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Sample records for prolonged glucocorticoid treatment

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

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    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.

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

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    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 difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years....... Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor...

  3. Islet-cell dysfunction induced by glucocorticoid treatment

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

    2013-01-01

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

  4. Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk.

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    Gutzwiller, Jean-Pierre; Aschwanden, Josef; Iff, Samuel; Leuenberger, Michèle; Perrig, Martin; Stanga, Zeno

    2011-12-01

    The hypothesis of this clinical study was to determine whether glucocorticoid use and immobility were associated with in-hospital nutritional risk. One hundred and one patients consecutively admitted to the medical wards were enrolled. Current medical conditions, symptoms, medical history, eating and drinking habits, diagnosis, laboratory findings, medications, and anthropometrics were recorded. The Nutrition Risk Score 2002 (NRS-2002) was used as a screening instrument to identify nutritional risk. The results confirmed that glucocorticoid use and immobility are independently associated with nutritional risk determined by the NRS-2002. Constipation could be determined as an additional cofactor independently associated with nutritional risk. Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk in a mixed hospitalized population. The presence of long-time glucocorticoid use, immobility, or constipation should alert the clinician to check for nutritional status, which is an important factor in mortality and morbidity.

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

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    de Quervain, Dominique J-F; Margraf, Jürgen

    2008-04-07

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

  6. Glucocorticoid receptors and extinction retention deficits in the single prolonged stress model.

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    Knox, D; Nault, T; Henderson, C; Liberzon, I

    2012-10-25

    Single prolonged stress (SPS) is a rodent model of post traumatic stress disorder that is comprised of serial application of restraint (r), forced swim (fs), and ether (eth) followed by a 7-day quiescent period. SPS induces extinction retention deficits and it is believed that these deficits are caused by the combined stressful effect of serial exposure to r, fs, and eth. However, this hypothesis remains untested. Neurobiological mechanisms by which SPS induces extinction retention deficits are unknown, but SPS enhances glucocorticoid receptor (GR) expression in the hippocampus, which is critical for contextual modulation of extinction retrieval. Upregulation of GRs in extinction circuits may be a mechanism by which SPS induces extinction retention deficits, but this hypothesis has not been examined. In this study, we systematically altered the stressors that constitute SPS (i.e. r, fs, eth), generating a number of partial SPS (p-SPS) groups, and observed the effects SPS and p-SPSs had on extinction retention and GR levels in the hippocampus and prefrontal cortex (PFC). PFC GRs were assayed, because regions of the PFC are critical for maintaining extinction. We predicted that only exposure to full SPS would result in extinction retention deficits and enhance hippocampal and PFC GR levels. Only exposure to full SPS induced extinction retention deficits. Hippocampal and PFC GR expression was enhanced by SPS and most p-SPSs, however hippocampal GR expression was significantly larger following the full SPS exposure than all other conditions. Our findings suggest that the combined stressful effect of serial exposure to r, fs, and eth results in extinction retention deficits. The results also suggest that simple enhancements in GR expression in the hippocampus and PFC are insufficient to result in extinction retention deficits, but raise the possibility that a threshold-enhancement in hippocampal GR expression contributes to SPS-induced extinction retention deficits

  7. Expressions of Hippocampal Mineralocorticoid Receptor (MR) and Glucocorticoid Receptor (GR) in the Single-Prolonged Stress-Rats

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    Zhe, Du; Fang, Han; Yuxiu, Shi

    2008-01-01

    Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experience. Single-prolonged stress (SPS) is one of the animal models proposed for PTSD. Rats exposed to SPS showed enhanced inhibition of the hypothalamo-pituitary-adrenal (HPA) axis, which has been reliably reproduced in patients with PTSD. Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hippocampus regulate HPA axis by glucocorticoid negative feedback. Abnormalities in negative feedback are found in PTSD, suggesting that GR and MR might be involved in the pathophysiology of these disorders. In the present study, we performed immunohistochemistry and western blotting to examine the changes in hippocampal MR- and GR-expression after SPS. Immunohistochemistry revealed decreased MR- and GR-immunoreactivity (ir) in the CA1 of hippocampus in SPS animals. Change in GR sub-distribution was also observed, where GR-ir was shifted from nucleus to cytoplasm in SPS rats. Western blotting showed that SPS induced significantly decreased MR- and GR-protein in the whole hippocampus, although the degree of decreased expression of both receptors was different. Meanwhile, we also found the MR/GR ratio decreased in SPS rats. In general, SPS induced down-regulation of MR- and GR-expression. These findings suggest that MR and GR play critical roles in affecting hippocampal function. Changes in MR/GR ratio may be relevant for behavioral syndrome in PTSD

  8. Prolonged Exposure: a Rapid Treatment for Phobias

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    Watson, J. P.; Gaind, R.; Marks, I. M.

    1971-01-01

    Ten adult patients with long-standing specific phobias were treated by prolonged continuous exposure to their phobic objects in fantasy and reality without avoidance. All patients were greatly helped by four to five hours' treatment in two or three sessions, and all improved more after practice than after imaginal sessions. The treatment method is more economical and efficient than other methods described so far. PMID:5539135

  9. Glucocorticoid Signaling and Bone Biology.

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    Komori, T

    2016-11-01

    Since glucocorticoids remain an effective therapeutic option for the treatment of many inflammatory and autoimmune diseases, glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. Fractures may occur in as many as 30-50% of patients receiving chronic glucocorticoid therapy. Under physiological conditions, glucocorticoids are required for normal bone development due to their regulation of osteoblast differentiation, possibly via the Wnt/β-catenin pathway and TSC22D3. However, serum levels of endogenous corticosterone are elevated in aged mice and glucocorticoids exert negative effects on the survival of osteoblasts and osteocytes as well as angiogenesis. Glucocorticoid treatments impair bone formation and enhance bone resorption. Excess glucocorticoids induce osteoblast and osteocyte apoptosis by increasing pro-apoptotic molecules, reactive oxygen species, and endoplasmic reticulum stress and suppressing the Wnt/β-catenin pathway. Autophagy protects osteocytes from glucocorticoid-induced apoptosis, but passed some threshold, the process of autophagy leads the cells to apoptosis. Excess glucocorticoids impair osteoblastogenesis by inducing Wnt antagonists, including Dkk1, Sost, and sFRP-1. However, the findings are controversial and the involvement of Wnt antagonists requires further study. Excess glucocorticoids reduce the phosphorylation of Akt and GSK3β, which enhances the degradation of β-catenin. Excess glucocorticoids have been shown to modulate the expression of miRNAs, including miR-29a, miR-34a-5p, and miR-199a-5p, which regulate the proliferation and differentiation of osteoblast lineage cells. Excess glucocorticoids also enhance bone resorption by reducing OPG expression, increasing Rankl expression and reactive oxygen species, and prolonging the life span of osteoclasts; however, they also suppress the bone-degrading capacity of osteoclasts by disturbing the organization of the cytoskeleton. © Georg Thieme Verlag KG

  10. QT interval prolongation associated with sibutramine treatment

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    Harrison-Woolrych, Mira; Clark, David W J; Hill, Geraldine R; Rees, Mark I; Skinner, Jonathan R

    2006-01-01

    Aims To investigate a possible association of sibutramine with QT interval prolongation. Methods Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. Results The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QTc at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. Conclusions This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. Further studies are required, but in the meantime we would recommend that sibutramine should be avoided in patients with long QT syndrome and in patients taking other medicines that may prolong the QT interval. PMID:16542208

  11. The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex.

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    George, Sophie A; Rodriguez-Santiago, Mariana; Riley, John; Rodriguez, Elizabeth; Liberzon, Israel

    2015-01-01

    Post-traumatic stress disorder (PTSD) is a chronic, debilitating disorder. Only two pharmacological agents are approved for PTSD treatment, and they often do not address the full range of symptoms nor are they equally effective in all cases. Animal models of PTSD are critical for understanding the neurobiology involved and for identification of novel therapeutic targets. Using the rodent PTSD model, single prolonged stress (SPS), we have implicated aberrant excitatory neural transmission and glucocorticoid receptor (GR) upregulation in the medial prefrontal cortex (mPFC) and hippocampus (HPC) in fear memory abnormalities associated with PTSD. The objective of this study is to examine the potential protective effect of antiepileptic phenytoin (PHE) administration on SPS-induced extinction retention deficits and GR expression. Forty-eight SPS-treated male Sprague Dawley rats or controls were administered PHE (40, 20 mg/kg, vehicle) for 7 days following SPS stressors; then, fear conditioning, extinction, and extinction retention were tested. Fear conditioning and extinction were unaffected by SPS or PHE, but SPS impaired extinction retention, and both doses of PHE rescued this impairment. Similarly, SPS increased GR expression in the mPFC and dorsal HPC, and PHE prevented SPS-induced GR upregulation in the mPFC. These data demonstrate that PHE administration can prevent the development of extinction retention deficits and upregulation of GR. PHE exerts inhibitory effects on voltage-gated sodium channels and decreases excitatory neural transmission via glutamate antagonism. If glutamate hyperactivity in the days following SPS contributes to SPS-induced deficits, then these data may suggest that the glutamatergic system constitutes a target for secondary prevention.

  12. Spectroscopic characterization of bone tissue of experimental animals after glucocorticoid treatment and recovery period

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    Mitić, Žarko J.; Najman, Stevo J.; Cakić, Milorad D.; Ajduković, Zorica R.; Ignjatović, Nenad L.; Nikolić, Ružica S.; Nikolić, Goran M.; Stojanović, Sanja T.; Vukelić, Marija Đ.; Trajanović, Miroslav D.

    2014-09-01

    The influence of glucocorticoids on the composition and mineral/organic content of the mandible in tested animals after recovery and healing phase was investigated in this work. The results of FTIR analysis demonstrated that bone tissue composition was changed after glucocorticoid treatment. The increase of calcium, magnesium, phosphorus content and mineral part of bones was statistically significant in recovery phase and in treatment phase that included calcitonin and thymus extract. Some changes also happened in the organic part of the matrix, as indicated by intensity changes for already present IR bands and the appearance of new IR bands in the region 3500-1300 cm-1.

  13. Glucocorticoid treatment and impaired mood, memory and metabolism in people with diabetes: the Edinburgh Type 2 Diabetes Study

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    Reynolds, Rebecca M; Labad, Javier; Sears, Alison V; Williamson, Rachel M; Strachan, Mark W J; Deary, Ian J; Lowe, Gordon D O; Price, Jackie F; Walker, Brian R

    2012-01-01

    Objective Both type 2 diabetes and glucocorticoid therapy are highly prevalent. Although people with type 2 diabetes may be more susceptible to adverse effects of glucocorticoids, and it is recommended that glucocorticoid therapy is avoided for fear of worsening glycaemic control, the extent to which this advice is followed and the consequences when glucocorticoids are prescribed are poorly documented. The aim was to assess the characteristics of people with type 2 diabetes prescribed glucocorticoids in a real-world setting and to quantify resulting adverse effects. Design Cross-sectional cohort study. Methods Cardiometabolic variables, body fat distribution, cognitive function and mood were studied in the 1066 participants of the Edinburgh Type 2 Diabetes Study, of whom 162 (15%) were taking systemic, topical or inhaled glucocorticoids. Results Glucocorticoid therapy was more common in women and in smokers but was not avoided in patients with diabetic complications or cardiovascular risk factors. People taking glucocorticoids were more centrally obese with slightly higher HbA1c and total serum cholesterol but were no more likely to have hepatic steatosis or hypertension. Glucocorticoid treatment was associated with substantially lower mood and greater anxiety. Women taking glucocorticoid therapy were twice as likely to report depressive symptoms compared with those not taking treatment. Glucocorticoid therapy was also associated with poorer cognitive function among those with subclinical atherosclerosis, as indicated by low ankle–brachial pressure index. Conclusions Glucocorticoids are prescribed commonly for people with type 2 diabetes despite being associated with adverse indices of glycaemic control, cardiovascular risk factors, mood and cognitive function. PMID:22408122

  14. Deciding about treatments that prolong life

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    ... you are receiving or may need in the future. Learn about the treatments and how they would ... patients and their families. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: ...

  15. Glucocorticoid-induced hyperglycaemia

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    Gerards, M.C.

    2018-01-01

    This thesis contains studies on current practice, clinical implications and treatment of excess glucocorticoid receptor (GCR) stimulation, with a focus on glucocorticoid-induced hyperglycaemia (GCIH). Chapter 1 is a general introduction to the glucocorticoid hormone. In chapter 2 , we have

  16. Streptococcus suis meningitis can require a prolonged treatment course

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    Jean Dejace

    2017-12-01

    Full Text Available We report a case of recrudescent Streptococcus suis meningitis requiring a prolonged treatment course. A few similar cases can be found in the burgeoning literature on what remains a relatively uncommon disease in humans, and these patients should be monitored carefully upon completion of therapy. Keywords: Meningitis, Relapse, Duration, Streptococcus suis

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

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    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.

  18. Prescription duration and treatment episodes in oral glucocorticoid users: application of the parametric waiting time distribution

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    Laugesen, Kristina; Støvring, Henrik; Hallas, Jesper

    2017-01-01

    for oral glucocorticoids and to describe continuous treatment episodes using the parametric waiting time distribution. Methods: We used Danish nationwide registries to identify all prescriptions for oral glucocorticoids during 1996-2014. We applied the parametric waiting time distribution to estimate...... duration of individual prescriptions each year by estimating the 80th, 90th, 95th and 99th percentiles for the interarrival distribution. These corresponded to the time since last prescription during which 80%, 90%, 95% and 99% of users presented a new prescription for redemption. We used the Kaplan...... of the interarrival distribution to apply as prescription duration has an impact on the level of misclassification. Use of the 80th percentile provides a measure of drug exposure that is specific, while the 99th percentile provides a sensitive measure....

  19. Antioxidant treatment alters peripheral vascular dysfunction induced by postnatal glucocorticoid therapy in rats.

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    Emilio A Herrera

    2010-02-01

    Full Text Available Postnatal glucocorticoid therapy in premature infants diminishes chronic lung disease, but it also increases the risk of hypertension in adulthood. Since glucocorticoid excess leads to overproduction of free radicals and endothelial dysfunction, this study tested the hypothesis that adverse effects on cardiovascular function of postnatal glucocorticoids are secondary to oxidative stress. Therefore, combined postnatal treatment of glucocorticoids with antioxidants may diminish unwanted effects.Male rat pups received a course of dexamethasone (Dex, or Dex with vitamins C and E (DexCE, on postnatal days 1-6 (P1-6. Controls received vehicle (Ctrl or vehicle with vitamins (CtrlCE. At P21, femoral vascular reactivity was determined via wire myography. Dex, but not DexCE or CtrlCE, increased mortality relative to Ctrl (81.3 versus 96.9 versus 90.6 versus 100% survival, respectively; P<0.05. Constrictor responses to phenylephrine (PE and thromboxane were enhanced in Dex relative to Ctrl (84.7+/-4.8 versus 67.5+/-5.7 and 132.7+/-4.9 versus 107.0+/-4.9% Kmax, respectively; P<0.05; effects that were diminished in DexCE (58.3+/-7.5 and 121.1+/-4.3% Kmax, respectively; P<0.05. Endothelium-dependent dilatation was depressed in Dex relative to Ctrl (115.3+/-11.9 versus 216.9+/-18.9, AUC; P<0.05; however, this effect was not restored in DexCE (68.3+/-8.3, AUC. Relative to Ctrl, CtrlCE alone diminished PE-induced constriction (43.4+/-3.7% Kmax and the endothelium-dependent dilatation (74.7+/-8.7 AUC; P<0.05.Treatment of newborn rats with dexamethasone has detrimental effects on survival and peripheral vasoconstrictor function. Coadministration of dexamethasone with antioxidant vitamins improves survival and partially restores vascular dysfunction. Antioxidant vitamins alone affect peripheral vascular function.

  20. Prolonged Remission in Neuromyelitis Optica Following Cessation of Rituximab Treatment.

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    Weinfurtner, Kelley; Graves, Jennifer; Ness, Jayne; Krupp, Lauren; Milazzo, Maria; Waubant, Emmanuelle

    2015-09-01

    Neuromyelitis optica is an autoimmune disease characterized by acute episodes of transverse myelitis and optic neuritis. Several small, open-label studies suggest rituximab, a monoclonal antibody against CD20, prevents relapses in neuromyelitis optica; however, there is little consensus on timing or duration of treatment. Here we report four patients with severe relapsing neuromyelitis optica who were stabilized on rituximab and, after discontinuing treatment, continued to experience prolonged remission of their disease. Remission ranged from 4.5 to 10.5 years total, including 3 to 9 years off all therapies. The patients had sustained clinical responses despite normal B-lymphocyte levels and, in at least 2 patients, continued seropositivity for aquaporin-4 antibodies. These cases suggest that rituximab may induce prolonged remission in certain neuromyelitis optica patients, and they highlight the need for further elucidation of rituximab's mechanism in neuromyelitis optica. © The Author(s) 2014.

  1. Treatment of frozen shoulder with subcutaneous TNF-alpha blockade compared with local glucocorticoid injection

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    Schydlowsky, Pierre; Szkudlarek, Marcin; Madsen, Ole Rintek

    2012-01-01

    We compared the effect of subcutaneous adalimumab injections with intraarticular glucocorticoid injections on frozen shoulder of 18 patients with unilateral joint involvement. Ten patients were randomised to subcutaneous injections with adalimumab and eight to intraarticular glucocorticoid inject...

  2. Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model.

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    Kohda, K; Harada, K; Kato, K; Hoshino, A; Motohashi, J; Yamaji, T; Morinobu, S; Matsuoka, N; Kato, N

    2007-08-10

    Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experience, and presents with characteristic symptoms, such as intrusive memories, a state of hyperarousal, and avoidance, that endure for years. Single-prolonged stress (SPS) is one of the animal models proposed for PTSD. Rats exposed to SPS showed enhanced inhibition of the hypothalamo-pituitary-adrenal (HPA) axis, which has been reliably reproduced in patients with PTSD, and increased expression of glucocorticoid receptor (GR) in the hippocampus. In this study, we characterized further neuroendocrinologic, behavioral and electrophysiological alterations in SPS rats. Plasma corticosterone recovered from an initial increase within a week, and gross histological changes and neuronal cell death were not observed in the hippocampus of the SPS rats. Behavioral analyses revealed that the SPS rats presented enhanced acoustic startle and impaired spatial memory that paralleled the deficits in hippocampal long-term potentiation (LTP) and depression. Contextual fear memory was enhanced in the rats 1 week after SPS exposure, whereas LTP in the amygdala was blunted. Interestingly, blockade of GR activation by administering 17-beta-hydroxy-11-beta-/4-/[methyl]-[1-methylethyl]aminophenyl/-17-alpha-[prop-1-ynyl]estra-4-9-diene-3-one (RU40555), a GR antagonist, prior to SPS exposure prevented potentiation of fear conditioning and impairment of LTP in the CA1 region. Altogether, SPS caused a number of behavioral changes similar to those described in PTSD, which marks SPS as a putative PTSD model. The preventive effects of a GR antagonist suggested that GR activation might play a critical role in producing the altered behavior and neuronal function of SPS rats.

  3. Dexamethasone-Induced Myeloid-Derived Suppressor Cells Prolong Allo Cardiac Graft Survival through iNOS- and Glucocorticoid Receptor-Dependent Mechanism

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    Yang Zhao

    2018-02-01

    Full Text Available How to induce immune tolerance without long-term need for immunosuppressive drugs has always been a central problem in solid organ transplantation. Modulating immunoregulatory cells represents a potential target to resolve this problem. Myeloid-derived suppressor cells (MDSCs are novel key immunoregulatory cells in the context of tumor development or transplantation, and can be generated in vitro. However, none of current systems for in vitro differentiation of MDSCs have successfully achieved long-term immune tolerance. Herein, we combined dexamethasone (Dex, which is a classic immune regulatory drug in the clinic, with common MDSCs inducing cytokine granulocyte macrophage colony stimulating factor (GM-CSF to generate MDSCs in vitro. Addition of Dex into GM-CSF system specifically increased the number of CD11b+ Gr-1int/low MDSCs with an enhanced immunosuppressive function in vitro. Adoptive transfer of these MDSCs significantly prolonged heart allograft survival and also favored the expansion of regulatory T cells in vivo. Mechanistic studies showed that inducible nitric oxide sythase (iNOS signaling was required for MDSCs in the control of T-cell response and glucocorticoid receptor (GR signaling played a critical role in the recruitment of transferred MDSCs into allograft through upregulating CXCR2 expression on MDSCs. Blockade of GR signaling with its specific inhibitor or genetic deletion of iNOS reversed the protective effect of Dex-induced MDSCs on allograft rejection. Together, our results indicated that co-application of Dex and GM-CSF may be a new and important strategy for the induction of potent MDSCs to achieve immune tolerance in organ transplantation.

  4. Prevention and treatment of glucocorticoid-induced osteoporosis in International and Italian scenarios

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    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.

  5. High-fat diet and glucocorticoid treatment cause hyperglycemia associated with adiponectin receptor alterations

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    Oller do Nascimento Cláudia

    2011-01-01

    Full Text Available Abstract Background Adiponectin is the most abundant plasma protein synthesized for the most part in adipose tissue, and it is an insulin-sensitive hormone, playing a central role in glucose and lipid metabolism. In addition, it increases fatty acid oxidation in the muscle and potentiates insulin inhibition of hepatic gluconeogenesis. Two adiponectin receptors have been identified: AdipoR1 is the major receptor expressed in skeletal muscle, whereas AdipoR2 is mainly expressed in liver. Consumption of high levels of dietary fat is thought to be a major factor in the promotion of obesity and insulin resistance. Excessive levels of cortisol are characterized by the symptoms of abdominal obesity, hypertension, glucose intolerance or diabetes and dyslipidemia; of note, all of these features are shared by the condition of insulin resistance. Although it has been shown that glucocorticoids inhibit adiponectin expression in vitro and in vivo, little is known about the regulation of adiponectin receptors. The link between glucocorticoids and insulin resistance may involve the adiponectin receptors and adrenalectomy might play a role not only in regulate expression and secretion of adiponectin, as well regulate the respective receptors in several tissues. Results Feeding of a high-fat diet increased serum glucose levels and decreased adiponectin and adipoR2 mRNA expression in subcutaneous and retroperitoneal adipose tissues, respectively. Moreover, it increased both adipoR1 and adipoR2 mRNA levels in muscle and adipoR2 protein levels in liver. Adrenalectomy combined with the synthetic glucocorticoid dexamethasone treatment resulted in increased glucose and insulin levels, decreased serum adiponectin levels, reduced adiponectin mRNA in epididymal adipose tissue, reduction of adipoR2 mRNA by 7-fold in muscle and reduced adipoR1 and adipoR2 protein levels in muscle. Adrenalectomy alone increased adiponectin mRNA expression 3-fold in subcutaneous adipose

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

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    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. Risk Factors for Prolonged Treatment of Whiplash-Associated Disorders.

    Directory of Open Access Journals (Sweden)

    Hiroyuki Oka

    Full Text Available Whiplash-associated disorders (WAD are the most common injuries that are associated with car collisions in Japan and many Western countries. However, there is no clear evidence regarding the potential risk factors for poor recovery from WAD. Therefore, we used an online survey of the Japanese population to examine the association between potential risk factors and the persistence of symptoms in individuals with WAD.An online survey was completed by 127,956 participants, including 4,164 participants who had been involved in a traffic collision. A random sample of the collision participants (n = 1,698 were provided with a secondary questionnaire. From among the 974 (57.4% respondents to the secondary questionnaire, we selected 183 cases (intractable neck pain that was treated over a period of 6 months and 333 controls (minor neck pain that was treated within 3 months. Multivariable logistic regression analysis was used to evaluate the potential risk factors for prolonged treatment of WAD.Female sex, the severity of the collision, poor expectations of recovery, victim mentality, dizziness, numbness or pain in the arms, and lower back pain were associated with a poor recovery from WAD.In the present study, the baseline symptoms (dizziness, numbness or pain in the arms, and lower back pain had the strongest associations with prolonged treatment for WAD, although the psychological and behavioral factors were also important. These risk factors should be considered when evaluating patients who may have the potential for poor outcomes.

  8. Adrenal gland hypofunction in active polymyalgia rheumatica. effect of glucocorticoid treatment on adrenal hormones and interleukin 6.

    Science.gov (United States)

    Cutolo, Maurizio; Straub, Rainer H; Foppiani, Luca; Prete, Camilla; Pulsatelli, Lia; Sulli, Alberto; Boiardi, Luigi; Macchioni, Pierluigi; Giusti, Massimo; Pizzorni, Carmen; Seriolo, Bruno; Salvarani, Carlo

    2002-04-01

    To evaluate hypothalamic-pituitary-adrenal (HPA) axis function in patients with recent onset polymyalgia rheumatica (PMR) not previously treated with glucocorticoids; and to detect possible correlations between adrenal hormone levels, interleukin 6 (IL-6), and other acute phase reactants at baseline and during 12 months of glucocorticoid treatment. Forty-one PMR patients of both sexes with recent onset disease and healthy sex and age matched controls were enrolled into a longitudinal study. Patients were monitored for serum cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione (ASD), and clinical and laboratory measures of disease activity such as C-reactive protein and IL-6 concentrations at baseline and after 1, 3, 6, 9 and 12 months of glucocorticoid treatment. To assess dynamic HPA axis function, serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were evaluated in another 8 patients with recent onset PMR not treated with glucocorticoid in comparison to controls after challenge with ovine corticotropin releasing hormone (oCRH) test. In addition, serum cortisol and 17-hydroxyprogesterone (17-OHP) levels were evaluated after stimulation with low dose (1 microg) intravenous ACTH. Serum cortisol and ASD levels of all PMR patients at baseline did not differ from controls. During followup, cortisol levels dipped at one and 3 months. Serum DHEAS levels in all patients were significantly lower than in controls at baseline. In female PMR patients a significant correlation was found at baseline between cortisol levels and duration of disease. Serum concentrations of IL-6 at baseline were significantly higher in PMR patients than in controls. During 12 months of glucocorticoid treatment IL-6 levels dropped significantly at one month; thereafter they remained stable and did not increase again despite tapering of the glucocorticoid dose. After oCRH stimulation, a similar cortisol response was found in patients and controls. After ACTH

  9. Current smoking is an independent risk factor for new-onset diabetes mellitus during highdose glucocorticoid treatment.

    Science.gov (United States)

    Sugiyama, Takao; Sugimoto, Toyohiko; Suzuki, Sawako; Sato, Yuta; Tanaka, Tomoaki; Tatsuno, Ichiro

    2015-08-01

    Although high-dose glucocorticoids have been reported to cause new-onset diabetes mellitus (glucocorticoid-induced diabetes mellitus), its risk factors have remained to be determined. We investigated the risk factors related to glucocorticoid-induced diabetes mellitus diagnosed within 2 months after the high-dose treatment (newly treated with an initial high dose of > 20 mg prednisolone (PSL) equivalent per day for at least more than 6 months) in collagen vascular diseases. A total of 2,631 patients with collagen vascular diseases was registered between 1986 and 2006 in the Chiba-Shimoshizu Rheumatic Cohort. We analyzed 681 patients newly treated with high-dose glucocorticoid who did not have diabetes mellitus and/or its previous diagnosis (age: 46.3 ± 16.7 years, PSL dose: 40.0 ± 14.1 mg/day). Glucocorticoid-induced diabetes mellitus was diagnosed by two or more glucose measurements in patients with fasting glycaemia ≥ 7 mmol/L and 120 minutes post-load glycaemia ≥ 11.1 mmol/L. Glucocorticoid-induced diabetes mellitus was observed in 26.3% of patients, and the glucocorticoid-induced diabetes mellitus group had higher age, higher BMI, lower rates of females and systemic lupus erythematosus, higher rates of smoking, alcohol use, and microscopic polyangiitis. Multivariate logistic regression analysis demonstrated that the risk of glucocorticoid-induced diabetes mellitus was independently higher in every 10-year increment of initial age with adjusted odds ratio (OR) 1.556 (95% confidence interval: 1.359 - 1.783), in every 1 kg/m2 increment of BMI with OR 1.062 (1.002 - 1.124), in current smoking with OR 1.664 (1.057 - 2.622), and in every 10 mg increment of initial dose of prednisolone with OR 1.250 (1.074 - 1.454). High-dose glucocorticoids caused diabetes mellitus with high prevalence within a short period, and current smokers should be considered at higher risk of glucocorticoidinduced diabetes mellitus in addition to age, BMI, and initial dose.

  10. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Gordijn, Maartje S.; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.

    2012-01-01

    Background Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress

  11. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Gordijn, Maartje S.; Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.

    2015-01-01

    Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate

  12. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.

    2017-01-01

    Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate

  13. Identifying Molecular Targets for PTSD Treatment Using Single Prolonged Stress

    Science.gov (United States)

    2015-10-01

    in the locus coeruleus. Based on our findings we hypothesize that SPS alters glucocorticoid and beta adrenergic receptor (β-AR) expression leading...individual was a recent graduate from PhD training and came with expertise in animal behavioral tests of anxiety . During her first 6 months of work, she has... Anxiety Disorders, 2013, 3,22; Psychopharmacology, 2014, DOI:10.1007/s00213-014-3635-x). Dr. George has also been promoted within the University of

  14. Detection of glucocorticoid receptor agonists in effluents from sewage treatment plants in Japan.

    Science.gov (United States)

    Suzuki, Go; Sato, Kentaro; Isobe, Tomohiko; Takigami, Hidetaka; Brouwer, Abraham; Nakayama, Kei

    2015-09-15

    Glucocorticoids (GCs) are widely used as anti-inflammatory drugs. Our previous study demonstrated that several GCs such as cortisol and dexamethasone (Dex) were frequently detected in effluents collected from Japanese sewage treatment plants (STPs) in 2012. In this study, we used the GC-Responsive Chemical-Activated LUciferase gene eXpression (GR-CALUX) assay to elucidate GC receptor (GR) agonistic activities of ten pure synthetic GCs and selected STP effluents in Japan for assessment of the risks associated with the presence of GR agonists. The tested GCs demonstrated dose-dependent agonistic effects in the GR-CALUX assay and their EC50 values were calculated for estimation of relative potencies (REPs) compared to Dex. The GR agonistic potency was in the rank of: clobetasol propionate > clobetasone butyrate > betamethasone 17-valerate > difluprednate > betamethasone 17,21-dipropionate > Dex > betamethasone > 6α-methylprednisolone > prednisolone > cortisol. The GR agonistic activity in STP effluents as measured in Dex-equivalent (Dex-EQ) activities ranged from effluents in Japan. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Glucocorticoids in the treatment of asthma in children Los glucocorticoides en el tratamiento del asma en pediatría

    Directory of Open Access Journals (Sweden)

    Olga Francisca Salazar Blanco

    1998-04-01

    Full Text Available Today, asthma is considered an inflammatory disease; steroids could be the drugs of choice for its treatment since they work at different points of the asthmatic reaction, decreasing the infiltration of inflammatory cells, and inhibiting the production of some of them and the release of citokines and other proinflammatory agents; they also diminish mucus secretion in the submucosal glands, improve the response of B2 receptors to bronchodilators and reduce vascular permeability. These and other actions manifest themselves in clinical improvement, less frequent acute crises, hospitalizations and consultations, and lesser deterioration of pulmonary function. Though inhaled corticosteroids are safe and effective drugs in children, they must be used at minimal doses and during the shortest time required by patients. Inadequate use of systemic corticosteroids, either oral or parenteral, can have undesirable effects, some of them irreversible. Corticosteroids neither cure asthma nor reduce its mortality; that is the reason for the active search of other substances or strategies to reduce or block the inflammatory process or the disease itself. El asma se considera hoy una enfermedad inflamatoria para la cual los esteroides podrían ser fármacos de primera elección. Ellos actúan en diferentes puntos de la reacción asmática, disminuyen el infiltrado de células inflamatorias e inhiben la producción de algunas de ellas, así como la liberación de citoquinas y agentes proinflamatorios; reducen la secreción de moco en las glándulas submucosas, mejoran la respuesta de los receptores 82 a los broncodilatadores y controlan la permeabilidad vascular; éstas y otras acciones se traducen en una mejoría clínica de los pacientes que sufren crisis agudas, en disminución del número de hospitalizaciones y consultas y, a largo plazo, en un menor deterioro de la función pulmonar. Los esteroides por vía inhalatoria para el tratamiento del asma son f

  16. Glucocorticoid-related bone changes from endogenous or exogenous glucocorticoids.

    Science.gov (United States)

    Warriner, Amy H; Saag, Kenneth G

    2013-12-01

    Glucocorticoids have a negative impact on bone through direct effects on bone cells and indirect effects on calcium absorption. Here, recent findings regarding glucocorticoid-induced osteoporosis, bone changes in patients with endogenous glucocorticoid derangements, and treatment of steroid-induced bone disease are reviewed. Although the majority of our understanding arises from the outcomes of patients treated with exogenous steroids, endogenous overproduction appears to be similarly destructive to bone, but these effects are reversible with cure of the underlying disease process. Additionally, there are bone changes that occur in diseases that interrupt adrenal glucocorticoid production, both in response to our inability to perfectly match glucocorticoid replacement and also related to the underlying disease process. More investigation is required to understand which patients with endogenous overproduction or underproduction of glucocorticoid would benefit from osteoporosis treatment. Better understood is the benefit that can be achieved with currently approved treatments for glucocorticoid-induced osteoporosis from exogenous steroids. With growing concern of long-term use of bisphosphonates, however, further investigation into the duration of use and use in certain populations, such as children and premenopausal women, is essential. Glucocorticoid-induced osteoporosis is a complex disease that is becoming better understood through advances in the study of exogenous and endogenous glucocorticoid exposure. Further advancement of proper treatment and prevention is on the horizon.

  17. 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

  18. Identifying Molecular Targets For PTSD Treatment Using Single Prolonged Stress

    Science.gov (United States)

    2014-10-01

    Post - traumatic stress disorder ( PTSD ) is a chronic, debilitating psychiatric disorder that can...SPS animals. Post - traumatic stress disorder ( PTSD ) is associated with neurocognitive impairments that have been attributed to functional deficits...and resilience. 2. KEYWORDS Post - traumatic stress disorder , Single Prolonged Stress , Neurobiological Mechanisms 5 3. ACCOMPLISHMENTS

  19. Glucocorticoid-induced leucine zipper expression is associated with response to treatment and immunoregulation in systemic lupus erythematosus.

    Science.gov (United States)

    Mohammadi, Saeed; Ebadpour, Mohammad Reza; Sedighi, Sima; Saeedi, Mohsen; Memarian, Ali

    2017-08-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder in which cytokine balance is disturbed. Glucocorticoids (GCs) are shown to balance immune response by transcriptional regulation of glucocorticoid receptor target genes such as Glucocorticoid-induced leucine zipper (GILZ) which has been introduced as an endogenous anti-inflammatory mediator. In the present study, we assessed the expression of GILZ in association with interferon-γ (IFN-γ), interleukine-10 (IL-10), and B lymphocyte stimulator (BLyS) plasma levels in SLE patients. A total of 40 female patients (18 under treatment and 22 newly diagnosed) were recruited in this study. Real-time RT PCR was conducted to quantify the mRNA expression of GILZ. The plasma levels of IFN-γ, IL-10, and BLyS were evaluated using ELISA method. GILZ was overexpressed among under treatment SLE patients. The mRNA expression of GILZ was significantly correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. IFN-γ and BLyS were downregulated in response to therapies with negative correlations to GILZ. Moreover, IL-10 was upregulated among treated patients. The levels of IFN-γ and BLyS were correlated with the severity of disease, while IL-10 was negatively correlated with SLEDAI score. GILZ could be introduced as one of the acting molecules in mediating the regulatory effects of GCs on producing pro- and anti-inflammatory cytokines in SLE.

  20. Diverse definitions of prolonged labour and its consequences with sometimes subsequent inappropriate treatment

    OpenAIRE

    Nystedt, Astrid; Hildingsson, Ingegerd

    2014-01-01

    Background: Prolonged labour very often causes suffering from difficulties that may have lifelong implications. This study aimed to explore the prevalence and treatment of prolonged labour and to compare birth outcome and women's experiences of prolonged and normal labour. Method: Women with spontaneous onset of labour, living in a Swedish county, were recruited two months after birth, to a cross-sectional study. Women (n = 829) completed a questionnaire that investigated socio-demographic an...

  1. Short-and long-term glucocorticoid treatment enhances insulin signalling in human subcutaneous adipose tissue

    OpenAIRE

    Gathercole, LL; Morgan, SA; Bujalska, IJ; Stewart, PM; Tomlinson, JW

    2011-01-01

    Background: Endogenous or exogenous glucocorticoid (GC) excess (Cushing's syndrome) is characterized by increased adiposity and insulin resistance. Although GCs cause global insulin resistance in vivo, we have previously shown that GCs are able to augment insulin action in human adipose tissue, contrasting with their action in skeletal muscle. Cushing's syndrome develops following chronic GC exposure and, in addition, is a state of hyperinsulinemia. Objectives: We have therefore compared the ...

  2. Elevated glucocorticoid receptor binding in cultured human lymphoblasts following hydroxyurea treatment: lack of effect on steroid responsiveness

    International Nuclear Information System (INIS)

    Littlefield, B.A.; Hoagland, H.C.; Greipp, P.R.

    1986-01-01

    While studying the effects of chemotherapy on glucocorticoid receptor (GR) binding levels in hematological malignancies, we observed a sizable increase in nuclear GR binding of [ 3 H]dexamethasone in peripheral leukocytes from a chronic basophilic leukemia patient following treatment with hydroxyurea plus prednisone, but not after prednisone alone. This apparent clinical effect of hydroxyurea led to an examination of hydroxyurea effects on GR binding and sensitivity in the glucocorticoid-sensitive human lymphoblast cell line GM4672A. GR binding levels in GM4672A cells were measured following a 3-day exposure to 50 microM hydroxyurea, a concentration chosen to have a minimal but measurable effect on cellular growth rates with little or no effect on cellular viability. Under these conditions, nuclear [ 3 H]dexamethasone receptor binding measured by Scatchard analysis using a whole-cell assay was elevated 2.4-fold over control values (P less than 0.05), while cytosolic residual receptor binding (measured at 37 0 C) remained unchanged. Thus, the total cellular content of measurable GR was increased, and this increase was totally accounted for by GR capable of nuclear binding. Hydroxyurea treatment of GM4672A cells had no effect on the affinity of nuclear or cytosolic GR for [ 3 H]dexamethasone. The increase in measurable nuclear-bound receptors occurred in a time-dependent manner over a period of 3 days and was fully reversible within 3 days following removal of hydroxyurea. The increase in receptor binding could not be explained by the slight alterations in cell cycle kinetics which occur at this low level of hydroxyurea. Despite increased receptor binding, cellular glucocorticoid responsiveness was unaltered as assessed by dexamethasone inhibition of cell growth and dexamethasone inhibition of a urokinase-like plasminogen activator

  3. Predictors of Prolonged TB Treatment in a Dutch Outpatient Setting.

    Directory of Open Access Journals (Sweden)

    Natasha Van't Boveneind-Vrubleuskaya

    Full Text Available Standard treatment duration for drug-susceptible tuberculosis (TB treatment is 6 months. Treatment duration is often extended-and for various different reasons. The aim of this study was to determine the prevalence and to assess risk factors associated with extended TB treatment.A cross-sectional study was conducted. Data including demographic, clinical, radiological and microbiological information from the Netherlands TB Register (NTR of 90 patients with smear and culture positive pulmonary TB of the region Haaglanden, The Netherlands, was eligible for analysis.Treatment was extended to ≥ 200 days by 46 (51% patients. Extended TB treatment was associated with a higher frequency of symptoms, presumed to be due to adverse drug reactions (ADR; OR 2.39 95% CI: 1.01-5.69, drug-induced liver injury (DILI (OR: 13.51; 95% CI: 1.66-109.82 and longer than 2 month smear and culture conversion rate (OR: 11.00; 95% CI: 1.24-97.96 and OR: 8.56; 95% CI: 1.53-47.96. In the multivariable logistic analysis, development of DILI emerged as the single statistically strong risk factor necessitating extension of TB treatment.This finding will need further confirmation in a prospective study, exploring the possible mutual role of pharmacokinetic and pharmacogenetic determinants of DILI among TB patients.

  4. Unfavourable effect of prolonged treatment with antithyroid drugs on radioiodine therapy outcome in Graves' hyperthyroidism

    OpenAIRE

    Rajić, Milena; Vlajković, Marina; Ilić, Slobodan; Stević, Miloš; Sekulić, Vladan; Zečević, Mila

    2014-01-01

    Radioiodine therapy (RIT) of Graves' hyperthyroidism (GH) is usually recommended after failure of primary therapy with antithyroid drugs (ATDs), which are commonly prescribed for up to 18-24 months. However, in our region, the prolonged ATDs treatment of the disease is very common. Thus, we assessed the efficacy of RIT after prolonged continual pretreatment with ATDs in Graves' hyperthyroidism. Therapy outcome using a single dose of radioiodine was evaluated after one year in 91 patients (f/m...

  5. The significance of the glucocorticoid receptor measurement in the treatment of acute leukemia

    International Nuclear Information System (INIS)

    Wang Haodan

    1992-01-01

    We studied the method of measuring the glucocorticoid receptor (GCR) using whole peripheral leukocytes, and measured the GCR level of 20 healthy and 50 cases of acute leukemia. The Kd values were 5.51 ± 2.01 nmol/L and 5.38 ± 1.21 nmol/L. The normal R 0 value (x-bar ± s) was 6878 ±1563 sites/cell, and had no co-relationship with the serum level of total cortisol. The relationship between the GCR level and the effect of chemotherapy and short-term prognosis was also studied. The low affinitive binding sites of glucocorticoid hormone were for the first time observed in 9 normal persons and 5 cases of acute leukemia in the normal subjects, the Kd values were 0.8224±0.241 μmol/L and the R 0 values were 3614.43±1233.33 f mole/10 7 cells. In the leukemic patients, the Kd values were 1.067±0.456 μmol/L and the R 0 values were 3488.94 ± 2272.56 f mole/10 7 cells. The Scatchard curves were obviously of the concave

  6. Low liver stiffness among cirrhotic patients with hepatitis B after prolonged treatment with nucleoside analogs

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Weiland, Ola; Leutscher, Peter

    2011-01-01

    Case reports and short-term clinical trials have suggested that treatment for chronic hepatitis B (CHB) may lead to improvement of cirrhosis. The aim of the present study was to measure liver stiffness in patients diagnosed with advanced fibrosis or cirrhosis prior to prolonged treatment...

  7. Prolonged Exposure Treatment of Chronic PTSD in Juvenile Sex Offenders: Promising Results from Two Case Studies

    Science.gov (United States)

    Hunter, John A.

    2010-01-01

    Prolonged exposure (PE) was used to treat chronic PTSD secondary to severe developmental trauma in two adolescent male sex offenders referred for residential sex offender treatment. Both youth were treatment resistant prior to initiation of PE and showed evidence of long-standing irritability and depression/anxiety. Clinical observation and…

  8. Diverse definitions of prolonged labour and its consequences with sometimes subsequent inappropriate treatment

    Science.gov (United States)

    2014-01-01

    Background Prolonged labour very often causes suffering from difficulties that may have lifelong implications. This study aimed to explore the prevalence and treatment of prolonged labour and to compare birth outcome and women’s experiences of prolonged and normal labour. Method Women with spontaneous onset of labour, living in a Swedish county, were recruited two months after birth, to a cross-sectional study. Women (n = 829) completed a questionnaire that investigated socio-demographic and obstetric background, birth outcome and women’s feelings and experiences of birth. The prevalence of prolonged labour, as defined by a documented ICD-code and inspection of partogram was calculated. Four groups were identified; women with prolonged labour as identified by documented ICD-codes or by partogram inspection but no ICD-code; women with normal labour augmented with oxytocin or not. Results Every fifth woman experienced a prolonged labour. The prevalence with the documented ICD-code was (13%) and without ICD-code but positive partogram was (8%). Seven percent of women with prolonged labour were not treated with oxytocin. Approximately one in three women (28%) received oxytocin augmentation despite having no evidence of prolonged labour. The length of labour differed between the four groups of women, from 7 to 23 hours. Women with a prolonged labour had a negative birth experience more often (13%) than did women who had a normal labour (3%) (P women with prolonged labour were emergency Caesarean section (OR 9.0, 95% CI 1.2-3.0) and to strongly agree with the following statement ‘My birth experience made me decide not to have any more children’ (OR 41.3, 95% CI 4.9-349.6). The factors that contributed most strongly to a negative birth experience in women with normal labour were less agreement with the statement ‘It was exiting to give birth’ (OR 0.13, 95% CI 0.34-0.5). Conclusions There is need for increased clinical skill in identification and classification

  9. The effect of interruptions and prolonged treatment time in radiotherapy for nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Kwong, Dora L.W.; Sham, Jonathan S.T.; Chua, Daniel T.T.; Choy, Damon T.K.; Au, Gordon K.H.; Wu, P.M.

    1997-01-01

    Purpose: The effect of interruptions and prolonged overall treatment time in radiotherapy for nasopharyngeal carcinoma and the significance of timing of interruption was investigated. Methods and Materials: Treatment records of 229 patients treated with continuous course (CC) and 567 patients treated with split course (SC) radiotherapy for nonmetastatic NPC were reviewed. Overall treatment time without inclusion of time for boost was calculated. Treatment that extended 1 week beyond scheduled time was considered prolonged. Outcome in patients who completed treatment 'per schedule' were compared with those who had 'prolonged' treatment. Because of known patient selection bias between CC and SC, patients on the two schedules were analyzed separately. Multivariate analysis was performed for patients on SC. Total number of days of interruption, age, sex, T and N stage, and the use of boost were tested for the whole SC group. Analysis on the effect of timing of interruption was performed in a subgroup of 223 patients on SC who had a single unplanned interruption. Timing of interruption, either before or after the fourth week for the unplanned interruption, was tested in addition to the other variables in multivariate analysis for this subgroup of SC. Results: Twenty-seven (11.8%) patients on CC and 96 (16.9%) patients on SC had prolonged treatment. Patients on SC who had prolonged treatment had significantly poorer loco-regional control rate and disease free survival when compared with those who completed radiotherapy per schedule (p = 0.0063 and 0.001, respectively, with adjustment for stage). For CC, the effect of prolonged treatment on outcome was not significant. The small number of events for patients on CC probably account for the insignificant finding. The number of days of interruption was confirmed as prognostic factor, independent of T and N stages, for loco-regional control and disease-free survival in multivariate analysis for SC. The hazard rate for loco

  10. Defining futile life-prolonging treatments through Neo-Socratic Dialogue.

    Science.gov (United States)

    Aizawa, Kuniko; Asai, Atsushi; Bito, Seiji

    2013-12-09

    In Japan, people are negative towards life-prolonging treatments. Laws that regulate withholding or discontinuing life-prolonging treatments and advance directives do not exist. Physicians, however, view discontinuing life-prolonging treatments negatively due to fears of police investigations. Although ministerial guidelines were announced regarding the decision process for end-of-life care in 2007, a consensus could not be reached on the definition of end-of-life and conditions for withholding treatment. We established a forum for extended discussions and consensus building on this topic. We used the Neo-Socratic Dialogue (NSD) method which promotes philosophical discussion based on a case-study to address a question and formulate a consensus and answer in a group. The question chosen for the dialogue was: "What is a life-prolonging treatment?" A series of dialogues took place over a period of one and a half days. It was carried out by three groups in 2010 and 2011. Seven participants with diverse backgrounds were recruited per group. We analyzed the content of the discussion. Based on three case studies concerning different opinions about treatment options for an older dementia patient, a patient demanding chemotherapy, and a severely ill neonate, conditions for futile life-prolonging treatment were elucidated through NSD. Such treatments are those carried out for the sole purpose of prolonging life and are detrimental to the patient, and should be decided based foremost on the patient's lack of desire for treatment, the consensus of those involved, and through social acceptance. These arguments are essentially consistent with ones on medical futility in the United States. By expressing the objective of healthcare and the requirement of social acceptance, participants were also able to elucidate issues related to the awareness of those involved and the medical environment. Compared to the end-of-life guidelines in Japan, the objective of treatment, its effects

  11. Treatment of prolonged convulsive seizures in children; a single centre, retrospective, observational study

    NARCIS (Netherlands)

    Vlaskamp, Danique R. M.; Brouwer, Oebele F.; Callenbach, Petra M. C.

    2014-01-01

    Objectives: To evaluate treatment of children with Prolonged Convulsive Seizures (PCS) at the University Medical Centre Groningen (UMCG). Material and methods: PCS were identified from an UMCG database of children with epilepsy aged = 10 mm and occurred between January 2000 and October 2012 in

  12. Acute and chronic glucocorticoid treatments regulate astrocyte-enriched mRNAs in multiple brain regions in vivo

    Directory of Open Access Journals (Sweden)

    Bradley S. Carter

    2013-08-01

    Full Text Available Previous studies have primarily interpreted gene expression regulation by glucocorticoids in the brain in terms of impact on neurons; however, less is known about the corresponding impact of glucocorticoids on glia and specifically astrocytes in vivo. Recent microarray experiments have identified glucocorticoid-sensitive mRNAs in primary astrocyte cell culture, including a number of mRNAs that have reported astrocyte-enriched expression patterns relative to other brain cell types. Here, we have tested whether elevations of glucocorticoids regulate a subset of these mRNAs in vivo following acute and chronic corticosterone exposure in adult mice. Acute corticosterone exposure was achieved by a single injection of 10 mg/kg corticosterone, and tissue samples were harvested two hours post-injection. Chronic corticosterone exposure was achieved by administering 10 mg/mL corticosterone via drinking water for two weeks. Gene expression was then assessed in two brain regions associated with glucocorticoid action (prefrontal cortex and hippocampus by qPCR and by in situ hybridization. The majority of measured mRNAs regulated by glucocorticoids in astrocytes in vitro were similarly regulated by acute and/or chronic glucocorticoid exposure in vivo. In addition, the expression levels for mRNAs regulated in at least one corticosterone exposure condition (acute/chronic demonstrated moderate positive correlation between the two conditions by brain region. In situ hybridization analyses suggest that select mRNAs are regulated by chronic corticosterone exposure specifically in astroctyes based on (1 similar general expression patterns between corticosterone-treated and vehicle-treated animals and (2 similar expression patterns to the pan-astrocyte marker Aldh1l1. Our findings demonstrate that glucocorticoids regulate astrocyte-enriched mRNAs in vivo and suggest that glucocorticoids regulate gene expression in the brain in a cell type-dependent fashion.

  13. Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.

    Science.gov (United States)

    Shiber, Shachaf; Stiebel-Kalish, Hadas; Shimon, Ilan; Grossman, Alon; Robenshtok, Eyal

    2014-10-01

    Glucocorticoid (GC) therapy has been shown to prevent Graves' ophthalmopathy (GO) progression following radioactive iodine (RAI) treatment. However, the optimal regimen is controversial, with studies from recent years suggesting the use of lower doses and shorter GC treatment courses. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective controlled trials comparing GC regimens versus placebo, no treatment, or other GC regimens. Eight trials evaluating 850 patients fulfilled inclusion criteria. In patients with preexisting GO, standard dose prednisone (0.4-0.5 mg/kg tapered over 3 months) was very effective for prevention of GO progression (OR 0.14 [CI 0.06-0.35], phyperthyroidism resolution (OR 1.05 [CI 0.69-1.58]), and GC side effects were common but mild. Current evidence supports a three-tier approach for prevention of GO progression following RAI. Standard dose prednisone is the best validated regimen and should be used in patients with mild to moderate GO who have high risk of progression, while low dose prednisone can be used in patients with mild GO, and in patients without preexisting GO who have risk factors and are selected for GC prophylaxis. Patients without preexisting GO and without risk factors should not be treated with GC prophylaxis.

  14. Effect of prolonged isothermal heat treatment on the mechanical behavior of advanced NANOBAIN steel

    Science.gov (United States)

    Avishan, Behzad

    2017-09-01

    The microstructural evolution and consequent changes in strength and ductility of advanced NANOBAIN steel during prolonged isothermal heat-treatment stages were investigated. The microstructure and mechanical properties of nanostructured bainite were not expected to be influenced by extending the heat-treatment time beyond the optimum value because of the autotempering phenomenon and high tempering resistance. However, experimental results indicated that the microstructure was thermodynamically unstable and that prolonged austempering resulted in carbon depletion from high-carbon retained austenite and carbide precipitations. Therefore, austenite became thermally less stable and partially transformed into martensite during cooling to room temperature. Prolonged austempering did not lead to the typical tempering sequence of bainite, and the sizes of the microstructural constituents were independent of the extended heat-treatment times. This independence, in turn, resulted in almost constant ultimate tensile strength values. However, microstructural variations enhanced the yield strength and the hardness of the material at extended isothermal heat-treatment stages. Finally, although microstructural changes decreased the total elongation and impact toughness, considerable combinations of mechanical properties could still be achieved.

  15. The effect of duration of untreated psychosis and treatment delay on the outcomes of prolonged early intervention in psychotic disorders

    DEFF Research Database (Denmark)

    Albert, Nikolai; Melau, Marianne; Jensen, Heidi

    2017-01-01

    to the prolonged treatment with regards to disorganized and negative dimension. For participants with short duration from first symptom until start of SEI treatment there was a significant difference on the negative dimension favoring the prolonged OPUS treatment. The finding of an effect of prolonged treatment......The duration of untreated psychosis (DUP) has been shown to have an effect on outcome after first-episode psychosis. The premise of specialized early intervention (SEI) services is that intervention in the early years of illness can affect long-term outcomes. In this study, we investigate whether...... DUP affects treatment response after 5 years of SEI treatment compared to 2 years of SEI treatment. As part of a randomized controlled trial testing the effect of prolonged SEI treatment 400 participants diagnosed within the schizophrenia spectrum were recruited. For this specific study participants...

  16. QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy

    Directory of Open Access Journals (Sweden)

    Piccinelli Marco

    2005-01-01

    Full Text Available Abstract Background Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment. Method We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine or lithium. An Electrocardiogram (ECG was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic. Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test. Results Mean QTc intervals significantly increased in Group 2 (24 ± 21 ms however this was not the case in Group 1 (-1 ± 30 ms (Repeated measures ANOVA p Conclusions No significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a

  17. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline

    DEFF Research Database (Denmark)

    Krogh, Thøger Persson; Fredberg, Ulrich; Stengaard-Pedersen, Kristian

    2013-01-01

    Lateral epicondylitis (LE) is a common musculoskeletal disorder for which an effective treatment strategy remains unknown.......Lateral epicondylitis (LE) is a common musculoskeletal disorder for which an effective treatment strategy remains unknown....

  18. Low liver stiffness among cirrhotic patients with hepatitis B after prolonged treatment with nucleoside analogs

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Weiland, Ola; Leutscher, Peter

    2011-01-01

    Abstract Objective. Case reports and short-term clinical trials have suggested that treatment for chronic hepatitis B (CHB) may lead to improvement of cirrhosis. The aim of the present study was to measure liver stiffness in patients diagnosed with advanced fibrosis or cirrhosis prior to prolonged...... treatment with nucleoside or nucleotide analogs (NUCs) for CHB. Materials and methods. Patients with CHB and advanced fibrosis or cirrhosis prior to treatment with NUCs for at least 1 year were offered inclusion in the study. We measured liver stiffness using transient elastography (TE) at follow-up. TE cut...... duration was 50.5 months. Among patients with cirrhosis prior to treatment, 26 (49%) had liver stiffness below 11.0 kPa at follow-up, suggesting regression of cirrhosis. Among patients with advanced fibrosis (F3) prior to treatment, 10 (77%) had liver stiffness below 8.1 kPa after treatment, suggesting...

