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Objective: Patients presenting with neurological deficit secondary to metastatic epidural spinal cord compression (MESCC) are often treated with surgery in combination with high-dose corticosteroids. Despite steroids being commonly used, the evidence regarding the effect of corticosteroids on patient outcomes is limited. The objective of this study was to describe the effect of corticosteroid use on preoperative neurological function in patients with MESCC. Methods: Patients who underwent surgery between August 2013 and February 2017 for the treatment of spinal metastases and received steroids to prevent neurologic deficits were included. Data regarding demographics, diagnosis, treatment, neurological function, adverse events, health-related quality of life, and survival were extracted from an international multicenter prospective cohort. Results: A total of 30 patients treated surgically and receiving steroids at baseline were identified. Patients had a mean age of 58.2 years (standard deviation, 11.2 years) at time of surgery. Preoperatively, 50% of the patients experienced deterioration of neurological function, while in 30% neurological function was stable and 20% improved in neurological function. Lengthier steroid use did not correlate with improved or stabilized neurological function. Postoperative adverse events were observed in 18 patients (60%). Patients that stabilized or improved neurologically after steroid use showed a trend towards improved survival at 3- and 24-month postsurgery. Conclusion: This study described the effect of steroids on preoperative neurological function in patients with MESCC. Stabilization or improvement of preoperative neurological function occurred in 50% of the patients. [ABSTRACT FROM AUTHOR]

We aim to present a case of bilateral hip and knee osteonecrosis due to steroid use in an ankylosing spondylitis (AS) patient who developed immune thrombocytopenic purpura (ITP) after the use of nonsteroidal anti-inflammatory drugs (NSAID). A 60-year-old male patient was diagnosed with AS with bilateral sacroiliitis and inflammatory low back pain on sacroiliac radiography 10 years ago. He was followed up with NSAIDs. Intravenous steroid treatment was started in the hematology clinic to the patient who had developed ITP due to NSAID usage. The patient presented to our clinic with bilateral hip pain that developed after steroid therapy. He had limited hip joint movement and bilateral destructive hip joints in pelvic radiography. Bilateral total hip arthroplasty (THA) was performed by the Orthopedics and Traumatology Department at 1-year intervals because of osteonecrosis associated with steroid use. When he presented to our clinic 3 years later with bilateral knee pain, we detected osteonecrosis in the distal segments of bilateral femurs and proximal tibial diaphysis on knee MRI. We implemented a rehabilitation program with the conservative treatment recommendation of orthopedics. Comorbidities or drug side effects should be examined more carefully while treating peripheral joint involvement in patients with AS. [ABSTRACT FROM AUTHOR]

Abstract The present study evaluates whether increased water temperature induces reproduction by Lophiosilurus alexandri under controlled conditions, and investigates the effects of this procedure on sexual steroids, hematological profile and behavior. A 44-week experiment was performed with four wild males and 12 wild females that had been acclimatized to captive conditions. Water temperature was maintained at 24.4 ± 1.0 °C for weeks 1–22, and then at 29.0 ± 1.1 °C for weeks 22–44. Spawn weight, number of eggs/spawn and hatching rate were satisfactory and ranged 27.5–127.5 g, 1209–5183 and 83–89%, respectively. Hematocrit, leukocytes and glucose were not influenced by increased water temperature, while higher values for erythrocytes were observed for both sexes. The lowest value for plasma protein was for females maintained at 29.0 °C, while the lowest value for testosterone was obtained at the end of the study period at a temperature in 29.0 °C. Serum values of 17β-estradiol were higher in females than in males, however, there was no evidence of variation as a function of experimental temperature or interaction with sex. The reproductive behavior of L. alexandri in captivity is described for the first time. The present study demonstrates that adult individuals are able to maintain a stable hematological profile during an increase in mean water temperature from 24.4 °C to 29.0 °C, even during the reproductive period, and still produce good quality larvae. Nonetheless, whether spawning was associated with increased 17β-estradiol levels could not be determined. Highlights • Increasing the water temperature from 24.4 °C to 29.0 °C stimulated reproduction of L. alexandri. • Fish started exhibiting reproductive behaviors late in the afternoon. • No evidence of variation in serum values of 17β-estradiol as a function of increased temperature. • Adult L. alexandri were able to maintain stable hematological levels even during the reproductive period. [ABSTRACT FROM AUTHOR]

Omalizumab has been recognized to be effective in the treatment of chronic spontaneous urticaria (CSU). The Italian Medicines Agency authorizes two omalizumab courses, only for patients with CSU unresponsive to antihistamines, and this schedule may limit omalizumab use. Unfortunately, in the majority of CSU, the schedule is unsatisfactory because symptoms usually recur shortly after discontinuation of treatment. A case of a patient needing more than two treatment courses with omalizumab is reported, in order to discuss the rationale for its long-term use. Patient had needed systemic steroids almost continuously for 4 years. Two severe glucocorticoid-associated adverse events (GAEs) occurred during long-term treatment. Omalizumab 300 mg monthly was started with immediate disappearance of the urticarial lesions. Beneficial effects waned shortly after discontinuation of treatment, and further steroid use was needed. A second omalizumab course showed the same clinical pattern, with prompt response and recurrence of symptoms after suspension. Therefore, we decided to repeat the 6 months omalizumab treatment as soon as symptoms recurred, to avoid further emergency steroid treatments and GAEs. This experience suggests that long-term use of omalizumab could be useful. Evidences show that omalizumab is effective and safe for re-treatment and long-term use of responding patients after recurrence. [ABSTRACT FROM AUTHOR]

Alfaxalone is a neuroactive steroid used as a general anaesthetic in several species including dogs, cats, rabbits and ferrets. It has a wide margin of safety and a similar anaesthetic profile to propofol. To increase its aqueous solubility, a new formulation with cyclodextrins has been marketed recently. The objective of this study was to evaluate the anaesthetic effect of several doses of alfaxalone alone, considering differences between sexes, and alfaxalone combined with dexmedetomidine and fentanyl in the rat administered by the intraperitoneal route. A total of 40 Sprague Dawley rats, involved in three studies, were used. Firstly, 25, 35 and 45 mg kg–1 of alfaxalone alone were tested. In a second study, alfaxalone (25 mg kg–1, females; 75 mg kg–1, males) was combined with dexmedetomidine (0.05 mg kg–1). Finally, alfaxalone (20 mg kg–1, females; 60 mg kg–1, males) was combined with dexmedetomidine (0.05 mg kg–1) and fentanyl (0.1 mg kg–1). Times of onset and duration of anaesthesia, and analgesia, deemed as losing of withdrawal pedal reflex, were recorded. Alfaxalone alone produced a 2 - to 3-fold longer time of anaesthesia in females, although surgical anaesthesia was not achieved in either sex. The addition of dexmedetomidine and fentanyl to alfaxalone produced a similar time of analgesia as well as increased time of anaesthesia in both sexes. In conclusion, alfaxalone produces light anaesthesia in rats, and males required a higher dose. The combination with other sedatives or analgesics, such as dexmedetomidine or fentanyl, allows a more prolonged anaesthesia with analgesic effects, potentially suitable for invasive procedures. [ABSTRACT FROM AUTHOR]

Objectives: To compare death and/or neurodevelopmental outcomes of preterm infants exposed to inhaled and/or systemic steroids with those without exposure, and examine the impact of timing of exposure.Methods: Retrospective study of infants born <29 weeks gestation and assessed at 18-21 months corrected age (CA). Neurodevelopmental impairment (NDI) was defined as any Bayley Scales of Infant and Toddler Development-III (BSID-III) score <85, cerebral palsy ≥ grade one, and visual or hearing impairment. Significant NDI (sNDI) was defined as any Bayley Scales of Infant Development (BSID-III) score <70, cerebral palsy ≥ grade three, or severe vision or hearing impairment.Results: Of 2570 neonates, 1811 had no exposure, 125 were exposed to inhaled steroids, 522 to systemic steroids and 112 to both. Infants exposed to inhaled steroids had lower odds of bronchopulmonary dysplasia [adjusted odds ratio (AOR) 0.51, (0.33, 0.79)], and displayed no difference in death/NDI or death/significant neurodevelopmental impairment (sNDI), regardless of timing of exposure. Infants only exposed to systemic steroids before 4 weeks of age were at increased odds of death/NDI [AOR 1.83 (1.43, 2.34)] and death/sNDI [AOR 2.28 (1.76, 2.96)].Conclusions: Exposure to inhaled steroids was not associated with increased odds of death/NDI or death/sNDI. Systemic steroids use before 4 weeks of age was associated with significantly worse outcomes. [ABSTRACT FROM AUTHOR]

