GCS Treatment Research Articles

Exosomes from bone marrow mesenchymal stem cells ameliorate glucocorticoid-induced osteonecrosis of femoral head by transferring microRNA-210 into bone microvascular endothelial cells

ObjectivesBone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model.MethodsBMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA−210 mimic and BMSC-ExosmiRNA−210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA−210 mimic and BMSC-ExosmiRNA−210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague–Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA−210 mimic or BMSC-ExosmiRNA−210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model.ResultsDifferent concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA−210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA−210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA−210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads.ConclusionsBMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

Influence of perception of glucocorticoids on compliance of treatment in patients with rheumatoid arthritis and systemic lupus erythematosus

BackgroundGlucocorticoids (GCs) are alleged as hazardous medications among Egyptian patients and their relatives. Aim of the workTo highlight the beliefs held about GCs and the effect of these beliefs on adherence to GCs treatment. Patients and methodsThe study included 70 systemic lupus erythematosus (SLE) patients, 70 rheumatoid arthritis (RA) patients and 140 GC-naïve subjects as the control. The demographic and socioeconomic standards of the patients and control as well as the GCs use experience in patients were recorded. GCs perception was assessed by Beliefs about medication Questionnaire (BMQ). Adherence was assessed by Compliance Questionnaire of Rheumatology (CQR). ResultsGCs were significantly perceived as harmful and of low benefit by the control (p < 0.001, p < 0.001, respectively), a beneficial drug by SLE patients, while RA patients had significantly higher harm scores (p = 0.015 and p = 0.003 respectively). Most of SLE and RA patients were non-adherent (57.1% and 65.7%, respectively). Higher general-BMQ harm scores were significantly associated with a lower odd of adherence (OR: 0.25, 95%CI: 0.1–0.63). Reduced OR of necessity > concern was associated with higher socioeconomic standards and maximum oral GCs dose (OR:0.09 and 0.96, respectively). Increased OR of high necessity was significantly associated with number of currently used disease modifying anti-rheumatic drugs (DMARDs) (OR:5.54, p = 0.025). High OR of harm perception was significantly associated with higher socioeconomic standards (OR: 5.12, p = 0.016). ConclusionGCs are perceived as pillars in management by SLE and RA patients. Concerns about side effects and dependency are still troublesome. Improvement of patients’ GCs perception impacts level of adherence to treatment.

Myocarditis in patients treated with anti–programmed death-1/programmed death ligand 1 therapy.

e14579 Background: We retrospectively analysed the cases of immune checkpoint inhibitor(ICI) -associated myocarditis managed in PUMCH. We aim to investigate the clinical characteristics of myocarditis and the risk factors affecting the prognosis. Methods: Medical records of all checkpoint inhibitor-related myocarditis were reviewed retrospectively. Descriptive statistics were used for the report of clinical outcomes. Univariate and multivariate Logistic analyses were performed to establish a prognostic model. Results: The median age of 19 patients was 64 years old (range 39̃80 years). The median time of onset from the iniatial of ICIs was 21 days (ranging from 2 to 375 days). Seven cases were grade 4 (36.8%), 2 cases were grade 3 (10.5%), 8 cases were grade 2 (42.1%), and 2 cases were grade 1 (10.5%). Clinical symptoms included dyspnea (13/19, 68.4%), fatigue (11/19, 57.9%), myalgia/myasthenia (9/19, 47.4%), sweating (6/19, 31.6%) and palpitation (6/19, 31.6%) et al. 47.4% (9/19) of the patients showed cardiac insufficiency/hemodynamic instability at first, and 52.6% (10/19) of the patients showed symptoms related to myositis first. cTnI and CK increased in all patients. The level of cTnI was significantly higher in grade 3̃4 than that in grade 1-2. NTproBNP was elevated in all grade 4 cases and one grade 3 case. The LVEF decreased only in 4 patients with grade 4 myocarditis (4/19, 22.2%). The electrocardiogram showed ventricular arrhythmia in 4 cases and complete atrioventricular block (3°AVB) in 3 cases. All patients were treated with corticosteroids (GCS). Grade 4 (6 cases), grade 3 (1 case) and grade 2 (2 cases) were given GCS pulse dose. The median total duration of GCS treatment was 42 days (range: 14-60 days). Three patients were treated with tocilizumab and one patient with infliximab. All patients with grade 3-4 and 2 patients with grade 2 were also treated with IVIG. Pacemakers were implanted in 3 patients with 3°AVB. The mortality rate of 19 cases was 21.1% (4/19), and the mortality rate of grade 4 myocarditis was 42.9%(3/7). The longer course before GCS therapy (p = 0.023), the higher NTproBNP (p = 0.030) and the lower LVEF value (p = 0.014) were found in the death group compared to the survival group. Logistic regression analysis showed that LVEF is an independent risk factor. The myocarditis prognostic model was condstructed as follows: Y = 8.794-18.002*LVEF, the prognostic critical value of LVEF was 57.5%, the area under the ROC curve of the prognostic model was 0.894 (95%CI: 0.735̃1.000), the sensitivity was 0.769, and the specificity was 1.000. Conclusions: We describe the largest single-center immune myocarditis cohort to date. Paying attention to the symptoms related to myositis is helpful to find more grade 1-2 myocarditis. cTnI is sensitive to myocarditis, and NTproBNP is of great significance to grade 3 ̃ 4 cases. LVEF &lt; 57% may be an independent risk factor for poor prognosis.

