diuretic resp

  1. Educational climate seems unrelated to leadership skills of clinical consultants responsible of postgraduate medical education in clinical departments

    DEFF Research Database (Denmark)

    Malling, Bente Vigh; Mortensen, Lene Sundahl; Scherpbier, Albert J J;

    2010-01-01

    The educational climate is crucial in postgraduate medical education. Although leaders are in the position to influence the educational climate, the relationship between leadership skills and educational climate is unknown. This study investigates the relationship between the educational climate...... in clinical departments and the leadership skills of clinical consultants responsible for education....

  2. Stress and glucocorticoids impair memory retrieval via β2-adrenergic, Gi/o-coupled suppression of cAMP signaling.

    Science.gov (United States)

    Schutsky, Keith; Ouyang, Ming; Castelino, Christina B; Zhang, Lei; Thomas, Steven A

    2011-10-01

    Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating β(1)-adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, β(1), and cAMP signaling is transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs before testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of β(2) (but not β(1))-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and β(2) agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by G(i/o)-coupled receptors. In hippocampal slices, β(2) signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by β(1) signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic β(2) agonists or glucocorticoids. These results demonstrate that the β(2) receptor can be a critical effector of acute stress, and that β(1) and β(2) receptors can have quite distinct roles in CNS signaling and cognition.

  3. Glucocorticoid-like effects of antihepatocarcinogen Rotenone are mediated via enhanced serum corticosterone levels: Molecular Fitting and Receptor Activation Studies

    Directory of Open Access Journals (Sweden)

    Youssef Jihan

    2003-02-01

    diminished similarity with a value of 1 or higher excluding any such similarities. Results Although the stimulatory effect exerted by rotenone on hepatocellular apoptosis was in the opposite direction of that produced by the glucocorticoid antagonist RU 486, data suggested that rotenone does not directly activate the glucocorticoid receptor. Molecular fitting of rotenone to glucocorticoid receptor agonists and antagonists as well as examination of the transcriptional activation of a glucocorticoid-responsive reporter gene (Mouse MammaryTumorVirus in response to rotenone indicated that it is highly unlikely that rotenone interacts directly with the glucocorticoid receptor. However, feeding male B6C3F1 mice a diet containing rotenone (600 ppm for 7 days resulted in a 3-fold increase in serum levels of corticosterone relative to control animals. Corticosterone is the major glucocorticoid in rodents. Conclusion Rotenone does not interact directly with the glucocorticoid receptor. Elevation of serum corticosterone levels in response to rotenone may explain the glucocorticoid-like effects of this compound, and may play a role in its anti-hepatocarcinogenic effect.

  4. A Role for Glucocorticoids in Stress-Impaired Reproduction: Beyond the Hypothalamus and Pituitary

    OpenAIRE

    Whirledge, Shannon; Cidlowski, John A.

    2013-01-01

    In addition to the well-characterized role of the sex steroid receptors in regulating fertility and reproduction, reproductive events are also mediated by the hypothalamic-pituitary-adrenal axis in response to an individual's environment. Glucocorticoid secretion in response to stress contributes to the well-characterized suppression of the hypothalamic-pituitary-gonadal axis through central actions in the hypothalamus and pituitary. However, both animal and in vitro studies indicate that oth...

  5. Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy

    Directory of Open Access Journals (Sweden)

    Baiula M

    2014-06-01

    Full Text Available Monica Baiula,1 Andrea Bedini,1 Jacopo Baldi,1 Megan E Cavet,2 Paolo Govoni,3 Santi Spampinato11Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy; 2Global Pharmaceutical R&D, Bausch & Lomb Inc., Rochester, NY, USA; 3Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, ItalyBackground: Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6–10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines.Methods: In this study, mapracorat was administered into the conjunctival sac of ovalbumin (OVA-sensitized guinea pigs 2 hours after the induction of allergic conjunctivitis, with the aim of investigating its activity in reducing clinical signs of the late-phase ocular reaction and to determine its mechanism of anti-allergic effects with respect to apoptosis of conjunctival eosinophils and expression of the chemokines C-C motif ligand 5 (CCL5, C-C motif ligand 11 (CCL11, and interleukin-8 (IL-8 and the proinflammatory cytokines interleukin-1β (IL-1β and tumor necrosis factor-α (TNF

  6. Evaluating dose response from flexible dose clinical trials

    Directory of Open Access Journals (Sweden)

    Baron David

    2008-01-01

    Full Text Available Abstract Background The true dose effect in flexible-dose clinical trials may be obscured and even reversed because dose and outcome are related. Methods To evaluate dose effect in response on primary efficacy scales from 2 randomized, double-blind, flexible-dose trials of patients with bipolar mania who received olanzapine (N = 234, 5–20 mg/day, or patients with schizophrenia who received olanzapine (N = 172, 10–20 mg/day, we used marginal structural models, inverse probability of treatment weighting (MSM, IPTW methodology. Dose profiles for mean changes from baseline were evaluated using weighted MSM with a repeated measures model. To adjust for selection bias due to non-random dose assignment and dropouts, patient-specific time-dependent weights were determined as products of (i stable weights based on inverse probability of receiving the sequence of dose assignments that was actually received by a patient up to given time multiplied by (ii stable weights based on inverse probability of patient remaining on treatment by that time. Results were compared with those by unweighted analyses. Results While the observed difference in efficacy scores for dose groups for the unweighted analysis strongly favored lower doses, the weighted analyses showed no strong dose effects and, in some cases, reversed the apparent "negative dose effect." Conclusion While naïve comparison of groups by last or modal dose in a flexible-dose trial may result in severely biased efficacy analyses, the MSM with IPTW estimators approach may be a valuable method of removing these biases and evaluating potential dose effect, which may prove useful for planning confirmatory trials.

  7. Educational climate seems unrelated to leadership skills of clinical consultants responsible of postgraduate medical education in clinical departments

    Directory of Open Access Journals (Sweden)

    Scherpbier Albert JJ

    2010-09-01

    Full Text Available Abstract Background The educational climate is crucial in postgraduate medical education. Although leaders are in the position to influence the educational climate, the relationship between leadership skills and educational climate is unknown. This study investigates the relationship between the educational climate in clinical departments and the leadership skills of clinical consultants responsible for education. Methods The study was a trans-sectional correlation study. The educational climate was investigated by a survey among all doctors (specialists and trainees in the departments. Leadership skills of the consultants responsible for education were measured by multi-source feedback scores from heads of departments, peer consultants, and trainees. Results Doctors from 42 clinical departments representing 21 specialties participated. The response rate of the educational climate investigation was moderate 52% (420/811, Response rate was high in the multisource-feedback process 84.3% (420/498. The educational climate was scored quite high mean 3.9 (SD 0.3 on a five-point Likert scale. Likewise the leadership skills of the clinical consultants responsible for education were considered good, mean 5.4 (SD 0.6 on a seven-point Likert scale. There was no significant correlation between the scores concerning the educational climate and the scores on leadership skills, r = 0.17 (p = 0.29. Conclusions This study found no relation between the educational climate and the leadership skills of the clinical consultants responsible for postgraduate medical education in clinical departments with the instruments used. Our results indicate that consultants responsible for education are in a weak position to influence the educational climate in the clinical department. Further studies are needed to explore, how heads of departments and other factors related to the clinical organisation could influence the educational climate.

  8. Ozone Inhalation Provokes Glucocorticoid-Dependent and -Independent Effects on Inflammatory and Metabolic Pathways.

    Science.gov (United States)

    Thomson, Errol M; Pal, Shinjini; Guénette, Josée; Wade, Michael G; Atlas, Ella; Holloway, Alison C; Williams, Andrew; Vincent, Renaud

    2016-07-01

    Growing evidence implicates air pollutants in adverse health effects beyond respiratory and cardiovascular disease, including metabolic impacts (diabetes, metabolic syndrome, obesity) and neurological/neurobehavioral outcomes (neurodegenerative disease, cognitive decline, perceived stress, depression, suicide). We have shown that inhalation of particulate matter or ozone activates the hypothalamic-pituitary-adrenal axis in rats and increases plasma levels of the glucocorticoid corticosterone. To investigate the role of corticosterone in mediating inflammatory and metabolic effects of pollutant exposure, in this study male Fischer-344 rats were administered the 11β-hydroxylase inhibitor metyrapone (0, 50, 150 mg/kg body weight) and exposed by nose-only inhalation for 4 h to air or 0.8 ppm ozone. Ozone inhalation provoked a 2-fold increase in plasma corticosterone, an effect blocked by metyrapone, but did not alter epinephrine levels. Inhibition of corticosterone production was associated with increased inflammatory signaling in the lungs and plasma in response to ozone, consistent with a role for glucocorticoids in limiting local and systemic inflammatory responses. Effects of ozone on insulin and glucagon, but not ghrelin or plasminogen activator inhibitor-1, were modified by metyrapone, revealing glucocorticoid-dependent and -independent effects on circulating metabolic and hemostatic factors. Several immunosuppressive and metabolic impacts of ozone in the lungs, heart, liver, kidney, and spleen were blocked by metyrapone and reproduced through exogenous administration of corticosterone (10 mg/kg body weight), demonstrating glucocorticoid-dependent effects in target tissues. Our results support involvement of endogenous glucocorticoids in ozone-induced inflammatory and metabolic effects, providing insight into potential biological mechanisms underlying health impacts and susceptibility. PMID:27037194

  9. A comparison of techniques to assess skin blanching following the topical application of glucocorticoids.

    Science.gov (United States)

    Noon, J P; Evans, C E; Haynes, W G; Webb, D J; Walker, B R

    1996-05-01

    Glucocorticoid-induced dermal blanching provides a useful research tool to study steroid potency and sensitivity. Conventional measurement of the intensity of blanching relies on subjective assessment by a trained observer using a visual score. Several objective techniques have recently been reported to detect skin blanching, but their sensitivity has not been compared previously with subjective visual recordings. In this report we aimed to establish whether objective methods offer sufficient sensitivity to be employed in epidemiological studies of glucocorticoid responsiveness. In healthy subjects we applied beclomethasone dipropionate at three concentrations (1, 10 and 100 micrograms/ml) under an occluded dressing overnight. The following morning we measured blanching using a visual score, laser Doppler velocimetry with the MBF 3D monitor (Moor Instruments Ltd, U.K.) and a perfusion imager (Lisca, Sweden), and reflectance spectrophotometry with the Dia-Stron 'erythemameter'. Using the visual score, blanching was detected at all concentrations of steroid. Neither laser Doppler instrument detected vasoconstriction at any concentration. By contrast, the reflectance spectrophotometer successfully recorded blanching at 10 and 100 micrograms/ml, but not at 1 microgram/ml. We conclude that laser Doppler instruments, including the novel scanning perfusion imager, do not detect glucocorticoid-induced skin blanching, perhaps because it reflects venular rather than arteriolar vasoconstriction. By contrast, the Dia-Stron reflectance spectrophotometer has sufficient sensitivity to be used as an alternative to visual assessment in epidemiological studies of human glucocorticoid-induced dermal blanching.

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

    Science.gov (United States)

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

    2008-05-01

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

  11. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    Science.gov (United States)

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T; van der Horst, Geertje; Hemmer, Daniëlle M; Marijt, Koen A; Hwang, Ming S; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M; Meijer, Onno C; Culig, Zoran; van der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa. PMID:26483423

  12. Management of glucocorticoids-induced osteoporosis: role of teriparatide

    Directory of Open Access Journals (Sweden)

    Silvia Migliaccio

    2009-04-01

    Full Text Available Silvia Migliaccio1, Marina Brama1, Nazzarena Malavolta21Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Università degli Studi Sapienza di Roma, Italy; 2Dipartimento di Medicina Interna, Policlinico S Orsola Malpighi, Bologna, ItalyAbstract: Glucocorticoids (GC-induced osteoporosis (GIOP is the most common cause of secondary osteoporosis, which leads to an increased fracture risk in patients. The normal bone turnover depends on a balance between osteoblasts and osteoclasts activity and GC can cause a rapid bone loss, decreasing bone formation and increasing bone resorption. The decreased bone formation is mainly due to the GC-induced apoptosis of both osteoblasts and osteocytes, while the increased bone resorption is due to the increased life-span of pre-existing osteoclasts. Bisphosphonates are clearly effective in preventing and treating GIOP but anabolic therapeutic strategies are the new promising therapeutic alternative. Experimental and clinical studies indicate that teriparatide, the active (1–34 parathyroid hormone (PTH molecule, is efficacious for the treatment of GIOP, being able to induce an increase in bone mass in these patients. Intermittent administration of human PTH (1–34 stimulates bone formation by increasing osteoblast number. Additionally, human PTH (1–34 modulates the level and/or activity of locally produced growth factors and cytokines. Teriparatide has been demonstrated in several clinical studies to significantly decrease the incidence of fractures in patients affected by GIOP. It has recently received an indication for GIOP and its label indication has also been expanded.Keywords: glucocorticoids, osteoblasts, osteoclasts, osteoporosis, teriparatide

  13. Surgery as a Double-Edged Sword: A Clinically Feasible Approach to Overcome the Metastasis-Promoting Effects of Surgery by Blunting Stress and Prostaglandin Responses

    Energy Technology Data Exchange (ETDEWEB)

    Benish, Marganit; Ben-Eliyahu, Shamgar, E-mail: shamgar@post.tau.ac.il [Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv 69978 (Israel)

    2010-11-24

    Surgery remains an essential therapeutic approach for most solid malignancies, including breast cancer. However, surgery also constitutes a risk factor for promotion of pre-existing micrometastases and the initiation of new metastases through several mechanisms, including the release of prostaglandins and stress hormones (e.g., catecholamines and glucocorticoids). However, the perioperative period also presents an opportunity for cell mediated immunity (CMI) and other mechanisms to eradicate or control minimal residual disease, provided that the deleterious effects of surgery are minimized. Here, we discuss the key role of endogenous stress hormones and prostaglandins in promoting the metastatic process through their direct impact on malignant cells, and through their deleterious impact on anti-cancer CMI. We further discuss the effects of anesthetic techniques, the extent of surgery, pain alleviation, and timing within the menstrual cycle with respect to their impact on tumor recurrence and physiological stress responses. Last, we suggest an attractive perioperative drug regimen, based on a combination of a cyclooxygenase (COX)-2 inhibitor and a β-adrenergic blocker, which we found effective in attenuating immune suppression and the metastasis-promoting effects of surgery in several tumor models. This regimen is clinically applicable, and could potentially promote disease free survival in patients operated for breast and other types of cancer.

  14. Glucocorticoid-induced osteoporosis in rheumatic diseases

    Directory of Open Access Journals (Sweden)

    Rosa Maria Rodrigues Pereira

    2010-01-01

    Full Text Available The aim of this article is to review rheumatological diseases that are associated with glucocorticoid-induced osteoporosis or fractures and to perform a critical analysis of the current guidelines and treatment regimens. The electronic database MEDLINE was searched using the date range of July 1986 to June 2009 and the following search terms: osteoporosis, bone mineral density, fractures, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, vasculitis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis and juvenile dermatomyositis. Osteopenia and osteoporosis respectively account for 1.4 to 68.7% and 5.0 to 61.9% of adult rheumatological diseases. Among juvenile rheumatological disorders, the frequency of low bone mass ranges from 38.7 to 70%. In general, fracture rates vary from 0 to 25%. Although glucocorticoid-induced osteoporosis has a high rate of prevalence among rheumatic diseases, a relatively low number of patients on continuous glucocorticoid treatment receive adequate diagnostic evaluation or preventive therapy. This deficit in patient care may result from a lack of clear understanding of the attributed risks by the patients and physicians, the high complexity of the treatment guidelines and poor patient compliance.

  15. Glucocorticoid-induced osteoporosis: 2013 update.

    Science.gov (United States)

    Mazzantini, M; Di Munno, O

    2014-01-01

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

  16. Correlation between pretreatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts.

    Science.gov (United States)

    Arany, I; Tyring, S K; Brysk, M M; Stanley, M A; Tomai, M A; Miller, R L; Smith, M H; McDermott, D J; Slade, H B

    2000-07-01

    Imiquimod (IQ) has been successfully used in treatment of genital warts. In clinical settings, patients responded well but wart reduction rates varied. Our aim was to find a correlation between clinical responses and pretreatment (constitutive) levels of genes that might be involved in the molecular action of IQ. Since IQ is a cytokine inducer, we analyzed levels of expression of genes of the JAK/STAT signaling pathway and their inhibitors as well as interferon response factors (IRFs) in pretreatment biopsy specimens from complete responders (99 to 100% wart reduction rate) versus incomplete responders (75 to 92% wart reduction rate) by reverse transcription-PCR. We found that mRNA levels of signal transducer and activator of transcription 1 (STAT1) and IRF1 were higher in complete responders than in incomplete responders. Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment. We hypothesize that high-level expression of STAT1 and IRF1 is advantageous for a better IQ response. The observed differences in constitutive mRNA levels of these genes may be the consequence of alterations in cellular differentiation and/or variable expression of endogenous interferons. Previous in vitro studies showed that keratinocyte differentiation coordinates the balance between positive and negative signals along the JAK/STAT pathway by regulating the IRF1:IRF2 and STAT1:PIAS1 ratios and thus affecting induction of IQ-inducible genes. Specifically, differentiation supports constitutive expression of STAT1 and IRF1 mRNAs but not expression of IRF2 and PIAS1. Our data are in good agreement with studies that showed the importance of STAT1 in cytokine induction and activation of interferon-responsive genes by IQ.

  17. Icariin attenuates glucocorticoid insensitivity mediated by repeated psychosocial stress on an ovalbumin-induced murine model of asthma.

    Science.gov (United States)

    Li, Bei; Duan, Xiaohong; Xu, Changqing; Wu, Jinfeng; Liu, Baojun; Du, Yiji; Luo, Qingli; Jin, Hualiang; Gong, Weiyi; Dong, Jingcheng

    2014-04-01

    Evidence shows that psychosocial stress exacerbates asthma, but there is little intervention to alleviate negative effects of psychosocial stress on asthma. We investigated the role of icariin in anti-inflammation and anti-anxiety potential in a murine model combined psychosocial stress with allergic exposure. The results indicated that icariin administered remarkable increased activity in the center of the open field, reversed airway hyperresponsivenesss, reduced inflammatory cytokine infiltration to the lung and whole body and also in part recovered glucocorticoid responsiveness. Furthermore, our data also showed that icariin significantly inhibited increases of corticosterone and markedly increased glucocorticoid receptor mRNA and protein expression in the lungs of mice exposed to both stress and allergen. Collectively, we speculate that inducing glucocorticoid receptor modulation might be the potential mechanisms of icariin to facilitate corticosteroid responsiveness of cytokine production.

  18. Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism

    Science.gov (United States)

    Hassan-Smith, Zaki K; Doig, Craig L; Sherlock, Mark; Stewart, Paul M; Lavery, Gareth G

    2016-01-01

    The adverse metabolic effects of prescribed and endogenous glucocorticoid excess, ‘Cushing’s syndrome’, create a significant health burden. While skeletal muscle atrophy and resultant myopathy is a clinical feature, the molecular mechanisms underpinning these changes are not fully defined. We have characterized the impact of glucocorticoids upon key metabolic pathways and processes regulating muscle size and mass including: protein synthesis, protein degradation, and myoblast proliferation in both murine C2C12 and human primary myotube cultures. Furthermore, we have investigated the role of pre-receptor modulation of glucocorticoid availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these processes. Corticosterone (CORT) decreased myotube area, decreased protein synthesis, and increased protein degradation in murine myotubes. This was supported by decreased mRNA expression of insulin-like growth factor (IGF1), decreased activating phosphorylation of mammalian target of rapamycin (mTOR), decreased phosphorylation of 4E binding protein 1 (4E-BP1), and increased mRNA expression of key atrophy markers including: atrogin-1, forkhead box O3a (FOXO3a), myostatin (MSTN), and muscle-ring finger protein-1 (MuRF1). These findings were endorsed in human primary myotubes, where cortisol also decreased protein synthesis and increased protein degradation. The effects of 11-dehydrocorticosterone (11DHC) (in murine myotubes) and cortisone (in human myotubes) on protein metabolism were indistinguishable from that of CORT/cortisol treatments. Selective 11β-HSD1 inhibition blocked the decrease in protein synthesis, increase in protein degradation, and reduction in myotube area induced by 11DHC/cortisone. Furthermore, CORT/cortisol, but not 11DHC/cortisone, decreased murine and human myoblast proliferative capacity. Glucocorticoids are potent regulators of skeletal muscle protein homeostasis and myoblast proliferation. Our data underscores the potential use

  19. Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism.

    Science.gov (United States)

    Morgan, Stuart A; Hassan-Smith, Zaki K; Doig, Craig L; Sherlock, Mark; Stewart, Paul M; Lavery, Gareth G

    2016-06-01

    The adverse metabolic effects of prescribed and endogenous glucocorticoid excess, 'Cushing's syndrome', create a significant health burden. While skeletal muscle atrophy and resultant myopathy is a clinical feature, the molecular mechanisms underpinning these changes are not fully defined. We have characterized the impact of glucocorticoids upon key metabolic pathways and processes regulating muscle size and mass including: protein synthesis, protein degradation, and myoblast proliferation in both murine C2C12 and human primary myotube cultures. Furthermore, we have investigated the role of pre-receptor modulation of glucocorticoid availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these processes. Corticosterone (CORT) decreased myotube area, decreased protein synthesis, and increased protein degradation in murine myotubes. This was supported by decreased mRNA expression of insulin-like growth factor (IGF1), decreased activating phosphorylation of mammalian target of rapamycin (mTOR), decreased phosphorylation of 4E binding protein 1 (4E-BP1), and increased mRNA expression of key atrophy markers including: atrogin-1, forkhead box O3a (FOXO3a), myostatin (MSTN), and muscle-ring finger protein-1 (MuRF1). These findings were endorsed in human primary myotubes, where cortisol also decreased protein synthesis and increased protein degradation. The effects of 11-dehydrocorticosterone (11DHC) (in murine myotubes) and cortisone (in human myotubes) on protein metabolism were indistinguishable from that of CORT/cortisol treatments. Selective 11β-HSD1 inhibition blocked the decrease in protein synthesis, increase in protein degradation, and reduction in myotube area induced by 11DHC/cortisone. Furthermore, CORT/cortisol, but not 11DHC/cortisone, decreased murine and human myoblast proliferative capacity. Glucocorticoids are potent regulators of skeletal muscle protein homeostasis and myoblast proliferation. Our data underscores the potential use of

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

    Directory of Open Access Journals (Sweden)

    Metwalley Kotb A

    2012-04-01

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

  1. Use of recombinant feline interferon and glucocorticoid in the treatment of feline infectious peritonitis.

    Science.gov (United States)

    Ishida, T; Shibanai, A; Tanaka, S; Uchida, K; Mochizuki, M

    2004-04-01

    A total of 12 clinically ill cats previously diagnosed as feline infectious peritonitis (FIP) were treated with a combination of recombinant feline interferon and glucocorticoid. A complete remission (over 2 years) and a partial remission (2 to 5 months) were observed in four (33.3%) and four (33.3%) cases, respectively. Those that survived for more than 2 years were all older cats (6 to 16 years old) with the effusive form of FIP.

  2. Identification of the cellular mechanisms undelying the contribution of stress and glucocorticoids to Alzheimer's disease pathology

    OpenAIRE

    Sotiropoulos, Ioannis

    2006-01-01

    Clinical evidence suggests the involvement of stress and glucocorticoids (GC) in the etiopathogenesis of Alzheimer’s disease (AD), a disease marked by severe memory impairments as well as alterations in mood and emotional state. The experiments described in this dissertation represent an attempt to establish the cellular mechanisms through which stress and GC may impact on the development of AD. These studies focused on the hippocampus and prefrontal cortex (PFC), brain areas that are severel...

  3. Stress-Induced Sex Differences: Adaptations Mediated by the Glucocorticoid Receptor

    OpenAIRE

    Bourke, Chase H.; Harrell, Constance S.; Neigh, Gretchen N

    2012-01-01

    Clinical evidence has indicated that women are more susceptible to stress-related and autoimmune disorders than men. Although females may be more susceptible to some disease states, males do not escape unscathed and are more susceptible to metabolic dysfunction. The hypothalamic-pituitary-axis plays a pivotal role in the sexually dimorphic effects of chronic stress through alterations in negative feedback. Recent evidence has implicated the glucocorticoid receptor and its co-chaperones in the...

  4. Glucocorticoid use in acute lymphoblastic leukemia: comparison of prednisone and dexamethasone

    OpenAIRE

    Inaba, Hiroto; Pui, Ching-Hon

    2010-01-01

    Glucocorticoids (prednisone and dexamethasone) play an essential role in the treatment of acute lymphoblastic leukemia (ALL) but their optimal doses and bioequivalence have not been established. Pre-clinical studies showed that dexamethasone has a longer half-life and better central nervous system (CNS) penetration. In prospective randomized trials, dexamethasone yielded better control of CNS leukemia. At a prednisone (mg)/dexamethasone (mg) dose ratio less than 7, dexamethasone treatment (6–...

  5. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

    OpenAIRE

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han; Duan, Qiming; Sabeh, Mohamad; Prosdocimo, Domenick A.; Lemieux, Madeleine E.; Nordsborg, Nikolai; Russell, Aaron P; MacRae, Calum A.; Gerber, Anthony N.; Jain, Mukesh K.; Haldar, Saptarsi M.

    2015-01-01

    Classic physiological studies have documented the endurance-promoting effects of glucocorticoid (GC) hormones on skeletal muscle. Pharmacologic GC therapy also improves muscle function in patients with Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. Despite these well-established physiological and clinical observations, the molecular basis underlying the beneficial effects of GCs in skeletal muscle remains obscure. This study shows that physiological effects of GCs on mus...

  6. Glucocorticoids in juvenile idiopathic arthritis.

    Science.gov (United States)

    Malattia, Clara; Martini, Alberto

    2014-05-01

    Although the use of corticosteroids in juvenile idiopathic arthritis (JIA) is now much more limited owing to the availability of methotrexate and biological agents, there are clinical scenarios where it is still indicated. For example, corticosteroids may be indicated for intraarticular injections to prevent joint deformities, as a "bridge" drug to relieve symptoms in polyarticular disease while waiting for methotrexate and biologics to exert their full therapeutic effects, and in the treatment of chronic iridocyclitis, macrophage activation syndrome, and systemic JIA, although the advent of interleukin (IL)-1 and IL-6 blockers has greatly reduced the latter indication.

  7. The Progestin-Only Contraceptive Medroxyprogesterone Acetate, but Not Norethisterone Acetate, Enhances HIV-1 Vpr-Mediated Apoptosis in Human CD4+ T Cells through the Glucocorticoid Receptor

    OpenAIRE

    Michele Tomasicchio; Chanel Avenant; Andrea Du Toit; Ray, Roslyn M.; Hapgood, Janet P.

    2013-01-01

    The glucocorticoid receptor (GR) regulates several physiological functions, including immune function and apoptosis. The HIV-1 virus accessory protein, viral protein R (Vpr), can modulate the transcriptional response of the GR. Glucocorticoids (GCs) and Vpr have been reported to induce apoptosis in various cells, including T-cells. We have previously shown that the injectable contraceptive, medroxyprogesterone acetate (MPA) is a partial to full agonist for the GR, unlike norethisterone acetat...

  8. Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study

    DEFF Research Database (Denmark)

    Hetland, M.L.; Stengaard-Pedersen, K.; Junker, P.;

    2008-01-01

    OBJECTIVE: To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular c......OBJECTIVE: To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra...

  9. The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia

    Science.gov (United States)

    Ploner, C; Rainer, J; Niederegger, H; Eduardoff, M; Villunger, A; Geley, S; Kofler, R

    2016-01-01

    Glucocorticoid (GC)-induced apoptosis is essential in the treatment of acute lymphoblastic leukemia (ALL) and related malignancies. Pro- and anti-apoptotic members of the BCL2 family control many forms of apoptotic cell death, but the extent to which this survival ‘rheostat’ is involved in the beneficial effects of GC therapy is not understood. We performed systematic analyses of expression, GC regulation and function of BCL2 molecules in primary ALL lymphoblasts and a corresponding in vitro model. Affymetrix-based expression profiling revealed that the response included regulations of pro-apoptotic and, surprisingly, anti-apoptotic BCL2 family members, and varied among patients, but was dominated by induction of the BH3-only molecules BMF and BCL2L11/Bim and repression of PMAIP1/Noxa. Conditional lentiviral gene overexpression and knock-down by RNA interference in the CCRF-CEM model revealed that induction of Bim, and to a lesser extent that of BMF, was required and sufficient for apoptosis. Although anti-apoptotic BCL2 members were not regulated consistently by GC in the various systems, their overexpression delayed, whereas their knock-down accelerated, GC-induced cell death. Thus, the combined clinical and experimental data suggest that GCs induce both pro- and anti-apoptotic BCL2 family member-dependent pathways, with the outcome depending on cellular context and additional signals feeding into the BCL2 rheostat. PMID:18046449

  10. Inflammation in Parkinson’s disease: Role of glucocorticoids

    Directory of Open Access Journals (Sweden)

    Maria Trinidad eHerrero

    2015-04-01

    Full Text Available Chronic inflammation is a major characteristic feature of Parkinson’s disease (PD. Studies in PDpatients show evidence of augmented levels of potent pro-inflammatory molecules e.g. TNF-α, iNOS,IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergicneurons are particularly vulnerable to activated glia releasing these toxic factors. Recent geneticstudies point to the role of immune system in the etiology of PD, thus in combination withenvironmental factors, both peripheral and CNS-mediated immune responses could play importantroles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are knownto mediate chronic inflammation, the roles of other immune-competent cells are less well understood.Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis.Glucocorticoids released from adrenal glands upon stimulation of HPA axis, in response to either cellinjury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both throughdirect transcriptional action on target genes and by indirectly inhibiting transcriptional activities oftranscriptional factors such as NF-kB, AP-1 or interferon regulatory factors. In PD patients, the HPAaxis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GRfunction in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucialeffect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover,glucocorticoids are also known to regulate human brain vasculature as well as blood brain barrierpermeability, any dysfunction in their actions may influence infiltration of cytotoxic moleculesresulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation ofGR actions is likely important in dopamine neuron degeneration throughestablishment of chronic inflammation.

  11. Antenatal glucocorticoid treatment affects hippocampal development in mice.

    Directory of Open Access Journals (Sweden)

    Cornelle W Noorlander

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

  12. Antenatal glucocorticoid treatment affects hippocampal development in mice.

    Science.gov (United States)

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

    2014-01-01

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

  13. Short-term glucocorticoid administration in patients with protracted and chronic gout arthritis. Part 2 — comparison of different medication forms efficacy

    Directory of Open Access Journals (Sweden)

    A A Fedorova

    2008-01-01

    Full Text Available Objective. To compare efficacy of different glucocorticoid (GC medication forms in protracted and chronic gout arthritis. Material and methods. 59 pts with tophaceous gout (crystal-verified diagnosis and arthritis of three and more joints lasting more than a months in spite of treatment with sufficient doses of nonsteroidal anti-inflammatory drugs were included. Median age of pts was 56 [48;63], median disease duration — 15,2 years [7,4;20], median swollen joint count at the examination — 8 [5; 11]. The patients were randomized into 2 groups. Methylprednisolone (MP 500 mg/day iv during 2 days and placebo im once was administered in one of them, betamethasone (BM 7 mg im once and placebo iv twice — in the other. Results. Number of pts with full resolution of arthritis, recurrent exacerbation, insufficient arthritis resolution or clinically insignificant response was comparable in both groups. More rapid decrease of pain at moving was achieved during the first 2-3 days after GC administration in pts with full resolution of arthritis (p=0,03 in group receiving MP in comparison with BM. At day 14 joint damage measures did not differ between groups. Conclusion. Efficacy of short-term glucocorticoid administration does not depend on mode of administration and GC medication form (methylprednisolone 500 mg/day iv during 2 days or betamethasone 7 mg im once.

  14. Gender differences in the neural response to acupuncture: Clinical implications

    NARCIS (Netherlands)

    Yeo, S.; Rosen, B.; Bosch, M.P.C.; Noort, M.W.M.L. van den; Lim, S.

    2016-01-01

    Objective: To examine gender differences and similarities in the psychophysical and brain responses to acupuncture at GB34, a point that is frequently used to treat motor function issues in Traditional Chinese Medicine. Methods: Functional MRI (fMRI) was used to measure brain activation in response

  15. Educational climate seems unrelated to leadership skills of clinical consultants responsible of postgraduate medical education in clinical departments

    OpenAIRE

    Scherpbier Albert JJ; Mortensen Lene S; Malling Bente; Ringsted Charlotte

    2010-01-01

    Abstract Background The educational climate is crucial in postgraduate medical education. Although leaders are in the position to influence the educational climate, the relationship between leadership skills and educational climate is unknown. This study investigates the relationship between the educational climate in clinical departments and the leadership skills of clinical consultants responsible for education. Methods The study was a trans-sectional correlation study. The educational clim...