Small cell intestinal lymphoma has not been well characterized in dogs. The objective of this study was to describe clinical characteristics and outcome in dogs with small cell intestinal lymphoma. We hypothesized that affected dogs would have prolonged survival compared with high‐grade gastrointestinal (GI) lymphoma. Pathology records were searched for dogs with histologically confirmed small cell GI lymphoma. Seventeen dogs with confirmed small cell intestinal lymphoma were identified, and clinical and outcome data were retrospectively collected. Histopathology was reviewed by a board‐certified pathologist, and tissue sections were subjected to immunophenotyping and molecular clonality assessment. All dogs had small cell, T‐cell, lymphoma confirmed within various regions of small intestine, with 1 dog also having disease in abdominal lymph nodes. All dogs had clinical signs attributable to GI disease; diarrhoea (n = 13) was most common. Ultrasonographic abnormalities were present in 8 of 13 dogs with abnormal wall layering (n = 7) and hyperechoic mucosal striations (n = 7) representing the most common findings. In total, 14 dogs received some form of treatment. The median survival time (MST) for all dogs was 279 days and the MST for the 14 dogs that received any treatment was 628 days. Dogs with anaemia and weight loss at presentation had significantly shorter survival times and dogs that received a combination of steroids and an alkylating agent had significantly longer survival times. Small cell, T‐cell, intestinal lymphoma is a distinct disease process in dogs, and those undergoing treatment may experience prolonged survival. [ABSTRACT FROM AUTHOR]

Nitrate has the potential to affect steroid production. Nitrate concentrations in streams in agricultural areas may exceed concentrations showing effects in laboratory studies. The effects of nitrate and/or nitrite on endocrine relevant endpoints were tested in zebrafish and brown trout. Zebrafish were exposed in two experiments to nitrate (8.8 to 89 mg NO 3 − /L) and nitrite (3.6 to 19 mg NO 2 − /L) during the period of sexual differentiation and sex ratios were determined. Vitellogenin concentrations were determined in the second experiment. The sex ratio was unaffected by the exposure to nitrate and nitrite. Vitellogenin concentrations were slightly elevated in males (but not females) in all of the groups exposed to nitrate. Juvenile brown trout were exposed to 5.7, 14, and 31 mg NO 3 − /L for 8 days and vitellogenin levels in liver were determined. Vitellogenin concentrations in the females were not affected by exposure, but in the males, there was an overall statistically significant effect of exposure to nitrate with the group exposed to 5.7 mg NO 3 − /L showing a trend of higher vitellogenin concentrations than the control group; levels in the males of the groups exposed to 14 and 31 mg NO 3 − /L were not statistically different from those of the control group. In conclusion, some marginal effect of nitrate in male fish on endocrine activity was observed but the present results for zebrafish, using environmentally relevant concentrations, do not define nitrate and nitrite as endocrine disrupting chemicals according to the generally accepted WHO/IPCS definition because no adverse effects (altered sex ratios) were demonstrated. [ABSTRACT FROM AUTHOR]

Introduction and Aims: Emerging research suggests that the sub-population of anabolic-androgenic steroid (AAS) users who experience physical appearance concerns may suffer greater psychological dysfunction than other sub-populations, including users with athletic or occupational concerns. Thus, among current AAS users, we sought to determine whether, and to what extent, social physique anxiety-an established measure of appearance concern-was associated with psychological dysfunction.Design and Methods: Interviews were conducted with a sample of 74 male AAS users living in Australia. Users completed self-report instruments of the severity of AAS dependence, depression, hazardous and risky drinking, use of non-AAS illicit drugs, psychological side-effects due to AAS use and abnormal test results due to AAS use.Results: Multivariate analyses revealed that greater social physique anxiety was uniquely associated with more severe symptoms of both AAS dependence and depression. Moreover, the effect size of these relationships was large. Social physique anxiety was not associated with hazardous or risky drinking, non-AAS illicit drug use, psychological side-effects or abnormal test results.Discussion and Conclusions: Limitations notwithstanding, the study is consistent with the notion that AAS users who experience appearance concerns are at heightened risk of co-morbid psychological dysfunction. Given trends indicating an increase in the prevalence of AAS use in Australia and elsewhere, the findings suggest that health-care systems may need to consider prioritising the sub-population of AAS users who experience appearance concerns. Further investigation of the clinical syndrome of AAS dependence is required, including its relation to body image and eating disorders. [ABSTRACT FROM AUTHOR]

In seasonally breeding songbirds such as canaries, singing behavior is predominantly under the control of testosterone and its metabolites. Short daylengths in the fall that break photorefractoriness are followed by increasing daylengths in spring that activate singing via both photoperiodic and hormonal mechanisms. However, we observed in a group of castrated male Fife fancy canaries maintained for a long duration under a short day photoperiod a large proportion of subjects that sang at high rates. This singing rate was not correlated with variation in the low circulating concentrations of testosterone. Treatment of these actively singing castrated male canaries with a combination of an aromatase inhibitor (ATD) and an androgen receptor blocker (flutamide) only marginally decreased this singing activity as compared to control untreated birds and did not affect various measures of song quality. The volumes of HVC and of the medial preoptic nucleus (POM) were also unaffected by these treatments but were relatively large and similar to volumes in testosterone-treated males. In contrast, peripheral androgen-sensitive structures such as the cloacal protuberance and syrinx mass were small, similar to what is observed in castrates. Together these data suggest that after a long-term steroid deprivation singing behavior can be activated by very low concentrations of testosterone. Singing normally depends on the activation by testosterone and its metabolites of multiple downstream neurochemical systems such as catecholamines, nonapeptides or opioids. These transmitter systems might become hypersensitive to steroid action after long term castration as they probably are at the end of winter during the annual cycle in seasonally breeding temperate zone species. [ABSTRACT FROM AUTHOR]

Many athletes use anabolic-androgenic steroids (AAS) for physical enhancement but the magnitude of these gains and associated adverse effects has not been rigorously quantified. MEDLINE, EMBASE, Cochrane, SPORTDiscus, and PsycINFO were searched to identify randomized placebo-controlled trials of AAS in healthy exercising adults that reported one of the following outcomes: muscular strength, body composition, cardiovascular endurance, or power. Two authors appraised abstracts to identify studies for full-text retrieval; these were reviewed in duplicate to identify included studies. Study quality was assessed using the Cochrane method. Data were extracted in duplicate and pooled using the DerSimonian and Laird random effects model and to calculate the ratio of mean outcome improvement where possible. Pooled standardized mean difference (SMD) in muscle strength between AAS and placebo was 0.27 (95% confidence interval, 0.07-0.47; I = 12.7%; 21 studies). Change in strength was 52% greater in the AAS group compared to placebo. The SMD for change in lean mass between AAS and placebo was 0.62 (95% confidence interval, 0.35-0.89; I = 26%; 14 studies). Due to missing data, fat mass, cardiovascular endurance, power, and adverse effects were summarized qualitatively. Only 13 of 25 studies reported adverse effects including increased low density lipoprotein (LDL), decreased high density lipoprotein (HDL), irritability, and acne. In healthy exercising adults, AAS use is associated with a small absolute increase in muscle strength and moderate increase in lean mass. However, the transparency and completeness of adverse effect reporting varied, most studies were of short duration, and doses studied may not reflect actual use by athletes. [ABSTRACT FROM AUTHOR]

