Dexamethasone Challenge Research Articles

Effects of childhood trauma and anxiety on the hypothalamic-pituitary-adrenal axis in chronic subjective tinnitus with distress.

There is some evidence for hypothalamic-pituitary-adrenal (HPA) axis hypofunction in chronic tinnitus, but findings are contradicting possibly due to clinical heterogeneity. This study aims to assess differential effects of childhood trauma and anxiety on HPA-axis functioning in adults suffering from chronic subjective tinnitus with distress. Salivary cortisol data were collected in 22 chronic subjective tinnitus sufferers (without major depression) and 29 healthy controls after awakening, at baseline and after a low-dose (0.5 mg) dexamethasone challenge. A factorial ANCOVA was conducted to compare the main effects of group (tinnitus versus controls), trauma and their interaction effect on the cortisol awakening response (CAR). Linear mixed models were fitted for baseline and post-dexamethasone cortisol levels with group, sampling time, trauma and their interactions as fixed factors and subject as the random effect. The Beck Anxiety Index, Anxiety Sensitivity Index and Panic Disorder Severity Scale were included to investigate effects of anxiety. A significant interaction between group and trauma (F(1, 47) = 6.9755, p = 0.0112) was found, with the tinnitus group showing lower CARs (M = 5.1808, SD = 0.5821) than the comparison group (M = 5.9974; SD = 0.5251) in traumatised individuals only. No effects were found for baseline or post-dexamethasone cortisol. Anxiety scores had no effects on any of the outcome variables. A differential effect of childhood trauma, but not anxiety, on the HPA-axis function in chronic subjective tinnitus was partly confirmed by the finding of a blunted CAR in tinnitus sufferers reporting early-life adversity.

The development of a dexamethasone challenge model for evaluating feed additives in sheep.

To develop an accessible ruminant immune challenge model for rapid in vivo assessments of feed additives. 60 hair-breed ram lambs. Sheep were randomly assigned to 1 of 4 treatments: treatment 1, not immunosuppressed, control fed (n = 12); treatment 2, immunosuppressed, supplemented with a yeast and botanical extract (n = 18); treatment 3, immunosuppressed, supplemented with a blend of natural aluminosilicates and yeast components (n = 18); and treatment 4, immunosuppressed, control fed (n = 12). Twice-daily injections of dexamethasone (Dex; 0.1 mg/kg bodyweight, SC) were used to induce immunosuppression throughout the study (from September 25, 2020, to November 2, 2020). All sheep were immunized with keyhole limpet hemocyanin (KLH) on days 0 and 14 and injected with heat-aggregated KLH, ID, to induce a skin induration on day 15. Measurements included body weight (BW), average daily gain (ADG), CBC, and skin induration diameter. Dex treatment resulted in reduced BW and ADG that was not mitigated by either feed additive. Dex reduced lymphocyte percentage, RBC count, hemoglobin, hematocrit, and skin induration diameter and increased concentrations of granulocytes and granulocyte percentage. Effects on hematocrit, hemoglobin, RBC, and skin induration diameter were mitigated with the addition of feed additives. The described model is a tool to evaluate the ability of feed additives to mitigate the immunosuppressive effects of Dex.

Short-term induced hyperinsulinaemia and dexamethasone challenge do not affect circulating total adiponectin concentrations in insulin-sensitive ponies.

