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Lipocalin-2 (LCN2) has three main variants; polyaminated (hLCN2) and non-polyaminated (C87A and R81E). The polyaminated form is proposed to positively influence energy control, whereas the non-polyaminated forms negatively impact energy control in mice. Glucocorticoids negatively affect glucose regulation and exercise has a positive effect. We hypothesise that glucocorticoids will suppress, while exercise will increase hLCN2, and decrease C87A and R81E, which will be associated with improved insulin sensitivity. In a randomised crossover design, nine young healthy men (aged 27.8 ± 4.9 years; BMI 24.4 ± 2.4 kg/m 2 ) completed 30 min of high-intensity aerobic exercise (90–95% heart rate reserve) after glucocorticoid or placebo ingestion. Blood was collected and analyzed for LCN2 and its variants levels at baseline, immediately, 60 min and 180 min post-exercise. Insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamp. A main effect, increase in LCN2 was detected for prednisolone ingestion (overall treatment effect p  = 0.001), but not LCN2 variants (all p  > 0.05). Main effects for time were observed for exercise for LCN2 and all variants (overall time effect all p  < 0.02). Regardless of treatment, LCN2, C87A, R81E, and hLCN2 increased immediately after exercise compared with baseline (all p  < 0.04). C87A, but not LCN2 or its other variants, remained elevated at 180 min post-ex ( p  = 0.007). LCN2, but not its variants, was elevated in response to prednisolone ingestion. LCN2 and its variants are transiently increased by acute exercise, but this increase was not related to insulin sensitivity. The clinical implication of elevated LCN2 and its variants post-exercise on satiety and energy regulation, as well as the mechanisms involved warrant further investigation. Clinical trial registration : www.anzctr.org.au , ACTRN12615000755538.

Aim/hypothesis To assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses. Methods In a randomised placebo-controlled double-blind (participants and the investigators who performed the studies and assessed the outcomes were blinded) dose–response intervention study, 32 healthy men (age 22 ± 3 years; BMI 22.4 ± 1.7 kg/m 2 ) were allocated to prednisolone 7.5 mg once daily ( n  = 12), prednisolone 30 mg once daily ( n  = 12), or placebo ( n  = 8) for 2 weeks using block randomisation. Main outcome measures were glucose, lipid and protein metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp conducted in the Clinical Research Unit of the Academic Medical Centre, Amsterdam, the Netherlands Results Prednisolone, compared with placebo, dose dependently and significantly increased fasting plasma glucose levels, whereas only prednisolone 30 mg increased fasting insulin levels (29 ± 15 pmol/l). Prednisolone 7.5 mg and prednisolone 30 mg decreased the ability of insulin to suppress endogenous glucose production (by 17 ± 6% and 46 ± 7%, respectively, vs placebo). Peripheral glucose uptake was not reduced by prednisolone 7.5 mg, but was decreased by prednisolone 30 mg by 34 ± 6% ( p  < 0.0001). Compared with placebo, prednisolone treatment tended to decrease lipolysis in the fasted state ( p  = 0.062), but both prednisolone 7.5 mg and prednisolone 30 mg decreased insulin-mediated suppression of lipolysis by 11 ± 5% and 34 ± 6%, respectively. Finally, prednisolone treatment increased whole-body proteolysis during hyperinsulinaemia, which tended to be driven by prednisolone 30 mg (5 ± 2%; p  = 0.06). No side effects were reported by the study participants. All participants completed the study and were analysed. Conclusions/interpretation Not only at high doses but also at low doses, glucocorticoid therapy impaired intermediary metabolism by interfering with the metabolic actions of insulin on liver and adipose tissue. These data indicate that even low-dose glucocorticoids may impair glucose tolerance when administered chronically. Trial registration: ISRCTN83991850 Funding: The study was funded by the Dutch Top Institute Pharma T1-106.