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Steroid-induced avascular necrosis of femoral head (SANFH) occurs frequently in patients receiving high-dose steroid treatment for these underlying diseases. The target of this study is to investigate the effect of microRNA-320 (miR-320) on SANFH by targeting CYP1A2. CYP1A2 expression was detected using immunohistochemistry. Specimens were collected from patients with SANFH and femoral neck fracture. Seventy rats were assigned into seven groups. The targeting relationship between miR-320 and CYP1A2 was verified by bioinformatics website and dual luciferase reporter gene assay. RT-qPCR and Western blot analysis were used to detect miR-320 and CYP1A2 expressions. The enzymatic activity of CYP1A2 was detected by fluorescence spectrophotometry. Hemorheology and microcirculation were measured in rats. MiR-320 expression decreased and CYP1A2 expression and enzymatic activity increased in SANFH patients compared to those with femoral neck fracture. CYP1A2 was the target gene of miR-320. Hemorheology and microcirculation results showed that up-regulated expression of CYP1A2 promoted the development of SANFH while increased expression of miR-320 inhibited the development of SANFH. Compared with the SANFH group, the SANFH + miR-320 mimic group showed increased miRNA-320 expression, and decreased CYP1A2 expression and enzymatic activity. Opposite results were found in the SANFH + miR-320 inhibitor group. The SANFH + miR-320 inhibitor + pCR-CYP1A2_KO group showed decreased miRNA-320 expression and the SANFH + pCR-CYP1A2_KO group showed decreased CYP1A2 expression and enzymatic activity. Our findings provide evidences that miR-320 might inhibit the development of SANFH by targeting CYP1A2. [ABSTRACT FROM AUTHOR]

Introduction: We sought to determine whether protocol biopsies could be used to guide treatment and improve outcomes in simultaneous pancreas-kidney (SPK) patients. Methods: Between 2004 and 2013, protocol biopsies were performed on SPK patients at 3-6 months and one year post-transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, anti-proliferative agent, and corticosteroid. Corticosteroid was withdrawn in negative early biopsies, maintained in subclinical/borderline biopsies, and increased if Banff IB or greater rejection was identified. Endpoints included presence of interstitial fibrosis and tubular atrophy on biopsy at one year (IF/TA), rejection episodes, and renal and pancreas function at five years' followup. Results: Forty-one SPK transplant patients were reviewed and a total of 75 protocol biopsies were identified. On early biopsy, 51% had negative biopsies, 44% had borderline rejection, and 5% had subclinical rejection. Renal and pancreas function were not significantly different at one, two, and five years post-transplant between negative vs. borderline early biopsy patients. No difference in the degree of IF/TA was found between these two groups. Conclusions: To our knowledge, this is the first study to evaluate protocol biopsies as an investigative tool prior to steroid withdrawal in SPK patients. Our study suggests that there are no detrimental functional or histological effects at five years post-transplant, despite weaning steroids in the negative biopsy group. [ABSTRACT FROM AUTHOR]

Background: Marijuana is legal in a number of states for indications that include inflammatory bowel diseases (IBD), and patients are interested in its potential benefits.Aims: We aimed to describe the legal use of marijuana in individuals with IBD in the USA who participate within the CCFA Partners internet-based cohort.Methods: A total of 2357 participants who lived in states where prescription or recreational marijuana was legal, were offered the opportunity to complete a survey on marijuana use and IBD symptoms including perceived benefits of therapy. Bivariate statistics and logistic regression models were used to determine factors associated with marijuana use.Results: Surveys were completed by 1666 participants (71%) with only 214 (12.8%) indicating they had asked their medical doctor about its use and 73 actually using prescribed marijuana (4.4%). Within the respondent group (N = 1666), 234 participants lived where both medical and recreational marijuana is legal and 49 (20.9%) reported recreational marijuana use specifically for IBD. Users reported positive benefits (80.7%), but users also reported more depression, anxiety, pain interference, and lower social satisfaction than non-users. Those prescribed marijuana reported more active disease, and more use of steroids, narcotics, and zolpidem.Conclusions: Few IBD patients consulted their medical doctors about marijuana use or used prescription marijuana. Where recreational marijuana was available, usage rates were higher. Users reported benefits but also more IBD symptoms, depression, anxiety, and pain. Marijuana use may be higher in patients with IBD symptoms not well treated by conventional medical approaches. [ABSTRACT FROM AUTHOR]

Liquid chromatography tandem mass spectrometry (LC-MS/MS) assays are considered the reference standard for serum steroid hormone analyses, while full urinary steroid profiles are only achievable by gas chromatography (GC–MS). Both LC-MS/MS and GC–MS have well documented strengths and limitations. Recently, commercial ultra-high performance supercritical fluid chromatography–tandem mass spectrometry (UHPSFC-MS/MS) systems have been developed. These systems combine the resolution of GC with the high-throughput capabilities of UHPLC. Uptake of this new technology into research and clinical labs has been slow, possibly due to the perceived increase in complexity. Here we therefore present fundamental principles of UHPSFC-MS/MS and the likely applications for this technology in the clinical research setting, while commenting on potential hurdles based on our experience to date. [ABSTRACT FROM AUTHOR]

Corticosteroids are widely diffused drugs. An important side effect is the impairment of glycemic control both in patients with known diabetes and in normoglycemic ones potentially leading to steroid-induced diabetes mellitus (SIDM). In this review based on papers released on PubMed, MEDLINE, and EMBASE from January 2015 to October 2017, we summarized and discussed main updates about the definition, the diagnosis, and the pathophysiology of steroid-induced hyperglycemia (SIH), with a look to new therapies. Main alterations responsible for the diabetogenic effect of corticosteroids are a negative impact on insulin sensitivity along with a derangement on insulin secretion, explaining the typical post-prandial hyperglycemia linked to the promotion of gluconeogenesis. An early and precise diagnosis of SIH and/or SIDM is necessary, but current criteria do not seem sensible enough. As an afterthought, the treatment should be reasoned and tailored according to proposed glycemic thresholds and patient comorbidities, choosing between antidiabetic oral drugs and insulin, the latter being preferable among hospitalized patients. SIDM and SIH are frequent problems, but often underdiagnosed due to old diagnostic criteria. Dedicated guidelines universally shared are mandatory in order to harmonize the treatment of these conditions, thus overtaking single therapeutic strategies mostly arising from literature. [ABSTRACT FROM AUTHOR]

The enzyme steroid 5α-reductase 2 (5αR2) catalyzes the conversion of testosterone into the potent androgen 5α-dihydrotestosterone. Previous investigations showed that 5αR2 is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown. Here, we profiled the behavioral characteristics of 5αR2 heterozygous (HZ) and knockout (KO) mice, as compared with their wild-type (WT) littermates. While male 5αR2 KO mice displayed no overt alterations in motoric, sensory, information-processing and anxiety-related behaviors, they exhibited deficits in neurobehavioral correlates of dominance (including aggression against intruders, mating, and tube dominance) as well as novelty-seeking and risk-taking responses. Furthermore, male 5αR2 KO mice exhibited reduced D 2 -like dopamine receptor binding in the shell of the nucleus accumbens – a well-recognized molecular signature of social dominance. Collectively, these results suggest that 5αR2 is involved in the establishment of social dominance and its behavioral manifestations. Further studies are warranted to understand how the metabolic actions of 5αR2 on steroid profile may be implicated in social ranking, impulse control, and the modulation of dopamine receptor expression in the nucleus accumbens. [ABSTRACT FROM AUTHOR]