Hypoadiponectinaemia is a risk factor for endocrinopathic laminitis, but the directionality and nature of its association with insulin dysregulation is unclear. To investigate the effects of short-term induced hyperinsulinaemia and dexamethasone challenge on circulating [total adiponectin] and whole blood expression of adiponectin (AdipoR1 and AdipoR2), insulin, and insulin-like growth factor 1 (IGF-1) receptors in insulin-sensitive ponies. In vivo experiment. Six never-laminitic, insulin-sensitive, native-breed UK ponies first underwent a dexamethasone challenge (0.08 mg/kg i.v.) with blood samples collected every 15 min over 3 h. After a 14-day washout period, hyperinsulinaemia was induced for 9 h via a euglycaemic-hyperinsulinaemic clamp (EHC), with blood samples collected every 30 min. Serum [insulin], plasma [total adiponectin], and plasma [IGF-1] were measured using validated assays and receptor gene expression was assessed via quantitative polymerase chain reaction (qPCR). Finally, whole blood was incubated with 10-1000 ng/mL dexamethasone for 3 h at 37°C to investigate its direct effects on gene expression. There were no adverse effects observed during either protocol. Dexamethasone challenge did not alter circulating [insulin] or [total adiponectin] at any time-point, but significantly upregulated AdipoR1 and IGF-1R expression at 150 and 180 min. Ex vivo incubation of whole blood with dexamethasone did not alter expression of the genes examined. There was no change in [total adiponectin] or expression of the genes examined associated with EHC-induced hyperinsulinemia. This was a small sample size that included only native-breed ponies; total adiponectin was measured rather than high-molecular-weight adiponectin. Short-term induced hyperinsulinaemia and dexamethasone challenge did not affect circulating [total adiponectin] in insulin-sensitive ponies. However, dexamethasone administration was associated with upregulation of two receptors linked to adiponectin signalling, suggesting that a physiological response occurred possibly to counteract dexamethasone-associated changes in tissue insulin sensitivity.

Insights into the antiosteoporotic mechanism of the soy-derived isoflavone genistein: Modulation of the Wnt/beta-catenin signaling.

Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/β-catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid-induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy-derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO-A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 μM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/β-catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/β-catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and β. These data suggest that genistein could induce bone remodeling through Wnt/β-catenin pathway activation.

ODP599 Modulation of Wnt/b-catenin and Autophagy in an in vitro Model of Glucocorticoid-induced Osteoporosis

Abstract Background During bone aging and osteoporosis, formation and resorption are not tightly coupled; the main cells involved in bone remodeling are osteoblasts and osteoclast but also osteocytes play a pivotal role in this process. Osteocytes are the most abundant cell type in bone and are mainly responsible for sensing mechanical signals on the bones, controlling osteoblast and osteoclast activities through cell-to-cell communication and via secreted factors. In particular, osteocytes regulate bone resorption, thanks to the production of RANKL, reducing osteoclast activity. Ellagic acid, a natural polyphenolic compound derived from pomegranate, could modulate cell function via specific estrogen receptor b; activation of ERb plays a critical role in bone remodeling suppressing osteoclast differentiation and function, promoting osteoblast proliferation through the Wnt/b-catenin pathway, increasing osteoprotegerin levels. In addition, stimulation of ERb plays an anti-inflammatory effect, increasing the expression of IL-10 and reducing the expression of proinflammatory cytokines, such as IL-1β and TNF-α, and can regulate the expression of autophagy inhibiting the PI3K/Akt/mTOR pathway. The hypothesis here tested is that ellagic acid, through ERb modulation, could induce Wnt/b-catenin and autophagy pathways in osteocytes challenged with dexamethasone to mimic glucocorticoid-induced osteoporosis. Materials and methods The osteocyte cells MLO-A5 were differentiated into osteocytes under appropriate culturing conditions. Cells were treated with Ellagic acid (1µM) following dexamethasone (1µM) challenge for 24h to induce an in vitro model of osteoporosis. At the end of the treatment period, cell viability was evaluated by MTT assay; qPCR was performed to evaluate the expression of the genes involved in osteocyte function (SOST, RANKL, Destrin and Dmp1) and Wnt/B-catenin signaling pathway (Wnt5a, Wnt10b, B-Catenin and DKK1); Western Blot was performed to evaluate the expression of proteins involved in apoptosis (cleaved-Caspase3) and autophagy (Beclin-1, LC3 and p62). In addition, the expression of Sclerostin and nuclear translocation of B-Catenin was evaluated by immunofluorescence. Results Ellagic acid reduced the gene expression of SOST, RANKL, Dmp1 and increased the expression of Destrin compared to untreated cells stimulated with dexamethasone; caused a significant increase of Wnt5a, Wnt10b and B-Catenin expression and reduced significantly the expression of DKK1. CGS21680 inhibited dexamethasone-induced apoptosis, reducing the expression of Caspase3, and increased the expression of Beclin-1 and LC3 compared to cell treated with dexamethasone. Finally, treatment with Ellagic acid stimulated the nuclear translocation of B-Catenin, promoting the transcription of genes involved in osteogenesis. Conclusion These preliminary data suggest that stimulation of ERb through Ellagic acid could modulate bone remodelling through activation of Wnt/b-catenin pathway and autophagy, providing evidence on the possible use of this natural compound as a new therapeutic approach for osteoporosis. Presentation: No date and time listed

