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INTRODUCTION: Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption.OBJECTIVES: We examined whether intensive daily whole-body TCS treatment over two weeks followed by twice weekly application for four weeks could elicit insulin resistance and increase bone resorption in adults with AD.METHODS: A randomized parallel-group double-blind double-dummy non-corticosteroid-based active-comparator study design was completed in Copenhagen, Denmark. Thirty-six non-obese, non-diabetic adults with moderate-to-severe AD were randomized to whole-body treatment with betamethasone 17-valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after two weeks of daily treatment and after further four weeks of twice-weekly maintenance treatment.RESULTS: AD severity improved with both treatments and systemic inflammation was reduced. After two weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n=18) and tacrolimus (n=18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both two and six weeks but remained unchanged in the tacrolimus arm.CONCLUSIONS: Whole-body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short-term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS.

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes. Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes.

Protein phase separation is increasingly understood to be an important mechanism of biological organization and biomaterial formation. Intrinsically disordered protein regions (IDRs) are often significant drivers of protein phase separation. A number of protein phase-separation-prediction algorithms are available, with many being specific for particular classes of proteins and others providing results that are not amenable to the interpretation of the contributing biophysical interactions. Here, we describe LLPhyScore, a new predictor of IDR-driven phase separation, based on a broad set of physical interactions or features. LLPhyScore uses sequence-based statistics from the RCSB PDB database of folded structures for these interactions, and is trained on a manually curated set of phase-separation-driving proteins with different negative training sets including the PDB and human proteome. Competitive training for a variety of physical chemical interactions shows the greatest contribution of solvent contacts, disorder, hydrogen bonds, pi–pi contacts, and kinked beta-structures to the score, with electrostatics, cation–pi contacts, and the absence of a helical secondary structure also contributing. LLPhyScore has strong phase-separation-prediction recall statistics and enables a breakdown of the contribution from each physical feature to a sequence’s phase-separation propensity, while recognizing the interdependence of many of these features. The tool should be a valuable resource for guiding experiments and providing hypotheses for protein function in normal and pathological states, as well as for understanding how specificity emerges in defining individual biomolecular condensates.

AIMS: To evaluate the effect of curcumin treatment on hepatic fat content in obese individuals.MATERIALS AND METHODS: In a double-blind, parallel-group trial, 37 obese, non-diabetic individuals were randomised to placebo or curcumin treatment for six weeks. Curcumin was dosed as lecithin-formulated tablet; 200 mg twice daily. Primary endpoint was hepatic fat content as assessed by magnetic resonance spectroscopy (MRS). Other endpoints included anthropometric measurements, hepatic biomarkers including FibroScan® measurements, metabolic parameters, inflammation markers, appetite measures and ad libitum food intake.RESULTS: Baseline characteristics (mean ± SD): age 46 ±14 years; hepatic fat content 12.2 ± 8.8 percent points; body mass index 38.8 ±6.1 kg/m 2 ; waist circumference 125.8 ± 12.3 cm. After six weeks treatment with curcumin, hepatic fat content was changed by -0.86 percent points (95% CI -3.65;1.94) compared to 0.71 percent points (95% CI -2.08;3.51) with placebo, thus resulting in a non-significant estimated treatment difference of -1.57 percent points (95% CI -5.36; 2.22, P = 0.412). Compared to placebo, curcumin treatment caused small reductions in fasting plasma glucose (estimated treatment difference (ETD) -0.24 mmol/L (95% CI -0.45; -0.03)), triglycerides (ETD (percentage change) -20.22% (95% CI -33.21; -6.03)), and gamma glutamyltransferase (ETD (percentage change) -15.70 (95% CI -23.32; -7.32)), but except for gamma glutamyltransferase, none of these differences remained statistically significant after adjusting for multiple testing. Treatment was well tolerated. CONCLUSIONS: Compared to placebo, curcumin treatment for six weeks had no significant effect on MRS-assessed hepatic fat content in obese individuals with primarily mild steatosis. Curcumin was well tolerated. This article is protected by copyright. All rights reserved.

