Ventricular Tachycardia Crisis: Assessing Norepinephrine vs. Stress Steroids in the Battle Against Waterhouse-Friderichsen Syndrome With Distributive Shock.

Waterhouse-Friderichsen syndrome (WFS) is a rare but life-threatening complication associated with acute hemorrhagic necrosis of the adrenal glands, primarily linked to meningococcal infection. This report details the case of a 62-year-old female with HIV/AIDS and substance misuse who presented with ventricular tachycardia and hemodynamic instability. Subsequent evaluation revealed WFS in the context of disseminated meningococcal infection. The case highlights the diversity of WFS manifestations and the diagnostic challenges, particularly in patients with comorbidities. Managing WFS involves a delicate balance of steroids and vasopressors, necessitating a multidisciplinary approach. Timely diagnosis and intervention are critical in mitigating the high mortality associated with this syndrome.

Review of the Association Between Long-Term and Current Systemic Steroid Use With Electromechanical Complications and Inpatient Mortality After ST-Elevation Myocardial Infarction.

Background The impact of long-term systemic steroid use on electrical and mechanical complications following ST-segment elevation myocardial infarction (STEMI) has not been extensively studied. Methods In a retrospective cohort study of the National Inpatient Sample (NIS) from 2018 to 2020, adults admitted with STEMI were dichotomized based on the presence of long-term (current) systemic steroid (LTCSS) use. The primary outcome was all-cause mortality. Secondary outcomes included a composite of mechanical complications, electrical, hemodynamic, and thrombotic complications, as well as revascularization complexity, length of stay (LOS), and total charge. Multivariate linear and logistic regressions were used to adjust for confounders. Results Out of 608,210 admissions for STEMI, 5,310 (0.9%) had LTCSS use. There was no significant difference in the odds of all-cause mortality (aOR: 0.89, 95%CI: 0.74-1.08, p-value: 0.245) and the composite of mechanical complications (aOR: 0.74, 95%CI: 0.25-2.30, p-value: 0.599). LTCSS use was associated with lower odds of ventricular tachycardia, atrioventricular blocks, new permanent-pacemaker insertion, cardiogenic shock, the need for mechanical circulatory support, mechanical ventilation, cardioversion, a reduced LOS by 1 day, and a reduced total charge by 34,512 USD (all p-values: <0.05). There were no significant differences in the revascularization strategy (coronary artery bypass graft (CABG) vs. percutaneous coronary interventions (PCI)) or in the incidence of composite thrombotic events. Conclusion LTCSS use among patients admitted with STEMI was associated with lower odds of electrical dysfunction and hemodynamic instability but no difference in the odds of mechanical complications, CABG rate, all-cause mortality, cardiac arrest, or thrombotic complications. Further prospective studies are needed to evaluate these findings further.

A case of secondary multiple evanescent white dot syndrome in a patient with preexisting wet age-related macular degeneration.

Purpose: To report a case of secondary Multiple Evanescent White Dot Syndrome in a patient with preexisting wet age-related macular degeneration. Observation: A 75-year-old male on treat and extend regimen for wet age-related macular degeneration (AMD) presented with a sudden loss of vision and saw central dark shadow in the right eye (RE) for a duration of 1 week. There was no significant history preceding the visual loss. Examination showed a visual acuity (VA) of counting fingers at 1 meter in the right eye and 20/25 in the left eye. Anterior segment examination was unremarkable with dilated fundus examination showing a clear vitreous, tortuous blood vessel, a hyperemic disc and fibrosis at the macula. The left eye (LE) examination was unremarkable. Optical Coherence Tomography (OCT) showed fibrosis due to the previous wet AMD and hyperreflective excrescences projecting from the retinal pigment epithelium (RPE) outside of the old area of wet AMD. Fundus Fluorescein Angiogram (FFA) showed hyperfluorescent spots in a wreath-like pattern increasing in intensity in the early phase and showing late staining towards the late phase while Indocyanine green angiography (ICGA) did not clearly delineate the lesions. Fundus autofluorescence (FAF) revealed hyper Autofluorescence (AF) at the posterior pole. Optical Coherence Tomography Angiography (OCTA) revealed a flow reduction in the choriocapillaris of the affected area. Basic blood investigations with Venereal Disease Research Laboratory (VDRL), syphilitic IgM and IgG antibodies, Quantiferon TB gold test, complete renal function tests and liver function tests were performed. All the blood investigations were within normal limits and the workup for syphilis and tuberculosis was negative. The patient was started on 1mg/kg body weight of oral prednisolone (after the non-response to low dose of oral steroids) with the diagnosis of secondary multiple evanescent white dot syndrome (MEWDS) secondary to wet AMD. The patient was followed up every weekly and the last visit showed improvement in visual acuity to 20/50 with resolution of lesions on FAF and OCT macula. Conclusion and importance: Secondary MEWDS is extremely rare and unique in terms of its presentation and its association with preexisting chorioretinal disease where there is damage to the choriocapillaris- Bruch's membrane-RPE complex. This case report highlights one such rare case scenario and how multimodal imaging helps in the diagnosis, management and follow-up of patients with secondary MEWDS.