Chlorogenic acid improves growth performance and intestinal health through autophagy-mediated nuclear factor erythroid 2-related factor 2 pathway in oxidatively stressed broilers induced by dexamethasone

The effects of chlorogenic acid (CGA) on growth performance, intestinal morphology, antioxidant capacity, and the autophagy-mediated nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in oxidatively stressed broilers were investigated. A total of 400 one-day-old male Cobb broilers were divided randomly into 4 groups using a 2 × 2 factorial arrangement with 2 CGA supplemental levels (0 and 500 mg/kg) and 2 dexamethasone (DEX) challenge levels (0 and 3 mg/kg body weight). All the broilers were injected intraperitoneally with DEX or sterile saline beginning at the age of 15 d for 6 consecutive days. The experiment lasted for 21 d. The CGA increased average daily gain (ADG), villus height, villus height/crypt depth (V/C) value, and the protein expressions of Occludin and ZO-1 in the ileum and decreased the feed:gain (F:G) ratio, which were impaired by the DEX challenge. Superoxide dismutase (SOD), catalase (CAT), gutathione S-transferase (GST), and heme oxygenase-1 (HO-1) activities in the serum and ileum were increased by CGA, whereas protein carboxyl (PCO) level in the serum and ileum, and malondialdehyde (MDA) level in the ileum were decreased of the DEX challenged broilers. The DEX challenge decreased microtubule-associated protein 1 light chain 3 (LC3)-II, Beclin1, and autophagy-related gene (ATG) 7 mRNA expressions, and the LC3-II/LC3-I value and increased LC3-I, cysteinyl aspartate specific proteinase (Caspase)-3 and Caspase-9 mRNA expressions in the ileum, which were improved by CGA. DEX also decreased the protein expressions of Kelch-like ECH-associated protein-1 (Keap1), Nrf2, HO-1, NADPH quinone oxidoreductase-1(NQO-1) and increased sequestosome 1 (p62) in the ileum, which were improved by CGA. Interactions occurred between DEX and CGA for the ADG, F:G ratio, villus height, crypt depth, V/C value, and SOD, CAT, GST, and HO-1 activities, MDA and PCO levels, LC3-II/LC3-I value, and expressions of LC3-I, LC3-II, Beclin1, ATG7, Caspase-3, Caspase-9, Occludin, ZO-1, Keap1, Nrf2, HO-1, NQO-1, and p62. In conclusion, CGA improved the growth performance and intestinal health of oxidatively stressed broilers by activating the autophagy-mediated Nrf2 pathway.

Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance

SummarySingle traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Rodent studies suggested germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain to be seen. We find that acute administration of an agonist for the stress-sensitive Glucocorticoid receptor, using the common corticosteroid dexamethasone, affects the RNA payload of mature sperm as soon as 3 hr after exposure. It further impacts early embryonic transcriptional trajectories, as determined by single-embryo sequencing, and metabolism in the offspring.We show persistent regulation of tRNA fragments in sperm and descendant 2-cell embryos, suggesting transmission from sperm to embryo. Lastly, we unravel environmentally induced alterations in sperm circRNAs and their targets in the early embryo, highlighting this class as an additional candidate in RNA-mediated inheritance of disease risk.