  16. Timing is critical for effective glucocorticoid receptor mediated repression of the cAMP-induced CRH gene.

    Directory of Open Access Journals (Sweden)

    Siem van der Laan

    Full Text Available Glucocorticoid negative feedback of the hypothalamus-pituitary-adrenal axis is mediated in part by direct repression of gene transcription in glucocorticoid receptor (GR expressing cells. We have investigated the cross talk between the two main signaling pathways involved in activation and repression of corticotrophin releasing hormone (CRH mRNA expression: cyclic AMP (cAMP and GR. We report that in the At-T20 cell-line the glucocorticoid-mediated repression of the cAMP-induced human CRH proximal promoter activity depends on the relative timing of activation of both signaling pathways. Activation of the GR prior to or in conjunction with cAMP signaling results in an effective repression of the cAMP-induced transcription of the CRH gene. In contrast, activation of the GR 10 minutes after onset of cAMP treatment, results in a significant loss of GR-mediated repression. In addition, translocation of ligand-activated GR to the nucleus was found as early as 10 minutes after glucocorticoid treatment. Interestingly, while both signaling cascades counteract each other on the CRH proximal promoter, they synergize on a synthetic promoter containing 'positive' response elements. Since the order of activation of both signaling pathways may vary considerably in vivo, we conclude that a critical time-window exists for effective repression of the CRH gene by glucocorticoids.

  17. Traumatic Reticuloperitonitis in Water Buffalo (Bubalus bubalis): Clinical Findings and the Associated Inflammatory Response

    OpenAIRE

    Maged El-Ashker; Mohamed Salama; Mohamed El-Boshy

    2013-01-01

    The present study was carried out to describe the clinical picture of traumatic reticuloperitonitis (TRP) in water buffalo (Bubalus bubalis) and to evaluate the inflammatory and immunologic responses for this clinical condition. Twenty-two buffalo with acute local TRP were monitored in our study. Additionally, 10 clinically healthy buffalo were randomly selected and served as controls. Acute local TRP was initially diagnosed by clinical examination and confirmed by ultrasonographic (USG) exam...

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

    NARCIS (Netherlands)

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

    2005-01-01

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

  19. Modulatory effects of unsaturated fatty acids on the binding of glucocorticoids to rat liver glucocorticoid receptors.

    Science.gov (United States)

    Vallette, G; Vanet, A; Sumida, C; Nunez, E A

    1991-09-01

    Binding of the synthetic glucocorticoid dexamethasone to the rat liver cytosol glucocorticoid receptor was inhibited by physiological concentrations of nonesterified fatty acids as a function of increasing dose, degree of unsaturation, and chain length of the fatty acid. Polyunsaturated fatty acids were the most potent inhibitors. Scatchard analysis and Line-weaver-Burk plots of the binding data revealed that both the association constants and number of binding sites decreased and that polyunsaturated fatty acids inhibition was of a mixed non-competitive type. The dissociation rate constant of [3H]dexamethasone from glucocorticoid receptors was increased by up to 10 times in the presence of docosahexaenoic acid, whereas a competitive inhibitor like the glucocorticoid antagonist RU 38486 had no effect. Moreover, sucrose density gradient analysis showed that docosahexaenoic acid inhibited the binding of [3H] dexamethasone to both the 8.8S and 4S forms. The results strongly suggest that unsaturated fatty acids are interacting at a site on the receptor different from the hormone binding site and the heat shock protein and that by binding to a second site unsaturated fatty acids greatly change the conformation of the hormone binding site to reduce its affinity for the hormone, either partially or completely depending on the concentration and the class of the fatty acid. PMID:1874175

  20. The therapeutic effect of clinical trials: understanding placebo response rates in clinical trials – A secondary analysis

    Directory of Open Access Journals (Sweden)

    Walach Harald

    2005-08-01

    Full Text Available Abstract Background and purpose Placebo response rates in clinical trials vary considerably and are observed frequently. For new drugs it can be difficult to prove effectiveness superior to placebo. It is unclear what contributes to improvement in the placebo groups. We wanted to clarify, what elements of clinical trials determine placebo variability. Methods We analysed a representative sample of 141 published long-term trials (randomized, double-blind, placebo-controlled; duration > 12 weeks to find out what study characteristics predict placebo response rates in various diseases. Correlational and regression analyses with study characteristics and placebo response rates were carried out. Results We found a high and significant correlation between placebo and treatment response rate across diseases (r = .78; p Conclusion Medication response rates and placebo response rates in clinical trials are highly correlated. Trial characteristics can explain some portion of the variance in placebo healing rates in RCTs. Placebo response in trials is only partially due to methodological artefacts and only partially dependent on the diagnoses treated.

  1. Glucocorticoids facilitate the transcription from the human cytomegalovirus major immediate early promoter in glucocorticoid receptor- and nuclear factor-I-like protein-dependent manner

    Energy Technology Data Exchange (ETDEWEB)

    Inoue-Toyoda, Maki [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Kato, Kohsuke [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Nagata, Kyosuke, E-mail: knagata@md.tsukuba.ac.jp [University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Yoshikawa, Hiroyuki [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan)

    2015-02-27

    Human cytomegalovirus (HCMV) is a common and usually asymptomatic virus agent in healthy individuals. Initiation of HCMV productive infection depends on expression of the major immediate early (MIE) genes. The transcription of HCMV MIE genes is regulated by a diverse set of transcription factors. It was previously reported that productive HCMV infection is triggered probably by elevation of the plasma hydroxycorticoid level. However, it is poorly understood whether the transcription of MIE genes is directly regulated by glucocorticoid. Here, we found that the dexamethasone (DEX), a synthetic glucocorticoid, facilitates the transcription of HCMV MIE genes through the MIE promoter and enhancer in a glucocorticoid receptor (GR)-dependent manner. By competitive EMSA and reporter assays, we revealed that an NF-I like protein is involved in DEX-mediated transcriptional activation of the MIE promoter. Thus, this study supports a notion that the increased level of hydroxycorticoid in the third trimester of pregnancy reactivates HCMV virus production from the latent state. - Highlights: • DEX facilitates the transcription from the HCMV MIE promoter. • GR is involved in DEX-dependent transcription from the HCMV MIE promoter. • A 17 bp repeat is responsible for the HCMV MIE promoter activation by DEX. • An NF-I-like protein is involved in the HCMV MIE promoter activation by DEX.

  2. Glucocorticoid exerts its non-genomic effect on IPSC by activation of a phospholipase C-dependent pathway in prefrontal cortex of rats.

    Science.gov (United States)

    Teng, Zenghui; Zhang, Mingyue; Zhao, Minggao; Zhang, Weiqi

    2013-07-01

    In response to stressor, the brain activates a comprehensive stress system. Among others, this stress system causes release of glucocorticoids that also feed back to the brain. Glucocorticoids affect brain function by activation of both delayed, genomic and rapid, non-genomic mechanisms in rodents. Here we report that application of the potent glucocorticoid receptor agonist dexamethasone (DEX) caused a rapid increase of spontaneous and miniature inhibitory postsynaptic currents (IPSCs) and elicited intermittent burst activities through a non-genomic pathway, involving membrane-located receptors. The onset of the rapid effect in prefrontal cortex (PFC, hippocampus (glucocorticoids could rapidly enhance IPSCs and evoke burst activities by activation of at least two different signalling pathways in hippocampus and PFC of rats.

  3. Lipopolysaccharide induces intestinal glucocorticoid synthesis in a TNFalpha-dependent manner

    OpenAIRE

    Noti, Mario; Corazza, Nadia; Tuffin, Gèrald; Schoonjans, Kristina; Brunner, Thomas

    2010-01-01

    Stringent control of immune responses in the intestinal mucosa is critical for the maintenance of immune homeostasis and prevention of tissue damage, such as observed during inflammatory bowel disease. Intestinal epithelial cells, primarily thought to form a simple physical barrier, critically regulate intestinal immune cell functions by producing immunoregulatory glucocorticoids on T-cell activation. In this study we investigated whether stimulation of cells of the innate immune system resul...

  4. Paradoxical Benefits of Psychological Stress in Inflammatory Dermatoses Models Are Glucocorticoid Mediated

    OpenAIRE

    Lin, Tzu-Kai; Man, Mao-Qiang; Santiago, Juan-Luis; Scharschmidt, Tiffany C.; Hupe, Melanie; Martin-Ezquerra, Gemma; Youm, Jong-Kyung; Zhai, Yongjiao; Trullas, Carles; Feingold, Kenneth R.; Elias, Peter M.

    2014-01-01

    Acute psychological stress (PS) mobilizes metabolic responses that are of immediate benefit to the host, but the current medical paradigm holds that PS exacerbates systemic and cutaneous inflammatory disorders. Although the adverse consequences of PS are usually attributed to neuroimmune mechanisms, PS also stimulates an increase in endogenous glucocorticoids (GCs) that compromises permeability barrier homeostasis, stratum corneum cohesion, wound healing, and epidermal innate immunity in norm...

  5. Glucocorticoid receptor overexpression in forebrain: A mouse model of increased emotional lability

    OpenAIRE

    Wei, Qiang (Ethan); Lu, Xin-Yun; Liu, Li; Schafer, Gwen; Shieh, Kun-Ruey; Burke, Sharon; Robinson, Terry E; Watson, Stanley J.; Seasholtz, Audrey F.; Akil, Huda

    2004-01-01

    The molecular mechanisms that control the range and stability of emotions are unknown, yet this knowledge is critical for understanding mood disorders, especially bipolar illness. Here, we show that the glucocorticoid receptor (GR) modulates these features of emotional responsiveness. We generated transgenic mice overexpressing GR specifically in forebrain. These mice display a significant increase in anxiety-like and depressant-like behaviors relative to wild type. Yet, they are also superse...

  6. Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.

    Directory of Open Access Journals (Sweden)

    Kate Kosmac

    2013-03-01

    Full Text Available Infection of the developing fetus with human cytomegalovirus (HCMV is a major cause of central nervous system disease in infants and children; however, mechanism(s of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.

  7. Functional Role of Glycogen synthase Kinase-3β on Glucocorticoid-mediated signaling

    OpenAIRE

    Rubio Patiño, Camila

    2012-01-01

    Glucocorticoids (GC) induce cell cycle arrest and apoptosis in different cell types and therefore are widely used to treat a variety of diseases including autoimmune disorders and cancer. This effect is mediated by the GC receptor (GR), a ligandactivated transcription factor that translocates into the nucleus where it modulates transcription of target genes in a promoter-specific manner. Glycogen synthase kinase-3 (GSK3) regulates GR response by genomic and nongenomic mechanisms, although the...

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

    Science.gov (United States)

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

    2015-01-15

    Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients. PMID:25499819

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

    Directory of Open Access Journals (Sweden)

    Wen-biao ZHAO

    2014-10-01

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

  10. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.

    Science.gov (United States)

    Gao, Hui; Korn, Joshua M; Ferretti, Stéphane; Monahan, John E; Wang, Youzhen; Singh, Mallika; Zhang, Chao; Schnell, Christian; Yang, Guizhi; Zhang, Yun; Balbin, O Alejandro; Barbe, Stéphanie; Cai, Hongbo; Casey, Fergal; Chatterjee, Susmita; Chiang, Derek Y; Chuai, Shannon; Cogan, Shawn M; Collins, Scott D; Dammassa, Ernesta; Ebel, Nicolas; Embry, Millicent; Green, John; Kauffmann, Audrey; Kowal, Colleen; Leary, Rebecca J; Lehar, Joseph; Liang, Ying; Loo, Alice; Lorenzana, Edward; Robert McDonald, E; McLaughlin, Margaret E; Merkin, Jason; Meyer, Ronald; Naylor, Tara L; Patawaran, Montesa; Reddy, Anupama; Röelli, Claudia; Ruddy, David A; Salangsang, Fernando; Santacroce, Francesca; Singh, Angad P; Tang, Yan; Tinetto, Walter; Tobler, Sonja; Velazquez, Roberto; Venkatesan, Kavitha; Von Arx, Fabian; Wang, Hui Qin; Wang, Zongyao; Wiesmann, Marion; Wyss, Daniel; Xu, Fiona; Bitter, Hans; Atadja, Peter; Lees, Emma; Hofmann, Francesco; Li, En; Keen, Nicholas; Cozens, Robert; Jensen, Michael Rugaard; Pryer, Nancy K; Williams, Juliet A; Sellers, William R

    2015-11-01

    Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

  11. Role of serum- and glucocorticoid-inducible kinases in stroke.

    Science.gov (United States)

    Inoue, Koichi; Leng, Tiandong; Yang, Tao; Zeng, Zhao; Ueki, Takatoshi; Xiong, Zhi-Gang

    2016-07-01

    Increased expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) can be induced by stress and growth factors in mammals, and plays an important role in cancer, diabetes, and hypertension. A recent work suggested that SGK1 activity restores damage in a stroke model. To further investigate the role of SGKs in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome in vivo and neurotoxicity in vitro. Infarct volumes were compared in adult mice with middle cerebral artery occlusion, followed by 24 h reperfusion, in the absence or presence of SGK inhibitors. Neurotoxicity assay, electrophysiological recording, and fluorescence Ca(2+) imaging were carried out using cultured cortical neurons to evaluate the underlying mechanisms. Contrary to our expectation, infarct volume by stroke decreased significantly when SGK inhibitor, gsk650394, or EMD638683, was administrated 30 min before middle cerebral artery occlusion under normal and diabetic conditions. SGK inhibitors reduced neurotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors, a leading factor responsible for cell death in stroke. SGK inhibitors also ameliorated Ca(2+) increase and peak amplitude of NMDA current in cultured neurons. In addition, SGK inhibitor gsk650394 decreased phosphorylation of Nedd4-2 and inhibited voltage-gated sodium currents. These observations suggest that SGK activity exacerbates stroke damage and that SGK inhibitors may be useful candidates for therapeutic intervention. To investigate the role of serum- and glucocorticoid-inducible kinases (SGKs) in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome. Infarct volumes induced by middle cerebral artery occlusion were decreased significantly by SGK inhibitors. The inhibitors also reduced glutamate toxicity, at least partly, by attenuation of NMDA and voltage-gated sodium currents. Thus, SGK inhibition attenuates stroke damage. PMID:27123541

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

    Science.gov (United States)

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

    1995-03-24

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

  13. Clinical utility and validity of minoxidil response testing in androgenetic alopecia.

    Science.gov (United States)

    Goren, Andy; Shapiro, Jerry; Roberts, Janet; McCoy, John; Desai, Nisha; Zarrab, Zoulikha; Pietrzak, Aldona; Lotti, Torello

    2015-01-01

    Clinical response to 5% topical minoxidil for the treatment of androgenetic alopecia (AGA) is typically observed after 3-6 months. Approximately 40% of patients will regrow hair. Given the prolonged treatment time required to elicit a response, a diagnostic test for ruling out nonresponders would have significant clinical utility. Two studies have previously reported that sulfotransferase enzyme activity in plucked hair follicles predicts a patient's response to topical minoxidil therapy. The aim of this study was to assess the clinical utility and validity of minoxidil response testing. In this communication, the present authors conducted an analysis of completed and ongoing studies of minoxidil response testing. The analysis confirmed the clinical utility of a sulfotransferase enzyme test in successfully ruling out 95.9% of nonresponders to topical minoxidil for the treatment of AGA. PMID:25112173

  14. Membrane-Associated Glucocorticoid Activity Is Necessary for Modulation of Long-Term Memory via Chromatin Modification

    NARCIS (Netherlands)

    Roozendaal, Benno; Hernandez, Angelina; Cabrera, Sara M.; Hagewoud, Roelina; Malvaez, Melissa; Stefanko, Daniel P.; Haettig, Jakob; Wood, Marcelo A.

    2010-01-01

    Glucocorticoid hormones enhance the consolidation of long-term memory of emotionally arousing training experiences. This memory enhancement requires activation of the cAMP-dependent kinase pathway and the subsequent phosphorylation of cAMP response-element binding (CREB) protein. Here, we demonstrat

  15. A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD)

    NARCIS (Netherlands)

    Jazayeri, Omid; Liu, Xuanzhu; van Diemen, Cleo C.; Bakker-van Waarde, Willie M.; Sikkema-Raddatz, Birgit; Sinke, Richard J.; Zhang, Jianguo; van Ravenswaaij-Arts, Conny M. A.

    2015-01-01

    Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by low levels of cortisol despite high adrenocorticotropin (ACTH) levels, due to the reduced ability of the adrenal cortex to produce cortisol in response to stimulation by ACTH. FGD is a heterogeneous disorder

  16. [Application of three compartment model and response surface model to clinical anesthesia using Microsoft Excel].

    Science.gov (United States)

    Abe, Eiji; Abe, Mari

    2011-08-01

    With the spread of total intravenous anesthesia, clinical pharmacology has become more important. We report Microsoft Excel file applying three compartment model and response surface model to clinical anesthesia. On the Microsoft Excel sheet, propofol, remifentanil and fentanyl effect-site concentrations are predicted (three compartment model), and probabilities of no response to prodding, shaking, surrogates of painful stimuli and laryngoscopy are calculated using predicted effect-site drug concentration. Time-dependent changes in these calculated values are shown graphically. Recent development in anesthetic drug interaction studies are remarkable, and its application to clinical anesthesia with this Excel file is simple and helpful for clinical anesthesia.

  17. Impact of genetic polymorphisms on clinical response to antithrombotics

    OpenAIRE

    Lanham, Kena J; Oestreich, Julie H; Dunn, Steven P.; et al

    2010-01-01

    Kena J Lanham1,2, Julie H Oestreich3, Steven P Dunn1,2, Steven R Steinhubl41Pharmacy Services, UK HealthCare, University of Kentucky, Lexington, Kentucky, USA; 2Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA; 3Department of Pharmacy Practice, College of Pharmacy, University of Nebraska, Omaha, Nebraska, USA; 4The Medicines Company, Zurich, Switzerland and The Geisinger Clinic, Danville, Pennsylvania, USAAbstract: Antithrombot...

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    1998-01-01

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

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

    NARCIS (Netherlands)

    N.A.T.M. Huizenga (Nannette); J.W. Koper (Jan); P. de Lange (Pieter); H.A.P. Pols (Huib); R.P. Stolk (Ronald); H. Burger (Huibert); D.E. Grobbee (Diederick); A.O. Brinkmann (Albert); F.H. de Jong (Frank); S.W.J. Lamberts (Steven)

    1998-01-01

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

  1. Differential Expression of Glucocorticoid Receptor Noncoding RNA Repressor Gas5 in Autoimmune and Inflammatory Diseases.

    Science.gov (United States)

    Mayama, T; Marr, A K; Kino, T

    2016-08-01

    Glucocorticoids have strong regulatory actions on the immune system and act as potent therapeutic compounds for autoimmune and inflammatory diseases. We previously reported that the long noncoding RNA growth arrest-specific 5 (Gas5), which accumulates inside the cells in response to cellular starvation/growth arrest, functions as a potent repressor of the glucocorticoid receptor (GR) through its RNA "glucocorticoid response element (GRE)". To evaluate potential roles of Gas5 in immune-related disorders, we examined Gas5 RNA levels in various autoimmune, inflammatory, and infectious diseases using the microarray data available in the Gene Expression Omnibus. We found that Gas5 levels were altered in whole blood or leukocytes of the patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and sarcoidosis. Gas5 levels were also altered in infectious diseases, such as by the human immunodeficiency virus type-1 and influenza virus, and bacterial sepsis. In our experimental analysis using mice, Gas5 levels were kept at high basal levels and did not respond to fasting in immune organs, such as spleen and thymus, while its levels in metabolic organs, including liver, fat, and skeletal muscles, were low at baseline and were highly elevated upon this treatment, possibly through suppression of the mTOR pathway. These results suggest that Gas5 plays a role in the regulation of immune functions and pathogenesis/pathophysiology of autoimmune, inflammatory, and infectious diseases in part through modulation of the GR transcriptional activity via its decoy RNA "GRE". Changes in the Gas5 levels may also influence disease response to immunosuppressive glucocorticoid therapy. PMID:27214311

  2. Optogenetic elevation of endogenous glucocorticoid level in larval zebrafish

    Directory of Open Access Journals (Sweden)

    Rodrigo J De Marco

    2013-05-01

    Full Text Available The stress response is a suite of physiological and behavioral processes that help to maintain or reestablish homeostasis. The hypothalamic-pituitary-adrenal (HPA axis is central to the stress response, as it releases crucial hormones in response to stress. Glucocorticoids (GCs are the final effector hormones of the HPA axis and exert a variety of actions under both basal and stress conditions. Despite their far-reaching importance for health, specific GC effects have been difficult to pin-down due to a lack of methods for selectively manipulating endogenous GC levels. To study stress-induced GC effects, we developed a novel optogenetic approach to selectively manipulate the rise of GCs triggered by stress. Using this approach, we could induce both transient hypercortisolic states and persistent forms of hypercortisolaemia in freely behaving larval zebrafish. Our results also established that transient hypercortisolism leads to enhanced locomotion shortly after stressor exposure. Altogether, we present a highly specific method for manipulating the gain of the stress axis with high temporal accuracy, thereby altering endocrine and behavioral responses to stress as well as basal GC levels. Our study thus offers a powerful tool for the analysis of rapid (non-genomic and delayed (genomic GC effects on brain function and behavior, feedbacks within the stress axis and developmental programming by GCs. 

  3. Glucocorticoid-induced osteoporosis: 2013 update

    Directory of Open Access Journals (Sweden)

    M. Mazzantini

    2014-07-01

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

  4. Cutaneous inflammation and proliferation in vitro: differential effects and mode of action of topical glucocorticoids.

    Science.gov (United States)

    Lange, K; Kleuser, B; Gysler, A; Bader, M; Maia, C; Scheidereit, C; Korting, H C; Schäfer-Korting, M

    2000-01-01

    The nonhalogenated double ester of prednisolone, prednicarbate (PC), is the first topical glucocorticoid with an improved benefit/risk ratio verified clinically and in vitro. To evaluate if this is due to unique characteristics of this steroid, a new compound created according to an identical concept, prednisolone 17-ethylcarbonate, 21-phenylacetate (PEP), and the new halogenated monoester desoximetasone 21-cinnamate (DCE) were tested and compared to PC, desoximetasone (DM) and betamethasone 17-valerate (BMV). Isolated foreskin keratinocytes served for in vitro investigations of anti-inflammatory processes in the epidermis, fibroblasts of the same origin were used to investigate the atrophogenic potential. Inflammation was induced by TNFalpha, resulting in an increased interleukin 1alpha (Il-1alpha) synthesis. As quantified by ELISA, all drugs significantly reduced Il-1alpha production. But PC and BMV appeared particularly potent, followed by DM and the two new congeners, which revealed minor anti-inflammatory activity. Glucocorticoid esters including PEP are rapidly degraded in keratinocytes (85% within 12 h). Hence, a ribonuclease protection assay of Il-1alpha mRNA was performed allowing short incubation times and thus minimizing biodegradation. This assay confirmed the anti-inflammatory potency of native PC and BMV. In contrary DCE and PEP did not reduce Il-1alpha mRNA to a significant extent. Therefore PEP acts as a prodrug only. In fibroblasts, Il-1alpha and Il-6 syntheses indicate proliferation and inflammation, respectively. Whereas PC and PEP inhibited Il-1alpha and Il-6 production in fibroblasts only to a minor extent, cytokine synthesis was strongly affected by the conventional glucocorticoids BMV and DM, but also by DCE. The minor unwanted effect of PC and PEP on fibroblasts was also reflected by their low influence on cell proliferation as derived from (3)H-thymidine incorporation. Again, more pronounced antiproliferative features were seen with the

  5. Roles and Responsibilities, and Education and Training Requirements for Clinically Qualified Medical Physicists (Russian Edition)

    International Nuclear Information System (INIS)

    This publication addresses the shortfall of well trained and clinically qualified medical physicists working in radiation medicine. The roles, responsibilities and clinical training requirements of medical physicists have not always been well defined or well understood by health care professionals, health authorities and regulatory agencies. To fill this gap, this publication provides recommendations for the academic education and clinical training of clinically qualified medical physicists, including recommendations for their accreditation certification and registration, along with continuous professional development. The goal is to establish criteria that support the harmonization of education and clinical training worldwide

  6. A living biosensor model to dynamically trace glucocorticoid transcriptional activity during development and adult life in zebrafish.

    Science.gov (United States)

    Benato, Francesca; Colletti, Elisa; Skobo, Tatjana; Moro, Enrico; Colombo, Lorenzo; Argenton, Francesco; Dalla Valle, Luisa

    2014-07-01

    Glucocorticoids (GCs) modulate many cellular processes through the binding of the glucocorticoid receptor (GR) to specific responsive elements located upstream of the transcription starting site or within an intron of GC target genes. Here we describe a transgenic fish line harboring a construct with nine GC-responsive elements (GREs) upstream of a reporter (EGFP) coding sequence. Transgenic fish exhibit strong fluorescence in many known GC-responsive organs. Moreover, its enhanced sensitivity allowed the discovery of novel GC-responsive tissue compartments, such as fin, eyes, and otic vesicles. Long-term persistence of transgene expression is seen during adult stages in several organs. Pharmacological and genetic analysis demonstrates that the transgenic line is highly responsive to drug administration and molecular manipulation. Moreover, reporter expression is sensitively and dynamically modulated by the photoperiod, thus proving that these fish are an in vivo valuable platform to explore GC responsiveness to both endogenous and exogenous stimuli.

  7. Primary and secondary prophylaxis to the use of inhaled glucocorticoid in primary health care

    DEFF Research Database (Denmark)

    Nielsen, Barbara Rubek; Jørgensen, Niklas Rye; Schwarz, Peter

    2008-01-01

    To investigate the extent of inhaled glucocorticoid (IGC) treatment in general and to what extent general practitioners (GPs) manage the risk of glucocorticoid-induced osteoporosis.......To investigate the extent of inhaled glucocorticoid (IGC) treatment in general and to what extent general practitioners (GPs) manage the risk of glucocorticoid-induced osteoporosis....

  8. Glucocorticoids modulate BDNF mRNA expression in the rat hippocampus after traumatic brain injury.

    Science.gov (United States)

    Grundy, P L; Patel, N; Harbuz, M S; Lightman, S L; Sharples, P M

    2000-10-20

    Brain-derived neurotrophic factor (BDNF) expression in rat hippocampus is increased after experimental traumatic brain injury (TBI) and may be neuroprotective. Glucocorticoids are important regulators of brain neurotrophin levels and are often prescribed following TBI. The effect of adrenalectomy (ADX) on the expression of BDNF mRNA in the hippocampus after TBI has not been investigated to date. We used fluid percussion injury (FPI) and in situ hybridization to evaluate the expression of BDNF mRNA in the hippocampus 4 h after TBI in adrenal-intact or adrenalectomized rats (with or without corticosterone replacement). FPI and ADX independently increased expression of BDNF mRNA. In animals undergoing FPI, prior ADX caused further elevation of BDNF mRNA and this upregulation was prevented by corticosterone replacement in ADX rats. These findings suggest that glucocorticoids are involved in the modulation of the BDNF mRNA response to TBI.

  9. Host response to nontuberculous mycobacterial infections of current clinical importance.

    Science.gov (United States)

    Orme, Ian M; Ordway, Diane J

    2014-09-01

    The nontuberculous mycobacteria are a large group of acid-fast bacteria that are very widely distributed in the environment. While Mycobacterium avium was once regarded as innocuous, its high frequency as a cause of disseminated disease in HIV-positive individuals illustrated its potential as a pathogen. Much more recently, there is growing evidence that the incidence of M. avium and related nontuberculous species is increasing in immunocompetent individuals. The same has been observed for M. abscessus infections, which are very difficult to treat; accordingly, this review focuses primarily on these two important pathogens. Like the host response to M. tuberculosis infections, the host response to these infections is of the TH1 type but there are some subtle and as-yet-unexplained differences.

  10. Shame, honor and responsibility in clinical dialog about lifestyle issues

    DEFF Research Database (Denmark)

    Guassora, A.D.; Reventlow, S.; Malterud, K.

    2014-01-01

    presented themselves with an orientation toward responsibility in dialog about lifestyle. They described how they were taking care of themselves and doing their best. In this respect, they demonstrated their achievements as matters of honor. If one lifestyle issue was considered problematic, in some cases....... Failure to do so could lead to distance and hostility while a strategy to acknowledge the impact of shame could help develop and strengthen the doctor-patient relationship....

  11. An experimental analysis of the heritability of variation in glucocorticoid concentrations in a wild avian population

    Science.gov (United States)

    Jenkins, Brittany R.; Vitousek, Maren N.; Hubbard, Joanna K.; Safran, Rebecca J.

    2014-01-01

    Glucocorticoid hormones (CORT) are predicted to promote adaptation to variable environments, yet little is known about the potential for CORT secretion patterns to respond to selection in free-living populations. We assessed the heritable variation underlying differences in hormonal phenotypes using a cross-foster experimental design with nestling North American barn swallows (Hirundo rustica erythrogaster). Using a bivariate animal model, we partitioned variance in baseline and stress-induced CORT concentrations into their additive genetic and rearing environment components and estimated their genetic correlation. Both baseline and stress-induced CORT were heritable with heritability of 0.152 and 0.343, respectively. We found that the variation in baseline CORT was best explained by rearing environment, whereas the variation in stress-induced CORT was contributed to by a combination of genetic and environmental factors. Further, we did not detect a genetic correlation between these two hormonal traits. Although rearing environment appears to play an important role in the secretion of both types of CORT, our results suggest that stress-induced CORT levels are underlain by greater additive genetic variance compared with baseline CORT levels. Accordingly, we infer that the glucocorticoid response to stress has a greater potential for evolutionary change in response to selection compared with baseline glucocorticoid secretion patterns. PMID:25056627

  12. An experimental analysis of the heritability of variation in glucocorticoid concentrations in a wild avian population.

    Science.gov (United States)

    Jenkins, Brittany R; Vitousek, Maren N; Hubbard, Joanna K; Safran, Rebecca J

    2014-09-01

    Glucocorticoid hormones (CORT) are predicted to promote adaptation to variable environments, yet little is known about the potential for CORT secretion patterns to respond to selection in free-living populations. We assessed the heritable variation underlying differences in hormonal phenotypes using a cross-foster experimental design with nestling North American barn swallows (Hirundo rustica erythrogaster). Using a bivariate animal model, we partitioned variance in baseline and stress-induced CORT concentrations into their additive genetic and rearing environment components and estimated their genetic correlation. Both baseline and stress-induced CORT were heritable with heritability of 0.152 and 0.343, respectively. We found that the variation in baseline CORT was best explained by rearing environment, whereas the variation in stress-induced CORT was contributed to by a combination of genetic and environmental factors. Further, we did not detect a genetic correlation between these two hormonal traits. Although rearing environment appears to play an important role in the secretion of both types of CORT, our results suggest that stress-induced CORT levels are underlain by greater additive genetic variance compared with baseline CORT levels. Accordingly, we infer that the glucocorticoid response to stress has a greater potential for evolutionary change in response to selection compared with baseline glucocorticoid secretion patterns.

  13. THE RATE OF CLINICAL RESPONSE OF ORAL LOADING SODIUM VALPROATE IN ACUTELY MANLC PATIENT

    OpenAIRE

    K SHAFIEE; M BAREKATEYN; N BASHARDOOST; Mahmoudi, J

    2003-01-01

    Introduction: Acheiving accelerated clinical response is desirable in patients with acute manic episode. We conducted a prospective study to compare the rate of clinical response of oral loading sodium valproate versus standard dose titration. Methods: Fourty - two patients who met DSM - IV critevia for current manic episode and who had a "Young mania rating scale "score between 20 and 50 were randomly assigned on a double blind basis to recieve valproate oral "loading"(N = 21) at a dose...

  14. Serine / threonine protein phosphatase 5 (PP5 participates in the regulation of glucocorticoid receptor nucleocytoplasmic shuttling

    Directory of Open Access Journals (Sweden)

    Bueno Manuel

    2001-05-01

    Full Text Available Abstract Background In most cells glucocorticoid receptors (GR reside predominately in the cytoplasm. Upon hormone binding, the GR translocates into the nucleus, where the hormone-activated GR-complex regulates the transcription of GR-responsive genes. Serine/threonine protein phosphatase type 5 (PP5 associates with the GR-heat-shock protein-90 complex, and the suppression of PP5 expression with ISIS 15534 stimulates the activity of GR-responsive reporter plasmids, without affecting the binding of hormone to the GR. Results To further characterize the mechanism by which PP5 affects GR-induced gene expression, we employed immunofluorescence microscopy to track the movement of a GR-green fluorescent fusion protein (GR-GFP that retained hormone binding, nuclear translocation activity and specific DNA binding activity, but is incapable of transactivation. In the absence of glucocorticoids, GR-GFP localized mainly in the cytoplasm. Treatment with dexamethasone results in the efficient translocation of GR-GFPs into the nucleus. The nuclear accumulation of GR-GFP, without the addition of glucocorticoids, was also observed when the expression of PP5 was suppressed by treatment with ISIS 15534. In contrast, ISIS 15534 treatment had no apparent effect on calcium induced nuclear translocation of NFAT-GFP. Conclusion These studies suggest that PP5 participates in the regulation of glucocorticoid receptor nucleocytoplasmic shuttling, and that the GR-induced transcriptional activity observed when the expression of PP5 is suppressed by treatment with ISIS 15534 results from the nuclear accumulation of GR in a form that is capable of binding DNA yet still requires agonist to elicit maximal transcriptional activation.