Sex steroids play a major role in sexually dimorphic brain development during not only the perinatal period but also the pubertal period. We previously showed that, in male mice, the estrogen receptor-α (Esr1) and aromatase (Cyp19a1) genes are essential to the sexually dimorphic formation of the anteroventral periventricular nucleus (AVPV) and the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), but the estrogen receptor-β (Esr2) gene is not necessary. We also showed that the androgen receptor (Ar) gene is essential to the sexually dimorphic formation of the BNSTp. These genes are expressed in the AVPV and BNSTp of perinatal mice. However, it remains unknown whether these genes are expressed in the AVPV and BNSTp during puberty, and whether the expression, if any, differs by sex, age, and brain region. Here, we dissected the AVPV and BNSTp from Nissl-stained brain sections of male and female mice on postnatal day (PD) 20 (prepuberty), PD30 (puberty onset in females), PD40 (puberty onset in males), and PD60 (young adult) using a laser microdissection system. We then examined the mRNA levels of Esr1, Esr2, Cyp19a1, and Ar in these brain regions. In the AVPV, Esr1 mRNA levels were greater in females than males during PD20-60. Esr2 and Ar mRNA expressions did not differ between sexes. Ar mRNA levels were higher at PD30 than PD20. Cyp19a1 mRNA was not detected in the AVPV at PD20-60. In the BNSTp, Esr1 and Esr2 mRNA levels were higher in females than in males during PD20-60, although the mRNA levels of Cyp19a1 and Ar did not differ between sexes. Additionally, we revealed that orchiectomy at PD20 induced a failure of normal formation of the male BNSTp and testosterone replacement in the prepubertal period rescued the effect of orchiectomy at PD20. Taken together, it is suggested that pubertal testosterone transported to the AVPV is not converted to estradiol there and does not act via ESR1 and ESR2. By contrast, the formation of the male BNSTp may be affected by testicular testosterone during puberty via AR and/or via ESR1 after conversion to estradiol by CYP19A1. [ABSTRACT FROM AUTHOR]

The first and asymmetric total synthesis of cyclocitrinol, an unusual C25 steroid, has been accomplished in a linear sequence of 18 steps from commercially available compound 11. The synthetically challenging bicyclo[4.4.1] A/B ring system with a strained bridgehead (anti-Bredt) double bond of cyclocitrinol was constructed efficiently and diastereoselectively via a type II intramolecular [5 + 2] cycloaddition. [ABSTRACT FROM AUTHOR]

Background Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized. Objectives The authors sought to understand the presentation and clinical course of ICI-associated myocarditis. Methods After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block. Results The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates. Conclusions Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses. [ABSTRACT FROM AUTHOR]

The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits. [ABSTRACT FROM AUTHOR]

Understanding the organizing and activating effects of gonadal steroids on adult physiology can guide insight into sex differences in and hormonal influences on health and disease, ranging from diabetes and other metabolic disorders, emotion and stress regulation, substance abuse, pain perception, immune function and inflammation, to cognitive function and dysfunction accompanying neurological disorders. Because the brain is highly sensitive to many forms of estrogens, it is not surprising that many adult behaviors, including cognitive function, are modulated by estrogens. Estrogens are known for their facilitating effects on learning and memory, but it is becoming increasingly clear that they also can impair learning and memory of some classes of tasks and may do so through direct actions on specific neural systems. This review takes a multiple memory systems approach to understanding how estrogens can at the same time enhance hippocampus-sensitive place learning and impair striatum-sensitive response learning by exploring the role estrogen receptor signaling may play in the opposing cognitive effects of estrogens. Accumulating evidence suggests that neither receptor subtype nor the timing of treatment, i.e. rapid vs slow, explain the bidirectional effects of estrogens on different types of learning. New findings pointing to neural metabolism and the provision of energy substrates by astrocytes as a candidate mechanism for cognitive enhancement and impairment are discussed. [ABSTRACT FROM AUTHOR]

Skin toad secretion present physiologically active molecules to protect them against microorganisms, predators and infections. This work detailed the antiproliferative action of marinobufagin on tumor and normal lines, investigate its mechanism on HL-60 leukemia cells and its toxic effects on Allium cepa meristematic cells. Initially, cytotoxic action was assessed by colorimetric assays. Next, HL-60 cells were analyzed by morphological and flow cytometry techniques and growing A. cepa roots were examined after 72 h exposure. Marinobufagin presented high antiproliferative action against all human tumor lines [IC 50 values ranging from 0.15 (leukemia) to 7.35 (larynx) μM] and it failed against human erythrocytes and murine lines. Human normal peripheral blood mononuclear cells (PBMC) were up to 72.5-fold less sensitive [IC 50: 10.88 μM] to marinobufagin than HL-60 line, but DNA strand breaks were no detected. Leukemia treaded cells exhibited cell viability reduction, DNA fragmentation, phosphatidylserine externalization, binucleation, nuclear condensation and cytoplasmic vacuoles. Marinobufagin also reduced the growth of A. cepa roots (EC 50 : 7.5 μM) and mitotic index, caused cell cycle arrest and chromosomal alterations (micronuclei, delays and C-metaphases) in meristematic cells. So, to find out partially targeted natural molecules on human leukemia cells, like marinobufagin, is an amazing and stimulating way to continue the battle against cancer. [ABSTRACT FROM AUTHOR]

Neurotrophins are well-known growth factors which can play integral roles in the control and regulation of the gastrointestinal tract (GIT). The anabolic steroid testosterone is involved in altering the contractile function of the stomach and intestine. The interactions between neurotrophin factors and testosterone are strong in many systems such as the nervous and respiratory systems. However, these interactions are not clearly determined in the gastrointestinal tract. The aim of this study is to investigate the effect of the anabolic steroid sustanon on the expression levels of neurotrophins in the chicken GIT. Neurotrophins’ ELISA was done on normalized total protein extracts from the stomach, intestine, and colon, and the results were compared between control and sustanon-treated groups. BDNF, NGF, NT-3, and NT-4 are present at different levels in the entire wall of the chicken GIT. Sustanon increased BDNF levels in the stomach and intestine in dose-dependent manner and had no effect in the colon. Sustanon had no effect on NGF in the stomach and intestine; however, at high doses, it increased NGF levels in the colon. High dose of sustanon increased the levels of NT-3 in all regions of the chicken GIT. The effect on NT-4 was obviously region specific, where sustanon had an inhibiting effect in the stomach, augmenting effect in the intestine, and no effect in the colon. These results indicate that the anabolic steroid sustanon has differential effects on neurotrophins’ levels in the chicken GIT and this effect might explain the GIT symptoms associated with the use of these steroids. [ABSTRACT FROM AUTHOR]

Objective: To evaluate two interventions on anabolic-androgenic-steroids (AAS) dispensation in retail pharmacies.Material and Methods: The study was conducted in a north-western region of Spain. Data were the AAS supplied by wholesale drug distributors to retail pharmacies over a period of 102 months. It is designed as an ecological time-series study; the dependent variables were daily defined doses per 1,000 inhabitants per day of each drug. The two interventions evaluated were: (1) an inspection program intended for those retail pharmacies where there was an irregular dispensation and (2) a regulation put forth forcing these pharmacies to carry out additional registers. The medications studied were stanozolol, nandrolone, methenolone, testosterone and mesterolone.Results: The pre-intervention use of AAS displayed a rising trend. There was an immediate reduction of 30.56% after the first intervention, and a further reduction of 35.25% after the second. There was a seasonal pattern of use in the pre-intervention period, pointing to an increased demand at the end of spring and beginning of summer. The most abused drugs were stanozolol and nandrolone.Conclusion: The health actions were very effective, in that they brought about a sharp reduction in the illicit use of AAS. These interventions could be applied to other drugs in which abuse were detected. [ABSTRACT FROM AUTHOR]

Objectives Bipolar disorder (BD) is a severe mental illness characterized by episodes of mania and depression. Numerous studies have implicated the involvement of endogenous cardiac steroids (CS), and their receptor, Na + , K + -ATPase, in BD. The aim of the present study was to examine the role of brain oxidative stress in the CS-induced behavioral effects in mice. Methods Amphetamine (AMPH)-induced hyperactivity, assessed in the open-field test, served as a model for manic-like behavior in mice. A reduction in brain CS was obtained by specific and sensitive anti-ouabain antibodies. The level of oxidative stress was tested in the hippocampus and frontal cortex by measuring the activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as the levels of antioxidant non-protein thiols (NPSH) and oxidative damage biomarkers thiobarbituric acid reactive substances (TBARS) and protein carbonyl (PC). Results AMPH administration resulted in a marked hyperactivity and increased oxidative stress, as manifested by increased SOD activity, decreased activities of CAT and GPx, reduced levels of NPSH and increased levels of TBARS and PC. The administration of anti-ouabain antibodies, which reduced the AMPH-induced hyperactivity, protected against the concomitant oxidative stress in the brain. Conclusions Our results demonstrate that oxidative stress participates in the effects of endogenous CS on manic-like behavior induced by AMPH. These finding support the notion that CS and oxidative stress may be associated with the pathophysiology of mania and BD. [ABSTRACT FROM AUTHOR]