  19. Chronic stress effects on hippocampal structure and synaptic function: relevance for depression and normalization by anti-glucocorticoid treatment

    Directory of Open Access Journals (Sweden)

    Harmen J Krugers

    2010-07-01

    Full Text Available Exposure of an organism to environmental challenges activates two hormonal systems that help the organism to adapt. As part of this adaptational process, brain processes are changed such that appropriate behavioral strategies are selected that allow optimal performance at the short term, while relevant information is stored for the future. Over the past years it has become evident that chronic uncontrollable and unpredictable stress also exerts profound effects on structure and function of limbic neurons, but the impact of chronic stress is not a mere accumulation of repeated episodes of acute stress exposure. Dendritic trees are reduced in some regions but expanded in others, and cells are generally exposed to a higher calcium load upon depolarization. Synaptic strengthening is largely impaired. Neurotransmitter responses are also changed, e.g. responses to serotonin. We here discuss: a the main cellular effects after chronic stress with emphasis on the hippocampus, b how such effects could contribute to the development of psychopathology in genetically vulnerable individuals, and c their normalization by brief treatment with anti-glucocorticoids.

  20. Effect of prolonged and intermittent treatment on the clinical course of peptic ulcer.

    Science.gov (United States)

    Chornenka, Zhanetta A; Yasinska, Elvira Ts; Grytsiuk, Mariana I

    2018-01-01

    Introduction: The number of patients with peptic ulcer increases annually. According to published data, patients with peptic ulcer constitute about 15% of those hospitalized with gastrointestinal diseases. The aim: That is why we set the task to evaluate the methods of preventive treatment and to choose the most effective one. Materials and methods: For this purpose, we selected 103 patients with peptic ulcer without severe exacerbations and complications from one region (main group) and 101 patients from another region (control group) for observations. Making diagnosis was based on the study of complaints, anamnestic data, physical examination of the patient, evaluation of the functional state of the gastroduodenal system, as well as the X-ray and endoscopic examination. The sources of the study were medical records of outpatients, control cards for dispensary surveillance, registers of temporary disability records, sick leave records and others. Results: Most patients, from both the main and control groups, who were on prophylactic treatment, noticed that they had an increased working capacity, normalized sleep, better appetite and fewer dyspeptic disorders. Patients in the main group for two years were on prolonged prophylactic treatment according to the method that we had developed. by us. Patients in the control group received an intermittent preventive treatment twice a year (in spring and autumn). In the complex of therapeutic measures the following were used: dietary recommendations, antacids, cholinolytics, multivitamins, etc. Conclusions: Prolonged prophylactic treatment is an effective means to combat exacerbations and complications of peptic ulcer and can be recommended for implementation in practice.

  1. Optimal glucocorticoid replacement in adrenal insufficiency.

    Science.gov (United States)

    Øksnes, Marianne; Ross, Richard; Løvås, Kristian

    2015-01-01

    Adrenal insufficiency (glucocorticoid deficiency) comprises a group of rare diseases, including primary adrenal insufficiency, secondary adrenal insufficiency and congenital adrenal hyperplasia. Lifesaving glucocorticoid therapy was introduced over 60 years ago, but since then a number of advances in treatment have taken place. Specifically, little is known about short- and long-term treatment effects, and morbidity and mortality. Over the past decade, systematic cohort and registry studies have described reduced health-related quality of life, an unfavourable metabolic profile and increased mortality in patients with adrenal insufficiency, which may relate to unphysiological glucocorticoid replacement. This has led to the development of new modes of replacement that aim to mimic normal glucocorticoid physiology. Here, evidence for the inadequacy of conventional glucocorticoid therapy and recent developments in treatment are reviewed, with an emphasis on primary adrenal insufficiency. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. 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

  3. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  4. Arsenic in an alkaline AMD treatment sludge: Characterization and stability under prolonged anoxic conditions

    International Nuclear Information System (INIS)

    Beauchemin, Suzanne; Fiset, Jean-Francois; Poirier, Glenn; Ablett, James

    2010-01-01

    Lime treatment of acid mine drainage (AMD) generates large volumes of neutralization sludge that are often stored under water covers. The sludge consists mainly of calcite, gypsum and a widespread ferrihydrite-like Fe phase with several associated species of metal(loid) contaminants. The long-term stability of metal(loid)s in this chemically ill-defined material remains unknown. In this study, the stability and speciation of As in AMD sludge subjected to prolonged anoxic conditions is determined. The total As concentration in the sludge is 300 mg kg -1 . In the laboratory, three distinct water cover treatments were imposed on the sludge to induce different redox conditions (100%N 2 , 100%N 2 + glucose, 95%N 2 :5%H 2 ). These treatments were compared against a control of oxidized, water-saturated sludge. Electron micro-probe (EMP) analysis and spatially resolved synchrotron X-ray fluorescence (SXRF) results indicate that As is dominantly associated with Fe in the sludge. In all treatments and throughout the experiment, measured concentrations of dissolved As were less than 5 μg L -1 . Dissolved Mn concentration in the N 2 + glucose treatment increased significantly compared to other treatments. Manganese and As K-edge X-ray absorption near edge structure spectroscopy (XANES) analyses showed that Mn was the redox-active element in the solid-phase, while As was stable. Arsenic(V) was still the dominant species in all water-covered sludges after 9 months of anoxic treatments. In contrast, Mn(IV) in the original sludge was partially reduced into Mn(II) in all water-covered sludges. The effect was most pronounced in the N 2 + glucose treatment, suggesting microbial reduction. Micro-scale SXRF and XANES analysis of the treated sludge showed that Mn(II) accumulated in areas already enriched in Fe and As. Overall, the study shows that AMD sludges remain stable under prolonged anoxic conditions. External sources of chemical reductants or soluble C were needed to induce

  5. The Anabolic Effect of PTH on Bone is Attenuated by Simultaneous Glucocorticoid Treatment

    DEFF Research Database (Denmark)

    Oxlund, Hans; Ørtoft, Gitte; Thomsen, Jesper Skovhus

    2006-01-01

    . The pronounced anabolic effect of PTH injections on the endocortical and trabecular bone surfaces and less pronounced anabolic effect on periosteal surfaces were partially inhibited, but not prevented, by simultaneous GC treatment in old rats. Both cortical and cancellous bone possessed full mechanical...

  6. Fluoride in the prevention and treatment of glucocorticoid-induced osteoporosis

    NARCIS (Netherlands)

    Lems, WF; Jacobs, JWG; Bijlsma, JWJ

    2000-01-01

    Since the use of fluoride has been shown to stimulate bone formation and since decreased bone formation is a key feature in the pathogenesis of corticosteroid-induced osteoporosis (CIOP), fluoride is, at least theoretically, attractive for the prevention and treatment of CIOP. In postmenopausal

  7. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia

    Directory of Open Access Journals (Sweden)

    Arvind Chaturvedi

    2011-01-01

    Full Text Available Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  8. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia.

    Science.gov (United States)

    Chaturvedi, Arvind; Dash, Hh

    2011-07-01

    Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  9. Life-threatening asthma attack during prolonged fingolimod treatment: case report

    Directory of Open Access Journals (Sweden)

    Zecca C

    2014-07-01

    Full Text Available Chiara Zecca,1,* Matteo Caporro,1,* Sandor Györik,2 Claudio Gobbi11Neurocenter of Southern Switzerland, Department of Neurology, Ospedale Regionale di Lugano, Lugano, Switzerland; 2Department of Internal Medicine, Ospedale Regionale di Bellinzona, Bellinzona, Switzerland*These authors contributed equally to this workBackground: Fingolimod (FTY mediates bronchoconstriction by interacting with sphingosine-1-phosphate receptors. The majority of the reported adverse respiratory events occur during the first weeks of treatment.Case presentation: A 49-year-old woman developed a life-threatening asthma attack after 6 months of continuous FTY treatment. The adverse event required prolonged hospitalization, and the patient recovered without sequelae after FTY interruption. A history of previous airway hyperreactivity and a concurrent viral respiratory infection possibly acted as predisposing factors.Conclusion: This first description of a severe, life-threatening asthma attack during prolonged FTY treatment suggests the need for long-term clinical surveillance, especially in patients with known predisposing factors.Keywords: multiple sclerosis, bronchial hyper-reactivity

  10. Neural and behavioural changes in male periadolescent mice after prolonged nicotine-MDMA treatment.

    Science.gov (United States)

    Adeniyi, Philip A; Ishola, Azeez O; Laoye, Babafemi J; Olatunji, Babawale P; Bankole, Oluwamolakun O; Shallie, Philemon D; Ogundele, Olalekan M

    2016-02-01

    The interaction between MDMA and Nicotine affects multiple brain centres and neurotransmitter systems (serotonin, dopamine and glutamate) involved in motor coordination and cognition. In this study, we have elucidated the effect of prolonged (10 days) MDMA, Nicotine and a combined Nicotine-MDMA treatment on motor-cognitive neural functions. In addition, we have shown the correlation between the observed behavioural change and neural structural changes induced by these treatments in BALB/c mice. We observed that MDMA (2 mg/Kg body weight; subcutaneous) induced a decline in motor function, while Nicotine (2 mg/Kg body weight; subcutaneous) improved motor function in male periadolescent mice. In combined treatment, Nicotine reduced the motor function decline observed in MDMA treatment, thus no significant change in motor function for the combined treatment versus the control. Nicotine or MDMA treatment reduced memory function and altered hippocampal structure. Similarly, a combined Nicotine-MDMA treatment reduced memory function when compared with the control. Ultimately, the metabolic and structural changes in these neural systems were seen to vary for the various forms of treatment. It is noteworthy to mention that a combined treatment increased the rate of lipid peroxidation in brain tissue.

  11. Virtual reality exposure versus prolonged exposure for PTSD: Which treatment for whom?

    Science.gov (United States)

    Norr, Aaron M; Smolenski, Derek J; Katz, Andrea C; Rizzo, Albert A; Rothbaum, Barbara O; Difede, JoAnn; Koenen-Woods, Patricia; Reger, Mark A; Reger, Greg M

    2018-06-01

    The majority of studies comparing active psychological treatments for posttraumatic stress disorder (PTSD) do not find significant differences at posttreatment. This was the case in a recent trial examining prolonged exposure (PE) and virtual reality exposure (VRE) among active-duty soldiers with combat-related PTSD. Matching individual patients to specific treatments provides a potential avenue to improve significantly the public health impact of effective treatments for PTSD. A composite moderator approach was used to identify profiles of patients who would see superior PTSD symptom reduction in VRE or PE to inform future treatment matching. Active duty U.S. army soldiers (N = 108) were enrolled in a randomized clinical trial comparing VRE and PE in the treatment of PTSD stemming from deployments to Iraq or Afghanistan. Eighteen baseline variables were examined to identify treatment response heterogeneity in two patient groups: those with a superior response to PE and those with a superior response to VRE. The final composite moderator comprised four of 18 baseline variables. Results revealed that patients who were predicted to see greater PTSD symptom reduction in VRE were likely to be younger, not taking antidepressant medication, had greater PTSD hyperarousal symptoms, and were more likely to have greater than minimal suicide risk. Results suggest that treatment matching based on patient profiles could meaningfully improve treatment efficacy for combat-related PTSD. Future research can build on these results to improve our understanding of how to improve treatment matching for PTSD. © 2018 Wiley Periodicals, Inc.

  12. Glucocorticoid programming of neuroimmune function.

    Science.gov (United States)

    Walker, David J; Spencer, Karen A

    2018-01-15

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

  13. 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

  14. Antinociception induced by chronic glucocorticoid treatment is correlated to local modulation of spinal neurotransmitter content

    Directory of Open Access Journals (Sweden)

    Almeida Armando

    2009-07-01

    Full Text Available Abstract Background While acute effects of stress on pain are well described, those produced by chronic stress are still a matter of dispute. Previously we demonstrated that chronic unpredictable stress results in antinociception in the tail-flick test, an effect that is mediated by increased levels of corticosteroids. In the present study, we evaluated nociception in rats after chronic treatment with corticosterone (CORT and dexamethasone (DEX in order to discriminate the role of each type of corticosteroid receptors in antinociception. Results Both experimental groups exhibited a pronounced antinociceptive effect after three weeks of treatment when compared to controls (CONT; however, at four weeks the pain threshold in CORT-treated animals returned to basal levels whereas in DEX-treated rats antinociception was maintained. In order to assess if these differences are associated with altered expression of neuropeptides involved in nociceptive transmission we evaluated the density of substance P (SP, calcitonin gene-related peptide (CGRP, somatostatin (SS and B2-γ-aminobutiric acid receptors (GABAB2 expression in the spinal dorsal horn using light density measurements and stereological techniques. After three weeks of treatment the expression of CGRP in the superficial dorsal horn was significantly decreased in both CORT and DEX groups, while GABAB2 was significantly increased; the levels of SP for both experimental groups remained unchanged at this point. At 4 weeks, CGRP and SP are reduced in DEX-treated animals and GABAB2 unchanged, but all changes were restored to CONT levels in CORT-treated animals. The expression of SS remained unaltered throughout the experimental period. Conclusion These data indicate that corticosteroids modulate nociception since chronic corticosteroid treatment alters the expression of neuropeptides involved in nociceptive transmission at the spinal cord level. As previously observed in some supraspinal areas, the

  15. Growth hormone and somatomedin effects on calcification following X-irradiation, glucocorticoid treatment or fasting

    International Nuclear Information System (INIS)

    Dearden, L.C.; Mosier, H.D. Jr.

    1986-01-01

    Growth hormone (GH) is thought to activate the liver to produce a peptide called somatomedin (SM) and this substance putatively stimulates linear growth in long bones by its action on cartilagenous epiphyseal plates. These actions include stimulating chondrocytes to synthesize the carbohydrate and protein components of proteoglycan and of collagen, enhancing the synthesis of ribo and desoxyribonucleic acids, and possibly to increase cell division. In GH deficiencies there is a narrowing of the epiphyseal growth plate and cartilage calcification is enhanced concurrent with proteoglycan and collagen alterations in the extracellular matrix. Calcium and phosphate ions accumulate in mitochondria followed by their release as the calcification zone is approached, and matrix vesicles, which possess the chemical machinery necessary to induce the format0344of apatite crystals within them, increase. Therefore, if GH and/or SM levels are altered, there should be corresponding alterations in growth or in cartilage calcification. In the present study we have investigated rats after head X-irradiation, fasting, and corticosteroid treatment, and all of these treatments reduce GH and SM. (Auth.)

  16. Effects of prolonged agmatine treatment in aged male Sprague-Dawley rats.

    Science.gov (United States)

    Rushaidhi, M; Zhang, H; Liu, P

    2013-03-27

    Increasing evidence suggests that altered arginine metabolism contributes to cognitive decline during ageing. Agmatine, decarboxylated arginine, has a variety of pharmacological effects, including the modulation of behavioural function. A recent study demonstrated the beneficial effects of short-term agmatine treatment in aged rats. The present study investigated how intraperitoneal administration of agmatine (40mg/kg, once daily) over 4-6weeks affected behavioural function and neurochemistry in aged Sprague-Dawley rats. Aged rats treated with saline displayed significantly reduced exploratory activity in the open field, impaired spatial learning and memory in the water maze and object recognition memory relative to young rats. Prolonged agmatine treatment improved animals' performance in the reversal test of the water maze and object recognition memory test, and significantly suppressed age-related elevation in nitric oxide synthase activity in the dentate gyrus of the hippocampus and prefrontal cortex. However, this prolonged supplementation was unable to improve exploratory activity and spatial reference learning and memory in aged rats. These findings further demonstrate that exogenous agmatine selectively improves behavioural function in aged rats. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Influence of prolonged storage process, pasteurization, and heat treatment on biologically-active human milk proteins.

    Science.gov (United States)

    Chang, Jih-Chin; Chen, Chao-Huei; Fang, Li-Jung; Tsai, Chi-Ren; Chang, Yu-Chuan; Wang, Teh-Ming

    2013-12-01

    The bioactive proteins in human milk may be influenced by prolonged storage process, pasteurization, and heat treatment. This study was conducted to evaluate the effects of these procedures. Three forms of human milk - freshly expressed, frozen at -20°C for a prolonged duration, and pasteurized milk - were collected from 14 healthy lactating mothers and a milk bank. The concentrations of major bioactive proteins (secretory immunoglobulin A, lactoferrin, lysozyme, and leptin) were quantified using enzyme-linked immunosorbent assay kits. Changes in these proteins by heat treatment at 40°C or 60°C for 30 minutes were further evaluated. The mean concentrations of lactoferrin and secretory immunoglobulin A were significantly reduced by 66% and 25.9%, respectively, in pasteurized milk compared with those in freshly-expressed milk. Heat treatment at 40°C or 60°C did not cause significant changes in lactoferrin and secretory immunoglobulin A, but there was an apparent increase in lysozyme (p = 0.016). There were no significant differences in leptin level among these three forms of milk prior to (p = 0.153) or after heat treatment (p = 0.053). Various freezing/heating/pasteurization processes applied to human milk prior to delivery to neonates could affect the concentration of immunomodulatory proteins, especially lactoferrin, secretory immunoglobulin A, and lysozyme. Leptin was unaffected by the various handling processes tested. Fresh milk was found to be the best food for neonates. Further studies are warranted to evaluate the functional activity of these proteins and their effects on infants' immunological status. Copyright © 2013. Published by Elsevier B.V.

  18. Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP)

    NARCIS (Netherlands)

    Janssen, H. L.; Gerken, G.; Carreño, V.; Marcellin, P.; Naoumov, N. V.; Craxi, A.; Ring-Larsen, H.; Kitis, G.; van Hattum, J.; de Vries, R. A.; Michielsen, P. P.; ten Kate, F. J.; Hop, W. C.; Heijtink, R. A.; Honkoop, P.; Schalm, S. W.

    1999-01-01

    Interferon alfa (IFN-alpha) is the primary treatment for chronic hepatitis B. The standard duration of IFN-alpha therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-alpha treatment in patients

  19. Evaluating a patient's request for life-prolonging treatment: an ethical framework.

    Science.gov (United States)

    Winkler, Eva C; Hiddemann, Wolfgang; Marckmann, Georg

    2012-11-01

    Contrary to the widespread concern about over-treatment at the end of life, today, patient preferences for palliative care at the end of life are frequently respected. However, ethically challenging situations in the current healthcare climate are, instead, situations in which a competent patient requests active treatment with the goal of life-prolongation while the physician suggests best supportive care only. The argument of futility has often been used to justify unilateral decisions made by physicians to withhold or withdraw life-sustaining treatment. However, we argue that neither the concept of futility nor that of patient autonomy alone is apt for resolving situations in which physicians are confronted with patients' requests for active treatment. Instead, we integrate the relevant arguments that have been put forward in the academic discussion about 'futile' treatment into an ethical algorithm with five guiding questions: (1) Is there a chance that medical intervention will be effective in achieving the patient's treatment goal? (2) How does the physician evaluate the expected benefit and the potential harm of the treatment? (3) Does the patient understand his or her medical situation? (4) Does the patient prefer receiving treatment after evaluating the benefit-harm ratio and the costs? (5) Does the treatment require many resources? This algorithm shall facilitate approaching patients' requests for treatments deemed futile by the physician in a systematic way, and responding to these requests in an ethically appropriate manner. It thereby adds substantive considerations to the current procedural approaches of conflict resolution in order to improve decision making among physicians, patients and families.

  20. Short vs prolonged dual antiplatelet treatment upon endovascular stenting of peripheral arteries

    Directory of Open Access Journals (Sweden)

    Kronlage M

    2017-10-01

    Full Text Available Mariya Kronlage,1 Maximilian Wassmann,1 Britta Vogel,1 Oliver J Müller,1 Erwin Blessing,2 Hugo Katus,1,3 Christian Erbel1 1Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, 2SRH Klinikum Karlsbad Langensteinbach, Karlsbad, 3DZHK German Center for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Mannheim, Germany Introduction: Peripheral artery disease (PAD is a highly prevalent disorder with a substantial economical burden. Dual antiplatelet treatment (DAPT upon endovascular stenting to prevent acute thrombotic reocclusions is an universally accepted practice for postinterventional management of PAD patients. However, the optimal period of time for DAPT upon endovascular stenting is not known.Methods: In the current nonrandomized, retrospective monocentric study, we evaluated the duration of DAPT upon endovascular stenting. A total of 261 endovascular SFA and iliac stenting procedures were performed on 214 patients and these patients were subdivided into a short (4–6 weeks or a prolonged (8–12 weeks DAPT regime group. More than 65% of the patients included were male, approximately 35% were diabetic, and 61% had a history of smoking. Of all the patients, 90% exhibited a Rutherford stage 2–3, and approximately half of the patients had a moderate-to-severe calcified target lesion with a length of >13 cm. Major safety end points were defined as any bleeding, compartment syndrome, and ischemic events. In addition to this, patency, all-cause mortality, as well as amputation were followed up over a period of 12 months upon intervention.Results: Twelve months after endovascular stenting, primary patency in our cohort was comparable between the groups (83.94% short vs 79.8% long DAPT, P>0.05. Major bleeding occurred in 18 cases without any difference between the groups (P>0.05. In addition, during the 12-month follow-up, 6 (3.4% patients in the short and 3 (3.5% in the prolonged DAPT regime

  1. Evaluation of the collaborative network of highly correlating skin proteins and its change following treatment with glucocorticoids

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    Farman Nicolette

    2010-05-01

    Full Text Available Abstract Background Glucocorticoids (GC represent the core treatment modality for many inflammatory diseases. Its mode of action is difficult to grasp, not least because it includes direct modulation of many components of the extracellular matrix as well as complex anti-inflammatory effects. Protein expression profile of skin proteins is being changed with topical application of GC, however, the knowledge about singular markers in this regard is only patchy and collaboration is ill defined. Material/Methods Scar formation was observed under different doses of GC, which were locally applied on the back skin of mice (1 to 3 weeks. After euthanasia we analyzed protein expression of collagen I and III (picrosirius in scar tissue together with 16 additional protein markers, which are involved in wound healing, with immunhistochemistry. For assessing GC's effect on co-expression we compared our results with a model of random figures to estimate how many significant correlations should be expected by chance. Results GC altered collagen and protein expression with distinct results in different areas of investigation. Most often we observed a reduced expression after application of low dose GC. In the scar infiltrate a multivariate analysis confirmed the significant impact of both GC concentrations. Calculation of Spearman's correlation coefficient similarly resulted in a significant impact of GC, and furthermore, offered the possibility to grasp the entire interactive profile in between all variables studied. The biological markers, which were connected by significant correlations could be arranged in a highly cross-linked network that involved most of the markers measured. A marker highly cross-linked with more than 3 significant correlations was indicated by a higher variation of all its correlations to the other variables, resulting in a standard deviation of > 0.2. Conclusion In addition to immunohistochemical analysis of single protein markers

  2. 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...... logistic regression analysis was applied using the summarised descriptive data (for example, % with encephalopathy, mean bilirubin value) of the treatment and control groups of 12 controlled trials that gave this information. Despite evidence of publication bias favouring glucocorticoid treatment, its...... overall effect on mortality was not statistically significant (p = 0.20)--the relative risk (steroid/control) was 0.78 (95% confidence intervals 0.51, 1.18). There was indication of interaction between glucocorticoid therapy and gender, but not encephalopathy. Thus, the effect of glucocorticoid treatment...

  3. Glycyrrhizin Treatment Facilitates Extinction of Conditioned Fear Responses After a Single Prolonged Stress Exposure in Rats.

    Science.gov (United States)

    Lai, Shuhua; Wu, Gangwei; Jiang, Zhixian

    2018-01-01

    Impaired fear memory extinction is widely considered a key mechanism of post-traumatic stress disorder (PTSD). Recent studies have suggested that neuroinflammation after a single prolonged stress (SPS) exposure may play a critical role in the impaired fear memory extinction. Studies have shown that high mobility group box chromosomal protein 1 (HMGB-1) is critically involved in neuroinflammation. However, the role of HMGB-1 underlying the development of impairment of fear memory extinction is still not known. Thus, we examined the levels of HMGB-1 in the basolateral amygdala (BLA) following SPS using Western blot and evaluated the levels of microglia and astrocytes activation in the BLA after SPS using immunohistochemical staining. We then examined the effects of pre-SPS intra-BLA administration of glycyrrhizin, an HMGB1 inhibitor, or LPS-RS, a competitive TLR4 antagonist, on subsequent post-SPS fear extinction. We found that SPS treatment prolonged the extinction of contextual fear memory after the SPS. The impairment of SPS-induced extinction of contextual fear memory was associated with increased HMGB1 and Toll-like receptor 4 (TLR4) levels in the BLA. Additionally, the impairment of SPS-induced extinction of contextual fear memory was associated with increased activation of microglia and astrocyte in the BLA. Intra-BLA administrations of glycyrrhizin (HMGB-1 inhibitor) or LPS-RS (TLR4 antagonist) can prevent the development of SPS-induced fear extinction impairment. Taken together, these results suggested that SPS treatment may not only produce short term effects on the HMGB1/TLR4-mediated pro-inflammation, but alter the response of microglia and astrocytes to the exposure to fear associated contextual stimuli. © 2018 The Author(s). Published by S. Karger AG, Basel.

  4. Glycyrrhizin Treatment Facilitates Extinction of Conditioned Fear Responses After a Single Prolonged Stress Exposure in Rats

    Directory of Open Access Journals (Sweden)

    Shuhua Lai

    2018-03-01

    Full Text Available Background/Aims: Impaired fear memory extinction is widely considered a key mechanism of post-traumatic stress disorder (PTSD. Recent studies have suggested that neuroinflammation after a single prolonged stress (SPS exposure may play a critical role in the impaired fear memory extinction. Studies have shown that high mobility group box chromosomal protein 1 (HMGB-1 is critically involved in neuroinflammation. However, the role of HMGB-1 underlying the development of impairment of fear memory extinction is still not known. Methods: Thus, we examined the levels of HMGB-1 in the basolateral amygdala (BLA following SPS using Western blot and evaluated the levels of microglia and astrocytes activation in the BLA after SPS using immunohistochemical staining. We then examined the effects of pre-SPS intra-BLA administration of glycyrrhizin, an HMGB1 inhibitor, or LPS-RS, a competitive TLR4 antagonist, on subsequent post-SPS fear extinction. Results: We found that SPS treatment prolonged the extinction of contextual fear memory after the SPS. The impairment of SPS-induced extinction of contextual fear memory was associated with increased HMGB1 and Toll-like receptor 4 (TLR4 levels in the BLA. Additionally, the impairment of SPS-induced extinction of contextual fear memory was associated with increased activation of microglia and astrocyte in the BLA. Intra-BLA administrations of glycyrrhizin (HMGB-1 inhibitor or LPS-RS (TLR4 antagonist can prevent the development of SPS-induced fear extinction impairment. Conclusion: Taken together, these results suggested that SPS treatment may not only produce short term effects on the HMGB1/TLR4-mediated pro-inflammation, but alter the response of microglia and astrocytes to the exposure to fear associated contextual stimuli.

  5. QTc Prolongation in Veterans With Heroin Dependence on Methadone Maintenance Treatment.

    Science.gov (United States)

    Hassamal, Sameer; Fernandez, Antony; Moradi Rekabdarkolaee, Hossein; Pandurangi, Ananda

    2015-06-01

    QTc prolongation and Torsade de Ppointes have been reported in patients on methadone maintenance. In this study, QTc was compared before and after the veteran (n = 49) was on a stable dosage of methadone for 8.72 ± 4.50 years to treat heroin dependence. Risk factors were correlated with the QTc once the veteran was on a stable dose of methadone. Differences in the clinical risk factors in subgroups of veterans with below and above mean QTc change was compared. ECG data was obtained from a 12-lead electrocardiogram (pre-methadone and on methadone) on 49 veterans. Data and risk factors were retrospectively collected from the medical records. The mean QTc at baseline (pre-methadone) was 426 ± 34 msec and after being on methadone for an average of 8.72 ± 4.50 years was significantly higher at 450 ± 35 msec. No significant relationships were found between QTc prolongation and risk factors except for calcium. The methadone dosage was significantly higher in veterans with a QTc change above the mean change of ≥ 24 msec (88.48 ± 27.20 mg v.s 68.96 ± 19.84 mg). None of the veterans experienced cardiac arrhythmias. The low complexity of medical co-morbidities may explain the lack of a significant correlation between any risk factor with the QTc except calcium and methadone dosage. The absence of TdP may be explained by the low prevalence of QTc values > 500 msec as well as the retrospective design of the study. During long-term methadone treatment, there was a slight increase in the QTc interval but we did not find evidence of increased cardiac toxicity as a reason for treatment termination.

  6. Serum levels of parathyroid hormone and markers of bone metabolism in patients with rheumatoid arthritis. Relationship to disease activity and glucocorticoid treatment

    DEFF Research Database (Denmark)

    Jensen, Tonny Joran; Hansen, M; Madsen, J C

    2001-01-01

    OBJECTIVE: To evaluate the influence of inflammatory activity and glucocorticoid (GC) treatment on serum parathyroid hormone (s-PTH) and bone metabolism in patients with rheumatoid arthritis (RA). Furthermore, in patients with active RA, to examine the PTH secretion and Ca2+ set point before and ....... The increased levels of markers of type I collagen metabolism (s-ICTP, Pyr) and s-AlbCorrCa2+ in patients with active disease and patients treated with GC may be a result of increased degradation in synovium, cartilage and bone due to the inflammatory process.......OBJECTIVE: To evaluate the influence of inflammatory activity and glucocorticoid (GC) treatment on serum parathyroid hormone (s-PTH) and bone metabolism in patients with rheumatoid arthritis (RA). Furthermore, in patients with active RA, to examine the PTH secretion and Ca2+ set point before...... groups. The levels of urine pyridinoline (Pyr) and s-albumin-corrected calcium (s-AlbCorrCa2+) were elevated in patients with active disease and patients treated with GC. S-PTH and s-phosphate were within normal ranges. S-TAP, s-ICTP, Pyr and s-AlbCorrCa2+ correlated positively with indices of disease...

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

    DEFF Research Database (Denmark)

    Olsson, A.; Oturai, D B; Sørensen, P S

    2015-01-01

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

  8. 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

    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...... treatment. A population-based sample of 1369 people newly diagnosed with clinical type 2 diabetes underwent a clinical examination at diagnosis, and surviving patients were followed up 6 and 14 years later. Patients receiving oral GC treatment at diagnosis were compared with the other patients. Of 1369......Chronic exposure to glucocorticoids (GCs) has many side effects including glucose intolerance and diabetes and may accelerate the occurrence of cardiovascular disease and increase mortality. We studied the 14-year clinical development of diabetes in patients diagnosed with diabetes during GC...

  9. Antibiotic-eluting hydrophilized PMMA bone cement with prolonged bactericidal effect for the treatment of osteomyelitis.

    Science.gov (United States)

    Oh, Eun Jo; Oh, Se Heang; Lee, In Soo; Kwon, Oh Soo; Lee, Jin Ho

    2016-05-01

    Osteomyelitis is still considered to be one of the major challenges for orthopedic surgeons despite advanced antiseptic surgical procedures and pharmaceutical therapeutics. In this study, hydrophilized poly(methyl methacrylate) (PMMA) bone cements containing Pluronic F68 (EG79PG28EG79) as a hydrophilic additive and vancomycin (F68-VAcements) were prepared to allow the sustained release of the antibiotic for adequate periods of time without any significant loss of mechanical properties. The compressive strengths of the bone cements with Pluronic F68 compositions less than 7 wt% were not significantly different compared with the control vancomycin-loaded bone cement (VAcement). TheF68 (7 wt%)-VAcement showed sustained release of the antibiotic for up to 11 weeks and almost 100% release from the bone cement. It also prohibited the growth ofS. aureus(zone of inhibition) over six weeks (the required period to treat osteomyelitis), and it did not show any notable cytotoxicity. From an animal study using a femoral osteomyelitis rat model, it was observed that theF68 (7 wt%)-VAcement was effective for the treatment of osteomyelitis, probably as a result of the prolonged release of antibiotic from the PMMA bone cement. On the basis of these findings, it can be suggested that the use of Pluronic F68 as a hydrophilic additive for antibiotic-eluting PMMA bone cement can be a promising strategy for the treatment of osteomyelitis. © The Author(s) 2016.

  10. One-Year Outcome of Geriatric Hip-Fracture Patients following Prolonged ICU Treatment

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    Daphne Eschbach

    2016-01-01

    Full Text Available Purpose. Incidence of geriatric fractures is increasing. Knowledge of outcome data for hip-fracture patients undergoing intensive-care unit (ICU treatment, including invasive ventilatory management (IVM and hemodiafiltration (CVVHDF, is sparse. Methods. Single-center prospective observational study including 402 geriatric hip-fracture patients. Age, gender, the American Society of Anesthesiologists (ASA classification, and the Barthel index (BI were documented. Underlying reasons for prolonged ICU stay were registered, as well as assessed procedures like IVM and CVVHDF. Outcome parameters were in-hospital, 6-month, and 1-year mortality and need for nursing care. Results. 15% were treated > 3 days and 68% 3d cohort were significantly increased (p=0.001. Most frequent indications were cardiocirculatory pathology followed by respiratory failure, renal impairment, and infection. 18% of patients needed CVVHDF and 41% IVM. In these cohorts, 6-month mortality ranged > 80% and 12-month mortality > 90%. 100% needed nursing care after 6 and 12 months. Conclusions. ICU treatment > 3 days showed considerable difference in mortality and nursing care needed after 6 and 12 months. Particularly, patients requiring CVVHDF or IVM had disastrous long-term results. Our study may add one further element in complex decision making serving this vulnerable patient cohort.

  11. Experimental therapy of epilepsy with transcranial magnetic stimulation: lack of additional benefit with prolonged treatment

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    Brasil-Neto Joaquim P.

    2004-01-01

    Full Text Available OBJECTIVE: To investigate the effect of three months of low-frequency repetitive transcranial magnetic stimulation (rTMS treatment in intractable epilepsy. METHODS: Five patients (four males, one female; ages 6 to 50 years, were enrolled in the study; their epilepsy could not be controlled by medical treatment and surgery was not indicated. rTMS was performed twice a week for three months; patients kept records of seizure frequency for an equal period of time before, during, and after rTMS sessions. rTMS was delivered to the vertex with a round coil, at an intensity 5 % below motor threshold. During rTMS sessions, 100 stimuli (five series of 20 stimuli, with one-minute intervals between series were delivered at a frequency of 0.3 Hz. RESULTS: Mean daily number of seizures (MDNS decreased in three patients and increased in two during rTMS- one of these was treated for only one month; the best result was achieved in a patient with focal cortical dysplasia (reduction of 43.09 % in MDNS. In the whole patient group, there was a significant (p<0.01 decrease in MDNS of 22.8 %. CONCLUSION: Although prolonged rTMS treatment is safe and moderately decreases MDNS in a group of patients with intractable epilepsy, individual patient responses were mostly subtle and clinical relevance of this method is probably low. Our data suggest, however, that patients with focal cortical lesions may indeed benefit from this novel treatment. Further studies should concentrate on that patient subgroup.

  12. Efficacy and Safety of Prolonged Rituximab Treatment in Patients with Systemic Juvenile Idiopathic Arthritis

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    E. I. Alexeeva

    2013-01-01

    Full Text Available Aim: to assess efficacy and safety of rituximab treatment in children with systemic juvenile idiopathic arthritis under prolonged follow-up. Patients and methods: results of treatment of 60 children (33 girls and 27 boys with systemic variant of juvenile idiopathic arthritis being followed-up in rheumatology department of the Federal State Institution «Scientific Centre of Children Health» of RAMS (FSI «SCCH» RAMS were analyzed. The mean age of children was 8,7 years. The mean duration of disease course at the moment of first rituximab administration was 5,3 years. At the beginning of rituximab therapy all children had active articular syndrome, severe systemic manifestations and significantly increased laboratory markers of activity. As the signs of improvement the authors used pediatric criteria of the American College of Rheumatology. The treatment was approved by the local ethic committee of the FSI «SCCH» RAMS; the patients’ representatives and patients older than 14 years old had signed informed agreement. Results: remission was induced in 26 of 60 (43% patients: in 9 of them after the 1st course of treatment, in 8 — after the 2nd, in 6 — after the 3d and in 3 — after the 4th. The maximal duration of remission was 5 years 4 months, minimal — 6 months. Other genetically engineered drugs were administered to 34 (57% of the patients: due to the primary inefficiency in 15, secondary inefficiency — in 10; due to partial inefficiency — in 9 children. The drug was well-tolerated in most of the patients. Undesirable effects were represented by transfusional reactions to the rituximab infusion, infections with different severity and granulocytopenia. Conclusions: rituximab has high efficiency in patients with severe systemic variant of juvenile idiopathic arthritis. The drug induced remission in patients who had been considered almost incurable, with low status of physical and social adaptation.

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

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    Rosa Maria Rodrigues Pereira

    2012-08-01

    Full Text Available Os glicocorticoides (GC são prescritos por praticamente todas as especialidades médicas, e cerca de 0,5% da população geral do Reino Unido utiliza esses medicamentos. Com o aumento da sobrevida dos pacientes com doenças reumatológicas, a morbidade secundária ao uso dessa medicação representa um aspecto importante que deve ser considerado no manejo de nossos pacientes. As incidências de fraturas vertebrais e não vertebrais são elevadas, variando de 30%-50% em pessoas que usam GC por mais de três meses. Assim, a osteoporose e as fraturas por fragilidade devem ser prevenidas e tratadas em todos os pacientes que iniciarão ou que já estejam em uso desses esteroides. Diversas recomendações elaboradas por várias sociedades internacionais têm sido descritas na literatura, porém não há consenso entre elas. Recentemente, o Americam College of Rheumatology publicou novas recomendações, porém elas são fundamentadas na FRAX (WHO Fracture Risk Assessment Tool para analisar o risco de cada indivíduo e, dessa maneira, não podem ser completamente utilizadas pela população brasileira. Dessa forma, a Comissão de Osteoporose e Doenças Osteometabólicas da Sociedade Brasileira de Reumatologia, em conjunto com a Associação Médica Brasileira e a Associação Brasileira de Medicina Física e Reabilitação, implementou as diretrizes brasileiras de osteoporose induzida por glicocorticoide (OPIG, baseando-se na melhor evidência científica disponível e/ou experiência de experts. DESCRIÇÃO DO MÉTODO DE COLETA DE EVIDÊNCIA: A revisão bibliográfica de artigos científicos desta diretriz foi realizada na base de dados MEDLINE. A busca de evidência partiu de cenários clínicos reais, e utilizou as seguintes palavras-chave (MeSH terms: Osteoporosis, Osteoporosis/chemically induced*= (Glucocorticoids= Adrenal Cortex Hormones, Steroids, Glucocorticoids, Glucocorticoids/administration and dosage, Glucocorticoids/therapeutic use

  14. Prolonged methylprednisolone therapy after the pulse treatment for patients with moderate-to-severe paraquat poisoning: A retrospective analysis.

    Science.gov (United States)

    Gao, Jie; Feng, ShunYi; Wang, Jian; Yang, SiYuan; Li, Yong

    2017-06-01

    This retrospective study aims to evaluate the effect of prolonged methylprednisolone (MP) therapy on the mortality of patients with moderate-to-severe paraquat (PQ) poisoning after the pulse treatment.We performed a retrospective analysis of patients with acute moderate-to-severe PQ poisoning that were admitted to the emergency department from May 2012 to August 2016. Out of 138 patients, 60 were treated with pulse treatment (15 mg kg day MP for 3 days) and 78 were treated with prolonged MP therapy after pulse treatment (15 mg kg day MP for 3 days; afterward, the dosage was reduced in half every 2 days, and the MP therapy was terminated until 0.47 mg kg day). Kaplan-Meier method was used to compare the mortality between the 2 groups. Cox proportional hazard models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI).The mortality of the prolonged MP therapy after pulse treatment group was lower than that of the pulse group (47.4% vs 63.3%; log-rank tests, P  =  .003). According to the multivariate Cox analysis, the prolonged MP therapy after pulse treatment was significantly associated with a lower mortality risk (HR: 0.31, 95% CI: 0.19-0.52, P treatment caused more incidences of leucopenia than the pulse treatment alone (25.6% vs 11.7%, P  =  .04).The prolonged MP therapy after pulse treatment can reduce the mortality of moderate-to-severe PQ poisoning patients.

  15. Nonuremic calciphylaxis precipitated by teriparatide [rhPTH(1-34)] therapy in the setting of chronic warfarin and glucocorticoid treatment.

    Science.gov (United States)

    Spanakis, E K; Sellmeyer, D E

    2014-04-01

    Calciphylaxis occurs rarely in the absence of end stage renal disease. Predisposing factors for nonuremic calciphylaxis (NUC) include hyperparathyroidism, coagulopathies, connective tissue disease, liver disease, glucocorticoid use, and malignancy. Warfarin can facilitate vascular calcification by reducing vitamin K-dependent carboxylation of matrix-Gla proteins. An 86-year-old Caucasian woman with a history of polymyalgia rheumatica, two spontaneous deep venous thromboses (DVTs) and multiple fractures was treated with calcium, vitamin D, prednisone, and warfarin. The patient's low bone density was treated initially with estrogen, then oral bisphosphonate, which was discontinued due to upper gastrointestinal symptoms. Nasal calcitonin was initiated. After 10 years of calcitonin treatment, she was changed to teriparatide. Two months after initiating teriparatide, she developed lower extremity edema and painful erythematous nodular lesions on her calves bilaterally, that progressed to necrotic ulcers despite antibiotic therapy. Biopsy of the lesions showed calcification in the media of small blood vessels and subcutaneous fat with fat necrosis, consistent with calciphylaxis. Teriparatide was discontinued. Aggressive wound care, antibiotics, and intravenous zoledronic acid were initiated. With cessation of teriparatide therapy and intensive wound care, the patient's lesions resolved over 8 months. We report the first case of NUC precipitated by teriparatide therapy. Our patient had multiple underlying predisposing factors including a connective tissue disorder, glucocorticoid therapy, warfarin use, and possible underlying coagulopathy given her history of multiple DVTs. In such patients, alternative osteoporosis therapies may be preferred.

  16. Prolonged Minocycline Treatment Impairs Motor Neuronal Survival and Glial Function in Organotypic Rat Spinal Cord Cultures

    Science.gov (United States)

    Pinkernelle, Josephine; Fansa, Hisham; Ebmeyer, Uwe; Keilhoff, Gerburg

    2013-01-01

    Background Minocycline, a second-generation tetracycline antibiotic, exhibits anti-inflammatory and neuroprotective effects in various experimental models of neurological diseases, such as stroke, Alzheimer’s disease, amyotrophic lateral sclerosis and spinal cord injury. However, conflicting results have prompted a debate regarding the beneficial effects of minocycline. Methods In this study, we analyzed minocycline treatment in organotypic spinal cord cultures of neonatal rats as a model of motor neuron survival and regeneration after injury. Minocycline was administered in 2 different concentrations (10 and 100 µM) at various time points in culture and fixed after 1 week. Results Prolonged minocycline administration decreased the survival of motor neurons in the organotypic cultures. This effect was strongly enhanced with higher concentrations of minocycline. High concentrations of minocycline reduced the number of DAPI-positive cell nuclei in organotypic cultures and simultaneously inhibited microglial activation. Astrocytes, which covered the surface of the control organotypic cultures, revealed a peripheral distribution after early minocycline treatment. Thus, we further analyzed the effects of 100 µM minocycline on the viability and migration ability of dispersed primary glial cell cultures. We found that minocycline reduced cell viability, delayed wound closure in a scratch migration assay and increased connexin 43 protein levels in these cultures. Conclusions The administration of high doses of minocycline was deleterious for motor neuron survival. In addition, it inhibited microglial activation and impaired glial viability and migration. These data suggest that especially high doses of minocycline might have undesired affects in treatment of spinal cord injury. Further experiments are required to determine the conditions for the safe clinical administration of minocycline in spinal cord injured patients. PMID:23967343

  17. The effect of duration of untreated psychosis and treatment delay on the outcomes of prolonged early intervention in psychotic disorders.

    Science.gov (United States)

    Albert, Nikolai; Melau, Marianne; Jensen, Heidi; Hastrup, Lene Halling; Hjorthøj, Carsten; Nordentoft, Merete

    2017-09-26

    The duration of untreated psychosis (DUP) has been shown to have an effect on outcome after first-episode psychosis. The premise of specialized early intervention (SEI) services is that intervention in the early years of illness can affect long-term outcomes. In this study, we investigate whether DUP affects treatment response after 5 years of SEI treatment compared to 2 years of SEI treatment. As part of a randomized controlled trial testing the effect of prolonged SEI treatment 400 participants diagnosed within the schizophrenia spectrum were recruited. For this specific study participants were dichotomized based on DUP, treatment delay, and time from first symptom until start of SEI treatment. The groups were analyzed with regard to treatment response on psychopathology, level of functioning, and cognitive functioning. The participants with a short DUP had a tendency to respond better to the prolonged treatment with regards to disorganized and negative dimension. For participants with short duration from first symptom until start of SEI treatment there was a significant difference on the negative dimension favoring the prolonged OPUS treatment. The finding of an effect of prolonged treatment for participants with a short total treatment delay could mean that prolonged SEI treatment is more beneficial than treatment as usual (TAU) so long as it is provided in the early years of illness and not just in the early years after diagnosis. THE EARLIER THE BETTER: The duration of untreated psychosis influences the long-term outcomes of treatment. Nikolai Albert, at the Copenhagen Mental Health Centre, and a team of Danish researchers have investigated the effects of a specialized early intervention program (OPUS) in 400 patients diagnosed with schizophrenia spectrum disorders and compared the effects of OPUS after two and five years. Their findings suggest that five years of specialized early intervention was most beneficial when the total duration from symptom start to

  18. [Glucocorticoid induced osteoporosis].

    Science.gov (United States)

    Anić, Branimir; Mayer, Miroslav

    2014-01-01

    Secondary osteoporosis most often develops due to glucocorticoid therapy. Glucocorticoids affect all stages of the bone remodeling cycle, its formation and resorption. Osteoblasts are primarily affected, decreasing their activity and enhancing apoptosis. Patients treated with glucocorticoids have lower bone mineral density and increased fracture risk. Glucocorticoid-induced osteoporosis can be prevented by administering the minimal effective dose of glucocorticoids, calcium and vitamin D supplementation or, if possible, by hormone replace- ment therapy. Moreover, appropriate physical activity should be encouraged. Patients who are at higher risk for low-energy fractures (for example post-menopausal women) have to be actively treated, usually with antiresorptive drugs among which bisphosphonates are currently the first line therapy.

  19. Glucocorticoid receptor modulators.

    Science.gov (United States)

    Meijer, Onno C; Koorneef, Lisa L; Kroon, Jan

    2018-06-01

    The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  20. Neural changes in extinction recall following prolonged exposure treatment for PTSD: A longitudinal fMRI study

    Directory of Open Access Journals (Sweden)

    Liat Helpman, PhD

    2016-01-01

    Conclusions: Prolonged exposure treatment appears to alter neural activation in PTSD patients during recall of fear extinction, and change in extinction recall (measured by SCR is associated with symptom reduction. We discuss results in the context of neural systems involved in response to affective stimuli.

  1. Tacrolimus in the treatment of myasthenia gravis in patients with an inadequate response to glucocorticoid therapy: randomized, double-blind, placebo-controlled study conducted in China.

    Science.gov (United States)

    Zhou, Lei; Liu, Weibin; Li, Wei; Li, Haifeng; Zhang, Xu; Shang, Huifang; Zhang, Xu; Bu, Bitao; Deng, Hui; Fang, Qi; Li, Jimei; Zhang, Hua; Song, Zhi; Ou, Changyi; Yan, Chuanzhu; Liu, Tao; Zhou, Hongyu; Bao, Jianhong; Lu, Jiahong; Shi, Huawei; Zhao, Chongbo

    2017-09-01

    To determine the efficacy of low-dose, immediate-release tacrolimus in patients with myasthenia gravis (MG) with inadequate response to glucocorticoid therapy in a randomized, double-blind, placebo-controlled study. Eligible patients had inadequate response to glucocorticoids (GCs) after ⩾6 weeks of treatment with prednisone ⩾0.75 mg/kg/day or 60-100 mg/day. Patients were randomized to receive 3 mg tacrolimus or placebo daily (orally) for 24 weeks. Concomitant glucocorticoids and pyridostigmine were allowed. Patients continued GC therapy from weeks 1-4; from week 5, the dose was decreased at the discretion of the investigator. The primary efficacy outcome measure was a reduction, relative to baseline, in quantitative myasthenia gravis (QMG) score assessed using a generalized linear model; supportive analyses used alternative models. Of 138 patients screened, 83 [tacrolimus ( n = 45); placebo ( n = 38)] were enrolled and treated. The change in adjusted mean QMG score from baseline to week 24 was -4.9 for tacrolimus and -3.3 for placebo (least squares mean difference: -1.7, 95% confidence interval: -3.5, -0.1; p = 0.067). A post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group (68.2%) versus the placebo group (44.7%; p = 0.044). Adverse event profiles were similar between treatment groups. Tacrolimus 3 mg treatment for patients with MG and inadequate response to GCs did not demonstrate a statistically significant improvement in the primary endpoint versus placebo over 24 weeks; however, a post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group versus the placebo group. This study was limited by the low number of patients, the absence of testing for acetylcholine receptor antibody and the absence of stratification by disease duration (which led to a disparity between the two groups). Clinical

  2. Effects of prolonged treatment with memantine in the MRL model of CNS lupus.

    Science.gov (United States)

    Marcinko, Katarina; Parsons, Tiffany; Lerch, Jason P; Sled, John G; Sakic, Boris

    2012-09-01

    Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease. A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE. Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups. Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.

  3. 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.M.J.

    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.

  4. Glucocorticoids and fetal programming part 2: Mechanisms.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

    The lifelong health of an individual is shaped during critical periods of development. The fetus is particularly susceptible to internal and external stimuli, many of which can alter developmental trajectories and subsequent susceptibility to disease. Glucocorticoids are critical in normal development of the fetus, as they are involved in the growth and maturation of many organ systems. The surge in fetal glucocorticoid levels that occurs in most mammalian species over the last few days of pregnancy is an important developmental switch leading to fundamental changes in gene regulation in many organs, including the brain. These changes are important for the transition to postnatal life. Exposure of the fetus to increased levels of glucocorticoids, resulting from maternal stress or treatment with synthetic glucocorticoids, can lead to long-term 'programming' of hypothalamic-pituitary-adrenal function and behaviours. Glucocorticoids act at multiple levels within the fetal brain. Growing evidence indicates that they can exert powerful effects on the epigenome, including on DNA methylation, histone acetylation and microRNA, to influence gene expression. Such influences probably represent a critical component of the 'programming' process, and might be partly responsible for the transgenerational effects of antenatal glucocorticoid exposure on neurologic, cardiovascular and metabolic function.

  5. Glucocorticoid treatment of brain tumor patients: changes of apparent diffusion coefficient values measured by MR diffusion imaging

    International Nuclear Information System (INIS)

    Minamikawa, Sosuke; Kono, Kinuko; Nakayama, Keiko; Yokote, Hiroyuki; Tashiro, Takahiko; Inoue, Yuichi; Nishio, Akimasa; Hara, Mitsuhiro

    2004-01-01

    Glucocorticoids (GCC) generally are administered to patients with brain tumors to relieve neurological symptoms by decreasing the water content in a peritumoral zone of edema. We hypothesized that diffusion imaging and apparent diffusion coefficient (ADC) values could detect subtle changes of water content in brain tumors and in peritumoral edema after GCC therapy. The study consisted of 13 patients with intra-axial brain tumor, and ADC was measured in the tumor, within peritumoral edema, and in normal white matter remote from the tumor before and after GCC therapy. ADC also was measured in normal white matter in four control patients with no intracranial disease who were treated with GCC for other indications. Conventional MR images showed no visually evident interval change in tumor size or the extent of peritumoral edema in any subject after GCC therapy, which nonetheless resulted in a decrease in mean ADC of 7.0% in tumors (P 0.05, not significant) and 5.8% in normal white matter (P<0.05). In patients with no intracranial disease, GCC therapy decreased mean ADC in white matter by 5.4% (P<0.05). ADC measurement can demonstrate subtle changes in the brain after GCC therapy that cannot be observed by conventional MR imaging. Measurement of ADC proved to be a sensitive means of assessing the effect of GCC therapy, even in the absence of visually discernible changes in conventional MR images. (orig.)

  6. New developments in the treatment of primary insomnia in elderly patients: focus on prolonged-release melatonin

    Directory of Open Access Journals (Sweden)

    Vigo DE

    2012-10-01

    Full Text Available Daniel P Cardinali, María F Vidal, Daniel E VigoDepartment of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, ArgentinaAbstract: A temporal relationship between the nocturnal rise in melatonin secretion and the increase in sleep propensity at the beginning of the night, coupled with the sleep-promoting effects of exogenous melatonin, indicate that melatonin is involved in the regulation of sleep. This action is attributed to the MT1 and MT2 melatonin receptors present in the hypothalamic suprachiasmatic nucleus and other brain areas. The sleep-promoting actions of melatonin, which are demonstrable in healthy humans, have been found to be useful in subjects suffering from circadian rhythm sleep disorders and in elderly patients, who had low nocturnal melatonin production and secretion. The effectiveness of melatonin in treating sleep disturbances in these patients is relevant because the sleep-promoting compounds that are usually prescribed, such as benzodiazepines and related drugs, have many adverse effects, such as next-day hangover, dependence, and impairment of memory. Melatonin has been used for improving sleep in patients with insomnia mainly because it does not cause any hangover or show any addictive potential. However, there is a lack of consistency concerning its therapeutic value (partly because of its short half-life and the small quantities of melatonin used. Thus, attention has been focused either on the development of more potent melatonin analogs with prolonged effects or on the design of slow-release melatonin preparations. A prolonged-release preparation of melatonin 2 mg (Circadin® has been approved for the treatment of primary insomnia in patients aged ≥55 years in the European Union. This prolonged-release preparation of melatonin had no effect on psychomotor functions, memory recall, or driving skills during the night or the next morning relative to placebo

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

    Science.gov (United States)

    Olsson, A; Oturai, D B; Sørensen, P S; Oturai, P S; Oturai, A B

    2015-10-01

    Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD. Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients. © The Author(s), 2015.

  8. Work-related limitations and return-to-work experiences in prolonged fatigue: workers' perspectives before and after vocational treatment.

    Science.gov (United States)

    Joosen, Margot C W; Frings-Dresen, Monique H W; Sluiter, Judith K

    2011-01-01

    To gain insight into fatigued workers' perspectives regarding work experience before and after receiving vocational rehabilitation (VR) treatments. A qualitative survey was conducted using semi-structured interviews with 21 fatigued workers who attended an outpatient multi-component VR treatment. Six months after treatment, work-related limitations and employed VR strategies at work before treatment were explored. Next, VR treatment experiences regarding return-to-work (RTW) were explored. Two researchers performed partially independent, qualitative analyses that revealed topics, discussed by the project team, and organised into domains, categories and sub-categories. Work-related limitations were: symptoms of prolonged fatigue, personal limitations (e.g. lack of self-reflection on individual capacity and limitations), interpersonal factors, activities and conditions at work and life/work imbalance. Before the treatment, VR strategies such as work adaptations, well-intentioned advice and support, and/or referral to psychological or physical care were employed. VR treatment experiences on RTW were: personal challenges (e.g. gained awareness and coping skills), improved activities during work, work adaptations and unresolved problems (e.g. remaining fatigue symptoms and sickness absence). New information about work experiences before and after multi-component VR treatments in workers with prolonged fatigue may help employers, occupational physicians and other caregivers to develop VR strategies that better meet individuals' needs.

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

    Directory of Open Access Journals (Sweden)

    Keith Bruce D

    2008-03-01

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

  10. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia

    OpenAIRE

    Arvind Chaturvedi; H H Dash

    2011-01-01

    Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and...

  11. Endoscopic stent suture fixation for prevention of esophageal stent migration during prolonged dilatation for achalasia treatment.