Developmental and adult stress: effects of steroids and neurosteroids.

In humans, exposure to early life adversity has profound implications for susceptibility to developing neuropsychiatric disorders later in life. Studies in rodents have shown that stress experienced during early postnatal life can have lasting effects on brain development. Glucocorticoids and sex steroids are produced in endocrine glands and the brain from cholesterol; these molecules bind to nuclear and membrane-associated steroid receptors. Unlike other steroids that can also be made in the brain, neurosteroids bind specifically to neurotransmitter receptors, not steroid receptors. The relationships among steroids, neurosteroids, and stress are multifaceted and not yet fully understood. However, studies demonstrating altered levels of progestogens, androgens, estrogens, glucocorticoids, and their neuroactive metabolites in both developmental and adult stress paradigms strongly suggest that these molecules may be important players in stress effects on brain circuits and behavior. In this review, we discuss the influence of developmental and adult stress on various components of the brain, including neurons, glia, and perineuronal nets, with a focus on sex steroids and neurosteroids. Gaining an enhanced understanding of how early adversity impacts the intricate systems of brain steroid and neurosteroid regulation could prove instrumental in identifying novel therapeutic targets for stress-related conditions.

Establishment of a graphene quantum dot (GQD) based steroid binding assay for the nuclear progesterone receptor (pgr).

Previously, we established a homogeneous assay for membrane progesterone receptor alpha (mPRα) ligands by conjugating semiconductor nanoparticles known as graphene quantum dots (GQDs) to mPRα. When mixed with a progesterone-BSA-fluorescein isothiocyanate conjugate (P4-BSA-FITC), fluorescence occurred by fluorescence resonance energy transfer (FRET) but was reduced by the ligand-receptor binding activity. The established way showed ligand specificity as mPRα protein. In this study, we tried to establish the same way for nuclear progesterone receptor (Pgr). The ligand-binding domain (LBD) of zebrafish Pgr (zPgrLBD) was expressed as a fusion protein with glutathione S-transferase (GST) (GST-zPgrLBD). The recombinant protein was then purified and coupled with GQDs to produce GQD-conjugated GST-zPgrLBD (GQD-GST-zPgrLBD). When mixed with a P4-BSA-FITC and activated by 370 nm light, fluorescence at 520 nm appeared by FRET mechanism. Fluorescence at 520 nm was reduced by adding free progesterone to the reaction mixture. Reduction of fluorescence was induced by zPgr ligands but not by steroids or chemicals that do not interact with zPgr. The results showed the formation of a complex of GQD-GST-zPgrLBD and P4-BSA-FITC with ligand-receptor binding. The binding of the compounds was further confirmed by a radiolabeled steroid binding assay. A homogenous ligand-binding assay for nuclear progesterone receptor has been established.

Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension.

Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.

Excessive androgen exposure and risk of malignancies: A cohort study.

BACKGROUND: A link between androgen use and the risk of cancers, especially prostate and breast cancer, has been suggested. The knowledge about a possible association is limited. OBJECTIVE: The study aimed to investigate cancer incidence rates, particularly those related to prostate and breast cancer, in male androgen users and compare them to a control group. METHODS: We included male androgen users identified through a nationwide anti-doping testing program in Danish fitness centers from 2006 to 2018. We paired each case with 50 male controls of the same age, selected randomly. The cohort was followed from baseline and until 2023. The outcome was the incidence of prostate cancer, breast cancer, or any cancer excluding non-melanoma skin cancer. RESULTS: The study included 1,189 androgen users and 59,450 controls, with a mean age of 27 years at enrolment. During the follow-up period with a mean length of 11 years, 13 androgen users, and 612 controls were diagnosed with cancer. This resulted in an incidence rate ratio of 1.05 (95% CI: 0.55-1.81). None of the androgen users were diagnosed with prostate or breast cancer. DISCUSSION AND CONCLUSION: Male androgen users did not face an increased short-term risk of cancer, neither overall nor related to prostate or breast cancer. Our study indicates that the absolute risk of malignancies in androgen users is comparable to that in the background population. However, we cannot exclude androgens as a cancer risk factor due to the limited sample size, relatively short follow-up period, and subject age.