This brief commentary reviews key steps in the history of steroid endocrinology that have resulted in important conceptual shifts. Our understanding of the “Fast Effects of Steroids” now reflect substantial progress, including the major concept that steroids act rapidly on a variety of physiological and behavioral responses, via mechanisms that are too fast to be fully accounted for by classical receptor-dependent regulation of gene transcription. Several so-called ‘non-classical’ mechanisms have been identified and include binding to membrane receptors and regulating non genomic signaling cascades. We survey the discovery of steroids, the initial characterization of their intracellular receptors, key progress in the understanding of the genomic effects of steroids and then the progressive discovery of the rapid non-classical and membrane-initiated actions of steroids. Foundational discoveries about brain steroid synthesis in neural processes and terminals has converged with emerging evidence for the rapid actions of steroids on brain and behavior. Had the rapid effects of steroids in the central nervous system been discovered first, these molecules would likely now be considered as a class of neurotransmitter. [ABSTRACT FROM AUTHOR]

Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the effectiveness of the therapy. Progesterone can be rapidly metabolized into a number of steroids, but to date, there has been a lack of investigation into the fetal steroid profiles following administration and whether this impacts fetal neurodevelopment. The objective of this study was to determine the effect of progesterone treatment on allopregnanolone and cortisol levels in the fetus and on a marker of myelination in the fetal brain. We used a guinea pig model where pregnant dams were administered vehicle (β-cyclodextrin) or progesterone orally throughout pregnancy (GA29-61). Maternal and fetal fluids and tissues were collected at both preterm (GA61) and term (GA68) ages. Maternal and fetal progesterone and cortisol were analyzed by enzyme immunoassay and allopregnanolone by radioimmunoassay. Measurement of myelination of fetal brains (hippocampus, cingulum, and subcortical white matter) at preterm and term ages was performed by immunohistochemistry staining for myelin basic protein. We found that dams receiving progesterone had significantly elevated progesterone and cortisol concentrations, but there was no effect on allopregnanolone. Interestingly, the increased cortisol concentrations were not reflected in the fetuses, and there was no effect of progesterone treatment on myelination. Therefore, we conclude that in our guinea pig model, maternal administration of progesterone has no effect on cortisol levels or markers of mature oligodendrocytes in the fetus and suggest this is potentially due to the protective cortisol barrier in the placenta. [ABSTRACT FROM AUTHOR]

Background: The incidence of childhood nephrotic syndrome (NS) in Germany is not well known.Methods: An ESPED-based nationwide collection of epidemiological data of children in 2005 and 2006.Result: The mean age of NS at onset was 5.5 ± 3.7 years. The gender ratio of boys to girls was 1.8:1. The average length of stay was 15.5 ± 11.2 days, with younger children remaining significantly longer in hospital. Steroid-resistance was more common in children ≥8 years (p = 0.023). Focal-segmental glomerulosclerosis (FSGS) was more common in children >10 years (p = 0.029). The ratio of males to females with FSGS was 1:1.9, thus the FSGS risk for girls at onset was 3.3-times greater. Considering the available data, the incidence of NS in Germany is 1.2/100,000 in the population <18 years, of which 1.0/100,000 are steroid-sensitive.Conclusion: Compared with international data, which primarily focused on regional and small populations, this is the largest study about the incidence of the childhood NS. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? What are the contributions of allopregnanolone, the neuroactive metabolite of progesterone, and nuclear (nPR) and membrane (mPR) progesterone receptors to the respiratory effect of progesterone in newborn rats? What is the main finding and its importance? Acute progesterone injection increases the apnoea frequency, whereas finasteride (which blocks the conversion of progesterone to allopregnanolone) reduces apnoea frequency. An nPR agonist decreases apnoea frequency in males and an mPR agonist decreases apnoea frequency in males and females. Chronic injection of progesterone decreases the frequency of apnoea more efficiently in males than in females. We tested the hypothesis that the effects of progesterone on apnoea frequency in newborn rats are the result of a balance between its neuroactive metabolite, allopregnanolone (GABAA receptor modulator), and progesterone receptors. We used male and female rats between 10 and 12 days of age and recorded respiratory and metabolic parameters (whole‐body plethysmography), and assessed the frequency and duration of apnoeas in normoxia. We tested the effects of a single injection of progesterone (4 mg kg−1, i. p.), finasteride (10 mg kg−1, i. p.; a 5α‐reductase antagonist, which blocks the conversion of progesterone to allopregnanolone), finasteride plus progesterone, or agonists of the nuclear or membrane progesterone receptors (R5020 or Org‐od‐02‐0, 4 mg kg−1). To test the hypothesis that chronic exposure to progesterone reduces the frequency of apnoeas, we used male and female rats treated daily with progesterone between postnatal days 3 and 12. The acute injection of progesterone reduced minute ventilation and metabolic rate and increased the frequency of apnoeas. Finasteride decreased the frequency of apnoeas, and finasteride plus progesterone did not increase apnoea frequency but decreased minute ventilation in female rats. Although R5020 decreased apnoea frequency only in males, Org‐od‐02‐0 decreased apnoea frequency in males and females and decreased respiratory frequency in females. Chronic progesterone treatment reduced apnoea frequency more efficiently in males than in females, but in females (not in males) an acute injection of caffeine (the gold standard for the treatment of apnoea in preterm neonates) further reduced apnoea frequency. Apnoea frequency in newborn rats is, in part, determined by a sex‐specific balance between allopregnanolone, GABAA receptors and progesterone receptors. [ABSTRACT FROM AUTHOR]

Background: Cataracts could result in very dangerous consequences including worldwide blindness which imposes a great economic burden on people and health authorities. Objectives: Evaluate the knowledge of Saudi subjects in Tabuk City toward the cataract induced by chronic use of steroids. Methods: It is a cross sectional community survey based on a questionnaire sheet that was carried out among sample of adult subjects from different shopping malls, community pharmacists, coffees and masjids of Tabuk City from July to September 2017. Results: All the subjects have already heard about cataract and only 6.4% of them suffered from cataract. The most common source of knowledge among participants were relatives and friend (75.1%). Only 9.1% of the subjects used steroid therapy for long periods as 59.4% of them used topical steroids, followed by 20.3% by oral therapy. Most of the subjects (81.4%) showed inadequate knowledge about the steroid induced cataract. The older age had significant association with good knowledge. Conclusion: The level of knowledge about risks factors of chronic usage of steroid therapy and its effects on cataract was inadequate among most of the subjects, although they were university graduates. [ABSTRACT FROM AUTHOR]

Background: There is a perception that the prevalence of anabolic-androgenic steroid (AAS) use is increasing in the UK, with consequent individual and public health risks. Nevertheless, there is a lack of real-time surveillance data to support the development of effective policy. This paper explores the potential of Google Trends to complement existing surveillance methods by analysing user generated search term data.Methods: The Google Trends web tool was used to identify patterns of UK online interest in 15 AAS from January 2011 to December 2015, with 10 ultimately suitable for further analysis. Time series analysis was applied to the data.Results: 10 steroids were ranked from most to least popular. All compounds had peaks in interest between April to July, potentially indicating a consumer driven desire to attain a desired physique in time for summer. Oral steroids were among the most searched for drugs which may have relevance for current service provision to steroid users.Conclusion: Alternative data sources such Google Trends may provide useful additional information to supplement existing surveillance data. The limitations of this method however makes cautious interpretation and triangulation with other data sources essential. [ABSTRACT FROM AUTHOR]