    Science.gov (United States)

    Rieder, E; Asari, R; Paireder, M; Lenglinger, J; Schoppmann, S F

    2017-04-01

    The aim of this study is to compare endoscopic stent suture fixation with endoscopic clip attachment or the use of partially covered stents (PCS) regarding their capability to prevent stent migration during prolonged dilatation in achalasia. Large-diameter self-expanding metal stents (30 mm × 80 mm) were placed across the gastroesophageal junction in 11 patients with achalasia. Stent removal was scheduled after 4 to 7 days. To prevent stent dislocation, endoscopic clip attachment, endoscopic stent suture fixation, or PCS were used. The Eckardt score was evaluated before and 6 months after prolonged dilatation. After endoscopic stent suture fixation, no (0/4) sutured stent migrated. When endoscopic clips were used, 80% (4/5) clipped stents migrated (p = 0.02). Of two PCS (n = 2), one migrated and one became embedded leading to difficult stent removal. Technical adverse events were not seen in endoscopic stent suture fixation but were significantly correlated with the use of clips or PCS (r = 0.828, p = 0.02). Overall, 72% of patients were in remission regarding their achalasia symptoms 6 months after prolonged dilatation. Endoscopic suture fixation of esophageal stents but not clip attachment appears to be the best method of preventing early migration of esophageal stents placed at difficult locations such as at the naive gastroesophageal junction. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. [Prolonged blockade of nervus ischiadicus in a system of complex treatment of patients, suffering complicated diabetic foot syndrome].

    Science.gov (United States)

    Shapoval, S D; Savon, I L; Sofilkanych, M M

    2015-03-01

    General principles of treatment in patients, suffering diabetic foot syndrome, are adduced. There was proved, that reconvalescence of the patients depends not only on quality of complex treatment, but from optimal choice of anesthesia method, its impact on postoperative period course. Application of prolonged blockade of n. ischiadicus gives possibility to perform operative intervention on the lower extremity in full volume, guarantees sufficient motor and sensory block, permits patients to reject from application of narcotic analgetics, to reduce the dose of strong nonnarcotic analgetics, the terms of transition of the wound process phase I into phase II, promotes early activization of patients postoperatively, constitutes alternative for other methods of anesthesiological support.

  13. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations

    DEFF Research Database (Denmark)

    Strehl, Cindy; Bijlsma, Johannes W J; de Wit, Maarten

    2016-01-01

    literature search, breakout groups critically reviewed the evidence on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycaemia/diabetes mellitus, cardiovascular diseases and infections) and presented their results to the other group members following a structured...

  14. Prophylactic pamidronate partially protects from glucocorticoid-induced bone loss in the mdx mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Yoon, Sung-Hee; Chen, Jinghan; Grynpas, Marc D; Mitchell, Jane

    2016-09-01

    Glucocorticoids are extensively used to treat patients with Duchenne muscular dystrophy because of their ability to delay muscle damage, prolong ambulation and extend life. However, use of glucocorticoids significantly increases bone loss, fragility and fractures. To determine if antiresorptive bisphosphonates could prevent the effects of glucocorticoids on bone quality, we used dystrophic mdx mice treated with the glucocorticoid prednisone during 8weeks of rapid bone growth from 5 to 13weeks of age and treated some mice with the bisphosphonate pamidronate during the first two weeks of prednisone administration. Prednisone reduced long bone growth, decreased cortical bone thickness and area and decreased the strength of the femurs. Pamidronate treatment protected mice from cortical bone loss but did not increase bone strength. The combination of prednisone and pamidronate inhibited remodeling of metaphyseal trabecular bone with large numbers of trabeculae containing remnants of calcified cartilage. Prednisone improved muscle strength in the mdx mice and decreased serum creatine kinase with evidence of improved muscle histology and these effects were maintained in mice treated with pamidronate. Copyright © 2016. Published by Elsevier Inc.

  15. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  16. Glucocorticoid-Induced Osteoporosis

    Science.gov (United States)

    ... nervosa Cigarette smoking Alcohol abuse Low calcium and vitamin D, by low dietary intake or poor absorption in your gut Sedentary (inactive) lifestyle or immobility Certain medications besides glucocorticoids, including the following: excess thyroid hormone replacement the blood thinner heparin some ...

  17. On the retinal toxicity of intraocular glucocorticoids.

    Science.gov (United States)

    Torriglia, Alicia; Valamanesh, Fatemeh; Behar-Cohen, Francine

    2010-12-15

    Corticosteroids are hormones involved in many physiological responses such as stress, immune modulation, protein catabolism and water homeostasis. The subfamily of glucocorticoids is used systemically in the treatment of inflammatory diseases or allergic reactions. In the eye, glucocorticoides are used to treat macular edema, inflammation and neovascularization. The most commonly used glucocorticoid is triamcinolone acetonide (TA). The pharmaceutical formulation of TA is not adapted for intravitreal administration but has been selected by ophthalmologists because its very low intraocular solubility provides sustained effect. Visual benefits of intraocular TA do not clearly correlate with morpho-anatomical improvements, suggesting potential toxicity. We therefore studied, non-common, but deleterious effects of glucocorticoids on the retina. We found that the intravitreal administration of TA is beneficial in the treatment of neovascularization because it triggers cell death of endothelial cells of neovessels by a caspase-independent mechanism. However, this treatment is toxic for the retina because it induces a non-apoptotic, caspase-independent cell death related to paraptosis, mostly in the retinal pigmented epithelium cells and the Müller cells. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. 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

  19. Glucocorticoid administration for Graves' hyperthyroidism treated by radioiodine. A questionnaire survey among members of the European Thyroid Association

    NARCIS (Netherlands)

    Lazarus, J. H.; Bartalena, L.; Marcocci, C.; Kahaly, G. J.; Krassas, G.; Wiersinga, W. M.; Baldeschi, L.; Boboridis, K.; Boschi, A.; Currò, N.; Daumerie, C.; Dickinson, A. J.; Eckstein, A.; Kendall-Taylor, P.; Lane, C. M.; Ludgate, M. E.; Mann, K.; Marinò, M.; Mourits, M. P.; Nardi, M.; Neoh, C.; Orgiazzi, J.; Pearce, S.; Perros, P.; Pinchera, A.; Pitz, S.; Salvi, M.; Sivelli, P.; Stahl, M.; von Arx, G.

    2010-01-01

    Background: Glucocorticoid prophylaxis is required in some instances after radioiodine (RAI) treatment for Graves' hyperthyroidism to prevent progression of Graves' orbitopathy (GO). However, no randomized clinical trial has been performed to ascertain the optimum glucocorticoid therapy. Aim and

  20. Hypersensitivity Reactions from Excipients in Systemic Glucocorticoid Formulations

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  1. Therapeutic evaluation of prolonged infusions of β-lactam antibiotics in the treatment and management of critically ill patients

    Directory of Open Access Journals (Sweden)

    Jorge S. Amador

    2017-04-01

    Full Text Available Context: Critically ill patients has a large number of pathophysiological changes product of commitment and organ systems. Therefore, knowledge of the pharmacological properties of antimicrobials is essential to choose the best treatment. In order to optimize the response of antibiotic therapy and these drugs, new strategies have been proposed dosage, the most used drug application of the model, called: Pharmacokinetics/Pharmacodynamics (PK/PD. In the case of β-lactam antibiotics, the PK/PD model is known as time-dependent on the Minimum Inhibitory Concentration (Time > MIC. For optimal concentrations in β-lactam antibiotics, prolonged or continuous infusions, thus exposing the drug on the pathogen is achieved in a longer optimal concentrations through are used. Aims: To evaluate the therapeutic response of β-lactam antibiotics in critically ill patients with prolonged infusions by applying the model PK/ PD. Methods: Prospective observational study (concurrent cohort, taking as a control non-concurrent historic cohort, conducted for a period of seven months in the intensive care unit of the Hospital Clínico San Borja Arriarán (HCSBA, Santiago, Chile. Results: It was found a significant difference in number of days of hospitalization in ICU for the group bolus versus infusion group (12.5 ± 5.4 vs. 18 ± 9.7 days, IC: 1.5-9.5; p = 0.009. Conclusions: This study suggests that there would be a therapeutic advantage in the use of prolonged infusion in ICU stay duration.

  2. Cushing’s Syndrome: All variants, detection, and treatment

    Science.gov (United States)

    Sharma, Susmeeta T.; Nieman, Lynnette K.

    2010-01-01

    Synopsis Cushing’s syndrome is caused by prolonged exposure to excess glucocorticoids. Diagnosis of Cushing’s syndrome involves a step-wise approach and establishing the cause can be challenging in some cases. Hypertension is present in about 80% of patients with Cushing’s syndrome and can lead to significant morbidity and mortality. Several pathogenic mechanisms have been proposed for glucocorticoid-induced hypertension including a functional mineralocorticoid excess state, up-regulation of the renin angiotensin system and deleterious effects of cortisol on the vasculature. Surgical excision of the cause of excess glucocorticoids remains the optimal treatment for Cushing’s syndrome. Anti-glucocorticoid and antihypertensive agents and steroidogenesis inhibitors can be used as adjunctive treatment modalities in preparation for surgery, and in cases where surgery is contraindicated or has not led to cure. PMID:21565673

  3. Cultural Adaptations of Prolonged Exposure Therapy for Treatment and Prevention of Posttraumatic Stress Disorder in African Americans

    Directory of Open Access Journals (Sweden)

    Monnica T. Williams

    2014-05-01

    Full Text Available Posttraumatic stress disorder (PTSD is a highly disabling disorder, afflicting African Americans at disproportionately higher rates than the general population. When receiving treatment, African Americans may feel differently towards a European American clinician due to cultural mistrust. Furthermore, racism and discrimination experienced before or during the traumatic event may compound posttrauma reactions, impacting the severity of symptoms. Failure to adapt treatment approaches to encompass cultural differences and racism-related traumas may decrease treatment success for African American clients. Cognitive behavioral treatment approaches are highly effective, and Prolonged Exposure (PE in particular has the most empirical support for the treatment of PTSD. This article discusses culturally-informed adaptations of PE that incorporates race-related trauma themes specific to the Black experience. These include adding more sessions at the front end to better establish rapport, asking directly about race-related themes during the assessment process, and deliberately bringing to the forefront race-related experiences and discrimination during treatment when indicated. Guidelines for assessment and the development of appropriate exposures are provided. Case examples are presented demonstrating adaptation of PE for a survivor of race-related trauma and for a woman who developed internalized racism following a sexual assault. Both individuals experienced improvement in their posttrauma reactions using culturally-informed adaptations to PE.

  4. The cost effectiveness of teriparatide as a first-line treatment for glucocorticoid-induced and postmenopausal osteoporosis patients in Sweden

    Directory of Open Access Journals (Sweden)

    Murphy Daniel R

    2012-10-01

    Full Text Available Abstract Background This paper presents the model and results to evaluate the use of teriparatide as a first-line treatment of severe postmenopausal osteoporosis (PMO and Glucocorticoid-induced osteoporosis (GIOP. The study’s objective was to determine if teriparatide is cost effective against oral bisphosphonates for two large and high risk cohorts. Methods A computer simulation model was created to model treatment, osteoporosis related fractures, and the remaining life of PMO and GIOP patients. Natural mortality and additional mortality from osteoporosis related fractures were included in the model. Costs for treatment with both teriparatide and oral bisphosphonates were included. Drug efficacy was modeled as a reduction to the relative fracture risk for subsequent osteoporosis related fractures. Patient health utilities associated with age, gender, and osteoporosis related fractures were included in the model. Patient costs and utilities were summarized and incremental cost-effectiveness ratios (ICERs for teriparatide versus oral bisphosphonates and teriparatide versus no treatment were estimated. For each of the PMO and GIOP populations, two cohorts differentiated by fracture history were simulated. The first contained patients with both a historical vertebral fracture and an incident vertebral fracture. The second contained patients with only an incident vertebral fracture. The PMO cohorts simulated had an initial Bone Mineral Density (BMD T-Score of −3.0. The GIOP cohorts simulated had an initial BMD T-Score of −2.5. Results The ICERs for teriparatide versus bisphosphonate use for the one and two fracture PMO cohorts were €36,995 per QALY and €19,371 per QALY. The ICERs for teriparatide versus bisphosphonate use for the one and two fracture GIOP cohorts were €20,826 per QALY and €15,155 per QALY, respectively. Conclusions The selection of teriparatide versus oral bisphosphonates as a first-line treatment for the high risk PMO

  5. Donor dopamine treatment limits pulmonary oedema and inflammation in lung allografts subjected to prolonged hypothermia

    NARCIS (Netherlands)

    Hanusch, Christine; Nowak, Kai; Toerlitz, Patrizia; Gill, Ishar S.; Song, Hui; Rafat, Neysan; Brinkkoetter, Paul T.; Leuvenink, Henri G.; Van Ackern, Klaus C.; Yard, Benito A.; Beck, Grietje C.

    2008-01-01

    Background. Endothelial barrier dysfunction severely compromises organ function after reperfusion. Because dopamine pretreatment improves hypothermia mediated barrier dysfunction, we tested the hypothesis that dopamine treatment of lung allografts positively affects tissue damage associated with

  6. Pathophysiology of Glucocorticoid Signaling.

    Science.gov (United States)

    Vitellius, Géraldine; Trabado, Séverine; Bouligand, Jérôme; Delemer, Brigitte; Lombès, Marc

    2018-06-01

    Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  7. Glucocorticoid receptor polymorphism in obesity and glucose homeostasis.

    Science.gov (United States)

    Majer-Łobodzińska, Agnieszka; Adamiec-Mroczek, Joanna

    2017-01-01

    Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level. BclI polymorphism is associated with increased abdominal obesity, hyperinsulinaemia and increased insulin resistance. Another polymorphism, ER22/23EK, in contrast to the others, is associated with relative resistance to glucocoricides actions and more beneficial metabolic profile-lower insulin resistance level, decreased lower cardiovascular risk and subseuent prolongation of life time. More research is still needed to understand the mechanisms behind these associations at the molecular level.

  8. HDL cholesterol response to GH replacement is associated with common cholesteryl ester transfer protein gene variation (-629C>A) and modified by glucocorticoid treatment

    NARCIS (Netherlands)

    Dullaart, Robin P. F.; van den Berg, Gerrit; van der Knaap, Aafke M.; Dijck-Brouwer, Janneke; Dallinga-Thie, Geesje M.; Zelissen, Peter M. J.; Sluiter, Wim J.; van Beek, André P.

    2010-01-01

    GH replacement lowers total cholesterol and low-density lipoprotein cholesterol (LDL-C) in GH-deficient adults, but effects on high-density lipoprotein (HDL) cholesterol (HDL-C) are variable. Both GH and glucocorticoids decrease cholesteryl ester transfer protein (CETP) activity, which is important

  9. 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.

  10. 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...... that in response to glucocorticoid administration, induced autophagy aids to maintain proliferation and prevent apoptosis of BMSCs. Thus, it is hypothesized that autophagy may be a novel target in the treatment or prevention of osteoporosis....

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

    Science.gov (United States)

    Starkman, Monica N

    2013-09-01

    This article reviews the neuropsychiatric presentations elicited by spontaneous hypercortisolism and exogenous supraphysiologic glucocorticoids. Patients with Cushing disease and syndrome develop a depressive syndrome: irritable and depressed mood, decreased libido, disrupted sleep and cognitive decrements. Exogenous short-term glucocorticoid administration may elicit a hypomanic syndrome with mood, sleep and cognitive disruptions. Treatment options are discussed. Brain imaging and neuropsychological studies indicate elevated cortisol and other glucocorticoids are especially deleterious to hippocampus and frontal lobe. The research findings also shed light on neuropsychiatric abnormalities in conditions that have substantial subgroups exhibiting elevated and dysregulated cortisol: aging, major depressive disorder and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Quantitative expression of osteopontin in nasal mucosa of patients with allergic rhinitis: effects of pollen exposure and nasal glucocorticoid treatment

    Directory of Open Access Journals (Sweden)

    O'Neil Serena E

    2010-11-01

    Full Text Available Abstract Background Osteopontin (OPN is a multifunctional cytokine that has been primarily investigated in Th1 diseases. Recently, it has also been implicated in Th2-mediated allergic diseases, such as asthma. The expression of OPN in allergic rhinitis (AR is currently unknown, as is the effect of intranasal glucocorticosteroids (GCs on that expression. Methods Subjects with AR were randomised to receive treatment with fluticasone propionate (FP (n = 12 or a placebo (n = 16 over the grass pollen season and nasal biopsies were taken prior to, and during the season. OPN expression in the nasal mucosa was examined with immunohistochemistry. Healthy non-AR controls (n = 5 were used as a comparator. Results OPN expression was detected in epithelial cells, subepithelial infiltrating/inflammatory cells and cells lining the vessels and glands of all subjects. Comparison of the pre- and peak-pollen season biopsy sections in placebo treated patients revealed no increase in OPN expression during the grass pollen season (5.7% vs 6.4%. Treatment with a local glucocorticosteroid did not alter the expression of OPN during pollen exposure (6.2% vs 6.7%. Conclusion OPN has been increasingly associated with the pathogenesis of various Th2-mediated diseases. However, our finding that the OPN expression in the nasal mucosa of AR patients is not significantly affected by allergen exposure and is comparable to that of the healthy controls, suggests that intracellular OPN is not directly involved in the pathogenesis of allergic rhinitis.

  13. Prolonged decrease of adipocyte size after rosiglitazone treatment in high- and low-fat-fed rats.

    Science.gov (United States)

    Johnson, Julia A; Trasino, Steven E; Ferrante, Anthony W; Vasselli, Joseph R

    2007-11-01

    The anti-diabetic thiazolidinediones (TZDs) stimulate adipocyte differentiation and decrease mean adipocyte size. However, whether these smaller, more insulin-sensitive adipocytes maintain their size after TZD therapy is discontinued has not been studied. Adult female Sprague-Dawley rats were fed a low-fat (10% fat) diet or, to elevate body weight (BW), a high-fat (HF) diet (45% fat) for 6 weeks. Rats were initially randomized to groups (n = 12) fed either low-fat or HF diets, with or without the TZD rosiglitazone (ROSI; 5 mg/kg per day), for 6 weeks. ROSI was then discontinued, and all animals were fed HF for another 6 weeks before sacrifice. Retroperitoneal (RP) adipose tissue morphology was determined from tissue collected by serial biopsies before and after 6 weeks of ROSI treatment and at sacrifice. Measures of BW and adiposity did not differ among groups 6 weeks after stopping ROSI treatment. However, during treatment, ROSI in both diets significantly decreased RP adipocyte size and increased RP DNA content, and these effects continued to be observed after discontinuing treatment. ROSI administration also decreased circulating insulin, leptin, and triglycerides and increased circulating adiponectin levels; however, these effects were reversed on stopping treatment. These results demonstrated that TZD-induced effects on adipocyte size and number were maintained after discontinuing treatment, even with consumption of an obesigenic diet. However, additional studies are needed to determine whether TZD-treated animals eventually achieve an adipocyte size similar to that of untreated animals at the expense of a higher BW.

  14. Changes in the radiation sensitivity of mouse skin during fractionated and prolonged treatments

    International Nuclear Information System (INIS)

    Ruifrok, A.C.C.; Mason, K.A.; Hunter, N.; Thames, H.D.

    1994-01-01

    Reactions of the skin of the right thigh of mice were used as an experimental model to test possible changes in the radiosensitivity of mouse skin, as represented by changes in the linear-quadratic (LQ) model parameters α and β, as a function of fractionation interval and overall treatment time. In the first series of experiments, variable numbers of 3-Gy fractions with intervals of 6, 24 or 48 h were applied, followed by top-up doses to increase the skin damage to a level that could be scored. The results showed that mouse skin is more sensitive to 3-Gy fractions applied with 48-h intervals than to 3-Gy fractions applied with 6- or 24-h intervals. In the second series of experiments we used single-dose or fractonated test treatments for previously unirradiated mice and mice treated with priming doses of 10, 20 or 30 Gy given 1-18 days before the test treatment. The sensitivity appeared to be higher after intervals of 14-18 days than after 1-10 days after priming treatments of 20 and 30 Gy. The increased sensitivity 18 days after 20 Gy was mainly the result of an increase in the β component of the LQ model; higher values of α were also determined. We conclude that the radiosensitivity of mouse skin is higher during a radiation-induced proliferative response. 28 refs., 3 figs., 7 tabs

  15. Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome.

    Science.gov (United States)

    Masha, A; Manieri, C; Dinatale, S; Bruno, G A; Ghigo, E; Martina, V

    2009-12-01

    Nitric oxide (NO) plays a wide spectrum of biological actions including a positive role in oocyte maturation and ovulation. Free radicals levels have been shown elevated in polycystic ovary syndrome (PCOS) and therefore would be responsible for quenching NO that, in turn, would play a role in determining oligo- or amenorrhea connoting PCOS. Eight patients with PCOS displaying oligo-amenorrhea from at least 1 yr underwent a combined treatment with N-acetylcysteine (NAC) (1200 mg/die) plus L-arginine (ARG) (1600 mg/die) for 6 months. Menstrual function, glucose and insulin levels, and, in turn, homeostasis model assessment (HOMA) index were monitored. Menstrual function was at some extent restored as indicated by the number of uterine bleedings under treatment (3.00, 0.18-5.83 vs 0.00, 0.00-0.83; p<0.02). Also, a well-defined biphasic pattern in the basal body temperature suggested ovulatory cycles. The HOMA index decreased under treatment (2.12, 1.46-4.42 vs 3.48, 1.62-5.95; p<0.05). In conclusion, this preliminary, open study suggests that prolonged treatment with NAC+ARG might restore gonadal function in PCOS. This effect seems associated to an improvement in insulin sensitivity.

  16. Prolonged utilization of proton pump inhibitors in patients with ischemic and valvular heart disease is associated with surgical treatments, weight loss and aggravates anemia.

    Science.gov (United States)

    Boban, Marko; Zulj, Marinko; Persic, Viktor; Medved, Igor; Zekanovic, Drazen; Vcev, Aleksandar

    2016-09-15

    Proton pump inhibitors (PPIs) are among the commonest drugs used nowadays. The aim of our study was to analyze prolonged utilization of proton pump inhibitors in medical therapy of patients with ischemic and valvular heart disease. Secondly, profile of utilization was scrutinized to patient characteristics and type of cardiovascular treatments. The study included consecutive patients scheduled for cardiovascular rehabilitation 2-6months after index cardiovascular treatment. Two hundred ninety-four patients (n=294/604; 48.7%) have been using proton pump inhibitor in their therapy after index cardiovascular treatment. Cardiovascular treatments were powerfully connected with utilization of PPIs; surgery 5.77 (95%-confidence intervals [CI]: 4.05-8.22; pvalvular heart disease utilized proton pump inhibitor in prolonged courses. Prolonged courses of PPIs were connected with existence and worsening of red blood count indexes, older age, lesser weight of patients and underutilization of cardioprotective drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Colorectal Transit and Volume During Treatment With Prolonged-release Oxycodone/Naloxone Versus Oxycodone Plus Macrogol 3350.

    Science.gov (United States)

    Poulsen, Jakob L; Mark, Esben B; Brock, Christina; Frøkjær, Jens B; Krogh, Klaus; Drewes, Asbjørn M

    2018-01-30

    Opioid-induced constipation (OIC) is the most common gastrointestinal (GI) side effect to opioid treatment. Opioid receptor antagonists against OIC have been introduced, but their efficacy has not been directly compared to conventional laxatives. Our aim was to compare symptoms and objective parameters of gut function in an experimental model of OIC during treatment with the opioid antagonist naloxone and oxycodone in prolonged-release (PR) formulation versus oxycodone plus macrogol 3350. In this randomized, double-blind, crossover trial 20 healthy men received a 5-day treatment of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Regional GI transit times and segmental colorectal transit were assessed with the Motilis 3D-Transit electromagnetic capsule system. Colorectal volumes were determined by MRI. OIC symptoms were assessed with validated questionnaires, along with stool frequency and consistency. Total colorectal volume did not change after 5 days' treatment with PR oxycodone/naloxone (941 vs 1036 mL; P = 0.091), but increased significantly after PR oxycodone plus macrogol treatment (912 vs 1123 mL; P transit times nor segmental colorectal transit differed between the treatments (all P > 0.05). The Patient Assessment of Constipation Symptom Questionnaire abdominal symptoms score was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (0.2 vs 3.2; P = 0.002). Stool frequency was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (4.2 vs 5.4; P = 0.035). PR oxycodone plus macrogol increases colorectal volume, but does not improve GI transit compared to PR oxycodone/naloxone. However, PR oxycodone/naloxone results in a lower abdominal symptom burden, despite higher stool frequency during macrogol treatment.

  18. High-dose radiation therapy alone for inoperable non-small cell lung cancer. Experience with prolonged overall treatment times

    International Nuclear Information System (INIS)

    Willers, H.; Wuerschmidt, F.; Buenemann, H.; Heilmann, H.P.

    1998-01-01

    The purpose of this study was to determine the impact of overall treatment time on long-term survival after high-dose radiation therapy alone for inoperable non-small cell lung cancer (NSCLC). Between 1978 and 1990, 229 patients with stage I-III disease and Karnofsky Performance Scores of 80-100 received a conventionally fractionated total dose of 70 Gy through a split-course technique. After a first treatment course of 40 or 50 Gy, a rest aging was performed and only patients without any contraindications, such as newly diagnosed distant metastases or serious deterioration of performance status, were given a second course. In 83% of patients this break lasted for 4-6 weeks. Overall treatment time ranged between 7 and 24 weeks (median 12 weeks). Median follow-up time was 6.6 years (range 4.0-9.3 years). Actuarial overall survival rates at 2 and 5 years were 28% and 7% respectively. Complete radiological tumor response was observed in 31% of patients, and was found to be the strongest positive predictor of survival with 2- and 5-year rates of 50% and 12% respectively compared with 17% and 4% for patients without complete response. Treatment duration was not found to be a significant prognostic factor in univariate or multivariate analysis. For overall treatment times of 7-11 weeks (n=50), 12 weeks (n=79) and >12 weeks (n=100), 5-year survival was 4%, 6%, and 8%, respectively (p=0.6). To conclude, in our experience and in contrast to other studies, prolonged overall treatment times in radiation therapy alone for inoperable NSCLC had no negative impact on long-term survival. It is hypothesized that accelerated tumor cell repopulation is absent in a significant number of these patients with the time-factor playing no apparent role for outcome of treatment. (orig.)

  19. Successful treatment of massive pulmonary embolism with prolonged catheter-directed thrombolysis.

    LENUS (Irish Health Repository)

    Kelly, Peter

    2012-02-03

    This is a case report of a young woman who presented with an extensive pulmonary embolism and echocardiographic evidence of right ventricular dysfunction. Although hemodynamically stable, the patient\\'s clinical condition failed to improve with standard heparin anticoagulation. Successful local catheter-directed thrombolysis was performed over an extended period of 48 h with regular monitoring of response to therapy by computed tomography-pulmonary angiography and echocardiography. To our knowledge, treatment of a pulmonary embolism by catheter-directed thrombolytic infusion over an extended period of 48 h has not previously been described.

  20. The Relationship between Posttraumatic and Depressive Symptoms during Prolonged Exposure with and without Cognitive Restructuring for the Treatment of Posttraumatic Stress Disorder

    Science.gov (United States)

    Aderka, Idan M.; Gillihan, Seth J.; McLean, Carmen P.; Foa, Edna B.

    2013-01-01

    Objective: In the present study, we examined the relationship between posttraumatic and depressive symptoms during prolonged exposure (PE) treatment with and without cognitive restructuring (CR) for the treatment of posttraumatic stress disorder (PTSD). Method: Female assault survivors (N = 153) with PTSD were randomized to either PE alone or PE…

  1. Influence of chronic x-ray exposure on adrenal glucocorticoid function and adrenocorticocyte membrane potential

    International Nuclear Information System (INIS)

    Gorban', Je.M.; Topol'nikova, N.V.

    1998-01-01

    The peculiarities of adrenal glucocorticoid function and membrane potential (MP) of zona fasciculata adrenocorticocyte (ACC) in rats after chronic x-ray exposure was studied. The changes of adrenal glucocorticoid function caused by chronic x-ray exposure within a relatively small period of irradiation (1.5 months) are obscure and manifest themselves only at physiological load. With the prolongation of the period (8 and 15 months), more considerable inhibition of the adrenal glucocorticoid function and disturbances in the membrane mechanisms of ACC MP level regulation are revealed

  2. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Sheela Vyas

    2016-01-01

    Full Text Available Stress and stress hormones, glucocorticoids (GCs, exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer’s (AD and Parkinson’s (PD diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

  3. New approach for treatment of prolonged postoperative pain: APS Out-Patient Clinic.

    Science.gov (United States)

    Tiippana, Elina; Hamunen, Katri; Heiskanen, Tarja; Nieminen, Teija; Kalso, Eija; Kontinen, Vesa K

    2016-07-01

    Persistent postoperative pain (PPP) is a significant clinical problem. Several patient-related risk factors for PPP have been identified, including a previous chronic pain problem, young age, female gender and psychological vulnerability. Intra- and postoperative risk factors include surgical complications such as infections, haematoma, nerve damage and repeated surgery. As the length of hospital stay has been shortened, some patients may be discharged despite ongoing pain and insufficient analgesic medication. The challenge is to identify patients at high risk of developing PPP and to create a targeted care pathway to ensure effective and safe pain treatment especially in the subacute postoperative phase at home. This observational study describes the first two years of the Acute Pain Service Out-Patient Clinic (APS-OPC) at the Helsinki University Hospital. Patient characteristics, known risk factors, and details of treatment of PPP for the first 200 patients referred to our APS-OPC were retrospectively collected from the medical records. The APS-OPC clinic functions in close collaboration with the Multidisciplinary Pain Clinic (MPC), and the number of patients in need of physiotherapist, psychologist or psychiatrist counselling was recorded, as well as the number of patients referred to the MPC for further PPP management. Patients were referred to the APS-OPC from different surgical specialities, the two most common being thoracic and orthopaedic surgery. Seventy per cent of the patients (139/200) presented symptoms indicating neuropathic postsurgical pain. The patients had, on average, five risk factors for PPP. The median time from surgery to the first contact to the APS-OPC was two months, and the median duration of follow-up was 2.8 months (0-16 months). The median number of contacts with APS-OPC was 3 (range 1-14). Every fourth patient needed only one contact to the APS-OPC. Nineteen per cent of the patients had an appointment with the physiotherapist and 20

  4. Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination

    Directory of Open Access Journals (Sweden)

    Gemignani F

    2016-04-01

    Full Text Available Franco Gemignani,1 Andrea Melpignano,1,2 Giulia Milioli,1,2 Silvia Riccardi,1,2 Liborio Parrino1,2 1Neurology Unit, Department of Neurosciences, University of Parma, Parma, Italy; 2Sleep Disorders Center, Department of Neurosciences, University of Parma, Parma, Italy Abstract: Restless legs syndrome (RLS is a disorder of sensorimotor integration characterized by an urge to move the legs when at rest, especially at night or in the evening, which is relieved by movement. Sensory symptoms may be prominent, often exhibiting features consistent with neuropathic pain. Iron deficiency and genetic factors are implicated in RLS causation in most patients. The pathogenetic model of impaired circadian dopaminergic modulation of sensorimotor integration circuitry at the spinal level is fitting with the co-occurrence of movement disorders, sensory symptoms, and sleep disruption in RLS. Accordingly, levodopa and dopamine agonists are effective for RLS symptoms, which compensate for the impaired descending control by diencephalo-spinal dopa(minergic pathway. Dopamine agonists are usually indicated as the first-line therapy, but their use in long-term treatment is often complicated by augmentation and impulse control disorder, thus alpha-2-delta ligands also are now considered the first line of treatment. It has been recognized that endogenous opioid system is also involved in the mechanisms generating RLS, possibly through an impaired modulation of pain pathways. Opioids can be considered as an alternative therapy, particularly in patients with augmentation and/or refractory to other treatments. Recently introduced prolonged-release oxycodone–naloxone was efficacious for short-term treatment of patients with severe RLS inadequately controlled with previous treatment. It will be important to assess whether opioids, as well as other drugs, are especially effective in definite RLS subtypes such as the painful phenotype. Keywords: small fiber neuropathy

  5. Cardiomyocyte apoptosis vs autophagy with prolonged doxorubicin treatment: comparison with osteosarcoma cells.

    Science.gov (United States)

    Tacar, Oktay; Indumathy, Sivanjah; Tan, Mei Lin; Baindur-Hudson, Swati; Friedhuber, Anna M; Dass, Crispin R

    2015-02-01

    Doxorubicin (Dox) is a frontline chemotherapeutic against osteosarcoma (OS) that is plagued by side effects, particularly in the heart. The specific objective of this article is to investigate whether low-dose Dox treatment had pro-autophagic effects in cardiomyocytes as well as osteosarcoma cells. This study characterises apoptotic (Bax) and autophagic (Beclin-1) biomarker levels in human OS and cardiomyocyte cell lines as well as in various tissues when mice are exposed to low (1 mg/kg, thrice weekly) and high (3 mg/kg thrice weekly) dose Dox for a month. There was a decrease in Bax and increase in Beclin-1 in cardiac tissue in the high-dose group. Dox decreased Beclin-1 in the skin and liver, with no clear indication in the stomach, small intestine and testis. At low Dox doses of 10 and 100 nm in cardiomyocytes and OS cells, there is a pro-apoptotic effect, with a quicker response in the 100-nm condition, and a slower but steady increase of a pro-apoptotic response at the lower 10-nm dose. However, electron microscopy images revealed changes to human OS cells that resembled autophagy. Human prostate, breast and colorectal cells treated with 10-nm Dox showed ∼ 40% reduction in cell viability after 24 h. In culture, cells of both cardiomyocytes and OS revealed a predominant pro-apoptotic response at the expense of autophagy, although both seemed to be occurring in vivo. © 2014 Royal Pharmaceutical Society.

  6. An exploratory study: prolonged periods of binocular stimulation can provide an effective treatment for childhood amblyopia.

    Science.gov (United States)

    Knox, Pamela J; Simmers, Anita J; Gray, Lyle S; Cleary, Marie

    2012-02-21

    The purpose of the present study was to explore the potential for treating childhood amblyopia with a binocular stimulus designed to correlate the visual input from both eyes. Eight strabismic, two anisometropic, and four strabismic and anisometropic amblyopes (mean age, 8.5 ± 2.6 years) undertook a dichoptic perceptual learning task for five sessions (each lasting 1 hour) over the course of a week. The training paradigm involved a simple computer game, which required the subject to use both eyes to perform the task. A statistically significant improvement (t(₁₃) = 5.46; P = 0.0001) in the mean visual acuity (VA) of the amblyopic eye (AE) was demonstrated, from 0.51 ± 0.27 logMAR before training to 0.42 ± 0.28 logMAR after training with six subjects gaining 0.1 logMAR or more of improvement. Measurable stereofunction was established for the first time in three subjects with an overall significant mean improvement in stereoacuity after training (t(₁₃) =2.64; P = 0.02). The dichoptic-based perceptual learning therapy employed in the present study improved both the monocular VA of the AE and stereofunction, verifying the feasibility of a binocular approach in the treatment of childhood amblyopia.

  7. Glucocorticoids, chronic stress, and obesity

    NARCIS (Netherlands)

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

    2006-01-01

    Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a

  8. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Saurabh Mehandru

    2006-12-01

    Full Text Available During acute and early HIV-1 infection (AEI, up to 60% of CD4(+ T cells in the lamina propria of the lower gastrointestinal (GI tract are lost as early as 2-4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART is well established. However, the extent of immune reconstitution in the GI tract is unknown.Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1-7 y of uninterrupted therapy. Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%-60% depletion of lamina propria lymphocytes despite 1-7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO+ HLA-DR+, returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4+ T cell depletion despite therapy. Rare HIV-1 RNA-expressing cells were detected by in situ hybridization.Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically

  9. Current health and preferences for life-prolonging treatments: an application of prospect theory to end-of-life decision making.

    Science.gov (United States)

    Winter, Laraine; Parker, Barbara

    2007-10-01

    As a substantial body of research attests, the acceptability of life-prolonging treatment (e.g., tube feeding) tends to be greater among people in worse health than among healthier ones. Because a decision for or against a life-prolonging treatment represents a choice between two prospects-life (usually in poor health) and death-we propose a decision model, Prospect Theory, as a theoretical account of this phenomenon. Prospect Theory postulates that pairs of distant prospects are less distinguishable than pairs of closer ones. Thus, to healthy individuals, the prospects of death and life in poor health would both be remote, and therefore, the distinction between them, small. To less healthy individuals, however, the difference between the same pairs of prospects would appear greater, and therefore, life-prolonging treatment may be more acceptable. In a cross-sectional study of 304 community-dwelling people, aged 60 years and over in the Philadelphia area, USA, preferences for 4 life-prolonging treatments in 9 health scenarios were examined in relation to participants' current health, operationalized as number of deficits in physical functioning. As predicted, less healthy people expressed stronger preferences for all life-prolonging treatments compared with healthier ones, with differences greatest in the worse-health scenarios. Preferences also varied by health scenario, with any treatment preferred in the better health scenarios. Treatment preferences did not differ by type of treatment, depressed mood or any demographic characteristic except race, with African-Americans expressing stronger treatment preferences. Implications for advance care planning are discussed.

  10. Agitation during prolonged mechanical ventilation at a long-term acute care hospital: risk factors, treatments, and outcomes.

    Science.gov (United States)

    O'Connor, Heidi; Al-Qadheeb, Nada S; White, Alexander C; Thaker, Vishal; Devlin, John W

    2014-01-01

    The prevalence, risk factors, treatment practices, and outcomes of agitation in patients undergoing prolonged mechanical ventilation (PMV) in the long-term acute care hospital (LTACH) setting are not well understood. We compared agitation risk factors, management strategies, and outcomes between patients who developed agitation and those who did not, in LTACH patients undergoing PMV. Patients admitted to an LTACH for PMV over a 1-year period were categorized into agitated and nonagitated groups. The presence of agitation risk factors, management strategies, and relevant outcomes were extracted and compared between the 2 groups. A total of 80 patients were included, 41% (33) with agitation and 59% (47) without. Compared to the nonagitated group, the agitated group had a lower Sequential Organ Failure Assessment score (P agitated group, use of benzodiazepines (P = .16), opioids (P = .11), or psychiatric evaluation (P = .90) was not. Weaning success, duration of LTACH stay, and daily costs were similar. Agitation among the LTACH patients undergoing PMV is associated with greater delirium and use of antipsychotics and restraints but does not influence weaning success or LTACH stay. Strategies focused on agitation prevention and treatment in this population need to be developed and formally evaluated. © The Author(s) 2013.

  11. Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1 Mice

    Directory of Open Access Journals (Sweden)

    Gotkine Marc

    2013-01-01

    Full Text Available Objective. Previous research suggests that acetylcholinesterase (AChE may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101, which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model. Methods. ALS (G93A-SOD1 mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose. Results. mEN101 given at the presymptomatic (but not symptomatic stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters. Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.

  12. Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice

    International Nuclear Information System (INIS)

    Hillerdal, Victoria; Ramachandran, Mohanraj; Leja, Justyna; Essand, Magnus

    2014-01-01

    Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer. We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student’s t-test), proliferation (paired Student’s t-test), CD107a expression (paired Student’s t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves). PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice. Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer

  13. Glucocorticoid-Induced Avascular Bone Necrosis: Diagnosis and Management

    Science.gov (United States)

    Chan, KL; Mok, CC

    2012-01-01

    Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty. PMID:23115605

  14. Glucocorticoid-induced avascular bone necrosis: diagnosis and management.

    Science.gov (United States)

    Chan, K L; Mok, C C

    2012-01-01

    Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty.

  15. Serum proteomic changes after randomized prolonged erythropoietin treatment and/or endurance training: detection of novel biomarkers.

    Directory of Open Access Journals (Sweden)

    Britt Christensen

    Full Text Available Despite implementation of the biological passport to detect erythropoietin abuse, a need for additional biomarkers remains. We used a proteomic approach to identify novel serum biomarkers of prolonged erythropoiesis-stimulating agent (ESA exposure (Darbepoietin-α and/or aerobic training.Thirty-six healthy young males were randomly assigned to the following groups: Sedentary-placebo (n = 9, Sedentary-ESA (n = 9, Training-placebo (n = 10, or Training-ESA (n = 8. They were treated with placebo/Darbepoietin-α subcutaneously once/week for 10 weeks followed by a 3-week washout period. Training consisted of supervised biking 3/week for 13 weeks at the highest possible intensity. Serum was collected at baseline, week 3 (high dose Darbepoietin-α, week 10 (reduced dose Darbepoietin-α, and after a 3-week washout period.Serum proteins were separated according to charge and molecular mass (2D-gel electrophoresis. The identity of proteins from spots exhibiting altered intensity was determined by mass spectrometry.Six protein spots changed in response to Darbepoietin-α treatment. Comparing all 4 experimental groups, two protein spots (serotransferrin and haptoglobin/haptoglobin related protein showed a significant response to Darbepoietin-α treatment. The haptoglobin/haptoglobin related protein spot showed a significantly lower intensity in all subjects in the training-ESA group during the treatment period and increased during the washout period.An isoform of haptoglobin/haptoglobin related protein could be a new anti-doping marker and merits further research.ClinicalTrials.gov NCT01320449.

  16. Glucocorticoids and Preterm Hypoxic-Ischemic Brain Injury: The Good and the Bad

    Directory of Open Access Journals (Sweden)

    Laura Bennet

    2012-01-01

    Full Text Available Fetuses at risk of premature delivery are now routinely exposed to maternal treatment with synthetic glucocorticoids. In randomized clinical trials, these substantially reduce acute neonatal systemic morbidity, and mortality, after premature birth and reduce intraventricular hemorrhage. However, the overall neurodevelopmental impact is surprisingly unclear; worryingly, postnatal glucocorticoids are consistently associated with impaired brain development. We review the clinical and experimental evidence on how glucocorticoids may affect the developing brain and highlight the need for systematic research.

  17. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy

    DEFF Research Database (Denmark)

    Marcocci, Claudio; Watt, Torquil; Altea, Maria Antonietta

    2012-01-01

    The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO).......The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO)....

  18. Changes in quality and biochemical parameters in 'Idared' apples during prolonged shelf life and 1-MCP treatment.

    Science.gov (United States)

    Bizjak, Jan; Slatnar, Ana; Stampar, Franci; Veberic, Robert

    2012-12-01

    In this study, changes in quality and various biochemical parameters of 'Idared' apples during prolonged shelf life period after ultra-low oxygen (ULO) storage were investigated. Additionally, the impact of the postharvest application of 1-methylcyclopropene (1-MCP) on different parameters was evaluated. After the harvest, apples were stored in the ULO storage for 6 months and then exposed to room temperature. Fruit firmness, peel color, and changes in sugars, organic acids and phenolics were monitored during the 3 weeks of shelf life. Malic acid, sugars and firmness decreased at room temperature. However, the color of the apples remained unchanged. The level of citric and ascorbic acid remained constant. Levels of phenolics in the peel increased significantly, whereas remained constant in the pulp of apples. 1-MCP treatment resulted in higher amounts of fructose and glucose, malic acid and greater firmness of apples. However, 1-MCP did not influence the phenolic content, ascorbic acid or color. The results obtained indicate that the content of different health-promoting compounds of apples does not change dramatically at room temperature. At the same time these results suggest that 1-MCP could be useful for maintaining certain quality and biochemical parameters and might extend the shelf life of apples.

  19. Xenobiotics and the Glucocorticoid Receptor

    International Nuclear Information System (INIS)

    Gulliver, Linda S M

    2017-01-01

    Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

  20. Xenobiotics and the Glucocorticoid Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Gulliver, Linda S M, E-mail: linda.gulliver@otago.ac.nz

    2017-03-15

    Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

  1. The parents' ability to take care of their baby as a factor in decisions to withhold or withdraw life-prolonging treatment in two Dutch NICUs

    NARCIS (Netherlands)

    Moratti, Sofia

    In The Netherlands, it is openly acknowledged that the parents' ability to take care of their child plays a role in the decision-making process over administration of life-prolonging treatment to severely defective newborn babies. Unlike other aspects of such decision-making process up until the

  2. Study On Irradiated Vietnam Java Rambutan Fruit Which Was Postharvested Treatment To Prolong The Shelflife For Export Purposes

    International Nuclear Information System (INIS)

    Nguyen Thuy Khanh; Nguyen Thi Ly; Doan Thi The; Cao Van Chung; Nguyen Van Phong

    2014-01-01

    The research - Study on irradiated Vietnam Java rambutan fruit which was postharvested treatment to prolong the shelflife for export purposes - was conducted at Research and Development Center for Radiation Technology and Southern Horticultural Research Institute for 12 months. On the one hand, the theme was to study the effects of low-dose radiation in the range (200-500 Gy) combined with two types of packaging: carton boxes and carton boxes + PE perforated cover 0.5% of the area bags. After 13 days monitoring in 13 o C, RH= 85-90% the results showed that Java rambutan fruit which was packed in carton boxes combined PE bags then irradiated at 300 Gy dose could limit the browning pericarp, dehydration through the rate of browning, browning level and the percentage of weight loss. Irradiated ramtuban also remains their pulp quality when testing the soluble solids, the titratable acidity and the ascorbic acid content. Irradiation did not affect the cell structure of pericarp and pulp by investigating the total ion leakage. On the other hand, the topics also examined the influence of some postharvest handling and low-dose radiation on Java rambutan. The results showed that pre-irradiation processing: hot water treatment at 43 o C in 6 minute, dipping in cloruacalxi 0.4% + citric acid 0.5% solution in 3 minutes, packed in carton boxes + PE bags and irradiated at 300 Gy dose capable of maintaining the quality which extends the shelflife of Java rambutan more 4 days when kept under conditions of 13 o C, RH= 85-90%. (author)

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    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...

  4. Impact of glucocorticoid on neurogenesis

    Directory of Open Access Journals (Sweden)

    Haruki Odaka

    2017-01-01

    Full Text Available Neurogenesis is currently an area of great interest in neuroscience. It is closely linked to brain diseases, including mental disorders and neurodevelopmental disease. Both embryonic and adult neurogeneses are influenced by glucocorticoids secreted from the adrenal glands in response to a variety of stressors. Moreover, proliferation/differentiation of the neural stem/progenitor cells (NSPCs is affected by glucocorticoids through intracellular signaling pathways such as phosphoinositide 3-kinase (PI3K/Akt, hedgehog, and Wnt. Our review presents recent evidence of the impact of glucocorticoids on NSPC behaviors and the underlying molecular mechanisms; this provides important information for understanding the pathological role of glucocorticoids on neurogenesis-associated brain diseases.

  5. Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival.

    Science.gov (United States)

    Kadera, Brian E; Sunjaya, Dharma B; Isacoff, William H; Li, Luyi; Hines, O Joe; Tomlinson, James S; Dawson, David W; Rochefort, Matthew M; Donald, Graham W; Clerkin, Barbara M; Reber, Howard A; Donahue, Timothy R

    2014-02-01

    ), also correlated with OS. On multivariate Cox proportional hazard modeling of HP and prognostic biomarkers, only SMAD4 protein loss was significant (hazard ratio, 9.3; P=.004). Our approach to patients with LA/BR PDAC, which includes prolonged preoperative chemotherapy, is associated with a high incidence of LN-negative disease and excellent OS. After surgical resection, HP treatment response, perineural invasion, and SMAD4 status should help determine who should receive adjuvant therapy in this select subset of patients.

  6. Optimal glucocorticoid therapy.

    Science.gov (United States)

    Debono, Miguel; Ross, Richard J

    2011-01-01

    The rhythmic regulation of human physiology and behaviour is controlled by a central endogenous clock located in the suprachiasmatic nucleus. Most tissues have peripheral clocks that oscillate in time with this central clock. How the central time keeper controls peripheral clocks is not established, however there is evidence to suggest that the cortisol rhythm is one important secondary messenger. Loss of the endogenous cortisol rhythm is associated with sleep disturbance, depression, and metabolic abnormalities. In adrenal insufficiency, current glucocorticoid replacement regimens cannot replace the normal circadian rhythm of cortisol, and patients have an increased mortality and impaired quality of life. We propose that reproducing circadian cortisol levels may improve quality of life in patients with adrenal insufficiency and we have been investigating the impact of circadian hydrocortisone replacement. Using Chronocort, a modified release preparation of hydrocortisone, we have demonstrated that it is possible to simulate the overnight rise in cortisol release and, in preliminary studies in patients with congenital adrenal hyperplasia, control morning androgen levels. Future studies are now required to determine whether Chronocort can improve quality of life in patients with adrenal insufficiency. Copyright © 2011 S. Karger AG, Basel.

  7. Long-term safety, efficacy, and patient acceptability of teriparatide in the management of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    Dore RK

    2013-05-01

    Full Text Available Robin K DoreDavid Geffen School of Medicine, University of California, Los Angeles, CA, USAAbstract: Glucocorticoids are commonly prescribed medications to treat multiple diseases across many medical specialties. One of the most common yet largely unappreciated side effect of glucocorticoid use is increased risk of fracture. Many different therapies are indicated to prevent and treat this condition; many guidelines exist that suggest appropriate use of both glucocorticoids and the medications approved to prevent this common side effect of glucocorticoid therapy. Nevertheless, 30%–50% of patients on long-term glucocorticoid therapy sustain a fracture. Teriparatide, recombinant human parathyroid hormone (1–34, is a daily self-injectable therapy for 24 months approved for use in patients taking long-term glucocorticoids. Teriparatide has been shown to increase bone mineral density and reduce vertebral fracture risk in glucocorticoid-treated patients. Glucocorticoids have many adverse effects on bone that teriparatide has been shown to prevent or negate. Given the fact that preventive therapy for glucocorticoid-induced osteoporosis is often not prescribed, one wonders whether a daily self-injectable therapy for this condition would be prescribed by physicians and accepted by patients. This article reviews the epidemiology, pathophysiology, treatment, guidelines, and persistence data (when available for patients with glucocorticoid-induced osteoporosis treated with teriparatide.Keywords: glucocorticoid-induced osteoporosis, teriparatide, anabolic, PTH, parathyroid hormone

  8. Prolonged Treatment Duration is Required for Successful Helicobacter pylori Eradication with Proton Pump Inhibitor Triple Therapy in Canada

    Directory of Open Access Journals (Sweden)

    Carlo A Fallone

    2013-01-01

    Full Text Available BACKGROUND: Traditional seven-day proton pump inhibitor triple therapy for Helicobacter pylori eradication has recently shown disappointing results outside of Canada. Prolonging therapy may be associated with poorer compliance and, hence, may not have a better outcome in a real-world setting.

  9. The effect of shorter exposure versus prolonged exposure on treatment outcome in Tourette syndrome and chronic tic disorders - an open trial.

    Science.gov (United States)

    van de Griendt, Jolande M T M; van Dijk, Maarten K; Verdellen, Cara W J; Verbraak, Marc J P M

    2018-01-11

    Exposure and response prevention has shown to be an effective strategy and is considered a first-line intervention in the behavioural treatment of tic disorders. Prior research demonstrated significant tic reduction after 12 two hour sessions. In this open trial, the question is addressed whether, relative to these prolonged sessions, exposure sessions of shorter duration yield differential outcome for patients with tic disorders. A total of 29 patients diagnosed with Tourette syndrome (TS) or chronic tic disorder were treated with shorter exposure sessions (1 h), and these data were compared to the data from a study about prolonged exposure (2 h, n = 21). Outcome was measured by the Yale Global Tic Severity Scale (YGTSS). Results suggest that after taking the difference in illness duration between the two groups into account, the effectiveness of shorter exposure sessions is not inferior to that of prolonged exposure. Results suggest that treatment with shorter exposure might be more efficient and more patients can be reached. Future research is needed to gain more insight into the mechanisms underlying the efficacy of behavioural treatments for tics.

  10. Total brain, cortical and white matter volumes in children previously treated with glucocorticoids

    DEFF Research Database (Denmark)

    Holm, Sara K; Madsen, Kathrine S; Vestergaard, Martin

    2018-01-01

    BACKGROUND: Perinatal exposure to glucocorticoids and elevated endogenous glucocorticoid-levels during childhood can have detrimental effects on the developing brain. Here, we examined the impact of glucocorticoid-treatment during childhood on brain volumes. METHODS: Thirty children and adolescents...... with rheumatic or nephrotic disease previously treated with glucocorticoids and 30 controls matched on age, sex, and parent education underwent magnetic resonance imaging (MRI) of the brain. Total cortical grey and white matter, brain, and intracranial volume, and total cortical thickness and surface area were...... were mainly driven by the children with rheumatic disease. Total cortical thickness and cortical surface area did not significantly differ between groups. We found no significant associations between glucocorticoid-treatment variables and volumetric measures. CONCLUSION: Observed smaller total brain...

  11. The role of glucocorticoids in emotional memory reconsolidation.

    Science.gov (United States)

    Meir Drexler, Shira; Wolf, Oliver T

    2017-07-01

    Glucocorticoids are secreted following exposure to stressful events. Their modulating role on memory reconsolidation, a post-retrieval process of re-stabilization, has been investigated only recently, at times with conflicting results. The goal of this review is twofold. First, to establish the modulating role of glucocorticoids on memory reconsolidation. Second, to point the potential factors and confounds that might explain the seemingly paradoxical findings. Here we review recent pharmacological studies, conducted in rodents and humans, which suggest a critical role of glucocorticoids in this post-retrieval process. In particular, the activation of glucocorticoid receptors in the amygdala and hippocampus is suggested to be involved in emotional memories reconsolidation, pointing to a similarity between post-retrieval reconsolidation and initial memory consolidation. In addition, based on the general reconsolidation literature, we suggest several factors that might play a role in determining the direction and strength of the reconsolidation effect following glucocorticoids treatment: memory-related factors, manipulation-related factors, and individual differences. We conclude that only when taking these additional factors into account can the paradox be resolved. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Stress-induced enhancement of mouse amygdalar synaptic plasticity depends on glucocorticoid and ß-adrenergic activity.

    Directory of Open Access Journals (Sweden)

    Ratna Angela Sarabdjitsingh

    Full Text Available BACKGROUND: Glucocorticoid hormones, in interaction with noradrenaline, enable the consolidation of emotionally arousing and stressful experiences in rodents and humans. Such interaction is thought to occur at least partly in the basolateral nucleus of the amygdala (BLA which is crucially involved in emotional memory formation. Extensive evidence points to long-term synaptic potentiation (LTP as a mechanism contributing to memory formation. Here we determined in adolescent C57/Bl6 mice the effects of stress on LTP in the LA-BLA pathway and the specific roles of corticosteroid and β-adrenergic receptor activation in this process. PRINCIPAL FINDINGS: Exposure to 20 min of restraint stress (compared to control treatment prior to slice preparation enhanced subsequent LTP induction in vitro, without affecting baseline fEPSP responses. The role of glucocorticoid receptors, mineralocorticoid receptors and β2-adrenoceptors in the effects of stress was studied by treating mice with the antagonists mifepristone, spironolactone or propranolol respectively (or the corresponding vehicles prior to stress or control treatment. In undisturbed controls, mifepristone and propranolol administration in vivo did not influence LTP induced in vitro. By contrast, spironolactone caused a gradually attenuating form of LTP, both in unstressed and stressed mice. Mifepristone treatment prior to stress strongly reduced the ability to induce LTP in vitro. Propranolol normalized the stress-induced enhancement of LTP to control levels during the first 10 min after high frequency stimulation, after which synaptic responses further declined. CONCLUSIONS: Acute stress changes BLA electrical properties such that subsequent LTP induction is facilitated. Both β-adrenergic and glucocorticoid receptors are involved in the development of these changes. Mineralocorticoid receptors are important for the maintenance of LTP in the BLA, irrespective of stress-induced changes in the

  13. Add-on treatment with intermediate-acting insulin versus sliding-scale insulin for patients with type 2 diabetes or insulin resistance during cyclic glucocorticoid-containing antineoplastic chemotherapy: a randomized crossover study

    NARCIS (Netherlands)

    Gerards, M. C.; de Maar, J. S.; Steenbruggen, T. G.; Hoekstra, J. B. L.; Vriesendorp, T. M.; Gerdes, V. E. A.

    2016-01-01

    The aim of this study was to compare the effectiveness and safety of intermediate-acting insulin (IMI) titrated on body weight and glucocorticoid dose with that of short-acting sliding-scale insulin (SSI) in patients on recurrent high-dose glucocorticoid-containing chemotherapy. We enrolled 26

  14. Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: a meta-analysis.