Management of acute exacerbations of COPD in the emergency department and its associations with clinical variables.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause for emergency department (ED) visits. Still, large scale studies that assess the management of AECOPD in the ED are limited. Our aim was to evaluate treatment characteristics of AE-COPD in the ED on a national scale. A prospective study as part of the COPD Israeli survey, conducted between 2017 and 2019, in 13 medical centers. Patients hospitalized with AECOPD were included and interviewed. Clinical data related to their ED and hospital stay were collected. 344 patients were included, 38% females, mean age of 70 ± 11 years. Median (IQR) time to first ED treatment was 59 (23-125) minutes and to admission 293 (173-490) minutes. Delayed ED treatment (> 1 h) was associated with older age (p = 0.01) and lack of a coded diagnosis of COPD in hospital records (p = 0.01). Long ED length-of-stay (> 5 h) was linked with longer hospitalizations (p = 0.01). Routine ED care included inhalations of short-acting bronchodilators (246 patients, 72%) and systemic steroids (188 patients, 55%). Receiving routine ED care was associated with its continuation during hospitalization (p < 0.001). In multivariate analysis, predictors for patients not receiving routine care were obesity (adjusted odds ratio 0.5, 95% CI 0.3-0.8, p = 0.01) and fever (AOR 0.3, 95% CI 0.1-0.6, p < 0.01), while oxygen saturation < 91% was an independent predictor for ED routine treatment (AOR 3.6, 95% CI 2.1-6.3, p < 0.01). Our findings highlight gaps in the treatment of AECOPD in the ED on a national scale, with specific predictors for their occurrence.

New steroids with anti-inflammatory activity from the whole plants of Physalis minima.

Two new steroids, phyminiolide J (1) and phyministerol A (2), along with three known compounds (3-5) were isolated from the whole plants of Physalis minima. The structures of the new compounds were elucidated by comprehensive spectroscopic analysis and the absolute configurations were determined by using computational ECD calculations. All isolates were evaluated for their anti-inflammatory activity via inhibiting the production of nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells, and the results indicated that 1-3 exposed moderate inhibition with IC50 values ranging from 9.73 to 23.26 µM.

Prediction model for anabolic androgenic steroid positivity in forensic autopsy cases - a new tool to the autopsy room.

Non-prescription use of anabolic androgenic steroids (AAS) is associated with an increased risk of premature death. However, these substances are seldom screened in connection with forensic cause-of-death investigation, unless the forensic pathologist specifically suspects use, often based on a positive AAS use history. Since AAS use is often concealed from others, this practice may lead to mistargeting of these analyses and significant underestimation of the true number of AAS positive cases undergoing forensic autopsy. Thus, more accurate diagnostic tools are needed to identify these cases. The main objective of this study was to determine, whether a multivariable model could predict AAS urine assay positivity in forensic autopsies. We analyzed retrospectively the autopsy reports of all cases that had been screened for AAS during forensic cause-of-death investigation between 2016-2019 at the Finnish Institute for Health and Welfare forensic units (n = 46). Binary logistic regression with penalized maximum likelihood estimation was used to generate a nine-variable model combining circumferential and macroscopic autopsy-derived variables. The multivariable model predicted AAS assay positivity significantly better than a "conventional" model with anamnestic information about AAS use only (area under the receiver operating characteristic curve [AUC] = 0.968 vs. 0.802, p = 0.005). Temporal validation was conducted in an independent sample of AAS screened cases between 2020-2022 (n = 31), where the superiority of the multivariable model was replicated (AUC = 0.856 vs. 0.644, p = 0.004). Based on the model, a calculator predicting AAS assay positivity is released as a decision-aiding tool for forensic pathologists working in the autopsy room.