Objective To assess the frequency of steroid-induced hyperglycemia in patients taking systemic steroids (30mg or more of prednisolone or equivalent) for dermatological disorders. Methods We included 150 patients of either sex and with ages between 12 and 70 years in this cross-sectional study, carried out in the department of dermatology, Jinnah Hospital, Lahore for a duration of 6 months. Their baseline fasting blood glucose level prior to the start of steroid treatment was recorded. Patients taking 30mg or more of prednisolone (or equivalent) were followed up after one week of treatment and their random blood sugar levels were checked by the same laboratory on venous blood, to see whether they developed hyperglycemia or not after treatment with steroids. Results Mean age of the patients was 41.83±16.42 years. Ninety-four (62.7%) patients were male while 56 (37.3%) were female. Hyperglycemia was found in 28 out of 150 (18.7%) patients. Conclusion Steroid induce hyperglycemia occurred in 18.7% of the study population. [ABSTRACT FROM AUTHOR]

One of the effective strategies for prevention of steroid-associated osteonecrosis (SAON) is to inhibit bone resorption and fat formation and promote bone formation at osteonecrotic sensitive skeletal sites. We identified a novel phytomolecule that showed positive effects on osteogenesis, anti-bone resorption and anti-adipogenesis in vitro and also developed a bone-targeting delivery system (BTDS) for in vivo experimental study. The study investigated if our innovative synthesized BTDS carrying this phytomolecule would be able to effectively prevent SAON in a rat model. SAON was induced by combined injections of lipopolysaccharide and methylprednisolone. SAON rats were divided into four groups, one SAON untreated control group and three SAON treatment groups with different types of delivery systems (Asp 8 -liposome-icaritin, liposome-icaritin and Asp 8 -liposome) for two weeks. SAON lesions were identified and osteoclasts activity, osteogenesis and adipogenesis at these sites were evaluated by immunohistochemistry. Ex vitro study was also designed to evaluate the osteogenic and adipogenic potential of the isolated bone marrow stromal cells (BMSCs) via real-time PCR and histochemical staining. Our results showed that as a bone surface-specific BTDS, Asp 8 -liposome-icaritin effectively prevented steroids-treated rats from SAON with significantly decreased osteocytes apoptosis, down-regulated osteoclatsogenesis and up-regulated osteogenesis. However, both liposome-icaritin and Asp 8 -liposome treatment did not show significant efficacy for SAON prevention. In summary, this proof-concept-study showed for the first time that the innovative Asp 8 -liposome-icaritin BTDS was effective for prevention of SAON in terms of bone resorption prevention, adipogenesis suppression, and bone-formation enhancement. [ABSTRACT FROM AUTHOR]

Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis (SREAT) is a diagnostic conundrum as it may present with a myriad of nonspecific clinical features and laboratory and neuroimaging investigations are not diagnostic. We report a case of a 65-year-old female who presented with an acute febrile illness associated with headache and confusion, tangential thoughts, and loose association. Based on neutrophil leukocytosis in the full blood count and elevated inflammatory markers, she was commenced on empirical intravenous antibiotics suspecting meningoencephalitis. Further evaluation found a very high titer of both anti-thyroid peroxidase (anti-TPO) antibodies and anti-thyroid globulin antibodies. She was clinically and biochemically euthyroid. EEG showed right sided frontal intermittent rhythmic delta activity (FIRDA). Cranial MRI revealed age related cerebral atrophy and nonspecific periventricular white matter changes. A diagnosis of SREAT was made and she was treated with intravenous methylprednisolone followed by oral prednisolone. Her condition improved dramatically within 48 hours of starting steroids. SREAT is a diagnosis of exclusion in patients with a central nervous system disorder. There are no specific clinical features or investigative findings. Elevated anti-TPO antibodies are considered a hallmark of SREAT and steroid responsiveness supports the diagnosis. Prompt diagnosis and treatment reverses the neurological dysfunction in most cases. [ABSTRACT FROM AUTHOR]

The synthesis and cytotoxic activities determination of new steroidal mono- and bis(thiazolidin-4-ones) 4a – f and 5a – f have been performed. Their anticancer action was also evaluated in comparison to previously synthesized and reported corresponding steroidal thiosemicarbazones. All compounds were obtained as stereoisomeric mixtures with different configuration ( E or Z ) in the hydrazone moiety at the C-3 position. After several consecutive crystallizations diastereomerically pure major ( E )-isomers of mono-thiazolidin-4-ones were isolated. The structure and stereochemistry of 2,4-thiazolidinedione,2-[(17-oxoandrost-4-en-3-ylidene)hydrazone] were confirmed by X-ray analysis. A pathway for the formation of thiazolidin-4-one ring was proposed. The steroid thiazolidinone derivatives examined in this study exerted selective concentration-dependent cytotoxic activities on six tested malignant cell lines. Ten out of twelve examined compounds exhibited strong cytotoxic effects on K562 cells (IC 50 values from 8.5 μM to 14.9 μM), eight on HeLa cells (IC 50 values ranging from 8.9 μM to 15.1 μM) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC 50 values from 12.7 μM to 25.6 μM) than cisplatin (21.5 μM) which served as a positive control. Eight of these ten compounds showed high selectivity in the cytotoxic action against HeLa and K562 cancer cell lines when compared with normal human fibroblasts MRC-5 and normal human PBMC. The study of mechanisms of the anticancer activity of the two selected compounds, mono- and bis(thiazolidin-4-one) derivatives of 19-norandrost-4-ene-3,17-dione 4a and 5a, revealed that both of these compounds induced apoptosis in HeLa cells through extrinsic and intrinsic signalling pathways. Treatment of EA.hy926 cells with sub-toxic concentrations of these compounds led to the inhibition of cell connecting and sprouting, and tube formation. The synthesized compounds exhibited poor antioxidant activity. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the effects of resistance training associated with testosterone administration in the neuromuscular junction (NMJ) postsynaptic region of different skeletal muscle types of aged rats. Wistar rats were divided into: SEI – 20-months-old control, SEF – 24-months-old control, T – 20-months-old with testosterone, S – 20-months-old resistance trained and ST – 20-months-old with resistance training associated with testosterone propionate. All groups were submitted to familiarization and maximum load carrying testing (MLCT). The MLCT was applied before and after the resistance training (RT) period. RT (6–8 ×/session with progressive loads of 50 to 100%, 3 ×/week and 120 s interval) was performed in ladder climbing for 15 weeks. The administration of testosterone propionate was performed 2 ×/week (10 mg/kg/body weight). After euthanize, soleus and plantaris muscles were removed and prepared for histochemistry and cytofluorescence. T, S and ST significantly increased their maximum carrying load capacity compared to SEI and SEF ( p < 0.05). For soleus postsynaptic region, ST had lower total and stained area than SEF ( p < 0.05). For plantaris, the postsynaptic component of T was statistically larger than SEI ( p < 0.05). For soleus histochemistry, T, S and ST groups showed the same magnitude of type I myofibers hypertrophy, thus statistically different from SEI and SEF ( p < 0.05). The cross-sectional area of the type IIa myofibers of the ST was larger than SEF ( p < 0.05). The volume density of type I myofibers show to be lower in ST than SEI ( p < 0.05). As for type IIa myofibers, ST increased Vv [type IIa] compared to SEI and SEF ( p < 0.05). For plantaris, T significantly hypertrophied type I myofibers compared to SEI and SEF ( p < 0.05). S and ST demonstrated significant increases of type I myofibers compared to SEI and SEF ( p < 0.05). As for type IIx myofibers, both S and ST showed myofibers larger than SEI ( p < 0.05). However, only the ST had significant difference compared to SEF ( p < 0.05). In conclusion, both therapies, alone or combined, have little effect on the morphology of the NMJ postsynaptic region of distinct muscles. Moreover, the three therapies are potentially stimulating for strength gains and muscle hypertrophy. [ABSTRACT FROM AUTHOR]

We performed an updated meta-analysis incorporating the results of recent randomised controlled trials (RCTs) to measure the effectiveness of probiotic supplementation in preventing necrotising enterocolitis (NEC) and death in very low-birth-weight (VLBW) infants, and to investigate any differences in efficacy by probiotic agent. Using meta-regression analysis, we assessed the contribution of other measured variables on the overall effect size and between-study variability.Conclusion: Overall, probiotics lead to significant reductions in NEC incidence and mortality in VLBW infants. Differences in probiotic agents and the influence of prenatal steroids and feeding regimens may explain the differences in outcomes between studies. [ABSTRACT FROM AUTHOR]

