Dexamethasone attenuates the modulatory effect of the insular cortex on the baroreflex in anesthetized rat.

The arterial baroreflex (BR) is an important neural mechanism for the stabilization of arterial pressure (AP). It is known that the insular cortex (IC) and other parts of the central autonomic network (CAN) are able to modulate the BR arc, altering baroreflex sensitivity (BRS). In addition, the sensitivity of the BR changes under the influence of hormones, in particular glucocorticoids (GCs). It has been suggested that GCs may influence BRS by altering the ability of the IC to modulate the BR. This hypothesis has been tested in experiments on rats anesthetized with urethane. It was found that microelectrostimulation of the visceral area in the left IC causes a short-term drop in AP, which is accompanied by bradycardia and impairs BRS. The synthetic GC dexamethasone (DEX) did not significantly affect the magnitude of depressor responses but increased BRS and impaired the effect of IC stimulation on the BR. The results obtained confirm the hypothesis put forward and suggest that GC can attenuate the inhibitory effects of the IC on the BR arc, thereby enhancing the sensitivity of the BR.

A meta-analysis of anthropogenic impacts on physiological stress in wild primates.

As humanity continues to alter the environment extensively, comprehending the effect of anthropogenic disturbances on the health, survival, and fitness of wildlife is a crucial question for conservation science. Many primate populations occupy suboptimal habitats prone to diverse anthropogenic disturbances that may be sources of acute and chronic stress. Quantification of glucocorticoid (GC) concentrations has repeatedly been used to explore the impact of disturbances on physiological stress. Although it is still debated, prolonged elevation of GC levels may impair reproduction, growth, and immune system activity of individuals. We quantified the effect of anthropogenic disturbances on physiological stress in primates with a global meta-analysis based on data from 26 articles, covering 24 distinct species in 13 different countries. Anthropogenic disturbances were classified into 6 distinct categories: habitat loss, habitat degradation, ongoing logging, hunting, tourism, and other human activities. We calculated effect sizes (Hedges' g) with the standardized mean difference in GC concentrations between primates affected by human activity and their undisturbed conspecifics. We ran random-effects models and subgroup analyses to estimate the overall effect as well as a cumulative effect size for each disturbance category. Overall, primates inhabiting sites subject to anthropogenic disturbances exhibited significantly higher GC levels (g = 0.60; 95% CI: 0.28-0.93). Habitat loss and hunting were overall associated with increased GC concentrations, whereas the cumulative effects of the other disturbances were not statistically significant. Biologically, high GC levels may increase fitness by enabling individuals to overcome the challenges linked to anthropogenic disturbances. However, primates in disturbed environments may have sustained elevated GC levels. To strengthen future research, it is necessary to control confounding factors systematically (e.g., diet, reproductive status, predatory pressure, and resource availability) and improve understanding of the link between GC levels and the health, fitness, and survival of animals.