Aldicarb disturbed bile acid, steroid hormone and oxylipin homeostasis in C57BL/6 J mice.

Mounting evidence has shown that the gut microbiota plays a key role in human health. The homeostasis of the gut microbiota could be affected by many factors, including environmental chemicals. Aldicarb is a carbamate insecticide used to control a variety of insects and nematode pests in agriculture. Aldicarb is highly toxic and its wide existence has become a global public health concern. In our previous study, we have demonstrated that aldicarb disturbed the gut microbial community structure and composition. However, the impacts of aldicarb on gut microbiota-derived metabolites, bile acids, remain elusive. In present study, we performed targeted metabolomics analysis to explore the effects of aldicarb exposure on bile acids, as well as steroid hormones and oxylipins in the serum, feces and liver of C57BL/6 J mice. Our results showed that aldicarb exposure disturbed the level of various bile acids, steroid hormones and oxylipins in the serum and feces of C57BL/6 J mice. In the liver, the level of cortisol was decreased, meanwhile 15,16-dihydroxyoctadeca-9,12-dienoic acid was increased in aldicarb-treated mice. Metagenomic sequencing analysis showed that the relative abundance of a bile salt hydrolase, choloylglycine hydrolase (EC:3.5.1.24) and a sulfatase enzyme involved in steroid hormone metabolism, arylsulfatase, was significantly increased by aldicarb exposure. Furthermore, correlations were found between gut microbiota and various serum metabolites. The results from this study are helpful to improve the understanding of the impact of carbamate insecticides on host and microbial metabolism.

Anaplastic lymphoma kinase-positive pulmonary inflammatory myofibroblastic tumour: a case report.

BACKGROUND: Pulmonary inflammatory myofibroblastic tumour (IMT) is a rare condition that usually presents in young individuals and is associated with anaplastic lymphoma kinase (ALK)-translocation. CASE PRESENTATION: We report a case of an 18-year-old Caucasian man with ALK-translocated pulmonary IMT treated with multimodality therapy. The patient presented with breathlessness and was found to have a collapsed left lung. Further investigations revealed an ALK-translocated pulmonary IMT. This is usually treated with an ALK-inhibitor but patient declined after discussing potential side-effects and had repeated rigid bronchoscopic interventions for local disease control. Due to persistent local recurrence, patient received radical external beam radiotherapy (EBRT) with pulse steroids, and one year later started on Ibuprofen, a non-steroidal anti-inflammatory agent (NSAID). Following multimodality treatment, he developed a complete response. He remains treatment-free for the past seven years. Eleven years on from his diagnosis, he remains in remission with a ECOG performance status of zero. CONCLUSIONS: Achieving long-term local control in pulmonary IMT can be challenging. Multimodality treatment is sometimes needed but the overall outlook remains good.

Anti-inflammatory therapies are associated with delayed onset of anemia and reduction in transfusion requirements in critically ill patients: results from two studies.

BACKGROUND: Anemia is a hallmark of critical illness, which is largely inflammatory driven. We hypothesized that the use of anti-inflammatory agents limits the development of anemia and reduces the need for red blood cell (RBC) transfusions in patients with a hyper-inflammatory condition due to COVID-19. METHODS: An observational cohort (n = 772) and a validation cohort (a subset of REMAP-CAP, n = 119) of critically ill patients with hypoxemic respiratory failure due to COVID-19 were analyzed, who either received no treatment, received steroids or received steroids plus IL-6 blocking agents. The trajectory of hemoglobin (Hb) decline and the need for RBC transfusions were compared using descriptive statistics as well as multivariate modeling. RESULTS: In both cohorts, Hb level was higher in the treated groups compared to the untreated group at all time points. In the observational cohort, incidence and number of transfused patients were lower in the group receiving the combination treatment compared to the untreated groups. In a multivariate analysis controlling for baseline Hb imbalance and mechanical ventilation, receipt of steroids remained associated with a slower decline in Hb level and the combination treatment remained associated with a slower decline of Hb and with less transfusions. Results remained the same in the validation cohort. CONCLUSION: Immunomodulatory treatment was associated with a slower decline in Hb level in critically ill patients with COVID-19 and with less transfusion. Findings point toward inflammation as an important cause for the occurrence of anemia in the critically ill.

Methylation of phase II metabolites of endogenous anabolic androgenic steroids to improve analytical performance.