  15. Strategic Clinical Networks: Alberta's Response to Triple Aim.

    Science.gov (United States)

    Noseworthy, Tom; Wasylak, Tracy; O'Neill, Blair J

    2016-01-01

    Verma and Bhatia make a compelling case for the Triple Aim to promote health system innovation and sustainability. We concur. Moreover, the authors offer a useful categorization of policies and actions to advance the Triple Aim under the "classic functions" of financing, stewardship and resource generation (Verma and Bhatia 2016). The argument is tendered that provincial governments should embrace the Triple Aim in the absence of federal government leadership, noting that, by international standards, we are at best mediocre and, more realistically, fighting for the bottom in comparative, annual cross-country surveys. Ignoring federal government participation in Medicare and resorting solely to provincial leadership seems to make sense for the purposes of this discourse; but, it makes no sense at all if we are attempting to achieve high performance in Canada's non-system (Canada Health Action: Building on the Legacy 1997; Commission on the Future of Health Care in Canada 2002; Lewis 2015). As for enlisting provincial governments, we heartily agree. A great deal can be accomplished by the Council of the Federation of Canadian Premiers. But, the entire basis for this philosophy and the reference paper itself assumes a top-down approach to policy and practice. That is what we are trying to change in Alberta and we next discuss. Bottom-up clinically led change, driven by measurement and evidence, has to meet with the top-down approach being presented and widely practiced. While true for each category of financing, stewardship and resource generation, in no place is this truer than what is described and included in "health system stewardship." This commentary draws from Verma and Bhatia (2016) and demonstrates how Alberta, through the use of Strategic Clinical Networks (SCNs), is responding to the Triple Aim. We offer three examples of provincially scaled innovations, each representing one or more arms of the Triple Aim. PMID:27009587

  16. Genetic, functional and molecular features of glucocorticoid receptor binding.

    Directory of Open Access Journals (Sweden)

    Francesca Luca

    Full Text Available Glucocorticoids (GCs are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR, which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI and 4 Tuscans (TSI lymphoblastoid cell lines (LCLs, we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-κB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.

  17. No association of glucocorticoid receptor gene polymorphism (rs6190 with unipolar and bipolar disorder

    Directory of Open Access Journals (Sweden)

    Nemec, Dominika

    2013-07-01

    Full Text Available Aim. Functional polymorphism ER22/23EK glucocorticoid receptor leads to reduction of its resistance and to increase in its sensitivity to the glucocorticoid that regulate the functioning of the axis hypothalamus - pituitary - adrenal glands. Disturbances in the regulation of this axis are observed in patients with psychiatric disorders. The aim of this study was to demonstrate the association ER22/23EK polymorphism with bipolar disorder and major depressive disorders.Methods. In the study 144 patients with unipolar disorders and 479 patients with bipolar disorder were included. Patients were diagnosed by two psychiatrists on the basis of medical records and interview based on SCID criteria (Structured Clinical Interview for DSM Disorders. The control group comprised 595 healthy subjects. As the research material peripheral blood was used, from which DNA was obtained. Genotyping was performed using PCR - RFLP method.Results. No association of ER22/23EK polymorphism with unipolar disorder or with bipolar disorder was found. GA genotype was not observed in any of the subjects.Conclusion. ER22/23EK functional polymorphism of the glucocorticoid receptor gene is not associated with unipolar and bipolar disorder.

  18. Educational climate seems unrelated to leadership skills of clinical consultants responsible of postgraduate medical education in clinical departments

    DEFF Research Database (Denmark)

    Malling, Bente Vigh; Mortensen, Lene S.; Scherpbier, Albert J J;

    2010-01-01

    The educational climate is crucial in postgraduate medical education. Although leaders are in the position to influence the educational climate, the relationship between leadership skills and educational climate is unknown. This study investigates the relationship between the educational climate ...... clinical departments and the leadership skills of clinical consultants responsible for education.......The educational climate is crucial in postgraduate medical education. Although leaders are in the position to influence the educational climate, the relationship between leadership skills and educational climate is unknown. This study investigates the relationship between the educational climate in...

  19. Prolonged Glucocorticoid Treatment in ARDS: Impact on Intensive Care Unit-Acquired Weakness

    Science.gov (United States)

    Meduri, Gianfranco Umberto; Schwingshackl, Andreas; Hermans, Greet

    2016-01-01

    Systemic inflammation and duration of immobilization are strong independent risk factors for the development of intensive care unit-acquired weakness (ICUAW). Activation of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) results in muscle wasting during disuse-induced skeletal muscle atrophy (ICU bed rest) and septic shock. In addition, NF-κB-mediated signaling plays a significant role in mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Older trials investigating high dose glucocorticoid treatment reported a lack of a sustained anti-inflammatory effects and an association with ICUAW. However, prolonged low-to-moderate dose glucocorticoid treatment of sepsis and ARDS is associated with a reduction in NF-κB DNA-binding, decreased transcription of inflammatory cytokines, enhanced resolution of systemic and pulmonary inflammation, leading to fewer days of mechanical ventilation, and lower mortality. Importantly, meta-analyses of a large number of randomized controlled trials investigating low-to-moderate glucocorticoid treatment in severe sepsis and ARDS found no increase in ICUAW. Furthermore, while the ARDS network trial investigating methylprednisolone treatment in persistent ARDS is frequently cited to support an association with ICUAW, a reanalysis of the data showed a similar incidence with the control group. Our review concludes that in patients with sepsis and ARDS, any potential direct harmful neuromuscular effect of glucocorticoids appears outweighed by the overall clinical improvement and reduced duration of organ failure, in particular ventilator dependency and associated immobilization, which are key risk factors for ICUAW. PMID:27532030

  20. Prolonged Glucocorticoid Treatment in ARDS: Impact on Intensive Care Unit-Acquired Weakness.

    Science.gov (United States)

    Meduri, Gianfranco Umberto; Schwingshackl, Andreas; Hermans, Greet

    2016-01-01

    Systemic inflammation and duration of immobilization are strong independent risk factors for the development of intensive care unit-acquired weakness (ICUAW). Activation of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) results in muscle wasting during disuse-induced skeletal muscle atrophy (ICU bed rest) and septic shock. In addition, NF-κB-mediated signaling plays a significant role in mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Older trials investigating high dose glucocorticoid treatment reported a lack of a sustained anti-inflammatory effects and an association with ICUAW. However, prolonged low-to-moderate dose glucocorticoid treatment of sepsis and ARDS is associated with a reduction in NF-κB DNA-binding, decreased transcription of inflammatory cytokines, enhanced resolution of systemic and pulmonary inflammation, leading to fewer days of mechanical ventilation, and lower mortality. Importantly, meta-analyses of a large number of randomized controlled trials investigating low-to-moderate glucocorticoid treatment in severe sepsis and ARDS found no increase in ICUAW. Furthermore, while the ARDS network trial investigating methylprednisolone treatment in persistent ARDS is frequently cited to support an association with ICUAW, a reanalysis of the data showed a similar incidence with the control group. Our review concludes that in patients with sepsis and ARDS, any potential direct harmful neuromuscular effect of glucocorticoids appears outweighed by the overall clinical improvement and reduced duration of organ failure, in particular ventilator dependency and associated immobilization, which are key risk factors for ICUAW. PMID:27532030

  1. Ontogeny of hippocampal corticosteroid receptors: effects of antenatal glucocorticoids in human and mouse.

    Science.gov (United States)

    Noorlander, C W; De Graan, P N E; Middeldorp, J; Van Beers, J J B C; Visser, G H A

    2006-12-20

    Women at risk for preterm delivery are treated with synthetic glucocorticoids (GCs) to enhance fetal lung maturation. GCs can bind to two intracellular receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which function as transcription factors. Both are highly expressed in the hippocampus. Several studies have focused on adverse side effects of antenatal GC treatment. However, relatively little is known about the ontogeny of GR and MR, especially in human. Therefore, we studied the ontogeny of both receptors in the human and mouse hippocampus and investigated the effects of antenatal dexamethasone (dex) treatment, a synthetic glucocorticoid, on MR and GR mRNA levels during hippocampal development. The results demonstrate that MR mRNA was first expressed in mouse hippocampus at embryonic day (E)15.5, at the timepoint when dex was administered. In contrast, GR mRNA expression was first observed after birth at postnatal day (P)5. However, in the human hippocampus both receptors are expressed at 24 weeks of gestation, when antenatal GCs are administered in clinical practice. Quantitative in situ hybridization demonstrated that MR mRNA levels were reduced only shortly after dex treatment at E16, but were unaffected from E18 onwards. These findings indicate that a single antenatal dex administration at E15.5 transiently affects MR mRNA levels in the mouse hippocampus. No effect of antenatal dex treatment was found on the human hippocampus at the third trimester of pregnancy. These data on the prenatal ontogeny of both corticosteroid receptors in the human hippocampus is important for understanding the significance of fetal glucocorticoid or stress exposure and its potential effects on health and disease.

  2. Effect of glucocorticoid administration on adrenal gland size and sonographic appearance in beagle dogs.

    Science.gov (United States)

    Pey, Pascaline; Daminet, Sylvie; Smets, Pascale M Y; Duchateau, Luc; Travetti, Olga; Saunders, Jimmy H

    2012-01-01

    Our aim was to evaluate the influence of glucocorticoids on the adrenal gland using ultrasonography. Eleven healthy beagles were used in a prospective placebo-controlled study. All dogs received hydrocortisone at 10 mg/kg twice a day per os for 4 months or a gelatin capsule twice a day per os as a placebo. Clinical and endocrinologic examination of the dogs and ultrasonographic evaluation of adrenal echogenicity, shape, and measurement of the length and height of the cranial and caudal pole were performed at baseline (TO), at 1 (T1) and 4 months (T4) after the beginning of treatment, and 2 months after the end of the treatment including 1 month of tapering and 1 month without treatment (T6). The dogs were assigned randomly to the glucocorticoid (n = 6) and placebo groups (n = 5). At T1, the difference between the two groups for the height of the cranial and caudal pole was not ultrasonographically remarkable despite a statistically significant difference (P = 0.0165 and P = 0.0206). Decreased height and length of entire gland were observed at T4 (P < 0.0001, P = 0.0015, and P = 0.0035, respectively). Percentages of atrophy were variable between dogs. Both adrenal glands regained normal size and shape 1 month after cessation of glucocorticoid administration. As not all dogs developed marked adrenal gland atrophy and the degree of atrophy varied widely between individuals, ultrasonography cannot be the technique of choice to detect iatrogenic hypercortisolism. Ultrasonographic changes are reversible within 1 month after the end of glucocorticoid administration. PMID:22092685

  3. Addison disease in patients treated with glucocorticoid therapy.

    LENUS (Irish Health Repository)

    Cronin, C C

    2012-02-03

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

  5. Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans.

    Science.gov (United States)

    Cao, Yun; Bender, Ingrid K; Konstantinidis, Athanasios K; Shin, Soon Cheon; Jewell, Christine M; Cidlowski, John A; Schleimer, Robert P; Lu, Nick Z

    2013-02-28

    Although glucocorticoids are a profoundly important class of anti-inflammatory and immunosuppressive agents, their actions in dendritic cells (DCs) are not well understood. We found that dexamethasone, a potent glucocorticoid, selectively induced apoptosis in mature, but not in immature, DCs in healthy mice, in mice with experimental airway inflammation, and in vitro in bone marrow–derived DCs. Distinct glucocorticoid receptor (GR) translational isoforms expressed in immature and mature DCs probably contribute to the DC maturational stage-specific glucocorticoid sensitivity. The GR-D isoforms were the predominant isoforms in immature DCs, whereas the proapoptotic GR-A isoform was the main isoform in mature DCs. Ectopic expression of the GR-A isoform in immature DCs increased glucocorticoid sensitivity and RU486, a selective GR antagonist, inhibited the glucocorticoid sensitivity of mature DCs. Furthermore, the distinct expression pattern of GR isoforms in immature and mature murine DCs was also observed in human monocyte–derived DCs. These studies suggest that glucocorticoids may spare immature DCs and suppress mature DCs and inflammation via differential expression of GR translational isoforms. PMID:23297131

  6. Diretrizes para prevenção e tratamento da osteoporose induzida por glicocorticoide Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    Rosa Maria Rodrigues Pereira

    2012-08-01

    and treated in all patients initiating or already on GC. There are several recommendations on this topic elaborated by several international societies, but consensus still lacks. Recently, the American College of Rheumatology has published new recommendations, but they are based on the WHO Fracture Risk Assessment Tool (FRAX® to evaluate the risk for each individual, and, thus, cannot be completely used for the Brazilian population. Thus, the Committee for Osteoporosis and Bone Metabolic Disorders of the Brazilian Society of Rheumatology, along with the Brazilian Medical Association and the Brazilian Association of Physical Medicine and Rehabilitation, has elaborated the Brazilian Guidelines for Glucocorticoid-Induced Osteoporosis (GIO, based on the better available scientific evidence and/or expert experience. METHOD OF EVIDENCE COLLECTION: The bibliographic review of scientific articles of this guideline was performed in the MEDLINE database. The search for evidence was based on real clinical scenarios, and used the following keywords (MeSH terms: Osteoporosis, Osteoporosis/ chemically induced*= (Glucocorticoids= Adrenal Cortex Hormones, Steroids, Glucocorticoids, Glucocorticoids/administration and dosage, Glucocorticoids/therapeutic use, Glucocorticoids/adverse effects, Prednisone/adverse effects, Dose-Response Relationship, Drug, Bone Density/drug effects, Bone Density Conservation Agents/pharmacological action, Osteoporosis/prevention & control, Calcium, Vitamin D, Vitamin D deficiency, Calcitriol, Receptors, Calcitriol; 1-hydroxycholecalciferol, Hydroxycholecalciferols, 25-Hydroxyvitamin D3 1-alpha-hydroxylase OR Steroid Hydroxylases, Prevention and Control, Spinal fractures/prevention & control, Fractures, Spontaneous, Lumbar Vertebrae/injuries, Lifestyle, Alcohol Drinking, Smoking OR tobacco use disorder, Movement, Resistance Training, Exercise Therapy, Bone density OR Bone and Bones, Dual-Energy X-Ray Absorptiometry OR Absorptiometry Photon OR DXA

  7. Rebuttal to Nelson et al. 'Response to Bodin and Grote regarding postdoctoral recruitment in clinical neuropsychology'.

    Science.gov (United States)

    Bodin, Doug; Grote, Christopher L

    2016-07-01

    Nelson et al. provided a response to our commentary on the postdoctoral match in clinical neuropsychology. In this brief rebuttal, we will focus on statements from Nelson et al. that we believe are factual inaccuracies or misunderstandings of some of the points we made in our commentary. In addition, we will comment briefly on the proposed guidelines offered in their response.

  8. Survey Response Rates and Survey Administration in Counseling and Clinical Psychology: A Meta-Analysis

    Science.gov (United States)

    Van Horn, Pamela S.; Green, Kathy E.; Martinussen, Monica

    2009-01-01

    This article reports results of a meta-analysis of survey response rates in published research in counseling and clinical psychology over a 20-year span and describes reported survey administration procedures in those fields. Results of 308 survey administrations showed a weighted average response rate of 49.6%. Among possible moderators, response…

  9. The antidepressant fluoxetine normalizes the nuclear glucocorticoid receptor evoked by psychosocial stress

    Science.gov (United States)

    Mitić, M.; Simić, I.; Djordjević, J.; Radojčić, M. B.; Adžić, M.

    2011-12-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of depression and stress disorders. Glucocorticoids, key regulators of the stress response, exert diverse effects on cellular processes in the hippocampus. Beside non-genomic pathways, glucocorticoid effects are mediated through activation of the glucocorticoid receptor (GR), a ligand activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. We analysed the GR protein levels both in the cytoplasmic and nuclear compartments of the hippocampus of Wistar rats exposed to chronic psychosocial isolation stress upon chronic fluoxetine (FLU) treatment. Under chronic stress, corticosterone levels (CORT) were decreased compared to the control, and treatment with FLU did not change its level in the stressed rats. At the molecular level, FLU normalized the level of nuclear GR protein in the hippocampus of the stressed rats. Discrepancy between normalization of nuclear GR in the hippocampus and lack of normalization of HPA axis activity judged by CORT, suggests that other brain structures such as the amygdale and prefrontal cortex that also regulate HPA axis activity, seem not to be normalized by the FLU treatment used in our study.

  10. Percutaneous sclerotherapy of foot venous malformations: Evaluation of clinical response

    International Nuclear Information System (INIS)

    Aim: To evaluate a single institutional experience with percutaneous sclerotherapy of venous malformations (VM) of the foot. Materials and methods: Sixteen patients (mean age 14.6 years; range 6–27.3 years), who underwent 34 sclerotherapy procedures were retrospectively analysed. Technical success, Puig classification, VM size reduction, and the complication rate were evaluated. In procedures in which C-arm computed tomography (CT) was performed, the VM-to-skin surface distance was measured. Additionally, an e-mail-based questionnaire to evaluate the response to sclerotherapy was answered by the patients. Results: Technical success was 97%. The mean number of procedures per patient was 2.1 (range 1–5). In all procedures, sodium tetradecyl sulphate foam was used. Appropriate follow-up was available for 29/33 procedures (88%). Post-procedural complications occurred after 6/29 procedures (21%), all of which were self-limited skin complications. C-arm CT was performed in 19/33 procedures (58%). The lesion-to-skin surface distance was significantly shorter in patients with skin post-procedural complications (p < 0.001). The e-mail-based questionnaire was completed by 13/16 patients (81%). Decrease in swelling, improvement of foot function and a significant decrease in pain (p = 0.003) was reported. No patient reported dis-improvement after sclerotherapy. Conclusion: Percutaneous sclerotherapy is an effective option for treating foot VMs. Skin complication rates are higher with shorter VM-to-skin surface distance. - Highlights: • Treatment of foot venous malformations is a challenge due to their diffuse nature. • Percutaneous sclerotherapy is an effective treatment option. • Patients reported decrease in swelling and pain, and improvement of foot function. • Self limited post-procedural skin complications occur after 21% of the procedures. • A shorter lesion to skin surface distance was related to higher complications

  11. β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids.

    Science.gov (United States)

    Holden, Neil S; Bell, Matthew J; Rider, Christopher F; King, Elizabeth M; Gaunt, David D; Leigh, Richard; Johnson, Malcolm; Siderovski, David P; Heximer, Scott P; Giembycz, Mark A; Newton, Robert

    2011-12-01

    In asthma and chronic obstructive pulmonary disease, activation of G(q)-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β(2)-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G(q) signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases. PMID:22080612

  12. Raman spectroscopy detects deterioration in biomechanical properties of bone in a glucocorticoid-treated mouse model of rheumatoid arthritis

    Science.gov (United States)

    Maher, Jason R.; Takahata, Masahiko; Awad, Hani A.; Berger, Andrew J.

    2011-08-01

    Although glucocorticoids are frequently prescribed for the symptomatic management of inflammatory disorders such as rheumatoid arthritis, extended glucocorticoid exposure is the leading cause of physician-induced osteoporosis and leaves patients at a high risk of fracture. To study the biochemical effects of glucocorticoid exposure and how they might affect biomechanical properties of the bone, Raman spectra were acquired from ex vivo tibiae of glucocorticoid- and placebo-treated wild-type mice and a transgenic mouse model of rheumatoid arthritis. Statistically significant spectral differences were observed due to both treatment regimen and mouse genotype. These differences are attributed to changes in the overall bone mineral composition, as well as the degree of phosphate mineralization in tibial cortical bone. In addition, partial least squares regression was used to generate a Raman-based prediction of each tibia's biomechanical strength as quantified by a torsion test. The Raman-based predictions were as accurate as those produced by microcomputed tomography derived parameters, and more accurate than the clinically-used parameter of bone mineral density. These results suggest that Raman spectroscopy could be a valuable tool for monitoring bone biochemistry in studies of bone diseases such as osteoporosis, including tests of drugs being developed to combat these diseases.

  13. Synapse loss from chronically elevated glucocorticoids: relationship to neuropil volume and cell number in hippocampal area CA3.

    Science.gov (United States)

    Tata, Despina A; Marciano, Veronica A; Anderson, Brenda J

    2006-09-20

    Individuals with clinical disorders associated with elevated plasma glucocorticoids, such as major depressive disorder and Cushing's syndrome, are reported to have smaller hippocampal volume. To understand how the hippocampus responds at the cellular and subcellular levels to glucocorticoids and how such changes are related to volume measures, we have undertaken a comprehensive study of glucocorticoid effects on hippocampal CA3 volume and identified elements in the neuropil including astrocytic volume and cell and synapse number and size. Male Sprague-Dawley rats were injected with corticosterone (40 mg/kg), the primary glucocorticoid in rodents, or vehicle for 60 days. The CA3 was further subdivided so that the two-thirds of CA3 (nearest the dentate gyrus) previously shown to be vulnerable to corticosterone could be analyzed as two separate subfields. Corticosterone had no effect on neuropil volume or glial volume in the proximal subfield but caused a strong tendency for astrocytic processes to make up a larger proportion of the tissue and for volume of tissue made of constituents other than glial cells (primarily neuronal processes) to be smaller in the middle subfield. Within the neuropil, there were no cellular or subcellular profiles that indicated degeneration, suggesting that corticosterone does not cause prolonged damage. Corticosterone did not reduce cell number or cell or nonperforated synapse size but did cause a pronounced loss of synapses. This loss occurred in both subfields and, therefore, was independent of volume loss. Together, the findings suggest that volume measures can underestimate corticosterone effects on neural structure.

  14. Stress-induced glucocorticoids as a neuroendocrine alarm signal of danger.

    Science.gov (United States)

    Frank, Matthew G; Watkins, Linda R; Maier, Steven F

    2013-10-01

    A considerable number of studies demonstrate that acute and chronic stressors prime CNS innate immune responses to subsequent pro-inflammatory challenges and that glucocorticoids mediate, in part, stress-induced sensitization of pro-inflammatory immune responses. Here, we explore the notion that GCs produce a persisting sensitization of CNS innate immune effectors (e.g. microglia) so that they will generate a potentiated pro-inflammatory response after the GC rise has dissipated, thereby enhancing the sickness response to infection or injury and maximizing the animal's ability to neutralize danger. The stress-induced GC response is conceptualized here as an neuroendocrine warning signal or alarmin to the innate immune system, which prepares or sensitizes the innate immune response to potential danger. Thus, a new understanding of the stress response and its function (priming CNS innate immune responses to infection or injury during a fight/flight emergency) would be suggested.

  15. General Practitioners’ responses to global climate change - lessons from clinical experience and the clinical method

    Directory of Open Access Journals (Sweden)

    Blashki Grant

    2012-08-01

    Full Text Available Abstract Background Climate change is a global public health problem that will require complex thinking if meaningful and effective solutions are to be achieved. In this conceptual paper we argue that GPs have much to bring to the issue of climate change from their wide-ranging clinical experience and from the principles underpinning their clinical methods. This experience and thinking calls forth particular contributions GPs can and should make to debate and action. Discussion We contend that the privileged experience and GP way of thinking can make valuable contributions when applied to climate change solutions. These include a lifetime of experience, reflection and epistemological application to first doing no harm, managing uncertainty, the ability to make necessary decisions while possessing incomplete information, an appreciation of complex adaptive systems, maintenance of homeostasis, vigilance for unintended consequences, and an appreciation of the importance of transdisciplinarity and interprofessionalism. Summary General practitioners have a long history of public health advocacy and in the case of climate change may bring a way of approaching complex human problems that could be applied to the dilemmas of climate change.

  16. Genomic and non-genomic actions of glucocorticoids in asthma

    OpenAIRE

    Alangari Abdullah

    2010-01-01

    Glucocorticoids are the mainstay of asthma therapy. They are primarily used to suppress airway inflammation, which is the central pathological change in asthmatic patients′ airways. This is achieved by many different mechanisms. The classical mechanism is by suppression of the genetic transcription of many inflammatory cytokines that are key in asthma pathophysiology (transrepression). On the other hand, the transcription of certain inhibitory cytokines is activated by glucocorticoids ...

  17. Glucocorticoids and Type 2 Diabetes: From Physiology to Pathology

    Directory of Open Access Journals (Sweden)

    Guido Di Dalmazi

    2012-01-01

    Full Text Available Type 2 diabetes mellitus is the result of interaction between genetic and environmental factors, leading to heterogeneous and progressive pancreatic β-cell dysfunction. Overweight and obesity are major contributors to the development of insulin resistance and impaired glucose tolerance. The inability of β cells to secrete enough insulin produces type 2 diabetes. Abnormalities in other hormones such as reduced secretion of the incretin glucagon-like peptide 1 (GLP-1, hyperglucagonemia, and raised concentrations of other counterregulatory hormones also contribute to insulin resistance, reduced insulin secretion, and hyperglycaemia in type 2 diabetes. Clinical-overt and experimental cortisol excess is associated with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance, and low HDL-cholesterol levels, which can lead to diabetes. It was therefore suggested that subtle abnormalities in cortisol secretion and action are one of the missing links between insulin resistance and other features of the metabolic syndrome. The aim of this paper is to address the role of glucocorticoids on glucose homeostasis and to explain the relationship between hypercortisolism and type 2 diabetes.

  18. The Non-Conventional Effects of Glucocorticoids in Cancer.

    Science.gov (United States)

    Azher, Simra; Azami, Omid; Amato, Caterina; McCullough, Michael; Celentano, Antonio; Cirillo, Nicola

    2016-11-01

    Synthetic corticosteroids are widely used for the treatment of a variety of diseases, including pre-malignant and malignant conditions. In striking contrast, recent evidence suggests that corticosteroids can bear tumor-promoting effects in solid tumors of epithelial origin. We have recently shown that epithelial tissues, including the mucosa of the oral cavity and the skin, are able to modulate the local concentration of active corticosteroids and to produce steroids de novo. This has important clinical and physiopathological implications, because tissue-specific regulation of glucocorticoids plays a key role in the overall effect of these molecules. In the present review of the current English literature, performed using MEDLINE/PubMed/Ovid databases, we collected published evidence to demonstrate that corticosteroids induce effects that are more complex and controversial than previously acknowledged. Published studies clearly demonstrate that this class of molecules influences pathophysiological processes that are strictly related to malignancy, providing the rationale for further investigation. J. Cell. Physiol. 231: 2368-2373, 2016. © 2016 Wiley Periodicals, Inc. PMID:27115293

  19. Genomic and non-genomic actions of glucocorticoids in asthma

    Directory of Open Access Journals (Sweden)

    Alangari Abdullah

    2010-01-01

    Full Text Available Glucocorticoids are the mainstay of asthma therapy. They are primarily used to suppress airway inflammation, which is the central pathological change in asthmatic patients′ airways. This is achieved by many different mechanisms. The classical mechanism is by suppression of the genetic transcription of many inflammatory cytokines that are key in asthma pathophysiology (transrepression. On the other hand, the transcription of certain inhibitory cytokines is activated by glucocorticoids (transactivation, a mechanism that also mediates many of the adverse effects of glucocorticoids. The onset of action through these mechanisms is often delayed (4-24 hours. Other mechanisms mediated through non-genomic pathways are increasingly appreciated. These are delivered in part by binding of glucocorticoids to nonclassical membrane-bound glucocorticoid receptors or by potentiating the a1-adrenergic action on the bronchial arterial smooth muscles, in addition to other mechanisms. These effects are characterized by their rapid onset and short duration of action. Understanding these different mechanisms will help in the development of new and better drugs to treat this common disease and to develop new improved strategies in our approach to its management. Here, the genomic and non-genomic mechanisms of actions of glucocorticoids in asthma are briefly reviewed, with special emphasis on the current updates of the non-genomic mechanisms.

  20. The Pro-inflammatory Effects of Glucocorticoids in the Brain.

    Science.gov (United States)

    Duque, Erica de Almeida; Munhoz, Carolina Demarchi

    2016-01-01

    Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein-protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain. PMID:27445981

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

    Science.gov (United States)

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

  2. Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients.

    LENUS (Irish Health Repository)

    Behan, Lucy-Ann

    2012-02-01

    BACKGROUND: The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15-30 mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. OBJECTIVE: Primarily to define the hydrocortisone regimen which results in a 24 h cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). DESIGN: Ten male hypopituitary patients with severe ACTH deficiency (basal cortisol <100 nm and peak response to stimulation <400 nm) were enrolled in a prospective, randomized, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24 h serum cortisol sampling and QoL assessment with the Short Form 36 (SF36) and the Nottingham Health Profile (NHP) questionnaires. Free cortisol was calculated using Coolen\\'s equation. All results were compared to those of healthy, matched controls. RESULTS: Corticosteroid binding globulin (CBG) was significantly lower across all dose regimens compared to controls (P < 0.05). The lower dose regimen C (10 mg mane\\/5 mg tarde) produced a 24 h free cortisol profile (FCP) which most closely resembled that of controls. Both regimen A(20 mg mane\\/10 mg tarde) and B(10 mg mane\\/10 mg tarde) produced supraphysiological post-absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (P < 0.001). CONCLUSIONS: The lower dose of hydrocortisone (10 mg\\/5 mg) produces a more physiological cortisol profile, without compromising QoL, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality.

  3. Optimising glucocorticoid replacement therapy in severely adrenocorticotropin (ACTH) deficient hypopituitary male patients.

    LENUS (Irish Health Repository)

    Behan, Lucy-Ann

    2011-04-18

    Context:  The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15mg to 30mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. Objective:  Primarily to define the hydrocortisone regimen which results in a 24hour cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). Design:  10 male hypopituitary patients with severe ACTH deficiency (basal cortisol <100nM and peak response to stimulation <400nM) were enrolled in a prospective, randomised, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24hour serum cortisol sampling and QoL assessment with the Short Form 36 and the Nottingham Health Profile questionnaires. Free cortisol was calculated using Coolen\\'s equation. All results were compared to those of healthy, matched controls. Results:  CBG was significantly lower across all dose regimens compared to controls (p<0.05). The lower dose regimen C(10mg mane\\/5mg tarde) produced a 24hour free cortisol profile which most closely resembled that of controls. Both regimen A(20mg mane\\/10mg tarde) and B(10mg mane\\/10mg tarde) produced supraphysiological post-absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (p<0.001). Conclusions:  The lower dose of HC(10mg\\/5mg) produces a more physiological cortisol profile, without compromising quality of life, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality.

  4. Clinical application of FDG PET for pathological response of breast cancer after neo-adjuvant chemotherapy

    International Nuclear Information System (INIS)

    The purpose of this study was to assess the clinical usefulness of FDG PET in predicting the pathological response in breast cancer after neoadjuvant chemotherapy. 33 patients with newly diagnosed, locally advanced breast cancer had PET scans before and after chemotherapy to assess tumor response, and then pathology was confirmed after surgery. FDG PET for assessing tumor response was done by measuring peak SUV (pSUV) and then calculating reduction rate (RR). RR was stratified into RR complete response (rrCR) at >88% reduction, RR partial response (rrPR) at RR between 56∼87%, and no response (rrNR) in reductions <55%. Clinical assessment was done with physical exams, U/S, and CT. Histopathological response were classified into pathological no response(pNR), pathological partial response (pPR) and pathological complete response (pCR). 15% (5 of 33) patients had pCR, 85% (28 of 33) had pPR. Using a 88% reduction in SUV as a threshold value for differentiation between pCR from pPR, PET scans correctly differentiated pCR in 3 patients out of 5. When using a cut off value of 55% reduction rate, PET scans correctly differentiated pPR in 19 patients out of 21, and for pNR, the PET scans correctly differentiated only 2 patients out of 7. Diagnostic accuracy of PET for pathologic response was 25 out of 33 cases (75.8%). The diagnostic accuracy of clinical assessment was 25 of 33 cases (72.7%). This study suggests that pSUV reduction rate can be a useful tool when predicting the pathological response of primary breast cancers after neo-adjuvant chemotherapy

  5. Effect of glucocorticoids on the activity, expression and proximal promoter of type II deiodinase in rat brown adipocytes.