Age and sex modify cellular proliferation responses to oxidative stress and glucocorticoid challenges in baboon cells

Aging is associated with progressive loss of cellular homeostasis resulting from intrinsic and extrinsic challenges. Lack of a carefully designed, well-characterized, precise, translational experimental model is a major limitation to understanding the cellular perturbations that characterize aging. Here, we tested the feasibility of primary fibroblasts isolated from nonhuman primates (baboons) as a model of cellular resilience in response to homeostatic challenge. Using a real-time live-cell imaging system, we precisely defined a protocol for testing effects of prooxidant compounds (e.g., hydrogen peroxide (H2O2), paraquat), thapsigargin, dexamethasone, and a low glucose environment on cell proliferation in fibroblasts derived from baboons across the life course (n = 11/sex). Linear regression analysis indicated that donor age significantly reduced the ability of cells to proliferate following exposure to H2O2 (50 and 100µM) and paraquat (100 and 200µM) challenges in cells from males (6.4-21.3years; average lifespan 21years) but not cells from females (4.3-15.9years). Inhibitory effects of thapsigargin on cell proliferation were dependent on challenge duration (2 vs 24h) and concentration (0.1 and 1µM). Cells from older females (14.4-15.9years) exhibited greater resilience to thapsigargin (1µM; 24h) and dexamethasone (500µM) challenges than did those from younger females (4.3-6.7years). The cell proliferation response to low glucose (1mM) was reduced with age in both sexes. These data indicate that donor's chronological age and sex are important variables in determining fibroblast responses to metabolite and other challenges.

Hypothalamic-pituitary-adrenal axis regulation and organization in urban and rural song sparrows

Urban habitats present animals with persistent disturbances and acute stressors not present in rural habitats or present at significantly lower levels. Differences in the glucocorticoid stress response could underlie colonization of these novel habitats. Despite urban habitats characterization as more stressful, previous comparisons of urban and rural birds have failed to find consistent differences in baseline and stress induced glucocorticoid levels. Another aspect of glucocorticoid regulation that could underlie an animal’s ability to inhabit novel habitats, but has yet to be well examined, is more efficient termination of the glucocorticoid stress response which would allow birds in urban habitats to recover more quickly after a disturbance. The glucocorticoid stress response is terminated by negative feedback achieved primarily through their binding of receptors in the hippocampus and hypothalamus and subsequent decreased synthesis and release from the adrenals. We investigated if male song sparrows (Melospiza melodia) in urban habitats show more efficient termination of the glucocorticoid stress response than their rural counterparts using two approaches. First, we measured glucocorticoid receptor, mineralocorticoid receptor and 11β-HSD2 (an enzyme that inactivates corticosterone) mRNA expression in negative feedback targets of the brain (the hippocampus and hypothalamus) as a proxy measure of sensitivity to negative feedback. Second, we measured plasma corticosterone levels after standardized restraint and again following a challenge with the synthetic glucocorticoid, dexamethasone, as a means of assessing how quickly birds decreased glucocorticoid synthesis and release. Though there were no differences in the hypothalamus of urban and rural song sparrows, urban birds had lower glucocorticoid receptor and 11β-HSD2 mRNA expression in the hippocampus. Further, urban and rural birds had similar reductions in corticosterone following the dexamethasone challenge, suggesting that they do not differ in how quickly they decrease glucocorticoid synthesis and release. Thus, urban and rural song sparrows display similar termination of the glucocorticoid stress response even though urban birds have decreased hippocampal glucocorticoid receptor and 11β-HSD2 abundance.

Changes in glucocorticoid receptor sensitivity following long‐term ethanol self‐administration in male and female rhesus macaques