Background Sodium-glucose transporter 2 inhibitors (SGLT2-is) appear to have rapid clinical cardiovascular benefits in type 2 diabetes. Furthermore, SGLT2-is have known effects on fat metabolism. Cardiac adipose tissue (CAT) correlates with known markers of cardiovascular risk and left ventricular function. The effects of SGLT2-i treatment on CAT is largely unknown. Objective In this exploratory sub-study from the SIMPLE-trial, we investigated whether empagliflozin affects CAT volume in patients with type 2 diabetes. Methods Between April 4, 2017, and May 11, 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to either 25 mg empagliflozin or placebo for 13 weeks. The primary focus of this sub-study was change in CAT evaluated by computer-tomography (CT). The analysis included 78 patients who had at least one CT scan. Furthermore, we investigated the effect of empagliflozin on left ventricular mass (LVM), end-diastolic volume (EDV) and end-systolic volume (ESV) evaluated by rest and stress 82Rubidium Positron Emission Tomography CT and changes in whole-body metabolism evaluated by fat mass distribution via dual x-ray absorptiometry and measurements of various parameters of glucose, ketone and lipid metabolism. Results Mean ±SD baseline CAT volume was 258.5 mL ±117.9. Empagliflozin reduced CAT after 13 weeks by 12.41 mL (95%CI [-23.83 to -0.99], P=0. 034) as compared with placebo. LVM (-5.16 g, 95%CI [-8.80 to -1.52], P=0. 006), EDV (-7.90 mL, 95%CI [-13.70 to -2.10], P=0. 008) and ESV (-5.46 mL 95%CI [-9.78 to -1.15], P=0. 014) decreased with empagliflozin when comparing groups at week 13. In addition, improvements were observed in whole body metabolic parameters: mean total body weight (-1.48 kg, 95%CI [-2.41 to -0.55], P=0. 002), total fat mass (-0.81 kg, 95%CI [-1.40 to -0.22], P=0. 008), fasting plasma (-1.82 mmol/L, 95%CI [-2.83 to -0.80], P=0. 001), HbA1c (NGSP: -0.76%, 95%CI [-1. 00 to -0.51], P Conclusion Treatment with empagliflozin provides an early reduction of CAT and improves myocardial structure and function which may explain some of this SGLT2-i's clinical cardiovascular benefits. Presentation: No date and time listed

INTRODUCTION: Major advances have been achieved in suicide prevention over the past decades. Effective suicide prevention requires vigilant monitoring of suicide trends. The aim of this study was to assess the change in the Danish suicide rate over time using joinpoint regression analysis and to examine the distribution of suicide methods in the 1980-2015 period.METHODS: Nationwide register data were obtained from the Central Research Register and the Danish Cause of Death Register. Rates were calculated per 100,000 persons by gender and agegroup. Joinpoint regression analysis was used to assess changes over time in the overall suicide rate.RESULTS: The suicide rate declined from 40.4 (95% confidence interval (CI): 38.4-42.3) in 1980 to 11.9 (95% CI: 10.9-12.9) in 2015. A significant reduction ranging between 2 and 6% was observed during 1980-1999 after which the decrease was modest. The rate was higher for men than for women (rate ratio 1.9; 95% CI: 1.7-2.1), and more so by the end of the period (rate ratio = 2.4; 95% CI: 1.9-2.8). The suicide rate was found to increase with increasing age. Hanging, poisoning and shooting were the most frequent methods for men, whereas poisoning followed by hanging and drowning were the most frequent methods for women.CONCLUSIONS: The suicide rate fell sharply between 1980 and 1999 in Denmark, but since then the decrease has been modest, especially since 2007. Further reduction in the suicide rate requires new and effective measures.FUNDING: none.TRIAL REGISTRATION: not relevant.

Prostanoids play an important role throughout all of pregnancy and during the initiation and progress of labor. The human placenta at term produces large quantities of prostanoids, yet little is known of the factors regulating their biosynthesis. In a previous study we observed that insulin-like growth factor I (IGF-I) specifically inhibits thromboxane B2 (TxB2) and prostaglandin F2 alpha (PGF2 alpha) from human term placental explants. In these studies we have defined the dose-related action of IGF-I on the release of placental prostanoids. With use of a perifusion system, the basal release of prostaglandin E2 (PGE2), PGF2 alpha, TxB2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) from human term placental explants increased from the fifth hour in culture, while the release of 13,14-dihydro-15-keto-PGF2 alpha (PGFM) remained constant. The addition of IGF-I (5.2-83.3 ng/mL) to the perifusing medium effected an inhibition of TxB2 and PGF2 alpha. The release of TxB2 was inhibited in a dose-related fashion from the initiation of IGF-I treatment and throughout the five hours of treatment, whereas the inhibition of PGF2 alpha was significant only at a dose of 83.3 ng/mL of IGF-I. Yet, the release of 6-keto-PGF1 alpha, PGE2, or PGFM was not altered by any dose of IGF-I studied. Because both TxB2 and PGF2 alpha are vasoconstrictors, we have proposed that IGF-I may enhance vasodilation in the placenta. Therefore, IGF-I may allow for increased blood flow, thus affecting the maintenance of pregnancy and the supply of nutrients available for the growth of the fetus.