    Science.gov (United States)

    Teo, Jocelyn; Liew, Yixin; Lee, Winnie; Kwa, Andrea Lay-Hoon

    2014-05-01

    The clinical advantages of prolonged (extended/continuous) infusion remain controversial. Previous studies and reviews have failed to show consistent clinical benefits of extending the infusion time. This meta-analysis sought to determine whether prolonged β-lactam infusions were associated with a reduction in mortality and improvement in clinical success. A search of PubMed, EMBASE and The Cochrane Library for randomised controlled trials (RCTs) and observational studies comparing prolonged infusion with intermittent bolus administration of the same antibiotic in hospitalised adult patients was conducted. Primary outcomes evaluated were mortality and clinical success. A total of 29 studies with 2206 patients (18 RCTs and 11 observational studies) were included in the meta-analysis. Compared with intermittent boluses, use of prolonged infusion appeared to be associated with a significant reduction in mortality [pooled relative risk (RR) = 0.66, 95% confidence interval (CI) 0.53-0.83] and improvement in clinical success (RR = 1.12, 95% CI 1.03-1.21). Statistically significant benefit was supported by non-randomised studies (mortality, RR = 0.57, 95% CI 0.43-0.76; clinical success, RR = 1.34, 95% CI 1.02-1.76) but not by RCTs (mortality, RR = 0.83, 95% CI 0.57-1.21; clinical success, RR = 1.05, 95% CI 0.99-1.12). The positive results from observational studies, especially in the face of increasing antibiotic resistance, serve to justify the imperative need to conduct a large-scale, well-designed, multicentre RCT involving critically ill patients infected with high minimum inhibitory concentration pathogens to clearly substantiate this benefit. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  15. 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 antibiotics and bronchiolytics. When the sedation was lifted on day 10, the patient was awake but quadriplegic. Blood samples revealed elevated muscle enzymes, electromyography showed myopathy, and a muscle biopsy was performed. Glucocorticoid-induced myopathy was suspected, GC treatment was tapered...

  16. Glucocorticoid Steroid and Alendronate Treatment Alleviates Dystrophic Phenotype with Enhanced Functional Glycosylation of α-Dystroglycan in Mouse Model of Limb-Girdle Muscular Dystrophy with FKRPP448L Mutation.

    Science.gov (United States)

    Wu, Bo; Shah, Sapana N; Lu, Peijuan; Richardson, Stephanie M; Bollinger, Lauren E; Blaeser, Anthony; Madden, Kyle L; Sun, Yubo; Luckie, Taylor M; Cox, Michael D; Sparks, Susan; Harper, Amy D; Lu, Qi Long

    2016-06-01

    Fukutin-related protein-muscular dystrophy is characterized by defects in glycosylation of α-dystroglycan with variable clinical phenotypes, most commonly as limb-girdle muscular dystrophy 2I. There is no effective therapy available. Glucocorticoid steroids have become the standard treatment for Duchenne and other muscular dystrophies with serious adverse effects, including excessive weight gain, immune suppression, and bone loss. Bisphosphonates have been used to treat Duchenne muscular dystrophy for prevention of osteoporosis. Herein, we evaluated prednisolone and alendronate for their therapeutic potential in the FKRPP448L-mutant mouse representing moderate limb-girdle muscular dystrophy 2I. Mice were treated with prednisolone, alendronate, and both in combination for up to 6 months. Prednisolone improved muscle pathology with significant reduction in muscle degeneration, but had no effect on serum creatine kinase levels and muscle strength. Alendronate treatment did not ameliorate muscle degeneration, but demonstrated a limited enhancement on muscle function test. Combined treatment of prednisolone and alendronate provided best improvement in muscle pathology with normalized fiber size distribution and significantly reduced serum creatine kinase levels, but had limited effect on muscle force generation. The use of alendronate significantly mitigated the bone loss. Prednisolone alone and in combination with alendronate enhance functionally glycosylated α-dystroglycan. These results, for the first time, demonstrate the efficacy and feasibility of this alliance treatment of the two drugs for fukutin-related protein-muscular dystrophy. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Instructions for producing a mouse model of glucocorticoid-induced osteoporosis

    DEFF Research Database (Denmark)

    Thiele, S.; Baschant, U.; Rauch, A.

    2014-01-01

    Glucocorticoids are effective drugs used for the treatment of inflammatory diseases such as rheumatoid arthritis or asthma. Furthermore, they regulate various physiological processes, including bone remodeling. However, long-term high- and even low-dose glucocorticoid use is associated...... with a compromised bone quality and an increased fracture risk. At the cellular level, glucocorticoids suppress bone formation and stimulate bone resorption, which leads to loss of bone mass. To investigate the underlying mechanisms and new therapeutic strategies, the in vivo model for glucocorticoid-induced bone...... loss is widely used. This protocol outlines the common procedure that is currently used for the induction of bone loss in mice using glucocorticoids. It further provides useful hints and highlights possible pitfalls to take into account before starting an experiment....

  18. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. [The prevention and treatment of suppurative-inflammatory complications in the bronchopulmonary system during prolonged artificial ventilation].

    Science.gov (United States)

    Mozhaev, G A; Tikhonovskiĭ, I Iu

    1992-01-01

    The use of physical methods, namely low frequency magnetic field in critically ill patients under respiratory therapy made it possible to prevent and in case of their development to effectively treat pyoinflammatory bronchopulmonary complications that accompany prolonged controlled lung ventilation. The results obtained were due to the elimination of an unfavourable effect of controlled lung ventilation on natural resistance and immune response of the respiratory tract because of normalization of physicochemical properties of the tracheobronchial tree secretion, enhanced functional capacities of phagocytes, repaired bonds between cellular and humoral local immunity in the lungs.

  20. Prolonging the duration of masseter muscle reduction by adjusting the masticatory movements after the treatment of masseter muscle hypertrophy with botulinum toxin type a injection.

    Science.gov (United States)

    Wei, Jiao; Xu, Hua; Dong, Jiasheng; Li, Qingfeng; Dai, Chuanchang

    2015-01-01

    Botulinum toxin type A (BTX-A) is widely used for the clinical treatment of masseteric hypertrophy. Until now, few reports have discussed how to prolong the duration of its effectiveness. This study evaluated that purposely adjusting the masticatory movements is possible of postponing the masseter muscle rehypertrophy. Ninety-eight patients were randomly and equally divided into 2 groups, and 35 U BTX-A per side was injected into the masseters. The thickness and volume of the masticatory muscles were measured by ultrasound and computerized tomography, respectively. Patients in Group 1 were instructed to strengthen their masticatory effort during the denervated atrophic stage of the masseter (the interval was evaluated by real-time ultrasound monitoring), whereas patients in Group 2 were not given this instruction. When the masseter muscle began to recover, patients in both groups were instructed to reduce their chewing. The duration of the masseter muscle rehypertrophy was significantly prolonged in Group 1 patients. The thickness and the volume of the other masticatory muscles were significantly increased in Group 1 but were either slightly decreased or insignificantly different in Group 2. Purposely strengthening masticatory muscle movement during the denervated atrophic stage of the masseter can prolong the duration of masseter rehypertrophy.

  1. Pre-treatment Predictors of Dropout from Prolonged Exposure Therapy in Patients with Chronic Posttraumatic Stress Disorder and Comorbid Substance Use Disorders

    Science.gov (United States)

    Belleau, Emily L.; Chin, Eu Gene; Wanklyn, Sonya G.; Zambrano-Vazquez, Laura; Schumacher, Julie A.; Coffey, Scott F.

    2017-01-01

    Posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) are commonly co-occurring disorders associated with more adverse consequences than PTSD alone. Prolonged exposure therapy (PE) is one of the most efficacious treatments for PTSD. However, among individuals with PTSD-SUD, 35–62% of individuals drop out of trauma-focused exposure treatments. Thus, it is important to identify predictors of PTSD treatment dropout among substance abusers with PTSD in order to gain information about adapting treatment strategies to enhance retention and outcomes. The current study explored pre-treatment predictors of early termination from PE treatment in a sample of 85 individuals receiving concurrent treatment for PTSD and a SUD in a residential treatment facility as part of a randomized controlled trial. The results indicated that less education and more anxiety sensitivity uniquely predicted PE treatment dropout. Demographic variables, PTSD severity, SUD severity, mental health comorbidities, and emotion regulation difficulties did not predict treatment dropout. These results suggest that adding pre-treatment interventions that address anxiety sensitivity, and promote social adjustment and cognitive flexibility, could possibly improve PE retention rates in clients with high anxiety or low education. PMID:28147254

  2. Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

    Science.gov (United States)

    Jackson, Daniel J; Bacharier, Leonard B; Mauger, David T; Boehmer, Susan; Beigelman, Avraham; Chmiel, James F; Fitzpatrick, Anne M; Gaffin, Jonathan M; Morgan, Wayne J; Peters, Stephen P; Phipatanakul, Wanda; Sheehan, William J; Cabana, Michael D; Holguin, Fernando; Martinez, Fernando D; Pongracic, Jacqueline A; Baxi, Sachin N; Benson, Mindy; Blake, Kathryn; Covar, Ronina; Gentile, Deborah A; Israel, Elliot; Krishnan, Jerry A; Kumar, Harsha V; Lang, Jason E; Lazarus, Stephen C; Lima, John J; Long, Dayna; Ly, Ngoc; Marbin, Jyothi; Moy, James N; Myers, Ross E; Olin, J Tod; Raissy, Hengameh H; Robison, Rachel G; Ross, Kristie; Sorkness, Christine A; Lemanske, Robert F

    2018-03-08

    Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma

  3. Prolonged conservative treatment or 'early' surgery in sciatica caused by a lumbar disc herniation: rationale and design of a randomized trial [ISRCT 26872154

    Science.gov (United States)

    Peul, Wilco C; van Houwelingen, Hans C; van der Hout, Wilbert B; Brand, Ronald; Eekhof, Just AH; Tans, Joseph ThJ; Thomeer, Ralph TWM; Koes, Bart W

    2005-01-01

    Background The design of a randomized multicenter trial is presented on the effectiveness of a prolonged conservative treatment strategy compared with surgery in patients with persisting intense sciatica (lumbosacral radicular syndrome). Methods/design Patients presenting themselves to their general practitioner with disabling sciatica lasting less than twelve weeks are referred to the neurology outpatient department of one of the participating hospitals. After confirmation of the diagnosis and surgical indication MRI scanning is performed. If a distinct disc herniation is discerned which in addition covers the clinically expected site the patient is eligible for randomization. Depending on the outcome of the randomization scheme the patient will either be submitted to prolonged conservative care or surgery. Surgery will be carried out according to the guidelines and between six and twelve weeks after onset of complaints. The experimental therapy consists of a prolonged conservative treatment under supervision of the general practitioner, which may be followed by surgical intervention in case of persisting or progressive disability. The main primary outcome measure is the disease specific disability of daily functioning. Other primary outcome measures are perceived recovery and intensity of legpain. Secondary outcome measures encompass severity of complaints, quality of life, medical consumption, absenteeism, costs and preference. The main research question will be answered at 12 months after randomization. The total follow-up period covers two years. Discussion Evidence is lacking concerning the optimal treatment of lumbar disc induced sciatica. This pragmatic randomized trial, focusses on the 'timing' of intervention, and will contribute to the decision of the general practictioner and neurologist, regarding referral of patients for surgery. PMID:15707491

  4. Prolonged first-line PEG-asparaginase treatment in pediatric acute lymphoblastic leukemia in the NOPHO ALL2008 protocol-Pharmacokinetics and antibody formation

    DEFF Research Database (Denmark)

    Tram Henriksen, Louise; Gottschalk Højfeldt, Sofie; Schmiegelow, Kjeld

    2017-01-01

    BACKGROUND: As pegylated asparaginase is becoming the preferred first-line asparaginase preparation in the chemotherapy regimens of childhood acute lymphoblastic leukemia (ALL), there is a need to evaluate this treatment. METHODS: The aim of this study was to evaluate the pharmacokinetics...... of prolonged upfront biweekly PEG-asparaginase (where PEG is polyethylene glycol) treatment by measuring serum l-asparaginase activity and formation of anti-PEG-asparaginase antibodies. A total of 97 evaluable patients (1-17 years), diagnosed with ALL, and treated according to the NOPHO ALL2008 protocol (where...... NOPHO is Nordic Society of Paediatric Haematology and Oncology) were included. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar(®) ) 1,000 IU/m²/dose, at 2-week or 6-week intervals with a total of 30-week treatment (Clinical trials...

  5. A Comparison of Cognitive-Processing Therapy With Prolonged Exposure and a Waiting Condition for the Treatment of Chronic Posttraumatic Stress Disorder in Female Rape Victims

    Science.gov (United States)

    Resick, Patricia A.; Nishith, Pallavi; Weaver, Terri L.; Astin, Millie C.; Feuer, Catherine A.

    2010-01-01

    The purpose of this study was to compare cognitive-processing therapy (CPT) with prolonged exposure and a minimal attention condition (MA) for the treatment of posttraumatic stress disorder (PTSD) and depression. One hundred seventy-one female rape victims were randomized into 1 of the 3 conditions, and 121 completed treatment. Participants were assessed with the Clinician-Administered PTSD Scale, the PTSD Symptom Scale, the Structured Clinical Interview for DSM–IV, the Beck Depression Inventory, and the Trauma-Related Guilt Inventory. Independent assessments were made at pretreatment, posttreatment, and 3 and 9 months posttreatment. Analyses indicated that both treatments were highly efficacious and superior to MA. The 2 therapies had similar results except that CPT produced better scores on 2 of 4 guilt subscales. PMID:12182270

  6. General effect of endotoxin on glucocorticoid receptors in mammalian tissues

    International Nuclear Information System (INIS)

    Stith, R.D.; McCallum, R.E.

    1986-01-01

    Considering the ubiquitous nature of glucocorticoid actions and the fact that endotoxin inhibits glucocorticoid action in the liver, we proposed to examine whether endotoxin affected extrahepatic actions of glucocorticoids. Fasted C57BL/6J mice were injected intraperitoneally with endotoxin (LD50) at 0800 and were killed 6 h later. Control mice were injected with an equal volume of saline. 3 H-dexamethasone binding, measured by a new cytosol exchange assay utilizing molybdate plus dithiothreitol, in liver, kidney, skeletal muscle, spleen, lung, and heart tissue was significantly lower in treated than in control mice. The equilibrium dissociation constants were not significantly different, but the number of available binding sites in each tissue was reduced by endotoxin treatment. Phosphoenolpyruvate carboxykinase activity was significantly reduced in liver but not in kidney. Endotoxin treatment lowered glycogen content in liver but not in skeletal muscle. The reduction observed in the a form of liver glycogen synthase due to endotoxin was not seen in skeletal muscle glycogen synthase a. These data support the proposal that endotoxin or a mediator of its action inhibits systemic glucocorticoid action. The results also emphasize the central role of the liver in the metabolic disturbances of the endotoxin-treated mouse

  7. Postreactivation glucocorticoids impair recall of established fear memory.

    Science.gov (United States)

    Cai, Wen-Hui; Blundell, Jacqueline; Han, Jie; Greene, Robert W; Powell, Craig M

    2006-09-13

    Pavlovian fear conditioning provides one of the best rodent models of acquired anxiety disorders, including posttraumatic stress disorder. Injection of a variety of drugs after training in fear-conditioning paradigms can impair consolidation of fear memories. Indeed, early clinical trials suggest that immediate administration of such drugs after a traumatic event may decrease the risk of developing posttraumatic stress disorder in humans (Pitman et al., 2002; Vaiva et al., 2003). The use of such a treatment is limited by the difficulty of treating every patient at risk and by the difficulty in predicting which patients will experience chronic adverse consequences. Recent clinical trials suggest that administration of glucocorticoids may have a beneficial effect on established posttraumatic stress disorder (Aerni et al., 2004) and specific phobia (Soravia et al., 2006). Conversely, glucocorticoid administration after training is known to enhance memory consolidation (McGaugh and Roozendaal, 2002; Roozendaal, 2002). From a clinical perspective, enhancement of a fear memory or a reactivated fear memory would not be desirable. We report here that when glucocorticoids are administered immediately after reactivation of a contextual fear memory, subsequent recall is significantly diminished. Additional experiments support the interpretation that glucocorticoids not only decrease fear memory retrieval but, in addition, augment consolidation of fear memory extinction rather than decreasing reconsolidation. These findings provide a rodent model for a potential treatment of established acquired anxiety disorders in humans, as suggested by others (Aerni et al., 2004; Schelling et al., 2004), based on a mechanism of enhanced extinction.

  8. Glucocorticoids and hemopoietic stem cells

    International Nuclear Information System (INIS)

    Romashko, O.O.; Berin, G.I.

    1978-01-01

    Analyzing the data of home and foreign investigators the problems of the glucocorticoid effect on blood and bone marrow of experimental (including irradiated ones) animals are discussed. Considered are a character and mechanism of the adrenal cortex hormones effect on blood formation, as well as the effect of pharmacological doses of corticosteroids on CFU, their erythropoietic effect in physiological doses on a morphological picture of bone marrow after irradiation and subsequent introduction of hormones and the hormone effect on intensity of erythropoiesis recovery in irradiated mice. Presented are the experimental data on studying the effect of endogenic hypercorticoidism and a reduced level of endogenic corticosteroids on blood-forming stem cells in the irradiated mice and the data on the ACTH injection effect on CFU migration after irradiation. Evaluated are already available data and further investigations to ground advisability and conditions of using corticosteroids as well as determining rational therapeutic effects on secretion of endogenic glucocorticoids when treating blood system diseases

  9. Bone and glucocorticoids.

    Science.gov (United States)

    Briot, Karine

    2018-06-01

    Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the most frequent cause of osteoporosis in young people. Bone loss and fracture risk increase rapidly after the initiation of corticosteroid therapy and are proportional to dose and treatment duration. The increase in fracture risk is not fully assessed by bone mineral density measurement, as it is also related to impaired bone quality and increased risk of falls. Prevention should be considered in all patients beginning corticosteroid therapy, especially as the underlying inflammation in itself impairs bone quality. Bisphosphonates and teriparatide have shown efficacy in the treatment of corticosteroid-induced osteoporosis. Several national and international guidelines are available to improve management of corticosteroid-induced osteoporosis, which remains inadequate. Duration of anti-osteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics and on the progression of the underlying inflammation. Copyright © 2018. Published by Elsevier Masson SAS.

  10. Glucocorticoid receptor signaling in health and disease

    Science.gov (United States)

    Kadmiel, Mahita; Cidlowski, John A.

    2013-01-01

    Glucocorticoids are steroid hormones regulated in a circadian and stres-associated manner to maintain various metabolic and homeostatic functions that are necessary for life. Synthetic glucocorticoids are widely prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD), and inflammatory disorders of the eye. Research in the last few years has begun to unravel the profound complexity of glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies. Glucocorticoids signal through the glucocorticoid receptor, a member of the superfamily of nuclear receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review, we will provide an update on glucocorticoid receptor signaling and highlight the role of GR signaling in physiological and pathophysiological conditions in the major organ systems in the human body. PMID:23953592

  11. Learned Avoidance in the Male Syrian Hamster: Investigating the Outcome of a Glucocorticoid Antagonist on Reconsolidation

    Directory of Open Access Journals (Sweden)

    Erik Haugsnes

    2015-02-01

    Full Text Available In this experiment, we used our Conflict Alleyway Apparatus and a glucocorticoid antagonist, mifepristone, to investigate the role of glucocorticoids in the reconsolidation of learned avoidance in defeated male Syrian hamsters. Subjects were tested for memory deficits 48 hours and 96 hours after the drug/vehicle was administered. It were hypothesized that mifepristone administration would produce memory deficits when the defeat memory had been reactivated, and that this deficit would be present 48 hours and 96 hours after the administration. Prolonged deficits that are dependent upon memory reactivation would suggest that glucocorticoids play a role in reconsolidation of learned avoidance. Our results indicated a strong evidence for learned avoidance after defeat; however, we did not find any significant drug effect.

  12. Clinical Outcome with Oral Linezolid and Rifampin Following Recurrent Methicillin-Resistant Staphylococcus aureus Bacteremia Despite Prolonged Vancomycin Treatment

    Directory of Open Access Journals (Sweden)

    Jon-David Schwalm

    2004-01-01

    Full Text Available Drug-resistant Gram-positive bacteria, especially Staphylococcus aureus, are emerging as the predominant organisms involved in both nosocomial and community-acquired infections. Since the 1980s, vancomycin has been the first-line antibiotic used to treat methicillin-resistant S aureus. However, allergy and intolerance to vancomycin, the increasing number of vancomycin clinical failures and the existence of vancomycin intermediate-susceptible isolates of S aureus suggest that new antibiotics are needed. This paper reports the only known case of a successful clinical outcome with long term oral linezolid and rifampin therapy in the management of recurrent and persistent methicillin-resistant S aureus bacteremia with metastatic infections despite prolonged vancomycin use. More than two years since the initiation of linezolid and rifampin, the study patient has been clinically well with no evidence of adverse drug reactions including cytopenia and hepatic toxicities. Physicians must be aware of the novel developments in antibiotic therapy to treat drug-resistant bacterial infections.

  13. Complete Response after Treatment with Neoadjuvant Chemoradiation with Prolonged Chemotherapy for Locally Advanced, Unresectable Adenocarcinoma of the Pancreas

    Directory of Open Access Journals (Sweden)

    Tiffany A. Pompa

    2017-01-01

    Full Text Available Surgery is the only chance for cure in pancreatic ductal adenocarcinoma. In unresectable, locally advanced pancreatic cancer (LAPC, the National Comprehensive Cancer Network (NCCN suggests chemotherapy and consideration for radiation in cases of unresectable LAPC. Here we present a rare case of unresectable LAPC with a complete histopathological response after chemoradiation followed by surgical resection. A 54-year-old female presented to our clinic in December 2013 with complaints of abdominal pain and 30-pound weight loss. An MRI demonstrated a mass in the pancreatic body measuring 6.2×3.2 cm; biopsy revealed proven ductal adenocarcinoma. Due to splenic vein/artery and contiguous celiac artery encasement, she was deemed surgically unresectable. She was started on FOLFIRINOX therapy (three cycles, intensity modulated radiation to a dose of 54 Gy in 30 fractions concurrent with capecitabine, followed by FOLFIRI, and finally XELIRI. After 8 cycles of ongoing XELIRI completed in March 2015, restaging showed a remarkable decrease in tumor size, along with PET-CT revealing no FDG-avid uptake. She was reevaluated by surgery and taken for definitive resection. Histopathological evaluation demonstrated a complete R0 resection and no residual tumor. Based on this patient and literature review, this strategy demonstrates potential efficacy of neoadjuvant chemoradiation with prolonged chemotherapy, followed by surgery, which may improve outcomes in patients deemed previously unresectable.

  14. Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

    Directory of Open Access Journals (Sweden)

    Sabrina Paolino

    2017-08-01

    Full Text Available Morning symptoms of rheumatoid arthritis (RA are linked to circadian increase of night inflammation, supported by inadequate cortisol secretion in active disease. Therefore, exogenous glucocorticoid administration in RA is recommended by EULAR and ACR from the beginning of the diagnosis, since may partially act like a “replacement therapy”. In addition, the prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective when exogenous glucocorticoid administration is managed with a night-time-release formulation. Despite a considerably higher cost than conventional prednisone (immediate release, chronotherapy with night-time-release prednisone has been recognized a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic disease-modifying antirheumatic drugs (DMARDs. Interestingly, since different cell populations involved in the inflammatory process are particularly activated during the night (i.e. monocytes, macrophages, other therapeutical approaches used in RA, such as conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs should follow the same concepts of glucocorticoid chronotherapy. Therefore, bedtime methotrexate chronotherapy was found to better manage RA symptoms, and several available NSAIDs (i.e. indomethacin, aceclofenac, ketoprofen, flurbiprofen, lornoxicam have been recently modified in their formulation, in order to obtain more focused night action.

  15. Inhibition of glycogen synthase kinase-3β attenuates glucocorticoid-induced suppression of myogenic differentiation in vitro.

    Directory of Open Access Journals (Sweden)

    Zhenyu Ma

    Full Text Available Glucocorticoids are the only therapy that has been demonstrated to alter the progress of Duchenne muscular dystrophy (DMD, the most common muscular dystrophy in children. However, glucocorticoids disturb skeletal muscle metabolism and hamper myogenesis and muscle regeneration. The mechanisms involved in the glucocorticoid-mediated suppression of myogenic differentiation are not fully understood. Glycogen synthase kinase-3β (GSK-3β is considered to play a central role as a negative regulator in myogenic differentiation. Here, we showed that glucocorticoid treatment during the first 48 h in differentiation medium decreased the level of phosphorylated Ser9-GSK-3β, an inactive form of GSK-3β, suggesting that glucocorticoids affect GSK-3β activity. We then investigated whether GSK-3β inhibition could regulate glucocorticoid-mediated suppression of myogenic differentiation in vitro. Two methods were employed to inhibit GSK-3β: pharmacological inhibition with LiCl and GSK-3β gene knockdown. We found that both methods resulted in enhanced myotube formation and increased levels of muscle regulatory factors and muscle-specific protein expression. Importantly, GSK-3β inhibition attenuated glucocorticoid-induced suppression of myogenic differentiation. Collectively, these data suggest the involvement of GSK-3β in the glucocorticoid-mediated impairment of myogenic differentiation. Therefore, the inhibition of GSK-3β may be a strategy for preventing glucocorticoid-induced muscle degeneration.

  16. Work-related limitations and return-to-work experiences in prolonged fatigue: workers' perspectives before and after vocational treatment

    NARCIS (Netherlands)

    Joosen, Margot C. W.; Frings-Dresen, Monique H. W.; Sluiter, Judith K.

    2011-01-01

    To gain insight into fatigued workers' perspectives regarding work experience before and after receiving vocational rehabilitation (VR) treatments. A qualitative survey was conducted using semi-structured interviews with 21 fatigued workers who attended an outpatient multi-component VR treatment.

  17. 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

  18. Glucocorticoid induced osteopenia in cancellous bone of sheep: validation of large animal model for spine fusion and biomaterial research.

    Science.gov (United States)

    Ding, Ming; Cheng, Liming; Bollen, Peter; Schwarz, Peter; Overgaard, Søren

    2010-02-15

    Glucocorticoid with low calcium and phosphorus intake induces osteopenia in cancellous bone of sheep. To validate a large animal model for spine fusion and biomaterial research. A variety of ovariectomized animals has been used to study osteoporosis. Most experimental spine fusions were based on normal animals, and there is a great need for suitable large animal models with adequate bone size that closely resemble osteoporosis in humans. Eighteen female skeletal mature sheep were randomly allocated into 3 groups, 6 each. Group 1 (GC-1) received prednisolone (GC) treatment (0.60 mg/kg/day, 5 times weekly) for 7 months. Group 2 (GC-2) received the same treatment as GC-1 for 7 months followed by 3 months without treatment. Group 3 was left untreated and served as the controls. All sheep received restricted diet with low calcium and phosphorus during experiment. After killing the animals, cancellous bone specimens from the vertebra, femurs, and tibias were micro-CT scanned and tested mechanically. Serum biomarkers were determined. In lumbar vertebra, the GC treatment resulted in significant decrease of cancellous bone volume fraction and trabecular thickness, and bone strength. However, the microarchitecture and bone strength of GC-2 recovered to a similar level of the controls. A similar trend of microarchitectural changes was also observed in the distal femur and proximal tibia of both GC treated sheep. The bone formation marker serum-osteocalcin was largely reduced in GC-1 compared to the controls, but recovered with a rebound increase at month 10 in GC-2. The current investigation demonstrates that the changes in microarchitecture and mechanical properties were comparable with those observed in humans after long-term GC treatment. A prolonged GC treatment is needed for a long-term observation to keep osteopenic bone. This model resembles long-term glucocorticoid treated osteoporotic model, and is useful in preclinical studies.

  19. A case report: Familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Ram Nanik

    2012-12-01

    Full Text Available Abstract Background Familial glucocorticoid deficiency (FGD is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency in the presence of normal plasma renin and aldosterone level. Focal segmental glomerulosclerosis (FSGS is a form of glomerular disease associated with proteinuria and nephritic syndrome. This is the first case of familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis. Case presentation An eight month old boy presented with increased genital pigmentation. Initial investigation revealed that he was glucocorticoid deficient and was started on hydrocortisone and fludrocortisone with a diagnosis of primary adrenal insufficiency. Later fludrocortisone was withdrawn and he was diagnosed to have isolated glucocorticoid deficiency. He later developed focal segmental glomerulosclerosis for which he underwent renal transplantation at the age of five years. Now at the age of twelve years, this boy is doing well on hydrocortisone treatment. His two siblings and a first degree cousin also had isolated glucocorticoid deficiency. One of the above two siblings died due to renal failure secondary to focal segmental glomerulosclerosis. Conclusion Patients with familial glucocorticoid deficiency should be carefully followed for development of features of nephrotic syndrome.

  20. FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.

    Science.gov (United States)

    Malyukova, A; Brown, S; Papa, R; O'Brien, R; Giles, J; Trahair, T N; Dalla Pozza, L; Sutton, R; Liu, T; Haber, M; Norris, M D; Lock, R B; Sangfelt, O; Marshall, G M

    2013-04-01

    Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.

  1. 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

    2010-01-01

    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...... by glucocorticoid treatment and the changes in properties of cancellous bone were comparable with those observed in humans after long-term glucocorticoid treatment. However, the influence on cortical bone has not been thoroughly elucidated. This study aimed to investigate the influence of glucocorticoid on sheep...

  2. Severe, multimodal stress exposure induces PTSD-like characteristics in a mouse model of single prolonged stress.

    Science.gov (United States)

    Perrine, Shane A; Eagle, Andrew L; George, Sophie A; Mulo, Kostika; Kohler, Robert J; Gerard, Justin; Harutyunyan, Arman; Hool, Steven M; Susick, Laura L; Schneider, Brandy L; Ghoddoussi, Farhad; Galloway, Matthew P; Liberzon, Israel; Conti, Alana C

    2016-04-15

    Appropriate animal models of posttraumatic stress disorder (PTSD) are needed because human studies remain limited in their ability to probe the underlying neurobiology of PTSD. Although the single prolonged stress (SPS) model is an established rat model of PTSD, the development of a similarly-validated mouse model emphasizes the benefits and cross-species utility of rodent PTSD models and offers unique methodological advantages to that of the rat. Therefore, the aims of this study were to develop and describe a SPS model for mice and to provide data that support current mechanisms relevant to PTSD. The mouse single prolonged stress (mSPS) paradigm, involves exposing C57Bl/6 mice to a series of severe, multimodal stressors, including 2h restraint, 10 min group forced swim, exposure to soiled rat bedding scent, and exposure to ether until unconsciousness. Following a 7-day undisturbed period, mice were tested for cue-induced fear behavior, effects of paroxetine on cue-induced fear behavior, extinction retention of a previously extinguished fear memory, dexamethasone suppression of corticosterone (CORT) response, dorsal hippocampal glucocorticoid receptor protein and mRNA expression, and prefrontal cortex glutamate levels. Exposure to mSPS enhanced cue-induced fear, which was attenuated by oral paroxetine treatment. mSPS also disrupted extinction retention, enhanced suppression of stress-induced CORT response, increased mRNA expression of dorsal hippocampal glucocorticoid receptors and decreased prefrontal cortex glutamate levels. These data suggest that the mSPS model is a translationally-relevant model for future PTSD research with strong face, construct, and predictive validity. In summary, mSPS models characteristics relevant to PTSD and this severe, multimodal stress modifies fear learning in mice that coincides with changes in the hypothalamo-pituitary-adrenal (HPA) axis, brain glucocorticoid systems, and glutamatergic signaling in the prefrontal cortex

  3. Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System

    Directory of Open Access Journals (Sweden)

    Natalie G. Burford

    2017-10-01

    Full Text Available The collective of endocrine organs acting in homeostatic regulation—known as the hypothalamic-pituitary-adrenal (HPA axis—comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart.

  4. Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System.

    Science.gov (United States)

    Burford, Natalie G; Webster, Natalia A; Cruz-Topete, Diana

    2017-10-16

    The collective of endocrine organs acting in homeostatic regulation-known as the hypothalamic-pituitary-adrenal (HPA) axis-comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart.

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

    NARCIS (Netherlands)

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

    2010-01-01

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

  6. Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes

    DEFF Research Database (Denmark)

    Vestergaard, H; Bratholm, P; Christensen, N J

    2001-01-01

    decreased significantly after intensive insulin treatment. A close correlation was found between increments in glucose uptake during intensive treatment and decrements in skeletal muscle total GCR mRNA (r=0.95, Pmultiple regression analysis), and between glucose uptake and alpha/alpha 2 GCR m RNA...

  7. [Glucocorticoid therapy: what is the information sought by patients? Traffic analysis of the website cortisone-info.fr].

    Science.gov (United States)

    Poisson, J; Six, M; Morin, C; Fardet, L

    2013-05-01

    About 1% of the general population are receiving systemic glucocorticoids. The information about this treatment sought by patients is unknown. The website www.cortisone-info.fr aims to provide therapeutic information about glucocorticoids and glucocorticoid therapy. It was posted on January 16, 2012. The information available on the website is documented and based on the recent medical literature. The website is made of 43 pages divided into five main sections (generalities about glucocorticoids, adverse events, measures associated with glucocorticoid therapy, discontinuation of glucocorticoids and, situations requiring attention). The website traffic between February 1st, 2012 and January 4, 2013 was analyzed using Google Analytics. During the study period, the website was visited by 67,496 people (average number of visitors per day: 33 in February 2012, 326 in December 2012). The number of page views was 230,496 or an average of 3.5 pages per visitor. Of these 230,496 page views, 145,431 (63.1%) were related to adverse events and 37,722 (16.4%) were related to generalities about glucocorticoids (e.g., what is cortisone? For which disease? How does it work?). Information particularly sought by visitors was related to the diet to follow during glucocorticoid therapy (page accessed 11,946 times), data about what cortisone is (page accessed 11,829 times) and the effects of glucocorticoids on weight (page accessed 10,442 times). Knowledge of glucocorticoid-treated patients' expectations may help physicians to optimize information they give, thereby helping to reduce patients' concerns about glucocorticoids and to improve adherence to the treatment. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  8. SDF-1 improves wound healing ability of glucocorticoid-treated adipose tissue-derived mesenchymal stem cells.

    Science.gov (United States)

    Kato, Toshiki; Khanh, Vuong Cat; Sato, Kazutoshi; Takeuchi, Kosuke; Carolina, Erica; Yamashita, Toshiharu; Sugaya, Hisashi; Yoshioka, Tomokazu; Mishima, Hajime; Ohneda, Osamu

    2017-11-18

    Glucocorticoids cause the delayed wound healing by suppressing inflammation that is required for wound healing process. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) play an important role for wound healing by their cytokine productions including stromal derived factor 1 (SDF-1). However, it has not been clear how glucocorticoids affect the wound healing ability of AT-MSCs. In this study, we found that glucocorticoid downregulated SDF-1 expression in AT-MSCs. In addition, glucocorticoid-treated AT-MSCs induced less migration of inflammatory cells and impaired wound healing capacity compared with glucocorticoid-untreated AT-MSCs. Of note, prostaglandin E2 (PGE2) synthesis-related gene expression was downregulated by glucocorticoid and PGE2 treatment rescued not only SDF-1 expression in the presence of glucocorticoid but also their wound healing capacity in vivo. Furthermore, we found SDF-1-overexpressed AT-MSCs restored wound healing capacity even after treatment of glucocorticoid. Consistent with the results obtained from glucocorticoid-treated AT-MSCs, we found that AT-MSCs isolated from steroidal osteonecrosis donors (sAT-MSCs) who received chronic glucocorticoid therapy showed less SDF-1 expression and impaired wound healing capacity compared with traumatic osteonecrosis donor-derived AT-MSCs (nAT-MSCs). Moreover, the SDF-1 level was also reduced in plasma derived from steroidal osteonecrosis donors compared with traumatic osteonecrosis donors. These results provide the evidence that concomitant application of AT-MSCs with glucocorticoid shows impaired biological modulatory effects that induce impaired wound healing. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. 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

  10. Enzyme pretreatment of fats, oil and grease from restaurant waste to prolong septic soil treatment system effectiveness.

    Science.gov (United States)

    Dong, Younsuk; Safferman, Steven I; Ostahowski, Jeff; Herold, Tom; Panter, Ronald

    2017-01-02

    When a fast-food restaurant's wastewater containing fats, oil and grease (FOG) is discharged into a collection system, it builds up over time and clogs pipes. Similarly, when such wastewater flows into a septic soil treatment system, it adheres to the surface of inlet pipes, gravel/distribution media and soil, restricting the flow and eventually clogging the septic soil treatment system. In this study, an enzymatic pretreatment system was tested on wastewater from a fast-food restaurant to determine its effectiveness in preventing septic soil treatment system clogging. This system used aeration equipment, baffles and a one-time inoculum that excretes enzymes to reduce the molecular weight and number of double bonds associated with FOG. FOG containing triglycerides having lower molecular weights and fewer double bonds are less sticky. The enzymatic pretreatment system was found to cause these changes as verified by measuring the types of triglycerides (compounds in FOG) using liquid chromatography/mass spectrometry. A unique bench-scale septic soil treatment system (soil trench) was also used. Each contained six soil moisture sensors to enable the determination of moisture saturation trends among the five tested conditions: sanitary wastewater only, a combination of sanitary and kitchen wastewater, enzymatically pretreated sanitary and kitchen wastewater, kitchen wastewater, and enzymatically pretreated kitchen wastewater. For all influent types, a significant amount of FOG and other pollutants were removed, regardless of the initial concentrations. Moisture sensor readings showed differences among the tested conditions, indicating that septic soil treatment system clogging was delayed. Inspection of the influent pipe and gravel at the end of testing verified these differences as did the measurements of volatile solids.

  11. Post-Stress Combined Administration of Beta-Receptor and Glucocorticoid Antagonists as a Novel Preventive Treatment in an Animal Model of PTSD

    Science.gov (United States)

    2009-07-01

    reduced extinction of cue- conditioned fear. The temporal characteristics of the model must be amenable to testing acute drug treatment in the...that is sensitive to both enhanced and attenuated fear conditioning and extinction -Established a drug treatment regimen that is feasible in the...nonassociative theories of the UCS preexposure phenomenon: Implications for Pavlovian conditioning . Psychol Bull 86: 523-548 Stam R (2007) PTSD and stress

  12. Limitation of life-sustaining treatment in patients with prolonged admission to the ICU. Current situation in Spain as seen from the EPIPUSE Study.

    Science.gov (United States)

    Hernández-Tejedor, A; Martín Delgado, M C; Cabré Pericas, L; Algora Weber, A

    2015-10-01

    Limitation of life-sustaining treatment (LLST) is a recommended practice in certain circumstances. Limitation practices are varied, and their application differs from one center to another. The present study evaluates the current situation of LLST practices in patients with prolonged admission to the ICU who suffer worsening of their condition. A prospective, observational cohort study was carried out. Seventy-five Spanish ICUs. A total of 589 patients suffering 777 complications or adverse events with organ function impairment after day 7 of admission, during a three-month recruitment period. The timing of limitation, the subject proposing LLST, the degree of agreement within the team, the influence of LLST upon the doctor-patient-family relationship, and the way in which LLST is implemented. LLST was proposed in 34.3% of the patients presenting prolonged admission to the ICU with severe complications. The incidence was higher in patients with moderate to severe lung disease, cancer, immunosuppressive treatment or dependence for basic activities of daily living. LLST was finally implemented in 97% of the cases in which it was proposed. The decision within the medical team was unanimous in 87.9% of the cases. The doctor-patient-family relationship usually does not change or even improves in this situation. LLST in ICUs is usually carried out under unanimous decision of the medical team, is performed more frequently in patients with severe comorbidity, and usually does not have a negative impact upon the relationship with the patients and their families. Copyright © 2013 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

  13. ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments.

    Science.gov (United States)

    Hatakeyama, Shinji; Summermatter, Serge; Jourdain, Marie; Melly, Stefan; Minetti, Giulia C; Lach-Trifilieff, Estelle

    2016-01-01

    Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time

  14. Limited prolonged effects of rifaximin treatment on irritable bowel syndrome-related differences in the fecal microbiome and metabolome.

    Science.gov (United States)

    Zeber-Lubecka, Natalia; Kulecka, Maria; Ambrozkiewicz, Filip; Paziewska, Agnieszka; Goryca, Krzysztof; Karczmarski, Jakub; Rubel, Tymon; Wojtowicz, Wojciech; Mlynarz, Piotr; Marczak, Lukasz; Tomecki, Roman; Mikula, Michal; Ostrowski, Jerzy

    2016-09-02

    Irritable bowel syndrome (IBS) is a chronic functional disorder and its development may be linked, directly and indirectly, to intestinal dysbiosis. Here we investigated the interactions between IBS symptoms and the gut microbiome, including the relation to rifaximin (1200 mg daily; 11.2 g per a treatment). We recruited 72 patients, including 31 with IBS-D (diarrhea), 11 with IBS-C (constipation), and 30 with IBS-M (mixed constipation and diarrhea) and 30 healthy controls (HCs). Of them, 68%, 64%, and 53% patients with IBS-D, IBS-C, and IBS-M, respectively, achieved 10-12 week-term improvement after the rifaximin treatment. Stool samples were collected before and after the treatment, and fecal microbiotic profiles were analyzed by deep sequencing of 16S rRNA, while stool metabolic profiles were studied by hydrogen 1-nuclear magnetic resonance ((1)H-NMR) and gas chromatography-mass spectrometry (GC-MS). Of 26 identified phyla, only Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria were consistently found in all samples. Bacteroidetes was predominant in fecal samples from HCs and IBS-D and IBS-M subjects, whereas Firmicutes was predominant in samples from IBS-C subjects. Species richness, but not community diversity, differentiated all IBS patients from HCs. Metabolic fingerprinting, using NMR spectra, distinguished HCs from all IBS patients. Thirteen metabolites identified by GC-MS differed HCs and IBS patients. However, neither metagenomics nor metabolomics analyses identified significant differences between patients with and without improvement after treatment.

  15. Glucocorticoids as mediators of developmental programming effects.

    Science.gov (United States)

    Khulan, Batbayar; Drake, Amanda J

    2012-10-01

    Epidemiological evidence suggests that exposure to an adverse environment in early life is associated with an increased risk of cardio-metabolic and behavioral disorders in adulthood, a phenomenon termed 'early life programming'. One major hypothesis for early life programming is fetal glucocorticoid overexposure. In animal studies, prenatal glucocorticoid excess as a consequence of maternal stress or through exogenous administration to the mother or fetus is associated with programming effects on cardiovascular and metabolic systems and on the brain. These effects can be transmitted to subsequent generations. Studies in humans provide some evidence that prenatal glucocorticoid exposure may exert similar programming effects on glucose/insulin homeostasis, blood pressure and neurodevelopment. The mechanisms by which glucocorticoids mediate these effects are unclear but may include a role for epigenetic modifications. This review discusses the evidence for glucocorticoid programming in animal models and in humans. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Locomotor therapy with extended-release crystalline glucocorticoids

    Directory of Open Access Journals (Sweden)

    Vladimir Vasilyevich Badokin

    2013-01-01

    Full Text Available Topical glucocorticoid (GC therapy for locomotor diseases is an extremely important component of a comprehensive program to treat inflammatory and, to a lesser extent, degenerative diseases. It reduces the time of hospitalization by 5—10 days in this category of patients, has a prompt and potent anti-inflammatory effect, and shows predictable efficiency. This therapy shows good tolerability and high safety and prevents serious adverse reactions to GC treatment.

  17. Stress, glucocorticoids and memory: implications for treating fear-related disorders.

    Science.gov (United States)

    de Quervain, Dominique; Schwabe, Lars; Roozendaal, Benno

    2017-01-01

    Glucocorticoid stress hormones are crucially involved in modulating mnemonic processing of emotionally arousing experiences. They enhance the consolidation of new memories, including those that extinguish older memories, but impair the retrieval of information stored in long-term memory. As strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias, the memory-modulating properties of glucocorticoids have recently become of considerable translational interest. Clinical trials have provided the first evidence that glucocorticoid-based pharmacotherapies aimed at attenuating aversive memories might be helpful in the treatment of fear-related disorders. Here, we review important advances in the understanding of how glucocorticoids mediate stress effects on memory processes, and discuss the translational potential of these new conceptual insights.

  18. Arginase treatment prevents the recovery of canine lymphoma and osteosarcoma cells resistant to the toxic effects of prolonged arginine deprivation.

    Science.gov (United States)

    Wells, James W; Evans, Christopher H; Scott, Milcah C; Rütgen, Barbara C; O'Brien, Timothy D; Modiano, Jaime F; Cvetkovic, Goran; Tepic, Slobodan

    2013-01-01

    Rapidly growing tumor cells require a nutrient-rich environment in order to thrive, therefore, restricting access to certain key amino acids, such as arginine, often results in the death of malignant cells, which frequently display defective cell cycle check-point control. Healthy cells, by contrast, become quiescent and remain viable under arginine restriction, displaying full recovery upon return to arginine-rich conditions. The use of arginase therapy to restrict available arginine for selectively targeting malignant cells is currently under investigation in human clinical trials. However, the suitability of this approach for veterinary uses is unexplored. As a prelude to in vivo studies in canine malignancies, we examined the in vitro effects of arginine-deprivation on canine lymphoid and osteosarcoma cell lines. Two lymphoid and 2 osteosarcoma cell lines were unable to recover following 6 days of arginine deprivation, but all remaining cell lines displayed full recovery upon return to arginine-rich culture conditions. These remaining cell lines all proved susceptible to cell death following the addition of arginase to the cultures. The lymphoid lines were particularly sensitive to arginase, becoming unrecoverable after just 3 days of treatment. Two of the osteosarcoma lines were also susceptible over this time-frame; however the other 3 lines required 6-8 days of arginase treatment to prevent recovery. In contrast, adult progenitor cells from the bone marrow of a healthy dog were able to recover fully following 9 days of culture in arginase. Over 3 days in culture, arginase was more effective than asparaginase in inducing the death of lymphoid lines. These results strongly suggest that short-term arginase treatment warrants further investigation as a therapy for lymphoid malignancies and osteosarcomas in dogs.

  19. Arginase treatment prevents the recovery of canine lymphoma and osteosarcoma cells resistant to the toxic effects of prolonged arginine deprivation.

    Directory of Open Access Journals (Sweden)

    James W Wells

    Full Text Available Rapidly growing tumor cells require a nutrient-rich environment in order to thrive, therefore, restricting access to certain key amino acids, such as arginine, often results in the death of malignant cells, which frequently display defective cell cycle check-point control. Healthy cells, by contrast, become quiescent and remain viable under arginine restriction, displaying full recovery upon return to arginine-rich conditions. The use of arginase therapy to restrict available arginine for selectively targeting malignant cells is currently under investigation in human clinical trials. However, the suitability of this approach for veterinary uses is unexplored. As a prelude to in vivo studies in canine malignancies, we examined the in vitro effects of arginine-deprivation on canine lymphoid and osteosarcoma cell lines. Two lymphoid and 2 osteosarcoma cell lines were unable to recover following 6 days of arginine deprivation, but all remaining cell lines displayed full recovery upon return to arginine-rich culture conditions. These remaining cell lines all proved susceptible to cell death following the addition of arginase to the cultures. The lymphoid lines were particularly sensitive to arginase, becoming unrecoverable after just 3 days of treatment. Two of the osteosarcoma lines were also susceptible over this time-frame; however the other 3 lines required 6-8 days of arginase treatment to prevent recovery. In contrast, adult progenitor cells from the bone marrow of a healthy dog were able to recover fully following 9 days of culture in arginase. Over 3 days in culture, arginase was more effective than asparaginase in inducing the death of lymphoid lines. These results strongly suggest that short-term arginase treatment warrants further investigation as a therapy for lymphoid malignancies and osteosarcomas in dogs.

  20. Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era.

    Science.gov (United States)

    Riess, Jonathan W; Nagpal, Seema; Iv, Michael; Zeineh, Michael; Gubens, Matthew A; Ramchandran, Kavitha; Neal, Joel W; Wakelee, Heather A

    2014-05-01

    Leptomeningeal carcinomatosis (LM) is a severe complication of non-small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM. Patients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3. LM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007). In this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical remission in difficult-to-treat pemphigus vulgaris.

    Science.gov (United States)

    Behzad, M; Möbs, C; Kneisel, A; Möller, M; Hoyer, J; Hertl, M; Eming, R

    2012-04-01

    Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune bullous disorder which is characterized by blisters and erosions of the skin and mucous membranes. A frequently applied first-line therapy for PV consists of systemic corticosteroids (CS) combined with immunosuppressive agents. In refractory cases, novel therapeutic strategies such as immunoadsorption (IA) and the anti-CD20 antibody rituximab (Rtx) aim at directly interfering with pathogenic autoantibodies (auto-Abs). To investigate the long-term efficacy of IA in combination with Rtx in patients with difficult-to-treat PV, we assessed the clinical response to treatment by monitoring the Autoimmune Bullous Skin Disorder Intensity Score, IgG auto-Abs against desmoglein 1 and 3 (Dsg1 and Dsg3) and the dose of systemic CS. We retrospectively analysed clinical and serological parameters of 10 patients with difficult-to-treat PV who received IA at 4-week intervals, followed by Rtx either twice at 1000 mg or four times at 375mg m(-2) . During a 12-month follow-up period, CS were tapered according to the individual clinical status. Six months after the first IA treatment eight of 10 patients were in complete remission on therapy while one patient showed a partial response and one patient was unresponsive to the treatment. At 12 months, six of eight patients were in complete remission on therapy, one patient showed stable disease and one patient had relapsed. Overall, anti-Dsg3 IgG and anti-Dsg1 IgG auto-Abs correlated well with the clinical activity and systemic CS were tapered gradually. The present findings show that the combination of IA and Rtx induces rapid clinical remission and long-term control in difficult-to-treat pemphigus. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

  2. Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial.

    Science.gov (United States)

    Hartman, Linda; Rasch, Linda A; Klausch, Thomas; Bijlsma, Hans W J; Christensen, Robin; Smulders, Yvo M; Ralston, Stuart H; Buttgereit, Frank; Cutolo, Maurizio; Da Silva, Jose A P; Opris, Daniela; Rovenský, Jozef; Szamosi, Szilvia; Middelink, Leonie M; Lems, Willem F; Boers, Maarten

    2018-01-25

    Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA. The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of

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

    Directory of Open Access Journals (Sweden)

    Chengcheng Liu

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

  4. IL-7 treatment augments and prolongs sepsis-induced expansion of IL-10-producing B lymphocytes and myeloid-derived suppressor cells.

    Science.gov (United States)

    Kulkarni, Upasana; Herrmenau, Christoph; Win, Stephanie J; Bauer, Michael; Kamradt, Thomas

    2018-01-01

    Immunological dysregulation in sepsis is associated with often lethal secondary infections. Loss of effector cells and an expansion of immunoregulatory cell populations both contribute to sepsis-induced immunosuppression. The extent and duration of this immunosuppression are unknown. Interleukin 7 (IL-7) is important for the maintenance of lymphocytes and can accelerate the reconstitution of effector lymphocytes in sepsis. How IL-7 influences immunosuppressive cell populations is unknown. We have used the mouse model of peritoneal contamination and infection (PCI) to investigate the expansion of immunoregulatory cells as long-term sequelae of sepsis with or without IL-7 treatment. We analysed the frequencies and numbers of regulatory T cells (Tregs), double negative T cells, IL-10 producing B cells and myeloid-derived suppressor cells (MDSCs) for 3.5 months after sepsis induction. Sepsis induced an increase in IL-10+ B cells, which was enhanced and prolonged by IL-7 treatment. An increased frequency of MDSCs in the spleen was still detectable 3.5 months after sepsis induction and this was more pronounced in IL-7-treated mice. MDSCs from septic mice were more potent at suppressing T cell proliferation than MDSCs from control mice. Our data reveal that sepsis induces a long lasting increase in IL-10+ B cells and MDSCs. Late-onset IL-7 treatment augments this increase, which should be relevant for clinical interventions.

  5. Deposition of intranasal glucocorticoids--preliminary study.

    Science.gov (United States)

    Rapiejko, Piotr; Sosnowski, Tomasz R; Sova, Jarosław; Jurkiewicz, Dariusz

    2015-01-01

    Intranasal glucocorticoids are the treatment of choice in the therapy of rhinitis. The differences in efficiency of particular medications proven by therapeutic index may result from differences in composition of particular formulations as well as from diverse deposition in nasal cavities. Intranasal formulations of glucocorticoids differ in volume of a single dose in addition to variety in density, viscosity and dispenser nozzle structure. The aim of this report was to analyze the deposition of most often used intranasal glucocorticoids in the nasal cavity and assessment of the usefulness of a nose model from a 3D printer reflecting anatomical features of a concrete patient. Three newest and most often used in Poland intranasal glucocorticoids were chosen to analysis; mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF). Droplet size distribution obtained from the tested formulations was determined by use of a laser aerosol spectrometer Spraytec (Malvern Instruments, UK). The model of the nasal cavity was obtained using a 3D printer. The printout was based upon a tridimensional reconstruction of nasal cavity created on the basis of digital processing of computed tomography of paranasal sinuses. The deposition of examined medications was established by a method of visualization combined with image analysis using commercial substance which colored itself intensively under the influence of water being the dominant ingredient of all tested preparations. On the basis of obtained results regions of dominating deposition of droplets of intranasal medication on the wall and septum of the nasal cavity were compared. Droplet size of aerosol of tested intranasal medications typically lies within the range of 25-150 µm. All tested medications deposited mainly on the anterior part of inferior turbinate. FP preparation deposited also on the anterior part of the middle nasal turbinate, marginally embracing a fragment of the central part of this

  6. Treatment of hemodialysis vascular access rupture irresponsive to prolonged balloon tamponade: Retrospective evaluation of the effectiveness of N-butyl cyanoacrylate seal-off technique

    Energy Technology Data Exchange (ETDEWEB)

    Weng, Mei Jul; Liang, Huei Lung; Pan, Huay Ben [Dept. of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung (China); Chen, Matt Chiung Yu [Dept. of Radiology, Yuan' s General Hospital, Kaohsiung (China)

    2013-01-15

    The current study retrospectively evaluated whether the percutaneous N-butyl cyanoacrylate (NBCA) seal-off technique is an effective treatment for controlling the angioplasty-related ruptures, which are irresponsive to prolonged balloon tamponade, during interventions for failed or failing hemodialysis vascular accesses. We reviewed 1588 interventions performed during a 2-year period for dysfunction and/or failed hemodialysis vascular access sites in 1569 patients. For the angioplasty-related ruptures, which could not be controlled with repeated prolonged balloon tamponade, the rupture sites were sealed off with an injection of a glue mixture (NBCA and lipiodol), via a needle/needle sheath to the rupture site, under a sonographic guidance. Technical success rate, complications and clinical success rate were reported. The post-seal-off primary and secondary functional patency rates were calculated by a survival analysis with the Kaplan-Meier method. Twenty ruptures irresponsive to prolonged balloon tamponade occurred in 1588 interventions (1.3%). Two technical failures were noted; one was salvaged with a bailout stent-graft insertion and the other was lost after access embolization. Eighteen accesses (90.0%) were salvaged with the seal-off technique; of them, 16 ruptures were completely sealed off, and two lesions were controlled as acute pseudoaneurysms. Acute pseudoaneurysms were corrected with stentgraft insertion in one patient, and access ligation in the other. The most significant complication during the follow-up was delayed pseudoaneurysm, which occurred in 43.8% (7 of 16) of the completely sealed off accesses. Delayed pseudoaneurysms were treated with surgical revision (n = 2), access ligation (n = 2) and observation (n = 3). During the follow-up, despite the presence of pseudoaneurysms (acute = 1, delayed = 7), a high clinical success rate of 94.4% (17 of 18) was achieved, and they were utilized for hemodialysis at the mean of 411.0 days. The post

  7. Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial)

    DEFF Research Database (Denmark)

    Hartman, Linda; Rasch, Linda A; Klausch, Thomas

    2018-01-01

    experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA. METHODS: The GLORIA study is a pragmatic multicentre, 2-year, randomised......, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2...... on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585258...

  8. Long-Term Haloperidol Treatment Prolongs QT Interval and Increases Expression of Sigma 1 and IP3 Receptors in Guinea Pig Hearts.