Stress can alter ethanol consumption and long-term use results in adaptation of the stress response, highlighting a bidirectional relationship that remains poorly understood. Non-human primates are an excellent model to investigate the interaction of stress and long-term ethanol use due to their similar neuroendocrine system to humans and propensity to chronically drink intoxicating amounts of alcohol. Here, circulating stress hormones (adrenocorticotropin hormone (ACTH) and cortisol) were measured in response to a low (17 mg/kg) and high (130 mg/kg) dose of dexamethasone, a potent glucocorticoid receptor (GR) agonist. The dexamethasone response was compared before (baseline) and after 7 months of daily 22 h/d ethanol self-administration in young adult male (n=6) and female (n=6) rhesus macaques. At both timepoints, the high dose dexamethasone challenge resulted in 90-100% suppression of both ACTH and cortisol with no difference between sexes. At baseline, low dose dexamethasone reduced both ACTH and cortisol, but to a lesser degree and with greater between-subject variability, 0 – 60%. Following seven-months of daily ethanol consumption (average intakes ranging from 0.6 – 4.0 g/kg/day) the response to low dose dexamethasone was greater. This effect was more robust in females compared to males. Additionally, the change in suppression between baseline and following long-term daily ethanol consumption correlated with daily intake, such that the magnitude of change over time was greater in heavier drinkers. Because stress increases reliance on putamen-dependent or habitual behavior and heavy ethanol drinking leads to excitatory-inhibitory neurotransmission imbalance within the putamen, we tested the hypothesis that long-term ethanol self-administration will alter striatal transmission via the GR. Therefore, we used whole cell patch clamp electrophysiology to investigate the effect of bath application of dexamethasone onto putamen medium spiny neurons (MSNs). Dexamethasone rapidly decreased the area and amplitude of spontaneous inhibitory postsynaptic currents among binge drinkers. These data show that acute dexamethasone, presumably via activation of the membrane bound GR, activated fewer GABAergic receptors among binge drinkers. These data highlight a unique role of the GR within the putamen that may mediate stress dependent changes contributing to addiction vulnerability, particularly among binge drinkers.

Single-cell immunopathology of systemic contact allergy associated with corticosteroids

Rationale Allergic contact dermatitis (ACD) is a classic delayed hypersensitivity reaction commonly associated with corticosteroids that can rarely manifest as a delayed rash following systemic administration. Methods A 50-year old woman developed local edema and delayed spreading rash following interarticular injection with dexamethasone and methylprednisolone acetate (MA). 6-months following this intradermal skin testing (IDST) was positive to MA and methylprednisolone sodium succinate, and IDST and patch test negative to other corticosteroids. She tolerated dexamethasone challenge. Cells were isolated from 4-mm punch biopsies from 48-hour positive IDST and unaffected skin with liberase digestion and sorted on CD3. scTCR and scRNA-seq were performed using plate-based assays (Smart-seq-2). Data was filtered using Seurat and analysed with Visual Genomics Analysis Studio (VGAS) software. Results Histopathology showed a superficial perivascular dermatitis with epidermal spongiosis in keeping with ACD. T-cells were 18x more prevalent in affected skin and those from both affected and unaffected sites were predominantly CD8+ T-cells that expressed CD45RO and polyclonal TCR alpha beta. Differentially expressed genes (DEG) in T-cells from affected skin reflected homing (CCR7,S1PR1), T-cell activation and proliferation (TNFRS9, GRAP2, ZYG11A, ZHX1), T-cell effector differentiation (IL-21R), and stress survival (EEF1A1, IFI6) without representation of markers of T-cell residency (ITGAE) or regulation. Conclusions We demonstrate insights into the immunopathogenesis of drug-induced ACD by showing that IDST+ methylprednisolone associated ACD is corticosteroid-specific and associated with a polyclonal population of primarily CD45RO+ memory CD8+ T-cells showing upregulation of markers of homing, T-cell activation, proliferation and differentiation but lacking markers of T-cell residency and regulation.

Impaired hypothalamic feedback dysregulates brain glucocorticoid signaling in genetically-selected Marchigian Sardinian alcohol-preferring rats.

Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats display comorbid symptoms of increased alcohol preference and elevated anxiety-like behavior. Heightened stress sensitivity in msPs is influenced by genetic polymorphisms of the corticotropin-releasing factor receptor in the central nucleus of the amygdala (CeA), as well as reduced influence of anti-stress mechanisms that normally constrain the stress response. Given this propensity for stress dysregulation, in this study, we expand on the possibility that msPs may display differences in neuroendocrine processes that normally terminate the stress response. We utilized behavioral, biochemical, and molecular assays to compare basal and restraint stress-induced changes in the hypothalamic-pituitary-adrenal (HPA) axis of male and female msPs relative to their nonselected Wistar counterparts. The results showed that msPs display deficits in marble-burying behavior influenced by environmental factors and procedures that modulate arousal states in a sex-dependent manner. Whereas male msPs display evidence of dysregulated neuroendocrine function (higher adrenocorticotropic hormone levels and subthreshold reductions in corticosterone), females display restraint-induced elevations in corticosterone levels that were persistently higher in msPs. A dexamethasone challenge reduced the circulation of these stress hormones, although the reduction in corticosterone was generally attenuated in msP versus Wistar rats. Finally, we found evidence of diminished stress-induced glucocorticoid receptor (GR) phosphorylation in the hypothalamic paraventricular nucleus of msPs, as well as innate increases in phosphorylated GR levels in the CeA of male msPs. Collectively, these findings suggest that negative feedback processes regulating HPA responsiveness are diminished in msP rats, possibly underlying differences in the expression of anxiety-like behaviors.

P.599 Differential responsiveness to a dexamethasone challenge of vulnerable and resilient animals previously exposed to the chronic mild stress paradigm

Cajal–Retzius cells (CRc) represent a mostly transient neuronal cell type localized in the uppermost layer of the developing neocortex. The observation that CRc are a major source of the extracellular matrix protein reelin, which is essential for the laminar development of the cerebral cortex, attracted the interest in this unique cell type. In this review we will (i) describe the morphological and molecular properties of neocortical CRc, with a special emphasize on the question which markers can be used to identify CRc, (ii) summarize reports that identified the different developmental origins of CRc, (iii) discuss the fate of CRc, including recent evidence for apoptotic cell death and a possible persistence of some CRc, (iv) provide a detailed description of the electrical membrane properties and transmitter receptors of CRc, and (v) address the role of CRc in early neuronal circuits and cortical development. Finally, we speculate whether CRc may provide a link between early network activity and the structural maturation of neocortical circuits.

Glycemic Response to Oral Dexamethasone Predicts Incident Prediabetes in Normoglycemic Subjects With Parental Diabetes.

BackgroundPrediabetes, an often unrecognized precursor of type 2 diabetes (T2DM), is associated with cardiometabolic complications. Here, we investigated the utility of dexamethasone challenge in predicting incident prediabetes among normoglycemic subjects with parental T2DM enrolled in the prospective Pathobiology of Prediabetes in a Biracial Cohort study.Design and MethodsAfter documenting normoglycemic status with an oral glucose tolerance test (OGTT), participants ingested dexamethasone (2 mg) at 10:00 pm, and fasting plasma glucose (FPG-Dex) and cortisol were measured at 8:00 am the next day. Subjects were followed quarterly for 5 years, the primary outcome being incident prediabetes. Serial assessments included body composition, blood chemistry, OGTT, insulin sensitivity, and secretion.ResultsWe analyzed data from 190 participants (107 Black, 83 white; mean age 44.7 ± 10.0 years; body mass index [BMI] 29.8 ± 6.8 kg/m2; fasting plasma glucose [FPG] 90.9 ± 5.7 mg/dL). Following dexamethasone ingestion, plasma cortisol was < 5 µg/dL; FPG-Dex levels displayed marked variability (81-145 mg/dL) as did delta FPG (–7 to +48 mg/dL). During 5 years of follow-up, 58 of 190 subjects (30.5%) progressed to prediabetes. FPG-Dex (116.8 ± 10.9 vs 106.9 ± 10.8 mg/dL, P < 0.0001) and delta FPG (23.4 ± 10.1 vs 17.0 ± 10.2 mg/dL, P < 0.0001) were higher in progressors than nonprogressors. FPG-Dex (P = 0.007) was an independent predictor of incident prediabetes in a multivariate model that included age, race, gender, BMI, waist circumference, FPG, insulin sensitivity, and secretion. In further analyses, an FPG-Dex level ≥ 107 mg/dL predicted incident prediabetes with 88% sensitivity and 49% specificity.ConclusionsThe glycemic response to dexamethasone significantly predicted incident prediabetes among offspring of parents with T2DM, and may be a tool for uncovering latent risk of dysglycemia.