The dose-related effect of gonadotropin-releasing hormone on placental prostanoids was studied with a perifusion system. Villous tissues were perifused with medium 199 (1 ml/hr) and at the beginning of the fifth hour, either 0, 10(-10), 10(-9), 10(-8), 10(-7), or 10(-6) mol/L gonadotropin-releasing hormone was added to the medium of triplicate chambers. The concentration of prostaglandin E, prostaglandin F, 13,14-dihydro-15-keto-prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 in the effluent medium, collected every hour, was determined by specific radioimmunoassay. The cumulative release after gonadotropin-releasing hormone treatment for each chamber was calculated, and replicate chambers were averaged. Linear regression analysis of the average for each dose from three different placentas was used to determine the dose-response relationship. Gonadotropin-releasing hormone significantly inhibited the release of placental prostaglandin E, prostaglandin F, and thromboxane B2 in a dose-dependent fashion. Gonadotropin-releasing hormone had no significant effect on 13,14-dihydro-15-keto-prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha, although there was an apparent increase in 13,14-dihydro-15-keto-prostaglandin F2 alpha. These data support the hypothesis that chorionic gonadotropin-releasing hormone inhibits prostanoid production from the placenta, which in turn may regulate various functions of prostanoids during pregnancy.

Prostanoids play an important role throughout all of pregnancy and during the initiation and progress of labor. The human placenta, at term, produces large quantities of prostanoids, yet little is known of the steps regulating their biosynthesis. In these studies, the effect of IGF-I on the release of placental prostanoids was investigated. The basal release of prostaglandin E (PGE), prostaglandin F (PGF), thromboxane (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) increased from the fifth hour in culture, while the release of 13, 14-dihydro-15-keto-PGF2 alpha (PGFM) remained constant and hCG release decreased. The addition of IGF-I (10(-8) M) to the perfusing medium effected an inhibition of TxB2 and PGF within two and one-half hours of exposure. However, the release of PGE, PGFM, 6-keto-PGF1 alpha or hCG was not altered by IGF-I. Because both TxB2 and PGF are vaso-constrictors, we have proposed that IGF-I may enhance vasodilation in the placenta. Therefore, IGF-I may allow increased blood flow, thus affecting the maintenance of pregnancy and supply of nutrients for the growth of the fetus.

It has become popular to use the gonadotropin-primed immature rat to study ovulation. The ovarian content of progesterone, estradiol, PGE2, PGF2 alpha, and 6-keto-PGF1 alpha during the ovulatory process was determined in this model. Also, the effect of three anti-ovulatory agents on the ovarian levels of the above substances was determined. At 23 days of age, Wistar rats were primed with pregnant mares serum gonadotropin (PMSG) sc, and two days later the ovulatory process was initiated with human chorionic gonadotropin (hCG) sc. The ovarian follicles began rupturing 12 h later. Ovaries were assayed for the two steroids and prostanoids at 2-h intervals before and several 4-h intervals after ovulation. The ovarian estradiol level increased slightly between 0 and 2 h after hCG, while the progesterone level increased sharply between 2 and 4 h after hCG--at a time when the estradiol declined markedly. All three prostanoids increased concomitantly with progesterone. When the PG synthesis was blocked by indomethacin treatment at 1 h before hCG, ovarian progesterone levels still increased. In contrast, when steroidogenic activity was inhibited by aminoglutethimide, the ovarian prostanoid levels also decreased. Cycloheximide had little effect on the steroids and prostanoids. It is concluded that ovarian prostanoid synthesis might be influenced by ovarian steroid output.

INTRODUCTION: The aim of this study was to assess the association between multivitamin intake during pregnancy and the risk of preterm birth and very preterm birth. METHODS: The study population comprised 15,629 women from the Copenhagen Pregnancy Cohort with data on pregnancy multivitamin intake during their first trimester who gave birth to singletons from October 2012 to October 2016. Data on pregnancy multivitamin intake were linked to the Medical Birth Registry to identify the birth outcome. The main outcome measures were preterm birth before 37 weeks of gestation and very preterm birth before 32 weeks of gestation. RESULTS: Among the included women, 85.6% had taken daily pregnancy multivitamins during their first trimester. We found no evidence that pregnancy multivitamin intake during the first trimester was associated with a decreased risk of preterm birth (adjusted odds ratio (OR) = 1.01; 95% confidence interval (CI): 0.77-1.33) or very preterm birth (adjusted OR = 1.06; 95% CI: 0.63-1.77). Stratification for BMI into < 25 kg/m2 and ≥ 25 kg/m2 did not alter these findings. CONCLUSIONS: Pregnancy multivitamin intake during the first trimester was not associated with a decreased risk of preterm birth or very preterm birth among women in a high-income population.