11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18–55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: −4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: −0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest

Energy compensation following consumption of sugar-reduced products: a randomized controlled trial

PURPOSE: Consumption of sugar-reformulated products (commercially available foods and beverages that have been reduced in sugar content through reformulation) is a potential strategy for lowering sugar intake at a population level. The impact of sugar-reformulated products on body weight, energy balance (EB) dynamics and cardiovascular disease risk indicators has yet to be established. The REFORMulated foods (REFORM) study examined the impact of an 8-week sugar-reformulated product exchange on body weight, EB dynamics, blood pressure, arterial stiffness, glycemia and lipemia. METHODS: A randomized, controlled, double-blind, crossover dietary intervention study was performed with fifty healthy normal to overweight men and women (age 32.0 ± 9.8 year, BMI 23.5 ± 3.0 kg/m2) who were randomly assigned to consume either regular sugar or sugar-reduced foods and beverages for 8 weeks, separated by 4-week washout period. Body weight, energy intake (EI), energy expenditure and vascular markers were assessed at baseline and after both interventions. RESULTS: We found that carbohydrate (P < 0.001), total sugars (P < 0.001) and non-milk extrinsic sugars (P < 0.001) (% EI) were lower, whereas fat (P = 0.001) and protein (P = 0.038) intakes (% EI) were higher on the sugar-reduced than the regular diet. No effects on body weight, blood pressure, arterial stiffness, fasting glycemia or lipemia were observed. CONCLUSIONS: Consumption of sugar-reduced products, as part of a blinded dietary exchange for an 8-week period, resulted in a significant reduction in sugar intake. Body weight did not change significantly, which we propose was due to energy compensation

Exploring the role of Emotional Intelligence on disorder eating psychopathology

Purpose: This study aims to explore the role of emotional intelligence (EI) and specific facets that may underpin the aetiology of disordered eating attitudes and behaviours, as a means to understand what aspects of these deficits to target within treatments. Methods: Participants were recruited from the UK and Ireland. Among the sample of 355 participants, 84% were women and 16% were men. Regarding age, 59% were between 18 and 29, 30% were between 30 and 49, and 11% were 50 or older. Using a cross-sectional design, participants completed the Schutte Self-Report Emotional Intelligence Test to measure levels of trait EI and The Eating Attitudes Test (EAT-26) as a measure of eating disorder risk and presence of disordered eating attitudes. Results: EAT-26 scores were negatively correlated with total EI scores and with the following EI subscales: appraisal of own emotions, regulation of emotions, utilization of emotions, and optimism. Also, compared to those without an eating disorder history, participants who reported having had an eating disorder had significantly lower total EI scores and lower scores on four EI subscales: appraisal of others emotions, appraisal of own emotions, regulation of emotions, and optimism. Conclusions: Considering these findings, EI (especially appraisal of own emotions, regulation of emotions, and optimism) may need to be addressed by interventions and treatments for eating disorders

Modeling of miRNA and Drug Action in the EGFR Signaling Pathway

MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR) signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs) on this pathway and propose that the embedded miRNA-network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer

Cranial Ontogeny in Stegoceras validum (Dinosauria: Pachycephalosauria): A Quantitative Model of Pachycephalosaur Dome Growth and Variation

Historically, studies of pachycephalosaurs have recognized plesiomorphically flat-headed taxa and apomorphically domed taxa. More recently, it has been suggested that the expression of the frontoparietal dome is ontogenetic and derived from a flat-headed juvenile morphology. However, strong evidence to support this hypothesis has been lacking. Here we test this hypothesis in a large, stratigraphically constrained sample of specimens assigned to Stegoceras validum, the best known pachycephalosaur, using multiple independent lines of evidence including conserved morphology of ornamentation, landmark-based allometric analyses of frontoparietal shape, and cranial bone histology. New specimens show that the diagnostic ornamentation of the parietosquamosal bar is conserved throughout the size range of the sample, which links flat-headed specimens to domed S. validum. High-resolution CT scans of three frontoparietals reveal that vascularity decreases with size and document a pattern that is consistent with previously proposed histological changes during growth. Furthermore, aspects of dome shape and size are strongly correlated and indicative of ontogenetic growth. These results are complementary and strongly support the hypothesis that the sample represents a growth series of a single taxon. Cranial dome growth is positively allometric, proceeds from a flat-headed to a domed state, and confirms the synonymy of Ornatotholus browni as a juvenile Stegoceras. This dataset serves as the first detailed model of growth and variation in a pachycephalosaur. Flat-headed juveniles possess three characters (externally open cranial sutures, tuberculate dorsal surface texture, and open supratemporal fenestrae) that are reduced or eliminated during ontogeny. These characters also occur in putative flat-headed taxa, suggesting that they may also represent juveniles of domed taxa. However, open cranial sutures and supratemporal fenestrae are plesiomorphic within Ornithischia, and thus should be expected in the adult stage of a primitive pachycephalosaur. Additional lines of evidence will be needed to resolve the taxonomic validity of flat-headed pachycephalosaur taxa

Measurement of melatonin in body fluids: Standards, protocols and procedures

Abstract: The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6‐ sulphatoxymelatonin in urine, is a defining feature of suprachiasmatic nucleus function, the endogenous oscillatory pacemaker. These measurements are useful to evaluate problems related to the onset or offset of sleep and for assessing phase delays or advances of rhythms in entrained individuals. Additionally, they have become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood disorders. Thus, the development of sensitive and selective methods for the precise detection of melatonin in tissues and fluids of animals emerges as necessary. Due to its low concentration and the co‐existence of many other endogenous compounds in blood, the determination of melatonin has been an analytical challenge. This review discusses current methodologies employed for detection and quantification of melatonin in biological fluids and tissues

The N-Terminal Domain of the Drosophila Retinoblastoma Protein Rbf1 Interacts with ORC and Associates with Chromatin in an E2F Independent Manner

The retinoblastoma (Rb) tumor suppressor protein can function as a DNA replication inhibitor as well as a transcription factor. Regulation of DNA replication may occur through interaction of Rb with the origin recognition complex (ORC).We characterized the interaction of Drosophila Rb, Rbf1, with ORC. Using expression of proteins in Drosophila S2 cells, we found that an N-terminal Rbf1 fragment (amino acids 1-345) is sufficient for Rbf1 association with ORC but does not bind to dE2F1. We also found that the C-terminal half of Rbf1 (amino acids 345-845) interacts with ORC. We observed that the amino-terminal domain of Rbf1 localizes to chromatin in vivo and associates with chromosomal regions implicated in replication initiation, including colocalization with Orc2 and acetylated histone H4.Our results suggest that Rbf1 can associate with ORC and chromatin through domains independent of the E2F binding site. We infer that Rbf1 may play a role in regulating replication directly through its association with ORC and/or chromatin factors other than E2F. Our data suggest an important role for retinoblastoma family proteins in cell proliferation and tumor suppression through interaction with the replication initiation machinery

At the bottom of the differential diagnosis list: unusual causes of pediatric hypertension

Hypertension affects 1–5% of children and adolescents, and the incidence has been increasing in association with obesity. However, secondary causes of hypertension such as renal parenchymal diseases, congenital abnormalities and renovascular disorders still remain the leading cause of pediatric hypertension, particularly in children under 12 years old. Other less common causes of hypertension in children and adolescents, including immobilization, burns, illicit and prescription drugs, dietary supplements, genetic disorders, and tumors will be addressed in this review

ICAR: endoscopic skull‐base surgery

n/