Factors Associated With Low Lean Mass in Early Rheumatoid Arthritis: A Cross- Sectional Study.

Background and Objectives: The aim of the study was to evaluate body composition (BC) of rheumatoid arthritis (RA) patients at disease onset compared to population controls focusing on the associations between low lean mass and disease specific parameters, nutritional factors and physical activity. Materials and Methods: 91 patients with early rheumatoid arthritis (ERA) (72% female) and 328 control subjects (54% female) were studied. BC-lean and fat mass parameters were measured with a Lunar Prodigy Dual Energy X-Ray Absorptiometry (DXA) machine. The prevalence, age and gender adjusted odds ratios of having low lean mass and overfat, associations between nutrition, physical activity, and ERA disease specific parameters and the presence of low lean mass were evaluated. Results: We found that the BC of patients with recent onset RA differs from control subjects—ERA patients had a higher mean body fat percentage (BFP) and lower appendicular lean mass (ALM). 41.8% of the ERA patients and 19.8% of the controls were classified as having low lean mass adjusted OR 3.3 (95% C.I. 1.9–5.5, p < 0.001). 68.1% of the ERA subjects and 47.3% of the controls were overfat (adjusted OR 1.9 (95% C.I. 1.1–3.3, p = 0.02)) and the adjusted odds of having both low lean mass and overfat were 4.4 times higher (26.4% vs. 7.0% 95% C.I. 2.3–8.4, p < 0.001) among the ERA group. Higher ESR (OR 1.03, C.I. 1.002–1.051, p = 0.03), CRP (OR 1.03, C.I. 1.002–1.061, p = 0.04), lower protein intake (OR 0.98 C.I. 0.96–0.99, p = 0.04), corticosteroid usage (OR 3.71 C.I. 1.4–9.9, p < 0.01) and lower quality of life (higher HAQ score OR 2.41 C.I. 1.24–4.65, p < 0.01) were associated with having low lean mass in the ERA group (adjusted to age and gender). Conclusions: Patients with early RA have lower appendicular lean mass and higher body fat percentage compared to healthy controls. Loss of lean mass in early RA is associated with elevated inflammatory markers inducing catabolism, lower protein intake and also with GCS treatment.

Comparative Antidiabetic Potential Assessment of Herbal Formulation of Gymnemic Acid and Curcumin

Standardization of polyherbal formulations with respect to bioactive phytocompounds is the need of the time for registration and marketing authorization in developed countries. This has prompted to prepare and evaluate a standardized bioactive phyotcompounds containing formulation. The study aims at development and screening of a standardized antidiabetic suspension containing active isolated phytoconstituents targeting better therapeutic effect with reduced bioburden. Suspension of isolated gymnemic acid and curcumin (GCS) was prepared, evaluated and authenticated by TLC and HPTLC. Antidiabetic efficacy of GCS was screened against alloxan induced diabetes on rats following 28 days of treatment comparative to Hyponidd tablet and Madhumehari granules. Body weight, relative organ weight, blood glucose, cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) level was measured. The formulation having pH 6.0, refractive index 1.41 and 45.58 mg/ml total solid content showed high alcohol and water soluble extractive value. The GCS treatment normalized liver and kidney weight, decreased body weight gain, TC, TG, LDL and VLDL level along with an increase in HDL level. Study outcome signifies similar antidiabetic potential of standardized formulation GCS compared to marketed Polyherbal formulation with antihyperlipidemic activity signifying as a promising natural and safe remedy for the prevention of diabetic complications.