    Science.gov (United States)

    Martinez-deMena, Raquel; Calvo, Rosa-Maria; Garcia, Laura; Obregon, Maria Jesus

    2016-06-15

    Triiodothyronine (T3) is important for thermogenesis in brown adipose tissue (BAT). Type II deiodinase (DIO2) produces T3 required for intracellular needs in BAT. Brown adipocytes in culture require T3 for the adrenergic stimulation of DIO2. Glucocorticoids induce adipocyte differentiation (lipogenesis). We investigated the regulation of DIO2 activity, Dio2 mRNA and Dio2 promoter activity by glucocorticoids in primary cultures of rat brown adipocytes using dexamethasone (DEX) and hydrocortisone (HC). DEX and HC regulated the adrenergic stimulation of DIO2 activity in a dose- and time-dependent manner, inhibiting DIO2 activity at short treatment times and large doses (1-10 μM) and stimulating DIO2 at low HC doses (1-100 nM) and longer times (DEX). Insulin depletion reduced DIO2 activity but the response to glucocorticoids remained unchanged. DEX and HC inhibited basal DIO2 activity. DEX had no effect on DIO2 half-life, whereas HC stabilized DIO2 activity. DEX and HC inhibited the adrenergic stimulation of Dio2 mRNA expression (100-10000 nM, 14-96 h), but stabilized Dio2 mRNA, particularly DEX. DEX increased basal Dio2 mRNA levels, possibly through stabilization of Dio2 mRNA. An 807 bp construct of the murine Dio2 proximal promoter showed maximal reporter activity, with the cAMP response element (CRE) essential for transcriptional activity. DEX caused inhibition in most constructs containing the CRE element whereas HC stimulated reporter activity in the 807 bp construct. Glucocorticoids inhibited the adrenergic stimulation of Dio2 at the transcriptional level in brown adipocytes, although DIO2 activity increased with HC, possibly due to stabilization of Dio2 activity and mRNA. The CRE and cEBP elements of the Dio2 promoter seem involved in the regulation by glucocorticoids. PMID:26994513

  6. Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

    Energy Technology Data Exchange (ETDEWEB)

    Togi, Sumihito; Nakasuji, Misa; Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako; Kitai, Yuichi; Kon, Shigeyuki [Department of Immunology, Graduate School of Pharmaceutical Sciences Hokkaido University, Sapporo 060-0812 (Japan); Oritani, Kenji [Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Matsuda, Tadashi, E-mail: tmatsuda@pharm.hokudai.ac.jp [Department of Immunology, Graduate School of Pharmaceutical Sciences Hokkaido University, Sapporo 060-0812 (Japan)

    2015-07-31

    Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA), which interacts with cellular proteins, plays a central role in modification of viral and/or cellular gene expression. Here, we show that LANA associates with glucocorticoid receptor (GR), and that LANA enhances the transcriptional activity of GR. Co-immunoprecipitation revealed a physical interaction between LANA and GR in transiently transfected 293T and HeLa cells. In human B-lymphoma cells, LANA overexpression enhanced GR activity and cell growth suppression following glucocorticoid stimulation. Furthermore, confocal microscopy showed that activated GR was bound to LANA and accumulated in the nucleus, leading to an increase in binding of activated GR to the glucocorticoid response element of target genes. Taken together, KSHV-derived LANA acts as a transcriptional co-activator of GR. Our results might suggest a careful use of glucocorticoids in the treatment of patients with KSHV-related malignancies such as Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. - Highlights: • KSHV-LANA enhances the transcriptional activity of GR in 293T and HeLa cells. • KSHV-LANA physically associates with GR. • KSHV-LANA enhances GR activation and cell growth suppression in human B-lymphocytes. • KSHV-LANA influences the nuclear retention and DNA binding activity of GR.

  7. Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

    International Nuclear Information System (INIS)

    Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA), which interacts with cellular proteins, plays a central role in modification of viral and/or cellular gene expression. Here, we show that LANA associates with glucocorticoid receptor (GR), and that LANA enhances the transcriptional activity of GR. Co-immunoprecipitation revealed a physical interaction between LANA and GR in transiently transfected 293T and HeLa cells. In human B-lymphoma cells, LANA overexpression enhanced GR activity and cell growth suppression following glucocorticoid stimulation. Furthermore, confocal microscopy showed that activated GR was bound to LANA and accumulated in the nucleus, leading to an increase in binding of activated GR to the glucocorticoid response element of target genes. Taken together, KSHV-derived LANA acts as a transcriptional co-activator of GR. Our results might suggest a careful use of glucocorticoids in the treatment of patients with KSHV-related malignancies such as Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. - Highlights: • KSHV-LANA enhances the transcriptional activity of GR in 293T and HeLa cells. • KSHV-LANA physically associates with GR. • KSHV-LANA enhances GR activation and cell growth suppression in human B-lymphocytes. • KSHV-LANA influences the nuclear retention and DNA binding activity of GR

  8. Oxidative stress in the developing brain: effects of postnatal glucocorticoid therapy and antioxidants in the rat.

    Directory of Open Access Journals (Sweden)

    Emily J Camm

    Full Text Available In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on long-term neurological function. Glucocorticoid excess promotes free radical overproduction. We hypothesised that the adverse effects of postnatal glucocorticoid therapy on the developing brain are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Male rat pups received a clinically-relevant tapering course of dexamethasone (DEX; 0.5, 0.3, and 0.1 mg x kg(-1 x day(-1, with or without antioxidant vitamins C and E (DEXCE; 200 mg x kg(-1 x day(-1 and 100 mg x kg(-1 x day(-1, respectively, on postnatal days 1-6 (P1-6. Controls received saline or saline with vitamins. At weaning, relative to controls, DEX decreased total brain volume (704.4±34.7 mm(3 vs. 564.0±20.0 mm(3, the soma volume of neurons in the CA1 (1172.6±30.4 µm(3 vs. 1002.4±11.8 µm(3 and in the dentate gyrus (525.9±27.2 µm(3 vs. 421.5±24.6 µm(3 of the hippocampus, and induced oxidative stress in the cortex (protein expression: heat shock protein 70 [Hsp70]: +68%; 4-hydroxynonenal [4-HNE]: +118% and nitrotyrosine [NT]: +20%. Dexamethasone in combination with vitamins resulted in improvements in total brain volume (637.5±43.1 mm(3, and soma volume of neurons in the CA1 (1157.5±42.4 µm(3 and the dentate gyrus (536.1±27.2 µm(3. Hsp70 protein expression was unaltered in the cortex (+9%, however, 4-HNE (+95% and NT (+24% protein expression remained upregulated. Treatment of neonates with vitamins alone induced oxidative stress in the cortex (Hsp70: +67%; 4-HNE: +73%; NT: +22% and in the hippocampus (NT: +35%. Combined glucocorticoid and antioxidant therapy in premature infants may be safer for the developing brain than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.

  9. Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Levinsen, Mette; Taskinen, Mervi; Abrahamsson, Jonas;

    2014-01-01

    BACKGROUND: Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) remains a therapeutic challenge. PROCEDURE: To explore leukemia characteristics of patients with CNS involvement at ALL diagnosis, we analyzed clinical features and early treatment response of 744....... Symptoms or clinical findings were present among 27 of 54 patients with CNS3 versus only 7 of 39 patients with CNS2 and 15 of 75 patients with TLP+ (P bone marrow residual disease level did...

  10. Learning in clinical practice: Stimulating and discouraging response to social comparison

    OpenAIRE

    Raat, Janet; Kuks, Jan; Cohen-Schotanus, Janke

    2010-01-01

    Background: Social comparison theory is relevant for learning in general. In a clinical context, we examined four hypotheses concerning: preferred other to compare with, preferred direction of comparison, response to social comparison and influence of personal social comparison orientation (SCO). Aim: To investigate the relevance of social comparison for clinical workplace learning. Method: Students (n = 437) from nine different hospitals completed two questionnaires measuring their SCO and t...

  11. Induction of digitoxigenin monodigitoxoside UDP-glucuronosyltransferase activity by glucocorticoids and other inducers of cytochrome P-450p in primary monolayer cultures of adult rat hepatocytes and in human liver.

    Science.gov (United States)

    Schuetz, E G; Hazelton, G A; Hall, J; Watkins, P B; Klaassen, C D; Guzelian, P S

    1986-06-25

    We have recently proposed that glucocorticoids induce cytochrome P-450p, a liver microsomal hemoprotein originally isolated from rats treated with the antiglucocorticoid pregnenolone 16 alpha-carbonitrile (PCN), through a mechanism that involves a stereospecific recognition system clearly distinguishable from the classic glucocorticoid receptor (Schuetz, E. G., Wrighton, S. A., Barwick, J. L., and Guzelian, P. S. (1984) J. Biol. Chem. 259, 1999-2012). We now report that digitoxigenin monodigitoxoside UDP-glucuronosyltransferase (DIG UDP-glucuronosyltransferase), a liver microsomal enzyme activity induced by PCN in rats, is also inducible, as is P-450p, in primary monolayer cultures of adult rat hepatocytes. DIG UDP-glucuronosyltransferase activity closely resembled reported characteristics of induction of P-450p in its time course of induction, concentration-response relationships, exclusivity of induction by steroids with glucocorticoid properties, unusual rank order of potency of glucocorticoid agonists, unusually high ED50 for induction by glucocorticoids, enhanced induction rather than inhibition by anti-glucocorticoids in the presence of glucocorticoids, and finally, induction by nonsteroidal inducers of P-450p. DIG UDP-glucuronosyltransferase activity was also readily detected in human liver microsomes and was elevated in two patients who had received inducers of P-450p. We conclude that the liver enzymes controlled by the postulated PCN recognition system include not only P-450p but also one or more UDP-glucuronosyltransferases.

  12. Effects of glucocorticoids on the growth and chemosensitivity of carcinoma cells are heterogeneous and require high concentration of functional glucocorticoid receptors

    Institute of Scientific and Technical Information of China (English)

    Yen-Shen Lu; Huang-Chun Lien; Pei-Yen Yeh; Kun-Huei Yeh; Min-Liang Kuo; Sung-Hsin Kuo; Ann-Lii Cheng

    2005-01-01

    AIM: To determine how glucocorticoids (GCs) may affect the growth and chemosensitivity of common carcinoma cells.METHODS: The effect of dexamethasone (DEX) on growth and chemosensitivity was assessed in 14 carcinoma cell lines. The function of GC receptors (GR) was assessed by MMTV reporter assay. Overexpression of GR was done by in vitro transfection and expression of a GR-expressing vector. Immunohistochemical stain of tissues and cells were done by PA1-511A, an anti-GR monoclonal antibody.RESULTS: DEX inhibited cell growth of four (MCF-7, MCF-7/MXR1, MCF-7/TPT300, and HeLa), increased cisplatin cytotoxicity of one (SiHa), and decreased cisplatin cytotoxicity of two (H460 and Hep3B) cell lines. The GR content of the seven cell lines affected by DEX was significantly higher than those of the seven cell lines unaffected by DEX(5.2±2.5×104 sites/cell vs 1.3±1.4×104 sites/cell, P= 0.005).Only two DEX-unresponsive cell lines (NPC-TW01 and NPCTW04) contained high GR amounts in the range (1.9-8.1×104sites/cell) of the seven DEX-responsive cell lines. The GR function of NPC-TW01 and NPC-TW04, however, was found to be impaired. The importance of high cellular amount of GR in mediating DEX susceptibility of the cells was further exemplified by GR dose-dependent drug resistance to cisplatin of AGS, a cell line with low GR content and was unaffected by DEX before transfection of GR-expressing vector. Immunohistochemical studies of human cancer tissues showed that 5 of the 45 (11.1%) breast cancer and 43 of the 85 (50.6%) non-small cell lung cancer had high GR contents at the ranges of the GC-responsive carcinoma cell lines.CONCLUSION: The growth and chemosensitivity of human carcinomas with high GR contents may be affected by GC. However, in light of the heterogeneous and even contradictive effects of GC on these cells, routine examination of GR contents of human carcinoma tissues may not be clinically useful until other markers that help predict the ultimate effect of

  13. Stress in wildlife species: noninvasive monitoring of glucocorticoids.

    Science.gov (United States)

    Romano, Marta C; Rodas, Alba Zulema; Valdez, Ricardo A; Hernández, Sandra Elizabeth; Galindo, Francisco; Canales, Domingo; Brousset, Dulce Maria

    2010-01-01

    Depression and stress are related pathologies extensively studied in humans. However, this relationship is not well known in animals kept in zoos and even less known in wild animals. In zoo animals, acute and chronic stress caused by difficulties in coping with stressors such as public presence and noise, among others, can induce the appearance of repetitive pathological behaviors such as stereotypies, many times associated with organic pathologies that deeply affect their health and welfare. In the wild, factors such as deforestation, habitat fragmentation, lack of food and water, and human disturbances are potential causes of acute and chronic stress for the resident fauna. Glucocorticoids (GC) have been extensively used as stress indicators in many species including humans. Since chase and handling of wild animals immediately raise their GC serum levels, noninvasive methods have been developed to assess stress without interference caused by sample collection. The hormones and their metabolites can be measured in various body fluids and excreta and detect basal feedback free hormone concentrations as well as the response to ACTH and handling. In order to study the influence of disturbing factors we have measured GC as stress indicators by noninvasive techniques in dolphins and felids (ocelots, jaguarundis and margays) and cortisol and testosterone in spider monkeys. PMID:20134205

  14. 他克莫司联合LED红光治疗糖皮质激素依赖性皮炎的疗效观察%Clinical Observation of the Treatment of Facial Dermatitis Glucocorticoid-dependent Through Tacrolimus and Combined LED Red Light

    Institute of Scientific and Technical Information of China (English)

    罗海军

    2013-01-01

    目的:探索他莫克司软膏和LED红光对面部糖皮激素皮炎的疗效。方法:选取我院2008年2月至2013年5月的30例激素依赖面部皮肤炎症患者进行回顾性分析。使用波长(633±3)nm LED红光治疗,每周2~3次,10次为1个疗程。0.1%他克莫司软膏,在患处皮肤外涂,2次/1d。治疗共5周,对治疗前、治疗后的1、3、5周和停止治疗后3周进行回访。结果:30例患者中29例完成本次实验。1、3、5周的分别临床治疗显效率为20.6%、48.3%、55.2%,在停药后的3周后,显效患者为41.4%。结论:采取LED红光、0.1%他克莫司联合对面部激素依赖性的皮炎患者进行治疗,临床疗效显著,且安全,值得临床推广。%Objective To explore the curative effect of tacromilus ointment and LED red on facial glucocorticoids dermatitis. Methods 30 cases with hormone dependent facial skin inflammation in the hospital from February 2008 to May 2013 were retrospectively analyzed. LED red light with(633±3)nm wave length was used in the treatment with 3~4 times a week,and 10 times as a course. Every time after phototherapy,0.1%tacrolimus was used on wounded part 2 times a day. Treatment for 5 weeks,a return visit was doing after 1, 3,and 5 weeks of treatment and 3 weeks after cessation of treatment. Results 29 of 30 cases completed the experiment. Clinical treatment rate was 20.6%,48.3% and 55.2% after 1,3,5 weeks’treatment respectively, with 41.4% patients having significant effect. Conclusion Treatment of facial hormone dependent dermatitis through LED red light combined with 0.1% tacrolimus has clinical efficacy,and is safe and worth clinical promotion.

  15. Current practice of glucocorticoid replacement therapy and patient-perceived health outcomes in adrenal insufficiency - a worldwide patient survey

    OpenAIRE

    Forss M; Batcheller G; Skrtic S; Johannsson G

    2012-01-01

    Abstract Background The aim was to survey current practice in glucocorticoid replacement therapy and self-perceived health outcomes in patients with adrenal insufficiency. Methods Participants were recruited via patient organizations to respond anonymously to a web-based survey developed by clinical experts. Unique entries were set up for each patient organization enabling geographical localization of the entries. Results 1245 participants responded (primary adrenal insufficiency: 84%; second...

  16. Evaluation of the response to treatment and clinical evolution in patients with burning mouth syndrome

    OpenAIRE

    M.E. Rodríguez de Rivera Campillo; López López, José

    2013-01-01

    Objective: the aim of this study is to investigate the clinical evolution, the spontaneous remission of the symptomatology and the response to different treatments in a group of burning mouth syndrome patients. Study Design: the sample was formed by a group of patients that were visited in the Unit of Oral Medicine of the Dentistry Clinic of the University of Barcelona, from the year 2000 to 2011. After revising the clinical records of all the patients that had been under control for a period...

  17. Quantification of clinical scores through physiological recordings in low-responsive patients: a feasibility study

    Directory of Open Access Journals (Sweden)

    Wieser Martin

    2012-05-01

    Full Text Available Abstract Clinical scores represent the gold standard in characterizing the clinical condition of patients in vegetative or minimally conscious state. However, they suffer from problems of sensitivity, specificity, subjectivity and inter-rater reliability. In this feasibility study, objective measures including physiological and neurophysiological signals are used to quantify the clinical state of 13 low-responsive patients. A linear regression method was applied in nine patients to obtain fixed regression coefficients for the description of the clinical state. The statistical model was extended and evaluated with four patients of another hospital. A linear mixed models approach was introduced to handle the challenges of data sets obtained from different locations. Using linear backward regression 12 variables were sufficient to explain 74.4% of the variability in the change of the clinical scores. Variables based on event-related potentials and electrocardiogram account for most of the variability. These preliminary results are promising considering that this is the first attempt to describe the clinical state of low-responsive patients in such a global and quantitative way. This new model could complement the clinical scores based on objective measurements in order to increase diagnostic reliability. Nevertheless, more patients are necessary to prove the conclusions of a statistical model with 12 variables.

  18. m-Chlorophenylpiperazine challenge in borderline personality disorder: relationship of neuroendocrine response, behavioral response, and clinical measures.

    Science.gov (United States)

    Stein, D J; Hollander, E; DeCaria, C M; Simeon, D; Cohen, L; Aronowitz, B

    1996-09-15

    We have previously found that a subgroup of patients with impulsive personality disorders respond to m-chlorophenylpiperazine (m-CPP) administration with a distinctive spacy/high behavioral reaction and with increased cortisol responses. In this report we analyzed the relationship between behavioral and neuroendocrine responses to m-CPP in an enlarged sample of patients with borderline personality disorder (BPD). We also assessed the association of behavioral and neuroendocrine responses with clinical symptoms and with m-CPP blood levels. We found that in BPD patients the presence of a spacy/high behavioral response was significantly associated with increased prolactin and cortisol responses to m-CPP. In BPD patients increased m-CPP levels were significantly associated with neuroendocrine hypersensitivity and with a spacy/high behavioral response, while in controls increased m-CPP levels were not significantly associated with neuroendocrine hypersensitivity but were significantly associated with dysphoric behavioral responses. Taken together with previous work on m-CPP in obsessive-compulsive disorder, these results are partially consistent with the hypothesis that compulsive and impulsive symptoms fall at opposite ends of a phenomenologic and neurobiologic spectrum.

  19. 老年慢性阻塞性肺气肿采用抗生素联合糖皮质激素治疗的临床观察%Clinical Observation of Elderly Patients With Chronic Obstructive Pulmonary Emphysema With Antibiotic and Glucocorticoid Therapy

    Institute of Scientific and Technical Information of China (English)

    张全军

    2015-01-01

    ObjectiveTo observe the effect of antibiotics combined with glucocorticoid in the treatment of elderly patients with chronic obstructive pulmonary emphysema effect.Methods A total of 110 elderly patients with chronic obstructive pulmonary emphysema patients were given conventional treatment with antibiotics and glucocorticoid treatment.ResultsThe total efficiency of the observation group after treatment,arterial partial pressure of oxygen, carbon dioxide partial pressure were better than the control group. ConclusionIn elderly patients with chronic obstructive pulmonary emphysema and effect of antibiotics and glucocorticoid treatment was significantly.%目的:观察抗生素联合糖皮质激素治疗中老年慢性阻塞性肺气肿的效果。方法110例慢性阻塞性肺气肿老年患者分别给予常规治疗与抗生素联合糖皮质激素治疗。结果观察组治疗总有效率、治疗后血氧分压、二氧化碳分压均优于对照组。结论抗生素联合糖皮质激素治疗中老年慢性阻塞性肺气肿效果显著。

  20. Clinicians' emotional responses and Psychodynamic Diagnostic Manual adult personality disorders: A clinically relevant empirical investigation.

    Science.gov (United States)

    Gazzillo, Francesco; Lingiardi, Vittorio; Del Corno, Franco; Genova, Federica; Bornstein, Robert F; Gordon, Robert M; McWilliams, Nancy

    2015-06-01

    The aim of this study is to explore the relationship between level of personality organization and type of personality disorder as assessed with the categories in the Psychodynamic Diagnostic Manual (PDM; PDM Task Force, 2006) and the emotional responses of treating clinicians. We asked 148 Italian clinicians to assess 1 of their adult patients in treatment for personality disorders with the Psychodiagnostic Chart (PDC; Gordon & Bornstein, 2012) and the Personality Diagnostic Prototype (PDP; Gazzillo, Lingiardi, & Del Corno, 2012) and to complete the Therapist Response Questionnaire (TRQ; Betan, Heim, Zittel-Conklin, & Westen, 2005). The patients' level of overall personality pathology was positively associated with helpless and overwhelmed responses in clinicians and negatively associated with positive emotional responses. A parental and disengaged response was associated with the depressive, anxious, and dependent personality disorders; an exclusively parental response with the phobic personality disorder; and a parental and criticized response with narcissistic disorder. Dissociative disorder evoked a helpless and parental response in the treating clinicians whereas somatizing disorder elicited a disengaged reaction. An overwhelmed and disengaged response was associated with sadistic and masochistic personality disorders, with the latter also associated with a parental and hostile/criticized reaction; an exclusively overwhelmed response with psychopathic patients; and a helpless response with paranoid patients. Finally, patients with histrionic personality disorder evoked an overwhelmed and sexualized response in their clinicians whereas there was no specific emotional reaction associated with the schizoid and the obsessive-compulsive disorders. Clinical implications of these findings were discussed.

  1. Typhoid fever in young children in Bangladesh: clinical findings, antibiotic susceptibility pattern and immune responses.

    Directory of Open Access Journals (Sweden)

    Farhana Khanam

    2015-04-01

    Full Text Available Children bear a large burden of typhoid fever caused by Salmonella enterica serotype Typhi (S. Typhi in endemic areas. However, immune responses and clinical findings in children are not well defined. Here, we describe clinical and immunological characteristics of young children with S. Typhi bacteremia, and antimicrobial susceptibility patterns of isolated strains.As a marker of recent infection, we have previously characterized antibody-in-lymphocyte secretion (TPTest during acute typhoid fever in adults. We similarly assessed membrane preparation (MP IgA responses in young children at clinical presentation, and then 7-10 days and 21-28 days later. We also assessed plasma IgA, IgG and IgM responses and T cell proliferation responses to MP at these time points. We compared responses in young children (1-5 years with those seen in older children (6-17 years, adults (18-59 years, and age-matched healthy controls.We found that, compared to age-matched controls patients in all age cohorts had significantly more MP-IgA responses in lymphocyte secretion at clinical presentation, and the values fell in all groups by late convalescence. Similarly, plasma IgA responses in patients were elevated at presentation compared to controls, with acute and convalescent IgA and IgG responses being highest in adults. T cell proliferative responses increased in all age cohorts by late convalescence. Clinical characteristics were similar in all age cohorts, although younger children were more likely to present with loss of appetite, less likely to complain of headache compared to older cohorts, and adults were more likely to have ingested antibiotics. Multi-drug resistant strains were present in approximately 15% of each age cohort, and 97% strains had resistance to nalidixic acid.This study demonstrates that S. Typhi bacteremia is associated with comparable clinical courses, immunologic responses in various age cohorts, including in young children, and that TPTest

  2. Clinical Predictors of Drug Response in Patients with Obsessive-Compulsive Disorder

    OpenAIRE

    Kim, Chan-Hyung; Jeong, Jae-Wook; Kim, Eun Ju; Shin, Yoon Shick; Suh, Ho Suk; Lee, Hong Shick; Koo, Min-Seong

    2011-01-01

    Objective The aim of this study was to evaluate which clinical variables might influence the antiobsessional responses to proserotonergic drugs in a sample of patients with obsessive-compulsive disorder (OCD). Methods Two hundred forty-nine patients with DSM-IV OCD under-gone mean 13-month treatments with selective serotonin reuptake inhibitors. According to the treatment response, defined as a reductions of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score ≥35%, patients were di...

  3. The Relationship between Stress Levels and Biological Responses in a Clinical Nursing Practicum

    OpenAIRE

    Chikamura, Chiho; Iida, Tadayuki; Ishizaki, Fumiko; Aoi, Satomi; Kobayashi, Toshio; Kataoka, Tsuyoshi

    2008-01-01

    We evaluated the association between the stress levels and biological responses of nursing students in a clinical practicum. The subjects consisted of 28 third-year nursing students at the nursing department of College A. The degree of stress was evaluated using the Japanese version of the State Trait Anxiety Inventory (STAI). As parameters of biological responses, serum estrogen, salivary cortisol, and salivary IgA were measured. These measurements were performed twice (before and during the...

  4. Glucocorticoids enhance extinction-based psychotherapy.

    Science.gov (United States)

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

    2011-04-19

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

  5. Hepatitis B vaccine antibody response and the risk of clinical AIDS or death.

    Directory of Open Access Journals (Sweden)

    Michael L Landrum

    Full Text Available BACKGROUND: Whether seroresponse to a vaccine such as hepatitis B virus (HBV vaccine can provide a measure of the functional immune status of HIV-infected persons is unknown.This study evaluated the relationship between HBV vaccine seroresponses and progression to clinical AIDS or death. METHODS AND FINDINGS: From a large HIV cohort, we evaluated those who received HBV vaccine only after HIV diagnosis and had anti-HBs determination 1-12 months after the last vaccine dose. Non-response and positive response were defined as anti-HBs <10 and ≥ 10 IU/L, respectively. Participants were followed from date of last vaccination to clinical AIDS, death, or last visit. Univariate and multivariable risk of progression to clinical AIDS or death were evaluated with Cox regression models. A total of 795 participants vaccinated from 1986-2010 were included, of which 41% were responders. During 3,872 person-years of observation, 122 AIDS or death events occurred (53% after 1995. Twenty-two percent of non-responders experienced clinical AIDS or death compared with 5% of responders (p<0.001. Non-response to HBV vaccine was associated with a greater than 2-fold increased risk of clinical AIDS or death (HR 2.47; 95% CI, 1.38-4.43 compared with a positive response, after adjusting for CD4 count, HIV viral load, HAART use, and delayed type hypersensitivity skin test responses (an in vivo marker of cell-mediated immunity. This association remained evident among those with CD4 count ≥ 500 cells/mm³ (HR 3.40; 95% CI, 1.39-8.32. CONCLUSIONS: HBV vaccine responses may have utility in assessing functional immune status and risk stratificating HIV-infected individuals, including those with CD4 count ≥ 500 cells/mm³.

  6. Distribution and Abundance of Glucocorticoid and Mineralocorticoid Receptors throughout the Brain of the Great Tit (Parus major.

    Directory of Open Access Journals (Sweden)

    Rebecca A Senft

    Full Text Available The glucocorticoid stress response, regulated by the hypothalamic-pituitary-adrenal (HPA axis, enables individuals to cope with stressors through transcriptional effects in cells expressing the appropriate receptors. The two receptors that bind glucocorticoids-the mineralocorticoid receptor (MR and glucocorticoid receptor (GR-are present in a variety of vertebrate tissues, but their expression in the brain is especially important. Neural receptor patterns have the potential to integrate multiple behavioral and physiological traits simultaneously, including self-regulation of glucocorticoid secretion through negative feedback processes. In the present work, we quantified the expression of GR and MR mRNA throughout the brain of a female great tit (Parus major, creating a distribution map encompassing 48 regions. This map, the first of its kind for P. major, demonstrated a widespread but not ubiquitous distribution of both receptor types. In the paraventricular nucleus of the hypothalamus (PVN and the hippocampus (HP-the two brain regions that we sampled from a total of 25 birds, we found high GR mRNA expression in the former and, unexpectedly, low MR mRNA in the latter. We examined the covariation of MR and GR levels in these two regions and found a strong, positive relationship between MR in the PVN and MR in the HP and a similar trend for GR across these two regions. This correlation supports the idea that hormone pleiotropy may constrain an individual's behavioral and physiological phenotype. In the female song system, we found moderate GR in hyperstriatum ventrale, pars caudalis (HVC, and moderate MR in robust nucleus of the arcopallium (RA. Understanding intra- and interspecific patterns of glucocorticoid receptor expression can inform us about the behavioral processes (e.g. song learning that may be sensitive to stress and stimulate future hypotheses concerning the relationships between receptor expression, circulating hormone concentrations

  7. Greater glucocorticoid receptor activation in hippocampus of aged rats sensitizes microglia.

    Science.gov (United States)

    Barrientos, Ruth M; Thompson, Vanessa M; Kitt, Meagan M; Amat, Jose; Hale, Matthew W; Frank, Matthew G; Crysdale, Nicole Y; Stamper, Christopher E; Hennessey, Patrick A; Watkins, Linda R; Spencer, Robert L; Lowry, Christopher A; Maier, Steven F

    2015-03-01

    Healthy aging individuals are more likely to suffer profound memory impairments following an immune challenge than are younger adults. These challenges produce a brain inflammatory response that is exaggerated with age. Sensitized microglia found in the normal aging brain are responsible for this amplified response, which in turn interferes with processes involved in memory formation. Here, we examine factors that may lead aging to sensitize microglia. Aged rats exhibited higher corticosterone levels in the hippocampus, but not in plasma, throughout the daytime (diurnal inactive phase). These elevated hippocampal corticosterone levels were associated with increased hippocampal 11β-hydroxysteroid dehydrogenase type 1 protein expression, the enzyme that catalyzes glucocorticoid formation and greater hippocampal glucocorticoid receptor (GR) activation. Intracisternal administration of mifepristone, a GR antagonist, effectively reduced immune-activated proinflammatory responses, specifically from hippocampal microglia and prevented Escherichia coli-induced memory impairments in aged rats. Voluntary exercise as a therapeutic intervention significantly reduced total hippocampal GR expression. These data strongly suggest that increased GR activation in the aged hippocampus plays a critical role in sensitizing microglia.

  8. In vivo/In vitro immune responses to L. major isolates from patients with no clinical response to Glucantime

    Science.gov (United States)

    Saberi, Sedigheh; Arjmand, Reza; Soleimanifard, Simindokht; Khamesipour, Ali; Hosseini, Seyed Mohsen; Salehi, Mansoor; Varshosaz, Jaleh; Palizban, Abbas Ali; Hejazi, Seyed Hossein

    2016-01-01

    Background: Leishmaniasis is a major health problem in some endemic areas of tropical and subtropical areas of the world. Interleukin-12 (IL-12) and interferon gamma (IFN-γ) are essential cytokines associated with initiation of Th1 response. The main objective of this study was to evaluate of the type of immune response to L. major isolates from patients with no clinical response to antimonite (Glucantime). Materials and Methods: This experimental study was carried out during 2013–2014. In the current study Leishmania major were isolated from 10 CL patients with a history of at least one course of treatment with Meglumine antimonate (Sb5). The isolates were used to evaluate in vitro and in vivo response to Sb5. J774 murine macrophage cell line was used for in vitro tests and Balb/c mice was used for in vivo studies. IL-12 gene expression was evaluated using Real-time PCR and IFN-γ serum level was quantified using ELISA technique. SPSS (version: 20), analysis of Covariance (ANCOVA) was used for statistical analysis. Results: PCR results confirmed that all 10 isolates were L. major. The mean of IL-12 gene expression in vitro, in vivo and IFN-γ serum levels (pg/ml) after 2 and 3 weeks treatment in vivo, increased significantly following the treatment with Glucantime in the two groups of Balb/c mice infected either with patients' isolates or standard L. major. No significant difference was seen between the patients' isolates and standard species. Conclusions: Although the L. major were isolated from patients with active lesion and no clinical response to Glucantime after at least one courses of Glucantime treatment but in vivo and in vitro immune response of L. major isolates showed no difference between the patients' isolates and standard L. major. PMID:27563636

  9. Learning in clinical practice : Stimulating and discouraging response to social comparison

    NARCIS (Netherlands)

    Raat, Janet; Kuks, Jan; Cohen-Schotanus, Janke

    2010-01-01

    Background: Social comparison theory is relevant for learning in general. In a clinical context, we examined four hypotheses concerning: preferred other to compare with, preferred direction of comparison, response to social comparison and influence of personal social comparison orientation (SCO). Ai

  10. Refining Video Game Use Questionnaires for Research and Clinical Application: Detection of Problematic Response Sets

    Science.gov (United States)

    Faust, Kyle A.; Faust, David; Baker, Aaron M.; Meyer, Joseph F.

    2012-01-01

    Even when relatively infrequent, deviant response sets, such as defensive and careless responding, can have remarkably robust effects on individual and group data and thereby distort clinical evaluations and research outcomes. Given such potential adverse impacts and the widespread use of self-report measures when appraising addictions and…

  11. The Value of Item Response Theory in Clinical Assessment: A Review

    Science.gov (United States)

    Thomas, Michael L.

    2011-01-01

    Item response theory (IRT) and related latent variable models represent modern psychometric theory, the successor to classical test theory in psychological assessment. Although IRT has become prevalent in the measurement of ability and achievement, its contributions to clinical domains have been less extensive. Applications of IRT to clinical…

  12. Predictive Power of the Baseline QRS Complex Duration for Clinical Response to Cardiac Resynchronisation Therapy

    Directory of Open Access Journals (Sweden)

    Ali Kazemisaeid

    2011-02-01

    Full Text Available Background: Determination of predictors of response to cardiac resynchronisation therapy (CRT in patients with moderate to severe heart failure accompanied by a ventricular dyssynchrony can play a major role in improving candidate selection for CRT.Objectives: We evaluated whether the baseline QRS duration could be used to discriminate responders from non-responders to CRT.Methods: Eighty three consecutive patients with moderate to severe heart failure and with successful implantation of a CRT device at our centre were included in the study. QRS durations were measured on 12-lead surface electrocardiogram before and 6 months after implantation of the CRT device, using the widest QRS complex in leads II, V1 and V6. Clinical response to CRT was defined as an improvement of ≥1 grade in NYHA class.Results: Optimal cut-off value to discriminate baseline QRS duration for predicting clinical response to CRT was identified at 152 ms, yielding a sensitivity of 73.3%, a specificity of 56.5% as well as positive and negative predictive values of 81.5% and 44.8%, respectively. The discriminatory pow- er of the baseline QRS duration for response to CRT assessed by the ROC curve was 0.6402 (95% CI: 0.4976 – 0.7829. Baseline QRS duration ≥ 152 ms could effectively predict clinical response to CRT after adjusting for covariates (OR = 3.743, p = 0.017.Conclusion: Baseline QRS duration can effectively predict clinical response to CRT and optimal cut-off value to discriminate baseline QRS duration for response to CRT is 152 ms.