Apigenin, a common flavonoid, has extensive pharmacological activities. Apigenin inhibits some steroid biosynthetic enzymes, suggesting that it may block neurosteroid synthesis. Neurosteroids play many important roles in neurological functions. The objective of the present study is to investigate effects of apigenin on neurosteroidogenic enzymes, 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C9), and retinol dehydrogenase 2 (RoDH2), in rats. SRD5A1, AKR1C9, and RoDH2 were expressed in COS-1 cells and the effects of apigenin on these enzymes and modes of action were explored using radiolabeled substrates and thin-layer chromatographic separation coupled with radiometry. Apigenin inhibited SRD5A1, AKR1C9, and RoDH2 activities with IC 50 values of 100, 0.891 ± 0.065, and >100 μM, respectively. Apigenin competitively inhibited rat AKR1C9 when its substrate 5α-dihydrotestosterone was used and uncompetitively inhibited the enzyme when cofactor NADPH was used. In conclusion, apigenin is a potent inhibitor of rat AKR1C9, thereby controlling the rate of neurosteroid biosynthesis. [ABSTRACT FROM AUTHOR]

Purpose: The originator abiraterone acetate (OAA) formulation is used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioavailability and bioequivalence of a novel formulation, abiraterone acetate fine particle (AAFP), versus OAA on a steady-state background of steroids.Methods: Thirty-seven healthy male subjects were randomized in a crossover design to receive methylprednisolone (4 mg twice daily) or prednisone (5 mg twice daily) for 12 days in Period 1. On Day 11 of Period 1, subjects given methylprednisolone received a single dose of AAFP 500 mg, and subjects given prednisone received a single dose of OAA 1000 mg under fasted conditions. After a 2-week steroid washout period, subjects received the alternate treatments in Period 2.Results: There were no statistical differences regarding area under the curve (AUC) and maximum concentration (C max) between AAFP and OAA. The bioavailability of abiraterone from AAFP versus OAA by geometric mean ratio was AUC0-∞, 95.9% (90% confidence interval [CI] 86.0-106.9); AUC0-t , 99.2% (88.7-110.9); and C max, 116.8% (102.2-133.4). The coefficient of variation (CV) was smaller for AAFP versus OAA (AUC0-∞, CV 44.23 vs. 55.61%; AUC0-t , 45.17 vs. 58.16%; C max, 54.55 vs. 65.65%, respectively). Both treatments were safe and well tolerated.Conclusions: AAFP plus methylprednisolone provided abiraterone exposure that was comparable to OAA plus prednisone with respect to C max and AUC. Less drug exposure variability was observed with AAFP compared with OAA. Reduced pharmacokinetic variability may positively influence clinical outcomes and warrants further study in mCRPC patients. [ABSTRACT FROM AUTHOR]

Background Prolonged high-dose anabolic-androgenic steroid (AAS) use has been associated with psychiatric symptoms and cognitive deficits, yet we have almost no knowledge of the long-term consequences of AAS use on the brain. The purpose of this study is to investigate the association between long-term AAS exposure and brain morphometry, including subcortical neuroanatomical volumes and regional cortical thickness. Methods Male AAS users and weightlifters with no experience with AASs or any other equivalent doping substances underwent structural magnetic resonance imaging scans of the brain. The current paper is based upon high-resolution structural T1-weighted images from 82 current or past AAS users exceeding 1 year of cumulative AAS use and 68 non–AAS-using weightlifters. Images were processed with the FreeSurfer software to compare neuroanatomical volumes and cerebral cortical thickness between the groups. Results Compared to non–AAS-using weightlifters, the AAS group had thinner cortex in widespread regions and significantly smaller neuroanatomical volumes, including total gray matter, cerebral cortex, and putamen. Both volumetric and thickness effects remained relatively stable across different AAS subsamples comprising various degrees of exposure to AASs and also when excluding participants with previous and current non-AAS drug abuse. The effects could not be explained by differences in verbal IQ, intracranial volume, anxiety/depression, or attention or behavioral problems. Conclusions This large-scale systematic investigation of AAS use on brain structure shows negative correlations between AAS use and brain volume and cortical thickness. Although the findings are correlational, they may serve to raise concern about the long-term consequences of AAS use on structural features of the brain. [ABSTRACT FROM AUTHOR]

Background. Steroid-avoidance protocols have gained popularity in pediatric kidney transplant recipients at low immunologic risk. The long-term safety of steroid avoidance in children with immunologic risk factors remains unknown. Methods. Pediatric kidney transplant recipients from 2004 to 2014 in the Organ Procurement and Transplantation Network database who received tacrolimus and mycophenolate immunosuppression were investigated. Propensity score matching was used to compare graft survival in 1624 children who received steroid avoidance with 1624 children who received steroidbased immunosuppression. The effect of steroid avoidance on graft failure among immunologic risk strata was estimated using Cox proportional hazards regression in this propensity scorematched cohort. Results. It was observed that 5-year graft survival was mildly improved in children receiving steroid avoidance (84.8% versus 81.2%, P=0.03). This improvement in graft survival occurred in the first 2 years following transplant, when the hazard ratio (HR) for allograft failure in children receiving steroid avoidance was 0.62 [95% confidence interval (CI) 0.45-0.86]. In contrast, steroid avoidance was not associated with improved allograft survival during Years 2-10 following transplant (HR=0.93; 95% CI 0.75-1.15). During this time period, HRs (95% CIs) for allograft failure within immunologic risk strata were not significantly different from the null value of 1: repeat kidney transplants, 1.84 (0.84-4.05); African-Americans, 1.02 (0.67-1.56); sensitized recipients, 1.24 (0.63-2.43); recipients of deceased donor kidneys, 1.02 (0.79-1.32); recipients of completely human leukocyte antigen-mismatched kidneys, 0.80 (0.47- 1.37); and recipients with pretransplant glomerular disease, 0.94 (0.71-1.23). Conclusions. In pediatric kidney transplant recipients receiving tacrolimus- and mycophenolate-based immunosuppression, steroid avoidance can be safely practiced in children with immunologic risk factors. [ABSTRACT FROM AUTHOR]

This study examined the effect of playing matches against different opponent teams (hard match; HM, medium match; MM, and easy match; EM) on pre-match testosterone concentration (T), pre-to-post match cortisol (C) concentration, and pre-competitive anxiety (CSAI-2 questionnaire) in 20 elite male basketball players. One training session (TS) was also assessed (control condition). Saliva steroids were determined by ELISA. The pre-T concentration was significantly lower for the TS (163 ± 54 pmol L − 1 ), compared to the three official matches (EM: 208 ± 82 pmol L − 1 , MM: 213 ± 57 pmol L − 1 , and HM: 218 ± 37 pmol L − 1 ) (p < 0.05). A significant change in C from pre-to-post was observed for all conditions (TS [5.8 ± 3.7 vs 14.4 ± 9.4 ƞmol L − 1 ], EM [10.1 ± 4.9 vs 17.3 ± 10.2 ƞmol L − 1 ], MM [13.0 ± 7.4 vs 21.5 ± 8.3 ƞmol L − 1 ], and HM [18.9 ± 5.8 vs 31.4 ± 5.3 ƞmol L − 1 ] (p < 0.05). A higher PRE-C was observed for the HM, compared to TS and EM (p < 0.05) and a higher POST-C concentration for the HM was detected, compared to the TS, EM, and MM (p < 0.05). A lower anxiety level was observed for the EM (somatic: 15.0 ± 3.7; cognitive: 15.8 ± 4.5 arbitrary units [AU]) compared, to the MM (somatic: 16.4 ± 3.5; cognitive: 17.7 ± 4.0 AU) and HM (somatic: 15.8 ± 3.9; cognitive: 18.3 ± 3.9 AU) (p < 0.05) and a higher self-confidence was observed for the TS (28.9 ± 5.1 AU), compared to the HM (26.7 ± 3.0 AU) (p < 0.05). These results suggest that playing against a high-level opponent may cause a higher psychobiological stress, likely because opponent level may be perceived as threating to the social status in a given hierarchy. [ABSTRACT FROM AUTHOR]