Stereotactic Catheter Drainage Versus Conventional Craniotomy for Severe Spontaneous Intracerebral Hemorrhage in the Basal Ganglia

Intracerebral hemorrhage (ICH) is one of the most devastating forms of cerebrovascular pathology. However, its treatment remains a matter of debate among neurosurgeons and neurologists. The study was to explore the efficacy of minimally invasive surgery (stereotactic catheter drainage, SCD) for patients with severe intracerebral hemorrhage (Glasgow Coma Scale, GCS) score ≤ 8 and hematoma volume ≥ 30 cm3) and to determine predisposing factors for good clinical outcome. A total of 75 patients with severe ICH were included in this retrospective study. Patients were assigned to the SCD group (n=38) or the conventional craniotomy group (n=37). Patients were followed up for 12 months postoperatively, and their clinical parameters were compared. During the operation, the SCD group exhibited a lower bleeding volume (p<0.001) and shorter operating time (p<0.001) than the conventional craniotomy group. For postoperative efficacy, the rates of pneumonia and tracheotomy were lower (p=0.002 and p=0.027, respectively), and the duration of hospital and neurosurgery intensive care unit (NSICU) in days were significantly shorter in the SCD group (p=0.046 and p=0.047, respectively). Furthermore, patients in the SCD group showed improved modified Rankin Scale (mRS) scores at discharge (p<0.018) and at 12-month follow up (p<0.001). Predisposing factors for good clinical outcomes were hematoma volume (<50 cm3, 95% confidence interval (CI): 1.043–1.956, p<0.046), initial GCS score (>6, 95% CI: 3.248–187.466, p<0.001), hypertension (none, 95% CI: 1.440–2.922, p<0.001), and treatment modality (SCD, 95% CI: 1.422–3.226, p<0.001). Taken together, SCD surgery is safe and effective in patients with severe ICH and has fewer complications and better clinical outcomes than conventional craniotomy.

Neutrophil/lymphocyte ratio (NLR) may predict prognostic factor with gemcitabine/cisplatin/S-1 (GCS) for patients with advanced biliary tract cancer (MITSUBA /KHBO1401-1B).

e15656 Background: There is little information available about prognostic markers of gemcitabine, cisplatin, and S-1 (GCS) in patients with advanced biliary tract cancer (aBTC). Neutrophil/lymphocyte ratio (NLR) in several cancers including aBTC was reported to be a prognostic and/or predictive factor associated with clinical outcomes. There are no data about relation between NLR and clinical outcome in patient with aBTC who underwent GCS. Methods: Baseline demographics and NLR at enrollment were retrospectively evaluated in 119 patients who received GCS treatment in MITSUBA / KHBO1401 randomized phase III trial, which showed significant superiority of GCS to GC. The clinical utility of the NLR was evaluated by receiver operating characteristic (ROC) curves, and the cutoff values for NLR were 3.7. We divided these patients based on estimated NLR, and evaluated the clinicopathological factors and survival in the two groups (NLR ≧ 3.7 or &lt; 3.7). Results: 32 patients were in NLR ≧ 3.7group and 87 patients were in NLR &lt; 3.7 group. The progression-free survival between two groups was not significantly different (p = 0.45). Although, the median overall survival (OS) of NLR ≧ 3.7 group was 10.4 months, while OS of NLR &lt; 3.7 group was 18.5 months (HR 0.55, 95% confidential interval [CI] 0.36-0.87; p = 0.01).The ratio that was able to continue chemotherapy from initial administration six months later was 83.4%of NLR &lt; 3.7 group, and 65.6% of NLR ≧ 3.7 group (p = 0.04). Conclusions: Our study confirmed that high NLR is associated with worse OS, and suggested it may be a predictive marker for GCS chemotherapy in patients with aBTC.