  13. Glucocorticoids both stimulate and inhibit production of pulmonary surfactant protein A in fetal human lung.

    OpenAIRE

    Liley, H G; White, R T; Benson, B J; Ballard, P L

    1988-01-01

    Pulmonary surfactant is a mixture of phospholipids and proteins which stabilizes lung alveoli and prevents respiratory failure. The surfactant-associated protein of Mr = 28,000-36,000 (SP-A) influences the structure, function (film formation), and metabolism of surfactant. We have characterized glucocorticoid regulation of SP-A and SP-A mRNA in explants of fetal human lung. The time course of response to dexamethasone was biphasic, with early stimulation and later inhibition of SP-A accumulat...

  14. Luman/CREB3 recruitment factor regulates glucocorticoid receptor activity and is essential for prolactin-mediated maternal instinct.

    Science.gov (United States)

    Martyn, Amanda C; Choleris, Elena; Gillis, Daniel J; Armstrong, John N; Amor, Talya R; McCluggage, Adam R R; Turner, Patricia V; Liang, Genqing; Cai, Kimberly; Lu, Ray

    2012-12-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a major part of the neuroendocrine system in animal responses to stress. It is known that the HPA axis is attenuated at parturition to prevent detrimental effects of glucocorticoid secretion including inhibition of lactation and maternal responsiveness. Luman/CREB3 recruitment factor (LRF) was identified as a negative regulator of CREB3 which is involved in the endoplasmic reticulum stress response. Here, we report a LRF gene knockout mouse line that has a severe maternal behavioral defect. LRF(-/-) females lacked the instinct to tend pups; 80% of their litters died within 24 h, while most pups survived if cross-fostered. Prolactin levels were significantly repressed in lactating LRF(-/-) dams, with glucocorticoid receptor (GR) signaling markedly augmented. In cell culture, LRF repressed transcriptional activity of GR and promoted its protein degradation. LRF was found to colocalize with the known GR repressor, RIP140/NRIP1, which inhibits the activity by GR within specific nuclear punctates that are similar to LRF nuclear bodies. Furthermore, administration of prolactin or the GR antagonist RU486 restored maternal responses in mutant females. We thus postulate that LRF plays a critical role in the attenuation of the HPA axis through repression of glucocorticoid stress signaling during parturition and the postpartum period.

  15. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  16. Glucocorticoid and progesterone receptors in yolk sac placenta.

    Science.gov (United States)

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

    1986-01-01

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

  17. Lymphocyte glucocorticoid receptor resistance and depressive symptoms severity : A preliminary report

    NARCIS (Netherlands)

    Tanke, M. A. C.; Bosker, F. J.; Gladkevich, An.; Medema, H. M.; den Boer, J. A.; Korf, J.

    2008-01-01

    Objective: Assessment of the temporal interrelationship of neuropsychiatric parameters requires technologies allowing frequent biological measurements. We propose glucocorticoid receptor (GR) function of lymphocytes to assess the temporal relationship between glucocorticoid resistance and the course

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  19. Meta-analysis on the effect of the N363S polymorphism of the glucocorticoid receptor gene (GRL on human obesity

    Directory of Open Access Journals (Sweden)

    Martínez-González Miguel

    2006-05-01

    Full Text Available Abstract Background Since both excess glucocorticoid secretion and central obesity are clinical features of some obese patients, it is worthwhile to study a possible association of glucocorticoid receptor gene (GRL variants with obesity. Previous studies have linked the N363S variant of the GRL gene to increased glucocorticoid effects such as higher body fat, a lower lean-body mass and a larger insulin response to dexamethasone. However, contradictory findings have been also reported about the association between this variant and obesity phenotypes. Individual studies may lack statistical power which may result in disparate results. This limitation can be overcome using meta-analytic techniques. Methods We conducted a meta-analysis to assess the association between the N363S polymorphism of the GRL gene and obesity risk. In addition to published research, we included also our own unpublished data -three novel case-control studies- in the meta-analysis The new case-control studies were conducted in German and Spanish children, adolescents and adults (total number of subjects: 1,117. Genotype was assessed by PCR-RFLP (Tsp509I. The final formal meta-analysis included a total number of 5,909 individuals. Results The meta-analysis revealed a higher body mass index (BMI with an overall estimation of +0.18 kg/m2 (95% CI: +0.004 to +0.35 for homo-/heterozygous carriers of the 363S allele of the GRL gene in comparison to non-carriers. Moreover, differences in pooled BMI were statistically significant and positive when considering one-group studies from the literature in which participants had a BMI below 27 kg/m2 (+ 0.41 kg/m2 [95% CI +0.17 to +0.66], but the differences in BMI were negative when only our novel data from younger (aged under 45 and normal weight subjects were pooled together (-0.50 kg/m2 [95% CI -0.84 to -0.17]. The overall risk for obesity for homo-/heterozygous carriers of the 363S allele was not statistically significant in the meta

  20. Allergic and pseudoallergic reactions induced by glucocorticoids: a review.

    Science.gov (United States)

    Ventura, M T; Muratore, L; Calogiuri, G F; Dagnello, M; Buquicchio, R; Nicoletti, A; Altamura, M; Sabbà, C; Tursi, A

    2003-01-01

    Glucocorticoids (GCs) represent the most effective treatment for autoimmune and allergic diseases, even if collateral effects are not rare, especially endocrine and immunosuppressive manifestations. Moreover, these drugs can develop adverse immunological reactions of I, III or IV type. Though immediate adverse reactions caused by systemic therapy with GCs are not very frequent, the possible beginning of anaphylactic and pseudo-anaphylactic manifestations in patients undergoing therapy with these drugs has to be considered. It has been observed that immediate adverse reactions usually are happened in asthmatic patients and in patients obliged to assume GCs again and again because of their pathology (e.g, kidney transplant). Other risk factors resulted to be female sex and hypersensibility to acetylsalicylic acid (ASA). Both in the cases of pseudo-allergic and allergic reactions, the pharmacological principle is hardly the responsible agent for the reaction; instead the excipients in drugs are often implicated (succinate salt, sulphites and carboxy-methyl-cellulose). It is possible that the IgE-response is highly specific for a fixed GC molecule as well depending on the way of administration and its salification. Moreover, it has been hypothesized that in patients with a first type allergic reaction to GCs there is a fourth type, sensitization to GCs, which is not usually diagnosed and even comes before IgE sensitization. Third type hypersensibility reactions may occur, too. Since GCs are large-scale drugs, also in emergency medicine and reanimation, allergic sensitization towards them, although infrequent, gives many interventionist problems. In the light of this feature, it seems of crucial importance to verify the tolerance toward other GC molecules. And in particular, it has been noted that patients presenting immediate reactions to hydrocortisone (HC) and methylprednisolone (MP) could tolerate prednisone and prednisolone per os and second-generation GCs, such as

  1. Ethical responsibilities toward indirect and collateral participants in pragmatic clinical trials.

    Science.gov (United States)

    Smalley, Jaye Bea; Merritt, Maria W; Al-Khatib, Sana M; McCall, Debbe; Staman, Karen L; Stepnowsky, Carl

    2015-10-01

    Pragmatic clinical trials are designed to inform decision makers about the benefits, burdens, and risks of health interventions in real-world settings. Pragmatic clinical trials often use for research purposes data collected in the course of clinical practice. The distinctive features of pragmatic clinical trials demand fresh thinking about what is required to act properly toward people affected by their conduct, in ways that go beyond ensuring the protection of rights and welfare for "human research subjects" under conventional research ethics regulations. To stimulate such work, we propose to distinguish among categories of research participants in pragmatic clinical trials as follows: Direct participants: (1) individuals being directly intervened upon and/or (2) individuals from whom personal identifiable data are being collected for the purposes of the pragmatic clinical trial. Indirect participants: individuals who are (1) not identified as direct participants and (2) whose rights and welfare may be affected by the intervention through their routine exposure to the environment in which the intervention is being deployed. Collateral participants: patient groups and other stakeholder communities who may be otherwise affected by the occurrence and findings of the pragmatic clinical trial. We illustrate these distinctions with case examples and discuss the distinctive responsibilities of researchers and pragmatic clinical trial leadership toward each type of participant. We suggest that pragmatic clinical trial investigators, institutional review boards, health systems leaders, and others engaged in the research enterprise work together to identify these participants. For indirect participants, risks and benefits to which they are exposed should be weighed to ensure that their rights and welfare are protected accordingly, and communication strategies should be considered to help them make well-informed decisions. Collateral participants could provide input on the

  2. Ethical responsibilities toward indirect and collateral participants in pragmatic clinical trials.

    Science.gov (United States)

    Smalley, Jaye Bea; Merritt, Maria W; Al-Khatib, Sana M; McCall, Debbe; Staman, Karen L; Stepnowsky, Carl

    2015-10-01

    Pragmatic clinical trials are designed to inform decision makers about the benefits, burdens, and risks of health interventions in real-world settings. Pragmatic clinical trials often use for research purposes data collected in the course of clinical practice. The distinctive features of pragmatic clinical trials demand fresh thinking about what is required to act properly toward people affected by their conduct, in ways that go beyond ensuring the protection of rights and welfare for "human research subjects" under conventional research ethics regulations. To stimulate such work, we propose to distinguish among categories of research participants in pragmatic clinical trials as follows: Direct participants: (1) individuals being directly intervened upon and/or (2) individuals from whom personal identifiable data are being collected for the purposes of the pragmatic clinical trial. Indirect participants: individuals who are (1) not identified as direct participants and (2) whose rights and welfare may be affected by the intervention through their routine exposure to the environment in which the intervention is being deployed. Collateral participants: patient groups and other stakeholder communities who may be otherwise affected by the occurrence and findings of the pragmatic clinical trial. We illustrate these distinctions with case examples and discuss the distinctive responsibilities of researchers and pragmatic clinical trial leadership toward each type of participant. We suggest that pragmatic clinical trial investigators, institutional review boards, health systems leaders, and others engaged in the research enterprise work together to identify these participants. For indirect participants, risks and benefits to which they are exposed should be weighed to ensure that their rights and welfare are protected accordingly, and communication strategies should be considered to help them make well-informed decisions. Collateral participants could provide input on the

  3. OPPORTUNITY: a randomized clinical trial of growth hormone on outcome in hemodialysis patients

    DEFF Research Database (Denmark)

    Kopple, J.D.; Cheung, A.K.; Christiansen, J.S.;

    2008-01-01

    BACKGROUND: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health......, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy. CONCLUSIONS: The OPPORTUNITY Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers...

  4. Mapping acute systemic effects of inhaled particulate matter and ozone: multiorgan gene expression and glucocorticoid activity.

    Science.gov (United States)

    Thomson, Errol M; Vladisavljevic, Djordje; Mohottalage, Susantha; Kumarathasan, Prem; Vincent, Renaud

    2013-09-01

    Recent epidemiological studies have demonstrated associations between air pollution and adverse effects that extend beyond respiratory and cardiovascular disease, including low birth weight, appendicitis, stroke, and neurological/neurobehavioural outcomes (e.g., neurodegenerative disease, cognitive decline, depression, and suicide). To gain insight into mechanisms underlying such effects, we mapped gene profiles in the lungs, heart, liver, kidney, spleen, cerebral hemisphere, and pituitary of male Fischer-344 rats immediately and 24h after a 4-h exposure by inhalation to particulate matter (0, 5, and 50mg/m(3) EHC-93 urban particles) and ozone (0, 0.4, and 0.8 ppm). Pollutant exposure provoked differential expression of genes involved in a number of pathways, including antioxidant response, xenobiotic metabolism, inflammatory signalling, and endothelial dysfunction. The mRNA profiles, while exhibiting some interorgan and pollutant-specific differences, were remarkably similar across organs for a set of genes, including increased expression of redox/glucocorticoid-sensitive genes and decreased expression of inflammatory genes, suggesting a possible hormonal effect. Pollutant exposure increased plasma levels of adrenocorticotropic hormone and the glucocorticoid corticosterone, confirming activation of the hypothalamic-pituitary-adrenal axis, and there was a corresponding increase in markers of glucocorticoid activity. Although effects were transient and presumably represent an adaptive response to acute exposure in these healthy animals, chronic activation and inappropriate regulation of the hypothalamic-pituitary-adrenal axis are associated with adverse neurobehavioral, metabolic, immune, developmental, and cardiovascular effects. The experimental data are consistent with epidemiological associations of air pollutants with extrapulmonary health outcomes and suggest a mechanism through which such health effects may be induced.

  5. Glucocorticoid ultradian rhythmicity directs cyclical gene pulsing of the clock gene period 1 in rat hippocampus.

    Science.gov (United States)

    Conway-Campbell, B L; Sarabdjitsingh, R A; McKenna, M A; Pooley, J R; Kershaw, Y M; Meijer, O C; De Kloet, E R; Lightman, S L

    2010-10-01

    In vivo glucocorticoid (GC) secretion exhibits a distinctive ultradian rhythmicity. The lipophilic hormone can rapidly diffuse into cells, although only the pulse peak is of sufficient amplitude to activate the low affinity glucocorticoid receptor (GR). Discrete pulses readily access brain regions such as the hippocampus where GR expression is enriched and known to regulate neuronal function, including memory and learning processes. In the present study, we have tested the hypothesis that GR brain targets are responsive to ultradian GC rhythmicity. We have used adrenalectomised rats replaced with pulses of corticosterone to determine the transcriptional effects of ultradian pulses in the hippocampus. Confocal microscopy confirmed that each GC pulse results in transient GR nuclear localisation in hippocampal CA1 neurones. Concomitant GR activation and DNA binding was demonstrated by synthetic glucocorticoid response element oligonucleotide binding, and verified for the Clock gene Period 1 promoter region by chromatin immunoprecipitation assays. Strikingly each GC pulse induced a 'burst' of transcription of Period 1 measured by heterogeneous nuclear RNA quantitative polymerase chain reaction. The net effect of pulsatile GC exposure on accumulation of the mature transcript was also assessed, revealing a plateau of mRNA levels throughout the time course of pulsatile exposure, indicating the pulse timing works optimally for steady state Per1 expression. The plateau dropped to baseline within 120 min of the final pulse, indicating a relatively short half-life for hippocampal Per1. The significance of this strict temporal control is that any perturbation to the pulse frequency or duration would have rapid quantitative effects on the levels of Per1. This in turn could affect hippocampal function, especially circadian related memory and learning processes.

  6. Glucocorticoids are required for meal-induced changes in the expression of hypothalamic neuropeptides.

    Science.gov (United States)

    Uchoa, Ernane Torres; Silva, Lilian Eslaine C M; de Castro, Margaret; Antunes-Rodrigues, Jose; Elias, Lucila L K

    2012-06-01

    Glucocorticoid deficiency is associated with a decrease of food intake. Orexigenic peptides, neuropeptide Y (NPY) and agouti related protein (AgRP), and the anorexigenic peptide proopiomelanocortin (POMC), expressed in the arcuate nucleus of the hypothalamus (ARC), are regulated by meal-induced signals. Orexigenic neuropeptides, melanin-concentrating hormone (MCH) and orexin, expressed in the lateral hypothalamic area (LHA), also control food intake. Thus, the present study was designed to test the hypothesis that glucocorticoids are required for changes in the expression of hypothalamic neuropeptides induced by feeding. Male Wistar rats (230-280 g) were subjected to ADX or sham surgery. ADX animals received 0.9% NaCl in the drinking water, and half of them received corticosterone in the drinking water (B: 25 mg/L, ADX+B). Six days after surgery, animals were fasted for 16 h and they were decapitated before or 2 h after refeeding for brain tissue and blood collections. Adrenalectomy decreased NPY/AgRP and POMC expression in the ARC in fasted and refed animals, respectively. Refeeding decreased NPY/AgRP and increased POMC mRNA expression in the ARC of sham and ADX+B groups, with no effects in ADX animals. The expression of MCH and orexin mRNA expression in the LHA was increased in ADX and ADX+B groups in fasted condition, however there was no effect of refeeding on the expression of MCH and orexin in the LHA in the three experimental groups. Refeeding increased plasma leptin and insulin levels in sham and ADX+B animals, with no changes in leptin concentrations in ADX group, and insulin response to feeding was lower in this group. Taken together, these data demonstrated that circulating glucocorticoids are required for meal-induced changes in NPY, AgRP and POMC mRNA expression in the ARC. The lower leptin and insulin responses to feeding may contribute to the altered hypothalamic neuropeptide expression after adrenalectomy.

  7. Glucocorticoid Ultradian Rhythmicity Directs Cyclical Gene Pulsing of the Clock Gene Period 1 in Rat Hippocampus

    Science.gov (United States)

    McKenna, M. A.; Pooley, J. R.; Kershaw, Y. M.; Meijer, O. C.; de Kloet, E. R.; Lightman, S. L.

    2016-01-01

    In vivo glucocorticoid (GC) secretion exhibits a distinctive ultradian rhythmicity. The lipophilic hormone can rapidly diffuse into cells, although only the pulse peak is of sufficient amplitude to activate the low affinity glucocorticoid receptor (GR). Discrete pulses readily access brain regions such as the hippocampus where GR expression is enriched and known to regulate neuronal function, including memory and learning processes. In the present study, we have tested the hypothesis that GR brain targets are responsive to ultradian GC rhythmicity. We have used adrenalectomised rats replaced with pulses of corticosterone to determine the transcriptional effects of ultradian pulses in the hippocampus. Confocal microscopy confirmed that each GC pulse results in transient GR nuclear localisation in hippocampal CA1 neurones. Concomitant GR activation and DNA binding was demonstrated by synthetic glucocorticoid response element oligonucleotide binding, and verified for the Clock gene Period 1 promoter region by chromatin immunoprecipitation assays. Strikingly each GC pulse induced a ‘burst’ of transcription of Period 1 measured by heterogeneous nuclear RNA quantitative polymerase chain reaction. The net effect of pulsatile GC exposure on accumulation of the mature transcript was also assessed, revealing a plateau of mRNA levels throughout the time course of pulsatile exposure, indicating the pulse timing works optimally for steady state Per1 expression. The plateau dropped to baseline within 120 min of the final pulse, indicating a relatively short half-life for hippocampal Per1. The significance of this strict temporal control is that any perturbation to the pulse frequency or duration would have rapid quantitative effects on the levels of Per1. This in turn could affect hippocampal function, especially circadian related memory and learning processes. PMID:20649850

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

    Science.gov (United States)

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

    2011-05-25

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

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

    Science.gov (United States)

    Schoenfeld, Timothy J; Gould, Elizabeth

    2013-01-01

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

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

    Science.gov (United States)

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

    2013-07-01

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

  11. Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation.

    Science.gov (United States)

    Wang, Meina; Hill, Matthew N; Zhang, Longhua; Gorzalka, Boris B; Hillard, Cecilia J; Alger, Bradley E

    2012-01-01

    Exposure to behavioural stress normally triggers a complex, multilevel response of the hypothalamic-pituitary-adrenal (HPA) axis that helps maintain homeostatic balance. Although the endocannabinoid (eCB) system (ECS) is sensitive to chronic stress, few studies have directly addressed its response to acute stress. Here we show that acute restraint stress enhances eCB-dependent modulation of GABA release measured by whole-cell voltage clamp of inhibitory postsynaptic currents (IPSCs) in rat hippocampal CA1 pyramidal cells in vitro. Both Ca(2+)-dependent, eCB-mediated depolarization-induced suppression of inhibition (DSI), and muscarinic cholinergic receptor (mAChR)-mediated eCB mobilization are enhanced following acute stress exposure. DSI enhancement is dependent on the activation of glucocorticoid receptors (GRs) and is mimicked by both in vivo and in vitro corticosterone treatment. This effect does not appear to involve cyclooxygenase-2 (COX-2), an enzyme that can degrade eCBs; however, treatment of hippocampal slices with the L-type calcium (Ca(2+)) channel inhibitor, nifedipine, reverses while an agonist of these channels mimics the effect of in vivo stress. Finally, we find that acute stress produces a delayed (by 30 min) increase in the hippocampal content of 2-arachidonoylglycerol, the eCB responsible for DSI. These results support the hypothesis that the ECS is a biochemical effector of glucocorticoids in the brain, linking stress with changes in synaptic strength. PMID:21890595

  12. Glucocorticoids exert context-dependent effects on cells of the joint in vitro

    DEFF Research Database (Denmark)

    Madsen, Suzi H; Andreassen, Kim V; Christensen, Søren T;

    2011-01-01

    Glucocorticoids are known to attenuate bone formation in vivo leading to decreased bone volume and increased risk of fractures, whereas effects on the joint tissue are less characterized. However, glucocorticoids appear to have a reducing effect on inflammation and pain in osteoarthritis. This st....... This study aimed at characterizing the effect of glucocorticoids on chondrocytes, osteoclasts, and osteoblasts....

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  14. Traumatic Reticuloperitonitis in Water Buffalo (Bubalus bubalis: Clinical Findings and the Associated Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Maged El-Ashker

    2013-01-01

    Full Text Available The present study was carried out to describe the clinical picture of traumatic reticuloperitonitis (TRP in water buffalo (Bubalus bubalis and to evaluate the inflammatory and immunologic responses for this clinical condition. Twenty-two buffalo with acute local TRP were monitored in our study. Additionally, 10 clinically healthy buffalo were randomly selected and served as controls. Acute local TRP was initially diagnosed by clinical examination and confirmed by ultrasonographic (USG examination and/or necropsy findings. Blood samples were collected from all examined buffalo to measure the respective levels of tumor necrosis factor alpha (TNF-α, interleukin (IL-1β, IL-6, IL-10 and interferon gamma (INF-γ, serum amyloid A (SAA, C-reactive protein (CRP, haptoglobin (Hp, fibrinogen (Fb, and serum sialic acid (SSA. It was found that TNF-α, IL-1β, IL-6, IL-10, SAA, CRP, Hp, Fb, and SSA were significantly higher in buffalo with TRP than the controls. Our findings suggest that the examined immunologic variables were helpful in documenting the inflammatory response in buffalo with TRP. However, their diagnostic usefulness only becomes apparent when considered in tandem with the clinical findings for any given animal, its anamnesis, and a subsequent USG assessment. Due to the frequent complications of TRP, more accurate indicators of its occurrence and severity would be useful.

  15. Preoperative neutrophil response as a predictive marker of clinical outcome following open heart surgery and the impact of leukocyte filtration.

    LENUS (Irish Health Repository)

    Soo, Alan W

    2010-11-01

    Open heart surgery is associated with a massive systemic inflammatory response. Neutrophils, are the main mediator of this response. We hypothesised that the degree of neutrophil activation and inflammatory response to open heart surgery varies individually and correlates with clinical outcome. The aim of this study was to determine if individual clinical outcome can be predicted preoperatively through assessment of in-vitro stimulated neutrophil responses. Following that, the effects of neutrophil depletion through leukocyte filters are examined.

  16. Clinical analysis of adverse reactions on rheumatoid arthritis treated with leflunomide and methotrexate and glucocorticoid%来氟米特和甲氨蝶呤联合糖皮质激素治疗类风湿关节炎不良反应的临床分析

    Institute of Scientific and Technical Information of China (English)

    丁从珠; 汪悦; 王红; 梁军; 孙凌云

    2010-01-01

    目的 分析来氟米特和甲氨蝶呤联合糖皮质激素(GCs)治疗类风湿关节炎(RA)的不良反应, 提高在临床上使用来氟米特和甲氨蝶呤规范化治疗RA时,对应用糖皮质激素的认识.方法 记录226例RA患者的临床资料,均使用来氟米特和甲氨蝶呤治疗,分为未用GCs治疗组、联合GCs的小剂量组(≤10mg)、中剂量组(11~30mg),用X~2检验或确切概率法比较3组患者的药物不良反应.结果 随访24周,71例未用过GCs组发生皮疹、口腔溃疡、肝损害、血白细胞减少的分别17%、16%、24%、17%;72例小剂量组分别为3%、4%、7%、7%;34例中剂量组分别为3%、3%、9%、3%,小、中剂量组与未用过GCs组相比发生率显著减少(P0.05).结论 来氟米特和甲氨蝶呤联合GCs治疗RA,皮疹、肝损害、口腔溃疡等不良反应的发生率降低;小剂量GCs治疗者对骨密度、血糖和血压的影响不明显;中剂量GCs治疗发生骨质疏松及非外伤骨折、高血糖、高血脂、高血压的风险增加.%Objective To analyze the adverse reactions of leflunomide and methotrexate combined with glucocorticoids (GCs) on the treatment of patients with rheumatoid arthritis (RA), and to improve the understanding of GCs. Methods The clinical data of 226 cases with RA were collected. All the cases received treatment of leflunomide and methotrexate for RA. The patients were divided into three groups, including non- GCs group, small-dose GCs group (≤ 10 mg) and middle-dose GCs group (11~30 mg). The adverse reactions of the three groups were compared by Chi-square test or Fisher's exact test. Results At the 24th weeks of follow-up,the non-GCs group had high incidence of skin rash (16.9%), mouth ulcers (15.5%), blood leuco-penia (23.9%), and liver damage (16.9%). The incidence of above adverse reactions in the small-dose GCs and middle-dose GCs group was 2.8-4.2-6.9-6.9% and 2.9-2.9-8.8-2.9%, respectively, both were significantly lower than that of the

  17. Glucocorticoids Suppress Renal Cell Carcinoma Progression by Enhancing Na,K-ATPase Beta-1 Subunit Expression

    Science.gov (United States)

    Huynh, Thu P.; Barwe, Sonali P.; Lee, Seung J.; McSpadden, Ryan; Franco, Omar E.; Hayward, Simon W.; Damoiseaux, Robert; Grubbs, Stephen S.; Petrelli, Nicholas J.; Rajasekaran, Ayyappan K.

    2015-01-01

    Glucocorticoids are commonly used as palliative or chemotherapeutic clinical agents for treatment of a variety of cancers. Although steroid treatment is beneficial, the mechanisms by which steroids improve outcome in cancer patients are not well understood. Na,K-ATPase beta-subunit isoform 1 (NaK-β1) is a cell-cell adhesion molecule, and its expression is down-regulated in cancer cells undergoing epithelial-to mesenchymal-transition (EMT), a key event associated with cancer progression to metastatic disease. In this study, we performed high-throughput screening to identify small molecules that could up-regulate NaK-β1 expression in cancer cells. Compounds related to the glucocorticoids were identified as drug candidates enhancing NaK-β1 expression. Of these compounds, triamcinolone, dexamethasone, and fluorometholone were validated to increase NaK-β1 expression at the cell surface, enhance cell-cell adhesion, attenuate motility and invasiveness and induce mesenchymal to epithelial like transition of renal cell carcinoma (RCC) cells in vitro. Treatment of NaK-β1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-β1. Furthermore, we demonstrated that these compounds attenuate tumor growth in subcutaneous RCC xenografts and reduce local invasiveness in orthotopically-implanted tumors. Our results strongly indicate that the addition of glucocorticoids in the treatment of RCC may improve outcome for RCC patients by augmenting NaK-β1 cell-cell adhesion function. PMID:25836370

  18. Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia.

    LENUS (Irish Health Repository)

    Niemeyer, Charlotte M

    2015-01-01

    Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.

  19. Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.

    LENUS (Irish Health Repository)

    Gallagher, David J

    2012-02-01

    BACKGROUND: Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond. OBJECTIVE: To identify predictors of response to sunitinib. DESIGN, SETTING, AND PARTICIPANTS: Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib. MEASUREMENTS: BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria. RESULTS AND LIMITATIONS: Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3\\/4 hypertension compared with grade 0. Response was associated with low HIF-1alpha expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 x 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1alpha (p = 0.008). Results are limited by small numbers. CONCLUSIONS: Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.

  20. An urban American Indian health clinic's response to a community needs assessment.

    Science.gov (United States)

    Dennis, Mary Kate; Momper, Sandra L

    2016-01-01

    Utilizing community-based methods, we assessed the behavioral and physical health needs of a Detroit metropolitan Indian health clinic. The project goal was to identify health service needs for urban American Indians/Alaska Natives and develop the infrastructure for culturally competent and integrative behavioral and physical health care. We conducted 38 semi-structured interviews and 12 focus groups with service providers and community members. Interview and focus group data indicated a need for 1) more culturally competent services and providers, 2) more specialized health services, and 3) more transportation options. We then report on the Indian health clinic's and community's accomplishments in response to the needs assessment. PMID:27668592

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

    Institute of Scientific and Technical Information of China (English)

    Ejder Kardesoglu; Zafer Isilak; Omer Uz; Turgay Celik

    2010-01-01

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

  2. Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

    DEFF Research Database (Denmark)

    Eriksen, Marie; Jensen, David H; Tribler, Siri;

    2015-01-01

    AIMS/HYPOTHESIS: We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoid-induced insulin resistance. METHODS: Nineteen healthy....... In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l. RESULTS: After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose...... concentrations, while beta cell function indices generally increased according to the increased resistance. First-phase insulin responses induced by GLP-1 and GIP at 7 mmol/l and maximal beta cell secretory capacity did not differ before and after dexamethasone, while second-phase responses to 7 mmol/l and first...

  3. Genetic studies of DRD4 and clinical response to neuroleptic medications

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, J.L.; Petronis, A.; Gao, J. [Univ. of Toronto, Ontario (Canada)] [and others

    1994-09-01

    Clozapine is an atypical antipsychotic drug that, like most other medications, is effective for some people and not for others. This variable response across individuals is likely significantly determined by genetic factors. An important candidate gene to investigate in clozapine response is the dopamine D4 receptor gene (DRD4). The D4 receptor has a higher affinity for clozapine than any of the other dopamine receptors. Furthermore, recent work by our consortium has shown a remarkable level of variability in the part of the gene coding for the third cytoplasmic loop. We have also identified polymorphisms in the upstream 5{prime} putative regulatory region and at two other sites. These polymorphisms were typed in a group of treatment-resistant schizophrenia subjects who were subsequently placed on clozapine (n = 60). In a logistic regression analysis, we compared genotype at the DRD4 polymorphism to response versus non-response to clozapine. Neither the exon-III nor any of the 5{prime} polymorphisms alone significantly predicted response; however, when the information from these polymorphisms was combined, more predictive power was obtained. In a correspondence analysis of the four DRD4 polymorphisms vs. response, we were able to predict 76% of the variance in response. Refinement of the analyses will include assessment of subfactors involved in clinical response phenotype and incorporation of the debrisoquine metabolizing locus (CYP2D6) into the prediction algorithm.

  4. Stress, glucocorticoids and absences in a genetic epilepsy model.

    Science.gov (United States)

    Tolmacheva, Elena A; Oitzl, Melly S; van Luijtelaar, Gilles

    2012-05-01

    Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij rats, non-epileptic inbred ACI rats and outbred Wistar rats. The WAG/Rij strain is a genetic model for absence epilepsy and comorbidity for depression, which originates from the population of Wistar rats and, therefore, shares their genetic background. In a separate experiment, WAG/Rij rats were exposed to FS on three consecutive days. Electroencephalograms (EEGs) were recorded before and after FS, and the number of absence seizures (spike-wave-discharges, SWDs) was quantified. Both WAG/Rij rats and ACI rats exhibited elevated basal levels of corticosterone and a rapid corticosterone increase in response to acute stress. The WAG/Rij rats also displayed the most rapid normalization of corticosterone during the recovery phase compared to that of ACI and Wistar rats. FS had a biphasic effect on SWDs; an initial suppression was followed by an aggravation of the SWDs. By the third day, this aggravation of seizures was present in the hour preceding FS. This increase in SWDs may arise from anticipatory stress about the upcoming FS. Together, these results suggest that the distinct secretion profile of corticosterone found in WAG/Rij rats may contribute to the severity of the epileptic phenotype. Although the acute stressor results in an initial suppression of SWDs followed by an increase in SWDs, stress prior to a predictable negative event aggravates absences.

  5. Predicting Ovarian Cancer Patients' Clinical Response to Platinum-Based Chemotherapy by Their Tumor Proteomic Signatures.