    Science.gov (United States)

    Stracina, Tibor; Slaninova, Iva; Polanska, Hana; Axmanova, Martina; Olejnickova, Veronika; Konecny, Petr; Masarik, Michal; Krizanova, Olga; Novakova, Marie

    2015-07-01

    Haloperidol is a neuroleptic drug used for a medication of various psychoses and deliria. Its administration is frequently accompanied by cardiovascular side effects, expressed as QT interval prolongation and occurrence of even lethal arrhythmias. Despite these side effects, haloperidol is still prescribed in Europe in clinical practice. Haloperidol binds to sigma receptors that are coupled with inositol 1,4,5-trisphosphate (IP3) receptors. Sigma receptors are expressed in various tissues, including heart muscle, and they modulate potassium channels. Together with IP3 receptors, sigma receptors are also involved in calcium handling in various tissues. Therefore, the present work aimed to study the effects of long-term haloperidol administration on the cardiac function. Haloperidol (2 mg/kg once a day) or vehiculum was administered by intraperitoneal injection to guinea pigs for 21 consecutive days. We measured the responsiveness of the hearts isolated from the haloperidol-treated animals to additional application of haloperidol. Expression of the sigma 1 receptor and IP3 receptors was studied by real time-PCR and immunohistochemical analyses. Haloperidol treatment caused the significant decrease in the relative heart rate and the prolongation of QT interval of the isolated hearts from the haloperidol-treated animals, compared to the hearts isolated from control animals. The expression of sigma 1 and IP3 type 1 and type 2 receptors was increased in both atria of the haloperidol-treated animals but not in ventricles. The modulation of sigma 1 and IP3 receptors may lead to altered calcium handling in cardiomyocytes and thus contribute to changed sensitivity of cardiac cells to arrhythmias.

  9. CHLORPYRIFOS DEVELOPMENTAL NEUROTOXICITY: INTERACTION WITH GLUCOCORTICOIDS IN PC12 CELLS

    Science.gov (United States)

    Slotkin, Theodore A.; Card, Jennifer; Seidler, Frederic J.

    2012-01-01

    Prenatal coexposures to glucocorticoids and organophosphate pesticides are widespread. Glucocorticoids are elevated by maternal stress and are commonly given in preterm labor; organophosphate exposures are virtually ubiquitous. We used PC12 cells undergoing neurodifferentiation in order to assess whether dexamethasone enhances the developmental neurotoxicity of chlorpyrifos, focusing on concentrations relevant to human exposures. By themselves, each agent reduced the number of cells and the combined exposure elicited a correspondingly greater effect than with either agent alone. There was no general cytotoxicity, as cell growth was actually enhanced, and again, the combined treatment evoked greater cellular hypertrophy than with the individual compounds. The effects on neurodifferentiation were more complex. Chlorpyrifos alone had a promotional effect on neuri to genesis whereas dexamethasone impaired it; combined treatment showed an overall impairment greater than that seen with dexamethasone alone. The effect of chlorpyrifos on differentiation into specific neurotransmitter phenotypes was shifted by dexamethasone. Either agent alone promoted differentiation into the dopaminergic phenotype at the expense of the cholinergic phenotype. However, in dexamethasone-primed cells, chlorpyrifos actually enhanced cholinergic neurodifferentiation instead of suppressing this phenotype. Our results indicate that developmental exposure to glucocorticoids, either in the context of stress or the therapy of preterm labor, could enhance the developmental neurotoxicity of organophosphates and potentially of other neurotoxicants, as well as producing neurobehavioral outcomes distinct from those seen with either individual agent. PMID:22796634

  10. The parents' ability to take care of their baby as a factor in decisions to withhold or withdraw life-prolonging treatment in two Dutch NICUs.

    Science.gov (United States)

    Moratti, Sofia

    2010-06-01

    In The Netherlands, it is openly acknowledged that the parents' ability to take care of their child plays a role in the decision-making process over administration of life-prolonging treatment to severely defective newborn babies. Unlike other aspects of such decision-making process up until the present time, the 'ability to take care' has not received specific attention in regulation or in empirical research. The present study is based on interviews with neonatologists in two Dutch NICUs concerning their definition of the ability to take care and its relevance in non-treatment decisions. All of the respondents think that the ability to take care consists of more than one factor. Most doctors mention the parents' emotional state, social network and cognitive abilities. Some doctors mention the presence of psychological conditions in the parents, their financial situation and physical condition. A few refer to the parents' experience and age, their chances to have another baby and their cultural background. Most doctors think the ability to take care has a secondary relevance in the decision-making process, while the primary concern is assessing the condition of the child. A substantial minority thinks the ability to take care does not play any role, while one doctor thinks it is a factor of primary importance. The study constitutes an important stepping-stone for future research in The Netherlands and elsewhere.

  11. Bone mineral density among systemic lupus erythematosus patient age 5-18 years with glucocorticoid treatment in child and adolescent outpatient clinic, Cipto Mangunkusumo Hospital, Jakarta

    Science.gov (United States)

    Indriyani, N.; Tridjaja, B.; Medise, B. E.; Kurniati, N.

    2017-08-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease affecting children; its morbidity and mortality rates are significant. One risk factor for morbidity is chronic corticosteroid use. The aim of this study is to determine the occurrence rate of low bone mineral density; discuss the characteristics, including cumulative and daily doses of corticosteroid, body mass index, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), calcium, and vitamin D intake; and assess bone metabolism laboratory parameters, including serum calcium, vitamin D, alkaline phosphatase (ALP), phosphorus, and cortisol among children with SLE receiving corticosteroids. This was a descriptive, cross-sectional study involving 16 children with SLE attending the child and adolescent outpatient clinic at Cipto Mangunkusumo Hospital in November-December 2016. Low bone mineral density occurred among 7/16 patients. The mean total bone mineral density was 0.885 ± 0.09 g/cm2. Children with SLE receiving corticosteroid had low calcium (8.69 ± 0.50 mg/dl), vitamin D (19.3 ± 5.4 mg/dl), ALP (79.50 [43.00-164.00] U/l), and morning cortisol level (1.20 [0.0-10.21] ug/dl), as well as calcium (587.58 ± 213.29 mg/d) and vitamin D (2.9 [0-31.8] mcg/d) intake. The occurrence of low bone mineral density was observed among children with SLE receiving corticosteroid treatment. Low bone mineral density tends to occur among patients with higher cumulative doses and longer duration of corticosteroid treatments.

  12. Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations.

    Science.gov (United States)

    McKeever, Tricia; Mortimer, Kevin; Wilson, Andrew; Walker, Samantha; Brightling, Christopher; Skeggs, Andrew; Pavord, Ian; Price, David; Duley, Lelia; Thomas, Mike; Bradshaw, Lucy; Higgins, Bernard; Haydock, Rebecca; Mitchell, Eleanor; Devereux, Graham; Harrison, Timothy

    2018-03-08

    Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma. We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma. A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group. In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology

  13. Circumvention of glucocorticoid resistance in childhood leukemia.

    Science.gov (United States)

    Haarman, E G; Kaspers, G J L; Pieters, R; Rottier, M M A; Veerman, A J P

    2008-09-01

    In this study, we determined if in vitro resistance to prednisolone and dexamethasone could be circumvented by cortivazol or methylprednisolone, or reversed by meta-iodobenzylguanidine in pediatric lymphoblastic and myeloid leukemia. As there were strong correlations between the LC50 values (drug concentration inducing 50% leukemic cell kill, LCK) of the different glucocorticoids and median prednisolone/methylprednisolone, prednisolone/dexamethasone and prednisolone/cortivazol LC50 ratios did not differ between the leukemia subtypes, we conclude that none of the glucocorticoids had preferential anti-leukemic activity. Meta-iodobenzylguanidine however, partially reversed glucocorticoid resistance in 19% of the lymphoblastic leukemia samples.

  14. Complete Restoration of Refractory Mandibular Osteoradionecrosis by Prolonged Treatment with a Pentoxifylline-Tocopherol-Clodronate Combination (PENTOCLO): A Phase II Trial

    International Nuclear Information System (INIS)

    Delanian, Sylvie; Chatel, Cecile; Porcher, Raphael; Depondt, Joel; Lefaix, Jean-Louis

    2011-01-01

    Purpose: Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Combined treatment with pentoxifylline and vitamin E reduces radiation-induced fibrosis and ORN with a good prognosis. We previously showed that the combination of pentoxifylline and vitamin E with clodronate (PENTOCLO) is useful in healing sternocostal and some mandibular ORN. Is PENTOCLO effective in ORN of poor prognosis? Methods: 54 eligible patients previously irradiated for head and neck cancer (among 72 treated) a mean 5 years previously received exteriorized refractory mandibular ORN for 1.4 ± 1.8 years, mainly after local surgery and hyperbaric oxygen had been ineffective. The mean length of exposed bone (D) was 17 ± 8 mm as primary endpoint, and the mean Subjective, Objective, Management, and Analytic evaluation of injury (SOMA) score was 16 ± 4. Between August 2000 and August 2008, all patients were given daily oral PENTOCLO: 800 mg pentoxifylline, 1,000 IU vitamin E, and 1,600 mg clodronate 5 days per week alternating with 20 mg prednisone and 1,000 mg ciprofloxacin 2 days per week. The duration of treatment was related to consolidated healing. Results: Prolonged treatment (16 ± 9 months) was safe and well tolerated. All patients improved, with an exponential progressive-(f[t] = a.exp(-b.t)-and significant (p 2 -42%, D 4 -62%, D 6 -77%, D 12 -92%, and D 18 -96%, combined with iterative spontaneous sequestrectomies in 36 patients. All patients experienced complete recovery in a median of 9 months. Clinical improvement was measured in terms of discontinuation of analgesics, new fracture, closed skin fistulae, and delayed radiologic improvement: SOMA 6 -64%, SOMA 12 -89%, and SOMA 30 -96%. Conclusion: Long-term PENTOCLO treatment is effective, safe, and curative for refractory ORN and induces mucosal and bone healing with significant symptom improvement. These findings will need to be confirmed in a randomized trial.

  15. Prolonged exposure therapy for the treatment of patients diagnosed with psychogenic non-epileptic seizures (PNES) and post-traumatic stress disorder (PTSD).

    Science.gov (United States)

    Myers, Lorna; Vaidya-Mathur, Urmi; Lancman, Marcelo

    2017-01-01

    Although there is general consensus that psychogenic non-epileptic seizures (PNES) are treated with psychotherapy, the effectiveness of most psychotherapeutic modalities remains understudied. In this treatment series of 16 patients dually diagnosed with PNES and post-traumatic stress disorder (PTSD), we evaluated the effect of prolonged exposure therapy (PE) on reduction of PNES. Secondary measures included Beck Depression Inventory (BDI-II) and Post-Traumatic Disorder Diagnostic Scale (PDS). Subjects diagnosed with video EEG-confirmed PNES and PTSD confirmed through neuropsychological testing and clinical interview were treated with traditional PE psychotherapy with certain modifications for the PNES. Treatment was conducted over the course of 12-15 weekly sessions. Seizure frequency was noted in each session by examining the patients' seizure logs, and mood and PTSD symptomatology was assessed at baseline and on the final session. Eighteen subjects enrolled, and 16 (88.8%) completed the course of treatment. Thirteen of the 16 (81.25%) therapy completers reported no seizures by their final PE session, and the other three reported a decline in seizure frequency (Z=-3.233, p=0.001). Mean scores on scales of depression (M=-13.56, SD=12.27; t (15)=-4.420, pPTSD symptoms (M=-17.1875, SD=13.01; t (15)=-5.281, pPTSD reduced the number of PNES and improved mood and post traumatic symptomatology. Follow-up revealed that gains made in seizure control on the last day of treatment were maintained over time. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  16. 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.

  17. 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.

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

    International Nuclear Information System (INIS)

    Sato, Shoko; Shirakawa, Hitoshi; Tomita, Shuhei; Tohkin, Masahiro; Gonzalez, Frank J.; Komai, Michio

    2013-01-01

    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

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

    Science.gov (United States)

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

    2015-05-01

    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 glycol twice daily for 3 days and were randomly assigned to a single intramuscular injection with sterile isotonic saline solution (n = 14) or dexamethasone-21-isonicotinate (n = 17). Metabolic blood variables were monitored for 6 days and adipose tissue variables for 3 days. β-Hydroxybutyrate (BHBA) concentrations in blood decreased in all cows during treatment, but were lower in glucocorticoid-treated cows. Cows treated with glucocorticoids had higher plasma glucose and insulin concentrations, whereas concentrations of non-esterified fatty acids, 3-methylhistidine and growth hormone were unaffected. mRNA expression of hormone-sensitive lipase, BHBA receptor and peroxisome proliferator-activated receptor type γ in adipose tissue was not affected. This shows that lipolytic effects do not appear to be important in ketotic cows when glucocorticoids are combined with PG. Plasma 3-methyl histidine concentrations were similar in both groups, suggesting that glucocorticoids did not increase muscle breakdown and that the greater rise in plasma glucose in glucocorticoid-treated cows may not be due to increased supply of glucogenic amino acids from muscle. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing’s syndrome: cohort study

    Science.gov (United States)

    Petersen, Irene; Nazareth, Irwin

    2012-01-01

    Objective To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing’s syndrome during treatment with glucocorticoids. Design Cohort study. Setting 424 UK general practices contributing to The Health Improvement Network database. Participants People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome (n=547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatrogenic Cushing’s syndrome (n=3231) and those not prescribed systemic glucocorticoids (n=3282). Main outcome measures Incidence of cardiovascular events within a year after diagnosis of iatrogenic Cushing’s syndrome or after a randomly selected date, and association between iatrogenic Cushing’s syndrome and risk of cardiovascular events. Results 417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n=177, heart failure n=101, ischaemic stroke n=63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing’s syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing’s syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4

  1. Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing's syndrome: cohort study.

    Science.gov (United States)

    Fardet, Laurence; Petersen, Irene; Nazareth, Irwin

    2012-07-30

    To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing's syndrome during treatment with glucocorticoids. Cohort study. 424 UK general practices contributing to The Health Improvement Network database. People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing's syndrome (n = 547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatrogenic Cushing's syndrome (n = 3231) and those not prescribed systemic glucocorticoids (n = 3282). Incidence of cardiovascular events within a year after diagnosis of iatrogenic Cushing's syndrome or after a randomly selected date, and association between iatrogenic Cushing's syndrome and risk of cardiovascular events. 417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n = 177, heart failure n = 101, ischaemic stroke n = 63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing's syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing's syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing's syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4.16 (2.98 to 5.82) when the group prescribed glucocorticoids and with

  2. 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.

  3. Extended ankle and foot fasciotomy as an enhancement to the surgical treatment of patients with prolonged ischemia of the lower extremities

    Directory of Open Access Journals (Sweden)

    Mišović Sidor

    2005-01-01

    Full Text Available Aim. To present the technique and efficacy of extended ankle and foot fasciotomy, as a surgical limb-salvage procedure associated with the successful revascularization after the gold interval. Method. A retrospective review of six patients at the age of 16−79 years (mean 39 in the period from 1996 to 2003, treated with the extended ankle and foot fasciotomy. There were four males undergoing the delayed treatment of war injuries to the lower extremity, and two females with atherosclerotic occlusive disease (a. illiacae dex and a. poplitealis dex.. The average ishemic time in the wounded patients was 22 hours (range, 14−30 hours, and ischemic time in occlusive disease (range, 48−72 hours. Clinical signs, indications, surgical access and the technique of extended ankle and foot fasciotomy was reported. Results. The obtained results were classified as early and late. There was no cases with lethal outcome. Incisional wounds closed 15 days after the intervention, using secondary suture or skin transplant sec. Thiersch. The satisfactory functional results were achieved in 4 of the patients, 1 had a small edema, while amputation was performed in 1 patient. Conclusion. In cases of prolonged foot ischemia with edema and paresthesia in the toes, extended ankle and foot fasciotomy should be performed as a surgical limb-salvage procedure.

  4. Prolonged Response and Restoration of Functional Independence with Bevacizumab plus Vinorelbine as Third-Line Treatment for Breast Cancer-Related Leptomeningeal Metastases

    Directory of Open Access Journals (Sweden)

    Emilie Le Rhun

    2015-02-01

    Full Text Available Background: Survival of patients with leptomeningeal metastases (LM and impaired functional status is limited to several months, and rarely does neurological function improve with treatment. Case Report: A 34-year-old female with hormone-negative and HER2-positive metastatic breast cancer was diagnosed with bulky radiographic LM 45 months after initial diagnosis. She was treated with intra-CSF trastuzumab followed by intra-CSF liposomal cytarabine; however, the cancer progressed 8 months after the diagnosis of LM. At the time of the third LM progression, the patient presented with a cauda equina syndrome and cerebellar impairment resulting in an inability to walk. She was treated with CNS-directed radiotherapy (lumbosacral and cerebellar and bevacizumab plus vinorelbine. Rapid functional improvement occurred, and the patient regained the ability to walk and independently manage her daily activities. Twelve months later, she presented with rapid progression of the LM resulting in death within several weeks. Conclusion: In radiographically defined bulky LM, the combination of systemic therapy and CNS-directed radiotherapy likely is more active than intra-CSF therapy only. In lieu of the rapid and significant improvement in neurological function combined with the prolonged response, bevacizumab alone or in combination with chemotherapy and CNS-directed radiotherapy may be considered in select patients with radiographically bulky breast cancer-related LM.

  5. Contribution of glucocorticoids and glucocorticoid receptors to the regulation of neurodegenerative processes.

    Science.gov (United States)

    Vyas, Sheela; Maatouk, Layal

    2013-12-01

    Isolation of glucocorticoids (GCs) from adrenal glands followed by synthesis led rapidly to their first clinical application, about 70 years ago, for treatment of rheumatoid arthritis. To this day GCs are used in diseases that have an inflammatory component. However, their use is carefully monitored because of harmful side effects. GCs are also synonymous with stress and adaptation. In CNS, GC binds and activates high affinity mineralocorticoid receptor (MR) and low affinity glucocorticoid receptor (GR). GR, whose expression is ubiquitous, is only activated when GC levels rise as during circadian peak and in response to stress. Numerous recent studies have yielded important and new insights on the mechanisms concerning pulsatile secretory pattern of GCs as well as various processes that tightly control their synthesis via hypothalamic-pituitary-adrenal (HPA) axis involving regulated release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) from hypothalamus and pituitary, respectively. GR modulates neuronal functions and viability through both genomic and non-genomic actions, and importantly its transcriptional regulatory activity is tightly locked with GC secretory pattern. There is increasing evidence pointing to involvement of GC-GR in neurodegenerative disorders. Patients with Alzheimer's or Parkinson's or Huntington's disease show chronically high cortisol levels suggesting changes occurring in controls of HPA axis. In experimental models of these diseases, chronic stress or GC treatment was found to exacerbate both the clinical symptoms and neurodegenerative processes. However, recent evidence also shows that GC-GR can exert neuroprotective effects. Thus, for any potential therapeutic strategies in these neurodegenerative diseases we need to understand the precise modifications both in HPA axis and in GR activity and find ways to harness their protective actions.

  6. Prolonged-release fampridine treatment improved subject-reported impact of multiple sclerosis: Item-level analysis of the MSIS-29.

    Science.gov (United States)

    Gasperini, Claudio; Hupperts, Raymond; Lycke, Jan; Short, Christine; McNeill, Manjit; Zhong, John; Mehta, Lahar R

    2016-11-15

    Prolonged-release (PR) fampridine is approved to treat walking impairment in persons with multiple sclerosis (MS); however, treatment benefits may extend beyond walking. MOBILE was a phase 2, 24-week, double-blind, placebo-controlled exploratory study to assess the impact of 10mg PR-fampridine twice daily versus placebo on several subject-assessed measures. This analysis evaluated the physical and psychological health outcomes of subjects with progressing or relapsing MS from individual items of the Multiple Sclerosis Impact Scale (MSIS-29). PR-fampridine treatment (n=68) resulted in greater improvements from baseline in the MSIS-29 physical (PHYS) and psychological (PSYCH) impact subscales, with differences of 89% and 148% in mean score reduction from baseline (n=64) at week 24 versus placebo, respectively. MSIS-29 item analysis showed that a higher percentage of PR-fampridine subjects had mean improvements in 16/20 PHYS and 6/9 PSYCH items versus placebo after 24weeks. Post hoc analysis of the 12-item Multiple Sclerosis Walking Scale (MSWS-12) improver population (≥8-point mean improvement) demonstrated differences in mean reductions from baseline of 97% and 111% in PR-fampridine MSIS-29 PHYS and PSYCH subscales versus the overall placebo group over 24weeks. A higher percentage of MSWS-12 improvers treated with PR-fampridine showed mean improvements in 20/20 PHYS and 8/9 PSYCH items versus placebo at 24weeks. In conclusion, PR-fampridine resulted in physical and psychological benefits versus placebo, sustained over 24weeks. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  7. Prolonged treatment with transcutaneous electrical nerve stimulation (TENS) modulates neuro-gastric motility and plasma levels of vasoactive intestinal peptide (VIP), motilin and interleukin-6 (IL-6) in systemic sclerosis.

    Science.gov (United States)

    McNearney, Terry A; Sallam, Hanaa S; Hunnicutt, Sonya E; Doshi, Dipti; Chen, Jiande D Z

    2013-01-01

    We assessed the effects of transcutaneous electrical nerve stimulation (TENS) on neurogastric functioning in scleroderma patients. Seventeen SSc patients underwent 30 min TENS treatment >10Hz at GI acupuncture points PC6 and ST36, once (acute TENS) and then after two weeks of TENS sessions for 30 min twice daily (prolonged TENS). Data collected at Visits 1 and 2 included gastric myoelectrical activity (GMA) by surface electrogastrography (EGG), heart rate variability (HRV) by surface electrocardiography (EKG), GI specific symptoms and health related SF-36 questionnaires. Plasma VIP, motilin and IL-6 levels were determined. Statistical analyses were performed by Student's t-test, Spearman Rank and p-values TENS, the percentages of normal slow waves and average slow wave coupling (especially channels 1, 2 reflecting gastric pacemaker and corpus regions) were significantly increased; 2. the percentage of normal slow waves was significantly correlated to sympathovagal balance; 3. Mean plasma VIP and motilin levels were significantly decreased after acute TENS, (vs. baseline), generally maintained in the prolonged TENS intervals. Compared to baseline, mean plasma IL-6 levels were significantly increased after acute TENS, but significantly decreased after prolonged TENS. 4. After prolonged TENS, the frequency of awakening due to abdominal pain and abdominal bloating were significantly and modestly decreased, respectively. In SSc patients, two weeks of daily TENS improved patient GMA scores, lowered plasma VIP, motilin and IL-6 levels and improved association between GMA and sympathovagal balance. This supports the therapeutic potential of prolonged TENS to enhance gastric myoelectrical functioning in SSc.

  8. Raised urinary glucocorticoid and adrenal androgen precursors in the urine of young hypertensive patients: possible evidence for partial glucocorticoid resistance

    Science.gov (United States)

    Shamim, W; Yousufuddin, M; Francis, D; Gualdiero, P; Honour, J; Anker, S; Coats, A

    2001-01-01

    OBJECTIVE—To evaluate urinary glucocorticoid excretion profiles in a cohort of recently diagnosed young hypertensive patients.
METHODS—After excluding patients with secondary causes, 60 individuals with premature hypertension were recruited (diagnosed by ambulatory blood pressure monitoring before the age of 36 years). In addition, 30 older hypertensive controls (age of onset > 36 years, "middle aged hypertensive controls"), and 30 normal controls (age matched to the young hypertensive group) were studied. All provided 24 hour urine collections for mass spectrometry for total cortisol metabolites and total androgen metabolites by gas chromatography.
RESULTS—Among male patients, those with premature hypertension had higher total urinary excretion of cortisol metabolites (mean (SD), 13 332 (6472) µg/day) than age matched normal controls (7270 (1788) µg/day; p = 0.00001) or middle aged hypertensive controls (8315 (3565) µg/day; p = 0.002). A similar increase was seen among the female patients, although the absolute concentrations were lower. There was no significant difference between middle aged hypertensive patients and normal controls. Urinary total androgen excretion profiles in female patients also showed an unusual increase in the premature hypertension group (2958 (1672) µg/day) compared with the other groups (middle aged hypertensive controls, 1373 (748) µg/day, p = 0.0003; normal controls, 1687 (636) µg/day, p = 0.002). In all subjects, serum sodium and creatinine concentrations were within the normal range; serum potassium concentrations were found to be low before the start of treatment.
CONCLUSIONS—Individuals presenting with premature hypertension have an abnormally high excretion of glucocorticoid metabolites in the urine. While the mechanism remains uncertain, these findings are compatible with partial resistance of the glucocorticoid receptors, with a compensatory increase in cortisol and androgen

  9. Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial

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    Francine Foss

    2016-03-01

    Full Text Available Abstract Background Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD. Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25 % (33/130, including 15 % with confirmed/unconfirmed complete response and a median duration of response of 28 months. Our objective was to further study the clinical benefits of romidepsin in patients that had the best response of SD. Methods Patients with PTCL relapsed/refractory to ≥1 prior therapy were treated with the approved dose of 14 mg/m2 romidepsin on days 1, 8, and 15 of six 28-day cycles; patients with SD or response after cycle 6 were allowed to continue on study until progression. By protocol amendment, patients treated for ≥12 cycles could receive maintenance dosing twice per cycle; after cycle 24, dosing could be further reduced to once per cycle in those who had received maintenance dosing for ≥6 months. Results Of the 32 patients (25 % with the best response of SD, 22 had SD for ≥90 days (SD90; cycle 4 response assessment. The longest SD was >3 years in a patient who received maintenance dosing of 14 mg/m2 on days 1 and 15 beginning in cycle 13. Patients with the best response of SD90 or partial response achieved similar overall and progression-free survival. Prolonged dosing of romidepsin was well tolerated. Conclusions We concluded that patients who achieve SD may consider continuing treatment because the clinical benefits of romidepsin may extend beyond objective responses. Trial registration NCT00426764

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

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    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

  11. The decreased influence of overall treatment time on the response of human breast tumor xenografts following prolongation of the potential doubling time (T{sub pot})

    Energy Technology Data Exchange (ETDEWEB)

    Sarkaria, Jann N; Fowler, John F; Lindstrom, Mary J; Jordan, V Craig; Mulcahy, R Timothy

    1995-02-15

    Purpose: Repopulation during fractionated radiotherapy has been postulated to result in a significant loss in local control in rapidly proliferating tumors. Clinical data suggest that accelerated fractionation schedules can overcome the influence of repopulation by limiting the overall treatment time. Unfortunately, accelerated therapy frequently leads to increased acute reactions, which may become dose limiting. An alternative to accelerated fractionation would be to decrease the rate of repopulation during therapy. To test the potential efficacy of this alternative, we examined the effect of reducing tumor proliferation rate on the response of MCF-7 human breast carcinoma xenografts treated with a short vs. a long course of fractionated therapy. To reduce the proliferation rate, we deprived nude mice transplanted with MCF-7 xenografts of the growth-stimulating hormone estradiol (E{sub 2}). We have previously reported that E{sub 2} deprivation increases the potential doubling time (T{sub pot}) for MCF-7 xenografts from a mean of 2.6 days to 5.3 days (p < 0.001). Methods and Materials: E{sub 2}-stimulated and E{sub 2}-deprived MCF-7 breast carcinoma xenografts were clamped hypoxically and irradiated with four fractions of 5 Gy each, using either a short (3-day) or long (9-day) treatment course. E{sub 2} stimulation was restored in all animals at the completion of irradiation. Radiation response was determined by regrowth time and regrowth delay of the irradiated tumors as compared to unirradiated controls. Results: Prolongation of therapy in rapidly proliferating, E{sub 2}-stimulated tumors (T{sub pot} {approx} 2.6 days) resulted in a significant decrease in regrowth time in two identical experiments. With results pooled for analysis, the regrowth times for the short and long treatments were 62 and 32 days, respectively (combined p < 0.001). The shorter regrowth times suggest that there was less overall tumor damage with the longer fractionated radiotherapy course

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

    DEFF Research Database (Denmark)

    Lunn, T H; Kehlet, H

    2013-01-01

    with systemic glucocorticoid. Pain was reduced with high-dose systemic and local glucocorticoid, but not with low-dose systemic glucocorticoid. Systemic inflammatory markers were reduced with low-dose and high-dose systemic glucocorticoid, and with local glucocorticoid. Functional recovery was improved...... 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 was performed. In conclusion, in addition to PONV reduction with low-dose systemic glucocorticoid, this review supports high-dose systemic glucocorticoid to ameliorate post-operative pain after hip and knee surgery. However, large-scale safety and dose-finding studies are warranted before final recommendations....

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

    NARCIS (Netherlands)

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

    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

  14. 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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  16. Consenso expandido do BCTRIMS para o tratamento da esclerose múltipla: II. As evidências para o uso de glicocorticóides e imunomoduladores The BCTRIMS expanded consensus on treatment of multiple sclerosis: II. The evidences for the use of glucocorticoids and immunomodulatory treatments

    Directory of Open Access Journals (Sweden)

    Marcos Aurélio Moreira

    2002-09-01

    Full Text Available A esclerose múltipla (EM é doença inflamatória em que mecanismos imunológicos desempenham importante papel na patogênese das lesões do sistema nervoso central. Drogas que agem em diferentes etapas destes mecanismos têm sido usadas em seu tratamento. O presente artigo analisa com base nas classes de evidências científicas e tipos de recomendações propostos pela comunidade científica, os mais importantes ensaios clínico-terapêuticos com os glicocorticóides e os imunomoduladores, incluindo a imunoglobulina humana endovenosa, no tratamento da esclerose múltipla. Ele tem por objetivo fornecer subsídios para a formulação do Consenso Expandido para o Tratamento da Esclerose Múltipla.Multiple sclerosis is an inflammatory disease in which immunological mechanisms play an important role in causing demyelinating lesions in the central nervous system. A number of drugs acting in different stages of these mechanisms have been tested for its treatment. This paper analyses the most important clinical trials with glucocorticoids and immunomodulatory treatments, including human immunoglobulin, using the classes of evidences and types of recommendations as have been defined and widely accepted by the international scientific community. It aims to provide sufficient information to support the BCTRIMS Expanded Consensus on Treatment of MS.

  17. Glucocorticoids and fetal programming part 1: Outcomes.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

    Fetal development is a critical period for shaping the lifelong health of an individual. However, the fetus is susceptible to internal and external stimuli that can lead to adverse long-term health consequences. Glucocorticoids are an important developmental switch, driving changes in gene regulation that are necessary for normal growth and maturation. The fetal hypothalamic-pituitary-adrenal (HPA) axis is particularly susceptible to long-term programming by glucocorticoids; these effects can persist throughout the life of an organism. Dysfunction of the HPA axis as a result of fetal programming has been associated with impaired brain growth, altered behaviour and increased susceptibility to chronic disease (such as metabolic and cardiovascular disease). Moreover, the effects of glucocorticoid-mediated programming are evident in subsequent generations, and transmission of these changes can occur through both maternal and paternal lineages.

  18. Assessment of faecal glucocorticoid metabolite excretion in captive female fishing cats (Prionailurus viverinus) in Thailand.

    Science.gov (United States)

    Khonmee, Jaruwan; Vorawattanatham, Narathip; Pinyopummin, Anuchai; Thitaram, Chatchote; Somgird, Chaleamchat; Punyapornwithaya, Veerasak; Brown, Janine L

    2016-01-01

    There is little information on the endocrinology of fishing cats (Prionailurus viverinus), an endangered species in Southeast Asia, especially that pertaining to adrenal function. This study characterized faecal glucocorticoid metabolites in female fishing cats housed at Chiang Mai Night Safari to investigate seasonal and age relationships in hormone patterns. Faecal samples were collected 3 days/week for 1 year from seven females ranging in age from 4.5 to 9.6 years. A corticosterone enzyme immunoassay was validated for fishing cats by showing increases (∼60%) in faecal glucocorticoid immunoactivity above pre-treatment baseline levels within 1-2 days after an adrenocorticotrophic hormone injection. Faecal glucocorticoid metabolite concentrations were not related to age (P > 0.05), but there was a seasonal effect, with concentrations being higher (P fishing cats, and we found that glucocorticoid metabolite production was influenced by seasonal factors, but not by age. We conclude that weather patterns should be taken into consideration in future studies of glucocorticoid activity in this endangered species, especially those studies aimed at improving captive management to create self-sustaining and healthy populations.

  19. Standard and biological treatment in large vessel vasculitis: guidelines and current approaches.

    Science.gov (United States)

    Muratore, Francesco; Pipitone, Nicolò; Salvarani, Carlo

    2017-04-01

    Giant cell arteritis and Takayasu arteritis are the two major forms of idiopathic large vessel vasculitis. High doses of glucocorticoids are effective in inducing remission in both conditions, but relapses and recurrences are common, requiring prolonged glucocorticoid treatment with the risk of the related adverse events. Areas covered: In this article, we will review the standard and biological treatment strategies in large vessel vasculitis, and we will focus on the current approaches to these diseases. Expert commentary: The results of treatment trials with conventional immunosuppressive agents such as methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide have overall been disappointing. TNF-α blockers are ineffective in giant cell arteritis, while observational evidence and a phase 2 randomized trial support the use of tocilizumab in relapsing giant cell arteritis. Observational evidence strongly supports the use of anti-TNF-α agents and tocilizumab in Takayasu patients with relapsing disease. However biological agents are not curative, and relapses remain common.

  20. Daptomycin in the treatment of prosthetic joint infection by Enterococcus faecalis: safety and efficacy of high-dose and prolonged therapy

    OpenAIRE

    José Ramón Yuste; Milena Quesada; Pablo Díaz-Rada; José Luis Del Pozo

    2014-01-01

    Enterococci are implicated in less than 2.3% of prosthetic joint infections. These infections can be difficult to treat and therapeutic failures are not uncommon. In these situations, daptomycin is a safe and effective alternative. We present a clinical case with a successful response to the prolonged use of high-dose daptomycin.

  1. Daptomycin in the treatment of prosthetic joint infection by Enterococcus faecalis: safety and efficacy of high-dose and prolonged therapy

    Directory of Open Access Journals (Sweden)

    José Ramón Yuste

    2014-10-01

    Full Text Available Enterococci are implicated in less than 2.3% of prosthetic joint infections. These infections can be difficult to treat and therapeutic failures are not uncommon. In these situations, daptomycin is a safe and effective alternative. We present a clinical case with a successful response to the prolonged use of high-dose daptomycin.

  2. Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

    International Nuclear Information System (INIS)

    Aguilar, David; Strom, Joshua; Chen, Qin M.

    2014-01-01

    Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found Glucocorticoid-Induced Leucine Zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. - Highlights: • Corticosteroids act as a cytoprotective agent in cardiomyocytes • Corticosteroids induce GILZ expression in cardiomyocytes • Elevated GILZ results in resistance against apoptosis induced by doxorubicin • GILZ induces Bcl-xL protein without inducing Bcl-xL mRNA

  3. 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.

  4. DOSAGEM DE METABÓLITOS DE GLUCOCORTICOIDES E PROGESTERONA EM FEZES DE PAPAGAIO-VERDADEIRO (AMAZONA AESTIVA

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    Caroline Junko Fujihara

    2014-09-01

    Full Text Available The objectives of the present study were to evaluate fecal concentrations of metabolites of glucocorticoids, measured by enzyme immunoassay with a cortisol antibody and by radioimmunoassay with a corticosterone antibody, and progesterone by radioimmunoassay with a progesterone antibody in blue-fronted parrot (Amazona aestiva after ACTH challenge. The adrenal stimulation with ACTH (25 UI/animal resulted in an increase of fecal glucocorticoids metabolites concentration, but it did not affect the concentrations of fecal progesterone metabolites. Although there were no synchronized peaks of glucocorticoid metabolites excretion measured by enzyme immunoassay and radioimmunoassay, there were two peaks of excretion, one at 2-4 hours and other at 8-10 hours. Despite the occurrence of peaks, the analysis of fecal glucocorticoids metabolites and progesterone metabolites showed no effect of group (control and treatment, moment (hours of sampling and sex.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Tumour necrosis factor-α inhibitors are glucocorticoid-sparing in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Nilsson, Anna Christine; Christensen, Anne Friesgaard; Junker, Peter

    2011-01-01

    Rheumatoid arthritis (RA) is a chronic disease with autoimmune traits of unknown aetiology which primarily affects synovial joints. Glucocorticoids (GCs) are still widely used in RA treatment despite the expanding use of targeted and very efficient agents. The objective of this study was to assess...

  7. Efficacy of Vitamin K2 for Glucocorticoid-induced Osteoporosis in Patients with Systemic Autoimmune Diseases.

    Science.gov (United States)

    Shikano, Kotaro; Kaneko, Kaichi; Kawazoe, Mai; Kaburaki, Makoto; Hasunuma, Tomoko; Kawai, Shinichi

    2016-01-01

    Objective Vitamin K2 (menatetrenone) is an effective treatment for patients with postmenopausal osteoporosis. We herein performed a subanalysis of patients with systemic autoimmune diseases undergoing glucocorticoid therapy in our previous prospective study. Methods Sixty patients were categorized into a group with vitamin K2 treatment (n=20, Group A) and a group without vitamin K2 treatment (n=40, Group B). All patients were treated with bisphosphonates. Results Serum levels of osteocalcin and undercarboxylated osteocalcin decreased significantly after the start of glucocorticoid therapy in both groups, while the serum osteocalcin level was significantly higher in Group A than Group B during the third (p=0.0250) and fourth weeks (p=0.0155). The serum level of the N-terminal peptide of type I procollagen, a bone formation marker, decreased during glucocorticoid therapy, but was significantly higher in Group A than Group B during the fourth week (p=0.0400). The bone mineral density and fracture rate showed no significant differences between the two groups. Conclusion Although vitamin K2 improves bone turnover markers in patients with osteoporosis on glucocorticoid therapy, it has no significant effect on the bone mineral density and fracture rate after 1.5 years of treatment.

  8. A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep

    DEFF Research Database (Denmark)

    Andreasen, Christina Møller; Ding, Ming; Overgaard, Søren

    2015-01-01

    Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss...... in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid-induced osteoporosis in postmenopausal women, making it a relevant preclinical model for orthopaedic implant and biomaterial research........ Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6mg/kg/day, 5 times weekly) for 7months. At 7months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed...

  9. Exhaustion from prolonged gambling

    Directory of Open Access Journals (Sweden)

    Fatimah Lateef

    2013-01-01

    Full Text Available Complaints of fatigue and physical exhaustion are frequently seen in the acute medical setting, especially amongst athletes, army recruits and persons involved in strenuous and exertional physical activities. Stress-induced exhaustion, on the other hand, is less often seen, but can present with very similar symptoms to physical exhaustion. Recently, three patients were seen at the Department of Emergency Medicine, presenting with exhaustion from prolonged involvement in gambling activities. The cases serve to highlight some of the physical consequences of prolonged gambling.

  10. Systems Biology of Glucocorticoids in Muscle Disease

    Science.gov (United States)

    2010-10-01

    Introduction Duchenne muscular dystrophy (DMD) is the most common and incurable muscular dystrophy of childhood. Muscle regeneration fails with...SUBJECT TERMS Duchenne Muscular dystrophy , Glucocorticoids, Systems biology, Drug mechanism 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION...better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant proposal is led by Dr. Eric Hoffman, and it

  11. Are BDNF and glucocorticoid activities calibrated?

    Science.gov (United States)

    Jeanneteau, Freddy; Chao, Moses V.

    2012-01-01

    One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by enhancing survival, synapse formation and synaptic plasticity. Implementation of ‘BDNF therapies’, however, faces numerous methodological and pharmacokinetic issues. Identifying BDNF mimetics that activate the BDNF receptor or downstream targets of BDNF signaling represent an alternative approach. One mechanism that shows great promise is to study the interplay of BDNF and glucocorticoid hormones, a major class of natural steroid secreted during stress reactions and in synchrony with circadian rhythms. While small amounts of glucocorticoids support normal brain function, excess stimulation by these steroid hormones precipitate stress-related affective disorders. To date, however, because of the paucity of knowledge of underlying cellular mechanisms, deleterious effects of glucocorticoids are not prevented following extreme stress. In the present review, we will discuss the complementary roles share by BDNF and glucocorticoids in synaptic plasticity, and delineate possible signaling mechanisms mediating these effects. PMID:23022538

  12. From receptor balance to rational glucocorticoid therapy.

    Science.gov (United States)

    de Kloet, E Ron

    2014-08-01

    Corticosteroids secreted as end product of the hypothalamic-pituitary-adrenal axis act like a double-edged sword in the brain. The hormones coordinate appraisal processes and decision making during the initial phase of a stressful experience and promote subsequently cognitive performance underlying the management of stress adaptation. This action exerted by the steroids on the initiation and termination of the stress response is mediated by 2 related receptor systems: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). The receptor types are unevenly distributed but colocalized in abundance in neurons of the limbic brain to enable these complementary hormone actions. This contribution starts from a historical perspective with the observation that phasic occupancy of GR during ultradian rhythmicity is needed to maintain responsiveness to corticosteroids. Then, during stress, initially MR activation enhances excitability of limbic networks that are engaged in appraisal and emotion regulation. Next, the rising hormone concentration occupies GR, resulting in reallocation of energy to limbic-cortical circuits with a role in behavioral adaptation and memory storage. Upon MR:GR imbalance, dysregulation of the hypothalamic-pituitary-adrenal axis occurs, which can enhance an individual's vulnerability. Imbalance is characteristic for chronic stress experience and depression but also occurs during exposure to synthetic glucocorticoids. Hence, glucocorticoid psychopathology may develop in susceptible individuals because of suppression of ultradian/circadian rhythmicity and depletion of endogenous corticosterone from brain MR. This knowledge generated from testing the balance hypothesis can be translated to a rational glucocorticoid therapy.

  13. Safety and tolerability of high doses of glucocorticoides

    Directory of Open Access Journals (Sweden)

    Rakić Branislava D.

    2016-01-01

    Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

  14. Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus.

    Science.gov (United States)

    Osborne, Danielle M; O'Leary, Kelsey E; Fitzgerald, Dennis P; George, Alvin J; Vidal, Michael M; Anderson, Brian M; McNay, Ewan C

    2017-01-01

    Recurrent hypoglycaemia is primarily caused by repeated over-administration of insulin to patients with diabetes. Although cognition is impaired during hypoglycaemia, restoration of euglycaemia after recurrent hypoglycaemia is associated with improved hippocampally mediated memory. Recurrent hypoglycaemia alters glucocorticoid secretion in response to hypoglycaemia; glucocorticoids are well established to regulate hippocampal processes, suggesting a possible mechanism for recurrent hypoglycaemia modulation of subsequent cognition. We tested the hypothesis that glucocorticoids within the dorsal hippocampus might mediate the impact of recurrent hypoglycaemia on hippocampal cognitive processes. We characterised changes in the dorsal hippocampus at several time points to identify specific mechanisms affected by recurrent hypoglycaemia, using a well-validated 3 day model of recurrent hypoglycaemia either alone or with intrahippocampal delivery of glucocorticoid (mifepristone) and mineralocorticoid (spironolactone) receptor antagonists prior to each hypoglycaemic episode. Recurrent hypoglycaemia enhanced learning and also increased hippocampal expression of glucocorticoid receptors, serum/glucocorticoid-regulated kinase 1, cyclic AMP response element binding (CREB) phosphorylation, and plasma membrane levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors. Both hippocampus-dependent memory enhancement and the molecular changes were reversed by glucocorticoid receptor antagonist treatment. These results indicate that increased glucocorticoid signalling during recurrent hypoglycaemia produces several changes in the dorsal hippocampus that are conducive to enhanced hippocampus-dependent contextual learning. These changes appear to be adaptive, and in addition to supporting cognition may reduce damage otherwise caused by repeated exposure to severe hypoglycaemia.

  15. [Pathophysiology of prolonged hypokinesia].

    Science.gov (United States)

    Kovalenko, E A

    1976-01-01

    Hypokinesia is an important problem in modern medicine. In the pathogenetic effect of prolonged hypokinesia the main etiological factor is diminished motor activity; of major importance are disorders in the energy and plastic metabolism which affect the muscle system; the contributing factors are cardiovascular deconditioning and orthostatic intolerance. This is attributed to a decreased oxygen supply and eliminated hydrostatic influences during a prolonged recumbency. Blood redistribution in the vascular bed is related to the Gauer-Henry reflex and subsequent changes in the fluid-electrolyte balance. Decreased load on the bone system induces changes in the protein-phosphate-calcium metabolism, diminished bone density and increased calcium content in the blood and urine. Changes in the calcium metabolism are systemic. The activity of the higher nervous system and reflex functions is lowered. Changes in the function of the autonomic nervous system which include a noticeable decline of its adaptive-trophic role as a result of the decrease of afferent and efferent impulsation are of great importance. Changes in the hormonal function involve a peculiar stress-reaction which develops at an early stage of hypokinesia as a response to an unusual situation. Prolonged hypokinesia may result in a disturbed function of the pituitary-adrenal system. It is assumed that prolonged hypokinesia may induce a specific disease of hypokinesia during which man cannot lead a normal mode of life and work.

  16. Behavioral neuroadaptation to alcohol : from glucocorticoids to histone acetylation

    Directory of Open Access Journals (Sweden)

    Daniel Beracochea

    2016-10-01

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

  17. Assessment of faecal glucocorticoid metabolite excretion in captive female fishing cats (Prionailurus viverinus) in Thailand

    Science.gov (United States)

    Khonmee, Jaruwan; Vorawattanatham, Narathip; Pinyopummin, Anuchai; Thitaram, Chatchote; Somgird, Chaleamchat; Punyapornwithaya, Veerasak; Brown, Janine L.

    2016-01-01

    There is little information on the endocrinology of fishing cats (Prionailurus viverinus), an endangered species in Southeast Asia, especially that pertaining to adrenal function. This study characterized faecal glucocorticoid metabolites in female fishing cats housed at Chiang Mai Night Safari to investigate seasonal and age relationships in hormone patterns. Faecal samples were collected 3 days/week for 1 year from seven females ranging in age from 4.5 to 9.6 years. A corticosterone enzyme immunoassay was validated for fishing cats by showing increases (∼60%) in faecal glucocorticoid immunoactivity above pre-treatment baseline levels within 1–2 days after an adrenocorticotrophic hormone injection. Faecal glucocorticoid metabolite concentrations were not related to age (P > 0.05), but there was a seasonal effect, with concentrations being higher (P < 0.05) during the winter (1.54 ± 0.04 µg/g) and rainy season (1.43 ± 0.04 µg/g) compared with the summer (1.22 ± 0.05 µg/g). Significant relationships were found between faecal glucocorticoids and rainfall (positive) and day length (negative), but not a temperature–humidity index. This is the first study to assess adrenal steroidogenic activity in female fishing cats, and we found that glucocorticoid metabolite production was influenced by seasonal factors, but not by age. We conclude that weather patterns should be taken into consideration in future studies of glucocorticoid activity in this endangered species, especially those studies aimed at improving captive management to create self-sustaining and healthy populations. PMID:27293767

  18. Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone

    Science.gov (United States)

    Michailidou, Zoi; Coll, Anthony P; Kenyon, Christopher J; Morton, Nicholas M; O'Rahilly, Stephen; Seckl, Jonathan R; Chapman, Karen E

    2007-01-01

    Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc−/− mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc−/− mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11β-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc−/− mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc−/− mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc−/− mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc−/− mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc−/− mice, independently of adipose or liver renin–angiotensin system activation. These data suggest that CORT-inducible 11β-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver. PMID:17592030

  19. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

    Science.gov (United States)

    Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

    1991-10-01

    Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

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

    Directory of Open Access Journals (Sweden)

    Xin-Yi Liu

    2016-01-01

    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.

  1. 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.

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

    International Nuclear Information System (INIS)

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-01

    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 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.

  3. Autoimmune hyperthyroidism due to secondary adrenal insufficiency: resolution with glucocorticoids.

    Science.gov (United States)

    Skamagas, Maria; Geer, Eliza B

    2011-01-01

    To describe the course of autoimmune hyperthyroid disease in a patient with corticotropin (ACTH) deficiency treated with glucocorticoids. We report the clinical presentation, laboratory data, imaging studies, and management of a patient with weight loss, fatigue, apathy, hallucinations, and arthritis. Autoimmune hyperthyroidism (positive thyroperoxidase and thyroglobulin antibodies and borderline positive thyrotropin receptor antibody) was diagnosed in a 71-year-old woman. New psychotic symptoms prompted brain magnetic resonance imaging, which revealed a partially empty sella. Undetectable morning cortisol, undetectable ACTH, and failure to stimulate cortisol with synthetic ACTH (cosyntropin 250 mcg) secured the diagnosis of long-standing secondary adrenal insufficiency. Hydrocortisone replacement improved the patient's symptoms, resolved the thyroid disease, and decreased thyroid antibody titers. In retrospect, the patient recalled severe postpartum hemorrhage requiring blood transfusion at age 38 years. A Sheehan event probably occurred 33 years before the patient presented with corticotropin deficiency. Hyperthyroidism accelerated cortisol metabolism and provoked symptoms of adrenal insufficiency. The hypocortisolemic state may precipitate hyperimmunity and autoimmune thyroid disease. Rapid resolution of hyperthyroidism and decreased thyroid antibody titers with glucocorticoid treatment support this hypothesis.

  4. Independent association of glucocorticoids with damage accrual in SLE.

    Science.gov (United States)

    Apostolopoulos, Diane; Kandane-Rathnayake, Rangi; Raghunath, Sudha; Hoi, Alberta; Nikpour, Mandana; Morand, Eric F

    2016-01-01

    To determine factors associated with damage accrual in a prospective cohort of patients with SLE. Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual. A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and non-glucocorticoid related domains of the SDI. Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains.

  5. Glucocorticoids Enhance Muscle Proteolysis through a Myostatin-Dependent Pathway at the Early Stage.

    Science.gov (United States)

    Wang, Ruxia; Jiao, Hongchao; Zhao, Jingpeng; Wang, Xiaojuan; Lin, Hai

    2016-01-01

    Myostatin, a member of the TGF-β superfamily of secreted proteins, is expressed primarily in skeletal muscle. It negatively regulates muscle mass and is associated with glucocorticoid-induced muscle atrophy. However, it remains unclear whether myostatin is involved in glucocorticoid-induced muscle protein turnover. The aim of the present study was to investigate the role of myostatin in protein metabolism during dexamethasone (DEX) treatment. Protein synthesis rates and the expression of the genes for myostatin, ubiquitin-proteasome atrogin-1, MuRF1, FoxO1/3a and mTOR/p70S6K were determined. The results show that DEX decreased (Pmyostatin. DEX increased (P0.05). The phosphorylation levels of mTOR and p70S6K were decreased by DEX treatment (Pmyostatin (P 0.05). In conclusion, the present study suggests that the myostatin signalling pathway is associated with glucocorticoid-induced muscle protein catabolism at the beginning of exposure. Myostatin is not a main pathway associated with the suppression of muscle protein synthesis by glucocorticoids.

  6. Studies on Relationship between Serum Nitric Oxide and Plasma Cyclic Guanosine Monophosphate and Prolonged Bleeding after Medical Abortion as well as Prophylaxis and Treatment of Bleeding with Traditional Chinese Medicine

    Institute of Scientific and Technical Information of China (English)

    廖玎玲; 谭布珍; 辛华; 贺晓菊

    1999-01-01

    Objectives To study the relationship between serum nitric oxide(NO and plasma cyclic guanosine monophosphate(cGMP)and prolonged bleeding after medical abortion.Methods A total of 120women having received medical abortions at random were recruited and divided into two groups:the one(Group A,n=60) taking “Gong-Fu Mixture(Uterus-Recovering Mixture)”and the other(Group B,n=60)not taking it after abortion.On d 10,20 and 30 after medical abortion,serum NO and plasma cGMP were tested before and after mifepristone administration and 10 d later by Gresis reac-tion method and radioimmunoassay respectively.Results NO concentration in serum and cGMP concentration in plasma decreased signifi-cantly after taking mifeprlstone given(P<0. 05).Ten days later,the number of thos ewith bleeding discontinuation in the group A was significantly greater than that in the group B(P<0.05).Serum NO level and plasma cGMP level in the group A de-creased more significantly than those in the group B(P<0. 05).Conclusion The slow decrease of serum NO and plasma cGMP is closely related to prolonged bleeding after medical abortion.“Gong-Fu Mixture(uterus-recovering mixture)”is effective in prevention and treatment of prolonged bleeding.

  7. OSTEOPENIA in cancellous bone of sheep induced by Glucocorticoid alone

    DEFF Research Database (Denmark)

    Ding, Ming; Cheng, L.; Bollen, Peter

    2008-01-01

    Introduction: There is a great need for suitable large animal models that closely resemble osteoporosis in humans, and that they have adequate bone size for bone prosthesis and biomaterial research. Previous investigations have shown that osteoporotic sheep model requires glucocorticoid (GC......) microarchitectural properties and mechanical properties of sheep cancellous bone after a 7 months steroid treatment; and thus to validate a large animal model for orthopaedic implant/biomaterial research. Materials and Methods: Eighteen female sheep were randomly allocated into 3 groups: group 1 (GC-1) received GC......, osteocalcin was significantly reduced after 7 months but a rebound phenomenon was observed 3 months after cessation of GC. In conclusion, this study has validated an osteopenia sheep model. Bone quality was significantly reduced following a 7 months GC-treatment and recovered after further 3 month observation...

  8. 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.

  9. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

    Science.gov (United States)

    Brattsand, R; Linden, M

    1996-01-01

    Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in

  10. Glucocorticoid Availability in Colonic Inflammation of Rat

    Czech Academy of Sciences Publication Activity Database

    Ergang, Peter; Leden, Pavel; Bryndová, Jana; Žbánková, Šárka; Mikšík, Ivan; Kment, M.; Pácha, Jiří

    2008-01-01

    Roč. 53, č. 8 (2008), s. 2160-2167 ISSN 0163-2116 R&D Projects: GA MZd(CZ) NR8576; GA ČR GA305/07/0328 Grant - others:Univerzita Karlova(CZ) 77/2006C Institutional research plan: CEZ:AV0Z50110509 Keywords : glucocorticoids * 11beta hydroxisteroid dehydrogenase 1 Subject RIV: ED - Physiology Impact factor: 1.583, year: 2008

  11. Significance of glucocorticoids and their receptors in patients with nephritic syndrome

    International Nuclear Information System (INIS)

    Yang Liusong; Li Dapei; Liu Deyi; Wang Weiyue; Wang Haodan

    1996-01-01

    The glucocorticoid receptor (GCR) in 34 patients with nephritic syndrome (NS) and 40 normal controls is investigated by radioligand binding assay. The results show that the GCR levels of NS patients are correlated well with the treatment results by glucocorticoids (GC). These patients who are sensitive to GC treatment have much higher levels of GCR than those who are not responsive to GC treatment (P<0.01) and the normal controls. The plasma ACTH and cortisol in the same subjects are also measured and the results show that NS patients have much lower levels of these two hormones than the normal controls', but no significant correlation is noted between the levels and the GC treatment effects

  12. 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.

  13. Impact of HSCT conditioning and glucocorticoid dose on exercise adherence and response

    OpenAIRE

    Wiskemann, Joachim; Herzog, Benedikt; Kuehl, Rea; Schmidt, Martina E.; Steindorf, Karen; Schwerdtfeger, Rainer; Dreger, Peter; Bohus, Martin

    2017-01-01

    Abstract: Purpose: Evidence from randomized controlled trials (RCT) that exercise interventions have beneficial effects in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is growing. However, intensive chemotherapy conditioning and glucocorticoid (GC) treatment is always part of an allo-HSCT and possibly affect exercise adherence and training response. Therefore, we aimed to examine whether various conditioning protocols or different doses of GC treatment af...

  14. 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.

  15. Transcriptional regulation of the tyrosine hydroxylase gene by glucocorticoid and cyclic AMP

    International Nuclear Information System (INIS)

    Lewis, E.J.; Harrington, C.A.; Chikaraishi, D.M.