104 Administration of a DNA immunostimulant does not mitigate bovine herpesvirus-1 recrudescence in dexamethasone challenged beef cattle

Abstract The study objective was to determine the effect of a DNA immunostimulant on recrudescence of bovine herpesvirus-1 (BHV-1) after dexamethasone challenge in beef cattle. It was hypothesized that the DNA immunostimulant would mitigate stress-induced immunosuppression; thereby, reducing the incidence of BHV-1 recrudescence. Steers (n=10) and heifers (n=10; initial BW = 489 kg ± 57 kg) were stratified by pre-existing BHV-1 antibody titer, sex and initial BW and randomly assigned to treatment (n=4 pens/treatment; 2 or 3 animals/pen). All calves were administered 40 mg of dexamethasone i.v. at 0600 h from d 0 to 2, 166-d subsequent to BHV-1 challenge with 1.0 × 108 plaque-forming units per nostril. On d 1, calves were administered treatments consisting of 2 mL i.m. of DNA immunostimulant (Zelnate; ZEL) or sterile saline (CON). Once daily (0600) from d 0 to 12, a whole blood was obtained via jugular venipuncture for complete blood count (CBC) analysis and nasal swabs were collected to determine BHV-1 prevalence via virus isolation testing. A repeated measures mixed model was used to test the effect of treatment, day and their interaction for CBC variables. There was a treatment × day interaction for eosinophils (P = 0.02) and percent eosinophils (P = 0.03). Eosinophils were greater (P &lt; 0.01) for ZEL on d 3 and 6 post-dexamethasone challenge. On d 11 and 12, eosinophils for CON rebounded such that their concentration was greater than ZEL (P &lt; 0.01). Lymphocytes, neutrophil and monocyte concentration did not differ (P ≥ 0.44); however, a day effect (P ≤ 0.01) existed such that each variable increased transiently after dexamethasone challenge. All cattle had BHV-1 present in a nasal swab sample on at least one sample day, with prevalence of BHV-1 in nasal swab samples being greatest on d 5 (80% positive; P = 0.01). However, no treatment differences were detected for BHV-1 prevalence in this study. The DNA immunostimulant altered eosinophil concentrations but did not mitigate BHV-1 recrudesce after dexamethasone challenge

3 Administration of a DNA immunostimulant does not mitigate bovine herpesvirus-1 recrudescence in dexamethasone challenged beef cattle

Abstract The study objective was to determine the effect of a DNA immunostimulant on recrudescence of bovine herpesvirus-1 (BHV-1) after dexamethasone challenge in beef cattle. It was hypothesized that the DNA immunostimulant would mitigate stress-induced immunosuppression; thereby, reducing the incidence of BHV-1 recrudescence. Steers (n = 10) and heifers (n = 10; initial BW = 489 kg ± 57 kg) were stratified by pre-existing BHV-1 antibody titer, sex and initial BW and randomly assigned to treatment (n = 4 pens/treatment; 2 or 3 animals/pen). All calves were administered 40 mg of dexamethasone i.v. at 0600 h from d 0 to 2, 166-d subsequent to BHV-1 challenge with 1.0 × 108 plaque-forming units per nostril. On d 1, calves were administered treatments consisting of 2 mL i.m. of DNA immunostimulant (Zelnate; ZEL) or sterile saline (CON). Once daily (0600) from d 0 to 12, a whole blood was obtained via jugular venipuncture for complete blood count (CBC) analysis and nasal swabs were collected to determine BHV-1 prevalence via virus isolation testing. A repeated measures mixed model was used to test the effect of treatment, day and their interaction for CBC variables. There was a treatment × day interaction for eosinophils (P = 0.02) and percent eosinophils (P = 0.03). Eosinophils were greater (P &lt; 0.01) for ZEL on d 3 and 6 post-dexamethasone challenge. On d 11 and 12, eosinophils for CON rebounded such that their concentration was greater than ZEL (P &lt; 0.01). Lymphocytes, neutrophil and monocyte concentration did not differ (P ≥ 0.44); however, a day effect (P ≤ 0.01) existed such that each variable increased transiently after dexamethasone challenge. All cattle had BHV-1 present in a nasal swab sample on at least one sample day, with prevalence of BHV-1 in nasal swab samples being greatest on d 5 (80% positive; P = 0.01). However, no treatment differences were detected for BHV-1 prevalence in this study. The DNA immunostimulant altered eosinophil concentrations but did not mitigate BHV-1 recrudesce after dexamethasone challenge