Metaanálisis de los Impactos Antropogénicos sobre el Estrés Fisiológico de los Primates Salvajes Resumen Conforme la humanidad continúa alterando extensivamente el ambiente, comprender el efecto de las perturbaciones antropogénicas sobre la salud, supervivencia y la aptitud de la fauna silvestre es una cuestión muy importante para las ciencias de la conservación. Muchas poblaciones de primates ocupan hábitats subóptimos propensos a varias perturbaciones antropogénicas que pueden ser la fuente de estrés agudo y crónico. La cuantificación de las concentraciones de glucocorticoides se ha usado repetidamente para explorar el impacto de las perturbaciones sobre el estrés fisiológico. Aunque todavía es tema de debate, la elevación prolongada de los niveles de glucocorticoides puede afectar a la reproducción, el crecimiento y la actividad del sistema inmune de los individuos. Cuantificamos el efecto de las perturbaciones antropogénicas sobre el estrés fisiológico de los primates mediante un metaanálisis global basado en los datos tomados de 26 artículos, abarcando así a 24 especies distintas en 13 países diferentes. Las perturbaciones antropogénicas fueron clasificadas en seis categorías distintas: pérdida de hábitat, degradación del hábitat, explotación forestal en curso, cacería, turismo y otras actividades humanas. Calculamos los tamaños del efecto (la g de Hedges) con una diferencia media estandarizada en las concentraciones de glucocorticoides entre los primates afectados por la actividad humana y sus coespecíficos sin perturbaciones. Corrimos modelos de efectos al azar y análisis de subgrupos para estimar el efecto generalizado, así como un tamaño acumulativo de efecto para cada categoría de perturbación. En general, los primates que habitan sitios sujetos a alguna perturbación antropogénica exhibieron niveles de glucocorticoides significativamente más altos (g = 0.60, 95% CI 0.28 a 0.93). La pérdida de hábitat y la cacería fueron asociadas casi siempre con las concentraciones elevadas de glucocorticoides, mientras que los efectos acumulativos de las otras perturbaciones no fueron significativos estadísticamente. Biológicamente, los niveles altos de glucocorticoides pueden incrementar la aptitud al permitir que el individuo supere los retos relaciones con las perturbaciones antropogénicas. Sin embargo, los primates en los ambientes perturbados pueden tener niveles elevados sostenidos de glucocorticoides. Para fortalecer a las futuras investigaciones es necesario controlar sistemáticamente los factores desconcertantes (p. ej.: la dieta, el estado reproductivo, la presión por depredadores, la disponibilidad de recursos) y mejorar el entendimiento de la conexión entre los niveles de glucocorticoides y la salud, aptitud y supervivencia de los animales.

Changes in c-fos and p-CREB signaling following exposure to forced swim stress or exogenous corticosterone during morphine-induced place preference are dependent on glucocorticoid receptor in the basolateral amygdala.

Neural circuitry comprising the nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HIP) are the main components of the reward circuit. Our previous behavioral data showed that forced swim stress (FSS) and corticosterone administration could inhibit the acquisition of morphine-induced conditioned place preference (CPP), and this effect was blocked by intra-basolateral amygdala (BLA) administration of RU38486, glucocorticoid receptor (GR) antagonist. Therefore, we tried to evaluate the effect of intra-BLA administration of the GR antagonist during the conditioning phase on the c-fos and p-CREB/CREB ratio expression in the AMY, NAc, PFC, and HIP of rats that underwent FSS or received exogenous corticosterone (10 mg/kg; i.p.) before morphine injection (5 mg/kg; s.c.) during 3 conditioning days. Our results showed that morphine-induced CPP could increase c-fos level and p-CREB/CREB ratio in all regions (except in the HIP). In addition, c-fos expression was elevated by FSS in all regions and blockade of GR decreased this effect. In the PFC, in addition to FSS, corticosterone could raise c-fos expression, which was blocked by RU38486. In conclusion, it seems that the intra-BLA administration of RU38486 differently modulates the effect of morphine-induced CPP on the expression of c-fos and p-CREB/CREB ratio in animals that underwent FSS or corticosterone administration.

Mechanisms of NADPH - cytochrome P450 oxidoreductase induction by dexamethasone in the H4IIE rat hepatoma cell line.

Expression of NADPH - cytochrome P450 oxidoreductase (POR), electron donor for microsomal P450s, is induced in rat liver by dexamethasone (DEX), an activator of the glucocorticoid receptor (GR) and the pregnane X receptor (PXR). DEX induction of POR in rat liver is primarily PXR-mediated, although GR may contribute to mRNA effects. We examined the role of GR and PXR in the DEX induction of POR mRNA and protein in the H4IIE rat hepatoma cell line. The DEX EC50 for a PXR target, CYP3A23, exceeded that for the GR targets tyrosine aminotransferase and PXR as well as POR itself. POR protein levels were induced 3- and 4-fold, respectively, by DEX concentrations activating GR selectively (100 nM) or both GR and PXR (10 µM). POR was induced by triamcinolone acetonide, a selective GR agonist, but not pregnenolone-16α-carbonitrile, a selective PXR agonist. POR induction was blocked by the GR antagonist RU486 but minimally influenced by the PXR antagonist FLB-12. The half-life for POR mRNA was prolonged by DEX at both 100 nM and 10 µM. GR is more important in DEX-induced POR expression in H4IIE cells compared to rat liver in vivo, calling into question the suitability of this cell model for mechanistic studies.