    1987-01-01

    Glucocorticoid and cyclic AMP increase tyrosine hydroxylase (TH) activity and mRNA levels in pheochromocytoma cultures. The transcriptional activity of the TH gene, as measured by nuclear run-on assay, is also increased when cultures are treated with the synthetic glucocorticoid dexamethasone or agents that increase intracellular cyclic AMP, such as forskolin and 8-BrcAMP. Both inducers effect transcriptional changes within 10 min after treatment and are maximal after 30 min for forskolin and after 60 min for dexamethasone. The 5' flanking sequences of the TH gene were fused to the bacterial gene chloramphenicol acetyltransferase (CAT), and the hybrid gene was transfected into pheochromocytoma cultures and GH 4 pituitary cells. In both cell lines, a region of the TH gene containing bases -272 to +27 conferred induction of CAT by cyclic AMP, but not by glucocorticoid. The same results were found when a region of the TH gene containing -773 to + 27 was used. Thus, the sequences required for induction of TH by cyclic AMP are contained within 272 bases of 5' flanking sequence, but sequences sufficient for glucocorticoid regulation are not contained with 773 bases

  16. Management of prolonged pregnancy

    International Nuclear Information System (INIS)

    Iqbal, S.

    2004-01-01

    Objective: To compare two strategies for management of prolonged pregnancy (= or >294 days) i.e. induction (intervention) versus expectant management (non-intervention) and evaluate the associated feto-maternal risks. Subjects and Methods: One hundred cases of uncomplicated prolonged gestation were selected. The gestational age was confirmed by ultrasound in first trimester. One group (50 patients) was managed by intervention i.e. induction of labour (group A) and other group (50 patients) by non-intervention i.e. expectant management (group B). In group A intervention was done at 42 weeks. In expectant group, the methods of monitoring were fetal kick charting recorded daily by the patient, and ultrasound for amniotic fluid index. The biophysical profile score and NST (non stress test) were performed once a week till 42 weeks and then twice weekly. Results: The frequency of prolonged pregnancy was found to be 10.9%. There was no significant difference in the number of spontaneous vaginal deliveries between the two groups. The rate of LSCS (lower segment caesarean section) was higher in intervention group ( 30% versus 18% ). The neonatal depression at birth was more in group B ( 10% versus 4%) and at 5 minutes almost same between two groups (4% versus 2%). There were 11 cases of meconium aspiration syndrome, leading to one neonatal death. Among nine perinatal deaths two were neonatal deaths. Seven cases of intrauterine deaths in which antepartum deaths occurred because of non compliance of patients. No cause could be detected for the other three fetuses. Conclusion: There was increased LSCS rate in group A. However in expectant group B perinatal mortality was about twice more as compared to intervention group. Active early intervention at 42 weeks is warranted to reduce perinatal morbidity and mortality. (author)

  17. Glucocorticoid actions on L6 muscle cells in culture

    International Nuclear Information System (INIS)

    Max, S.R.; Konagaya, M.; Konagaya, Y.

    1986-01-01

    Glucocorticoids exert striking catabolic effects on skeletal muscle. The mechanism of these effects remains poorly understood. They employed L6 muscle cells in culture to ascertain whether intracellular glucocorticoid receptors are involved. Studies in vitro permit exploration of glucocorticoid effects in the absence of other hormonal influences. L6 myoblasts were induced to form differentiated myotubes by growth in 1% serum. L6 myotubes were found to possess a high-affinity, limited capacity intracellular glucocorticoid receptor (apparent K/sub D/ = 5 x 10 -10 M; B/sub max/ = 711 pmols/g protein) with ligand specificity similar to that of glucocorticoid receptors from classical glucocorticoid target tissues. Further, [ 3 H] triamcinolone acetonide specific binding to L6 cell homogenates was blocked by a glucocorticoid antagonist, RU38486 (11β-(4-dimethyl-aminophenyl)-17β-hydroxy-17α-(prop-l-ynyl)-estra-4,9-dien-3-one). Dexamethasone (10 -5 M) caused a 10-fold increase in the activity of gluatmine synthetase in L6 myotubes; this increase was prevented by RU38486. Similarly, dexamethasone (10 -5 M) caused a 20% decrease in [ 12 C] leucine incorporation into protein. This effect also was blocked by RU38486. Thus, induction of glutamine synthetase and diminution of protein synthesis by dexamethasone require intracellular glucocorticoid receptors. L6 cells should prove particularly valuable for further studies of glucocorticoid actions on skeletal muscle

  18. Membrane-Associated Effects of Glucocorticoid on BACE1 Upregulation and Aβ Generation: Involvement of Lipid Raft-Mediated CREB Activation.

    Science.gov (United States)

    Choi, Gee Euhn; Lee, Sei-Jung; Lee, Hyun Jik; Ko, So Hee; Chae, Chang Woo; Han, Ho Jae

    2017-08-30

    Glucocorticoid has been widely accepted to induce Alzheimer's disease, but the nongenomic effect of glucocorticoid on amyloid β (Aβ) generation has yet to be studied. Here, we investigated the effect of the nongenomic pathway induced by glucocorticoid on amyloid precursor protein processing enzymes as well as Aβ production using male ICR mice and human neuroblastoma SK-N-MC cells. Mice groups exposed to restraint stress or intracerebroventricular injection of Aβ showed impaired cognition, decreased intracellular glucocorticoid receptor (GR) level, but elevated level of membrane GR (mGR). In this respect, we identified the mGR-dependent pathway evoked by glucocorticoid using impermeable cortisol conjugated to BSA (cortisol-BSA) on SK-N-MC cells. Cortisol-BSA augmented the expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the level of C-terminal fragment β of amyloid precursor protein (C99) and Aβ production, which were maintained even after blocking intracellular GR. We also found that cortisol-BSA enhanced the interaction between mGR and Gαs, which colocalized in the lipid raft. The subsequently activated CREB by cortisol-BSA bound to the CRE site of the BACE1 promoter increasing its expression, which was downregulated by inhibiting CBP. Consistently, blocking CBP attenuated cognitive impairment and Aβ production induced by corticosterone treatment or intracerebroventricular injection of Aβ more efficiently than inhibiting intracellular GR in mice. In conclusion, glucocorticoid couples mGR with Gαs and triggers cAMP-PKA-CREB axis dependent on the lipid raft to stimulate BACE1 upregulation and Aβ generation. SIGNIFICANCE STATEMENT Patients with Alzheimer's disease (AD) have been growing sharply and stress is considered as the major environment factor of AD. Glucocorticoid is the primarily responsive factor to stress and is widely known to induce AD. However, most AD patients usually have impaired genomic pathway of glucocorticoid

  19. 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.

  20. Time trends for alendronate prescription practices in women with chronic obstructive pulmonary disease and women exposed to systemic glucocorticoids

    DEFF Research Database (Denmark)

    Brask-Lindemann, Dorthe; Eiken, P; Eskildsen, P

    2013-01-01

    Summary Chronic obstructive pulmonary disease (COPD) and systemic glucocorticoid exposure are well-known risk factors of osteoporosis. We evaluated alendronate prescription practices related to COPD and exposure to systemic corticosteroids from 1996 to 2008 and showed an increasing targeting...... of alendronate treatment in patients with COPD and patients with systemic corticosteroid exposure. Introduction COPD and systemic glucocorticoid exposure are well-known risk factors of osteoporosis and fragility fracture, but osteoporosis is often underdiagnosed and undertreated in these patients. This study...... aims to evaluate alendronate prescription practices related to COPD and/or to exposure to systemic glucocorticoids among Danish women. Methods A total of 388,314 female subjects >50 years old, 64,719 of whom initiated treatment with alendronate, and 323,595 age- and gender-matched controls were...

  1. Effect of a topical glucocorticoid, budesonide, on nasal mucosal blood flow as measured with 133Xe wash-out technique

    International Nuclear Information System (INIS)

    Bende, M.; Lindqvist, N.; Pipkorn, U.

    1983-01-01

    The ''vasoconstrictor'' effect of dermally applicated steroids is a widely used parameter when determining the potency of glucocorticoids. A similar effect on the nasal mucosa has been suggested as providing an explanation for the clinical effect of topically administered glucocorticoids in the treatment of nasal disorders such as allergic and vasomotor rhinitis. The recently described 133 Xe wash-out method was used for the purpose of blood flow determination in 11 healthy subjects. In a randomized double-blind cross-over study, the effect of topically administered budesonide, a non-halogenated glucocorticoid, for 1 week was compared with that of placebo. No difference was found to occur in the mucosal blood flow after the administration of budesonide, as compared with placebo. It seems likely that a more complex activity than vasoconstriction is responsible for the clinical effect in the treatment of nasal disorders, and further research is required in order to clarify this issue. (author)

  2. Ras-dva is a novel Pit-1- and glucocorticoid-regulated gene in the embryonic anterior pituitary gland.

    Science.gov (United States)

    Ellestad, Laura E; Porter, Tom E

    2013-01-01

    Glucocorticoids play a role in functional differentiation of pituitary somatotrophs and lactotrophs during embryogenesis. Ras-dva was identified as a gene regulated by anterior neural fold protein-1/homeobox expressed in embryonic stem cells-1, a transcription factor known to be critical in pituitary development, and has an expression profile in the chicken embryonic pituitary gland that is consistent with in vivo regulation by glucocorticoids. The objective of this study was to characterize expression and regulation of ras-dva mRNA in the developing chicken anterior pituitary. Pituitary ras-dva mRNA levels increased during embryogenesis to a maximum on embryonic day (e) 18 and then decreased and remained low or undetectable after hatch. Ras-dva expression was highly enriched in the pituitary gland on e18 relative to other tissues examined. Glucocorticoid treatment of pituitary cells from mid- and late-stage embryos rapidly increased ras-dva mRNA, suggesting it may be a direct transcriptional target of glucocorticoids. A reporter construct driven by 4 kb of the chicken ras-dva 5'-flanking region, containing six putative pituitary-specific transcription factor-1 (Pit-1) binding sites and two potential glucocorticoid receptor (GR) binding sites, was highly activated in embryonic pituitary cells and up-regulated by corticosterone. Mutagenesis of the most proximal Pit-1 site decreased promoter activity in chicken e11 pituitary cells, indicating regulation of ras-dva by Pit-1. However, mutating putative GR binding sites did not substantially reduce induction of ras-dva promoter activity by corticosterone, suggesting additional DNA elements within the 5'-flanking region are responsible for glucocorticoid regulation. We have identified ras-dva as a glucocorticoid-regulated gene that is likely expressed in cells of the Pit-1 lineage within the developing anterior pituitary gland.

  3. Constitutive differences in glucocorticoid responsiveness to stress are related to variation in aggression and anxiety-related behaviors.

    Science.gov (United States)

    Walker, Sophie E; Zanoletti, Olivia; Guillot de Suduiraut, Isabelle; Sandi, Carmen

    2017-10-01

    Glucocorticoids coordinate responses that enable an individual to cope with stressful challenges and, additionally, mediate adaptation following cessation of a stressor. There are important individual differences in the magnitude of glucocorticoid responsiveness to stressors. However, whether individual differences in glucocorticoid responsiveness to stress are linked to different behavioral strategies in coping with social and non-social challenges is not easily studied, owing to the lack of appropriate animal models. To address this, we generated three lines of Wistar rats selectively bred for the magnitude of their glucocorticoid responses following exposure to a variety of stressors over three consecutive days at juvenility. Here, we present findings following observations of a high level of variation in glucocorticoid responsiveness to stress in outbred Wistar rats, and the strong response to selection for this trait over a few generations. When challenged with different stressful challenges, rats from the three lines differed in their coping behaviors. Strikingly, the line with high glucocorticoid responsiveness to stress displayed enhanced aggression and anxiety-like behaviors. In addition, these rats also showed alterations in the expression of genes within both central and peripheral nodes of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced reactivity to acute stress exposure. Together, these findings strongly link differences in glucocorticoid responsiveness to stress with marked differences in coping styles. The developed rat lines are thus a promising model with which to examine the relationship between variation in reactivity of the HPA axis and stress-related pathophysiology and could be employed to assess the therapeutic potential of treatments modulating stress habituation to ameliorate psychopathology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. 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

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

    International Nuclear Information System (INIS)

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

    2016-01-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18 ± 5 ng/ml vs 472 ± 58 ng/ml; P < 0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%–93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P < 0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P < 0.01) and 82% (P < 0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P < 0.05), which translated into a 73% lower plasma total cholesterol level (P < 0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. - Highlights: • Cholestasis is associated with increased plasma glucocorticoid levels in mice. • Adrenalectomy lowers cholestasis-associated liver

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

    Energy Technology Data Exchange (ETDEWEB)

    Geest, Rick van der, E-mail: r.van.der.geest@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Ouweneel, Amber B., E-mail: a.b.ouweneel@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Sluis, Ronald J. van der, E-mail: r.vandersluis@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Groen, Albert K., E-mail: a.k.groen@umcg.nl [University Medical Center Groningen (Netherlands); Van Eck, Miranda, E-mail: m.eck@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Hoekstra, Menno, E-mail: hoekstra@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands)

    2016-09-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18 ± 5 ng/ml vs 472 ± 58 ng/ml; P < 0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%–93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P < 0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P < 0.01) and 82% (P < 0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P < 0.05), which translated into a 73% lower plasma total cholesterol level (P < 0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. - Highlights: • Cholestasis is associated with increased plasma glucocorticoid levels in mice. • Adrenalectomy lowers cholestasis-associated liver

  7. Glucocorticoid effect on melphalan cytotoxicity, cell-cycle position, cell size, and [3H]uridine incorporation in one of three human melanoma cell lines

    International Nuclear Information System (INIS)

    Benckhuijsen, C.; Osman, A.M.; Hillebrand, M.J.; Smets, L.A.

    1987-01-01

    Three human melanoma cell lines of known content of specific glucocorticoid-binding sites were studied for colony formation after a microM dose of glucocorticoid combined with melphalan. In one of the three cell lines, M-5A, subcloned from M-5 (formerly designated RPMI 8322), the effect of combined treatment was markedly increased compared to that of melphalan even if the glucocorticoid was applied for 1 h only, 10 h before the melphalan. Semilogarithmic dose-effect plots for a reduction of final plating efficiency by glucocorticoid were curvilinear, according to a receptor-mediated process. The effects of glucocorticoid, melphalan, and their combination were linearized by bilogarithmic median-effect plotting which allowed the quantitation of a synergism which was more marked in case of glucocorticoid pretreatment, for 1 or 24 h, than on simultaneous exposure. According to sequential DNA per cell cytophotometry, melphalan abolished in M-5A a glucocorticoid-induced arrest in the G1 phase of the cell cycle. The cytotoxic synergism correlated with an apparent stimulation by glucocorticoid of the rate of acid-insoluble incorporation of [ 3 H]uridine and [ 14 C]leucine and an increase in cell size and protein content in M-5A cells but not in the other two cell lines. The way in which glucocorticoids induce an enhanced susceptibility to melphalan is not clear. Our results appear compatible with a hypothesis that chromatin in a transcriptionally activated state is more vulnerable to cytotoxic attack by an alkylating agent than under average conditions

  8. PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting.

    Directory of Open Access Journals (Sweden)

    Estibaliz Castillero

    Full Text Available FOXO1 is involved in glucocorticoid- and sepsis-induced muscle wasting, in part reflecting regulation of atrogin-1 and MuRF1. Mechanisms influencing FOXO1 expression in muscle wasting are poorly understood. We hypothesized that the transcription factor peroxisome proliferator-activated receptor β/δ (PPARβ/δ upregulates muscle FOXO1 expression and activity with a downstream upregulation of atrogin-1 and MuRF1 expression during sepsis and glucocorticoid treatment and that inhibition of PPARβ/δ activity can prevent muscle wasting. We found that activation of PPARβ/δ in cultured myotubes increased FOXO1 activity, atrogin-1 and MuRF1 expression, protein degradation and myotube atrophy. Treatment of myotubes with dexamethasone increased PPARβ/δ expression and activity. Dexamethasone-induced FOXO1 activation and atrogin-1 and MuRF1 expression, protein degradation, and myotube atrophy were inhibited by PPARβ/δ blocker or siRNA. Importantly, muscle wasting induced in rats by dexamethasone or sepsis was prevented by treatment with a PPARβ/δ inhibitor. The present results suggest that PPARβ/δ regulates FOXO1 activation in glucocorticoid- and sepsis-induced muscle wasting and that treatment with a PPARβ/δ inhibitor may ameliorate loss of muscle mass in these conditions.

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

    NARCIS (Netherlands)

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

    1985-01-01

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

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

    NARCIS (Netherlands)

    Kroon, Jan; Kroon, Jan; Puhr, M.; Buijs, J.T.; van der Horst, G.; Hemmer, D.M.; Marijt, K.A.; Hwang, M.S.; Masood, M.; Grimm, S.; Storm, Gerrit; Metselaar, Josbert Maarten; Meijer, O.C.; Culig, Z.; van der Pluijm, M.

    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.

  11. 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.|info:eu-repo/dai/nl/244207690; 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.

  12. Using fecal glucocorticoids for stress assessment in Mourning Doves

    Science.gov (United States)

    Washburn, Brian E.; Millspaugh, Joshua J.; Schulz, John H.; Jones, Susan B.; Mong, T.

    2003-01-01

    Fecal glucocorticoid assays provide a potentially useful, noninvasive means to study physiological responses of wildlife to various stressors. The objective of our study was to validate a method for measuring glucocorticoid metabolites in Mourning Dove (Zenaida macroura) feces. We validated the assay using standard procedures (e.g., parallelism, recovery of exogenous corticosterone) to demonstrate that the assay accurately and precisely measured glucocorticoid metabolites in Mourning Dove fecal extracts. We conducted adrenocorticotropin (ACTH) challenge experiments to validate the assay's ability to determine biologically important changes in fecal glucocorticoids. Fecal glucocorticoid levels increased significantly approximately 2-3 hr after administration of ACTH at 50 IU per kg body mass to wild Mourning Doves held in captivity. In contrast, fecal glucocorticoid metabolites did not increase in control birds, birds that received saline injections, or a lower dose of ACTH (1 IU per kg body mass). Variation in overall fecal glucocorticoid metabolite levels may have been influenced by season and the length of time birds were held in captivity. Non-invasive fecal glucocorticoid metabolite analyses, in combination with demographic information, may have considerable utility for monitoring the effects of natural and anthropogenic disturbances on Mourning Dove populations.

  13. [High-dosage glucocorticoid therapy in acute heart infarct and in cardiogenic shock].

    Science.gov (United States)

    Krosch, H; Schäbitz, J

    1977-11-15

    40 patients with cardiogenic shock in consequence of contractility insufficiency of the heart were treated with high doses of prednisolon for short time. In 10 cases a good result of the treatment was to be seen so that the lethality quota was smaller than that of a reference group of the same age. The pharmacodynamic effect is seen in an improvement of the micro-circulation by a peripheric vasodilatation. 10 patients with acute myocardial infarction got a therapy with glucocorticoid combined with a treatment with anti-coagulants during the first both weeks. In this connection modern experimental examinations of animals are discussed which showed that glucocorticoides improve the anoxy tolerance of the heart muscle cell.

  14. 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

  15. Glucocorticoids promote a glioma stem cell-like phenotype and resistance to chemotherapy in human glioblastoma primary cells

    DEFF Research Database (Denmark)

    Kostopoulou, Ourania N; Mohammad, Abdul-Aleem; Bartek, Jiri

    2018-01-01

    Glioma stem cells (GSCs) are glioblastoma (GBM) cells that are resistant to therapy and can give rise to recurrent tumors. The identification of patient-related factors that support GSCs is thus necessary to design effective therapies for GBM patients. Glucocorticoids (GCs) are used to treat GBM......-associated edema. However, glucocorticoids participate in the physiological response to psychosocial stress, which has been linked to poor cancer prognosis. This raises concern that glucocorticoids affect the tumor and GSCs. Here, we treated primary human GBM cells with dexamethasone and evaluated GC......-driven changes in cell morphology, proliferation, migration, gene expression, secretory activity and growth as neurospheres. Dexamethasone treatment of GBM cells appeared to promote the development of a GSC-like phenotype and conferred resistance to physiological stress and chemotherapy. We also analyzed...

  16. 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.

  17. Seed Treatment Combined with a Spot Application of Clothianidin Granules Prolongs the Efficacy of Controlling Piercing-Sucking Insect Pests in Cotton Fields.

    Science.gov (United States)

    Zhang, Zhengqun; Zhao, Yunhe; Wang, Yao; Li, Beixing; Lin, Jin; Zhang, Xuefeng; Mu, Wei

    2017-09-13

    Seed treatments can directly protect cotton from early season piercing-sucking insect Aphis gossypii Glover but hardly provide long-term protection against Apolygus lucorum (Meyer-Dür). Therefore, the efficacy of clothianidin seed treatments combined with spot applications of clothianidin granules at the bud stage of cotton was evaluated to control piercing-sucking pests during the entire cotton growing season. Clothianidin seed treatments (at the rate of 4 g ai/kg seed) combined with a clothianidin granular treatment (even at low rate of 0.9 kg ai/ha) at the bud stage can effectively suppress A. gossypii and A. lucorum infestations throughout the seedling and blooming stages after planting and can improve cotton yield. The spot application of clothianidin granules also reduced the population densities of Bemisia tabaci (Gennadius). The dynamic changes of clothianidin residues demonstrated that the control efficacy of clothianidin against A. gossypii and A. lucorum might be related to the residues of this neonicotinoid in cotton leaves. This pest management practice provided long-term protection against cotton piercing-sucking pests for the entire growing season of cotton plants and could supplement the short-term control efficiency of clothianidin used as a seed treatment.

  18. Dexras1 links glucocorticoids to insulin-like growth factor-1 signaling in adipogenesis

    Science.gov (United States)

    Kim, Hyo Jung; Cha, Jiyoung Y.; Seok, Jo Woon; Choi, Yoonjeong; Yoon, Bo Kyung; Choi, Hyeonjin; Yu, Jung Hwan; Song, Su Jin; Kim, Ara; Lee, Hyemin; Kim, Daeun; Han, Ji Yoon; Kim, Jae-woo

    2016-01-01

    Glucocorticoids are associated with obesity, but the underlying mechanism by which they function remains poorly understood. Previously, we showed that small G protein Dexras1 is expressed by glucocorticoids and leads to adipocyte differentiation. In this study, we explored the mechanism by which Dexras1 mediates adipogenesis and show a link to the insulin-like growth factor-1 (IGF-1) signaling pathway. Without Dexras1, the activation of MAPK and subsequent phosphorylation of CCAAT/enhancer binding protein β (C/EBPβ) is abolished, thereby inhibiting mitotic clonal expansion and further adipocyte differentiation. Dexras1 translocates to the plasma membrane upon insulin or IGF-1 treatment, for which the unique C-terminal domain (amino acids 223–276) is essential. Dexras1-dependent MAPK activation is selectively involved in the IGF-1 signaling, because another Ras protein, H-ras localized to the plasma membrane independently of insulin treatment. Moreover, neither epidermal growth factor nor other cell types shows Dexras1-dependent MAPK activation, indicating the importance of Dexras1 in IGF-1 signaling in adipogenesis. Dexras1 interacts with Shc and Raf, indicating that Dexras1-induced activation of MAPK is largely dependent on the Shc-Grb2-Raf complex. These results suggest that Dexras1 is a critical mediator of the IGF-1 signal to activate MAPK, linking glucocorticoid signaling to IGF-1 signaling in adipogenesis. PMID:27345868

  19. Integrated MRSA-Management (IMM with prolonged decolonization treatment after hospital discharge is effective: a single centre, non-randomised open-label trial

    Directory of Open Access Journals (Sweden)

    Bernhard Jahn

    2016-06-01

    Full Text Available Abstract Background Guidelines for the control of hospital-acquired MRSA include decolonization measures to end MRSA carrier status in colonized and infected patients. Successful decolonization typically requires up to 22 days of treatment, which is longer than the average hospital length of stay (LOS. Incomplete decolonization is therefore common, with long-term MRSA carriage as a consequence. To overcome this, we developed an integrated MRSA Management (IMM by extending MRSA decolonization to the outpatient and domestic setting. The protocol makes use of polyhexanide-based products, in view of reported qac-mediated resistance to chlorhexidine in S. aureus and MRSA. Methods This is a prospective, single centre, controlled, non-randomized, open-label study to evaluate the efficiency of the IMM concept. The outcome of guideline-approved decolonization during hospital stay only (control group; n = 201 was compared to the outcome following IMM treatment whereby decolonization was continued after discharge in the domestic setting or in a long-term care facility (study group; n = 99. As a secondary outcome, the effect of MRSA-status of skin alterations was assessed. Results The overall decolonization rate was 47 % in the IMM patient group compared to 12 % in the control group (p  0.05. For patients with skin alterations (e.g. wounds and entry sites, decolonization success was 50 % if the skin alterations were MRSA-negative at baseline, compared to 22 % success for patients entering the study with MRSA-positive skin alterations (p < 0.01. Conclusions The IMM strategy offers an MRSA decolonization protocol that is feasible in the domestic setting and is equally effective compared with inpatient decolonization treatment when hospital LOS is long enough to complete the treatment. Moreover, for patients with average LOS, decolonization rates obtained with IMM are significantly higher than for in-hospital treatment. IMM is a promising

  20. [Efficacy of systemic glucocorticoids combined with inhaled steroid on children with acute laryngitis].

    Science.gov (United States)

    Chen, Q P; Zhou, R F; Zhang, Y M; Yang, L

    2018-01-07

    Objective: To evaluate the efficacy of systemic glucocorticoid (steroid) combined with high dose inhaled steroid in the treatment of children with acute laryngitis. Methods: A total of 78 children with acute laryngitis were randomly divided into study group( n =40) and control group( n =38) between November 2016 and April 2017. In addition to routine treatment of anti infection and symptomatic treatment, Dexamethasone injection(0.3-0.5 mg/kg, 1-3 d, according to the patient's condition) was provided to each group. In addition to the treatment mentioned above, the study group were assigned to receive 1.0 mg Budesonide suspension for inhalation, oxygen-driven atomizing inhalation, every/30 minutes, 2 times in a row, after that every 12 hours. The improvement of inspiratory dyspnea, hoarseness, barking cough and wheezing of both groups was evaluated at 30 min, 1 h, 2 h, 6 h, 12 h, 24 h and 72 h after treatment.Sigmaplot 11.5 software was used to analyze the data. Results: No significant difference was detected in terms of inspiratory dyspnea, hoarseness, barking cough or stridor score before treatment between the two groups( P >0.05). Compared with those before treatment, symptoms of inspiratory dyspnea, hoarseness, barking cough and stridor score of both groups improved markedly at 12 h and 24 h after treatment( P dyspnea, hoarseness, barking cough or stridor score at each time point after treatment between the two groups( P >0.05). The effective rate was 92.50% and 92.11% in study group and control group, respectively, and no significant difference was noted ( P >0.05). Conclusion: Compared with single systemic glucocorticoid, systemic glucocorticoids combined with inhaled steroid possessed similar efficacy in treating acute laryngitis and relieving laryngeal obstruction of children.

  1. Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome

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    Gustavo A.Rosa Maciel

    2014-03-01

    Full Text Available OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1 polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects. CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment.

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

    Science.gov (United States)

    Darjani, Abbas; Nickhah, Nahid; Hedayati Emami, Mohammad Hassan; Alizadeh, Narges; Rafiei, Rana; Eftekhari, Hojat; Gharaei Nejad, Kaveh

    2017-06-01

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

  3. [The effect of prolonged treatment of hypertensive rats with antihypertensive drugs of various actions on the arterial tension and noradrenaline level in the myocardium, brain and aortal].

    Science.gov (United States)

    Kiriakov, A; Khlebarova, M; Staneva-stoicheva, D; Panova, I

    1975-01-01

    The authors examined the changes in arterial blood pressure and the content of Noradrenaline in the myocardium, brain and aorta of rats with hypertension due to nephrectomy and treatment with desoxycorticosterone and NaCl, and after a chronic 6-month treatment of hypertension with various antihypertensive means. The most significant reduction of noradrenaline in the three of the examined tissues was found in rats, which received dic. sulfyram (100 mg/kg per os). Clondine (10 mkg/kg, per os) manifested the strongest hypotensive effect and lowered the level of noradrenaline in the myocardium, while it was raised in the aorta. Reserpine (10 mkg/kg, s. c) induced a clear reduction of Noradrenaline content in the brain, but an increase in the other two tissues. Insignificant hypotensive effect was observed in animals, treated with guanetidine (0.5 mg/kg, per os), which did not affect substantially noradrenaline in the examined organs. The increase of noradrenaline level was established in the three of the organs of animals, treated with alpha-methyl-DOFA (25 mg/kg, per os). Furosemide (1 mg/kg, s.c.) induced a statistically significant elevation of noradrenaline in the aorta, but was noneffective to noradrenaline in the myocardium and brain.

  4. [Androgens and prolonged complete remissions in acute non lymphoblastic leukemias. Results of a systematic treatment with stanozolol associated with chemotherapy (author's transl)].

    Science.gov (United States)

    Sotto, J J; Hollard, D; Schaerer, R; Bensa, J C; Seigneurin, D

    1975-01-01

    An androgen (stanozolol: 0,15 mg/kg/d) was systematically associated to the treatment of acute non lymphoblastic leukemias, since the beginning of induction therapy (vincristin, daunorubicin, prednisone) and throughout the maintenance period (6-mercaptopurine and methotrexate). Thirty-six patients less than 60 years old (median age: 44 years) presenting with acute non-lymphoblastic leukemia were entered to the study. Sixteen achieved complete remission (C.R.), i.e. 44% of the whole and 53% of treated patients. Out of 16 patients with complete remission, 4 relapsed during the observation period which lasted 4-1/2 years. The stability of the hematologic equilibrium in patients in C.R. is the main finding of the present study. The actuarial curve of the duration of the first complete remission reaches a "plateau"; after the 8th month only one relapse was observed in 9 patients. The rate of C.R. at 2 years is 76 +/- 23%. As compared to the results from other schedules of treatment, this rate appears significantly better, specially in the case of immunotherapy (p less than 0,001). A prospective randomized study is now suggested as to confirm this result; its therapeutic and theoretical basis and perspectives are discussed.

  5. Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with post-menopausal estrogen receptor-positive advanced breast cancer: a sub-group analysis of the JBCRG-C06 Safari study.

    Science.gov (United States)

    Kawaguchi, Hidetoshi; Masuda, Norikazu; Nakayama, Takahiro; Aogi, Kenjiro; Anan, Keisei; Ito, Yoshinori; Ohtani, Shoichiro; Sato, Nobuaki; Saji, Shigehira; Takano, Toshimi; Tokunaga, Eriko; Nakamura, Seigo; Hasegawa, Yoshie; Hattori, Masaya; Fujisawa, Tomomi; Morita, Satoshi; Yamaguchi, Miki; Yamashita, Hiroko; Yamashita, Toshinari; Yamamoto, Yutaka; Yotsumoto, Daisuke; Toi, Masakazu; Ohno, Shinji

    2018-01-01

    The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2-) cases. The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2-. Results Multivariate analysis showed that advanced age (≥65 years; p = .035), longer time (≥3 years) from ABC diagnosis to F500 use (p < .001), no prior chemotherapy (p < .001), and F500 treatment line (p < .001) were correlated with prolonged TTF (median = 5.39 months). In ER+/HER2- patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

  6. Down-regulation of dopamine D-2, 5-HT2 receptors and β-adrenoceptors in rat brain after prolonged treatment with a new potential antidepressant, Lu 19-005

    International Nuclear Information System (INIS)

    Nowak, G.; Arnt, J.; Hyttel, J.; Svendsen, O.

    1985-01-01

    Lu 19-005 is a new phenylindan derivative with strong and equipotent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake. The adaptive effects of 2 weeks treatment with Lu 19-005, on receptor binding in vitro and on d-amphetamine responsiveness in vivo have been investigated in rats. One or 3 days after the final dose the number of β-adrenoceptors and of 5-HT 2 and DA D-2 receptors was decreased by 20-30%, whereas αsub1-adrenoceptor number was slightly decreased only 1 day after withdrawal. The DA D-2 receptor number remained decreased at 7 days withdrawal, but returned to normal after another 3 days. The brain levels of DA, NA and 5-HT were not changed by 2 weeks' Lu 19-005 treatment. The down-regulation of DA D-2 receptors was accompanied by tolerance to d-amphetamine-induced hypermotility (after low doses) and stereotyped licking or biting (after a high dose). The tolerance to d-amphetamine-induced hypermotility was maximal 3-5 days withdrawal time, and remained significant also 15 days after the last dose. The results are discussed in relation to the effect of prolonged treatment with other antidepressant drugs. (Author)

  7. Prolonged efficacy of the 300IR 5-grass pollen tablet up to 2 years after treatment cessation, as measured by a recommended daily combined score

    DEFF Research Database (Denmark)

    Didier, Alain; Malling, Hans-Jørgen; Worm, Margitta

    2015-01-01

    BACKGROUND: The 300IR (index of reactivity) 5-grass pollen tablet has favorable short-term and sustained clinical efficacy in patients with grass pollen-induced allergic rhinoconjunctivitis (ARC). Here, we report maintenance of efficacy and safety over 2 years following treatment discontinuation....... METHODS: Randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial in patients aged 18-50 years with ARC. During study years 1-3, patients received a daily sublingual tablet containing either 300IR 5-grass pollen extract or placebo, according to a discontinuous pre...... medication score (DRMS). RESULTS: 633 patients with ARC were randomized to placebo (n = 219) or 300IR 5-grass pollen tablet, beginning 4 months (4 M, n = 207) or 2 months (2 M, n = 207) prior to the estimated start of the grass pollen season and continuing until season's end. During the first post...

  8. Prolonged treatment with imatinib mesylate in patients with advanced chronic myeloid leukemia causes a reduction of bcr/abl mRNA levels independent of cytogenetic response.

    Science.gov (United States)

    Cariani, E; Capucci, M; Micheletti, M; Spalenza, F; Zanella, I; Albertini, A; Rossi, G

    2003-06-01

    Bcr/abl mRNA levels were monitored in 13 patients with chronic myeloid leukemia receiving imatinib mesylate over a period of 78 weeks. During treatment median bcr/abl mRNA levels progressively declined from 77.2 normalized dose (nD) at baseline to 11.28 nD after 13 weeks ( P<0.05) and to 1.28 nD after 78 weeks ( P<0.05). After 13 weeks, bcr/abl mRNA levels were significantly lower in cytogenetic responders compared to nonresponders ( P<0.05), but subsequent decrease in the transcript levels caused the loss of any correlation to the cytogenetic status. These results suggest that bcr/abl mRNA levels may reflect cytogenetic response only during the early phases of imatinib therapy.

  9. The long-term effects of a life-prolonging heat treatment on the Drosophila melanogaster transcriptome suggest that heat shock proteins extend lifespan

    DEFF Research Database (Denmark)

    Sarup, Pernille Merete; Sørensen, Peter; Loeschcke, Volker

    2014-01-01

    Heat-induced hormesis, i.e. the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. This effect, which depends on the heat shock factor, decreases the log mortality rate weeks after the stress has ceased. To identify candidate genes that mediate......-treated flies. Several hsp70 probe sets were up-regulated 1.7–2-fold in the mildly stressed flies weeks after the last heat treatment (P shock protein, Hsp70, is reported to return to normal levels of expression shortly after heat stress. We...... conclude that the heat shock response, and Hsp70 in particular, may be central to the heat-induced increase in the average lifespan in flies that are exposed to mild heat stress early in life....

  10. Evaluation of the Methods of portective Treatment against microbiological damages and prolonged antimicrobic protection of the interior and the equipment of space objects

    Science.gov (United States)

    Deshevaya, E.; Novikova, N.; Polycarpov, N.; Poddubko, S.; Shumilina, G.; Bragina, M.; Zarubina, K.; Tverskoy, V.; Akova, M. D.

    The researches which have been carried out onboard the orbital complex (? C) MIR, testify that environment of the manned space object may be considered as peculiar ecological niche for development of the microbial community generated by microorganisms of various physiological and taxonomic groups. As a result of vital activity of fungi during OC MIR operation zones of fungi growth on various elements of interior and equipment, cases of destruction of the materials and attributes of corrosion of metals were noted. Existing methods of development of microorganisms on a surface of constructional materials using sanitary treatment of the accessible surfaces with disinfectants, represent the big labour input for the crew. More radical solution of the problem is the development and use of methods of superficial modification of constructional materials and use of methods of superficial modification of constructional materials and treatment of their surface of varnish or paint, resistant to biocontamination and growth of the microorganisms. As a result of the conducted research, the following methods of protection of constructional materials against development of microorganisms were chosen: - fluorination, sylilition, radiating graft polymerization etc., resulting in formation of the functional groups having biocide action; For varnish and paint coverings - coverings on a basis stoichiometrical interpolymeric polyelectrolytic complexes, organosilicone coverings, etc. For testing of the biological effects of samples of the materials subjected to the different methods of surface modification, researches were carried out and experimental models of typical biodestructive processes of the constructional materials are developed considering microclimatic parameters of local zones (the increased temperature and humidity), resistance of the materials to the influence of fungi and increased radiating background influence. Biological testing testifying the efficiency of developed

  11. Chronic glucocorticoid exposure-induced epididymal adiposity is associated with mitochondrial dysfunction in white adipose tissue of male C57BL/6J mice.

    Directory of Open Access Journals (Sweden)

    Jie Yu

    Full Text Available Prolonged and excessive glucocorticoids (GC exposure resulted from Cushing's syndrome or GC therapy develops central obesity. Moreover, mitochondria are crucial in adipose energy homeostasis. Thus, we tested the hypothesis that mitochondrial dysfunction may contribute to chronic GC exposure-induced epididymal adiposity in the present study. A total of thirty-six 5-week-old male C57BL/6J mice (∼20 g were administrated with 100 µg/ml corticosterone (CORT or vehicle through drinking water for 4 weeks. Chronic CORT exposure mildly decreased body weight without altering food and water intake in mice. The epididymal fat accumulation was increased, but adipocyte size was decreased by CORT. CORT also increased plasma CORT, insulin, leptin, and fibroblast growth factor 21 concentrations as measured by RIA or ELISA. Interestingly, CORT increased plasma levels of triacylglycerols and nonesterified fatty acids, and up-regulated the expression of both lipolytic and lipogenic genes as determined by real-time RT-PCR. Furthermore, CORT impaired mitochondrial biogenesis and oxidative function in epididymal WAT. The reactive oxygen species production was increased and the activities of anti-oxidative enzymes were reduced by CORT treatment as well. Taken together, these findings reveal that chronic CORT administration-induced epididymal adiposity is, at least in part, associated with mitochondrial dysfunction in mouse epididymal white adipose tissue.

  12. H2O2 homeostasis in wild-type and ethylene-insensitive Never ripe tomato in response to salicylic acid treatment in normal photoperiod and in prolonged darkness.

    Science.gov (United States)

    Takács, Zoltán; Poór, Péter; Borbély, Péter; Czékus, Zalán; Szalai, Gabriella; Tari, Irma

    2018-05-01

    Ethylene proved to be an important modulator of salicylic acid (SA) signalling pathway. Since SA may regulate both the production and scavenging of hydrogen peroxide (H 2 O 2 ), which show light-dependency, the aim of this study was to compare H 2 O 2 metabolism in the leaves of SA-treated wild-type (WT) tomato (Solanum lycopersicum L. cv. Ailsa Craig) and in ethylene receptor Never-ripe (Nr) mutants grown in normal photoperiod or in prolonged darkness. H 2 O 2 accumulation was higher in the WT than in the mutants in normal photoperiod after 1 mM SA treatment, while Nr leaves contained more H 2 O 2 after light deprivation. The expression of certain superoxide dismutase (SOD) genes and activity of the enzyme followed the same tendency as H 2 O 2 , which was scavenged by different enzymes in the two genotypes. Catalase (CAT, EC 1.11.1.6) activity was inhibited by SA in WT, while the mutants maintained enhanced enzyme activity in the dark. Thus, in WT, CAT inhibition was the major component of the H 2 O 2 accumulation elicited by 1 mM SA in a normal photoperiod, since the expression and/or activity of ascorbate (APX, EC 1.11.1.11) and guaiacol peroxidases (POD, EC 1.11.1.7) were induced in the leaves. The absence of APX and POD activation in mutant plants suggests that the regulation of these enzymes by SA needs functional ethylene signalling. While the block of ethylene perception in Nr mutants was overwritten in the transcription and activity of certain SOD and CAT isoenzymes during prolonged darkness, the low APX and POD activities led to H 2 O 2 accumulation in these tissues. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  13. Low socioeconomic status is associated with prolonged times to assessment and treatment, sepsis and infectious death in pediatric fever in El Salvador.

    Directory of Open Access Journals (Sweden)

    Ronald Gavidia

    Full Text Available BACKGROUND: Infection remains the most common cause of death from toxicity in children with cancer in low- and middle-income countries. Rapid administration of antibiotics when fever develops can prevent progression to sepsis and shock, and serves as an important indicator of the quality of care in children with acute lymphoblastic leukemia and acute myeloid leukemia. We analyzed factors associated with (1 Longer times from fever onset to hospital presentation/antibiotic treatment and (2 Sepsis and infection-related mortality. METHOD: This prospective cohort study included children aged 0-16 years with newly diagnosed acute leukemia treated at Benjamin Bloom Hospital, San Salvador. We interviewed parents/caregivers within one month of diagnosis and at the onset of each new febrile episode. Times from initial fever to first antibiotic administration and occurrence of sepsis and infection-related mortality were documented. FINDINGS: Of 251 children enrolled, 215 had acute lymphoblastic leukemia (85.7%. Among 269 outpatient febrile episodes, median times from fever to deciding to seek medical care was 10.0 hours (interquartile range [IQR] 5.0-20.0, and from decision to seek care to first hospital visit was 1.8 hours (IQR 1.0-3.0. Forty-seven (17.5% patients developed sepsis and 7 (2.6% died of infection. Maternal illiteracy was associated with longer time from fever to decision to seek care (P = 0.029 and sepsis (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.09-8.63; P = 0.034. More infectious deaths occurred in those with longer travel time to hospital (OR 1.36, 95% CI 1.03-1.81; P = 0.031 and in families with an annual household income treatment of fever and with sepsis and infectious mortality in pediatric leukemia. Providing additional education to high-risk families

  14. Osteoporosis prophylaxis in patients receiving chronic glucocorticoid therapy

    International Nuclear Information System (INIS)

    Ali, Mir Sadat; AlElq, Abdulmohsen H.; AlShafei, Badar A.; AbuJubarac, Mohammed A.; AlTurki, Haifa A.

    2009-01-01

    Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, yet few patients receive proper measures to prevent its development. We retrospectively searched prescription records to determine if patients receiving oral prednisolone were receiving prophylaxis or treatment for osteopenia and osteoporosis. Patients who were prescribed greater or equal to 7.5 milligrams of prednisolone for 6 months or longer during a 6- month period were identified through the prescription monitoring system. Demographic and clinical data were extracted from the patient records, and dual energy x-ray absorptiometry (DEXA) scans were retrieved, when available. Use of oral calcium, vitamin D and anti-resorptives was recorded. One hundred males and 65 females were receiving oral prednisolone for a mean (SD) duration of 40.4 (29.9) months in males and 41.2 (36.4) months in females. Twenty-one females (12.7%) and 5 (3%) males had bone mineral density measured by DEXA. Of those, 10 (47.6%) females and 3 (50%) males were osteoporotic and 11(52.4%) females and 2 (40%) males were osteopenic. Calcium and vitamin D were prescribed to the majority of patients (60% to 80%), but none were prescribed antiresorptive/anabolic therapy. Patients in this study were neither investigated properly nor treated according to the minimum recommendations for the management of GIOP. Physician awareness about the prevention and treatment of GIOP should be a priority for the local health care system. (author)

  15. Ways to Optimize Therapy of Prolonged Conjugation Jaundice in Infants

    Directory of Open Access Journals (Sweden)

    O.G. Shadrin

    2015-09-01

    Full Text Available The article is devoted to the optimization of the treatment of prolonged conjugation jaundice. Inclusion of ursodeoxycholic acid in the treatment of neonatal prolonged conjugation jaundice in a dose of 15–20 mg/kg of body mass per day increases the terms of regression of clinical and paraclinical signs of jaundice as much as 2 times and leads to cytolysis normalization. The preparation has a sufficient level of safety, there were not revealed side effects whilst its application.

  16. Both mineralocorticoid and glucocorticoid receptors regulate emotional memory in mice

    NARCIS (Netherlands)

    Zhou, M.; Bakker, E.H.M.; Velzing, E.; Berger, S.; Oitzl, M.; Joëls, M.; Krugers, H.J.

    2010-01-01

    Corticosteroid hormones are thought to promote optimal behavioral adaptation under fearful conditions, primarily via glucocorticoid receptors (GRs). Here, we examined - using pharmacological and genetic approaches in mice - if mineralocorticoid receptors (MRs) also play a role in fearful memory

  17. Exenatide improves glucocorticoid-induced glucose intolerance in mice

    Directory of Open Access Journals (Sweden)

    Ruiying Zhao

    2011-01-01

    Full Text Available Ruiying Zhao1,2*, Enrique Fuentes-Mattei1,2*, Guermarie Velazquez-Torres1,3, Chun-Hui Su1,2, Jian Chen1, Mong-Hong Lee1,2, Sai-Ching Jim Yeung4,51Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Program in Genes and Development, 3Program in Cancer Biology, Graduate School of Biomedical Sciences, University of Texas Health Science Center in Houston, Houston, TX, USA; 4Department of Endocrine Neoplasia and Hormonal Disorders, 5Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA *Both authors contributed equally.Abstract: Exenatide is an incretin mimetic that is recently available in the US for the treatment of diabetes. There is a paucity of information on the effects of exenatide in glucocorticoid (GC-induced diabetes. Although the effect of continuous intravenous infusion of exenatide on GC-induced glucose intolerance has been investigated before in healthy human males receiving oral prednisolone, we investigated the efficacy of a single subcutaneous dose of exenatide (3 µg/kg in lowering blood glucose in GC-induced glucose intolerance in C57BL/6 mice. In a longitudinal experiment, the area under the curve (AUC of oral glucose tolerance tests (OGTT significantly increased after dexamethasone (P = 0.004, which was subsequently decreased by exenatide (P < 0.001. A cross-sectional experiment showed that exenatide improved glucose tolerance compared with placebo in a mouse model of dexamethasone-induced glucose intolerance. AUC of OGTT in the exenatide group were significantly (P < 0.001 lower than in the placebo group. Insulin tolerance tests (ITT demonstrated that exenatide decreased the ability of the mice to tolerate insulin compared with placebo. The AUC of ITT in the exenatide group were also significantly (P = 0.006 lower than in the placebo group. In conclusion, a single dose of exenatide was able to decrease glucose intolerance and

  18. Infralimbic dopamine D2 receptors mediate glucocorticoid-induced facilitation of auditory fear memory extinction in rats.

    Science.gov (United States)

    Dadkhah, Masoumeh; Abdullahi, Payman Raise; Rashidy-Pour, Ali; Sameni, Hamid Reza; Vafaei, Abbas Ali

    2018-03-01

    The infralimbic (IL) cortex of the medial prefrontal cortex plays an important role in the extinction of fear memory. Also, it has been showed that both brain glucocorticoid and dopamine receptors are involved in many processes such as fear extinction that drive learning and memory; however, the interaction of these receptors in the IL cortex remains unclear. We examined a putative interaction between the effects of glucocorticoid and dopamine receptors stimulation in the IL cortex on fear memory extinction in an auditory fear conditioning paradigm in male rats. Corticosterone (the endogenous glucocorticoid receptor ligand), or RU38486 (the synthetic glucocorticoid receptor antagonist) microinfusion into the IL cortex 10 min before test 1 attenuated auditory fear expression at tests 1-3, suggesting as an enhancement of fear extinction. The effect of corticosterone, but not RU38486 was counteracted by the dopamine D2 receptor antagonist sulpiride pre-treatment administered into the IL (at a dose that failed to alter freezing behavior on its own). In contrast, intra-IL infusion of the dopamine D1 receptor antagonist SCH23390 pre-treatment failed to alter freezing behavior. These findings provide evidence for the involvement of the IL cortex D2 receptors in CORT-induced facilitation of fear memory extinction. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Glucocorticoid mechanisms of functional connectivity changes in stress-related neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Baila S. Hall

    2015-01-01

    Full Text Available Stress—especially chronic, uncontrollable stress—is an important risk factor for many neuropsychiatric disorders. The underlying mechanisms are complex and multifactorial, but they involve correlated changes in structural and functional measures of neuronal connectivity within cortical microcircuits and across neuroanatomically distributed brain networks. Here, we review evidence from animal models and human neuroimaging studies implicating stress-associated changes in functional connectivity in the pathogenesis of PTSD, depression, and other neuropsychiatric conditions. Changes in fMRI measures of corticocortical connectivity across distributed networks may be caused by specific structural alterations that have been observed in the prefrontal cortex, hippocampus, and other vulnerable brain regions. These effects are mediated in part by glucocorticoids, which are released from the adrenal gland in response to a stressor and also oscillate in synchrony with diurnal rhythms. Recent work indicates that circadian glucocorticoid oscillations act to balance synapse formation and pruning after learning and during development, and chronic stress disrupts this balance. We conclude by considering how disrupted glucocorticoid oscillations may contribute to the pathophysiology of depression and PTSD in vulnerable individuals, and how circadian rhythm disturbances may affect non-psychiatric populations, including frequent travelers, shift workers, and patients undergoing treatment for autoimmune disorders.

  20. Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Jeffery M. Vahrenkamp

    2018-03-01

    Full Text Available Summary: Steroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER and glucocorticoid receptor (GR are expressed in the uterus, and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic-binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is altered significantly by estradiol with GR recruited to ER-bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol but with additional regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer. : Estrogen receptor α (ER and glucocorticoid receptor (GR are expressed in the uterus and have differential effects on growth. Vahrenkamp et al. find that expression of both receptors is associated with poor outcome in endometrial cancer and that simultaneous induction of ER and GR leads to molecular interplay between the receptors. Keywords: estrogen receptor, glucocorticoid receptor, endometrial cancer

  1. Glucocorticoid Mechanisms of Functional Connectivity Changes in Stress-Related Neuropsychiatric Disorders.

    Science.gov (United States)

    Hall, Baila S; Moda, Rachel N; Liston, Conor

    2015-01-01

    Stress-especially chronic, uncontrollable stress-is an important risk factor for many neuropsychiatric disorders. The underlying mechanisms are complex and multifactorial, but they involve correlated changes in structural and functional measures of neuronal connectivity within cortical microcircuits and across neuroanatomically distributed brain networks. Here, we review evidence from animal models and human neuroimaging studies implicating stress-associated changes in functional connectivity in the pathogenesis of PTSD, depression, and other neuropsychiatric conditions. Changes in fMRI measures of corticocortical connectivity across distributed networks may be caused by specific structural alterations that have been observed in the prefrontal cortex, hippocampus, and other vulnerable brain regions. These effects are mediated in part by glucocorticoids, which are released from the adrenal gland in response to a stressor and also oscillate in synchrony with diurnal rhythms. Recent work indicates that circadian glucocorticoid oscillations act to balance synapse formation and pruning after learning and during development, and chronic stress disrupts this balance. We conclude by considering how disrupted glucocorticoid oscillations may contribute to the pathophysiology of depression and PTSD in vulnerable individuals, and how circadian rhythm disturbances may affect non-psychiatric populations, including frequent travelers, shift workers, and patients undergoing treatment for autoimmune disorders.

  2. The emerging importance of ultradian glucocorticoid rhythms within metabolic pathology.

    Science.gov (United States)

    Flynn, Benjamin P; Conway-Campbell, Becky L; Lightman, Stafford L

    2018-06-01

    Glucocorticoid (GC) hormones play significant roles within homeostasis and the chrono-dynamics of their regulatory role has become increasingly recognised within dysregulated GC pathology, particularly with metabolic phenotypes. Within this article, we will discuss the relevance of the ultradian homeostatic rhythm, how its dysregulation effects glucocorticoid receptor and RNA polymeraseII recruitment and may play a significant role within aberrant metabolic action. Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. Methods. A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout....... Conclusion. These results indicate that endogenous glucocorticoids contribute to the sodium retention in patients with alcoholic cirrhosis of the liver....

  4. 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.

  5. Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism.

    Science.gov (United States)

    Nikolopoulou, Elena; Mytilinaios, Dimitrios; Calogero, Aldo E; Kamilaris, Themis C; Troupis, Theodore; Chrousos, George P; Johnson, Elizabeth O

    2015-08-01

    Hyperthyroidism is associated with a significant increase in circulating glucocorticoid levels and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to examine whether the HPA axis hyperactivity observed in hyperthyroidism may be explained by a disturbed feedback inhibition of endogenous glucocorticoids through two specific intracellular receptors in the brain: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Cytosolic receptor binding and gene expression was assessed in rats with short (7 days) and long standing (60 days) eu- and hyperthyroidism. Glucocorticoid receptor number and binding affinity (Kd) in the hippocampus were measured using [(3)H2]-dexamethasone radioreceptor assay. In situ hybridization was employed to examine the effects of hyperthyroidism on the GR and MR mRNA levels in the hippocampus and the pituitary. Both short- and long-term hyperthyroid rats showed pronounced reduction in the concentration of cytosolic GR in the hippocampus, without changes in binding affinity or changes in GR expression. In contrast, GR mRNA in the pituitary increased after 7 days and decreased after 60 days of thyroxin treatment. MR mRNA was moderately affected. Hyperthyroidism is associated with significant decreases in hippocampal GR levels supporting the hypothesis that hyperactivity of the HPA axis observed in experimentally induced hyperthyroidism may be attributed, at least in part, to decreased negative feedback at the level of the hippocampus. These findings further support the notion that a central locus is principally responsible for the hyperactivity of the HPA axis observed in hyperthyroidism.

  6. Prolonged QRS Widening After Aripiprazole Overdose.

    Science.gov (United States)

    Mazer-Amirshahi, Maryann; Porter, Robert; Dewey, Kayla

    2018-05-05

    Aripiprazole is an atypical antipsychotic with a long half-life. Overdose can result in protracted somnolence and cardiac disturbances, particularly QT interval prolongation. This is a single case report of a 14-year-old boy who took an overdose of aripiprazole and developed QRS widening. A 14-year-old boy intentionally ingested 20 tablets of aripiprazole (5 mg). He was brought to the emergency department when his ingestion was discovered. The patient's vital signs were as follows: temperature, 37.7°C; heart rate, 108 beats/min; blood pressure, 138/98 mm Hg; and respirations, 16 breaths/min. Activated charcoal was administered within 90 minutes of ingestion. Initial electrocardiogram (EKG) showed sinus tachycardia, with a QRS of 138 ms and QT interval of 444 ms. QRS duration was 90 ms on an EKG performed 3 months earlier. A bolus of sodium bicarbonate was administered, and the patient was transferred to the pediatric intensive care unit. Repeat EKG demonstrated a QRS of 156 ms, and a sodium bicarbonate infusion was initiated. The patient continued to have QRS prolongation for the next 8 days, reaching a peak of 172 ms 3 days postingestion. Despite aggressive treatment with sodium bicarbonate, there was persistent QRS prolongation; however, the patient did not have any dysrhythmias and remained hemodynamically stable. The patient was discharged 9 days postingestion when the QRS duration normalized to 82 ms. Genetic testing revealed that the patient was a CYP2D6 poor metabolizer. This case suggests that aripiprazole toxicity may possibly be associated with QRS prolongation without associated dysrhythmias or cardiovascular compromise. In addition, toxicity may be prolonged in patients who are CYP2D6 poor metabolizers.

  7. 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

  8. Prolongation of islet allograft survival

    International Nuclear Information System (INIS)

    Lacy, P.E.; Davie, J.M.; Finke, E.H.; Scharp, D.W.

    1979-01-01

    Pretreatment of donor rats with irradiation and silica followed by in vitro culture of the islets for 1 to 2 days prolonged survival of allografts across a minor histocompatibility barrier if hand-picked, clean islets were used for transplantation. Pretreatment of donor rats with irradiation and silica in conjunction with a single injection of antilymphocyte serum (ALS) into the recipient produced a prolongation of survival of hand-picked islets transplanted across a major histocompatibility barrier

  9. Genetic influence on prolonged gestation

    DEFF Research Database (Denmark)

    Laursen, Maja; Bille, Camilla; Olesen, Annette Wind

    2004-01-01

    OBJECTIVE: The purpose of this study was to test a possible genetic component to prolonged gestation. STUDY DESIGN: The gestational duration of single, first pregnancies by both female and male twins was obtained by linking the Danish Twin Registry, The Danish Civil Registration System, and the D...... factors. CONCLUSION: Maternal genes influence prolonged gestation. However, a substantial paternal genetic influence through the fetus was not found....