The study of intact phase II metabolites of endogenous anabolic androgenic steroids (EAAS) gives important information about metabolism and has the potential to improve the detection of doping with testosterone. For analysis with liquid chromatography-mass spectrometry (LC-MS), chemical derivatization at the steroid moiety is a technique to improve the positive ionization efficiency of glucuronidated/sulfated EAAS under collision-induced dissociation (CID) conditions. However, regarding the chromatographic performance, there are still challenges to address, for example, poor peak shape, which is mainly caused by nondefined adsorption in the chromatographic system. Here, we show a novel derivatization technique for the analysis of selected phase II metabolites of EAAS, where the acidic moiety of the glucuronide/sulfate is methylated with different methylation reagents to reduce nondefined adsorption. The methylation reagent trimethylsilyl-diazomethane (TMSD) was preferred over the other tested reagents methyl iodide (MeI) and dimethyl sulfate (DMS). Glucuronidated and sulfated testosterone and epitestosterone were methylated, and their chromatographic performance and CID ion mass spectra obtained in positive ionization mode were investigated. The peak width and peak height were significantly improved for all substances. Methylated testosterone sulfate showed the best results with a 3.5 times narrower peak and 14 times increased intensity compared with underivatized testosterone sulfate. Furthermore, CID ion mass spectra obtained in positive ionization mode showed product ions characteristically for the steroidal backbone for all substances. This preliminary study shows the potential of methylation as a supplementary derivatization technique, which can assist in the development of more sensitive methods due to the improvements in method performance.

Synthesis, in vitro and in silico anticancer evaluation of novel pyridin-2-yl estra-1,3,5(10)-triene derivatives.

Aim: The aim of this study was the synthesis of steroid compounds with heterocyclic rings and good anticancer properties. Materials & methods: The synthesis, in silico and in vitro anticancer testing of novel pyridin-2-yl estra-1,3,5(10)-triene derivatives was performed. Results: All synthesized compounds have shown promising results for, antiproliferative activity, relative binding affinities for the ligand binding domains of estrogen receptors α, ß and androgen receptor, aromatase binding potential, and inhibition of AKR1C3 enzyme. Conclusion: 3-Benzyloxy (17E)-pycolinilidene derivative 9 showed the best antitumor potential against MDA-MB-231 cell line, an activity that can be explained by its moderate inhibition of AKR1C3. Molecular docking simulation indicates that it binds to AKR1C3 in a very similar orientation and geometry as steroidal inhibitor EM1404.

Multicenter registry of pediatric inflammatory bowel disease from a developing country.

BACKGROUND: Despite the rising incidence of pediatric inflammatory bowel disease (PIBD) globally, multicenter collaborative studies of PIBD children among developing countries remain sparse. We therefore aimed to define the initial presentation and short-term outcomes of Thai children with PIBD from a multicenter registry. METHODS: Four teaching hospitals participated in this study. A diagnosis of PIBD requires gastrointestinal endoscopy and histopathology in children aged < 19 years. Besides demographics, we collected clinical information and treatment with the data at 1-year follow up. RESULTS: We included 35 Crohn's disease (CD), one IBD-unclassified, and 36 ulcerative colitis (UC) children (total n = 72 with 60.6% males). The mean age at diagnosis was 7.9 years (SD 4.1) with 38% being very early onset IBD (VEO-IBD). When compared with UC, the CD children were more likely to exhibit fever (42.3 vs. 13.9%), weight loss/failure to thrive (68.6 vs. 33.3%), and hypoalbuminemia (62.9 vs. 36.1%) but less likely to have bloody stools (51.4 vs. 91.7%) (all P < 0.05). No significant differences in demographics, clinical data and medications used with regards to VEO-IBD status. At 1 year after diagnosis (n = 62), 30.7% failed to enter clinical remission and 43.7% remained on systemic corticosteroids. Diarrhea (OR 9.32) and weight issues (OR 4.92) at presentation were independent predictors of failure to enter clinical remission; and females (OR 3.08) and CD (vs. UC) (OR 3.03) were predictors of corticosteroids use at 1-year follow-up. CONCLUSIONS: A high proportion of VEOIBD is noted, and CD was more likely to present with significant inflammatory burden. Diarrhea and weight issues at presentation were independent predictors of failure to enter clinical remission; and females and CD (vs. UC) were predictors of corticosteroids use at 1-year follow-up.