The cardinal clinical features of complex regional pain syndrome type I (CRPS-I) are pain, edema, autonomic changes, and limitation of motoric movement, which may indicate the role of inflammation and cytokines. We report the effect of prednisolone on the clinical severity and mRNA profiling of proinflammatory (tumor necrosis factor (TNF)-α and interleukin (IL)-2) and anti-inflammatory cytokines (IL-10 and transforming growth factor (TGF)-β) in the patient with CRPS-I. Thirty-nine patients with CRPS-I of shoulder joint were enrolled. Their CRPS, Visual Analog Scale (VAS) and Daily Sleep Interference Scale (DSIS) scores were recorded. TNF-α, IL-2, IL-10, and TGF-β gene expressions at mRNA of whole blood were measured by reverse transcriptase polymerase chain reaction. Patients were randomized to prednisolone 20 mg or 40 mg using 1: 1 randomization. The primary outcome was change in VAS score, and secondary outcomes were change in CRPS and DSIS scores at 1 month. Side effects were noted. The patients had increased expressions of TNF-α (p < 0.001) and IL-2 (p < 0.001) and reduced IL-10 (p < 0.01) mRNA compared to the healthy controls. The baseline characteristics were matched between the two treatment arms. At 1 month, CRPS, VAS, and DSIS scores improved significantly compared to baseline, which paralleled with improvement in IL-10 (p < 0.032) and reduction in TNF-α (p = 0.046). The improvement in clinical and biomarkers was similar in prednisolone 20 mg and 40 mg arms. None had to be withdrawn due to severe side effects. Future study in larger cohort may validate these findings.

Objective The study evaluated the effectiveness of combination therapy with vigabatrin and prednisolone versus vigabatrin alone for treating infantile epileptic spasms syndrome (IESS). Methods This single‐center, single‐blind, randomized trial enrolled infants aged 2–14 months with new‐onset IESS, randomly assigned them (1:1) to receive either combination therapy with vigabatrin (100–150 mg/kg/day) and prednisolone (40–60 mg/day) or vigabatrin alone. The primary outcome was sustained spasm remission between days 14 and 42. The trial (ClinicalTrials.gov identifier) was terminated early due to an interim analysis revealing a significant difference between treatment groups. Results In all, 17 infants were assigned to combination therapy and 24 to vigabatrin alone. The median lead time to treatment for combination therapy was 30 days, compared to 60 days for the vigabatrin group (p = 0.442). Sustained spasm remission between days 14 and 42 occurred in 13 (77%) of 17 infants on combination therapy and in 8 (33%) of 24 infants on vigabatrin alone (OR 6.5, 95% CI 1.7, 29.6, p = 0.009). Combination therapy was more effective in achieving an electroclinical response by day 14 (OR 9.3, 95% CI 2.0, 54.3, p = 0.006) but not by day 42 (OR 1.9, 95% CI 0.5, 7.1, p = 0.351). Hospitalization occurred in six (35%) infants in the combination therapy group and two (8%) in the vigabatrin alone group (p = 0.05). One death was reported in the vigabatrin group. Interpretation Despite early termination, this study showed that combination therapy is significantly more effective in achieving clinical remission of spasms and an electroclinical response by day 14. Trial Registration NCT04302116

Glucocorticoids are the mainstay of asthma therapy. However, it is unclear whether the benefits of glucocorticoids in asthma are merely based on antiinflammatory properties. Glucocorticoids may also alter gene expression of airway smooth muscle (ASM). We hypothesized that the gene expression profile of the ASM layer in endobronchial biopsies of patients with asthma is altered by oral glucocorticoid therapy as compared with placebo. First, we investigated the change in ASM transcriptomic profile in endobronchial biopsies after 14 days of oral glucocorticoid therapy. Second, we investigated the association between changes in ASM transcriptomic profile and lung function. Twelve steroid-free patients with atopic asthma were included in this double-blind intervention study. Endobronchial biopsies were taken before and after 14 days of oral prednisolone (n = 6) or placebo (n = 6). RNA of laser-dissected ASM was sequenced (RNA-Seq) using GS FLX+ (454/Roche). Gene networks were identified by Ingenuity Pathway Analysis. RNA-Seq reads were assumed to follow a negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 3%. Fifteen genes were significantly changed by 14 days of oral prednisolone. Two of these genes (FAM129A, SYNPO2) were associated with airway hyperresponsiveness (provocative concentration of methacholine causing a 20% drop in FEV1: r = -0.740, P < 0.01; r = -0.746, P < 0.01). Pathway analysis revealed three gene networks that were associated with cellular functions including cellular growth, proliferation, and development. Oral prednisolone changes the transcriptomic profile of the ASM layer in asthma. This indicates that in parallel to antiinflammatory properties, glucocorticoids also exert effects on gene expression of ASM, which is correlated with improved airway function.

HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection. ClinicalTrials.gov NCT01299948.

Patients with major depression show hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, but the mechanisms underlying this abnormality are still unclear. We have compared two synthetic glucorticoids, dexamethasone and prednisolone, in their ability to suppress the hypothalamic-pituitary-adrenal (HPA) axis in depressed patients. Dexamethasone probes glucocorticoid receptor (GR) function, while prednisolone probes both GR and mineralocorticoid receptor (MR) function. We used a single-blind, repeated-measure design. We administered placebo, prednisolone (5 mg) or dexamethasone (0.5 mg), at 22:00, to 18 severe, treatment-resistant depressed inpatients (15 of them with a history of childhood trauma) and 14 healthy volunteers. On the following days, we collected salivary cortisol from 9:00 to 22:00. Depressed patients had higher salivary cortisol levels compared with controls, at baseline and after both prednisolone and dexamethasone (p<0.001). Consistent with previous studies, depressed inpatients showed impaired suppression by dexamethasone: based on the analysis of the areas under the curve (AUCs), suppression by dexamethasone (0.5 mg) was -85% in controls vs -46% in depressed patients (p=0.018). However, the same depressed patients showed normal suppression by prednisolone (5 mg): suppression was -41% in controls and -36% in depressed patients (p=0.6). We suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients.

ContextShort-term glucocorticoid exposure increases serum insulinlike growth factor I (IGF-I) concentrations but antagonizes IGF-I tissue signaling. The underlying mechanisms remain unknown.ObjectiveTo identify at which levels glucocorticoid inhibits IGF-I signaling.Design and MethodsNineteen healthy males received prednisolone (37.5 mg/d) and placebo for 5 days in a randomized, double-blinded, placebo-controlled crossover study. Serum was collected on days 1, 3, and 5, and abdominal skin suction blister fluid (SBF; ~interstitial fluid) was taken on day 5 (n = 9) together with muscle biopsy specimens (n = 19). The ability of serum and SBF to activate the IGF-I receptor (IGF-IR) (bioactive IGF) and its downstream signaling proteins was assessed using IGF-IR–transfected cells.ResultsPrednisolone increased IGF-I concentrations and bioactive IGF in serum (P ≤ 0.001) but not in SBF, which, compared with serum, contained less bioactive IGF (~28%) after prednisolone (P < 0.05). This observation was unexplained by SBF concentrations of IGFs and IGF-binding proteins (IGFBPs) 1 to 4. However, following prednisolone treatment, SBF contained less IGFBP-4 fragments (P < 0.05) generated by pregnancy-associated plasma protein A (PAPP-A). Concomitantly, prednisolone increased SBF levels of stanniocalcin 2 (STC2) (P = 0.02) compared with serum. STC2 blocks PAPP-A from cleaving IGFBP-4. Finally, prednisolone suppressed post–IGF-IR signaling pathways at the level of insulin receptor substrate 1 (P < 0.05) but did not change skeletal muscle IGF-IR, IGF-I, or STC2 messenger RNA.ConclusionPrednisolone increased IGF-I concentrations and IGF bioactivity in serum but not in tissue fluid. The latter may relate to a STC2-mediated inhibition of PAPP-A in tissue fluids. Furthermore, prednisolone induced post–IGF-IR resistance. Thus, glucocorticoid may exert distinct, compartment-specific effects on IGF action.Five days of prednisolone treatment (37.5 mg/d) increased the ability of serum but not tissue fluid to activate the IGF-I receptor (IGF-IR). In cells, prednisolone decreased post–IGF-IR signaling.