  10. Severe bradycardia and prolonged hypotension in ciguatera.

    Science.gov (United States)

    Chan, Thomas Yan Keung

    2013-06-01

    Ciguatera results when ciguatoxin-contaminated coral reef fish from tropical or subtropical waters are consumed. The clinical features that present in affected persons are mainly gastrointestinal, neurological, general, and much less commonly, cardiovascular. We report the case of a 50-year-old man who developed the characteristic combination of acute gastrointestinal and neurological symptoms after the consumption of an unidentified coral reef fish head. In addition to those symptoms, he developed dizziness, severe bradycardia (46 bpm) and prolonged hypotension, which required the administration of intravenous atropine and over three days of intravenous fluid replacement with dopamine infusion. Patients with ciguatera can develop severe bradycardia and prolonged hypotension. Physicians should recognise the possible cardiovascular complications of ciguatera and promptly initiate treatment with intravenous atropine, intravenous fluid replacement and inotropic therapy if such complications are observed.

  11. Combined Effects of Glucocorticoid and Noradrenergic Activity on Loss Aversion.

    Science.gov (United States)

    Margittai, Zsofia; Nave, Gideon; Van Wingerden, Marijn; Schnitzler, Alfons; Schwabe, Lars; Kalenscher, Tobias

    2018-01-01

    Loss aversion is a well-known behavioral regularity in financial decision making, describing humans' tendency to overweigh losses compared to gains of the same amount. Recent research indicates that stress and associated hormonal changes affect loss aversion, yet the underlying neuroendocrine mechanisms are still poorly understood. Here, we investigated the causal influence of two major stress neuromodulators, cortisol and noradrenaline, on loss aversion during financial decision making. In a double-blind, placebo-controlled between-subject design, we orally administered either the α2-adrenergic antagonist yohimbine (increasing noradrenergic stimulation), hydrocortisone, both substances, or a placebo to healthy young men. We tested the treatments' influence on a financial decision-making task measuring loss aversion and risk attitude. We found that both drugs combined, relative to either drug by itself, reduced loss aversion in the absence of an effect on risk attitude or choice consistency. Our data suggest that concurrent glucocorticoid and noradrenergic activity prompts an alignment of reward- with loss-sensitivity, and thus diminishes loss aversion. Our results have implications for the understanding of the susceptibility to biases in decision making.

  12. Glucocorticoid regulation of astrocytic fate and function.

    Directory of Open Access Journals (Sweden)

    Shuang Yu

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

  13. 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.

  14. Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

    International Nuclear Information System (INIS)

    Togi, Sumihito; Nakasuji, Misa; Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako; Kitai, Yuichi; Kon, Shigeyuki; Oritani, Kenji; Matsuda, Tadashi

    2015-01-01

    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

  15. 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.

  16. Glucocorticoid programming of the fetal male hippocampal epigenome.

    Science.gov (United States)

    Crudo, Ariann; Suderman, Matthew; Moisiadis, Vasilis G; Petropoulos, Sophie; Kostaki, Alisa; Hallett, Michael; Szyf, Moshe; Matthews, Stephen G

    2013-03-01

    The late-gestation surge in fetal plasma cortisol is critical for maturation of fetal organ systems. As a result, synthetic glucocorticoids (sGCs) are administered to pregnant women at risk of delivering preterm. However, animal studies have shown that fetal exposure to sGC results in increased risk of behavioral, endocrine, and metabolic abnormalities in offspring. Here, we test the hypothesis that prenatal GC exposure resulting from the fetal cortisol surge or after sGC exposure results in promoter-specific epigenetic changes in the hippocampus. Fetal guinea pig hippocampi were collected before (gestational day [GD52]) and after (GD65) the fetal plasma cortisol surge (Term∼GD67) and 24 hours after (GD52) and 14 days after (GD65) two repeat courses of maternal sGC (betamethasone) treatment (n = 3-4/gp). We identified extensive genome-wide alterations in promoter methylation in late fetal development (coincident with the fetal cortisol surge), whereby the majority of the affected promoters exhibited hypomethylation. Fetuses exposed to sGC in late gestation exhibited substantial differences in DNA methylation and histone h3 lysine 9 (H3K9) acetylation in specific gene promoters; 24 hours after the sGC treatment, the majority of genes affected were hypomethylated or hyperacetylated. However, 14 days after sGC exposure these differences did not persist, whereas other promoters became hypermethylated or hyperacetylated. These data support the hypothesis that the fetal GC surge is responsible, in part, for significant variations in genome-wide promoter methylation and that prenatal sGC treatment profoundly changes the epigenetic landscape, affecting both DNA methylation and H3K9 acetylation. This is important given the widespread use of sGC in the management of women in preterm labor.

  17. Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome.

    Science.gov (United States)

    Legeza, Balázs; Marcolongo, Paola; Gamberucci, Alessandra; Varga, Viola; Bánhegyi, Gábor; Benedetti, Angiolo; Odermatt, Alex

    2017-04-26

    The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β-HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β-HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome.

  18. Glucocorticoid effects on hippocampal protein synthesis

    International Nuclear Information System (INIS)

    Schlatter, L.K.

    1988-01-01

    Following subcutaneous injection of rats with 5 mg corticosterone, hippocampal slices in vitro show increased [ 35 S]-methionine labeling of a cytosolic protein with an apparent molecular weight (M 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 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 r . A second hippocampal protein with an M 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 r of 45,000 (IEP of 8.7-7.8) are increased in the liver following glucocorticoid administration

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Case-reports have made it evident that both inhaled, percutaneous, intranasal, intraarticular and ophthalmic administered glucocorticoids have the potential to cause life threatening adrenal insufficiency. With few and sometimes conflicting data and study methodology the prevalence of adrenal...... insufficiency secondary to locally applied glucocorticoids is not clear. Adrenal insufficiency can only be correctly evaluated by a stimulation test, and has by this procedure been reported in up to 40-50% of patients treated with high-dose inhaled glucocorticoids. Medium- to low-dose inhaled glucocorticoids...... have been shown to cause adrenal suppression in 0-16% of patients. Glucocorticoid creams and nasal glucocorticoids can cause adrenal insufficiency, also when used within prescribed doses, but the frequency seems to be less than with inhaled glucocorticoids. Intraarticularly administered glucocorticoids...

  20. Effects of glucocorticoid hormones on cell proliferation in dimethylhydrazine-induced tumours in rat colon.

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1981-01-01

    Adrenocortical hormones have previously been shown to influence cell proliferation in many tissues. In this report, their influence on cell proliferation in the colonic crypt epithelium and in colonic adenocarcinomata is compared. Colonic tumour cell proliferation was found to be retarded following adrenalectomy and this retardation was reversible by administration of hydrocortisone, or by administration of synthetic steroids with predominantly glucocorticoid activity. Tumour cell proliferation in adrenalectomized rats was not promoted by the mineralocorticoid hormone aldosterone. Neither adrenalectomy, nor adrenocortical hormone treatment, significantly influenced colonic crypt cell proliferation.

  1. Prolonged unexplained fatigue in paediatrics

    NARCIS (Netherlands)

    Bakker, R.J.

    2010-01-01

    Prolonged Unexplained Fatigue in Paediatrics. Fatigue, as the result of mental or physical exertion, will disappear after rest, drinks and food. Fatigue as a symptom of illness will recover with the recovering of the illness. But when fatigue is ongoing for a long time, and not the result of

  2. Physiology Of Prolonged Bed Rest

    Science.gov (United States)

    Greenleaf, John E.

    1991-01-01

    Report describes physiological effects of prolonged bed rest. Rest for periods of 24 hours or longer deconditions body to some extent; healing proceeds simultaneously with deconditioning. Report provides details on shifts in fluid electrolytes and loss of lean body mass, which comprises everything in body besides fat - that is, water, muscle, and bone. Based on published research.

  3. 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.

  4. The study of lymphocytes glucocorticoid receptor in severe head injury

    International Nuclear Information System (INIS)

    Li Dapei; Wang Haodan; Zhao Qihuang

    1994-01-01

    Glucocorticoid receptors (GCR) of peripheral lymphocytes from 14 patients with severe head injury and 11 normal volunteers are studied by means of single point method of radioligand binding assay. All these patients receive surgical therapy and glucocorticoid of routine dosage. The results show that the GCR level of these patients is lower than that of the normal, while the plasma cortisol level is much higher. These changes correlate closely to the patients' clinical outcome. It is indicated that the GCR level can reflect the degree of stress of these patients and their response to glucocorticoid therapy. Using peripheral lymphocytes instead of the brain biopsy for the measurement of GCR can reflect the GCR changes of brain tissue, it's more convenient to get the sample and more acceptable to the patients

  5. Osteoporosis secundaria y Osteoporosis inducida por glucocorticoides (OIG

    Directory of Open Access Journals (Sweden)

    Elías Forero Illera

    2006-01-01

    Full Text Available La osteoporosis es un problema de salud pública importante a nivel mundial, y su prevalencia está aumentando. La osteoporosis secundaria se puede producir por varias patologías y el uso de ciertos medicamentos. Los glucocorticoides son un grupo de fármacos usados extensamente en la práctica médica debido a su indiscutible utilidad. La osteoporosis inducida por glucocorticoides es un problema de salud pública. Aunque la patogénesis de la pérdida producida por los glucocorticoides en el hueso no se conoce totalmente, investigaciones recientes han proporcionado nuevas conocimientos en los mecanismos de estos fármacos a nivel celular y molecular. Diversas guías han sido propuestas por diversos grupos para el tratamiento de la OIG; desafortunadamente, las guías del tratamiento no se utilizan adecuadamente en los pacientes.

  6. Glucocorticoid receptors in monocytes in type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Damm, P; Binder, C

    1989-01-01

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

  7. Prevalent glucocorticoid and androgen activity in US water sources.

    Science.gov (United States)

    Stavreva, Diana A; George, Anuja A; Klausmeyer, Paul; Varticovski, Lyuba; Sack, Daniel; Voss, Ty C; Schiltz, R Louis; Blazer, Vicki S; Iwanowicz, Luke R; Hager, Gordon L

    2012-01-01

    Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations.

  8. Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test.

    Science.gov (United States)

    Pane, Marika; Fanelli, Lavinia; Mazzone, Elena Stacy; Olivieri, Giorgia; D'Amico, Adele; Messina, Sonia; Scutifero, Marianna; Battini, Roberta; Petillo, Roberta; Frosini, Silvia; Sivo, Serena; Vita, Gian Luca; Bruno, Claudio; Mongini, Tiziana; Pegoraro, Elena; De Sanctis, Roberto; Gardani, Alice; Berardinelli, Angela; Lanzillotta, Valentina; Carlesi, Adelina; Viggiano, Emanuela; Cavallaro, Filippo; Sframeli, Maria; Bello, Luca; Barp, Andrea; Bianco, Flaviana; Bonfiglio, Serena; Rolle, Enrica; Palermo, Concetta; D'Angelo, Grazia; Pini, Antonella; Iotti, Elena; Gorni, Ksenija; Baranello, Giovanni; Bertini, Enrico; Politano, Luisa; Sormani, Maria Pia; Mercuri, Eugenio

    2015-10-01

    The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Leonardo Rizzo

    2007-06-01

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

  10. Glucocorticoid receptor beta increases migration of human bladder cancer cells.

    Science.gov (United States)

    McBeth, Lucien; Nwaneri, Assumpta C; Grabnar, Maria; Demeter, Jonathan; Nestor-Kalinoski, Andrea; Hinds, Terry D

    2016-05-10

    Bladder cancer is observed worldwide having been associated with a host of environmental and lifestyle risk factors. Recent investigations on anti-inflammatory glucocorticoid signaling point to a pathway that may impact bladder cancer. Here we show an inverse effect on the glucocorticoid receptor (GR) isoform signaling that may lead to bladder cancer. We found similar GRα expression levels in the transitional uroepithelial cancer cell lines T24 and UMUC-3. However, the T24 cells showed a significant (p bladder cancer cells. Therefore, GRβ may have a significant role in bladder cancer, and possibly serve as a therapeutic target for the disease.

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

    Science.gov (United States)

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

    2016-01-20

    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. 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. After 1-month treatment, a dramatic improvement of muscle strength was found in riboflavin group (P riboflavin group (P 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. 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.

  12. Boehringer Ingleheim's selective glucocorticoid receptor agonist development candidate: evaluation of WO2010141331, WO2010141332 and WO2010141333.

    Science.gov (United States)

    Norman, Peter

    2011-07-01

    Three applications from Boehringer Ingelheim all relate to the preparation of non-steroidal glucocorticoid receptor agonists useful in the treatment of inflammatory respiratory diseases. The first two applications claim chiral processes for the preparation of these compounds or intermediates useful therein. These provide two alternative routes, respectively, using achiral and chiral reagents. The third application relates to the preparation of a crystalline salt of the preferred compound on a multi-kilogram scale in micronised form.

  13. Renal sodium retention in cirrhotic rats depends on glucocorticoid-mediated activation of mineralocorticoid receptor due to decreased renal 11beta-HSD-2 activity

    DEFF Research Database (Denmark)

    Thiesson, Helle; Jensen, Boye L; Bistrup, Claus

    2007-01-01

    Downregulation of the renal glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2) during liver cirrhosis may allow activation of the mineralocorticoid receptor (MR) by glucocorticoids and contribute to sodium retention. We tested this hypothesis in male Wistar...... rats with decompensated liver cirrhosis and ascites 7 wk after bile duct ligation (BDL). Renal 11beta-HSD-2 mRNA, protein, and activity were significantly decreased in decompensated rats. The urinary Na(+)/K(+) ratio was reduced by 40%. Renal epithelial sodium channel (ENaC) mRNA and immunostaining...... were only slightly affected. Complete metabolic studies, including fecal excretion, showed that the BDL rats had avid renal sodium retention. Treatment of the BDL rats with dexamethasone suppressed endogenous glucocorticoid production, normalized total sodium balance and renal sodium excretion...

  14. 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

  15. RD50 Prolongation Request 2018

    CERN Document Server

    Casse, Gianluigi

    2018-01-01

    With this document, we request the prolongation of the CERN RD50 research program for 5 years. A very brief historical review of the RD50 research program since the RD50 project approval by the Research Board in the year 2002 is presented and the biggest RD50 achievements are highlighted. The present composition of the collaboration, its organizational structure, and the research methodology are described. The role of RD50 in the present various upgrade and research programs of the LHC Experiments community is given and the overall work plan explained. Finally, a detailed 5-years work program with precise milestones and deliverables for the various research activities is presented. We conclude with our prolongation request towards the LHCC.

  16. Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

    NARCIS (Netherlands)

    Bartalena, L.; Veronesi, G.; Krassas, G. E.; Wiersinga, W. M.; Marcocci, C.; Marinò, M.; Salvi, M.; Daumerie, C.; Bournaud, C.; Stahl, M.; Sassi, L.; Azzolini, C.; Boboridis, K. G.; Mourits, M. P.; Soeters, M. R.; Baldeschi, L.; Nardi, M.; Currò, N.; Boschi, A.; Bernard, M.; von Arx, G.; Perros, P.; Kahaly, G. J.

    2017-01-01

    Intravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves' orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention)

  17. The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis

    NARCIS (Netherlands)

    Machold, Klaus P.; Landewé, Robert; Smolen, Josef S.; Stamm, Tanja A.; van der Heijde, Désirée M.; Verpoort, Kirsten N.; Brickmann, Kerstin; Vázquez-Mellado, Janitzia; Karateev, Dimitri E.; Breedveld, Ferdinand C.; Emery, Paul; Huizinga, Thomas W. J.

    2010-01-01

    Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). To test the effect of GCs on patients with very

  18. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta

    International Nuclear Information System (INIS)

    Robinson, B.G.; Emanuel, R.L.; Frim, D.M.; Majzoub, J.A.

    1988-01-01

    Primary cultures of purified human cytotrophoblasts have been used to examine the expression of the corticotropin-releasing hormone (CRH) gene in placenta. The authors report here that glucocorticoids stimulate placental CRH synthesis and secretion in primary cultures of human placenta. This stimulation is in contrast to the glucocorticoid suppression of CRH expression in hypothalamus. The positive regulation of CRH by glucocorticoids suggests that the rise in CRH preceding parturition could result from the previously described rise in fetal glucocorticoids. Furthermore, this increase in placental CRH could stimulate, via adrenocorticotropic hormone, a further rise in fetal glucocorticoids, completing a positive feedback loop that would be terminated by delivery

  19. Increase of glucocorticoids is not required for the acquisition, but hinders the extinction, of lithium-induced conditioned taste aversion.

    Science.gov (United States)

    Kim, Kyu-Nam; Kim, Bom-Taeck; Kim, Young-Sang; Lee, Jong-Ho; Jahng, Jeong Won

    2014-05-05

    Lithium chloride at doses sufficient to induce conditioned taste aversion (CTA) causes c-Fos expression in the paraventricular nucleus and increases the plasma level of corticosterone with activation of the hypothalamic-pituitary-adrenal axis. This study was conducted to define the role of glucocorticoid in the acquisition and extinction of lithium-induced CTA. In experiment 1, Sprague-Dawley rats received dexamethasone (2mg/kg) or RU486 (20mg/kg) immediately after 5% sucrose access, and then an intraperitoneal injection of isotonic lithium chloride (12ml/kg) was followed with 30min interval. Rats had either 1 or 7 days of recovery period before the daily sucrose drinking tests. In experiment 2, rats were conditioned with the sucrose-lithium pairing, and then received dexamethasone or vehicle at 30min before each drinking test. In experiment 3, adrenalectomized (ADX or ADX+B) rats were subjected to sucrose drinking tests after the sucrose-lithium pairing. Dexamethasone, but not RU486, pretreatment blunted the formation of lithium-induced CTA memory. Dexamethasone prior to each drinking test suppressed sucrose consumption and prolonged the extinction of lithium-induced CTA. Sucrose consumption was significantly suppressed not only in ADX+B rats but also in ADX rats during the first drinking session; however, a significant decrease was found only in ADX rats on the fourth drinking session. These results reveal that glucocorticoid is not a necessary component in the acquisition, but an important player in the extinction, of lithium-induced CTA, and suggest that a pulse increase of glucocorticoid may hinder the extinction memory formation of lithium-induced CTA. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Influencia de los glucocorticoides inhalados sobre la densidad mineral ósea y el metabolismo óseo Inhaled glucocorticoids: influence on bone mineral density and bone metabolism

    Directory of Open Access Journals (Sweden)

    Fernando D. Saraví

    2000-04-01

    Full Text Available Los glucocorticoides inhalados (GCI constituyen hoy un tratamiento de primera línea del asma bronquial. Los efectos sistémicos de los GCI, como la supresión del eje hipotalámico- hipofisario-adrenal, son en general menores que los de los glucocorticoides orales. Sin embargo, existe el riesgo de efectos adversos sobre el hueso a largo plazo. El objetivo del presente trabajo fue revisar los datos publicados acerca de los efectos de los GCI sobre los marcadores del metabolismo óseo y la densidad mineral ósea en adultos y en pacientes pediátricos. Aunque los estudios examinados no proporcionan resultados uniformes, en términos generales sugieren que los GCI pueden afectar al metabolismo y a la densidad mineral ósea, en particular 1 cuando se administran a dosis elevadas (más de 400 µg/día en niños y más de 800 µg/día en adultos; 2 en pacientes pediátricos, en los que también pueden afectar al crecimiento en estatura; 3 en pacientes cuya ingesta de calcio y vitamina D es inadecuada, y 4 en mujeres postmenopáusicas sin terapia de reposición hormonal. En general, a dosis terapéuticamente equivalentes, la beclometasona tiene mayor efecto deletéreo sobre el hueso que la budesonida, y esta mayor que la fluticasona. Además de la precaución obvia de utilizar la menor dosis eficaz, se proponen como medidas preventivas: 1 la adecuada instrucción sobre el uso de los aerosoles; 2 el uso de cámaras de inhalación; 3 el enjuague bucal tras la administración de GCI, y 4 ajustes o suplementos dietéticos para asegurar una adecuada ingesta de calcio y vitamina D.Inhaled glucocorticoids (IGs are today the first-line treatment for bronchial asthma. The systemic effects of inhaled glucocorticoids, such as suppressing the hypothalamic-pituitary-adrenal axis, are generally less than those with oral glucocorticoids. However, there is a long-term risk of adverse effects on bone. The objective of this piece was to review the published data on the

  1. 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

  2. CINRG: Systems Biology of Glucocorticoids in Muscle Disease

    Science.gov (United States)

    2013-10-01

    Contract W81XWH-09-1-0726 SYSTEMS BIOLOGY OF GLUCOCORTICOIDS IN MUSCLE DISEASE Introduction Duchenne muscular dystrophy (DMD) is the most... muscle and enable the development of better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant...common and incurable muscular dystrophy of childhood. Muscle regeneration fails with advancing age, leading to considerable fibrosis. Corticosteroid

  3. Glucocorticoids and inhibition of bone formation induced by skeletal unloading

    International Nuclear Information System (INIS)

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

    1988-01-01

    Skeletal unloading or loss of normal weight bearing in the growing animal inhibits bone formation and reduces bone calcium. To determine whether the inhibition of bone formation induced by skeletal unloading is a consequence of an increase in plasma glucocorticoids and/or an increase in bone sensitivity to glucocorticoids, the authors measured plasma corticosterone throughout the day in unloaded and normally loaded rats (hindlimb elevation model) and examined the effect of adrenalectomy on the response of bone to skeletal unloading. Plasma corticosterone levels were similar in normally loaded and unloaded rats at all times. Skeletal unloading in sham-adrenalectomized animals reduced tibial and vertebral calcium by 11.5 and 11.1%, respectively, and in adrenalectomized animals by 15.3 and 20.3%, respectively. Uptake of 45 Ca and [ 3 H]proline in the tibia was reduced by 8 and 14%, respectively, in the sham-adrenalectomized animals and by 13 and 19% in the adrenalectomized animals. Bone formation and apposition rates were reduced to the same level in sham- and adrenalectomized animals. These results suggest that the inhibition of bone formation induced by skeletal unloading is not a consequence of increased plasma glucocorticoids or an increase in bone sensitivity to the glucocorticoids but, rather, point to a local mediator in bone that senses mechanical load and transmits that information to the bone-forming cells directly

  4. Uso de glucocorticoides en enfermedades alérgicas

    Directory of Open Access Journals (Sweden)

    M Rodríguez-González

    2017-01-01

    Full Text Available Los glucocorticoides son análogos sintéticos de las hormonas adrenocorticales, de uso común, de gran utilidad en la práctica clínica del pediatra y se consideran la piedra angular del tratamiento farmacológico de enfermedades alérgicas.

  5. Adrenocorticotropic Hormone Secreting Pheochromocytoma Underlying Glucocorticoid Induced Pheochromocytoma Crisis

    Directory of Open Access Journals (Sweden)

    Gil A. Geva

    2018-01-01

    Full Text Available Context. Pheochromocytomas are hormone secreting tumors of the medulla of the adrenal glands found in 0.1–0.5% of patients with hypertension. The vast majority of pheochromocytomas secrete catecholamines, but they have been occasionally shown to also secrete interleukins, calcitonin, testosterone, and in rare cases adrenocorticotropic hormone. Pheochromocytoma crisis is a life threatening event in which high levels of catecholamines cause a systemic reaction leading to organ failure. Case Description. A 70-year-old man was admitted with acute myocardial ischemia following glucocorticoid administration as part of an endocrine workup for an adrenal mass. Cardiac catheterization disclosed patent coronary arteries and he was discharged. A year later he returned with similar angina-like chest pain. During hospitalization, he suffered additional events of chest pain, shortness of breath, and palpitations following administration of glucocorticoids as preparation for intravenous contrast administration. Throughout his admission, the patient demonstrated both signs of Cushing’s syndrome and high catecholamine levels. Following stabilization of vital parameters and serum electrolytes, the adrenal mass was resected surgically and was found to harbor an adrenocorticotropic hormone secreting pheochromocytoma. This is the first documented case of adrenocorticotropic hormone secreting pheochromocytoma complicated by glucocorticoid induced pheochromocytoma crisis. Conclusion. Care should be taken when administering high doses of glucocorticoids to patients with suspected pheochromocytoma, even in a patient with concomitant Cushing’s syndrome.

  6. The effect of early administration of glucocorticoids on learning and ...

    African Journals Online (AJOL)

    It has been observed that steroids administered postnatally may have transient retarding effect on learning and memory functions, and that animal age and sex may modify such effects. This study aims to illustrate the effect of early administration of glucocorticoids on learning and spatial memory. Wistar rat pups were ...

  7. 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…

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

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica)

    2008-01-01

    textabstractThomas Addison’s discovery in the mid-1800s that the adrenal cortex was essential for survival preceded by nearly a century the demonstration that this gland produced at least two distinct hormones, each essential for normal life. How glucocorticoids sustained life remained a mystery for

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

    Science.gov (United States)

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

    2013-01-01

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

  10. Positive and negative social support and HPA-axis hyperactivity: Evidence from glucocorticoids in human hair.

    Science.gov (United States)

    Iob, Eleonora; Kirschbaum, Clemens; Steptoe, Andrew

    2018-06-12

    While positive social support is associated with lower prevalence of disease and better treatment outcomes, negative social relationships can instead have unfavourable consequences for several physical and mental health conditions. However, the specific mechanisms by which this nexus might operate remain poorly understood. Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity owing to psychosocial stress has been proposed as a potential pathway underlying the link between social support and health. Hair glucocorticoids such as cortisol and cortisone are emerging as promising biomarkers of long-term retrospective HPA activation. Therefore, the aim of this investigation was to examine the effects of positive and negative experiences of social support within key relationships (i.e. spouse/partner, children, other family members, and friends) on cortisol and cortisone. These associations were tested in a sample of 2520 older adults (mean age 68.1) from the English Longitudinal Study of Ageing. Hair samples were collected in wave 6 (2012/13). To understand the impact of cumulative exposure to poor social support, the analysis used self-reported data from waves 4 (2008/09) and 6. Covariates included demographic, socioeconomic, lifestyle, and hair characteristics. In cross sectional analyses, lower positive support from all sources and specifically from children were associated with higher cortisol. Additionally, lower positive support from children was positively associated with cortisone. Similarly, higher overall negative support was related to higher cortisol, and greater negative support from children was also positively associated with cortisone. In longitudinal analyses, there was evidence for positive associations between hair glucocorticoids and cumulative exposure to poorer social support. Experiences of low positive and high negative social support, particularly from children, were both related to higher hair glucocorticoids. Hence, social relationships of

  11. Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor.

    Science.gov (United States)

    Schmidt, Stefan; Irving, Julie A E; Minto, Lynne; Matheson, Elizabeth; Nicholson, Lindsay; Ploner, Andreas; Parson, Walther; Kofler, Anita; Amort, Melanie; Erdel, Martin; Hall, Andy; Kofler, Reinhard

    2006-12-01

    Glucocorticoids (GCs) specifically induce apoptosis in malignant lymphoblasts and are thus pivotal in the treatment of acute lymphoblastic leukemia (ALL). However, GC-resistance is a therapeutic problem with an unclear molecular mechanism. We generated approximately 70 GC-resistant sublines from a GC-sensitive B- and a T-ALL cell line and investigated their mechanisms of resistance. In response to GCs, all GC-resistant subclones analyzed by real-time polymerase chain reaction (PCR) showed a deficient up-regulation of the GC-receptor (GR) and its downstream target, GC-induced leucine zipper. This deficiency in GR up-regulation was confirmed by Western blotting and on retroviral overexpression of GR in resistant subclones GC-sensitivity was restored. All GC-resistant subclones were screened for GR mutations using denaturing high-pressure liquid chromatography (DHPLC), DNA-fingerprinting, and fluorescence in situ hybridization (FISH). Among the identified mutations were some previously not associated with GC resistance: A484D, P515H, L756N, Y663H, L680P, and R714W. This approach revealed three genotypes, complete loss of functional GR in the mismatch repair deficient T-ALL model, apparently normal GR genes in B-ALLs, and heterozygosity in both. In the first genotype, deficiency in GR up-regulation was fully explained by mutational events, in the second by a putative regulatory defect, and in the third by a combination thereof. In all instances, GC-resistance occurred at the level of the GR in both models.

  12. Elucidation and modulation of glucocorticoid-induced apoptosis in acute lymphoblastic leukemia cells

    International Nuclear Information System (INIS)

    Eberhart, K.

    2011-01-01

    This thesis deals with the elucidation of the synergistic effect of the glucocorticoid dexamethasone and the metabolic modulator 2-deoxyglucose on apoptosis induction in two in vitro model systems of childhood acute lymphoblastic leukemia. 2-deoxyglucose accelerated the kinetics of, and increased the sensitivity to, glucocorticoid-induced apoptosis in two leukemia cell lines. In primary lymphocytes from healthy donors, in contrast, 2-deoxyglucose and dexamethasone did not act synergistically on apoptosis induction. To elucidate the molecular basis of the synergistic effect, glycolysis by means of glucose uptake, lactate production, ATP levels, glucose transporter and hexokinase expression and mitochondrial oxygen consumption was analyzed in treated vs. untreated cells. The study revealed a downregulation of gene expression of the glucose transporter GLUT1 and hexokinase 2 (HK2), release of HK2 from the outer mitochondrial membrane, as well as reduced glycolysis and mitochondrial respiration. Moreover, the analysis of the mitochondrial proteome by 2 dimensional differential gel electrophoresis after treatment with 2-deoxyglucose and dexamethasone revealed the regulation of several interesting candidate proteins involved in treatment related apoptosis. (author)

  13. Microarray analyses of glucocorticoid and vitamin D3 target genes in differentiating cultured human podocytes.

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    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.

  14. Selective Glucocorticoid Receptor (GR-II Antagonist Reduces Body Weight Gain in Mice

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    Tomoko Asagami

    2011-01-01

    Full Text Available Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (=8 received one of the following: CORT 108297 (80 mg/kg QD, CORT 108297 (40 mg/kg BID, mifepristone (30 mg/kg BID, rosiglitazone (10 mg/kg QD, or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

  15. Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells.

    Science.gov (United States)

    Benkhoucha, Mahdia; Molnarfi, Nicolas; Dunand-Sauthier, Isabelle; Merkler, Doron; Schneiter, Gregory; Bruscoli, Stefano; Riccardi, Carlo; Tabata, Yasuhiko; Funakoshi, Hiroshi; Nakamura, Toshikazu; Reith, Walter; Santiago-Raber, Marie-Laure; Lalive, Patrice H

    2014-09-15

    Autoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference-directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene-deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-β1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions. Copyright © 2014 by The American Association of Immunologists, Inc.

  16. Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas

    Science.gov (United States)

    Peyre, Matthieu; Cartalat-Carel, Stéphanie; Meyronet, David; Ricard, Damien; Jouvet, Anne; Pallud, Johan; Mokhtari, Karima; Guyotat, Jacques; Jouanneau, Emmanuel; Sunyach, Marie-Pierre; Frappaz, Didier; Honnorat, Jérôme; Ducray, François

    2010-01-01

    Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). PCV (procarbazine, CCNU, vincristine) chemotherapy has demonstrated efficacy in treating LGGs, but this therapy cannot be used for a prolonged period because of the cumulative toxicity. The aim of the present study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth kinetics. The mean tumor diameter (MTD) of 21 LGGs was measured on serial magnetic resonance images before (n=13), during, and after PCV onset (n=21). During PCV treatment, a decrease in the MTD was observed in all patients. After PCV discontinuation, an ongoing decrease in MTD was observed in 20 of the 21 patients. Median duration of the MTD decrease was 3.4 years (range, 0.8–7.7) after PCV onset and 2.7 years (range, 0–7) after the end of PCV treatment with 60% of LGGs, demonstrating an ongoing and prolonged (>2 years) response despite chemotherapy no longer being administered. According to McDonald's criteria, the rates of partial and minor responses were 5% and 38% at the end of PCV but 38% and 42% at the time of maximal MTD decrease, which occurred after a median period of 3.4 years after PCV onset. These results challenge the idea that a prolonged duration of chemotherapy is necessary for treating LGGs and raise the issue of understanding the mechanisms involved in the persistent tumor volume decrease once chemotherapy is terminated. PMID:20488959

  17. Glucocorticoid receptors in anorexia nervosa and Cushing's disease.

    Science.gov (United States)

    Invitti, C; Redaelli, G; Baldi, G; Cavagnini, F

    1999-06-01

    Patients with anorexia nervosa do not display cushingoid features in spite of elevated cortisol plasma levels. Whether a cortisol resistance or a reduced availability of the metabolic substrates necessary to develop the effect of glucocorticoids is responsible for this has not been established. Twenty-two patients with severe restrictive anorexia nervosa, 10 patients with active Cushing's disease, and 24 healthy volunteers without psychiatric disorders or mood alterations were investigated. Glucocorticoid receptor characteristics were examined on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which represents an index of DNA synthesis. The number of glucocorticoid receptors on mononuclear leukocytes (MNL) was comparable in patients with anorexia nervosa, patients with active Cushing's disease, and normal subjects (binding capacity 3.3 +/- 0.23 vs. 3.7 +/- 0.30 and 3.5 +/- 0.20 fmol/10(6) cells). Conversely, glucocorticoid receptor affinity was significantly decreased in anorexia nervosa as well as in Cushing's patients compared to control subjects (dissociation constant 4.0 +/- 0.31 and 4.1 +/- 0.34 vs. 2.9 +/- 0.29 nmol/L, p Cushing's patients compared to control subjects (p Cushing's disease. In patients with anorexia nervosa, the incorporation of [3H]thymidine into the MNL was inversely correlated with urinary free cortisol levels. These data indicate that the lack of cushingoid features in patients with anorexia nervosa is not ascribable to a reduced sensitivity to glucocorticoids but is more likely due to the paucity of metabolic substrates.

  18. Preadmission Use of Glucocorticoids and 30-Day Mortality After Stroke.

    Science.gov (United States)

    Sundbøll, Jens; Horváth-Puhó, Erzsébet; Schmidt, Morten; Dekkers, Olaf M; Christiansen, Christian F; Pedersen, Lars; Bøtker, Hans Erik; Sørensen, Henrik T

    2016-03-01

    The prognostic impact of glucocorticoids on stroke mortality remains uncertain. We, therefore, examined whether preadmission use of glucocorticoids is associated with short-term mortality after ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). We conducted a nationwide population-based cohort study using medical registries in Denmark. We identified all patients with a first-time inpatient diagnosis of stroke between 2004 and 2012. We categorized glucocorticoid use as current use (last prescription redemption ≤90 days before admission), former use, and nonuse. Current use was further classified as new or long-term use. We used Cox regression to compute 30-day mortality rate ratios with 95% confidence intervals (CIs), controlling for confounders. We identified 100 042 patients with a first-time stroke. Of these, 83 735 patients had ischemic stroke, 11 779 had ICH, and 4528 had SAH. Absolute mortality risk was higher for current users compared with nonusers for ischemic stroke (19.5% versus 10.2%), ICH (46.5% versus 34.4%), and SAH (35.0% versus 23.2%). For ischemic stroke, the adjusted 30-day mortality rate ratio was increased among current users compared with nonusers (1.58, 95% CI: 1.46-1.71), driven by the effect of glucocorticoids among new users (1.80, 95% CI: 1.62-1.99). Current users had a more modest increase in the adjusted 30-day mortality rate ratio for hemorrhagic stroke (1.26, 95% CI: 1.09-1.45 for ICH and 1.40, 95% CI: 1.01-1.93 for SAH) compared with nonusers. Former use was not substantially associated with mortality. Preadmission use of glucocorticoids was associated with increased 30-day mortality among patients with ischemic stroke, ICH, and SAH. © 2016 American Heart Association, Inc.

  19. What Are the Treatments for Cushing's Syndrome?

    Science.gov (United States)

    ... Pinterest Email Print What are the treatments for Cushing syndrome? Treatment for Cushing syndrome depends on the reason for the extra cortisol in the body. 1 , 2 Medicine If Cushing syndrome is caused by glucocorticoid medicine taken to treat ...

  20. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study.

    Science.gov (United States)

    McDonald, Craig M; Henricson, Erik K; Abresch, Richard T; Duong, Tina; Joyce, Nanette C; Hu, Fengming; Clemens, Paula R; Hoffman, Eric P; Cnaan, Avital; Gordish-Dressman, Heather

    2018-02-03

    Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of

  1. Effect of long-term inhalation of glucocorticoids on the level of leptin, IL-13 and IL-2 in bronchial asthmatic children

    International Nuclear Information System (INIS)

    Pan Jiongwei

    2011-01-01

    Objective: To determine the effect of long-term inhalation of glucocorticoids on the level of leptin, IL-13, and IL-2 in bronchial asthmatic patient. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum IL-13 and IL-2 level in 60 healthy persons (normal control group) and 70 bronchial asthma patients untreated and 3, 6, 12 months post-treatment, meanwhile leptin was determined by radio immunoassay. Results: The serum levels of leptin, Il-13, and IL-2 in were significantly increased in patient with bronchial asthma compared with that in the normal control group. The serum levels of leptin, IL-13, and IL-2 in children with asthma were decreased gradually after inhaling glucocorticoids for 3 months (P<0.05). The treatment of inhaled glucocorticoids for 6 and 12 months can attenuate the elevation of leptin, IL-13, and IL-2 compared with that before the treatment. Conclusion: Long-term inhaled glucocorticoid is an important means for asthma, and the effects are related to the decrease of level of leptin, IL-13, and IL-2. (authors)

  2. Alcohol dysregulates corticotropin-releasing-hormone (CRH promoter activity by interfering with the negative glucocorticoid response element (nGRE.

    Directory of Open Access Journals (Sweden)

    Magdalena M Przybycien-Szymanska

    Full Text Available EtOH exposure in male rats increases corticotropin-releasing hormone (CRH mRNA in the paraventricular nucleus of the hypothalamus (PVN, a brain region responsible for coordinating stress and anxiety responses. In this study we identified the molecular mechanisms involved in mediating these effects by examining the direct effects of EtOH on CRH promoter activity in a neuronal cell line derived from the PVN (IVB. In addition, we investigated the potential interactions of EtOH and glucocorticoids on the CRH promoter by concomitantly treating cells with EtOH and the glucocorticoid receptor (GR antagonist RU486, and by sequentially deleting GR binding sites within glucocorticoid response element (GRE on the CRH promoter. Cells were transiently transfected with a firefly luciferase reporter construct containing 2.5 kb of the rat wild type (WT or mutated CRH promoter. Our results showed that EtOH treatment induced a biphasic response in CRH promoter activity. EtOH exposure for 0.5 h significantly decreased promoter activity compared to vehicle treated controls, whereas promoter activity was significantly increased after 2.0 h of EtOH exposure. Treatment with RU486, or deletion of the GR binding sites 1 and 2 within the GRE, abolished the EtOH-induced increase in the promoter activity, however did not affect EtOH-induced decrease in CRH promoter activity at an earlier time point. Overall, our data suggest that alcohol exposure directly regulates CRH promoter activity by interfering with the normal feedback mechanisms of glucocorticoids mediated by GR signaling at the GRE site of the CRH promoter.

  3. Biochemical characterization of nuclear receptors for vitamin D3 and glucocorticoids in prostate stroma cell microenvironment

    International Nuclear Information System (INIS)

    Hidalgo, Alejandro A.; Montecinos, Viviana P.; Paredes, Roberto; Godoy, Alejandro S.; McNerney, Eileen M.; Tovar, Heribelt; Pantoja, Diego; Johnson, Candace; Trump, Donald; Onate, Sergio A.

    2011-01-01

    Highlights: → Fibroblasts from benign and carcinoma-associated stroma were biochemically characterized for VDR and GR function as transcription factors in prostate stroma cell microenvironment. → Decreased SRC-1/CBP coactivators recruitment to VDR and GR may result in hormone resistance to 1,25D 3 in stromal cell microenvironment prostate cancer. → 1a,25-Dyhidroxyvitamin D 3 (1,25D 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. 1α,25-Dihydroxyvitamin D 3 (1,25D 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 3 is mediated by the 1,25D 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 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 3 action. Conversely, VDR-mediated transcriptional activity was more efficient in 4 out of 13 CAS (30

  4. 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.

  5. Glucocorticoids Protect Neonatal Rat Brain in Model of Hypoxic-Ischemic Encephalopathy (HIE

    Directory of Open Access Journals (Sweden)

    Benjamin Harding

    2016-12-01

    Full Text Available Hypoxic-ischemic encephalopathy (HIE resulting from asphyxia in the peripartum period is the most common cause of neonatal brain damage and can result in significant neurologic sequelae, including cerebral palsy. Currently therapeutic hypothermia is the only accepted treatment in addition to supportive care for infants with HIE, however, many additional neuroprotective therapies have been investigated. Of these, glucocorticoids have previously been shown to have neuroprotective effects. HIE is also frequently compounded by infectious inflammatory processes (sepsis and as such, the infants may be more amenable to treatment with an anti-inflammatory agent. Thus, the present study investigated dexamethasone and hydrocortisone treatment given after hypoxic-ischemic (HI insult in neonatal rats via intracerebroventricular (ICV injection and intranasal administration. In addition, we examined the effects of hydrocortisone treatment in HIE after lipopolysaccharide (LPS sensitization in a model of HIE and sepsis. We found that dexamethasone significantly reduced rat brain infarction size when given after HI treatment via ICV injection; however it did not demonstrate any neuroprotective effects when given intranasally. Hydrocortisone after HI insult also significantly reduced brain infarction size when given via ICV injection; and the intranasal administration showed to be protective of brain injury in male rats at a dose of 300 µg. LPS sensitization did significantly increase the brain infarction size compared to controls, and hydrocortisone treatment after LPS sensitization showed a significant decrease in brain infarction size when given via ICV injection, as well as intranasal administration in both genders at a dose of 300 µg. To conclude, these results show that glucocorticoids have significant neuroprotective effects when given after HI injury and that these effects may be even more pronounced when given in circumstances of additional

  6. [Primary glucocorticoid resistance syndrome presenting as pseudo-precocious puberty and galactorrhea].

    Science.gov (United States)

    Xiang, Shu-lin; He, Li-ping; Ran, Xing-wu; Tian, Hao-ming; Li, Xiu-jun; Liang, Jin-zhong

    2008-09-01

    Primary glucocorticoid resistance syndrome (PGRS) is a rare condition characterized by hypercortisolism without Cushing's syndrome. This report describes a 7-year-old boy of PGRS with pseudo-precocious puberty and galactorrhea as the main manifestation. His height was 135 cm and body weight was 31 kg. Pigmentation could be seen in the skin, mammary areola and penis. He had hirsutism, low hair line, coarse voice, Tanner stage 3 pubic hair, penis in adult form, accelerated linear growth, and advanced bone age (13 yr.), but normal (for age) testes. Furthermore, he had mammoplasia and galactorrhea. There were no features of glucocorticoid (GC) excess. Hepatic function was impaired (ALT 1426 IU/L, AST 611 IU/L) with no definite causes. Serum cortisol concentration was 1294 nmol/L, 777 nmol/L, 199.3 nmol/L at 8:00, 16:00 and 24:00 respectively. Plasma adrenocorticotropic hormone (ACTH) was normal or a little higher (43.9-80 ng/L). Urinary-free cortisol (UFC) was normal (55.5-62.4 microg/24 h). Serum estradiol (E2), progesterone (P), testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were normal. Serum dehydroepiandrosterone sulfate (DHEAS, 60 microg/dL) and serum prolactin (PRL, 58.7-183.9 ng/mL) level were high, urinary dehydroepiandrosterone (DHEA) level was also elevated (0.96-3.2 mg/mL). Gonadotrophin hormone-releasing hormone (GnRH) stimulation test was negative. Serum cortisol responded normally to insulin-induced hypoglycemia. However, serum cortisol and plasma ACTH concentration was suppressed to more than 50% by 0.5 mg dexamethasone (DEX). The diagnosis of PGRS was made. TREATMENT AND FOLLOW-UP: The patient received a treatment of 0.75-1.0 mg/d DEX. Because of galactorrhea, bromocriptine was given by 1.25-3.75 mg/d. After 24 months follow-up, the pigmentation was relieved and galactorrhea disappeared. No advanced development of the external genitalia and breast was found. The acceleration of the bone age was also slowed down. But

  7. Expression of neuropeptide W in rat stomach mucosa: regulation by nutritional status, glucocorticoids and thyroid hormones.

    Science.gov (United States)

    Caminos, Jorge E; Bravo, Susana B; García-Rendueles, María E R; Ruth González, C; Garcés, Maria F; Cepeda, Libia A; Lage, Ricardo; Suárez, Miguel A; López, Miguel; Diéguez, Carlos

    2008-02-07

    Neuropeptide W (NPW) is a recently identified neuropeptide that binds to G-protein-coupled receptor 7 (GPR7) and 8 (GPR8). In rodent brain, NPW mRNA is confined to specific nuclei in hypothalamus, midbrain and brainstem. Expression of NPW mRNA has also been confirmed in peripheral organs such as stomach. Several reports suggested that brain NPW is implicated in the regulation of energy and hormonal homeostasis, namely the adrenal and thyroid axes; however the precise physiological role and regulation of peripheral NPW remains unclear. In this study, we examined the effects of nutritional status on the regulation of NPW in stomach mucosa. Our results show that in this tissue, NPW mRNA and protein expression is negatively regulated by fasting and food restriction, in all the models we studied: males, females and pregnant females. Next, we examined the effect of glucocorticoids and thyroid hormones on NPW mRNA expression in the stomach mucosa. Our data showed that NPW expression is decreased in this tissue after glucocorticoid treatment or hyperthyroidism. Conversely, hypothyroidism induces a marked increase in the expression of NPW in rat stomach. Overall, these data indicate that stomach NPW is regulated by nutritional and hormonal status.

  8. Differential response of risedronate on tibial and mandibular bone quality in glucocorticoid-treated growing rats

    International Nuclear Information System (INIS)

    Fujita, Yuko

    2008-01-01

    Glucocorticoids induce bone loss and retard bone growth in children. In this study we investigated the effect of treatment with risedronate on glucocorticoid -prednisolone-induced decreases in bone density, quality, strength and growth of the tibia and mandible in growing rats. Trabecular and cortical bone structure was measured by peripheral quantitative computed tomography (pQCT) and three-dimensional (3D) micro-computed tomography (micro-CT). Indicators of bone strength were calculated from cortical bone density and the modulus of sections obtained from pQCT analysis. Tibial and mandibular bone sizes were also measured. Prednisolone decreased the bone growth of both tibia and mandible. It also caused deterioration of trabecular and cortical bone structure and strength in the mandible, and in cortical bone in the tibia, but had no effect on trabecular bone in the tibia. Risedronate inhibited the prednisolone-induced decreases in tibial width and mandibular length and height but did not improve the retardation of longitudinal bone growth. Risedronate prevented prednisolone-induced deterioration of trabecular and cortical bone architecture. In the mandible, this protective effect of risedronate was accompanied by an increase in cortical bone density and in bone strength. These findings show that risedronate inhibits prednisolone-induced loss of bone density, structure, decrease in bone strength, and retardation of bone growth in the mandible in young growing rats. (author)

  9. Glucocorticoid Antagonism Reduces Insulin Resistance and Associated Lipid Abnormalities in High-Fructose-Fed Mice.

    Science.gov (United States)

    Priyadarshini, Emayavaramban; Anuradha, Carani Venkatraman

    2017-02-01

    High intake of dietary fructose causes perturbation in lipid metabolism and provokes lipid-induced insulin resistance. A rise in glucocorticoids (GCs) has recently been suggested to be involved in fructose-induced insulin resistance. The objective of the study was to investigate the effect of GC blockade on lipid abnormalities in insulin-resistant mice. Insulin resistance was induced in mice by administering a high-fructose diet (HFrD) for 60 days. Mifepristone (RU486), a GC antagonist, was administered to HFrD-fed mice for the last 18 days, and the intracellular and extracellular GC levels, the glucocorticoid receptor (GR) activation and the expression of GC-regulated genes involved in lipid metabolism were examined. HFrD elevated the intracellular GC content in both liver and adipose tissue and enhanced the GR nuclear translocation. The plasma GC level remained unchanged. The levels of free fatty acids and triglycerides in plasma were elevated, accompanied by increased plasma insulin and glucose levels and decreased hepatic glycogen content. Treatment with RU486 reduced plasma lipid levels, tissue GC levels and the expression of GC-targeted genes involved in lipid accumulation, and it improved insulin sensitivity. This study demonstrated that HFrD-induced lipid accumulation and insulin resistance are mediated by enhanced GC in liver and adipose tissue and that GC antagonism might reduce fructose-induced lipid abnormalities and insulin resistance. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  10. Melatonin protects chondrocytes from impairment induced by glucocorticoids via NAD+-dependent SIRT1.

    Science.gov (United States)

    Yang, Wei; Kang, Xiaomin; Qin, Na; Li, Feng; Jin, Xinxin; Ma, Zhengmin; Qian, Zhuang; Wu, Shufang

    2017-10-01

    Intra-articular injection of glucocorticoids is used to relieve pain and inflammation in osteoarthritis patients, which is occasionally accompanied with the serious side effects of glucocorticoids in collagen-producing tissue. Melatonin is the major hormone released from the pineal gland and its beneficial effects on cartilage has been suggested. In the present study, we investigated the protective role of melatonin on matrix degeneration in chondrocytes induced by dexamethasone (Dex). The chondrocytes isolated from mice knee joint were treated with Dex, melatonin, EX527 and siRNA targeted for SIRT6, respectively. Dex treatment induced the loss of the extracellular matrix, NAD + /NADH ratio and NADPH concentration in chondrocytes. Melatonin alone have no effect on the quantity of proteoglycans and collagen type IIa1, however, the pretreatment of melatonin reversed the negative effects induced by Dex. Meanwhile, the significant decrease in NAD + /NADH ratio and NADPH concentration in Dex group were up-regulated by pretreatment of melatonin. Furthermore, it was revealed that inhibition of SIRT1 blocked the protective effects of melatonin. The enhancement of NAD + -dependent SIRT1 activity contributes to the chondroprotecfive effects of melatonin, which has a great benefit to prevent dexamethasone-induced chondrocytes impairment. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells.

    Science.gov (United States)

    Dong, Hongli; Carlton, Michael E; Lerner, Adam; Epstein, Paul M

    2015-01-01

    Stimulation of cAMP signaling induces apoptosis in glucocorticoid-sensitive and resistant CEM leukemic and MM.1 multiple myeloma cell lines, and this effect is enhanced by dexamethasone in both glucocorticoid-sensitive cell types and in glucocorticoid-resistant CEM cells. Expression of the mRNA for the glucocorticoid receptor alpha (GR) promoters 1A3, 1B and 1C, expression of mRNA and protein for GR, and the BH3-only proapoptotic proteins, Bim and Bad, and the phosphorylation state of Bad were examined following stimulation of the cAMP and glucocorticoid signaling pathways. Expression levels of GR promoters were increased by cAMP and glucocorticoid signaling, but GR protein expression was little changed in CEM and decreased in MM.1 cells. Stimulation of these two signaling pathways induced Bim in CEM cells, induced Bad in MM.1 cells, and activated Bad, as indicated by its dephosphorylation on ser112, in both cell types. This study shows that leukemic and multiple myeloma cells, including those resistant to glucocorticoids, can be induced to undergo apoptosis by stimulating the cAMP signaling pathway, with enhancement by glucocorticoids, and the mechanism by which this occurs may be related to changes in Bim and Bad expression, and in all cases, to activation of Bad.

  12. Physiological response of rabbit bucks to prolonged feeding of ...

    African Journals Online (AJOL)

    Sixty-four (64) weanling rabbit bucks, 5 to 6 weeks old, were involved in a 2 x 4 factorial experiment to evaluate the effects of prolonged feeding of cottonseed cake (CSC) – based diets with or without vitamin E supplementation on the physiological response of the bucks. There were eight treatment combinations comprising ...

  13. Multifactorial QT Interval Prolongation and Takotsubo Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Michael Gysel

    2014-01-01

    Full Text Available A 71-year-old woman collapsed while working as a grocery store cashier. CPR was performed and an AED revealed torsades de pointes (TdP. She was subsequently defibrillated resulting in restoration of sinus rhythm with a QTc interval of 544 msec. Further evaluation revealed a diagnosis of Takotsubo Cardiomyopathy (TCM contributing to the development of a multifactorial acquired long QT syndrome (LQTS. The case highlights the role of TCM as a cause of LQTS in the setting of multiple risk factors including old age, female gender, hypokalemia, and treatment with QT prolonging medications. It also highlights the multifactorial nature of acquired LQTS and lends support to growing evidence of an association with TCM.

  14. Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad.

    Science.gov (United States)

    Bekhbat, Mandakh; Rowson, Sydney A; Neigh, Gretchen N

    2017-07-01

    Mutual regulation and balance between the endocrine and immune systems facilitate an organism's stress response and are impaired following chronic stress or prolonged immune activation. Concurrent alterations in stress physiology and immunity are increasingly recognized as contributing factors to several stress-linked neuropsychiatric disorders including depression, anxiety, and post-traumatic stress disorder. Accumulating evidence suggests that impaired balance and crosstalk between the glucocorticoid receptor (GR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) - effectors of the stress and immune axes, respectively - may play a key role in mediating the harmful effects of chronic stress on mood and behavior. Here, we first review the molecular mechanisms of GR and NFκB interactions in health, then describe potential shifts in the GR-NFκB dynamics in chronic stress conditions within the context of brain circuitry relevant to neuropsychiatric diseases. Furthermore, we discuss developmental influences and sex differences in the regulation of these two transcription factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. A radioreceptor assay for measurement of plasma glucocorticoid binding activity

    International Nuclear Information System (INIS)

    Fan Jie

    1990-01-01

    A radioreceptor assay (RRA) for plasma glucocorticoid binding activity (GCBA) has been developed using glucocorticoid receptor in rat thymocytes. Unlike other assays for natural and certain synthetic corticosteroids, RRA measures the GCBA of all natural and synthetic GC in plasma. The range of standard curve was 0 ∼ 1.00 mg/L. The sensitivity was 0.01 mg/l. The recovery rate was 92.1%, and the intra and inter assay CV was 0.7% (n = 3) and 4.4% (n = 3) respectively. The level of corticosterone in 9 rat plasma samples was determined by RRA and CBG-isotope binding assay. There was a general correlation over a wide range between the values determined by the two assays (r = 0.95; P < 0.001). The measuring condition was described in detail

  16. 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.

  17. Effect of glucocorticoids and gamma radiation on epidermal Langerhans cells

    International Nuclear Information System (INIS)

    Belsito, D.V.; Baer, R.L.; Thorbecke, G.J.; Gigli, I.

    1984-01-01

    The effect of 750 rads of gamma radiation on the rate of return of epidermal Langerhans cells (LC) following suppressive doses of topical glucorticoids was studied in guinea pigs. Gamma radiation alone had no effect on the LC as assessed by staining for cell membrane ATPase activity and Ia antigen. It did, however, delay the expected return of Ia but not ATPase surface markers on the LC after perturbation with glucocorticoids. The delayed return of surface Ia antigen is possibly related to a radiation-induced defect in the production of a required lymphokine and/or in intracellular Ia transport. Although our data do not rule out a cytolytic effect of steroids on the LC, they do strongly suggest that, at least in part, glucocorticoids act on the LC by altering cell surface characteristics

  18. Gastroprotective role of glucocorticoids during NSAID-induced gastropathy.

    Science.gov (United States)

    Filaretova, Ludmila

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) make significant contributions to gastric ulcer disease which remains widespread. Although several factors have been postulated as pathogenic elements of the gastric injury induced by NSAIDs, it is, however believed that prostaglandin deficiency plays a critical role in the pathogenesis of this injury. During prostaglandin deficiency, other defensive mechanisms might operate to attenuate NSAID-induced gastropathy. According to our results, NSAIDs, similar to stress, induce an increase in glucocorticoid production that in turn helps the gastric mucosa to resist the harmful actions of these drugs. In this article, we review our experimental data suggesting that glucocorticoids may play a role as natural defensive factors in maintaining the integrity of the gastric mucosa during NSAID therapy and might operate to attenuate NSAID-induced gastropathy.