AB026. S5A-2. The role of TS-1 in cholangiocarcinoma

: Gemcitabine plus platinum, notably cisplatin, is conceived as the standard regimen for advanced biliary tract cancer (ABTC). S-1 consists of tegafur and two biomodulators that maintain high serum 5-flurouracil concentrations while reducing gastrointestinal toxicity. A phase II study, JCOG0805 showed that gemcitabine plus S-1 was more promising than S-1 alone in ABTC, and a recently phase III JCOG1113 (FUGA-BT) showed gemcitabine plus S-1 (GS) is non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) benefit. Our TCOG T1308 trial also demonstrated that modified GS is an active regimen with excellent safety profiles as the first-line treatment in patients with ABTCs. For the triplet regimen, KHBO1002 trial, a single-arm phase II study of GC plus S-1 combination therapy (GCS), demonstrated a favorable survival benefit in ABTC patients. Recently, KHBO1401 trial was aimed to confirm the superiority of GCS to GC in terms of survival in patients with ABTC. This phase III study demonstrated the significant survival benefits of GCS treatment over GC treatment (13.5 versus 12.6 months, P=0.046), indicating that GCS could be a new standard treatment for patients with advanced BTC in Japan. In this talk, I will briefly introduce above clinical trials and share our experience of S-1 application in the treatment of ABTCs.

Pro-inflammatory Cytokines: Cellular and Molecular Drug Targets for Glucocorticoid-induced-osteoporosis via Osteocyte.

Glucocorticoids are widely used to treat varieties of allergic and autoimmune diseases, however, long-term application results in glucocorticoid-induced osteoporosis (GIOP). Inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) play important regulatory roles in bone metabolism, but their roles in GIOP remain largely unknown. Osteocytes can modulate the formation and function of both osteoblasts and osteoclasts, directly via gap junctions, or indirectly by transferring molecule signaling. Apoptotic osteocytes release RANKL, HMGB1 and pro-inflammatory cytokines to stimulate osteoclastogenesis. Moreover, osteocytes can secrete FGF23 to regulate bone metabolism. Exposure to high levels of GCs can drive osteocyte apoptosis and influence gap junctions, leading to bone loss. GCs treatment is regarded to produce more FGF23 to inhibit bone mineralization. GCs also disrupt the vascular to decrease osteocyte feasibility and mineral appositional rate, resulting in a decline in bone strength. Apoptotic bodies from osteocytes induced by GCs treatment can enhance production of TNF-α and IL-6. On the other hand, TNF-α and IL-6 show synergistic effects by altering osteocytes signaling towards osteoclasts and osteoblasts. In addition, TNF-α can induce osteocyte apoptosis and attribute to a worsened bone quality in GCs. IL-6 and osteocytes may interact with each other. Therefore, we hypothesize that GCs regulate osteocyteogenesis through TNF-α and IL-6, which are highly expressed around osteocyte undergoing apoptosis. In the present review, we summarized the roles of osteocytes in regulating osteoblasts and osteoclasts. Furthermore, the mechanism of GCs altered relationship between osteocytes and osteoblasts/osteoclasts. In addition, we discussed the roles of TNF-α and IL-6 in GIOP by modulating osteocytes. Lastly, we discussed the possibility of using pro-inflammatory signaling pathway as therapeutic targets to develop drugs for GIOP.

Estimations of a degree of steroid induced leukocytosis in patients with acute infections

BackgroundGlucocorticosteroids (GCS) are known to cause the hematologic effect of leukocytosis and neutrophilia. Leukocytosis is a key parameter in establishing the diagnosis of sepsis and in the estimation of its severity. ObjectiveTo quantify the effect of chronic or acute GCS treatment on the level of leukocytosis in patients with acute infectious process. MethodsWe conducted a retrospective cohort study of patients with an acute infection hospitalized in tertiary medical center between the years 2003–2014. Patients were classified into three categories: chronic GCS treatment, acute GCS treatment, no GCS treatment. The primary outcome was the maximal WBC count within the first 24h from admission. ResultsWe identified 5468 patients with acute infection: 333 of them with chronic GCS treatment, 213 with acute GCS treatment and 4922 with no GCS treatment. The overall maximal leukocytes count was higher in GCS therapy groups: 15.4±8.3×109/L for the acute GCS treatment, 14.9±7.4×109/L for chronic GCS treatment and 12.9±6.4×109/L for the no GCS group (P<0.001). ConclusionIn patients with acute infections chronically treated with GCS, an increase in the WBC is at average of 5×109/L. These data must be taken into consideration while using the level of leukocytosis as a parameter in the diagnosis of the infectious process.