HDAC2 is required by the physiological concentration of glucocorticoid to inhibit inflammation in cardiac fibroblasts.

We previously suggested that endogenous glucocorticoids (GCs) may inhibit myocardial inflammation induced by lipopolysaccharide (LPS) in vivo. However, the possible cellular and molecular mechanisms were poorly understood. In this study, we investigated the role of physiological concentration of GCs in inflammation induced by LPS in cardiac fibroblasts and explored the possible mechanisms. The results showed that hydrocortisone at the dose of 127 ng/mL (equivalent to endogenous basal level of GCs) inhibited LPS (100 ng/mL)-induced productions of TNF-α and IL-1ß in cardiac fibroblasts. Xanthine oxidase/xanthine (XO/X) system impaired the anti-inflammatory action of GCs through downregulating HDAC2 activity and expression. Knockdown of HDAC2 restrained the anti-inflammatory effects of physiological level of hydrocortisone, and blunted the ability of XO/X system to downregulate the inhibitory action of physiological level of hydrocortisone on cytokines. These results suggested that HDAC2 was required by the physiological concentration of GC to inhibit inflammatory response. The dysfunction of HDAC2 induced by oxidative stress might be account for GC resistance and chronic inflammatory disorders during the cardiac diseases.

The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats.

The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-α) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-α, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues.

Rank-dependent grooming patterns and cortisol alleviation in Barbary macaques.

Flexibly adapting social behavior to social and environmental challenges helps to alleviate glucocorticoid (GC) levels, which may have positive fitness implications for an individual. For primates, the predominant social behavior is grooming. Giving grooming to others is particularly efficient in terms of GC mitigation. However, grooming is confined by certain limitations such as time constraints or restricted access to other group members. For instance, dominance hierarchies may impact grooming partner availability in primate societies. Consequently specific grooming patterns emerge. In despotic species focusing grooming activity on preferred social partners significantly ameliorates GC levels in females of all ranks. In this study we investigated grooming patterns and GC management in Barbary macaques, a comparably relaxed species. We monitored changes in grooming behavior and cortisol (C) for females of different ranks. Our results show that the C-amelioration associated with different grooming patterns had a gradual connection with dominance hierarchy: while higher-ranking individuals showed lowest urinary C measures when they focused their grooming on selected partners within their social network, lower-ranking individuals expressed lowest C levels when dispersing their grooming activity evenly across their social partners. We argue that the relatively relaxed social style of Barbary macaque societies allows individuals to flexibly adapt grooming patterns, which is associated with rank-specific GC management.

Determining the Associations Between Glucocorticoid Use During Hematologic Chemotherapy Treatment and New-onset Diabetes and Hyperglycemia and Mortality: A Population-based Cohort Study.

OBJECTIVES: The aim of this study was to determine the associations between glucocorticoid administration during chemotherapy for hematologic malignancy and hyperglycemia, new-onset diabetes, and mortality in Ontario, Canada. Hospitalization and emergency room utilization during the chemotherapy treatment period were also described. METHODS: We conducted a retrospective cohort study using health administrative data from ICES, Ontario, to assess risk of new-onset diabetes, new-onset hyperglycemia, and hyperglycemia for individuals with leukemia, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) receiving glucocorticoids during chemotherapy between 2006 and 2016. Using multivariable regression models, we determined the associations between glucocorticoid exposure and our outcomes of interest, controlling for age, sex, marginalization, and comorbidities. RESULTS: Our cohort included 19,530 individuals; 71.1% (n=13,893) received a glucocorticoid. The highest proportion of hyperglycemia occurred with leukemia (25.4%, n=1,301). Of the 15,580 individuals with no history of diabetes, those with leukemia had the highest rate of new-onset diabetes (7.1%, n=279) and new-onset hyperglycemia (18.1%, n=641), and glucocorticoid exposure increased the risk of new-onset diabetes (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.01 to 1.64, p=0.04) and new-onset hyperglycemia (HR 1.28, 95% CI 1.09 to 1.5, p=0.003). Hyperglycemia during chemotherapy increased the risk of all-cause mortality for the combined (HR 1.18, 95% CI 1.09 to 1.27, p<0.0001) and NHL (HR 1.16, 95% CI 1.04 to 1.28, p=0.007) cohorts. CONCLUSIONS: Hyperglycemia is common during hematologic chemotherapy treatment and is associated with a modest increased risk of all-cause mortality. Routine screening, monitoring, and management of hyperglycemia should be an integral part of treatment plans for leukemia, NHL, or HL, with or without glucocorticoid administration.