  19. Prolonged Intermittent Renal Replacement Therapy.

    Science.gov (United States)

    Edrees, Fahad; Li, Tingting; Vijayan, Anitha

    2016-05-01

    Prolonged intermittent renal replacement therapy (PIRRT) is becoming an increasingly popular alternative to continuous renal replacement therapy in critically ill patients with acute kidney injury. There are significant practice variations in the provision of PIRRT across institutions, with respect to prescription, technology, and delivery of therapy. Clinical trials have generally demonstrated that PIRRT is non-inferior to continuous renal replacement therapy regarding patient outcomes. PIRRT offers cost-effective renal replacement therapy along with other advantages such as early patient mobilization and decreased nursing time. However, due to lack of standardization of the procedure, PIRRT still poses significant challenges, especially pertaining to appropriate drug dosing. Future guidelines and clinical trials should work toward developing consensus definitions for PIRRT and ensure optimal delivery of therapy. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  20. Social Regulation of Leukocyte Homeostasis: The Role of Glucocorticoid Sensitivity

    Science.gov (United States)

    Cole, Steve W.

    2010-01-01

    Recent small-scale genomics analyses suggest that physiologic regulation of pro-inflammatory gene expression by endogenous glucocorticoids may be compromised in individuals who experience chronic social isolation. This could potentially contribute to the elevated prevalence of inflammation-related disease previously observed in social isolates. The present study assessed the relationship between leukocyte distributional sensitivity to glucocorticoid regulation and subjective social isolation in a large population-based sample of older adults. Initial analyses confirmed that circulating neutrophil percentages were elevated, and circulating lymphocyte and monocyte percentages were suppressed, in direct proportion to circulating cortisol levels. However, leukocyte distributional sensitivity to endogenous glucocorticoids was abrogated in individuals reporting either occasional or frequent experiences of subjective social isolation. This finding held in both nonparametric univariate analyses and in multivariate linear models controlling for a variety of biological, social, behavioral, and psychological confounders. The present results suggest that social factors may alter immune cell sensitivity to physiologic regulation by the hypothalamic-pituitary-adrenal axis in ways that could ultimately contribute to the increased physical health risks associated with social isolation. PMID:18394861

  1. Cannabinoids and glucocorticoids modulate emotional memory after stress.

    Science.gov (United States)

    Akirav, Irit

    2013-12-01

    Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Regulation of NAD(P)H:quininone oxidoreductase by glucocorticoids

    International Nuclear Information System (INIS)

    Pinaire, J.A.; Xiao, G.-H.; Falkner, K.C.; Prough, R.A.

    2004-01-01

    Previous studies in neonatal and adolescent rats as well as adrenalectomized rats have demonstrated that glucocorticoids regulate the expression of the rat NAD(P)H:quinone oxidoreductase gene (QOR). We used primary cultures of rat adult hepatocytes to document that added glucorticoids repress both the basal and 1,2-benzanthracene-induced expression of QOR mRNA by 65-70%. QOR enzyme activity and protein were concomitantly suppressed as well. The monotonic concentration response for repression of QOR gene products up to 100 μM DEX concentration demonstrated that the glucocorticoid receptor (GR) was most likely involved in this process. The lack of effect at higher concentration rules out a role for the Pregnane X receptor in this regulation by DEX. In addition, the anti-glucorticoid RU38486 blocked this negative regulation and the protein synthesis inhibitor cycloheximide had no effect on this repression process. Similar results of GR dependence were observed using a luciferase reporter construct containing the 5'-flanking region of the human QOR gene using HepG2 cells. Collectively, these results demonstrate that GR must directly participate in the negative regulation of QOR gene expression by dexamethasone and other glucocorticoids in vivo

  3. Effects of Social Isolation on Glucocorticoid Regulation in Social Mammals

    Science.gov (United States)

    Hawkley, Louise C.; Cole, Steve W.; Capitanio, John P.; Norman, Greg J.; Cacioppo, John T.

    2012-01-01

    The regulation and function of the hypothalamic-pituitary-adrenocortical (HPA) axis and glucocorticoids have been well conserved across vertebrate species. Glucocorticoids influence a wide range of physiological functions that include glucose regulation, metabolism, inflammatory control, as well as cardiovascular, reproductive, and neuronal effects. Some of these are relatively quick-acting non-genomic effects, but most are slower-acting genomic effects. Thus, any stimulus that affects HPA function has the potential to exert wide-ranging short-term and long-term effects on much of vertebrate physiology. Here, we review the effects of social isolation on the functioning of the HPA axis in social species, and on glucocorticoid physiology in social mammals in particular. Evidence indicates that objective and perceived social isolation alter HPA regulation, although the nature and direction of the HPA response differs among species and across age. The inconsistencies in the direction and nature of HPA effects have implications for drawing cross-species conclusions about the effects of social isolation, and are particularly problematic for understanding HPA-related physiological processes in humans. The animal and human data are incommensurate because, for example, animal studies of objective isolation have typically not been modeled on, or for comparability with, the subjective experience of isolation in humans. An animal model of human isolation must be taken more seriously if we want to advance our understanding of the mechanisms for the effects of objective and perceived isolation in humans. PMID:22663934

  4. Disseminated Mycobacterium celatum disease with prolonged pulmonary involvement

    DEFF Research Database (Denmark)

    Patsche, Cecilie Blenstrup; Svensson, Erik; Wejse, Christian

    2014-01-01

    Mycobacterium celatum is a rare cause of human infection, causing disseminated disease in immunosuppressed individuals. Infections localized to the lungs and the lymph nodes have also been reported in immunocompetent individuals. The existing literature on the subject is limited as are experiences...... with treatment regimens and durations. In the case presented herein, two different treatment regimens were applied to an immunocompromised HIV-negative patient with primary skin involvement and extensive pulmonary involvement due to suspected relapse on isoniazid, ethambutol, and clarithromycin treatment....... The treatment regimen was changed to azithromycin, ciprofloxacin, and pyrazinamide and the treatment duration was prolonged to a total of 24 months, with good effect....

  5. Outcome following treatment of feline gastrointestinal mast cell tumours.

    Science.gov (United States)

    Barrett, L E; Skorupski, K; Brown, D C; Weinstein, N; Clifford, C; Szivek, A; Haney, S; Kraiza, S; Krick, E L

    2018-06-01

    Prognosis of feline gastrointestinal mast cell tumours (FGIMCT), based on limited available literature, is described as guarded to poor, which may influence treatment recommendations and patient outcome. The purpose of this study is to describe the clinical findings, treatment response, and outcome of FGIMCT. Medical records of 31 cats diagnosed with and treated for FGIMCT were retrospectively reviewed. Data collected included signalment, method of diagnosis, tumour location (including metastatic sites), treatment type, cause of death and survival time. Mean age was 12.9 y. Diagnosis was made via cytology (n = 15), histopathology (n = 13) or both (n = 3). Metastatic sites included abdominal lymph node (n = 10), abdominal viscera (n = 4) and both (n = 2). Therapeutic approaches included chemotherapy alone (n = 15), surgery and chemotherapy (n = 7), glucocorticoid only (n = 6) and surgery and glucocorticoid (n = 3). Lomustine (n = 15) and chlorambucil (n = 12) were the most commonly used chemotherapy drugs. Overall median survival time was 531 d (95% confidence interval 334, 982). Gastrointestinal location, diagnosis of additional cancers, and treatment type did not significantly affect survival time. Cause of death was tumour-related or unknown (n = 12) and unrelated (n = 8) in the 20 cats dead at the time of analysis. The prognosis for cats with FGIMCT may be better than previously reported, with 26% of cats deceased from an unrelated cause. Surgical and medical treatments (including prednisolone alone) were both associated with prolonged survival times. Treatment other than prednisolone may not be necessary in some cats. Continued research into prognostic factors and most effective treatment strategies are needed. © 2017 John Wiley & Sons Ltd.

  6. Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

    OpenAIRE

    Prigent, Hélène; Maxime, Virginie; Annane, Djillali

    2004-01-01

    This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoi...

  7. Assignment of the human gene for the glucocorticoid receptor to chromosome 5.

    OpenAIRE

    Gehring, U; Segnitz, B; Foellmer, B; Francke, U

    1985-01-01

    Human lymphoblastic leukemia cells of line CEM-C7 are glucocroticoid-sensitive and contain glucocorticoid receptors of wild-type characteristics. EL4 mouse lymphoma cells are resistant to lysis by glucocorticoids due to mutant receptors that exhibit abnormal DNA binding. Hybrids between the two cell lines were prepared and analyzed with respect to glucocorticoid responsiveness and to receptor types by DNA-cellulose chromatrography. Sensitive hybrid cell clones contained the CEM-C7-specific re...

  8. Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Serafin, Valentina; Capuzzo, Giorgia; Milani, Gloria; Minuzzo, Sonia Anna; Pinazza, Marica; Bortolozzi, Roberta; Bresolin, Silvia; Porcù, Elena; Frasson, Chiara; Indraccolo, Stefano; Basso, Giuseppe; Accordi, Benedetta

    2017-12-21

    Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific LCK gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperactivation in PPR patients upregulates the calcineurin/nuclear factor of activated T cells signaling triggering to interleukin-4 ( IL-4 ) overexpression. GC-sensitive cells cultured with IL-4 display an increased resistance to dexamethasone, whereas the inhibition of IL-4 signaling could increase GC-induced apoptosis in resistant cells. Treatment with dexamethasone and dasatinib also impaired engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients. © 2017 by The American Society of Hematology.

  9. Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells.

    Directory of Open Access Journals (Sweden)

    Moina Hasni Ebou

    Full Text Available Diabetes is a major complication of chronic Glucocorticoids (GCs treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1 and 2 (Tph2, leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells.

  10. Effect of the systemic versus inhalatory administration of synthetic glucocorticoids on the urinary steroid profile as studied by gas chromatography-mass spectrometry

    International Nuclear Information System (INIS)

    Mazzarino, Monica; Rossi, Francesca; Giacomelli, Laura; Botre, Francesco

    2006-01-01

    This paper presents a gas chromatography-mass spectrometry (GC-MS) study carried out on human urine to verify whether the administration of glucocorticoids can affect the urinary steroid profile, and especially the levels of endogenous glucocorticoids, androgens and their main metabolites. Betamethasone and beclomethasone, administered either systemically (per os or i.m.) or locally (by inhalation) have been studied. The determination of the urinary levels of endogenous glucocorticoids and androgens was carried out by GC-MS in electron impact ionization mode. Data were evaluated taking into account the baseline individual variability, and compared with values obtained on a control group. Detectable differences were recorded in the steroids metabolites excretion profiles between men and women. The circadian variability of the steroid profile was the same for both sexes, showing a maximum during the morning hours. After systemic treatment with synthetic glucocorticoids, the relative urinary concentrations of corticosteroids, androgens and of their metabolites were significantly altered, recording a transient decrease of the concentration of cortisol and tetrahydrocortisol and a parallel, although less pronounced, increase of the concentration of testosterone, epitestosterone and related androgenic steroids; while no effects were recorded if the administration was by inhalation

  11. Piper sarmentosum Effects on 11β-Hydroxysteroid Dehydrogenase Type 1 Enzyme in Serum and Bone in Rat Model of Glucocorticoid-Induced Osteoporosis.

    Science.gov (United States)

    Mohamad Asri, Siti Fadziyah; Mohd Ramli, Elvy Suhana; Soelaiman, Ima Nirwana; Mat Noh, Muhamad Alfakry; Abdul Rashid, Abdul Hamid; Suhaimi, Farihah

    2016-11-15

    Glucocorticoid-induced osteoporosis is one of the common causes of secondary osteoporosis. Piper sarmentosum ( Ps ) extract possesses antioxidant and anti-inflammatory activities. In this study, we determined the correlation between the effects of Ps leaf water extract with the regulation of 11β-hydroxysteroid dehydrogenase (HSD) type 1 enzyme activity in serum and bone of glucocorticoid-induced osteoporotic rats. Twenty-four Sprague-Dawley rats were grouped into following: G1: sham-operated group administered with intramuscular vehicle olive oil and vehicle normal saline orally; G2: adrenalectomized (adrx) control group given intramuscular dexamethasone (120 μg/kg/day) and vehicle normal saline orally; G3: adrx group given intramuscular dexamethasone (120 μg/kg/day) and water extract of Piper sarmentosum (125 mg/kg/day) orally. After two months, the femur and serum were taken for ELISA analysis. Results showed that Ps leaf water extract significantly reduced the femur corticosterone concentration ( p < 0.05). This suggests that Ps leaf water extract was able to prevent bone loss due to long-term glucocorticoid therapy by acting locally on the bone cells by increasing the dehydrogenase action of 11β-HSD type 1. Thus, Ps may have the potential to be used as an alternative medicine against osteoporosis and osteoporotic fracture in patients on long-term glucocorticoid treatment.

  12. Effect of the systemic versus inhalatory administration of synthetic glucocorticoids on the urinary steroid profile as studied by gas chromatography-mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Mazzarino, Monica [Laboratorio Antidoping, Federazione Medico Sportiva Italiana, Largo Giulio Onesti 1, 00197 Rome (Italy); Rossi, Francesca [Laboratorio Antidoping, Federazione Medico Sportiva Italiana, Largo Giulio Onesti 1, 00197 Rome (Italy); Giacomelli, Laura [Dipartimento di Scienze Chirurgiche, Universita La Sapienza, Viale Regina Elena 324, 00161 Rome (Italy); Botre, Francesco [Laboratorio Antidoping, Federazione Medico Sportiva Italiana, Largo Giulio Onesti 1, 00197 Rome (Italy) and Dipartimento CGMIA, Universita La Sapienza, Via del Castro Laurenziano 9, 00161 Rome (Italy)]. E-mail: francesco.botre@uniroma1.it

    2006-02-10

    This paper presents a gas chromatography-mass spectrometry (GC-MS) study carried out on human urine to verify whether the administration of glucocorticoids can affect the urinary steroid profile, and especially the levels of endogenous glucocorticoids, androgens and their main metabolites. Betamethasone and beclomethasone, administered either systemically (per os or i.m.) or locally (by inhalation) have been studied. The determination of the urinary levels of endogenous glucocorticoids and androgens was carried out by GC-MS in electron impact ionization mode. Data were evaluated taking into account the baseline individual variability, and compared with values obtained on a control group. Detectable differences were recorded in the steroids metabolites excretion profiles between men and women. The circadian variability of the steroid profile was the same for both sexes, showing a maximum during the morning hours. After systemic treatment with synthetic glucocorticoids, the relative urinary concentrations of corticosteroids, androgens and of their metabolites were significantly altered, recording a transient decrease of the concentration of cortisol and tetrahydrocortisol and a parallel, although less pronounced, increase of the concentration of testosterone, epitestosterone and related androgenic steroids; while no effects were recorded if the administration was by inhalation.

  13. Fatigue and gene expression in human leukocytes: Increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue

    Science.gov (United States)

    Bower, Julienne E.; Ganz, Patricia A.; Irwin, Michael R.; Arevalo, Jesusa M.G.; Cole, Steve W.

    2013-01-01

    Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n = 11) and non-fatigued controls (n = 10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p < .05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors. PMID:20854893

  14. Prolonged pregnancy: Methods, Causal Determinants and Outcome

    DEFF Research Database (Denmark)

    Olesen, Annette Wind

    Summary Prolonged pregnancy, defined as a pregnancy with a gestational length of 294 days or more, is a frequent condition. It is associated with an increased risk of fetal and maternal complications. Little is known about the aetiology of prolonged pregnancy. The aims of the thesis were 1......) to study the incidence of prolonged pregnancy as a function of methods for determining gestational age; 2) to determine the risk of obstetrical and fetal complications in prolonged pregnancy; 3) to validate the self-reported gestational age in the National Birth Cohort; 4) to determine whether...... the risk of recurrence of prolonged pregnancy as a function of change in male partner and social conditions (IV). The National Birth Cohort provided data for the study on prenatal risk indicators of prolonged pregnancy in a follow-up design (V). The self-reported gestational ages from this database...

  15. Glucocorticoids mediate stress-induced impairment of retrieval of stimulus-response memory.

    Science.gov (United States)

    Atsak, Piray; Guenzel, Friederike M; Kantar-Gok, Deniz; Zalachoras, Ioannis; Yargicoglu, Piraye; Meijer, Onno C; Quirarte, Gina L; Wolf, Oliver T; Schwabe, Lars; Roozendaal, Benno

    2016-05-01

    Acute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair the retrieval of non-hippocampal memories. In particular, stress shortly before retention testing was shown to impair the retrieval of striatal stimulus-response associations in humans. However, the mechanism underlying this stress-induced retrieval impairment of non-hippocampal stimulus-response memory remains elusive. In the present study, we investigated whether an acute elevation in glucocorticoid levels mediates the impairing effects of stress on retrieval of stimulus-response memory. Male Sprague-Dawley rats were trained on a stimulus-response task in an eight-arm radial maze until they learned to associate a stimulus, i.e., cue, with a food reward in one of the arms. Twenty-four hours after successful acquisition, they received a systemic injection of vehicle, corticosterone (1mg/kg), the corticosterone-synthesis inhibitor metyrapone (35mg/kg) or were left untreated 1h before retention testing. We found that the corticosterone injection impaired the retrieval of stimulus-response memory. We further found that the systemic injection procedure per se was stressful as the vehicle administration also increased plasma corticosterone levels and impaired the retrieval of stimulus-response memory. However, memory retrieval was not impaired when rats were tested 2min after the systemic vehicle injection, before any stress-induced elevation in corticosterone levels had occurred. Moreover, metyrapone treatment blocked the effect of injection stress on both plasma corticosterone levels and memory retrieval impairment, indicating that the endogenous corticosterone response mediates the stress-induced memory retrieval impairment. None of the treatments affected rats' locomotor activity or motivation to search for the food reward within the maze. These findings show that stress

  16. Expression microarray identifies the unliganded glucocorticoid receptor as a regulator of gene expression in mammary epithelial cells

    International Nuclear Information System (INIS)

    Ritter, Heather D; Mueller, Christopher R

    2014-01-01

    While glucocorticoids and the liganded glucocorticoid receptor (GR) have a well-established role in the maintenance of differentiation and suppression of apoptosis in breast tissue, the involvement of unliganded GR in cellular processes is less clear. Our previous studies implicated unliganded GR as a positive regulator of the BRCA1 tumour suppressor gene in the absence of glucocorticoid hormone, which suggested it could play a similar role in the regulation of other genes. An shRNA vector directed against GR was used to create mouse mammary cell lines with depleted endogenous levels of this receptor in order to further characterize the role of GR in breast cells. An expression microarray screen for targets of unliganded GR was performed using our GR-depleted cell lines maintained in the absence of glucocorticoids. Candidate genes positively regulated by unliganded GR were identified, classified by Gene Ontology and Ingenuity Pathway Analysis, and validated using quantitative real-time reverse transcriptase PCR. Chromatin immunoprecipitation and dual luciferase expression assays were conducted to further investigate the mechanism through which unliganded GR regulates these genes. Expression microarray analysis revealed 260 targets negatively regulated and 343 targets positively regulated by unliganded GR. A number of the positively regulated targets were involved in pro-apoptotic networks, possibly opposing the activity of liganded GR targets. Validation and further analysis of five candidates from the microarray indicated that two of these, Hsd11b1 and Ch25h, were regulated by unliganded GR in a manner similar to Brca1 during glucocorticoid treatment. Furthermore, GR was shown to interact directly with and upregulate the Ch25h promoter in the absence, but not the presence, of hydrocortisone (HC), confirming our previously described model of gene regulation by unliganded GR. This work presents the first identification of targets of unliganded GR. We propose that

  17. 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.

  18. A role for glucocorticoids in the long-term establishment of a social hierarchy.

    Science.gov (United States)

    Timmer, Marjan; Sandi, Carmen

    2010-11-01

    Stress can affect the establishment and maintenance of social hierarchies. In the present study, we investigated the role of increasing corticosterone levels before or just after a first social encounter between two rats of a dyad in the establishment and the long-term maintenance of a social hierarchy. We show that pre-social encounter corticosterone treatment does not affect the outcome of the hierarchy during a first encounter, but induces a long-term memory for the hierarchy when the corticosterone-injected rat becomes dominant during the encounter, but not when it becomes subordinate. Post-social encounter corticosterone leads to a long-term maintenance of the hierarchy only when the subordinate rat of the dyad is injected with corticosterone. This corticosterone effect mimics previously reported actions of stress on the same model and, hence, implicates glucocorticoids in the consolidation of the memory for a recently established hierarchy. Copyright © 2010 Elsevier Ltd. All rights reserved.

  19. Thyroid storm masked by hemodialysis and glucocorticoid therapy in a patient with rheumatoid arthritis.

    Science.gov (United States)

    Sasaki, Yohei; Shimizu, Yoshio; Nakata, Junichiro; Kameda, Toshiaki; Muto, Masahiro; Ohsawa, Isao; Io, Hiroaki; Hamada, Chieko; Horikoshi, Satoshi; Tomino, Yasuhiko

    2012-01-01

    Thyroid function test values are generally at low levels in patients with end-stage kidney disease. Life-threatening thyrotoxicosis or thyroid storm is rare, especially in hemodialysis (HD) patients, and is characterized by multisystem involvement and a high mortality rate if not immediately recognized and treated. Here, we report a female patient with severe symptomatic thyroid storm, receiving long-term HD and glucocorticoid therapy. Methimazole at a dose of 15 mg per day, β-adrenergic blockade and HD succeeded in controlling the patient's condition by gradually adjusting the target dry weight for hyperthyroidism-induced weight loss. When she was discharged from the hospital, her dry weight was reduced from 47.2 to 39.2 kg. The management of patients with severe symptomatic thyroid storm on HD represents a rare scenario. It is essential to initiate the available treatments as early as possible to reduce its mortality.

  20. Early adverse experience and substance addiction: dopamine, oxytocin, and glucocorticoid pathways

    Science.gov (United States)

    Kim, Sohye; Kwok, Stephanie; Mayes, Linda C.; Potenza, Marc N.; Rutherford, Helena J. V.; Strathearn, Lane

    2016-01-01

    Substance addiction may follow a chronic, relapsing course and critically undermine the physical and psychological well-being of the affected individual and the social units of which the individual is a member. Despite the public health burden associated with substance addiction, treatment options remain suboptimal, with relapses often seen. The present review synthesizes growing insights from animal and human research to shed light upon developmental and neurobiological pathways that may increase susceptibility to addiction. We examine the dopamine system, the oxytocin system, and the glucocorticoid system, as they are particularly relevant to substance addiction. Our aim is to delineate how early adverse experience may induce long-lasting alterations in each of these systems at molecular, neuroendocrine, and behavioral levels and ultimately lead to heightened vulnerability to substance addiction. We further discuss how substance addiction in adulthood may increase the risk of suboptimal caregiving for the next generation, perpetuating the intergenerational cycle of early adverse experiences and addiction. PMID:27508337

  1. Smoking prolongs the infectivity of patients with tuberculosis.

    LENUS (Irish Health Repository)

    Siddiqui, U A

    2010-10-01

    We sought to establish if smokers on anti-tuberculosis treatment are more likely to have a prolonged period of infectivity, compared to non-smoking tuberculosis patients, in a low tuberculosis prevalence country. We conducted a cross-sectional, retrospective study in Ireland that recruited 53 microbiologically confirmed cases of pulmonary tuberculosis (PTB). The age-sex adjusted odds ratios (AOR) suggest that the infectivity status of PTB on treatment was four times more likely to be prolonged beyond 6-8 weeks, if the cases had a smoking history (AOR: 4.42; 95% CI: 1.23; 15.9). Smoking was associated with delayed sputum smear conversion in PTB patients on treatment.

  2. Effects of glucocorticoid combined with antibiotics on serum infection indexes, acute phase proteins and stress hormones in patients with severe pneumonia

    Directory of Open Access Journals (Sweden)

    Yang Yu

    2017-10-01

    Full Text Available Objective: To study the effects of glucocorticoid combined with antibiotics on serum infection indexes, acute phase proteins and stress hormones in patients with severe pneumonia. Methods: a total of 80 patients with severe pneumonia who were hospitalized between August 2014 and January 2017 were retrospectively analyzed and divided into the routine treatment group (n=46 who received conventional antibiotic therapy and the combined treatment group (n=34 who received glucocorticoid combined with antibiotic therapy, and the differences in infection indexes, acute proteins and stress hormones were compared between the two groups of patients before and after treatment. Results: The differences in serum levels of infection indexes, acute phase proteins and stress hormones were not statistically significant between the two groups before treatment. After 1 week of treatment, serum infection indexes CRP and PCT levels of observation group were lower than those of control group; serum acute phase proteins α1-AT, α1-AG and CER levels were lower than those of control group; serum stress hormones Cor, AngⅠ and AngⅡ levels were lower than those of control group. Conclusion: Glucocorticoid combined with antibiotics can effectively inhibit systemic infection and stress and optimize the illness in patients with severe pneumonia.

  3. Clinical observation of alprostadil combined with glucocorticoids on acute optic neuritis

    Directory of Open Access Journals (Sweden)

    Ke-Shun Fan

    2015-09-01

    Full Text Available AIM: To study the clinical effect of alprostadil combined with glucocorticoids in the treatment of acute optic neuritis(AON.METHODS: Seventy patients(70 eyeswith AON from January, 2012 to June, 2014 were randomly divided into two groups. 35 patients in observation group were used 10ug alprostadil with 10mL normal saline(NSby intravenous injection, once/d for 7d/one treatment course, and 10mL NS was used by intravenous injection in 35 patients of control group. Besides, the two groups were treated with the combined therapy as follows: 20mg methylprednisolone was injected periglomerularly beside the eyeballs, once /3d for 3 times; 800~1 000mg of methylprednisolone through intravenous drip for 3d, once/d; after 3d, oral administration of prednisone acetate for 1wk, 1mg/(kg·d; after 1wk, the dose decreased to 5mg/wk until withdraw. Simultaneously, oral administration of ranitidine capsules, calcium carbonate and vitamin D3 tablets were combined in the supportive treament. The differences of curative effect between two groups were comparatively analyzed.RESULTS: In the observation group, 25 eyes(71.4%were markedly effective, 7 eyes(20.0%were valid and 3 eyes(8.6%were invalid, and the total effective rate was 91.4%. In the control group, 15 eyes(42.9%were markedly effective, 14 eyes(40.0%were valid and 6 eyes(17.1%were invalid, and the total effective rate was 82.9%. The difference of total effective rate between the two groups was not statistically significant(P=0.477, but there was a significant difference in markedly effective rate between the two groups(χ2=5.833, P=0.016.CONCLUSION: Alprostadil combined with glucocorticoids is effective for AON, and it is worth of advocation.

  4. Inherently variable responses to glucocorticoid stress among endogenous retroviruses isolated from 23 mouse strains.

    Science.gov (United States)

    Hsu, Karen; Lee, Young-Kwan; Chew, Alex; Chiu, Sophia; Lim, Debora; Greenhalgh, David G; Cho, Kiho

    2017-10-01

    Active participation of endogenous retroviruses (ERVs) in disease processes has been exemplified by the finding that the HERV (human ERV)-W envelope protein is involved in the pathogenesis of multiple sclerosis, an autoimmune disease. We also demonstrated that injury-elicited stressors alter the expression of murine ERVs (MuERVs), both murine leukemia virus-type and mouse mammary tumor virus (MMTV)-type (MMTV-MuERV). In this study, to evaluate MMTV-MuERVs' responses to stress (e.g., injury, infection)-elicited systemic glucocorticoid (GC) levels, we examined the GC-stress response of 64 MMTV-MuERV promoters isolated from the genomes of 23 mouse strains. All 64 promoters responded to treatment with a synthetic GC, dexamethasone (DEX), at a wide range from a 0.6- to 85.7-fold increase in reporter activity compared to no treatment. An analysis of the 10 lowest and 10 highest DEX responders revealed specific promoter elements exclusively present in either the three lowest or the two highest responders. Each promoter had a unique profile of transcription regulatory elements and the glucocorticoid response element (GRE) was identified in all promoters with the number of GREs ranging from 2 to 7. The three lowest DEX responders were the only promoters with two GREs. The findings from this study suggest that certain MMTV-MuERVs are more responsive to stress-elicited systemic GC elevation compared to the others. The mouse strain-specific genomic MMTV-MuERV profiles and individual MMTV-MuERVs' differential responses to GC-stress might explain, at least in part, the variable inflammatory responses to injury and/or infection, often observed among different mouse strains. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Glucocorticoids and laminitis in the horse.

    Science.gov (United States)

    Johnson, Philip J; Slight, Simon H; Ganjam, Venkataseshu K; Kreeger, John M

    2002-08-01

    The administration of exogenously administered GCs and syndromes associated with GC excess are both attended by increased risk for the development of laminitis in adult horses. However, there exists substantial controversy as to whether excess GCs cause laminitis de novo. If true, the pathogenesis of laminitis arising from the effects of GC excess is probably different from that associated with diseases of the gastrointestinal tract and endotoxemia. Although a satisfactory explanation for the development of laminitis as a consequence of GC action is currently lacking, numerous possible and plausible theoretical mechanisms do exist. Veterinarians must exert caution with respect to the use of GCs in adult horses. The extent to which individual horses are predisposed to laminitis as a result of GC effect cannot be predicted based on current information. However, the administration of systemic GCs to horses that have been previously affected by laminitis should be used only with extreme caution, and should be accompanied by careful monitoring for further signs of laminitis. The risk of laminitis appears to be greater during treatment using some GCs (especially dexamethasone and triamcinalone) compared with others (prednisone and prednisolone). Whenever possible, to reduce the risk of laminitis, GCs should be administered locally. For example, the risk of GC-associated laminitis is evidently considerably reduced in horses affected with chronic obstructive pulmonary disease (COPD) if GC treatment is administered via inhalation. We have hypothesized that structural changes in the equine hoof that resemble laminitis may arise as a consequence of excess GC effect. Although these changes are not painful per se, and are not associated with inflammation, they could likely predispose affected horses to the development of bona fide laminitis for other reasons. Moreover, the gross morphological appearance of the chronically GC-affected hoof resembles that of a chronically

  6. Methylprednisolone Pulse Treatment of Graves´Ophthalmopathy is not associated with secondary Adrenocortical insufficiency

    DEFF Research Database (Denmark)

    Nygaard, Birte; Kristensen, Lars Østergaard

    2015-01-01

    Objective: Graves' ophthalmopathy (GO) is an inflammatory disease in the orbital region. The first-line medical treatment is glucocorticoids. An important potential side effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal (HPA) axis with impairment of endogenous...

  7. Safety information on QT-interval prolongation

    DEFF Research Database (Denmark)

    Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H

    2014-01-01

    Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approve...

  8. Risk factors for QTc interval prolongation

    NARCIS (Netherlands)

    Heemskerk, Charlotte P.M.; Pereboom, Marieke; van Stralen, Karlijn; Berger, Florine A.; van den Bemt, Patricia M.L.A.; Kuijper, Aaf F.M.; van der Hoeven, Ruud T M; Mantel-Teeuwisse, Aukje K.; Becker, Matthijs L

    2018-01-01

    Purpose: Prolongation of the QTc interval may result in Torsade de Pointes, a ventricular arrhythmia. Numerous risk factors for QTc interval prolongation have been described, including the use of certain drugs. In clinical practice, there is much debate about the management of the risks involved. In

  9. Prenatal risk indicators of a prolonged pregnancy

    DEFF Research Database (Denmark)

    Olesen, Annette Wind; Westergaard, Jes Grabow; Olsen, Jørn

    2006-01-01

    BACKGROUND: Few prenatal risk factors of prolonged pregnancy, a pregnancy of 42 weeks or more, are known. The objective was to examine whether sociodemographic, reproductive, toxicologic, or medical health conditions were associated with the risk of prolonged pregnancy. METHODS: Data from...

  10. Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

    NARCIS (Netherlands)

    Roozendaal, Benno; McReynolds, Jayme R.; Van der Zee, Eddy A.; Lee, Sangkwan; McGaugh, James L.; McIntyre, Christa K.

    2009-01-01

    Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing

  11. [Brain function recovery after prolonged posttraumatic coma].

    Science.gov (United States)

    Klimash, A V; Zhanaidarov, Z S

    2016-01-01

    To explore the characteristics of brain function recovery in patients after prolonged posttraumatic coma and with long-unconscious states. Eighty-seven patients after prolonged posttraumatic coma were followed-up for two years. An analysis of a clinical/neurological picture after a prolonged episode of coma was based on the dynamics of vital functions, neurological status and patient's reactions to external stimuli. Based on the dynamics of the clinical/neurological picture that shows the recovery of functions of the certain brain areas, three stages of brain function recovery after a prolonged episode of coma were singled out: brain stem areas, diencephalic areas and telencephalic areas. These functional/anatomic areas of brain function recovery after prolonged coma were compared to the present classifications.

  12. 9. Nuclear power plant service life prolongation

    International Nuclear Information System (INIS)

    Evropin, S.V.

    1998-01-01

    The problem of prolongation of nuclear power plant service life duration is discussed. A schematic diagram of the program developed in the course of activities dealing with NPP service time prolongation is shown and analyzed in details. It is shown that the basic moment when determining the strategy for NPP service time prolongation is the positive confirmation of the agreement between the NPP safety provisions and modern safety requirements. The other very important aspect of the problem is engineering substantiation of the measures assuring the reactor operation prolongation. The conclusion is made that available methods of recovering reactor materials properties, main components repair and replacement, the modern techniques for nondestructive testing of metals and NPP pipelines, as well as the developed approaches to reactor facility safety improvements make the prolongation of the Russian NPP service lifetimes possible from engineering viewpoint and economically desirable

  13. Glucocorticoid receptor gene polymorphism and juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Scheplyagina Larisa A

    2011-01-01

    Full Text Available Abstract Background The glucocorticoid receptor gene (NR3C1 has been suggested as a candidate gene affecting juvenile idiopathic arthritis (JIA course and prognosis. The purpose of this study is to investigate the glucocorticoid receptor gene BclI polymorphism (rs41423247 in JIA patients, the gene's role in susceptibility to juvenile idiopathic arthritis, and its associations with JIA activity, course and bone mineralization. Methods One hundred twenty-two Caucasian children with JIA and 143 healthy ethnically matched controls were studied. We checked markers of clinical and laboratory activity: morning stiffness, Ritchie Articular Index (RAI, swollen joint count (SJC, tender joint count (TJC, physician's visual analog scale (VAS, hemoglobin level (Hb, leukocyte count (L, platelet count (Pl, Westergren erythrocyte sedimentation rate (ESR, C-reactive protein (CRP, albumin, DAS and DAS28. Bone mineralization was measured by dual-energy X-ray absorptiometry (DXA of lumbar spine L1-L4. Assessments of bone metabolism included osteocalcin, C-terminal telopeptide (CTT, parathyroid hormone (PTH, total and ionized calcium, inorganic phosphate and total alkaline phosphatase (TAP. BclI polymorphism was genotyped by polymerase chain reaction restriction fragment length polymorphism. Results No association was observed between glucocorticoid receptor gene polymorphism and the presence or absence of JIA. In girls with JIA, the presence of the G allele was associated with an unfavorable arthritis course, a younger age of onset of arthritis (p = 0.0017, and higher inflammatory activity. The higher inflammatory activity was demonstrated by the following: increased time of morning stiffness (p = 0.02, VAS (p = 0.014, RAI (p = 0.048, DAS (p = 0.035, DAS28 (p = 0.05, Pl (p = 0.003, L (p = 0.046, CRP (p = 0.01. In addition, these patients had bone metabolism disturbances as follows: decreased BA (p = 0.0001, BMC (p = 0.00007, BMD (0.005 and Z score (p = 0.002; and

  14. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

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

    2014-01-01

    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......-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...

  15. Glucocorticoid resistance as a major drive in sepsis pathology.

    Science.gov (United States)

    Dendoncker, Karen; Libert, Claude

    2017-06-01

    Sepsis is an acute systemic inflammatory disease. Glucocorticoids (GCs), which function by binding to the GC receptor GR have very powerful anti-inflammatory activities, yet they are hardly useful in sepsis. We can thus consider sepsis as a GC resistant disease. We here review the literature which has investigated this GC resistance, and summarize the mechanisms of GC resistance that have been observed in other diseases and in experimental models. We also discuss the importance of GC resistance in sepsis, in terms of the contribution of this phenomenon to the pathogenesis of sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Glucocorticoids Enhance Taste Aversion Memory via Actions in the Insular Cortex and Basolateral Amygdala

    Science.gov (United States)

    Miranda, Maria Isabel; Quirarte, Gina L.; Rodriguez-Garcia, Gabriela; McGaugh, James L.; Roozendaal, Benno

    2008-01-01

    It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function.…

  17. 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

  18. Investigation of radioprotective properties of synthetic antagonist of glucocorticoids RU 38 486

    International Nuclear Information System (INIS)

    Sejliev, A.A.; Zvonareva, N.B.; Zhivotovskij, B.D.; Khanson, K.P.; Akademiya Meditsinskikh Nauk SSSR, Leningrad

    1992-01-01

    Radioprotective properties of synthetic antiglucocorticoid RU 38 486 were investigated. It was demonstrated that this antigonist of glucocorticoids possesses radioprotective effect in vitro and in vivo systems. Radioprotective properties at molecular level exhibited in inhibition of postirradiation endonuclease activation and in prevention of internucleosome chromatin degradation. Involvement of cytosol glucocorticoid receptors in initiation of radiation-induced programmed cell death is discussed

  19. Pulsatile thyrotropin secretion in patients with Addison's disease during variable glucocorticoid therapy

    DEFF Research Database (Denmark)

    Hangaard, J; Andersen, M; Grodum, E

    1996-01-01

    , increasing significantly (P glucocorticoids, when the pulse frequency was also significantly reduced (P ... of glucocorticoids on the TSH response to TRH, our data indicate that even physiological serum levels of cortisol have an influence on endogenous TSH secretion, probably caused by regulation of the pituitary sensitivity to TRH....

  20. 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...

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

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Timm, Jeanette; Ibsen, Ida

    2012-01-01

    Quantification of glucocorticoid metabolites in feces has been shown to be a powerful tool in evaluating well-being in vertebrates. Little is known however about the hypothalamic–pituitary–adrenal axis response to stressors, and consequent glucocorticoid excretion, in reptiles. In a longitudinal...

  2. Glucocorticoid metabolites in newborns: A marker for traffic noise related stress?

    DEFF Research Database (Denmark)

    Lech Cantuaria, Manuella; Usermann, Jakob; Proietti, Elena

    2018-01-01

    Traffic noise has been associated with an increased risk for several non-auditory health effects, which may be explained by a noise-induced release of stress hormones (e.g. glucocorticoids). Although several studies in children and adults have indicated an increased secretion of glucocorticoids...

  3. 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. Published by Elsevier Ltd.

  4. Prolonged refractory dysphagia in polymyositis

    OpenAIRE

    Thomas Mathew; Mohan Muvvala; G R K Sarma; Raghunandan Nadig

    2015-01-01

    Herein, we report a patient with polymyositis (biopsy proved) with dysphagia that did not improve with conventional treatment. An upper gastrointestinal (GI) endoscopy showed esophageal stricture and a biopsy taken from the site revealed evidence of squamous cell carcinoma.

  5. Nicotinic Acid-Mediated Activation of Both Membrane and Nuclear Receptors towards Therapeutic Glucocorticoid Mimetics for Treating Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    W. Todd Penberthy

    2009-01-01

    Full Text Available Acute attacks of multiple sclerosis (MS are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA is now known to involve induction of indoleamine 2,3-dioxygenase (IDO and interleukin-10 (IL-10, where IL-10 requires subsequent heme oxygenase-1 (HMOX-1 induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2 can prevent demyelination in experimental autoimmune encephalomyelitis (EAE animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the prostaglandin 15-deoxy-Δ12,14-PGJ2. Nicotinamide profoundly ameliorates and prevents autoimmune-mediated demyelination in EAE via maintaining levels of nicotinamide adenine dinucleotide (NAD, without activating PPAR nor any G-protein-coupled receptor. By comparison, nicotinic acid provides even greater levels of NAD than nicotinamide in many tissues, while additionally activating the PPAR-dependent pathway already shown to provide relief in animal models of MS after activation of GPR109a/HM74a. Thus nicotinic acid is uniquely suited for providing therapeutic relief in MS. However nicotinic acid is unexamined in MS research. Nicotinic acid penetrates the blood brain barrier, cures pellagric dementia, has been used for over 50 years clinically without toxicity, and raises HDL concentrations to a greater degree than any pharmaceutical, thus providing unparalleled benefits against lipodystrophy. Summary analysis reveals that the expected therapeutic benefits of high-dose nicotinic

  6. Glucocorticoid effects on the programming of AT1b angiotensin receptor gene methylation and expression in the rat.

    Directory of Open Access Journals (Sweden)

    Irina Bogdarina

    2010-02-01

    Full Text Available Adverse events in pregnancy may 'programme' offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11beta-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence.

  7. The effects of glucocorticoids on the inhibition of emotional information: A dose-response study.

    Science.gov (United States)

    Taylor, Véronique A; Ellenbogen, Mark A; Washburn, Dustin; Joober, Ridha

    2011-01-01

    There is evidence that cortisol influences cognitive and affective processes such as selective attention and memory for emotional events, yet the effects of glucocorticoids on attentional inhibition in humans remain unknown. Consequently, this double-blind study examined dose-dependent effects of exogenous glucocorticoids on the inhibition of emotional information. Sixty-three university students (14 male, 49 female) ingested either a placebo pill or hydrocortisone (10mg or 40mg), and completed a negative priming task assessing the inhibition of pictures depicting angry, sad, and happy faces. The 10mg, but not the 40mg hydrocortisone dose elicited increased inhibition for angry faces relative to placebo. Thus, moderate glucocorticoid elevations may have adaptive effects on emotional information processing, whereas high glucocorticoid elevations appear to attenuate this effect, consistent with the view that there are dose-dependent effects of glucocorticoids on cognition. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle

    DEFF Research Database (Denmark)

    Søe, Kent; Delaissé, Jean-Marie

    2010-01-01

    that glucocorticoids deeply modify this resorptive behavior. First, glucocorticoids gradually induce excavations with a trenchlike morphology while reducing the time-dependent increase in excavation numbers. This indicates that glucocorticoids make osteoclasts elongate the excavations they initiated rather than...... migrating to a new resorption site, as in control conditions. Second, the round excavations in control conditions contain undegraded demineralized collagen as repeatedly reported earlier, whereas the excavations with a trenchlike morphology generated under glucocorticoid exposure appear devoid of leftovers...... of demineralized collagen. This indicates that collagenolysis proceeds generally at a lower rate than demineralization under control conditions, whereas collagenolysis rates are increased up to the level of demineralization rates in the presence of glucocorticoids. Taking these observations together leads...

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

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor (GR), which may compensate for diminished AR activity. The

  10. Expression and function of nuclear receptor coregulators in brain : understanding the cell-specific effects of glucocorticoids

    NARCIS (Netherlands)

    Laan, Siem van der

    2008-01-01

    Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding

  11. 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....

  12. A membrane glucocorticoid receptor mediates the rapid/non-genomic actions of glucocorticoids in mammalian skeletal muscle fibres.

    Science.gov (United States)

    Pérez, María Hernández-Alcalá; Cormack, Jonathan; Mallinson, David; Mutungi, Gabriel

    2013-10-15

    Glucocorticoids (GCs) are steroid hormones released from the adrenal gland in response to stress. They are also some of the most potent anti-inflammatory and immunosuppressive drugs currently in clinical use. They exert most of their physiological and pharmacological actions through the classical/genomic pathway. However, they also have rapid/non-genomic actions whose physiological and pharmacological functions are still poorly understood. Therefore, the primary aim of this study was to investigate the rapid/non-genomic effects of two widely prescribed glucocorticoids, beclomethasone dipropionate (BDP) and prednisolone acetate (PDNA), on force production in isolated, intact, mouse skeletal muscle fibre bundles. The results show that the effects of both GCs on maximum isometric force (Po) were fibre-type dependent. Thus, they increased Po in the slow-twitch fibre bundles without significantly affecting that of the fast-twitch fibre bundles. The increase in Po occurred within 10 min and was insensitive to the transcriptional inhibitor actinomycin D. Also, it was maximal at ∼250 nM and was blocked by the glucocorticoid receptor (GCR) inhibitor RU486 and a monoclonal anti-GCR, suggesting that it was mediated by a membrane (m) GCR. Both muscle fibre types expressed a cytosolic GCR. However, a mGCR was present only in the slow-twitch fibres. The receptor was more abundant in oxidative than in glycolytic fibres and was confined mainly to the periphery of the fibres where it co-localised with laminin. From these findings we conclude that the rapid/non-genomic actions of GCs are mediated by a mGCR and that they are physiologically/therapeutically beneficial, especially in slow-twitch muscle fibres.

  13. Stress impairs reconsolidation of drug memory via glucocorticoid receptors in the basolateral amygdala.

    Science.gov (United States)

    Wang, Xiao-Yi; Zhao, Mei; Ghitza, Udi E; Li, Yan-Qin; Lu, Lin

    2008-05-21

    Relapse to drug taking induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Previous studies indicate that drug seeking can be inhibited by disrupting the reconsolidation of a drug-related memory. Stress plays an important role in modulating different stages of memory including reconsolidation, but its role in the reconsolidation of a drug-related memory has not been investigated. Here, we examined the effects of stress and corticosterone on reconsolidation of a drug-related memory using a conditioned place preference (CPP) procedure. We also determined the role of glucocorticoid receptors (GRs) in the basolateral amygdala (BLA) in modulating the effects of stress on reconsolidation of this memory. We found that rats acquired morphine CPP after conditioning, and that this CPP was inhibited by stress given immediately after re-exposure to a previously morphine-paired chamber (a reconsolidation procedure). The disruptive effect of stress on reconsolidation of morphine related memory was prevented by inhibition of corticosterone synthesis with metyrapone or BLA, but not central amygdala (CeA), injections of the glucocorticoid (GR) antagonist RU38486 [(11,17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one]. Finally, the effect of stress on drug related memory reconsolidation was mimicked by systemic injections of corticosterone or injections of RU28362 [11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one] (a GR agonist) into BLA, but not the CeA. These results show that stress blocks reconsolidation of a drug-related memory, and this effect is mediated by activation of GRs in the BLA.

  14. Impact of vitamin D3 on cardiovascular responses to glucocorticoid excess.

    Science.gov (United States)

    Ahmed, Mona A

    2013-06-01

    Although the cardiovascular system is not a classical target for 1,25-dihydroxyvitamin D3, both cardiac myocytes and vascular smooth muscle cells respond to this hormone. The present study aimed to elucidate the effect of active vitamin D3 on cardiovascular functions in rats exposed to glucocorticoid excess. Adult male Wistar rats were allocated into three groups: control group, dexamethasone (Dex)-treated group receiving Dex (200 μg/kg) subcutaneously for 12 days, and vitamin D3-Dex-treated group receiving 1,25-(OH)2D3 (100 ng/kg) and Dex (200 μg/kg) subcutaneously for 12 days. Rats were subjected to measurement of systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressures and heart rate. Rate pressure product (RPP) was calculated. Rats' isolated hearts were perfused in Langendorff preparation and studied for basal activities (heart rate, peaked developed tension, time to peak tension, half relaxation time, and myocardial flow rate) and their responses to isoproterenol infusion. Blood samples were collected for determination of plasma level of nitrite, nitric oxide surrogate. Dex-treated group showed significant increase in SBP, DBP, MAP, and RPP, as well as cardiac hypertrophy and enhancement of basal cardiac performance evidenced by increased heart rate, rapid and increased contractility, and accelerated lusitropy, together with impaired contractile and myocardial flow rate responsiveness to beta-adrenergic activation and depressed inotropic and coronary vascular reserves. Such alterations were accompanied by low plasma nitrite. These changes were markedly improved by vitamin D3 treatment. In conclusion, vitamin D3 is an efficacious modulator of the deleterious cardiovascular responses induced by glucocorticoid excess, probably via accentuation of nitric oxide.

  15. Internalized stigma in adults with early phase versus prolonged psychosis.

    Science.gov (United States)

    Firmin, Ruth L; Lysaker, Paul H; Luther, Lauren; Yanos, Philip T; Leonhardt, Bethany; Breier, Alan; Vohs, Jenifer L

    2018-03-30

    Although internalized stigma is associated with negative outcomes among those with prolonged psychosis, surprisingly little work has focused on when in the course of one's illness stigma is internalized and the impact of internalization on symptoms or social functioning over the course of the illness. Therefore, this study investigated whether (1) internalized stigma is greater among those later in the course of psychosis and (2) whether internalized stigma has a stronger negative relationship with social functioning or symptoms among those with prolonged compared to early phase psychosis. Individuals with early phase (n = 40) and prolonged psychosis (n = 71) who were receiving outpatient services at an early-intervention clinic and a VA medical center, respectively, completed self-report measures of internalized stigma and interview-rated measures of symptoms and social functioning. Controlling for education, race and sex differences, internalized stigma was significantly greater among those with prolonged psychosis compared to early phase. Internalized stigma was negatively related to social functioning and positively related to symptoms in both groups. Furthermore, the magnitude of the relationship between cognitive symptoms and internalized stigma was significantly greater among those with early phase. Stereotype endorsement, discrimination experiences and social withdrawal also differentially related to symptoms and social functioning across the 2 samples. Findings suggest that internalized stigma is an important variable to incorporate into models of early psychosis. Furthermore, internalized stigma may be a possible treatment target among those with early phase psychosis. © 2018 John Wiley & Sons Australia, Ltd.

  16. Chemical pleurodesis for prolonged postoperative air leak in primary spontaneous pneumothorax

    Directory of Open Access Journals (Sweden)

    Cheng-Hung How

    2014-05-01

    Conclusion: Chemical pleurodesis using OK-432 or minocycline is safe and convenient for prolonged air leak after thoracoscopic treatment for PSP. Our experience suggested that OK-432 may be more effective than minocycline in reducing air leak.

  17. Prolonged CT urography in duplex kidney.

    Science.gov (United States)

    Gong, Honghan; Gao, Lei; Dai, Xi-Jian; Zhou, Fuqing; Zhang, Ning; Zeng, Xianjun; Jiang, Jian; He, Laichang

    2016-05-13

    Duplex kidney is a common anomaly that is frequently associated with multiple complications. Typical computed tomography urography (CTU) includes four phases (unenhanced, arterial, parenchymal and excretory) and has been suggested to considerably aid in the duplex kidney diagnosi. Unfortunately, regarding duplex kidney with prolonged dilatation, the affected parenchyma and tortuous ureters demonstrate a lack of or delayed excretory opacification. We used prolonged-delay CTU, which consists of another prolonged-delay phase (1- to 72-h delay; mean delay: 24 h) to opacify the duplicated ureters and affected parenchyma. Seventeen patients (9 males and 8 females; age range: 2.5-56 y; mean age: 40.4 y) with duplex kidney were included in this study. Unenhanced scans did not find typical characteristics of duplex kidney, except for irregular perirenal morphology. Duplex kidney could not be confirmed on typical four-phase CTU, whereas it could be easily diagnosed in axial and CT-3D reconstruction using prolonged CTU (prolonged-delay phase). Between January 2005 and October 2010, in this review board-approved study (with waived informed consent), 17 patients (9 males and 8 females; age range: 2.5 ~ 56 y; mean age: 40.4 y) with suspicious duplex kidney underwent prolonged CTU to opacify the duplicated ureters and confirm the diagnosis. Our results suggest the validity of prolonged CTU to aid in the evaluation of the function of the affected parenchyma and in the demonstration of urinary tract malformations.

  18. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis.

    Science.gov (United States)

    Hardy, Rowan; Juarez, Maria; Naylor, Amy; Tu, Jinwen; Rabbitt, Elizabeth H; Filer, Andrew; Stewart, Paul M; Buckley, Christopher D; Raza, Karim; Cooper, Mark S

    2012-10-18

    Inflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis. We examined expression and regulation of DKK1 in primary cultures of human synovial fibroblasts isolated from patients with inflammatory arthritis. The effect of TNFα, IL-1β and glucocorticoids on DKK1 mRNA and protein expression was examined by real-time PCR and ELISA. The ability of inflammatory cytokine-induced expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to sensitise fibroblasts to endogenous glucocorticoids was explored. Global expression of Wnt signalling and target genes in response to TNFα and glucocorticoids was assessed using a custom array. DKK1 expression in human synovial fibroblasts was directly regulated by glucocorticoids but not proinflammatory cytokines. Glucocorticoids, but not TNFα, regulated expression of multiple Wnt agonists and antagonists in favour of inhibition of Wnt signalling. However, TNFα and IL-1β indirectly stimulated DKK1 production through increased expression of 11β-HSD1. These results demonstrate that in rheumatoid arthritis synovial fibroblasts, DKK1 expression is directly regulated by glucocorticoids rather than TNFα. Consequently, the links between synovial inflammation, altered Wnt signalling and bone remodelling are not direct but are dependent on local activation of endogenous glucocorticoids.

  19. Risk Factors of Prolonged Hospitalization in Patients with Hyperemesis Gravidarum

    Directory of Open Access Journals (Sweden)

    Hasan Onur Topcu

    2015-03-01

    Conclusion: Number of vomiting per day and maternal serum TSH levels could help physicians to estimate the risk of prolonged hospitalization; however further investigations are needed in large population studies. Identifying the high risk patients is important both for prevention of HEG and beginning appropriate antiemetic treatment to avoid complications to reduce the economic costs. [Cukurova Med J 2015; 40(1.000: 113-118

  20. Stabilization of glucocorticoid receptors in isolated rat hepatocytes by radioprotectants

    International Nuclear Information System (INIS)

    Karle, J.M.; Ridder, W.E.; Wright, N.; Olmeda, R.; Nielsen, C.J.

    1986-01-01

    Previous work has shown that glucocorticoid receptors in rat liver homogenate can be stabilized by the addition of MoO 4 plus the sulfhydryl-containing compounds dithiothreitol and WR 1065. The latter is the dephosphorylated, principal metabolite of the radioprotectant WR 2721 (or S-2-(3-aminopropylamino)ethanesphosphorothioic acid). The current work results from applying this knowledge to intact rat hepatocytes. Cells were isolated by collagenase perfusion and incubated in supplemented minimum essential medium at 37 0 C with various concentrations of WR 2721, WR 1065, or vehicle. Samples of these cell suspensions were analyzed at various times for steroid binding capacity by incubating homogenates (27,000 x g supernates) with 50 nM 3 H-triamcinolone acetonide in the presence or absence of excess unlabelled dexamethasone. Concentrations of 10 mM WR 2721 provided marked preservation of the binding capacity (>85% of the initial value at 5 hours) compared to control at 60% of the binding capacity. WR 1065 at 10 mM provided no such protection. This is consistent with the observation that WR 1065 does not pass cell membranes. The authors propose that supplying reducing equivalents to intracellular components such as the glucocorticoid receptor may be one mechanism of the radioprotection afforded by WR 2721

  1. Fecal Glucocorticoid Analysis: Non-invasive Adrenal Monitoring in Equids.

    Science.gov (United States)

    Yarnell, Kelly; Purcell, Rebecca S; Walker, Susan L

    2016-04-25

    Adrenal activity can be assessed in the equine species by analysis of feces for corticosterone metabolites. During a potentially aversive situation, corticotrophin releasing hormone (CRH) is released from the hypothalamus in the brain. This stimulates the release of adrenocorticotrophic hormone (ACTH) from the pituitary gland, which in turn stimulates release of glucocorticoids from the adrenal gland. In horses the glucocorticoid corticosterone is responsible for several adaptations needed to support equine flight behaviour and subsequent removal from the aversive situation. Corticosterone metabolites can be detected in the feces of horses and assessment offers a non-invasive option to evaluate long term patterns of adrenal activity. Fecal assessment offers advantages over other techniques that monitor adrenal activity including blood plasma and saliva analysis. The non-invasive nature of the method avoids sampling stress which can confound results. It also allows the opportunity for repeated sampling over time and is ideal for studies in free ranging horses. This protocol describes the enzyme linked immunoassay (EIA) used to assess feces for corticosterone, in addition to the associated biochemical validation.