Glucocorticoid treatment facilitates development of a metabolic syndrome in ovariectomized Macaca Mulatta fed a high fat diet

Metabolic syndrome (MetS) is characterized by a cluster of key features, which include abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The aim of this study was to assess the impact of elevated glucocorticoid levels on the development of MetS in middle-aged female rhesus monkeys (Macaca Mulatta) after ovariectomy. Six female ovariectomized rhesus monkeys (9–13years) were randomly assigned to either a control group (normal diet, n=3) or a group in which MetS was facilitated (n=3). The MetS group fed with HFD (15% fat) and received oral prednisone acetate treatment (50mg/day). After 24months, the GCs treatment was withdrawn with continuation of high-fat feeding for a further 12months. After 24months, the MetS group displayed a significant increase in body weight and abdominal circumference. Additionally, the MetS animals displayed abnormal serum lipids, insulin resistance and impaired glucose tolerance. Histology of liver biopsies indicated marked accumulation of lipid droplets in hepatocytes of MetS animals. Withdrawal of GCs treatment led to recovery from above-mentioned metabolic disorders. Whereas GCs treatment increased leptin expression, it lowered expression of adiponectin and other factors in adipose tissue. Expression of Hydroxy-steroid dehydrogenase-1 and glucose transporter type-4 in the livers of MetS animals were reduced. We conclude that in the context of high fat diet, high levels of exogenous GCs contribute to the development of MetS in non-human primates.

Is high dose intravenous methylprednisolone pulse therapy in patients with Graves' orbitopathy safe?

High dose intravenous glucocorticoid pulse (i.v. GCS) therapy is a proven approach in patients with active, moderate to severe Graves' orbitopathy (GO) and dysthyroid optic neuropathy (DON). In moderate to severe GO, the European Group on Graves' Orbitopathy (EUGOGO) recommends a 12-week course of intravenous methylprednisolone (i.v. MP) pulse therapy with a cumulative dose of 4.5 g. The response rate of i.v. GCS treatment is significantly higher than oral glucocorticoid (oral GCS) therapy and is associated with fewer adverse events. However, a major concern was raised because of reports of fatal side effects which may be associated with this therapy, especially when single and cumulative doses of methylprednisolone (MP) are higher than recommended. The prevalence and severity of adverse effects during treatment have not been fully described. The aim of this review was to summarise the frequency of major adverse effects of i.v. GCS compared to oral GCS and attempt to propose some practical suggestions as to how to monitor and prevent the development of side effects.

Combined glucocorticoid and orbital radiation therapy – literature review and clinical experience

The aim of immunosuppressive treatment of Grave’s orbitopathy (GO) is to limit acute inflammation and congestion of orbital tissues. Application of intra-venous glucocorticoid (GCS) pulses is presently the treatment of choice in active (CAS≥3/7), moderate-to-severe, and severe GO. Randomised trials (RTC) have proved this treatment to be more efficient than oral glucocorticoid therapy. The response rate of this regimen is about 80%. However, exact schedules of GCS treatment have not yet been uniquely established and depend on the experience acquired in different centres. According to the EUGOGO (2008) Consensus, to avoid acute liver damage, the total GCS dose should not exceed 8.0g in a single therapy cycle. Typically, in current schedules, the applied CGS dose per pulse per week is limited and the duration of therapy extended to 12 weeks to deliver a total methylprednisolone dose of 4.5g. While this may not always be the optimum dose, according to the EUGUGU (2012) randomised trial of the efficacy and safety of three different cumulative doses of intravenous methylprednisolone (2.5; 5.0 or 7.5 g) for moderate to severe and active GO, the dose of 7.5g was found to be most effective. It appears therefore that intravenous methylprednisolone treatment should be individualised depending on the severity of GO (NOSPECS criteria) and inflammation activity (CAS). Orbital radiotherapy (RT) is less efficient in GO than in GCS but, as based on rather scarce RCT reports, oral glucocorticoid therapy combined with orbital radiotherapy (20 Gy) appears to give better results than GCS alone (efficacy of about 70-80%). Again, no single schedule of combined GCS and RT has been established since no randomised trials with intravenous glucocorticoid have been conducted. According to our experience of over a decade, GCS pulse treatment followed by orbital irradiation improves the treatment outcome, especially in patients with eye muscle involvement, and reduces the frequency of recurrence. Restoring permanent euthyroidism is very important in GO therapy. Radioiodine therapy should be considered in patients with poorly controlled hyperthyroidism. Oral GCS should be given to patients with risk factors or active GO for radioiodine use, however no randomised clinical trials have been performed to ascertain the optimum GCS dose. According to our experience, ablative 131-I doses should be applied to efficiently control thyroid function. Radioiodine therapy can also take place while GCS pulses are delivered, with RT supplied after completion of methylprednisolone treatment. Randomised prospective trials are also necessary to assess the efficacy of these treatment schedules. In our investigations, we have found that the group of patients who, following 131-I therapy, have reported to our Department with severe GO, demonstrated significantly higher levels of TSH and TRAb, than patients treated with anti-thyroid drugs. It is for this reason that to avoid hypothyroidism, early control of Grave’s disease patients treated with 131-I is essential. According to the Amsterdam Declaration, detailed knowledge of the course of disease, avoiding recurrence of hyperthyroidism, and prompt qualification for well-selected treatment by an experienced endocrinologist- ophthalmologist team will improve the efficacy of GO treatment and protect the patient against severe orbitopathy.