Development of a care protocol in pregnancy and chronic inflammatory arthritis, in a multidisciplinary work group.

OBJECTIVE: To design a care protocol in Chronic Inflammatory Arthritis during the pre-conceptional period, pregnancy, postpartum and lactation. This protocol aims to be practical and applicable in consultations where patients with chronic inflammatory rheumatological diseases are treated, thus helping to better control these patients. Likewise, recommendations are offered on when patients could be consulted/referred to a specialized center by the physician. METHODS: A multidisciplinary panel of expert physicians from different specialties identified the key points, analyzed the scientific evidence, and met to develop the care protocol. RESULTS: The recommendations prepared have been divided into three blocks: rheumatology, gynecology and pediatrics. The first block has been divided into pre-pregnancy, pregnancy and postpartum visits. CONCLUSIONS: This protocol tries to homogenize the follow-up of the patients from the moment of the gestational desire until the year of life of the infants. It is important to perform tests in patients of childbearing age and use drugs compatible with pregnancy. If appropriate, the patient should be referred to specialized units. Multidisciplinarity (rheumatology, gynecology and pediatrics) is essential to improve the control and monitoring of these patients and their offspring.

[Translated article] Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops.

OBJECTIVE: To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 and 10 mg/mL eye drops for use in ocular pathologies such as Sjögren's syndrome and dry eye syndrome. METHOD: The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5±3 °C), at room temperature (25±2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones. RESULTS: The eye drops stored at 5 °C were the most stable; in the 1 mg/mL eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/mL eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/mL, presented a white precipitate from day 14 and 28, respectively. Non-refrigerated 1 mg/mL eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers. CONCLUSIONS: 1 mg/mL MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/mL eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.

Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops. / Estudio de estabilidad fisicoquímica y microbiológica de dos nuevos colirios de metilprednisolona sin conservantes.

OBJECTIVE: To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 mg/ml and 10 mg/ml eye drops for use in ocular pathologies such as Sjögren's syndrome and dry eye syndrome. METHOD: The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5 ±3 °C), at room temperature (25 ± 2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones. RESULTS: The eye drops stored at 5 °C were the most stable; in the 1 mg/ml eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/ml eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/ml, presented a white precipitate from day 14 and 28 respectively. Non-refrigerated 1 mg/ml eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers. CONCLUSIONS: 1 mg/ml MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/ml eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.

Development of a web tool to calculate the cumulative dose of glucocorticoids.

INTRODUCTION: Glucocorticoids are associated with serious side effects related to dosing and time of use. Unfortunately, there is no standard method for determining glucocorticoid exposure, especially in patients undergoing long-term treatment. OBJECTIVE: The aim of this work was to create a free and easy-to-use web application to calculate, in a systematic way, the total cumulative dose of corticosteroids. METHODS: The total cumulative dose is calculated as the sum of all periods of treatment with different doses of corticosteroids, and is expressed as the equivalent dose of prednisone in mg. Glucocorticoid doses during periods in which the available information is missing or incomplete are estimated by systematic assumptions. RESULTS: A simulation exercise using standard patterns of steroid use in polymyalgia rheumatica, and giant cell arteritis showed that even when the period of no information reached 50% of the time, the accuracy of the calculator had a mean absolute percentage error (MAPE)<7%. CONCLUSION: This tool simplifies and standardizes the glucocorticoids cumulative dose calculation, thereby minimizing bias in the assessment of glucocorticoid cumulative dose.