Background: Withaferin-A (WF-A) is a well-known dietary compound isolated from Withania sominifera. It has tremendous pharmacological potential and has been shown to exhibit antiproliferative activity against several types of cancerous cells. Currently, the main focus of anti-cancer therapeutic development is to identify apoptosis inducing drug-like molecules. Osteosarcoma is a rare type of osteocancer, affecting human. The present study therefore focused on the evaluation of antitumor potential of WF-A against several osteosarcoma cell lines. Materials and Methods: MTT assay was used to evaluate WF-A against osteosarcoma cell lines and to calculate the IC50. DAPI staining was used to confirm the apoptosis inducing potential of WF-A. Mitochondrial membrane potential, reactive oxygen species (ROS) assay, and Western blotting were used to confirm the basis of apoptosis. Results: The results revealed that that WF-A exhibited strong antiproliferative activity against all the cells lines, with IC50 ranging from 0.32 to 7.6 μM. The lowest IC50 (0.32 μM) was observed against U2OS cell line and therefore it was selected for further analysis. DAPI staining indicated that WF-A exhibited antiproliferative activity via induction of apoptosis. Moreover, WF-A induced ROS-mediated reduction in mitochondrial membrane potential ΔΨm) in a dose-dependent manner and activation of caspase-3 in osteosarcoma cells. Conclusion: We propose that WF-A may prove a potent therapeutic agent for inducing apoptosis in osteosarcoma cell lines via generation of ROS and disruption of mitochondrial membrane potential. [ABSTRACT FROM AUTHOR]

Steroids accumulate in recirculating aquaculture system ( RAS), although explanatory factors for such accumulation are still poorly explored. This study investigated the effect of water exchange rate and pH in six replicated RAS on the concentration of the stress hormone cortisol in rainbow trout blood plasma and in the holding water and of the sex steroids testosterone, 11-ketotestosterone (11- KT) and 17,20β-dihydroxypregn-4-en-3-one (17,20β-P) over a 70-day experimental period. Three combinations of water exchange rate and pH were used each treatment, with two replications: (i) high water exchange rate (±1700 L kg−1 feed) and neutral pH (±7.3), (ii) low water exchange rate (±500 L kg−1 feed) and neutral pH (±7.3) and (iii) low water exchange rate (±500 L kg−1 feed) and low pH (±5.8). Plasma cortisol concentrations at day 70 were higher (24.4 ± 9.5 ng mL−1) for fish kept at low pH when compared to fish kept at neutral pH (12.0 ± 0.1 and 8.7 ± 0.2 ng mL−1). Water cortisol and testosterone concentrations at day 35 were higher at low pH than at neutral pH, whereas water 11- KT and 17,20β-P did not differ among treatments. At day 70, there were no significant differences between low and high pH. These results demonstrate that low pH contributes to increased plasma cortisol concentrations and to its accumulation in water, possibly indicating a stress response to low pH. The higher concentration of testosterone but not of the other sex hormones point to unspecified reproductive effects that need further investigation. [ABSTRACT FROM AUTHOR]

Normal physiology undergoes 24-h changes in function that include daily rhythms in circulating hormones, most notably melatonin and cortical steroids. This study focused on N-acetyltryptamine, a little-studied melatonin receptor mixed agonist-antagonist and the likely evolutionary precursor of melatonin. The central issue addressed was whether N-acetyltryptamine is physiologically present in the circulation. N-acetyltryptamine was detected by LC-MS/MS in daytime plasma of 3 different mammals in subnanomolar levels (mean ± SEM: rat, 0.29 ± 0.05 nM, n = 5; rhesus macaque, 0.54 ± 0.24 nM, n = 4; human, 0.03 ± 0.01 nM, n = 32). Analysis of 24-h blood collections from rhesus macaques revealed a nocturnal increase in plasma N-acetyltryptamine (p < 0.001), which varied from 2- to 15-fold over daytime levels among the 4 animals studied. Related RNA sequencing studies indicated that the transcript encoding the tryptamine acetylating enzyme arylalkylamine N-acetyltransferase (AANAT) is expressed at similar levels in the rhesus pineal gland and retina, thereby indicating that either tissue could contribute to circulating N-acetyltryptamine. The evidence that N-acetyltryptamine is a physiological component of mammalian blood and exhibits a daily rhythm, together with known effects as a melatonin receptor mixed agonist-antagonist, shifts the status of N-acetyltryptamine from pharmacological tool to candidate for a physiological role. This provides a new opportunity to extend our understanding of 24-h biology. [ABSTRACT FROM AUTHOR]

Bufalin is a bufanolide steroid compound in Chan Su. Chan Su is a traditional Chinese medicine prepared from the dried white secretion of the auricular and skin glands of toads and has been used as an oriental drug. However, the effect of bufalin on cardiac function and its underlying cellular mechanisms remain unclear. Here, we explore the cellular mechanisms of bufalin on myocardial protection via the whole-cell patch-clamp recording and video-based edge detection system. Exposure to bufalin resulted in a concentration-dependent blockade of ICa-L, with the half-maximal inhibitory concentration ( IC50) of 60 μ m and the maximal inhibitory effect of 71.50 ± 2.67%. Bufalin at 100 μ m reduced cell shortening by 33.83 ± 4.01%. Bufalin restrained L-type Ca2+ channels conductance, and contractility in rat ventricular myocytes. Thus, the protective effects of bufalin on the heart may be determined by the inhibitory effect on ICa-L and the negative inotropic action caused by the decrease of intracellular Ca2+ in rat myocardial cells. [ABSTRACT FROM AUTHOR]

Background: Patients with difficult-to-treat idiopathic nephrotic syndrome (INS), steroid-dependent nephrotic syndrome (SDNS), or frequently relapsing nephrotic syndrome (FRNS) require long-term immunosuppressive therapy. Rituximab offers an alternative treatment for patients with disease that has not responded to multiple therapies. Objective: Our objective was to determine the efficacy and safety of rituximab in adult patients with difficult-to-treat (SDNS or FRNS) INS. Methods: We performed a retrospective multicenter study that included 50 adults with difficult-to-treat INS in six Spanish centers. All patients were treated with steroids in combination with another immunosuppressant: 28 patients received rituximab as the additional treatment (rituximab group), and the other 22 patients not treated with rituximab served as the control group. Results: Of the patients treated with rituximab, 23 (82%) experienced complete remission, 20 (71%) had no relapses after receiving rituximab, and 13 (46%) did not receive any immunosuppressant. Of those in the control group, 14 (63%) experienced complete remission, including eight without immunosuppressants (29%). The rituximab group experienced highly significant reductions in total number of relapses per year ( p < 0.001), proteinuria ( p = 0.03), steroid doses ( p = 0.002), and tacrolimus doses ( p = 0.001). Mean follow-up after rituximab was 31 ± 26 months (range 8-86). The need for steroids and other immunosuppressants to achieve sustained remission was lower in the rituximab group than in the control group. Conclusions: Rituximab treatment was safe and well tolerated. It effectively reduced the incidence of relapses and need for maintenance immunosuppressive therapy in adults with difficult-to-treat INS. [ABSTRACT FROM AUTHOR]

Background: Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood.Methods: Using a cross-sectional cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting ≥2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume).Results: Compared with nonusers, AAS users demonstrated relatively reduced LV systolic function (mean±SD left ventricular ejection fraction = 52±11% versus 63±8%; P<0.001) and diastolic function (early relaxation velocity = 9.3±2.4 cm/second versus 11.1±2.0 cm/second; P<0.001). Users currently taking AAS at the time of evaluation (N=58) showed significantly reduced LV systolic (left ventricular ejection fraction = 49±10% versus 58±10%; P<0.001) and diastolic function (early relaxation velocity = 8.9±2.4 cm/second versus 10.1±2.4 cm/second; P=0.035) compared with users currently off-drug (N=28). In addition, AAS users demonstrated higher coronary artery plaque volume than nonusers (median [interquartile range] 3 [0, 174] mL3 versus 0 [0, 69] mL3; P=0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase [95% confidence interval] in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units [0.16-1.03 SD units]; P=0.008).Conclusions: Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem. [ABSTRACT FROM AUTHOR]