    Science.gov (United States)

    Yu, Kun-Hsing; Levine, Douglas A; Zhang, Hui; Chan, Daniel W; Zhang, Zhen; Snyder, Michael

    2016-08-01

    Ovarian cancer is the deadliest gynecologic malignancy in the United States with most patients diagnosed in the advanced stage of the disease. Platinum-based antineoplastic therapeutics is indispensable to treating advanced ovarian serous carcinoma. However, patients have heterogeneous responses to platinum drugs, and it is difficult to predict these interindividual differences before administering medication. In this study, we investigated the tumor proteomic profiles and clinical characteristics of 130 ovarian serous carcinoma patients analyzed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), predicted the platinum drug response using supervised machine learning methods, and evaluated our prediction models through leave-one-out cross-validation. Our data-driven feature selection approach indicated that tumor proteomics profiles contain information for predicting binarized platinum response (P drug responses as well as provided insights into the biological processes influencing the efficacy of platinum-based therapeutics. Our analytical approach is also extensible to predicting response to other antineoplastic agents or treatment modalities for both ovarian and other cancers. PMID:27312948

  6. Clinical and Laboratory Presentation of Hairy Cell Leukemia (Hcl and Rate of Response to Cladribine

    Directory of Open Access Journals (Sweden)

    M Forat Yazdi

    2008-04-01

    Full Text Available Introduction: HCL is a rare malignant condition that is curable if diagnosed early. HCL can present with reduced blood cells and splenomegaly which maybe misdiagnosed with other conditions. The aim of the present study was to determine the frequency of early clinical and laboratory findings as well as the response rate of patients to the standard treatment regimen of Cladribine. Methods: The study was an uncontrolled clinical trial including 25 HCL patients referring to Oncology Clinics of Shahid Sadoughi (Yazd - Iran and Shahid Beheshti (Tehran - Iran between 1999 and 2005. Data was gathered by a pre–designed questionnaire. 21 out of 25 patients were treated with Cladribine and the clinical and laboratory response was assessed. Results: Of the 25 patients studied, 20 patients (80% were male and 5 patients (20% were female. Most of the patients at diagnosis were 55–67 years old and the most common presenting symptom was fatigue and lassitude secondary to anemia. Two patients were asymptomatic and were diagnosed incidentally. Splenomegaly was the main clinical finding which was present in about 80% of the males and all of the females. Accordingly, hairy cells in the peripheral blood smear, leukopenia and anemia were the most common laboratory findings. In contrast to previous results, pancytopenia was found in only 60% of the patients. Response rate was 90% (19 out of 21 of which 61.9% (13 patients and 28.5% (6 patients had complete remission (CR and partial remission (PR, respectively. Conclusion: According to the results, it can be concluded that HCL should be considered as a possible diagnosis in the context of fatigue, splenomegaly and reduced blood cell count. The results of the present study were similar to other similar international studies.

  7. The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

    Directory of Open Access Journals (Sweden)

    Sarosh R Irani

    2012-04-01

    Full Text Available The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1, CASPR2 (contactin-associated protein 2, and contactin-2, and NMDA (N-methyl, D-aspartate -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field.

  8. Review of clinical studies on dendritic cell-based vaccination of patients with malignant melanoma: assessment of correlation between clinical response and vaccine parameters

    DEFF Research Database (Denmark)

    Engell-Noerregaard, Lotte; Hansen, Troels Holz; Andersen, Mads Hald;

    2009-01-01

    During the past years numerous clinical trials have been carried out to assess the ability of dendritic cell (DC) based immunotherapy to induce clinically relevant immune responses in patients with malignant diseases. A broad range of cancer types have been targeted including malignant melanoma w...

  9. 321 Clinical Analysis of Salbutamol Responsiveness after Acetylcholine-induced Bronchoconstriction in Childhood Asthma

    OpenAIRE

    Kondo, Tomio; Nakashima, Yoshiki; Shikano, Hiroaki

    2012-01-01

    Background The bronchodilator is usually inhaled after the acethylcholine (Ach) inhalation test for asthmatic patients. We investigated clinical characteristics of asthma about the response to a inhalation of salbutamol after the Ach provocation test. Methods Asthmatic patients from 6 to 18 years old were examined. They inhaled aerosol with increased concentration of Ach to produce 20% or more decrease in FEV1.0 (RT-Ach point). After then they inhaled salbutamol, and respiratory function was ...

  10. Evaluation of the response of thermoluminescent detectors in clinical beams dosimetry using different phantoms

    International Nuclear Information System (INIS)

    Radiotherapy is one of the three principal treatment modalities used in the treatment of malignant diseases such as cancer, the other two are chemotherapy and radiosurgery. In contrast to other medical specialties that rely mainly on the clinical knowledge and experience of medical specialists, radiotherapy, with its use of ionizing radiation in treatment of cancer, relies heavily on modern technology and the collaborative efforts of several professionals whose coordinated team approach greatly influences the outcome of the treatment. In the area of clinical dosimetry, an efficient and accurate calibration of the radiation beam ensures knowledge of the radiation dose delivered to the patient, allowing thus the success of radiotherapy. This study aims to compare the thermoluminescent response of calcium sulfate doped with dysprosium (CaSO4:Dy) dosimeters produced by IPEN (6 mm in diameter and 0,8 mm tick) with the response of lithium fluoride (3,15 x 3,15 x 0,9 mm3) doped with magnesium and titanium (LiF:Mg,Ti) in dosimetry of clinical photons (6 and 15 MV) and electrons beams (6 and 9 MeV) using solid water (RMI-457), water and PMMA phantoms. Initially, the dose-response curves were obtained for irradiation in cobalt-60 gamma radiation source in air (PMMA plates) and under electronic equilibrium conditions and for clinical electrons and photons beams at depth of maximum dose. The sensitivities of the thermoluminescent dosimeters were also evaluated and the values of their reproducibilities and intrinsic efficiency were determined for the response to different types of phantoms and radiation energy. The obtained results indicate that the main advantage of CaSO4:Dy dosimeters is the enhanced sensitivity to radiation doses measured for 60Co, photons and electrons beams, thus representing a viable alternative for application in dosimetry in the radiotherapy area. (author)

  11. The Fasting Family : Experiences of health, responsibility and healing in a Japanese medical clinic

    OpenAIRE

    2013-01-01

    Based on a fieldwork with a six month long duration this thesis explores how the concepts of responsibility and health relate to one another in the plural medical landscape of Japan. In a traditional clinic situated in a small city, the patients have chosen a somewhat different approach to healing than that of the conventional cosmopolitan approach of biomedicine. What this thesis explores, is in what ways an alternative approach to health and healing affects individual bodies, how these bodi...

  12. Outcome tools used for ambulatory children with cerebral palsy: responsiveness and minimum clinically important differences

    OpenAIRE

    Oeffinger, D; Bagley, A; Rogers, S.; Gorton, G; Kryscio, R; Abel, M.; Damiano, D; Barnes, D.; Tylkowski, C

    2008-01-01

    This prospective longitudinal multicenter study of ambulatory children with cerebral palsy (CP) examined changes in outcome tool score over time, tool responsiveness, and used a systematic method for defining minimum clinically important differences (MCIDs). Three hundred and eighty-one participants with CP (Gross Motor Function Classification System [GMFCS] Levels I–III; age range 4–18y, mean age 11y [SD 4y 4mo]; 265 diplegia, 116 hemiplegia; 230 males, 151 females). At baseline and follow-u...

  13. Vitamin D dose response is underestimated by Endocrine Society's Clinical Practice Guideline

    OpenAIRE

    McKenna, Malachi J; Murray, Barbara F

    2013-01-01

    Objective The recommended daily intakes of vitamin D according to the recent Clinical Practice Guideline (CPG) of the Endocrine Society are three- to fivefold higher than the Institute of Medicine (IOM) report. We speculated that these differences could be explained by different mathematical approaches to the vitamin D dose response. Methods Studies were selected if the daily dose was ≤2000 IU/day, the duration exceeded 3 months, and 25-hydroxyvitamin D (25OHD) concentrations were measured at...

  14. Endocrine-Disrupting Effects of Pesticides through Interference with Human Glucocorticoid Receptor.

    Science.gov (United States)

    Zhang, Jianyun; Zhang, Jing; Liu, Rui; Gan, Jay; Liu, Jing; Liu, Weiping

    2016-01-01

    Many pesticides have been identified as endocrine-disrupting chemicals (EDCs) due to their ability to bind sex-steroid hormone receptors. However, little attention has been paid to the ability of pesticides to interfere with other steroid hormone receptors such as glucocorticoid receptor (GR) that plays a critical role in metabolic, endocrine, immune, and nervous systems. In this study, the glucocorticoidic and antiglucocorticoidic effects of 34 pesticides on human GR were investigated using luciferase reporter gene assay. Surprisingly, none of the test chemicals showed GR agonistic activity, but 12 chemicals exhibited apparent antagonistic effects. Bifenthrin, λ-cyhalothrin, cypermethrin, resmethrin, o,p'-DDT, p,p'-DDT, methoxychlor, ethiofencarb, and tolylfluanid showed remarkable GR antagonistic properties with RIC20 values lower than 10(-6) M. The disruption of glucocorticoid-responsive genes in H4IIE and J774A.1 cells was further evaluated on these 12 GR antagonists. In H4IIEcells, four organochlorine insecticides, bifenthrin, and 3-PBA decreased cortisol-induced PEPCK gene expression, while o,p'-DDT and methoxychlor inhibited cortisol-stimulated Arg and TAT gene expression. Cypermethrin and tolyfluanid attenuated cortisol-induced TAT expression. In J774A.1 cells, λ-cyhalothrin, resmethrin, 3-PBA, o,p'-DDT, p,p'-DDT, p,p'-DDE, methoxychlor- and tolylfluanid-reduced cortisol-stimulated GILZ expression. Furthermore, molecular docking simulation indicated that different interactions may stabilize the binding between molecules and GR. Our findings suggest that comprehensive screening and evaluation of GR antagonists and agonists should be considered to better understand the health and ecological risks of man-made chemicals such as pesticides.

  15. Glucocorticoids Inhibit CRH/AVP-Evoked Bursting Activity of Male Murine Anterior Pituitary Corticotrophs.

    Science.gov (United States)

    Duncan, Peter J; Tabak, Joël; Ruth, Peter; Bertram, Richard; Shipston, Michael J

    2016-08-01

    Corticotroph cells from the anterior pituitary are an integral component of the hypothalamic-pituitary-adrenal (HPA) axis, which governs the neuroendocrine response to stress. Corticotrophs are electrically excitable and fire spontaneous single-spike action potentials and also display secretagogue-induced bursting behavior. The HPA axis function is dependent on effective negative feedback in which elevated plasma glucocorticoids result in inhibition at the level of both the pituitary and the hypothalamus. In this study, we have used an electrophysiological approach coupled with mathematical modeling to investigate the regulation of spontaneous and CRH/arginine vasopressin-induced activity of corticotrophs by glucocorticoids. We reveal that pretreatment of corticotrophs with 100 nM corticosterone (CORT; 90 and 150 min) reduces spontaneous activity and prevents a transition from spiking to bursting after CRH/arginine vasopressin stimulation. In addition, previous studies have identified a role for large-conductance calcium- and voltage-activated potassium (BK) channels in the generation of secretagogue-induced bursting in corticotrophs. Using the dynamic clamp technique, we demonstrated that CRH-induced bursting can be switched to spiking by subtracting a fast BK current, whereas the addition of a fast BK current can induce bursting in CORT-treated cells. In addition, recordings from BK knockout mice (BK(-/-)) revealed that CORT can also inhibit excitability through BK-independent mechanisms to control spike frequency. Thus, we have established that glucocorticoids can modulate multiple properties of corticotroph electrical excitability through both BK-dependent and BK-independent mechanisms. PMID:27254001

  16. Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal-Accumbens Plasticity After Stress.

    Science.gov (United States)

    Segev, Amir; Akirav, Irit

    2016-03-01

    Acute stress results in release of glucocorticoids, which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors have a key role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. Growing attention has been focused on nucleus accumbens (NAc) plasticity, which regulates mood and motivation. The NAc integrates affective and context-dependent input from the BLA and ventral subiculum (vSub), respectively. As our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity. Bilateral, ipsilateral, and contralateral BLA administration of RU or WIN reversed the stress-induced impairment in vSub-NAc long-term potentiation (LTP) and the decrease in cAMP response element-binding protein (CREB) activity in the NAc. BLA CB1 receptors were found to mediate the preventing effects of WIN on plasticity, but not the preventing effects of RU, after stress. Inactivating the ipsilateral BLA, but not the contralateral BLA, impaired LTP. The possible mechanisms underlying the effects of BLA on NAc plasticity are discussed; the data suggest that BLA-induced changes in the NAc may be mediated through neural pathways in the brain's stress circuit rather than peripheral pathways. The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may have a central role in the treatment of a variety of stress-related disorders. PMID:26289146

  17. Microarray analyses of glucocorticoid and vitamin D3 target genes in differentiating cultured human podocytes.

    Directory of Open Access Journals (Sweden)

    Xiwen Cheng

    Full Text Available Glomerular podocytes are highly differentiated epithelial cells that are key components of the kidney filtration units. Podocyte damage or loss is the hallmark of nephritic diseases characterized by severe proteinuria. Recent studies implicate that hormones including glucocorticoids (ligand for glucocorticoid receptor and vitamin D3 (ligand for vitamin D receptor protect or promote repair of podocytes from injury. In order to elucidate the mechanisms underlying hormone-mediated podocyte-protecting activity from injury, we carried out microarray gene expression studies to identify the target genes and corresponding pathways in response to these hormones during podocyte differentiation. We used immortalized human cultured podocytes (HPCs as a model system and carried out in vitro differentiation assays followed by dexamethasone (Dex or vitamin D3 (VD3 treatment. Upon the induction of differentiation, multiple functional categories including cell cycle, organelle dynamics, mitochondrion, apoptosis and cytoskeleton organization were among the most significantly affected. Interestingly, while Dex and VD3 are capable of protecting podocytes from injury, they only share limited target genes and affected pathways. Compared to VD3 treatment, Dex had a broader and greater impact on gene expression profiles. In-depth analyses of Dex altered genes indicate that Dex crosstalks with a broad spectrum of signaling pathways, of which inflammatory responses, cell migration, angiogenesis, NF-κB and TGFβ pathways are predominantly altered. Together, our study provides new information and identifies several new avenues for future investigation of hormone signaling in podocytes.

  18. X-ray Crystal Structure of the Novel Enhanced-Affinity Glucocorticoid Agonist Fluticasone Furoate in the Glucocorticoid Receptor−Ligand Binding Domain

    Energy Technology Data Exchange (ETDEWEB)

    Biggadike, Keith; Bledsoe, Randy K.; Hassell, Anne M.; Kirk, Barrie E.; McLay, Iain M.; Shewchuk, Lisa M.; Stewart, Eugene L. (GSKNC); (GSK)

    2008-07-08

    An X-ray crystal structure is reported for the novel enhanced-affinity glucocorticoid agonist fluticasone furoate (FF) in the ligand binding domain of the glucocorticoid receptor. Comparison of this structure with those of dexamethasone and fluticasone propionate shows the 17{alpha} furoate ester to occupy more fully the lipophilic 17{alpha} pocket on the receptor, which may account for the enhanced glucocorticoid receptor binding of FF.

  19. Catatonia: Etiopathological diagnoses and treatment response in a tertiary care setting: A clinical study

    Directory of Open Access Journals (Sweden)

    Santosh Ramdurg

    2013-01-01

    Full Text Available Aim: Catatonia is caused by a variety of psychiatric and organic conditions. The onset, clinical profile, and response to treatment may vary depending on the underlying cause. The study is an attempt to explore clinical profile, possible etiological correlates with neurotic/psychotic spectrum illnesses, and response to treatment and outcome in patients of catatonia. Materials and Methods: Retrospective chart analysis by using semistructured data sheet for the analysis of sociodemographic data, clinical profile, precipitating event, and response to treatment in patients with catatonic symptoms admitted to IHBAS (Institute of Human Behaviour and Allied Sciences, New Delhi, India from January 2009 to December 2010 was undertaken. Results: Catatonia was commonly observed in patients with the following profile - late twenties, female, Hindu religion, urban background, and housewives. Psychotic spectrum disorder (57%, N=35 was the most commonly entertained diagnosis and affective disorder (18%, N=11 being the second common. Thirty four percent of the subjects responded to lorazepam treatment and rest required modified electroconvulsive therapy (MECT. Conclusion: Catatonia is more likely to be associated with Schizophrenia and Other Psychotic Disorders in Indian settings. Majority of patients responded to therapy either by lorazepam alone or to its augmentation with modified ECT. The study being a retrospective one, the sample being representative of the treatment seeking group only, and unavailability of the follow up data were the limitations of the study

  20. THE RATE OF CLINICAL RESPONSE OF ORAL LOADING SODIUM VALPROATE IN ACUTELY MANLC PATIENT

    Directory of Open Access Journals (Sweden)

    K SHAFIEE

    2003-12-01

    Full Text Available Introduction: Acheiving accelerated clinical response is desirable in patients with acute manic episode. We conducted a prospective study to compare the rate of clinical response of oral loading sodium valproate versus standard dose titration. Methods: Fourty - two patients who met DSM - IV critevia for current manic episode and who had a "Young mania rating scale "score between 20 and 50 were randomly assigned on a double blind basis to recieve valproate oral "loading"(N = 21 at a dose of 20 mg/kg in divided doses for 7 days and valproate "non -loading" at a starting dose of 10 mg/kg followed by standard titration which at day 6 , they recieved 20 mg/kg valproate. Patients were scored at day 0, 3, 5 and 7 by a blindraterusing YMRS. Results: There was no significat differences between the groups in advers events and useing of adjunctive tranquilizer .The efficacy of valproate in both two groups was similar but " the rate of improvement on YMRS" over the first 3 days was significantly greater in loading group. Conclusion: Valproate oral loading with sodium valproate can induced a more rapid clinical response in acutely manic patient.

  1. Evaluation of the tip-bending response in clinically used endoscopes

    Science.gov (United States)

    Rozeboom, Esther D.; Reilink, Rob; Schwartz, Matthijs P.; Fockens, Paul; Broeders, Ivo A. M. J.

    2016-01-01

    Background and study aims: Endoscopic interventions require accurate and precise control of the endoscope tip. The endoscope tip response depends on a cable pulling system, which is known to deliver a significantly nonlinear response that eventually reduces control. It is unknown whether the current technique of endoscope tip control is adequate for a future of high precision procedures, steerable accessories, and add-on robotics. The aim of this study was to determine the status of the tip response of endoscopes used in clinical practice. Materials and methods: We evaluated 20 flexible colonoscopes and five gastroscopes, used in the endoscopy departments of a Dutch university hospital and two Dutch teaching hospitals, in a bench top setup. First, maximal tip bending was determined manually. Next, the endoscope navigation wheels were rotated individually in a motor setup. Tip angulation was recorded with a USB camera. Cable slackness was derived from the resulting hysteresis plot. Results: Only two of the 20 colonoscopes (10 %) and none of the five gastroscopes reached the maximal tip angulation specified by the manufacturer. Four colonoscopes (20 %) and none of the gastroscopes demonstrated the recommended cable tension. Eight colonoscopes (40 %) had undergone a maintenance check 1 month before the measurements were made. The tip responses of these eight colonoscopies did not differ significantly from the tip responses of the other colonoscopes. Conclusion: This study suggests that the majority of clinically used endoscopes are not optimally tuned to reach maximal bending angles and demonstrate adequate tip responses. We suggest a brief check before procedures to predict difficulties with bending angles and tip responses. PMID:27092330

  2. Observation on the clinical effects of cyclosporine A combined with glucocorticoids in children with primary nephrotic syndrome from a single center%环孢素A联合激素治疗儿童原发性肾病综合征的单中心临床疗效观察

    Institute of Scientific and Technical Information of China (English)

    宁文慧; 韩子明; 韩玫瑰

    2016-01-01

    ObjectiveTo observe the clinical effects and safe of cyclosporine A (CsA) in the treatment of primary nephrotic syndrome in children.MethodsThere were 40 child patients with nephrotic syndrome treated with CsA (3-5 mg²kg-1²d-1) combined with glucocorticoids, in which including steroid-resistant nephritic syndrome (SRNS) 13 cases, steroid-dependent nephrotic syndrome (SDNS) 18 cases, frequent-relapses nephrotic syndrome (FRNS) 9 cases. The concentration of CsA maintained 100-200μg/L. Total course of treatment was two years, the dose was tapered gradually in 9-12 months after onset, the remission rate of child patients, 24 h urine protein, plasma cholesterol, CD4+, CD8+, the ratio of CD4+/CD8+, and the occurrence of adverse drug reactions were observed closely.Results24 cases (60%) were completely remission, 7 cases (17.5%) were partially remission, whose short-term complete remission rate gradually increased along with the duration of treatment. 9 cases (22.5%) were ineffective who were given to adjust other immunosuppressants to further treat after the 3 months follow-up. After the 6, 9, 12 months follow-up, the 31 cases’ clinical biochemical parameters were significantly improved, serum albumin increased, 24 h urine protein, serum cholesterol, CD4+ and the ratio of CD4+/CD8+ decreased, there was significant difference after the treatment of CsA and before (P0.05). There was no significant difference in the efficacy of different pathological types. The main adverse effects of CsA included hirsutism, gingival hyperplasia, gastrointestinal reactions, mild hypertension, liver and renal function impairment, meanwhile, one case of reversible encephalopathy syndrome was in back of the brain, and all were acceptable.ConclusionIn small samples of clinical study, the application of CsA combined with hormone to treat children with NS were relatively safe and effective, a better efficacy for SDNS, adverse reactions should be paid attention to.%目的:观察环孢素 A

  3. Stress, glucocorticoids and absences in a genetic epilepsy model

    NARCIS (Netherlands)

    Tolmacheva, E.A.; Oitzl, M.S.; Luijtelaar, E.L.J.M. van

    2012-01-01

    Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij ra

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

    Science.gov (United States)

    Michaud, Kathy; Forget, Helene; Cohen, Henri

    2009-01-01

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

  5. Glucocorticoid-induced myopathy in the intensive care unit

    DEFF Research Database (Denmark)

    Eddelien, Heidi Shil; Hoffmeyer, Henrik Westy; Lund, Eva Charlotte Løbner;

    2015-01-01

    Glucocorticoids (GC) are used for intensive care unit (ICU) patients on several indications. We present a patient who was admitted to the ICU due to severe respiratory failure caused by bronchospasm requiring mechanical ventilation and treated with methylprednisolone 240 mg/day in addition to ant......, and muscle strength gradually returned. The patient made full recovery from the quadriplegia a few months later....

  6. Brief report: Glucocorticoid receptor polymorphism affects transrepression but not transactivation

    NARCIS (Netherlands)

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

    2006-01-01

    textabstractContext: Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC

  7. The effects of glucocorticoids on cultured human endothelial cells.

    Science.gov (United States)

    Maca, R D; Fry, G L; Hoak, J C

    1978-04-01

    The effects of hydrocortisone, dexamethasone and prednisone on the morphology, replication, DNA synthesis, cell protein content and protein synthesis of cultured, human endothelial cells were evaluated. After culturing the cells with these glucocorticoids for 24-48 h, the cells covered a greater portion of the culture surface area. The mean surface area of the individual endothelial cell treated with glucocorticoids was 1.53 times greater than that of the untreated control endothelial cell. When compared with controls, the endothelial cover provided by the cells treated with glucocorticoids was more extensive and in many instances covered the entire culture surface. The change in morphology was associated with an increase in protein synthesis and protein content of the cells without an increase in DNA synthesis or cellular replication. Dexamethasone was approximately 10-fold more effective than hydrocortisone, while prednisone was the least effective. Aldosterone, DOCA, testosterone, progesterone, oestradiol and oestriol were ineffective. These studies indicate that glucocorticoids can alter the morphology and biochemistry of cultured endothelial cells and may have implications for the effects of steroids in the treatment of thrombocytopenic states and vascular disorders in man. PMID:646949

  8. The Glucocorticoid Receptor Controls Hepatic Dyslipidemia through Hes1

    NARCIS (Netherlands)

    Lemke, U.; Krones-Herzig, A.; Berriel Diaz, M.; Narvekar, P.; Ziegler, A.; Vegiopoulos, A.; Cato, A.C.B.; Bohl, S.; Klingmüller, U.; Screaton, R.A.; Müller-Decker, K.; Kersten, A.H.; Herzig, S.

    2008-01-01

    Aberrant accumulation of lipids in the liver (¿fatty liver¿ or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of

  9. Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis

    NARCIS (Netherlands)

    Banciu, M.

    2007-01-01

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

  10. Flexible designs for phase II comparative clinical trials involving two response variables.

    Science.gov (United States)

    Bersimis, S; Sachlas, A; Papaioannou, T

    2015-01-30

    The aim of phase II clinical trials is to determine whether an experimental treatment is sufficiently promising and safe to justify further testing. The need for reduced sample size arises naturally in phase II clinical trials owing to both technical and ethical reasons, motivating a significant part of research in the field during recent years, while another significant part of the research effort is aimed at more complex therapeutic schemes that demand the consideration of multiple endpoints to make decisions. In this paper, our attention is restricted to phase II clinical trials in which two treatments are compared with respect to two dependent dichotomous responses proposing some flexible designs. These designs permit the researcher to terminate the clinical trial when high rates of favorable or unfavorable outcomes are observed early enough requiring in this way a small number of patients. From the mathematical point of view, the proposed designs are defined on bivariate sequences of multi-state trials, and the corresponding stopping rules are based on various distributions related to the waiting time until a certain number of events appear in these sequences. The exact distributions of interest, under a unified framework, are studied using the Markov chain embedding technique, which appears to be very useful in clinical trials for the sample size determination. Tables of expected sample size and power are presented. The numerical illustration showed a very good performance for these new designs.

  11. Maternal distress associates with placental genes regulating fetal glucocorticoid exposure and IGF2: Role of obesity and sex.

    Science.gov (United States)

    Mina, Theresia H; Räikkönen, Katri; Riley, Simon C; Norman, Jane E; Reynolds, Rebecca M

    2015-09-01

    Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11β-HSDs, NR3C1-α, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental samples from 43 lean (BMI≤25kg/m(2)) and 50 SO (BMI≥40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p≤0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11β-HSD1 mRNA levels in lean (p≤0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11β-HSD2, NR3C1-α and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood.

  12. [Prevention and treatment of glucocorticoid-induced osteoporosis in International and Italian scenarios].

    Science.gov (United States)

    Di Munno, O; Delle Sedie, A

    2011-01-01

    Osteoporosis (OP) and increased risk of fracture (Fx) associated with chronic glucocorticoid treatment pushed panels of experts and scientific societies to produce recommendations for both prevention and treatment of glucocorticoid-induced OP (GIO). Recently the American College of Rheumatology developed and/or endorsed their updated guidelines and recommendations for the prevention and treatment of GIO. In these recommendations the use of FRAX tool, for the 10-year probability of a major osteoporotic Fx, was integrated with other clinical risk factors to define low-, medium-, and high-risk patients. Updated approaches are delineated for post-menopausal women and men >50 years, pre-menopausal women not of childbearing potential, men 50 years, receiving >5 mg/day prednisone equivalent for >3 months; more recently teriparatide has also been included, only for those patients presenting ≥1 prevalent fragility Fx and receiving >5 mg/day prednisone equivalent for >12 months. Also zoledronic acid has been approved by Italian Agency of the Drug (AIFA, 30/08/10) for "... post-menopausal women and men chronically treated with GC ad high risk of Fx", but the drug is dispensed exclusively at the hospital.

  13. Prevention and treatment of glucocorticoid-induced osteoporosis in International and Italian scenarios

    Directory of Open Access Journals (Sweden)

    A. Delle Sedie

    2011-09-01

    Full Text Available Osteoporosis (OP and increased risk of fracture (Fx associated with chronic glucocorticoid treatment pushed panels of experts and scientific societies to produce recommendations for both prevention and treatment of glucocorticoid-induced OP (GIO. Recently the American College of Rheumatology developed and/or endorsed their updated guidelines and recommendations for the prevention and treatment of GIO. In these recommendations the use of FRAX tool, for the 10-year probability of a major osteoporotic Fx, was integrated with other clinical risk factors to define low-, medium-, and high-risk patients. Updated approaches are delineated for post-menopausal women and men >50 years, pre-menopausal women not of childbearing potential, men 50 years, receiving >5 mg/day prednisone equivalent for >3 months; more recently teriparatide has also been included, only for those patients presenting ≥1 prevalent fragility Fx and receiving >5 mg/day prednisone equivalent for >12 months. Also zoledronic acid has been approved by Italian Agency of the Drug (AIFA, 30/08/10 for “… post-menopausal women and men chronically treated with GC ad high risk of Fx”, but the drug is dispensed exclusively at the hospital.

  14. The evolution of the major hepatitis C genotypes correlates with clinical response to interferon therapy.

    Directory of Open Access Journals (Sweden)

    Phillip S Pang

    Full Text Available BACKGROUND: Patients chronically infected with hepatitis C virus (HCV require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV-a virus that is at least hundreds of years old-one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system. METHODS AND FINDINGS: We have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345. This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR. CONCLUSION: An evolutionary analysis of all

  15. RARtool : A MATLAB Software Package for Designing Response-Adaptive Randomized Clinical Trials with Time-to-Event Outcomes

    OpenAIRE

    Yevgen Ryeznik; Oleksandr Sverdlov; Weng Kee Wong

    2015-01-01

    Response-adaptive randomization designs are becoming increasingly popular in clinical trial practice. In this paper, we present RARtool, a user interface software developed in MATLAB for designing response-adaptive randomized comparative clinical trials with censored time-to-event outcomes. The RARtool software can compute different types of optimal treatment allocation designs, and it can simulate response-adaptive randomization procedures targeting selected optimal allocations. Through simu...

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

    Science.gov (United States)

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

    2012-06-01

    In this study, 18 female skeletally mature sheep were randomly allocated into three groups of six each. Group 1 (glucocorticoid-1) received prednisolone treatment (0.60 mg/kg/day, five times weekly) for 7 months. Group 2 (glucocorticoid-2) received the same treatment regime followed by observation of 3 months without treatment. Group 3 was left untreated and served as controls. All sheep received a restricted diet with low calcium and phosphorus. At sacrifice, cortical bone samples from the femur midshaft of each sheep were harvested, micro-CT scanned and subjected to three-point bending and tensile strength testing. Bone collagen and mineral were determined. Cortical porosity was significantly increased in the glucocorticoid-2 compared with the glucocorticoid-1 and control groups. Apparent density was significantly decreased in the glucocorticoid-2 compared with the glucocorticoid-1 group. Collagen content was significantly increased in the glucocorticoid-2 compared with the glucocorticoid-1 and control groups. Bone mineral content did not differ between the groups. Neither the three-point bending mechanical properties nor the tensile mechanical properties differed significantly between the groups, while there was a trend towards decreasing bending mechanical properties in the glucocorticoid-2 group. In conclusion, 7 months of glucocorticoid treatment with malnutrition had a significant impact on the cortical microarchitecture of the sheep femur midshaft. These observed changes occurred 3 months after glucocorticoid cessation, suggesting a delayed effect of glucocorticoid on cortical bone. Thus, changes in cortical bone beyond cancellous bone might further increase fracture risk in patients treated with glucocorticoids. This model might be used as a glucocorticoid-induced osteoporotic model for orthopaedic biomaterial, joint prosthesis and medical device researches.

  17. The Association between Clinical Response to Ustekinumab and Immunogenicity to Ustekinumab and Prior Adalimumab.

    Directory of Open Access Journals (Sweden)

    Hsien-Yi Chiu

    Full Text Available Immunogenicity due to antidrug antibodies (ADA to tumor necrosis factor (TNF-α antagonists is known to decrease treatment response. However, few studies have investigated ADA in ustekinumab, an interleukin-12 and -23 antagonist, in a clinical setting. This study aimed to investigate the immunogenicity of ustekinumab and its clinical consequences in psoriasis.This prospective observational study enrolled 76 patients with plaque psoriasis who were treated with ustekinumab for a minimum of 7 months. Blood samples were drawn just prior to scheduled ustekinumab injection during clinic visits. Levels of anti-ustekinumab antibody (AUA and serum ustekinumab concentration were measured respectively by radioimmunoassays and enzyme-linked immunoassays respectively, and correlated to clinical data and Psoriasis Area and Severity Index (PASI.AUA was detected in 6.5% of patients after a mean of 13 months of treatment. Patients with positive AUA had significantly lower serum ustekinumab concentrations (0.01 vs. 0.2 mg/L, p<0.001 and lower PASI 50 response than patients without AUA (0% vs. 69%, p = 0.004.The percentage of AUA formation was comparable between patients who had failed previous adalimumab with or without anti-adalimumab antibodies (AAA (14.3% vs. 12.5%, p = 1.00. However, a higher proportion of switchers without AAA obtaining PASI50 (71.4% vs. 37.5% and PASI75 response (42.9% vs.12.5% within 7 months of ustekinumab treatment than with AAA though this difference did not reach statistical significance.Our results suggest that presence of AUA was significantly associated with treatment failure for ustekinumab, though limited by a small sample size. Also, determining the presence of ADA to antecedent TNF-α antagonists may assist in choosing an optimized subsequent treatment modality achieving treatment success.

  18. Drug-Related Hyponatremic Encephalopathy: Rapid Clinical Response Averts Life-Threatening Acute Cerebral Edema

    Science.gov (United States)

    Siegel, Arthur J.; Forte, Sophie S.; Bhatti, Nasir A.; Gelda, Steven E.