Threshold based on bone mineral density for therapeutic decision-making in postmenopausal women and men over 50 years old under glucocorticoid therapy.

INTRODUCTION AND AIM: T-score bone mineral density (BMD) thresholds may influence guidance for treatment in patients under glucocorticoid (GC) therapy. Different BMD thresholds have been described but there is no international consensus. The aim of this study was to find a threshold to help in treatment decision-making in the population under GC therapy. METHODS: A working group representing three scientific societies from Argentina was convened. The first team was formed by specialists with expertise in glucocorticoid-induced osteoporosis (GIO) who voted according to summary of evidence. The second team was constituted by a methodology group who coordinated and supervised each stage. We conducted two systematic reviews to synthesize the evidence. The first included trials of drugs used in GIO to analyze the BMD cut-off used as inclusion criteria. In the second, we analyzed the evidence regarding the densitometric thresholds to discriminate between fractured and non-fractured patients under GC treatment. RESULTS: In the first review, 31 articles were included for qualitative synthesis and more than 90% of the trials included patients regardless of their densitometric T-score or range of osteopenia. In the second review, 4 articles were included and more than 80% of the T-scores were in the range -1.6 to -2.0. The summary of findings was analyzed and put to a vote. CONCLUSIONS: With more than 80% agreement of the voting expert panel, a T-score≤-1.7 was considered the most appropriate for treatment in postmenopausal women and men over 50 years of age under GC therapy. This study could help in treatment decision-making in patients under GC therapy without fractures but other fracture risk factors should certainly be considered.

Outcome of tocilizumab treatment in corticosteroid-resistant thyroid eye disease.

INTRODUCTION: Thyroid eye disease (TED) is a complex and incompletely understood rare autoimmune disorder. OBJECTIVES: To analyze the experience and the outcomes obtained with the use of intravenous tocilizumab in the treatment of TED. METHODS: A retrospective analysis of adult patients diagnosed with active TED resistant to intravenous corticosteroids treated in a tertiary hospital between May 2012 and May 2021. RESULTS: Eleven patients were included with a mean age of 52±12 (range 35-67) years. Nine patients were female and two were male. Patients received a median of 5±3.2 doses. Twenty out of twenty-four eyes achieved inactivation of TED at week 16. Proptosis response was achieved in 6/8 patients and diplopia response in 3/8 patients. The GO-QOL questionnaire showed clinically significant improvement in 9/11 patients. No serious adverse effects were reported during tocilizumab treatment. One patient required decompressive surgery 15 months after tocilizumab therapy. CONCLUSION: The results obtained show that the use of tocilizumab in the treatment of this pathology can be a good alternative.

Effects of prenatal exposure to the 1944-45 Dutch famine and glucocorticoid receptor polymorphisms on later life PTSD susceptibility.