Mitocentricity.

Worldwide, interest in mitochondria is constantly growing, as evidenced by scientific statistics, and studies of the functioning of these organelles are becoming more prevalent than studies of other cellular structures. In this analytical review, mitochondria are conditionally placed in a certain cellular center, which is responsible for both energy production and other non-energetic functions, without which the existence of not only the eukaryotic cell itself, but also the entire organism is impossible. Taking into account the high multifunctionality of mitochondria, such a fundamentally new scheme of cell functioning organization, including mitochondrial management of processes that determine cell survival and death, may be justified. Considering that this issue is dedicated to the memory of V. P. Skulachev, who can be called mitocentric, due to the history of his scientific activity almost entirely aimed at studying mitochondria, this work examines those aspects of mitochondrial functioning that were directly or indirectly the focus of attention of this outstanding scientist. We list all possible known mitochondrial functions, including membrane potential generation, synthesis of Fe-S clusters, steroid hormones, heme, fatty acids, and CO2. Special attention is paid to the participation of mitochondria in the formation and transport of water, as a powerful biochemical cellular and mitochondrial regulator. The history of research on reactive oxygen species that generate mitochondria is subject to significant analysis. In the section "Mitochondria in the center of death", special emphasis is placed on the analysis of what role and how mitochondria can play and determine the program of death of an organism (phenoptosis) and the contribution made to these studies by V. P. Skulachev.

Monitoring adrenal insufficiency through salivary steroids: a pilot study.

BACKGROUND: Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires. METHODS: Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis. RESULTS: Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores. CONCLUSIONS: None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.

Prevention of potential delayed hemolytic transfusion reaction in two sickle cell patients using intravenous immunoglobulins and steroids before and after red blood cell exchange with antigen positive units and review literature.

Emergent Red Blood Cell (RBC) exchange is indicated in sickle cell disease (SCD) patients with severe acute chest syndrome. However, fully matched RBC units may not be available for patients with multiple RBC antibodies. Intravenous immunoglobulin (IVIG) and steroids were reported for preventing potential delayed hemolytic transfusion reaction (HTR) in simple transfusion of antigen-positive RBCs. We investigated the efficacy and safety of IVIG and steroids in two SCD patients presented with acute chest syndrome receiving RBC exchange with multiple incompatible units. The first patient had multiple historical alloantibodies, including anti-Jsb, although none of them were reactive. IVIG (1 g/kg) was given before and after RBC exchange with methylprednisolone (500 mg IV) one hour before exchange. Her sickle hemoglobin (HbS) was reduced from 89.4% to 17.4% after the exchange with five Jsb-positive units. The patient improved clinically without acute or delayed hemolysis. The second patient had reactive anti-Jsb on two different admissions 18 months apart. Only one of the sixteen units used in the exchanges was Jsb negative. He received the same IVIG regimen during both admissions but 100 mg IV hydrocortisone instead of methylprednisolone. His HbS was reduced from 63.4% to 22.4% after the first exchange. Significant clinical improvements were achieved after both exchanges. No delayed HTR was observed. Our experience of these two patients suggested that IVIG and steroids may be used in preventing potential delayed HTR in some SCD patients with rare antibodies receiving large amounts of antigen-positive RBC products.

Exploration and biological evaluation of 20-vinyl pregnenes: A step forward toward selective modulators of the estrogen receptor α signaling for breast cancer treatment.

A series of D-ring modified steroids bearing a vinyl ketone pendant were synthesized and evaluated for antiproliferative activity against breast cancer cell line and cytochromes P450. The lead compound, 21-vinyl 20-keto-pregnene (2f) (IC50 = 2.4 µM), was shown to be a promising candidate for future anticancer drug design, particularly against estrogen receptor α (ERα)-positive breast cancer. The lead compound was found to have a significant effect on the signaling pathways in parental and 4-hydroxytamoxifen-resistant cells. Compound 2f modulated the ERK, cyclin D1, and CDK4 pathways and blocked the expression of ERα, the main driver of breast cancer growth. Compound 2f significantly reduced 17ß-estradiol-induced progesterone receptor expression. Accumulation of cleaved poly(ADP-ribose) polymerase in cells treated with compound 2f indicated induction of apoptosis. The selectivity analysis showed that lead compound 2f produces no significant effects on cytochromes P450, CYP19A1, CYP21A2, and CYP7B1.