Vulnerability and resilience to chronic stress exposure: Basal changes and responsiveness to a dexamethasone challenge

Vulnerability and resilience to chronic stress exposure: Basal changes and responsiveness to a dexamethasone challenge

HPA axis in psychotic major depression and schizophrenia spectrum disorders: Cortisol, clinical symptomatology, and cognition

The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.

1719-P: Plasma Glucose Response to Oral Dexamethasone Predicts Incident Prediabetes in Normoglycemic Offspring of Parents with Type 2 Diabetes

Background: Dexamethasone (dex) challenge was used historically to diagnose chemical diabetes. Here we determined its utility in predicting prediabetes in a biracial cohort. Methods: We studied 190 euglycemic subjects with parental type 2 diabetes. After a baseline 75-gram OGTT, subjects ingested 2 mg dex at 10 PM and returned at 8AM for measurement of plasma cortisol and glucose. Subjects were followed quarterly for incident prediabetes for 5 years. Serial assessments included OGTT, insulin secretion (IVGTT), and insulin sensitivity (euglycemic clamp). Results: Table 1 shows baseline characteristics and response to dex. Progressors to prediabetes had a higher glycemic response to dex than nonprogressors (&amp;lt;0.0001). In a regression model, post-dex fasting glucose level remained a significant predictor of Incident prediabetes after controlling for age, weight, waist, and baseline glucose (P&amp;lt;0.001). From ROC analysis, fasting plasma glucose ≥110 mg/dL after dex predicted incident prediabetes with 80% sensitivity and 60% specificity. Conclusion: Glycemic response to 2mg dex predicts incident prediabetes and could be useful for stratification and selection of high-risk subjects for lifestyle intervention. Table 1: Baseline demographic and glucoregulatory characteristics of subjects who developed prediabetes compared to those who remained normoglycemic. Disclosure E. Nyenwe: None. N.A. Umekwe: None. D.J. James: None. F. Ariganjoye: None. J.Y. Wan: None. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc. Funding American Diabetes Association (7-07-MN-13 to S.D-J.); National Institutes of Health

Depression-related behavioural and neuroendocrine changes in the Spontaneously Diabetic Torii (SDT) fatty rat, an animal model of type 2 diabetes mellitus.

Depression is one of the most common psychiatric diseases and is commonly comorbid with type 1 or 2 diabetes mellitus (DM). However, the pathophysiology underlying the depressive state in DM remains poorly understood. Animal models are useful tools to investigate the association between depression and DM. In the present study we investigated whether the Spontaneously Diabetic Torii (SDT) fatty rat, a novel animal model of type 2 DM, shows depression-related features. We assessed depression-like behaviour, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and neurotransmitter levels in the brain. Behaviour was evaluated using a forced swimming test, and the HPA axis was evaluated with changes in plasma corticosterone levels after a swimming stress exposure or dexamethasone challenge. In addition, serotonin (5-hydroxytryptamine; 5-HT), noradrenaline, glutamate and γ-aminobutyric acid (GABA) concentrations in the frontal cortex, hippocampus and brain stem were measured. In the forced swimming test, SDT fatty rats exhibited increased duration of immobility compared with control Sprague-Dawley (SD) rats. Moreover, basal corticosterone levels were significantly elevated in SDT fatty compared with control SD rats. However, there were no stress-induced increases or changes in dexamethasone-induced suppression of corticosterone in SDT fatty compared with control SD rats. Furthermore, there were significant changes in 5-HT concentrations in the prefrontal cortex, and in GABA and glutamate concentrations in the hippocampus in SDT fatty compared with controls. The results of the present study suggest that the SDT fatty rat may be an appropriate model for diabetes with comorbid depression associated with neurotransmitter impairments and aberrant basal HPA hyperactivity.