Background: Exposure to adversity in utero is thought to increase susceptibility to develop posttraumatic stress disorder (PTSD) following later life trauma, due to neurobiological programming effects during critical developmental periods. It remains unknown whether effects of prenatal adversity on PTSD susceptibility are modulated by genetic variations in neurobiological pathways implicated in PTSD susceptibility.Objective: We investigated whether genetic variation in the glucocorticoid receptor (GR) modulated effects of prenatal famine exposure on late adulthood PTSD symptom severity after trauma exposure in childhood and mid-to-late adulthood.Method: We included N = 439 term-born singleton adults (mean age: 72 years, 54.2% women) from the Dutch Famine Birth Cohort, born around the time of the Dutch Famine of 1944/1945, divided into exposure and control groups based on timing of the famine during gestation. Participants filled out self-report questionnaires on childhood (Childhood Trauma Questionnaire) and mid-to-late adulthood (Life Events Checklist for DSM-5) trauma, and current PTSD symptom severity (PTSD Checklist for DSM-5). GR haplotypes were determined from four functional GR single nucleotide polymorphisms (ER22/23EK, N363S, BclI and exon 9ß) in previously collected DNA. Linear regression analyses were performed to investigate associations of GR haplotype and prenatal famine exposure in conjunction with later life trauma on PTSD symptom severity.Results: We observed a significant three-way interaction between the GR Bcll haplotype, famine exposure during early gestation, and adulthood trauma exposure on PTSD symptom severity in late adulthood. Only participants exposed to famine during early gestation without the GR Bcll haplotype showed a significantly stronger positive association between adulthood trauma and PTSD symptom severity than non-exposed participants, indicating increased PTSD susceptibility.Conclusions: Our results illustrate the importance of integrated approaches considering genetics and environmental contexts throughout various life periods, including the rarely investigated prenatal environment, to elucidate how PTSD susceptibility evolves throughout life.HIGHLIGHTS Adversity during pregnancy is thought to increase offspring's PTSD risk following later life trauma, but exact neurobiological mechanisms underlying this process remain unknown.We found that effects of prenatal famine exposure on PTSD symptom severity were influenced by genetic variation in the glucocorticoid receptor, which signals effects of the stress hormone cortisol.Integrated approaches considering genetics and environmental contexts throughout both early and later life are important to understand how PTSD risk evolves throughout life.

Glucocorticoid-Induced Hyperglycemia in Oncologic Outpatients: A Narrative Review Using the Quadruple Aim Framework.

Glucocorticoids are a central part of cancer treatment protocols. Their use in patients receiving chemotherapy increases patient risk of hyperglycemia and associated adverse outcomes. Despite this, there have been few published protocols that guide the management of this patient group. In this narrative review, we use the quadruple aim as a framework to evaluate the current literature, including interventions, on glucocorticoid-induced hyperglycemia in patients receiving oncologic treatment, with a focus on the outpatient setting. Findings were drawn from published review articles, observational studies, qualitative reports and costing data. Results were synthesized using the framework's 4 dimensions of care: population health, provider experience, patient experience and cost. Prospective studies proposing an intervention on oncologic patients receiving glucocorticoids were identified as intervention studies. Management of glucocorticoid-induced hyperglycemia in oncologic patients is a complex problem with no published interventions addressing all components of the quadruple aim. Most evidence on this population is based on retrospective studies. Six prospective intervention studies were identified and highlighted in this review, and only 2 were exclusively in the outpatient context. Challenges included lack of standardization in screening strategies, paucity of interventions that have examined impact on patient and provider experience. There is limited evaluation of the impact of interventions targeting glycemic control on clinical outcomes and cost of care delivery, especially in the outpatient context. We propose a conceptual framework for evaluation of quality improvement programs. Management of glucocorticoid-induced hyperglycemia in the outpatient setting is complex and requires well-designed intervention studies evaluated across the quadruple aim.

Effectiveness of corticosteroids to treat coronavirus disease 2019 symptoms: A meta-analysis.

OBJECTIVE: Currently, corticosteroids are widely used to treat coronavirus disease 2019 (COVID-19) symptoms. However, the therapeutic role of corticosteroids remains highly controversial. To that end, we aimed to assess the efficacy of corticosteroids in treating COVID-19 patients. METHOD: We searched PubMed, Embase, and Cochrane Library to select suitable studies. Our primary study endpoint was all-cause mortality. The secondary study endpoint was the length of hospital stay. RESULTS: A total of 9 randomized controlled trials (RCTs) with 7907 patients were assessed. The pooled result indicated that corticosteroids treatment could significantly reduce all-cause mortality in patients with COVID-19 (RR=0.88, 95% CI [0.82, 0.95], P=0.002). When subgroup analyses were performed, we found that corticosteroids were associated with decreased all-cause mortality in severe COVID-19 patients (RR=0.77, 95% CI [0.68, 0.88], P<0.0001), however no obvious difference was observed in all-cause mortality of non-severe COVID-19 patients between the corticosteroid and control group (RR=0.96, 95% CI [0.86, 1.06], P=0.41), meanwhile, a low dose (RR=0.89, 95% CI [0.82, 0.97], P=0.007) of dexamethasone (RR=0.9, 95% CI [0.83, 0.98], P=0.01) with a long treatment course (RR=0.89, 95% CI [0.82, 0.98], P=0.02) was beneficial for all-cause mortality in COVID-19 patients. Additionally, we found that corticosteroids might be associated with a longer length of hospital stay in non-severe COVID-19 patients (MD=3.83, 95% CI [1.11, 6.56], P=0.006). CONCLUSION: Our results showed that corticosteroid therapy was related to a reduction in all-cause mortality in severe COVID-19 patients. However, in patients with non-severe COVID-19, the use of corticosteroids did not decrease all-cause mortality and may prolong the duration of hospital stay. In addition, we revealed that a low dose of dexamethasone with a long treatment course could reduce all-cause mortality in COVID-19 patients.