Kirenol upregulates nuclear Annexin-1 which interacts with NF-κB to attenuate synovial inflammation of collagen-induced arthritis in rats

Ethnopharmacological relevanceKirenol is a diterpenoid compound purified from the Chinese Herba Siegesbeckiae. Siegesbeckiae has been employed for the treatment of arthritis for centuries, its safety and efficacy are documented through a long history of human use. Aim of the studyTo investigate the effects on collagen-induced arthritis (CIA) and anti-inflammatory mechanism of Kirenol. Materials and methodsKirenol was administrated intragastrically in rats after the onset of CIA. Pathological changes were evaluated by paw swelling and histopathology. Concentration of IL-1β in synovial fluid and adrenal corticotropin (ACTH) in plasma were determined by Elisa. Western blot was performed to detect the expression of Annexin-1 and glucocorticoid receptor alpha (GRα) in synovium. NF-κB DNA binding activity was assessed by electrophoretic mobility shift assays (EMSA). ResultsKirenol (1, 2, and 4mg/kg) and Prednisolone depressed paw swelling and reduced IL-1β of synovial fluid in the CIA rats (p<0.05 or p<0.01). Kirenol and Prednisolone upregulated nuclear Annexin-1 and inhibited NF-κB activity in synovium of CIA. The inhibitory effect of Kirenol and Prednisolone on NF-κB activity was enhanced by anti-Annexin-1 Ab. Prednisolone, but not Kirenol, downregulated plasma ACTH and GRα expression significantly (p<0.01). ConclusionKirenol and Prednisolone can upregulate nuclear Annexin-1 which interacts with NF-κB to inhibit NF-κB activity, reduce cytokines expression and thereby attenuate inflammation of CIA joints. Kirenol does not lead to ACTH or GR downregulation, which is in contrast to classic glucocorticoid Prednisolone. Kirenol shares with GCs similar anti-inflammatory mechanism but bypass the considerable limitation of GCs treatment.

25-Hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in endogenous hypercortisolism

of vertebral fractures (OR=2.71; 95% CI 2.04–3.60 and OR=1.54 95% CI 1.26–1.88). The inclusion in the model of GCs treatment did not change the risk predictivity. In conclusion our findings indicate that both inhaled and oral GCs are associated with reduced values of Stiffness and support the usefulness of using QUS at calcaneous in COPD patients. Therefore in COPD patients the presence of reduced values of Stiffness could markedly increase the risk of vertebral fracture and could be a crucial element in the planning of further examination or adequate therapeutic intervention in individual patients.