Objective:To investigate the effects of short-term prednisolone ingestion combined with intense training on exercise performance, hormonal (adrenocorticotrophic hormone (ACTH), prolactin, luteinising hormone (LH), growth hormone (GH), thyroid-stimulating hormone (TSH), dehydroepiandrosterone (DHEA), testosterone, insulin) and metabolic parameters (blood glucose, lactate, bicarbonate, pH).Methods:Eight male recreational athletes completed four cycling trials at 70–75% peak O2 consumption until exhaustion just before (1) and after (2) either oral placebo or prednisolone (60 mg/day for 1 week) treatment coupled with standardised physical training (2 hours/day), according to a double-blind and randomised protocol. Blood samples were collected at rest, during exercise and passive recovery for the hormonal and metabolic determinations.Results:Time of cycling was not significantly changed after placebo but significantly increased (p<0.05) after prednisolone administration (50.4 (6.2) min for placebo 1, 64.0 (9.1) min for placebo 2, 56.1 (9.1) min for prednisolone 1 and 107.0 (20.7) min for prednisolone 2). There was no significant difference in any measured parameters after the week of training with placebo but a decrease in ACTH, DHEA, PRL, GH, TSH and testosterone was seen with prednisolone treatment during the experiment (p<0.05). No significant change in basal, exercise or recovery LH, insulin, lactate, pH or bicarbonate was found between the two treatment, but blood glucose was significantly higher under prednisolone (p<0.05) at all time points.Conclusion:Short-term glucocorticoid administration induced a marked improvement in endurance performance. Further studies are needed to determine whether these results obtained in recreational male athletes maintaining a rigorous training schedule are gender-dependent and applicable to elite athletes.

Insulin resistance (IR) is induced by chronic hepatitis C virus (HCV) genotypes 1 and 4 infections. It is not known whether drugs that affect IR such as Pioglitazone and Prednisone also affect serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The primary aim was to assess whether Pioglitazone by improving IR and/or inflammation decreases HCV viral load independently of standard of care HCV treatment. A secondary aim was to assess whether Prednisone, a drug that induces insulin resistance and stimulates HCV viral entry and replication in replicon culture systems, increases HCV viral load in this population. We designed a two-arm, parallel Pilot Study of overweight, treatment naïve genotype 4 HCV-infected patients at a public referral Liver Clinic in Giza, Egypt. The subjects received Pioglitazone (30 mg/day for 14 days) or Prednisone (40 mg/day for 4 days) in a randomized fashion, but the two arms can be considered independent pilot studies. Only changes from baseline within each arm were assessed and no contrasts of the interventions were made, as this was not an aim of the study. Among 105 consecutive HCV genotype 4 patients, 39 were enrolled based on the optimal sample size and power analysis according to the CONSORT statement; 20 to the Pioglitazone group and 19 to the Prednisone group. Pioglitazone was effective in decreasing serum HCV RNA at day-14 (n = 10; difference of means = 205,618 IU/ml; 95% CI 26,600 to 384,600; P<0.001). Although Prednisone did increase serum HCV RNA at day-4 (n = 10; change from baseline = -42,786 IU/ml; 95% CI -85,500 to -15,700; P = 0.049), the log(10) HCV RNA titers were statistically not different from baseline day-0. This is the first documentation that Pioglitazone decreases the serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The novel findings of our Study provide the foundation for basic and clinical investigations on the molecular mechanisms responsible for the Pioglitazone-induced decrease in HCV genotype 4 RNA titers. ClinicalTrials.gov NCT01157975.