    2016-01-01

    Patient: Female, 63 Final Diagnosis: Drug-induced hyponatremic encephalopathy Symptoms: Seizures • coma Medication: Hypertonic 3% saline infusion Clinical Procedure: — Specialty: Internal Medicine Objective: Unusual clinical course Background: Drug-induced hyponatremia characteristically presents with subtle psychomotor symptoms due to its slow onset, which permits compensatory volume adjustment to hypo-osmolality in the central nervous system. Due mainly to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), this condition readily resolves following discontinuation of the responsible pharmacological agent. Here, we present an unusual case of life-threatening encephalopathy due to adverse drug-related effects, in which a rapid clinical response facilitated emergent treatment to avert life-threatening acute cerebral edema. Case Report: A 63-year-old woman with refractory depression was admitted for inpatient psychiatric care with a normal physical examination and laboratory values, including a serum sodium [Na+] of 144 mEq/L. She had a grand mal seizure and became unresponsive on the fourth day of treatment with the dual serotonin and norepinephrine reuptake inhibitor [SNRI] duloxetine while being continued on a thiazide-containing diuretic for a hypertensive disorder. Emergent infusion of intravenous hypertonic (3%) saline was initiated after determination of a serum sodium [Na+] of 103 mEq/L with a urine osmolality of 314 mOsm/kg H20 and urine [Na+] of 12 mEq/L. Correction of hyposmolality in accordance with current guidelines resulted in progressive improvement over several days, and she returned to her baseline mental status. Conclusions: Seizures with life-threatening hyponatremic encephalopathy in this case likely resulted from co-occurring SIADH and sodium depletion due to duloxetine and hydrochlorothiazide, respectively. A rapid clinical response expedited diagnosis and emergent treatment to reverse life-threatening acute cerebral edema

  19. Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria.

    Science.gov (United States)

    Aichler, Michaela; Elsner, Mareike; Ludyga, Natalie; Feuchtinger, Annette; Zangen, Verena; Maier, Stefan K; Balluff, Benjamin; Schöne, Cédrik; Hierber, Ludwig; Braselmann, Herbert; Meding, Stephan; Rauser, Sandra; Zischka, Hans; Aubele, Michaela; Schmitt, Manfred; Feith, Marcus; Hauck, Stefanie M; Ueffing, Marius; Langer, Rupert; Kuster, Bernhard; Zitzelsberger, Horst; Höfler, Heinz; Walch, Axel K

    2013-08-01

    Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pretherapeutic oesophageal adenocarcinoma biopsies were analysed for proteomic changes associated with response to chemotherapy by MALDI imaging mass spectrometry. Resulting candidate proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated for functional relevance in vitro. Clinical impact was validated in pretherapeutic biopsies from an independent patient cohort. Studies on the incidence of these defects in other solid tumours were included. We discovered that clinical response to cisplatin correlated with pre-existing defects in the mitochondrial respiratory chain complexes of cancer cells, caused by loss of specific cytochrome c oxidase (COX) subunits. Knockdown of a COX protein altered chemosensitivity in vitro, increasing the propensity of cancer cells to undergo cell death following cisplatin treatment. In an independent validation, patients with reduced COX protein expression prior to treatment exhibited favourable clinical outcomes to chemotherapy, whereas tumours with unchanged COX expression were chemoresistant. In conclusion, previously undiscovered pre-existing defects in mitochondrial respiratory complexes cause cancer cells to become chemosensitive: mitochondrial defects lower the cells' threshold for undergoing cell death in response to cisplatin. By contrast, cancer cells with intact mitochondrial respiratory complexes are chemoresistant and have a high threshold for cisplatin-induced cell death. This connection between mitochondrial respiration and chemosensitivity is relevant to anticancer therapeutics that target the mitochondrial electron transport chain.

  20. Immune response phenotype of allergic versus clinically tolerant pigs in a neonatal swine model of allergy.

    Science.gov (United States)

    Schmied, Julie; Rupa, Prithy; Garvie, Sarah; Wilkie, Bruce

    2013-07-15

    The prevalence of childhood food allergy and the duration of these allergies, particularly those considered to be transient, like egg and milk allergy, are increasing. The identification of allergic individuals using minimally invasive, non-anaphylaxis-threatening methods is therefore of increasing importance. In this experiment, correlates were sought of an allergic immune response (IR) phenotype in pigs. Using pigs pre-treated with heat-killed bacteria or bacterial components before allergic sensitization with the egg white protein ovomucoid (Ovm), differences were determined in IR phenotype of pigs in the categories treated-allergic, treated-tolerant, control-allergic (CA) and control-tolerant. Phenotype was established by measuring immunoglobulin (Ig)-associated antibody activity (AbA), cytokine profiles and the proportion of blood T-regulatory cells (T-regs) and observing late-phase allergen-specific skin tests (ST). Although 100% of pigs became sensitized to Ovm, only 33% of pigs had clinical signs of allergy after oral challenge with egg white. Pigs without clinical signs were classified as clinically tolerant. Sixty-seven percent of allergic pigs had a positive, late-phase ST classified as very strong or strong, while 84% of clinically tolerant pigs did not have late-phase ST. Treated-allergic pigs and CA pigs had greater total antibody IgG (H+L), IgE and IgG1 AbA than clinically tolerant pigs. Cytokine profiles of allergic pigs and the proportion of circulating T-regs, did not differ significantly between allergic and clinically tolerant pigs. Therefore, measurement of allergen-specific IgG, IgG1 and/or IgE activity and evaluation of late-phase ID ST may be useful in identifying allergic IR phenotypes in swine models of food allergy, which may be extended toward human use.

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

    Directory of Open Access Journals (Sweden)

    Julie E Goodwin

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

  2. Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting

    Science.gov (United States)

    Wing, S. S.; Goldberg, A. L.; Goldberger, A. L. (Principal Investigator)

    1993-01-01

    Glucocorticoids are essential for the increase in protein breakdown in skeletal muscle normally seen during fasting. To determine which proteolytic pathway(s) are activated upon fasting, leg muscles from fed and fasted normal rats were incubated under conditions that block or activate different proteolytic systems. After food deprivation (1 day), the nonlysosomal ATP-dependent process increased by 250%, as shown in experiments involving depletion of muscle ATP. Also, the maximal capacity of the lysosomal process increased 60-100%, but no changes occurred in the Ca(2+)-dependent or the residual energy-independent proteolytic processes. In muscles from fasted normal and adrenalectomized (ADX) rats, the protein breakdown sensitive to inhibitors of the lysosomal or Ca(2+)-dependent pathways did not differ. However, the ATP-dependent process was 30% slower in muscles from fasted ADX rats. Administering dexamethasone to these animals or incubating their muscles with dexamethasone reversed this defect. During fasting, when the ATP-dependent process rises, muscles show a two- to threefold increase in levels of ubiquitin (Ub) mRNA. However, muscles of ADX animals failed to show this response. Injecting dexamethasone into the fasted ADX animals increased muscle Ub mRNA within 6 h. Thus glucocorticoids activate the ATP-Ub-dependent proteolytic pathway in fasting apparently by enhancing the expression of components of this system such as Ub.

  3. Functional interaction between the pro-apoptotic DAP3 and the glucocorticoid receptor.

    Science.gov (United States)

    Hulkko, Sanna M; Zilliacus, Johanna

    2002-07-19

    Apoptosis is an essential process for functions such as organ development and the immune response, and glucocorticoids are one of the important regulators of the cellular functions underlying these events. We have previously shown that the pro-apoptotic death-associated protein 3 (DAP3) directly interacts with the glucocorticoid receptor (GR), leading to the enhancement of the activity of the ligand-induced receptor. Here, we show that coexpression of DAP3 and GR results in an increased amount of cellular GR, as well as in partial translocation of DAP3 to the nucleus. Although the N-terminal domain of DAP3 is sufficient for interaction with GR, the full-length DAP3 is needed to efficiently increase GR levels and enhance the transcriptional activity of GR. Since full-length DAP3 is also necessary for the pro-apoptotic effect, the interplay between the N- and C-termini of DAP3 is probably essential for its cellular function. PMID:12099703

  4. Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag.

    Science.gov (United States)

    Kiessling, Silke; Eichele, Gregor; Oster, Henrik

    2010-07-01

    Jet lag encompasses a range of psycho- and physiopathological symptoms that arise from temporal misalignment of the endogenous circadian clock with external time. Repeated jet lag exposure, encountered by business travelers and airline personnel as well as shift workers, has been correlated with immune deficiency, mood disorders, elevated cancer risk, and anatomical anomalies of the forebrain. Here, we have characterized the molecular response of the mouse circadian system in an established experimental paradigm for jet lag whereby mice entrained to a 12-hour light/12-hour dark cycle undergo light phase advancement by 6 hours. Unexpectedly, strong heterogeneity of entrainment kinetics was found not only between different organs, but also within the molecular clockwork of each tissue. Manipulation of the adrenal circadian clock, in particular phase-shifting of adrenal glucocorticoid rhythms, regulated the speed of behavioral reentrainment. Blocking adrenal corticosterone either prolonged or shortened jet lag, depending on the time of administration. This key role of adrenal glucocorticoid phasing for resetting of the circadian system provides what we believe to be a novel mechanism-based approach for possible therapies for jet lag and jet lag-associated diseases. PMID:20577050

  5. Clinical predictors of an optimal response to natalizumab in multiple sclerosis.

    Science.gov (United States)

    Sargento-Freitas, João; Batista, Sonia; Macario, Carmo; Matias, Fernando; Sousa, Livia

    2013-05-01

    Despite the high level of effectiveness of natalizumab (NTZ) in the treatment of patients with multiple sclerosis (MS), concerns about its high direct cost and its safety have restricted its use. Our aim was to identify and quantify the clinical factors that predict an optimal response to NTZ. Patients with MS undergoing treatment with NTZ for at least 12 months were classified as optimal responders if, during treatment, they sustained a reduction in their Kurtzke Expanded Disability Status Scale (EDSS) score of 1 point or more or experienced a reduction in annualised relapse rate (ARR) of more than 1. The remaining patients were classified as suboptimal responders and non-responders. Our subject pool included 48 patients. The variables associated with optimal response included: ARR in the previous year of at least 2, an age at first administration of 37.5 years or less, a baseline EDSS score of 4.5 points or less, a disease duration of 9.5 years or less and, in patients with secondary-progressive MS, a progressive-phase duration of 4.5 years or less. The characteristics of the disease at its onset did not affect responsiveness, indicating that patients with highly active disease and low disability are the ideal candidates for NTZ treatment, regardless of previous clinical characteristics.

  6. Biomarkers for predicting clinical response to immunosuppressive therapy in aplastic anemia.

    Science.gov (United States)

    Narita, Atsushi; Kojima, Seiji

    2016-08-01

    The decision to select hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) as initial therapy in acquired aplastic anemia (AA) is currently based on patient age and the availability of a human leukocyte antigen (HLA)-matched donor. Although IST is a promising treatment option, the ability to predict its long-term outcomes remains poor due to refractoriness, relapses, and the risk of clonal evolution. Several predictive biomarkers for response to IST have been posited, including age, gender, pre-treatment blood cell counts, cytokines, gene mutations, paroxysmal nocturnal hemoglobinuria (PNH), and telomere length (TL). While previous studies have provided substantial biological insights into the utility of IST, the prognostic power of the reported biomarkers is currently insufficient to contribute to clinical decision making. Recently, a large retrospective analysis proposed the combination of minor PNH clones and TL as an efficient predictor of IST response. Identification of a reliable predictor would provide a useful tool for determining the most appropriate treatment choice for AA patients, including up-front HSCT from HLA-matched unrelated donor. The present review summarizes studies evaluating the utility of biomarkers in predicting the clinical response to IST of patients with AA, and provides a baseline for prospective studies aimed at validating previously reported biomarkers. PMID:27091471

  7. Inhibition of ATP-induced calcium influx in HT4 cells by glucocorticoids: involvement of protein kinase A

    Institute of Scientific and Technical Information of China (English)

    Jian-zhong HAN; Wen LIN; Yi-zhang CHEN

    2005-01-01

    Aim: In our previous observations, adenosine triphosphate (ATP) was found to evoke immediate elevations in intracellular free calcium concentration ([Ca2+]i) in HT4 neuroblastoma cells of mice. We tried to see if a brief pretreatment of glucocorticoids could inhibit the Ca2+ response and reveal the underlying signal ing mechanism. Methods: Measurement of [Ca2+]i was carried out using the dual-wavelength fluorescence method with Fura-2 as the indicator. Results: Pre incubation of HT4 cells for 5 min with corticosterone (B) or bovine serum albumin conjugated corticosterone (B-BSA) inhibited the peak [Ca2+]i increments in a concentration-dependent manner. Cortisol and dexamethasone had a similar action, while deoxycorticosterone and cholesterol were ineffective. Both extracellular Ca2+ influx and internal Ca2+ release contributed to ATP-induced [Ca2+]i elevation. The brief treatment with only B attenuated Ca2+ influx. Furthermore, the [Ca2+]i elevation induced by the P2X receptor agonist adenosine 5'-(β,γ-methylene) triphosphate (β,γ-meATP) was also suppressed. The rapid inhibitory effect of B can be reproduced by forskolin 1 mmol/L and blocked by H89 20 mmol/L. Neither nuclear glucocorticoid receptor antagonist mifepristone nor protein kinase C in hibitors influenced the rapid action of B. Conclusion: Our results suggest that glucocorticoids modulate P2X receptor-medicated Ca2+ influx through a membrane-initiated, non-genomic and PKA-dependent pathway in HT4 cells.

  8. The Brief Accessibility, Responsiveness, and Engagement Scale: A Tool for Measuring Attachment Behaviors in Clinical Couples.

    Science.gov (United States)

    Sandberg, Jonathan G; Novak, Joshua R; Davis, Stephanie Y; Busby, Dean M

    2016-01-01

    Measuring attachment behaviors is relevant to creating secure couple relationships. This article seeks to test and examine the reliability and validity of the Brief Accessibility, Responsiveness, and Engagement (BARE) Scale-a practical measure of couple attachment-in a clinical sample. Couples took the BARE and other assessments measuring relationship functioning (self and partner reports of relationship satisfaction, relationship stability, positive and negative communication, and attachment styles). Results suggest that the BARE appears to be a reliable and valid tool for assessing couple attachment and can accurately predict and classify whether the couples belong in the clinical or nonclinical group, as well as their level of relationship satisfaction. Results also indicate attachment behaviors are related to relationship outcomes. PMID:26748730

  9. Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids.

    Directory of Open Access Journals (Sweden)

    Galina T Shishkina

    Full Text Available Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg, and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg. Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.

  10. Roles and Responsibilities, and Education and Training Requirements for Clinically Qualified Medical Physicists

    International Nuclear Information System (INIS)

    The IAEA technical cooperation project Strengthening Medical Physics in Radiation Medicine was approved by the IAEA Board of Governors for the period 2009-2013 with the aim of ensuring the safe and effective diagnosis and treatment of patients. The IAEA, together with the World Health Organization and stakeholders from numerous medical physics professional societies worldwide, including the International Organization for Medical Physics (IOMP), the European Federation of Organisations for Medical Physics, the American Association of Physicists in Medicine (AAPM), the Latin American Medical Physics Association, the Asia-Oceania Federation of Organizations for Medical Physics, the European Society for Radiotherapy and Oncology, the European Commission and the International Radiation Protection Association, as well as regional counterparts from Africa, Asia, Europe and Latin America, met in Vienna in May 2009 to plan and coordinate the new project. A shortage of clinically qualified medical physicists (CQMPs), insufficient education and training (especially properly organized and coordinated clinical training), and lack of professional recognition were identified as the main problems to be addressed under this project. This publication was developed under the project framework in response to these findings. It aims, first, at defining appropriately and unequivocally the roles and responsibilities of a CQMP in specialties of medical physics related to the use of ionizing radiation, such as radiation therapy, nuclear medicine, and diagnostic and interventional radiology. Important, non-ionizing radiation imaging specialties, such as magnetic resonance and ultrasound, are also considered for completeness. On the basis of these tasks, this book provides recommended minimum requirements for the academic education and clinical training of CQMPs, including recommendations for their accreditation, certification and registration, along with continuing professional development

  11. Improved clinical response to Sr-89 with increasing dose in patients with metastatic prostate and breast cancer in bone

    International Nuclear Information System (INIS)

    The authors have investigated a possible dose-response effect with increasing therapeutic doses of Sr- 89. Thirty-two patients with painful metastatic skeletal deposits completed a phase I-II standard 3-month protocol. Sr-89 administered doses ranged from 25 to 85 μCi/kg body weight. Clinical response was graded on a five-point scale. The mean level of clinical response was calculated for each dose range. The mean response rating for 25 μCi/kg was 2.33; 40 μCi/kg, 3.55; 55 μCi/kg, 3.70; 70 μCi/kg, 4.60; and 85 μCi/kg, 4.00. Probit analysis demonstrated a highly significant dose-response curve. No patients exhibited unacceptable hematologic toxicity. Sr-89 administration at higher dose levels provides improved clinical response with acceptable hematologic toxicity

  12. The relationship between visual orienting responses and clinical characteristics in children attending special education for the visually impaired.

    Science.gov (United States)

    Kooiker, Marlou J G; Pel, Johan J M; van der Steen, Johannes

    2015-05-01

    We recently introduced a method based on quantification of orienting responses toward visual stimuli to assess the quality of visual information processing in children. In the present study, we examined the relationship between orienting responses and factors that are associated with visual processing impairments in current clinical practice. Response time and fixation quality to visual features such as form, contrast, motion, and color stimuli were assessed in 104 children from 1 to 12 years attending special education for the visually impaired. Using regression analysis, we investigated whether these parameters were affected by clinical characteristics of children. Response times significantly depended on stimulus type. Responses to high-contrast cartoons were significantly slower in children with a clinical diagnosis of cerebral visual impairment. Fixation quality was significantly affected by visual acuity and nystagmus. The results suggest that the quantitative measurement of orienting responses is strongly related to cerebral visual impairment in children.

  13. DBH gene as predictor of response in a cocaine vaccine clinical trial

    OpenAIRE

    Kosten, Thomas R.; Domingo, Coreen B.; Hamon, Sara C.; Nielsen, David A

    2013-01-01

    We examined a pharmacogenetic association of the dopamine β-hydroxylase (DBH) gene with a response to an anti-cocaine vaccine that was tested in a recent clinical trial. This gene is associated with cocaine-induced paranoia, which has a slower onset than the euphoria from cocaine. The vaccine reduced euphoria by slowing the entry of cocaine into the brain, but it may not reduce aversive symptoms like paranoia. A 16-week Phase IIb randomized double-blind placebo-controlled trial of 114 cocaine...

  14. The clinical features of 17 patients with steroid-responsive encephalopathy associated with autoimmune thyroiditis

    Directory of Open Access Journals (Sweden)

    CHEN Hai

    2013-06-01

    Full Text Available Objective To investigate the onset pattern, clinical manifestations, laboratory findings and imaging features of 17 Chinese patients with steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT. Methods The clinical data of 17 SREAT patients were collected. Retrospective analysis of their clinical features, as well as their serum levels of anti-thyroid, cerebrospinal fluid (CSF biochemical indicators, MRI and therapy was performed. Results The initial symptoms of those patients were seizures (4 cases, psychiatric symptoms (4 cases, hypomnesis (4 cases, walking unsteadiness (2 cases, headache (2 cases and dysarthria (1 case. Three cases were acute onset, 5 cases subacute onset and 9 cases chronic onset. The anti-thyroid peroxidase antibody (anti-TPO of 17 cases were significantly increased, average (928.63 ± 406.28 × 10 3 IU/L. The anti?thyroglobulin antibody (anti-TG of 15 cases was increased, average (601.27 ± 1014.12 × 10 3 IU/L. The protein in CSF was mildly increased, average (513.75 ± 283.15 mg/L. The EEG of 5 patients presented slow wave and the EEG of 2 patients showed epileptiform discharge. The brain MRI of 11 patients showed multifocal lesions in frontal lobe, temporal lobe, parietal lobe, basal ganglia, centrum ovale, corpus callosum, thalamus, cerebellum, and brain stem. The findings of clinical immunological index and tumor markers were normal. Besides, the prognosis of 11 patients treated with methylprednisolone and 3 patients treated with dexamethasone were good. Recurrence occurred in 2 patients. Conclusion Basically, the clinical features of Chinese SREAT patients present seizures, hypomnesis and psychiatric symptoms associated with increased anti-thyroid and multifocal lesions in gray and white matter of brain.

  15. Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report

    Directory of Open Access Journals (Sweden)

    Christian Meiners

    2011-03-01

    Full Text Available The present article describes the ongoing (partial remission of a female patient (41 years old from estrogen receptor (ER-positive/progesterone receptor (PR-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation, the suppression of NF-kappaB as a factor triggering the inflammatory response, and chemotherapy with capecitabine. The reduction of tumor mass was evidenced by a continuing decline of CA15-3 and CEA tumor marker serum levels and 18FDG-PET-CT plus magnetic resonance (MR imaging. It is concluded that such combination treatment might be a useful option for treating already formed metastases and for providing protection against the formation of metastases in ER positive breast cancer. The findings need to be corroborated by clinical trials. Whether similar results can be expected for other malignant tumor phenotypes relying on glycolysis as the main energy source remains to be elucidated.

  16. Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Meiners, Christian [Gautinger Straße 3b, D-82234 Wessling (Germany)

    2011-03-17

    The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the suppression of NF-kappaB as a factor triggering the inflammatory response, and chemotherapy with capecitabine. The reduction of tumor mass was evidenced by a continuing decline of CA15-3 and CEA tumor marker serum levels and {sup 18}FDG-PET-CT plus magnetic resonance (MR) imaging. It is concluded that such combination treatment might be a useful option for treating already formed metastases and for providing protection against the formation of metastases in ER positive breast cancer. The findings need to be corroborated by clinical trials. Whether similar results can be expected for other malignant tumor phenotypes relying on glycolysis as the main energy source remains to be elucidated.

  17. Increased hsp70 of glucocorticoid receptor complex induced by scald and heat stress and its possible effect on the affinity of glucocorticoid receptor

    Institute of Scientific and Technical Information of China (English)

    WANG Xiao-hui; TANG Hong-tai; LU Jian; XIA Zhao-fan

    2010-01-01

    Background Glucocorticoid (GC) insensitivity/GC resistance is an important etiological and prognostic factor in multiple diseases and pathophysiological processes such as scald, shock and asthma. The function of GC was mediated by glucocorticoid receptor (GR). Scald not only decreased the expression of GR but also reduced the affinity of GR, which played an important role in GC resistance in scalded rats. Whereas the molecular mechanism responsible for the decrease of GR affinity resulted from scald remains unclear. Recent studies showed that the changes of heat shock proteins (hsp) especially hsp90 and hsp70 of GR heterocomplex were associated with GR low affinity in vitro. Methods The affinity of GR in hepatic cytosols and in the cytosols of SMMC-7721 cells were determined by radioligand binding assay and scatchard plot. GR heterocomplex in cytosols were captured by coimmunoprecipation and the levels of hsp90 and hsp70 of GR complex were detected by quantitative Western blotting.Results Similar with that of hepatic cytosol of scalded rats, a remarkable decrease of GR affinity was also found in the cytosol of heat stressed SMMC-7721 cells. The level of hsp70 of GR complex in hepatic cytosol of scalded rats (30% total body surface area immersion scald) and in cytosol of heat stressed human hepatocarcinoma cell line SMMC-7721 were both increased by 1.5 fold, whereas no change of hsp90 in GR heterocomplex was found. According to the correlation analysis, there may be a positive relationship between increased hsp70 of GR complex and decreased GR affinity in the cytosols.Conclusions The primary results indicated that the level of hsp70 of GR heterocomplex was increased in the hepatic cytosol of scalded rats and the cytosol of heat stressed SMMC-7721 cells. The increase of hsp70 of GR complex might be associated with the decrease of GR affinity.

  18. Galantamine treatment in Alzheimer's disease: response and long-term outcome in a routine clinical setting

    Directory of Open Access Journals (Sweden)

    Wallin ÅK

    2011-09-01

    Full Text Available Åsa K Wallin, Carina Wattmo, Lennart MinthonClinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, SwedenBackground: In the absence of long-term, placebo-controlled studies of cholinesterase inhibitors in Alzheimer's disease (AD, analysis of the results of open-label trials becomes crucial. This study aimed to explore the three-year effects of galantamine treatment, as well as subgroups of response and adherence to treatment.Methods: Two hundred and eighty patients with a clinical diagnosis of AD were included in the prospective, open-label, multicenter Swedish Alzheimer Treatment Study, and received galantamine treatment. Efficacy measures included cognitive tests, ie, the Mini-Mental State Examination (MMSE and Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog, functional rating (Instrumental Activities of Daily Living Scale [IADL], and global rating. Assessments were carried out before treatment and every six months for a period of three years. K-means cluster analysis was used to identify response subgroups.Results: After three years of treatment, the mean change from baseline was 2.6 points in MMSE and 5.6 points in ADAS-cog scores. Globally, half of the patients improved or remained unchanged for two years. Cluster analysis identified two response clusters. Cluster 1 included patients with low ability in ADAS-cog and IADL scores at baseline. Even though the patients in cluster 1 were older and less educated, they responded better at six months compared with patients in cluster 2. Cluster 2 included patients with better ADAS-cog and IADL scores at baseline. Patients in cluster 2 had a higher frequency of the APOE ε4 allele, a slower pretreatment progression rate, and remained in the study longer than those in cluster 1. Three-year completers (n = 129, 46% received higher doses of galantamine compared with dropouts.Conclusion: AD patients who received long-term galantamine treatment were

  19. Integrative analysis of epigenetic modulation in melanoma cell response to decitabine: clinical implications.

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    Ruth Halaban

    Full Text Available Decitabine, an epigenetic modifier that reactivates genes otherwise suppressed by DNA promoter methylation, is effective for some, but not all cancer patients, especially those with solid tumors. It is commonly recognized that to overcome resistance and improve outcome, treatment should be guided by tumor biology, which includes genotype, epigenotype, and gene expression profile. We therefore took an integrative approach to better understand melanoma cell response to clinically relevant dose of decitabine and identify complementary targets for combined therapy. We employed eight different melanoma cell strains, determined their growth, apoptotic and DNA damage responses to increasing doses of decitabine, and chose a low, clinically relevant drug dose to perform whole-genome differential gene expression, bioinformatic analysis, and protein validation studies. The data ruled out the DNA damage response, demonstrated the involvement of p21(Cip1 in a p53-independent manner, identified the TGFbeta pathway genes CLU and TGFBI as markers of sensitivity to decitabine and revealed an effect on histone modification as part of decitabine-induced gene expression. Mutation analysis and knockdown by siRNA implicated activated beta-catenin/MITF, but not BRAF, NRAS or PTEN mutations as a source for resistance. The importance of protein stability predicted from the results was validated by the synergistic effect of Bortezomib, a proteasome inhibitor, in enhancing the growth arrest of decitabine in otherwise resistant melanoma cells. Our integrative analysis show that improved therapy can be achieved by comprehensive analysis of cancer cells, identified biomarkers for patient's selection and monitoring response, as well as targets for improved combination therapy.

  20. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit.

    Science.gov (United States)

    Yuan, Jianda; Gnjatic, Sacha; Li, Hao; Powel, Sarah; Gallardo, Humilidad F; Ritter, Erika; Ku, Geoffrey Y; Jungbluth, Achim A; Segal, Neil H; Rasalan, Teresa S; Manukian, Gregor; Xu, Yinyan; Roman, Ruth-Ann; Terzulli, Stephanie L; Heywood, Melanie; Pogoriler, Evelina; Ritter, Gerd; Old, Lloyd J; Allison, James P; Wolchok, Jedd D

    2008-12-23

    Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable clinical responses in patients with metastatic melanoma. The functional impact of anti-CTLA-4 therapy on human immune responses is still unclear. To explore this, we analyzed immune-related adverse events and immune responses in metastatic melanoma patients treated with ipilimumab, a fully human anti-CTLA-4 monoclonal antibody. Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. One NY-ESO-1 seronegative clinical responder also had a NY-ESO-1 CD4(+) and CD8(+) T cell response, possibly related to prior vaccination with NY-ESO-1. Among five clinical non-responders analyzed, only one had a NY-ESO-1 CD4(+) T cell response and this patient did not have detectable anti-NY-ESO-1 antibody. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1beta and TNF-alpha. We therefore suggest that CTLA-4 blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in patients with durable objective clinical responses and stable disease. These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade.

  1. Epidemiological and clinical characteristics, spirometric parameters and response to budesonide/formoterol in patients attending an asthma clinic: an experience in a developing country

    OpenAIRE

    Imad, Hassan; Yasir, Ged

    2015-01-01

    Introduction This study aims at describing the epidemiological and clinical characteristics, severity, reversibility testing and response to treatment using simple spirometry in asthmatic patients attending a model specialized Asthma Care Center. Methods Eligible subjects must have a suggestive clinical picture and confirmed by spirometry to have a 12% plus 200ml absolute increase in FEV1 either by reversibility testing or after a therapeutic trial with inhaled and/or oral steroid therapy. Bu...

  2. Clinical value of MRI and acute madopar responsiveness test in diagnosing progressive supranuclear palsy

    Directory of Open Access Journals (Sweden)

    LI Xiao-hong

    2013-07-01

    Full Text Available Objective To investigate the MRI abnormalities and acute madopar responsiveness test in diagnosing progressive supranuclear palsy (PSP and Parkinson's disease (PD. Methods Seventeen patients with PSP and 17 gender and age matched patients with PD were studied with cranial MRI examinations and results of acute madopar responsiveness test, and the clinical manifestations of PSP were summarized. Results The atrophy of the midbrain tegmentum and hummingbird sign was demonstrated in all of the PSP patients in our study, but was not observed in the PD patients. The areas of the midbrain on mid-sagittal MRI in PSP patients [(77.35 ± 15.30 mm2] were significantly smaller than that in those with PD [(142.35 ± 31.49 mm2]. The average ratio of the area of the midbrain to the area of pons in the patients with PSP [(14.31 ± 2.47%] was significantly smaller than that in those with PD [(24.08 ± 4.73%; P = 0.000, for all]. According to the result of acute madopar responsiveness test, the maximum Unified Parkinson's Disease Rating Scale (UPDRS Ⅲ improvement rate of 2 patients with PSP and 16 patients with PD was more than 30% (χ2 = 23.142, P = 0.000. Conclusion The assessment of the mid-sagittal MRI and acute madopar responsiveness test may be a useful method to differentiate PSP from PD.

  3. Histological, Immunohistochemical and clinical study of HEPATIC immune response in CHRONIC hepatitis C

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    Aboushady MA, Algyoushy AF, Elbaz TZ, Saleh SA and Ewees IE

    2004-03-01

    Full Text Available The factors that determine persistence or clearance of hepatitis C virus (HCV infection are poorly understood. Information in this area may lead to better understanding of the immune response against HCV infection. Such understanding can support the goal of development of a broad based cellular and humoral immune response to HCV which may be important for eradication of infection. In the present study, needle biopsy specimens from hepatitis C virus infected patients were prepared for histological, histopathological and immunohistochemical studies. Patient history, full clinical examination and biochemical investigations were recorded. Primary and secondary lymphoid follicles were evident in ABOUT 50% of the biopsies. Because CD4(+ T- helper (T-h lymphocytes provide help for humoral immunity, these cells were demonstrated in the liver biopsies by immunohistochemical methods. Positive fluorescence representing CD3(+/CD4(+ T-h was vigorous in liver residing lymph follicles. To test the possibility of T-h proliferation due to autoimmune reaction, the serum of patients was tested for the presence of antimitochondrial, antismooth muscle and antinuclear antibodies by immunohistochemical method. Analysis of the results eliminated the autoimmune response leaving the possibility of antiviral response. Histological examination indicated bile duct injury in areas occupied by secondary follicles. This may indicate that viral core proteins, with antigenic properties that elucidate immune response, may reach the portal area, in which the follicles are formed, via the bile canaliculi to the bile duct where antigen antibody complex is phagocytosed leading to bile duct injury. Unlike the case of patients who did not show follicles in their liver biopsy, those showing secondary follicles did not show liver cirrhosis or high grade fibrosis suggesting immune protection. Moreover, the incidence of secondary follicles in females was higher than males suggesting sex

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

    DEFF Research Database (Denmark)

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

    treatment. Group 3 was left untreated and served as the controls. All sheep received restricted diet with low calcium and phosphorus. At sacrifice, cortical bone samples from the femur midshaft of sheep were harvested, micro-CT scanned and tested in 3 point bending and in tensile. Bone collagen and mineral......The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone – Validation of large animal model for tissue engineering and biomaterial research Ming Ding,1* Carl Christian Danielsen,2 Søren Overgaard1 1Orthopaedic Research Laboratory......, Department of Orthopaedics and Traumatology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense C, Denmark 2Department of Connective Tissue Biology, Institute of Anatomy, University of Aarhus, Aarhus C, Denmark Osteopenia in sheep has been successfully induced...

  5. Adverse effects of perioperative paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations

    DEFF Research Database (Denmark)

    Mathiesen, O; Wetterslev, Jørn; Kontinen, V K;

    2014-01-01

    with the most common perioperative non-opioid analgesics: paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCCs), gabapentinoids and their combinations. The review is based on data from systematic reviews with meta-analyses of analgesic efficacy and/or adverse effects......Post-operative pain affects millions of patients worldwide and the post-operative period has high rates of morbidity and mortality. Some of this morbidity may be related to analgesics. The aim of this review was to provide an update of current knowledge of adverse events (AE) associated....... Gabapentinoid treatment was associated with increased sedation, dizziness and visual disturbances, but the clinical relevance needs clarification. Importantly, data on AEs of combinations of the above analgesics are sparse and inconclusive. Despite the potential adverse events associated with the most commonly...