Oral glucocorticoid treatment decreases interleukin-10 receptor expression on peripheral blood leucocyte subsets

Glucocorticoids (GCS) are capable of stimulating the secretion of interleukin (IL)-10 by leucocytes; however, the potential of GCS to modulate leucocyte susceptibility to IL-10-mediated actions has not yet been studied. In the current paper, we performed a detailed cross-sectional analysis of IL-10 receptor (IL-10R) expression by CD4(+) and CD8(+) T cells, natural killer (NK) cells, monocytes and neutrophils. Next, we analysed the effects of short-term oral GCS treatment on surface IL-10R expression by various leucocyte subpopulations in asthmatic patients. All leucocyte subsets studied presented with substantial levels of surface IL-10R. The highest levels of IL-10R were found on monocytes, predominantly with CD14(2+)CD16(+) and CD14(+)CD16(+) phenotypes, and on CD4(+)CD25(high) T cells. In contrast, levels of IL-10R on CD8(+) T cells, NK cells and neutrophils were significantly lower and similar to each other in intensity. GCS treatment resulted in a significant decrease of IL-10R expression on all analysed peripheral blood leucocyte subsets. Our data suggest that down-regulation of IL-10R could counterbalance the otherwise suppressive action of GCS.

Chemical and organic immobilization treatments for reducing phytoavailability of heavy metals in copper‐mine tailings

AbstractThis study was conducted to evaluate the efficiency of diammonium phosphate (DAP), agricultural limestone (lime), and green‐waste compost mixed with 30% treated sewage sludge (GCS) applied alone or in combination as chemical immobilization treatment using tomato as a test crop. Mine waste was collected from an abandoned copper‐mine tailing site at Mynydd Parys, Anglesey (UK). Lime was applied at the rate of CaCO3 equivalent (CCE, pH = 7), DAP at the rate of 23 g P per kg substrate, and 10% by weight, GCS as sole application. Half rate of each amendment was also tested as a combined treatment and an untreated substrate (control). Plant‐available metals (Cd, Cu, Fe, Pb, and Zn) were measured in substrate with conventional diethylenetriaminepentaacetic acid (DTPA) and sequential Ca(NO3)2 extraction. Plant–dry biomass yield was significantly (p &lt; 0.001) increased by the combined application of all the three amendments while sole application of DAP reduced yield by 4‐fold compared to unamended soil probably due to P toxicity. Addition of lime reduced the DTPA‐extractable Cu, Fe, and Zn by 75%, 81%, and 85%, respectively, while Pb availability was reduced by 88% in combined DAP + lime + GCS treatment compared to control. The extraction capacity of DTPA was higher than that of Ca(NO3)2 by 3‐fold for Cu and Fe, 8‐fold for Pb, and 2‐fold for Zn. The leaf‐tissue concentrations of Cu and Fe were reduced by 77% and 83% in the lime + GCS amendment, respectively, while both Pb and Zn were reduced by 89% and 33%, respectively, in substrate treated with the combined application of all three amendments. These results suggest that alkaline amendments (both lime and GCS) were effective in reducing the phytoavailability of Cu, Fe, and Zn while DAP mixed with either GCS or lime was effective in reducing Pb availability.

Glucocorticosteroids stimulate polyclonal immunoglobulin production by cord blood mononuclear cells.

Glucocorticosteroids (GCS) are in vitro polyclonal activators of immunoglobulin (Ig) production for human mononuclear cells (MC) from virtually all adult donors. However, GCS treatment of cord blood MC resulted in Ig production in only 12/41 samples. This GCS effect is T cell and monocyte dependent and is mediated in part by a soluble T cell replacing factor. The inconsistent response of cord MC could be due to either cellular or soluble factor differences from adults. In 11/12 samples tested, irradiated cord T cells did help adult B cells, but less than did irradiated allogeneic adult T cells. T cell suppression in cord samples is unlikely inasmuch as higher cord T cell numbers and proportions increased the number of responding cord samples. Cord monocytes function adequately, because monocytes supported GCS responses when cord non-T cells had sufficient T cell help. The T cell replacing factor was found in supernatants of unstimulated cord as well as in adult MC cultures, but was less than 50% as potent. Cord B cells did not develop GCS-induced Ig production with such supernatants, suggesting that cord B cells may require a higher concentration or more prolonged exposure to T cell help. With a 2:1 ratio of irradiated adult T cells to cord non-T cells, only 25% of cord samples responded to GCS (compared to greater than 95% of adult samples), but with a ratio of 4:1, 75% responded. IgM was the predominant isotype secreted by GCS-stimulated cord cells, but 6/14 samples also produced IgG and 8/14 produced IgA. Thus, the functional immaturity of both cord T and B cells exists for GCS-induced Ig production, but with appropriate conditions GCS can activate most samples of cord B cells to synthesize Ig.