Evaluation of a perioperative steroid coverage after pituitary surgery.

INTRODUCTION: Serum cortisol levels within the first days after pituitary surgery have been shown to be a predictor of post-surgical adrenal insufficiency. However, the indication of empirical glucocorticoids to avoid this complication remains controversial. The objective is to assess the role of cortisol in the early postoperative period as a predictor of long-term corticotropic function according to the pituitary perisurgical protocol with corticosteroid replacement followed in our center. METHODS: One hundred eighteen patients who underwent surgery in a single center between December 2012 and January 2020 for a pituitary adenoma were included. Of these, 54 patients with previous adrenal insufficiency (AI), Cushing's disease, or tumors that required treatment with high-dose glucocorticoids (GC) were excluded. A treatment protocol with glucocorticoids was established, consisting of its empirical administration at rapidly decreasing doses, and serum cortisol was determined on the third day after surgery. Subsequent adrenal status was assessed through follow-up biochemical and clinical evaluations. RESULTS: Out of the 64 patients treated, there were 56 macroadenomas and 8 microadenomas. The incidence of adrenal insufficiency after pituitary surgery was 4.7%. The optimal cut-off value that predicted an adequate corticotropic reserve, taking into account the best relationship of specificity and sensitivity, was ≥4.1 µg/dl for serum cortisol on the third day (sensitivity 95.1%, specificity 100%). CONCLUSION: Serum cortisol on the third day predicts the development of adrenal insufficiency. We suggest a cortisol cut-off point of ≥4.1 µg/dl on postoperative on the third day after surgery as a predictor of the adrenal reserve in the long-term.

Drugs Recommended in Adult Rheumatic Diseases, But Considered for Off-Label Use in Argentina.

BACKGROUND: Off-label (OL) drug use is the prescription of a drug for indications other than those authorised in its technical datasheet. The objective of this study was to identify drugs recommended in rheumatology but considered for off-label use in Argentina. METHODS: A list of medications for certain selected rheumatic conditions was compiled. A drug was considered recommended if it was endorsed by a) at least one Argentine or Pan-American treatment guideline or consensus, or b) two international treatment guidelines, or c) one international treatment guideline and one selected textbook. Approval of these drugs for any condition in Argentina until December 31st, 2018 was explored, and medicines were divided into those with on-label indications and those considered for OL use. RESULTS: One hundred and thirty-six medications were analysed in 13 clinical conditions. Sixty-seven OL recommendations (49%) were found, and several drugs had more than one. All the conditions included the recommendation of at least 1 OL drug except osteoporosis and rheumatoid arthritis. The frequency of OL recommendations for the following conditions was 100%: calcium pyrophosphate dihydrate crystal deposition disease, polymyalgia rheumatica, Sjögren syndrome, and systemic sclerosis. The drugs with the highest number of OL recommendations were methotrexate (in 7 conditions), and glucocorticoids and mycophenolate (in 4). There were 2 OL recommendations for rituximab and 1 for abatacept. CONCLUSIONS: Almost all the rheumatic disorders analysed involved the recommendation of at least 1 OL medication, and in 4 conditions all the recommendations were OL. Most OL drugs recommended in rheumatology are neither biological nor small-molecule therapies.