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

    Institute of Scientific and Technical Information of China (English)

    E.Brad Thompson

    2008-01-01

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

  7. The glucocorticoid/aggression relationship in animals and humans: an analysis sensitive to behavioral characteristics, glucocorticoid secretion patterns, and neural mechanisms.

    Science.gov (United States)

    Haller, József

    2014-01-01

    Glucocorticoids control a wide array of biological processes from glucose homeostasis to neuronal function. The mechanisms mediating their effects are similarly varied and include rapid and transient nongenomic effects on calcium trafficking, various neurotransmitter receptors, and other membrane/cytoplasmic proteins, as well as slowly developing but durable genomic effects that are mediated by a large number of glucocorticoid-sensitive genes that are affected after variable lag-times. Given this complexity, we suggest that the aggression/glucocorticoid relationship cannot be reduced to the simple "stimulation/inhibition" question. Here, we review the effects of glucocorticoids on aggression by taking into account the complexities of glucocorticoid actions. Acute and chronic effects were differentiated because these are mediated by different mechanisms. The effects of chronic increases and decreases in glucocorticoid production were discussed separately, because the activation of mechanisms that are not normally activated and the loss of normal functions should not be confounded. Findings in healthy/normal subjects and those obtained in subjects that show abnormal forms of behavior or psychopathologies were also differentiated, because the effects of glucocorticoids are indirect, and largely depend on the properties of neurons they act upon, which are altered in subjects with psychopathologies. In addition, the conditions of glucocorticoid measurements were also thoroughly evaluated. Although the role of glucocorticoids in aggression is perceived as controversial by many investigators, a detailed analysis that is sensitive to glucocorticoid and behavioral measure as well as to the mediating mechanism suggests that this role is rather clear-cut; moreover, there is a marked similarity between animal and human findings.

  8. Sexually dimorphic actions of glucocorticoids: beyond chromosomes and sex hormones.

    Science.gov (United States)

    Quinn, Matthew; Ramamoorthy, Sivapriya; Cidlowski, John A

    2014-05-01

    Sexual dimorphism is a well-documented phenomenon that is observed at all levels of the animal kingdom. Historically, sex hormones (testosterone and estrogen) have been implicated as key players in a wide array of pathologies displaying sexual dimorphism in their etiology and progression. While these hormones clearly contribute to sexually dimorphic diseases, other factors may be involved in this phenomenon as well. In particular, the stress hormone cortisol exerts differential effects in both males and females. The underlying molecular basis for the sexually dimorphic actions of glucocorticoids is unknown but clearly important to understand, since synthetic glucocorticoids are the most widely prescribed medication for the treatment of chronic inflammatory diseases and hematological cancers in humans. PMID:24739020

  9. Leber's optic neuropathy: clinical and visual evoked response studies in asymptomatic and symptomatic members of a 4-generation family.

    OpenAIRE

    Livingstone, I R; Mastaglia, F. L.; Howe, J W; Aherne, G E

    1980-01-01

    A clinical and neuro-ophthalmological examination using tests of visual acuity, quantitative visual field analysis, tests of colour discrimination, ophthalmoscopy, and pattern visual evoked responses was performed on 2 symptomatic and 16 asymptomatic members of a family with Leber's optic neuropathy. The visual evoked responses were abnormal in the 2 clinically affected males and in 1 asymptomatic male. Tests of colour discrimination with Ishihara plates, the Farnsworth-Munsell 100 hue test, ...

  10. Sparse Multi-Response Tensor Regression for Alzheimer's Disease Study With Multivariate Clinical Assessments.

    Science.gov (United States)

    Li, Zhou; Suk, Heung-Il; Shen, Dinggang; Li, Lexin

    2016-08-01

    Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that has recently seen serious increase in the number of affected subjects. In the last decade, neuroimaging has been shown to be a useful tool to understand AD and its prodromal stage, amnestic mild cognitive impairment (MCI). The majority of AD/MCI studies have focused on disease diagnosis, by formulating the problem as classification with a binary outcome of AD/MCI or healthy controls. There have recently emerged studies that associate image scans with continuous clinical scores that are expected to contain richer information than a binary outcome. However, very few studies aim at modeling multiple clinical scores simultaneously, even though it is commonly conceived that multivariate outcomes provide correlated and complementary information about the disease pathology. In this article, we propose a sparse multi-response tensor regression method to model multiple outcomes jointly as well as to model multiple voxels of an image jointly. The proposed method is particularly useful to both infer clinical scores and thus disease diagnosis, and to identify brain subregions that are highly relevant to the disease outcomes. We conducted experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and showed that the proposed method enhances the performance and clearly outperforms the competing solutions. PMID:26960221

  11. Clinical Response and Transfusion Reactions of Sheep Subjected to Single Homologous Blood Transfusion

    Directory of Open Access Journals (Sweden)

    Rejane Santos Sousa

    2014-01-01

    Full Text Available Studies in relation to blood conservation and responses to transfusion are scarce for ruminants. We evaluated the clinical manifestations of sheep that received a single homologous transfusion of whole blood, focusing on transfusion reactions. Eighteen adult sheep were subjected to a single phlebotomy to withdraw 40% of the total blood volume, which was placed into CPDA-1 bags and then divided into G0, animals that received fresh blood, and G15 and G35, animals that received blood stored for 15 or 35 days, respectively. Clinical observations were recorded throughout the transfusion, whereas heart rate, respiratory rate, and rectal temperature were assessed at the following times: 24 hours after phlebotomy and before transfusion; 30 minutes, six, twelve, 24, 48, 72, and 96 hours and eight and 16 days after transfusion. All groups presented transfusion reactions, among which hyperthermia was the most frequent (50% of animals. Tachycardia occurred most frequently in the G35 animals (50% of them. During transfusion G35 animals presented more clinical manifestation (P<0.05. Transfusion of fresh or stored total blood improved the blood volume, but transfusion reactions occurred, demonstrating that a single transfusion of fresh or stored blood can cause inflammatory and febrile nonhemolytic transfusion reactions in sheep.

  12. Transcriptomics in human blood incubation reveals the importance of oxidative stress response in Saccharomyces cerevisiae clinical strains

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    Llopis Silvia

    2012-08-01

    Full Text Available Abstract Background In recent years an increasing number of yeast infections in humans have been related to certain clinical isolates of Saccharomyces cerevisiae. Some clinical strains showed in vivo and in vitro virulence traits and were able to cause death in mice whereas other clinical strains were avirulent. Results In this work, we studied the transcriptional profiles of two S. cerevisiae clinical strains showing virulent traits and two control non-virulent strains during a blood incubation model and detected a specific transcriptional response of clinical strains. This response involves an mRNA levels increase of amino acid biosynthesis genes and especially oxidative stress related genes. We observed that the clinical strains were more resistant to reactive oxygen species in vitro. In addition, blood survival of clinical isolates was high, reaching similar levels to pathogenic Candida albicans strain. Furthermore, a virulent strain mutant in the transcription factor Yap1p, unable to grow in oxidative stress conditions, presented decreased survival levels in human blood compared with the wild type or YAP1 reconstituted strain. Conclusions Our data suggest that this enhanced oxidative stress response in virulent clinical isolates, presumably induced in response to oxidative burst from host defense cells, is important to increase survival in human blood and can help to infect and even produce death in mice models.

  13. Acute infectious diseases and immunologic responses. Some stories from clinical practice apropos the Influenza A (H1N1 pandemic

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    Alfredo Darío Espinosa Brito

    2011-04-01

    Full Text Available Apropos of the appearance of some unusual clinical pictures in the course of the recent epidemic of Influenza A (H1N1, and with the intention of sharing controversial ideas related to the immunologic responses of the patients to the infectious agents, we expose here a group of stories arisen from a clinical practice of almost five decades.

  14. Locomotor therapy with extended-release crystalline glucocorticoids

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    Vladimir Vasilyevich Badokin

    2013-01-01

    Full Text Available Topical glucocorticoid (GC therapy for locomotor diseases is an extremely important component of a comprehensive program to treat inflammatory and, to a lesser extent, degenerative diseases. It reduces the time of hospitalization by 5—10 days in this category of patients, has a prompt and potent anti-inflammatory effect, and shows predictable efficiency. This therapy shows good tolerability and high safety and prevents serious adverse reactions to GC treatment.

  15. Osteoprotegerin Prevents Glucocorticoid-Induced Osteocyte Apoptosis in Mice

    OpenAIRE

    Weinstein, Robert S; O'Brien, Charles A; Almeida, Maria; Zhao, Haibo; Roberson, Paula K.; Jilka, Robert L.; Manolagas, Stavros C.

    2011-01-01

    The adverse skeletal effects of glucocorticoid excess are due to increased osteoclast survival, decreased production of osteoblasts, and increased apoptosis of osteoblasts and osteocytes, but it remains unknown which of these is the principle cause of the decrease in bone strength. Previous studies suggested that osteocytes contribute to bone strength independently of changes in bone mass. Administration of the receptor activator for nuclear factor κB ligand (RANKL) antagonist osteoprotegerin...

  16. Glucocorticoids Enhance CD163 Expression in Placental Hofbauer Cells

    OpenAIRE

    Tang, Zhonghua; Niven-Fairchild, Tracy; Tadesse, Serkalem; Errol R Norwitz; Buhimschi, Catalin S; Buhimschi, Irina A.; Guller, Seth

    2012-01-01

    Periplacental levels of glucocorticoid (GC) peak at parturition, and synthetic GC is administered to women at risk for preterm delivery. However, little is known concerning cell-type-specific effects of GC in placenta. Hofbauer cells (HBCs) are fetal macrophages that are located adjacent to fetal capillaries in placenta. The goal of the current study was to determine whether GC treatment altered HBC gene expression and function. Western blotting and flow cytometry revealed CD163 and folate re...

  17. Inappropriate use of potent topical glucocorticoids in infants.

    Science.gov (United States)

    Ozon, Alev; Cetinkaya, Semra; Alikasifoglu, Ayfer; Gonc, E Nazli; Sen, Yaşar; Kandemir, Nurgün

    2007-02-01

    Topical therapy with glucocorticoids (GCs) is used commonly in chronic dermatoses. Side effects are less common compared to systemic use; however, newer potent preparations may have serious side effects. A potential danger is their inappropriate use. Three infants who developed iatrogenic Cushing's syndrome and prolonged adrenal suppression in the course of GC therapy for simple diaper dermatitis are described. One patient also developed steatohepatitis which is uncommon with local GCs. PMID:17396439

  18. Estrogen receptor beta activation prevents glucocorticoid receptor-dependent effects of the central nucleus of the amygdala on behavior and neuroendocrine function.

    Science.gov (United States)

    Weiser, Michael J; Foradori, Chad D; Handa, Robert J

    2010-06-01

    Neuropsychiatric disorders such as anxiety and depression have formidable economic and societal impacts. A dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis leading to elevated endogenous glucocorticoid levels is often associated with such disorders. Chronically high glucocorticoid levels may act upon the central nucleus of the amygdala (CeA) to alter normally adaptive responses into those that are maladaptive and detrimental. In addition to glucocorticoids, other steroid hormones such as estradiol and androgens can also modify hormonal and behavioral responses to threatening stimuli. In particular, estrogen receptor beta (ERbeta) agonists have been shown to be anxiolytic. Consequently, these experiments addressed the hypothesis that the selective stimulation of glucocorticoid receptor (GR) in the CeA would increase anxiety-like behaviors and HPA axis reactivity to stress, and further, that an ERbeta agonist could modulate these effects. Young adult female Sprague-Dawley rats were ovariectomized and bilaterally implanted via stereotaxic surgery with a wax pellet containing the selective GR agonist RU28362 or a blank pellet, to a region just dorsal to the CeA. Four days later, animals were administered the ERbeta agonist S-DPN or vehicle (with four daily sc injections). Anxiety-type behaviors were measured using the elevated plus maze (EPM). Central RU28362 implants caused significantly higher anxiety-type behaviors in the EPM and greater plasma CORT levels than controls given a blank central implant. Moreover, S-DPN treated animals, regardless of type of central implant, displayed significantly lower anxiety-type behaviors and post-EPM plasma CORT levels than vehicle treated controls or vehicle treated animals implanted with RU28362. These results indicate that selective activation of GR within the CeA is anxiogenic, and peripheral administration of an ERbeta agonist can overcome this effect. These data suggest that estradiol signaling via ERbeta

  19. Glucocorticoids entrain molecular clock components in human peripheral cells.

    Science.gov (United States)

    Cuesta, Marc; Cermakian, Nicolas; Boivin, Diane B

    2015-04-01

    In humans, shift work induces a desynchronization between the circadian system and the outside world, which contributes to shift work-associated medical disorders. Using a simulated night shift experiment, we previously showed that 3 d of bright light at night fully synchronize the central clock to the inverted sleep schedule, whereas the peripheral clocks located in peripheral blood mononuclear cells (PBMCs) took longer to reset. This underlines the need for testing the effects of synchronizers on both the central and peripheral clocks. Glucocorticoids display circadian rhythms controlled by the central clock and are thought to act as synchronizers of rodent peripheral clocks. In the present study, we tested whether the human central and peripheral clocks were sensitive to exogenous glucocorticoids (Cortef) administered in the late afternoon. We showed that 20 mg Cortef taken orally acutely increased PER1 expression in PBMC peripheral clocks. After 6 d of Cortef administration, the phases of central markers were not affected, whereas those of PER2-3 and BMAL1 expression in PBMCs were shifted by ∼ 9.5-11.5 h. These results demonstrate, for the first time, that human peripheral clocks are entrained by glucocorticoids. Importantly, they suggest innovative interventions for shift workers and jet-lag travelers, combining synchronizing agents for the central and peripheral clocks.

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

    Science.gov (United States)

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

    2013-03-01

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

  1. A Small-Molecule Smoothened Agonist Prevents Glucocorticoid-Induced Neonatal Cerebellar Injury

    OpenAIRE

    Heine, Vivi M.; Griveau, Amelie; Chapin, Cheryl; Ballard, Philip L.; Chen, James K.; Rowitch, David H.

    2011-01-01

    Glucocorticoids are used for treating preterm neonatal infants suffering from life-threatening lung, airway, and cardiovascular conditions. However, several studies have raised concerns about detrimental effects of postnatal glucocorticoid administration on the developing brain leading to cognitive impairment, cerebral palsy, and hypoplasia of the cerebellum, a brain region critical for coordination of movement and higher-order neurological functions. Previously, we showed that glucocorticoid...

  2. Interactions between glucocorticoid metabolism and inflammation in obesity and insulin resistance.

    OpenAIRE

    Nixon, Mark

    2011-01-01

    Inflammation plays a key role in the underlying pathogenesis of obesity and its associated health risks, with increased markers of inflammation evident in both liver and adipose tissue. In parallel, there is dysregulation of glucocorticoid metabolism in obesity, with increased adipose levels of the glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and increased hepatic levels of 5α-reductase type 1 (5αR1), which catalyses the reduction of glucocorticoids. Bo...

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

    OpenAIRE

    Fornari, Raquel V.; Wichmann, Romy; Atucha, Erika; Desprez, Tifany; Eggens-Meijer, Ellie; Roozendaal, Benno

    2012-01-01

    Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC) to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor (GR) agonist RU 2...

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

    OpenAIRE

    Raquel Fornari

    2012-01-01

    Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC) to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor agonist RU 2836...

  5. The clinical features, therapeutic responses, and prognosis of the patients with mantle cell lymphoma

    Directory of Open Access Journals (Sweden)

    Li-Juan Deng

    2012-07-01

    Full Text Available Mantle cell lymphoma(MCL, a special type of non-Hodgkin's lymphoma, is incurable through conventional treatment. This study aimed to analyze the clinical features, therapeutic responses, and prognosis of patients with MCL. Clinical data of 30 patients with MCL treated in our hospital between April 2006 and July 2011 were analyzed. Eighteen patients were treated with CHOP plus rituximab (R-CHOP regimen, 12 underwent conventional chemotherapy. The median age of the 30 patients was 58 years, 23 were men, all patients had Cyclin D1 overexpression, 29 (96.7% had advanced disease, 11 (36.7% had bone marrow involvement, 9 (30.0% had gastrointestinal involvement, and 15 (50.0% had splenomegaly. The complete response(CR rate and overall response rate(ORR were significantly higher in patients undergoing R-CHOP immunochemotherapy than in those undergoing conventional chemotherapy (38.9% vs. 16.7%, P = 0.187; 72.2% vs. 41.4%, P = 0.098. The difference of 2-year overall survival rate between the two groups was not significant (P = 0.807 due to the short follow-up time. The 2-year progression-free survival (PFS rate was higher in R-CHOP group than in conventional chemotherapy group (53% vs. 25%, P = 0.083, and was higher in patients with a lower mantle cell lymphoma international prognostic index (MIPI (51% for MIPI 0-3, 33% for MIPI 4-5, and 0% for MIPI 6-11, P = 0.059. Most patients with MCL were elderly; in an advanced stage; showed a male predominance; and usually had bone marrow involvement, gastrointestinal involvement, or splenomegaly. R-CHOP regimen could improve the CR rate and ORR of MCL patients. MIPI can be a new prognostic index for predicting the prognosis of advanced MCL.

  6. Clinic research of pediatric primary nephrotic syndrome of treatment of Huaiqihuang puls glucocorticoid%槐杞黄颗粒联合糖皮质激素治疗小儿原发性肾病综合征的临床研究

    Institute of Scientific and Technical Information of China (English)

    冯仕品; 谢敏; 王莉; 罗苇; 张伟; 翟洋

    2011-01-01

    目的 通过槐杞黄颗粒联合糖皮质激素治疗儿童原发性肾病综合征(PNS)与单纯糖皮质激素治疗儿童原发性肾病综合征的对比研究,探讨槐杞黄颗粒对肾病综合征患儿的疗效及其免疫调节作用,观察其不良反应.方法 将40例原发性肾病综合征患儿随机分为2组,治疗组20例采用槐杞黄联合糖皮质激素治疗,对照组20例单独服用糖皮质激素治疗,观察两组患儿水肿消退、蛋白尿转阴时间;观察期内感染例数;两组患儿治疗前后体液免疫:IgA、IgM、IgG,细胞免疫:CD3、CD4、CD8、CD4/CD8的变化情况;槐杞黄颗粒的不良反应;观察周期:连续观察12周.结果 治疗组尿蛋白转阴、水肿消退时间明显小于对照组(P<0.05),感染发生率小于对照组(P<0.05);治疗组患儿体液免疫及细胞免疫较对照组明显改善,IgC、CD3、CD4/CD8均增高(P<0.01);治疗组治疗后IgA、IgM有一定增高趋势,但与对照组比较,其差异无统计学意义(P>0.05);2例患儿出现恶心、呕吐、腹泻,未见皮疹、肝肾功能异常等不良反应.结论 槐杞黄颗粒辅助治疗肾病综合征患儿,可以缩短水肿消退、蛋白尿转阴的时间,可以增强肾脏病患儿的免疫调节功能、减少感染发生的机会,进而增强激素疗效改善预后,同时在治疗过程中未出现明显的不良反应,临床证实是安全有效的辅助治疗药物.%Objective To investigate the effects of Huaiqihuang granule on treatment, immune regulation and its side effect of pediatric primary nephrotic syndrome by the contrast research of Huaiqihuang granule puls glucocorticoid and glucocorti-coid only. Methods 40 children with primary nephrotic syndrome were randomly tow groups. The treatment group(20 children) were teated with Huaiqihuang granule puls glucocorticoid, the contrast group (20 children) had glucocorticoid only. The follow were obseved; the time of edema regression and prourine

  7. Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain.

    Science.gov (United States)

    Moisan, M P; Minni, A M; Dominguez, G; Helbling, J C; Foury, A; Henkous, N; Dorey, R; Béracochéa, D

    2014-03-01

    Corticosteroid binding globulin (CBG) is a glycoprotein synthesized in liver and secreted in the blood where it binds with a high affinity but low capacity glucocorticoid hormones, cortisol in humans and corticosterone in laboratory rodents. In mammals, 95% of circulating glucocorticoids are bound to either CBG (80%) or albumin (15%) and only the 5% free fraction is able to enter the brain. During stress, the concentration of glucocorticoids rises significantly and the free fraction increases even more because CBG becomes saturated. However, glucocorticoids unbound to CBG are cleared from the blood more quickly. Our studies on mice totally devoid of CBG (Cbg k.o.) showed that during stress these mutant mice display a lower rise of glucocorticoids than the wild-type controls associated with altered emotional reactivity. These data suggested that CBG played a role in the fast actions of glucocorticoids on behavior. Further analyses demonstrated that stress-induced memory retrieval impairment, an example of the fast action of glucocorticoids on the brain is abolished in the Cbg k.o. mice. This effect of stress on memory retrieval could be restored in the Cbg k.o. mice by infusing corticosterone directly in the hippocampus. The mechanisms explaining these effects involved an increased clearance but no difference in corticosterone production. Thus, CBG seems to have an important role in maintaining in blood a glucocorticoid pool that will be able to access the brain for the fast effects of glucocorticoids.

  8. Glucocorticoid receptor-mediated induction of glutamine synthetase in skeletal muscle cells in vitro

    Science.gov (United States)

    Max, Stephen R.; Thomas, John W.; Banner, Carl; Vitkovic, Ljubisa; Konagaya, Masaaki

    1987-01-01

    The regulation by glucocorticoids of glutamine synthetase in L6 muscle cells in culture is studied. Glutamine synthetase activity was strikingly enhanced by dexamethasone. The dexamethasone-mediated induction of glutamine synthetase activity was blocked by RU38486, a glucocorticoid antagonist, indicating the involvement of intracellular glucocorticoid receptors in the induction process. RU38486 alone was without effect. Northern blot analysis revealed that dexamethasone-mediated enhancement of glutamine synthetase activity involves increased levels of glutamine synthetase mRNA. Glucocorticoids regulate the expression of glutamine synthetase mRNA in cultured muscle cells via interaction with intracellular receptors. Such regulation may be relevant to control of glutamine production by muscle.

  9. TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

    Science.gov (United States)

    Kotsiou, Eleni; Okosun, Jessica; Besley, Caroline; Iqbal, Sameena; Matthews, Janet; Fitzgibbon, Jude; Gribben, John G.

    2016-01-01

    Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. PMID:27103745

  10. Comparative transcriptional analysis of clinically relevant heat stress response in Clostridium difficile strain 630.

    Directory of Open Access Journals (Sweden)

    Nigel G Ternan

    Full Text Available Clostridium difficile is considered to be one of the most important causes of health care-associated infections worldwide. In order to understand more fully the adaptive response of the organism to stressful conditions, we examined transcriptional changes resulting from a clinically relevant heat stress (41 °C versus 37 °C in C. difficile strain 630 and identified 341 differentially expressed genes encompassing multiple cellular functional categories. While the transcriptome was relatively resilient to the applied heat stress, we noted upregulation of classical heat shock genes including the groEL and dnaK operons in addition to other stress-responsive genes. Interestingly, the flagellin gene (fliC was downregulated, yet genes encoding the cell-wall associated flagellar components were upregulated suggesting that while motility may be reduced, adherence--to mucus or epithelial cells--could be enhanced during infection. We also observed that a number of phage associated genes were downregulated, as were genes associated with the conjugative transposon Tn5397 including a group II intron, thus highlighting a potential decrease in retromobility during heat stress. These data suggest that maintenance of lysogeny and genome wide stabilisation of mobile elements could be a global response to heat stress in this pathogen.

  11. Recent advances in the glucocorticoid-induced osteoporosis%糖皮质激素性骨质疏松致病机制最新研究进展

    Institute of Scientific and Technical Information of China (English)

    刘盛业; 付勤

    2015-01-01

    Glucocorticoid is widely used in anti-inlfammatory and immune-modulatory drugs while its related side effects shouldn’t allow to be neglected, such as osteoporosis, diabetes, and obesity. Clinical applications of it has also been greatly restricted. Improvement of results of these unnecessary outcomes also become the main challenge of medical work. To explore the pathogenetic mechanisms of glucocorticoid-induced osteoporosis ( GIO ) and its effects on bone and mineral metabolism are of crucial importance. Endogenous glucocorticoid of physiological-concentration is not only a key regulating factor for differentiation of mesenchymal stem cells and bone development, but also involved in regulating calcium handling by kidney and gastrointestinal tract. As supra-physiological concentration, it acts as a “double-edged sword” role, taking unfavorable effect in the same tissue. Over the years there has been a controversial paradox about GIO mechanism for the anabolic and catabolism of glucocorticoid, which needs to be further in-depth studied. This paper reviews highlighted recent advances on physiology and pathology of glucocorticoid for bone metabolism, and to provide new strategies for prophylaxis and treatment of GIO.

  12. Skin Metabolite, Farnesyl Pyrophosphate, Regulates Epidermal Response to Inflammation, Oxidative Stress, and Migration.

    Science.gov (United States)

    Pastar, Irena; Stojadinovic, Olivera; Sawaya, Andrew P; Stone, Rivka C; Lindley, Linsey E; Ojeh, Nkemcho; Vukelic, Sasa; Samuels, Herbert H; Tomic-Canic, Marjana

    2016-11-01

    Skin produces cholesterol and a wide array of sterols and non-sterol mevalonate metabolites, including isoprenoid derivative farnesyl pyrophosphate (FPP). To characterize FPP action in epidermis, we generated transcriptional profiles of primary human keratinocytes treated with zaragozic acid (ZGA), a squalene synthase inhibitor that blocks conversion of FPP to squalene resulting in endogenous accumulation of FPP. The elevated levels of intracellular FPP resulted in regulation of epidermal differentiation and adherens junction signaling, insulin growth factor (IGF) signaling, oxidative stress response and interferon (IFN) signaling. Immunosuppressive properties of FPP were evidenced by STAT-1 downregulation and prominent suppression of its nuclear translocation by IFNγ. Furthermore, FPP profoundly downregulated genes involved in epidermal differentiation of keratinocytes in vitro and in human skin ex vivo. Elevated levels of FPP resulted in induction of cytoprotective transcriptional factor Nrf2 and its target genes. We have previously shown that FPP functions as ligand for the glucocorticoid receptor (GR), one of the major regulator of epidermal homeostasis. Comparative microarray analyses show significant but not complete overlap between FPP and glucocorticoid regulated genes, suggesting that FPP may have wider transcriptional impact. This was further supported by co-transfection and chromatin immunoprecipitation experiments where we show that upon binding to GR, FPP recruits β-catenin and, unlike glucocorticoids, recruits co-repressor GRIP1 to suppress keratin 6 gene. These findings have many clinical implications related to epidermal lipid metabolism, response to glucocorticoid therapy as well as pleiotropic effects of cholesterol lowering therapeutics, statins. J. Cell. Physiol. 231: 2452-2463, 2016. © 2016 Wiley Periodicals, Inc. PMID:26916741

  13. Catatonia in DSM 5: controversies regarding its psychopathology, clinical presentation and treatment response.

    Science.gov (United States)

    Ungvari, Gabor S

    2014-12-01

    Over the past two decades, there has been an upsurge of interest in catatonia, which is reflected in the attention it received in DSM 5, where it appears as a separate subsection of the Schizophrenia Spectrum and Other Psychotic Disorders (APA, 2013). This commentary argues that due to the lack of solid scientific evidence, the extended coverage of catatonia in DSM 5 was a premature, and consequently, a necessarily ambiguous decision. The psychopathological foundations of the modern catatonia concept are lacking therefore its boundaries are fuzzy. There are only a few, methodologically sound clinical, treatment response and small-scale neurobiological studies. The widely recommended use of benzodiazepines for the treatment of catatonia is based on case reports and open-label studies instead of placebo-controlled, randomized trials. In conclusion, the catatonic concept espoused by DSM 5 is necessarily vague reflecting the current state of knowledge.

  14. Clinical study of the histologic host response of the patients with lung cancer during radiotherapy

    International Nuclear Information System (INIS)

    Serial bronchofiberscopic biopsies were performed during radiotherapy in 28 patients with squamous cell carcinoma of the lung. The effect of radiotherapy on tumor tissue was examined histologically as to the responsiveness of the host against tumor cells. The mononuclear cell infiltration induced in the tumor by irradiation correlated well with its direct effect on the tumor cells. The most remarkable infiltration was observed at the dose of 2000 rad and in the polypoid type. Indirect immunofluonescent technique with monoclonal anti OKT 3 and OKIa revealed that most of the infiltrated cells were T-lymphocytes. There was a good relationship between the grade of mononuclear cell infiltration and the survival period. These facts suggest that the mononuclear cells in the irradiated tumor tissues represent host resistance against cancer and the intensity of the infiltration correlates with the clinical course and prognosis of the lung cancer patients. (author)

  15. Local and systemic immune response in pigs during subclinical and clinical swine influenza infection.

    Science.gov (United States)

    Pomorska-Mól, M; Kwit, K; Markowska-Daniel, I; Kowalski, C; Pejsak, Z

    2014-10-01

    Local and systemic immune responses in pigs intranasally (IN) and intratracheally (IT) inoculated with swine influenza virus (SIV) were studied. No clinical signs were observed in IN-inoculated pigs, while IT-inoculated pigs developed typical signs of influenza. Significantly higher titres of specific antibodies and changes of haematological parameters were found only in IT-inoculated pigs. Because positive correlations between viral titre, local cytokine concentration, and lung pathology have been observed, we hypothesise that both viral load and the local secretion of cytokines play a role in the induction of lung lesions. It could be that a higher replication of SIV stimulates immune cells to secrete higher amounts of cytokines. The results of the present study indicate that pathogenesis of SIV is dependent on both, the damage caused to the lung parenchyma directly by virus, and the effects on the cells of the host's immune system.

  16. Clinical characteristics and treatment response to SSRI in a female pedophile.

    Science.gov (United States)

    Chow, Eva W C; Choy, Alberto L

    2002-04-01

    Although much investigation has been done with male sex offenders, there have been few studies on female sex offenders. Female sex offenders have been reported as having a high incidence of psychiatric disorders, but female paraphilics were rarely described. The literature on the treatment of female sex offenders is also limited and treatment with a selective serotonin reuptake inhibitor (SSRI) has not been reported. This paper presents the case of a woman with DSM-IV pedophilia. Her clinical characteristics, her offense history, and her positive response to treatment with sertraline (a SSRI) are described. This case adds to the limited literature on female pedophiles and suggests that SSRIs may be an effective treatment for paraphilic disorders in female sex offenders. PMID:11974646

  17. Needle EMG Response of Lumbar Multifidus to Manipulation in the Presence of Clinical Instability.

    Science.gov (United States)

    Tunnell, John

    2009-01-01

    A proposed mechanism for the persistence of low back pain due to clinical instability is a decrease in control of local spinal musculature, more specifically decreased recruitment of multifidus. Altered segmental mechanoreceptor input has been proposed as a contributing factor responsible for a decrease in local muscle recruitment. In this case report, immediate changes in the recruitment of the deep multifidus following manipulation were examined using needle EMG and isometric testing of trunk rotational force. Trunk rotational force appeared to improve while the multifidus demonstrated a decrease in activity as measured by needle EMG. No specific conclusions can be drawn from this report; however, the results do suggest that immediate multifidus function may be influenced with manipulation, resulting in improved muscular control of the trunk. PMID:20046558

  18. Clinical characteristics and treatment response to SSRI in a female pedophile.

    Science.gov (United States)

    Chow, Eva W C; Choy, Alberto L

    2002-04-01

    Although much investigation has been done with male sex offenders, there have been few studies on female sex offenders. Female sex offenders have been reported as having a high incidence of psychiatric disorders, but female paraphilics were rarely described. The literature on the treatment of female sex offenders is also limited and treatment with a selective serotonin reuptake inhibitor (SSRI) has not been reported. This paper presents the case of a woman with DSM-IV pedophilia. Her clinical characteristics, her offense history, and her positive response to treatment with sertraline (a SSRI) are described. This case adds to the limited literature on female pedophiles and suggests that SSRIs may be an effective treatment for paraphilic disorders in female sex offenders.

  19. The Efficacy of Exposure and Response Prevention for Geriatric Obsessive Compulsive Disorder: A Clinical Case Illustration

    Directory of Open Access Journals (Sweden)

    Mairwen K. Jones

    2012-01-01

    Full Text Available Obsessive compulsive disorder (OCD is one of the most frequently occurring psychiatric conditions in older adults. While exposure and response prevention (ERP is considered the most effective psychological treatment for children and adults with OCD, research investigating its effectiveness for older adults is scarce. This clinical case study investigates the effectiveness of ERP in an 80-year-old man with a 65-year history of OCD. The client received 14 individual, 50-minute ERP treatment sessions. Clinician-based Y-BOCS scores reduced by 65% from 20 (moderate at pretreatment to 7 (subclinical at 7-month posttreatment followup. OCI-R total scores reduced by 45% from 38 at baseline to 21 at 7-month follow-up. Despite his long history of the disorder, ERP was effective and well tolerated. The application of ERP for older adults with OCD, including age-specific modifications that may be required for this treatment approach, is discussed.

  20. Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation.

    Directory of Open Access Journals (Sweden)

    Ilse M Beck

    Full Text Available Compound A possesses glucocorticoid receptor (GR-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1, upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells.