Enhanced cortisol suppression following administration of low-dose dexamethasone in first-episode psychosis patients

OBJECTIVE Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis and hyper-activity of this system have been described in patients with psychosis. Conversely, some psychiatric disorders such as post-traumatic stress disorder (PTSD) are characterised by HPA hypo-activity, which could be related to prior exposure to trauma. This study examined the cortisol response to the administration of low-dose dexamethasone in first-episode psychosis (FEP) patients and its relationship to childhood trauma. METHOD The low-dose (0.25 mg) Dexamethasone Suppression Test (DST) was performed in 21 neuroleptic-naive or minimally treated FEP patients and 20 healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. RESULTS FEP patients reported significantly higher rates of childhood trauma compared to controls (p = 0.001) and exhibited lower basal (a.m.) cortisol (p = 0.04) and an increased rate of cortisol hyper-suppression following dexamethasone administration compared to controls (33% (7/21) vs 5% (1/20), respectively; p = 0.04). There were no significant group differences in mean cortisol decline or percent cortisol suppression following the 0.25 mg DST. This study shows for the first time that a subset of patients experiencing their first episode of psychosis display enhanced cortisol suppression. CONCLUSIONS These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored.

La stimulation du nerf vague pour le traitement de la dépression réfractaire : les résultats après un an de suivi

La stimulation du nerf vague (SNV) a reçu l’approbation de Santé Canada en 2001, comme en Europe, pour le traitement de la dépression réfractaire et en 2005 aux États-Unis. Les études européennes et américaines rapportent un taux de réponse de 50% et de rémission de 30% après un an de traitement. La sélection des patients, encadrée par la recherche de marqueurs biologiques et des critères de résistance, pourrait contribuer à améliorer les taux de réponse. Cette étude décrit le suivi des patients ambulatoires souffrant de dépression réfractaire, d’un spectre unipolaire ou bipolaire (n=13) sous SNV. Une révision exhaustive de l’histoire médicale et thérapeutique précède une évaluation clinique intensive. Si un consensus d’équipe est obtenu, une investigation clinique à la recherche des marqueurs biologiques est effectuée. Ceci inclut une tomographie par émission de photons simples (SPECT), une tomographie par émission de positrons (TEP), une formule sanguine complète, un test de suppression à la dexaméthasone (DST), une collecte d’urine 24h (catécholamines et cortisol), une polysomnographie et une évaluation neuropsychologique abrégée. Après 1 an de traitement, 61,5% (8/13) des patients ont atteint le seuil de réponse (diminution de 50% des symptômes), dont 87.5% (7/8) en rémission. Les patients diagnostiqués d’un trouble bipolaire, présentant un DST anormal et/ou avec déficits cognitifs ont répondu au traitement et poursuivent leur rémission après 2 ans. Une sélection minutieuse des patients pour le SNV serait une méthode efficace pour traiter les dépressions réfractaires, notamment pour prévenir les rechutes, amenant un état euthymique durable pour la plupart des patients.

Prolonged Physical Training Decreases mRNA Levels of Glucocorticoid Receptor and Inflammatory Genes

Background/Aims: Prolonged physical exercise induces adaptive alterations in the hypothalamic-pituitary axis, increasing cortisol metabolism, and reducing cortisol synthesis and glucocorticoid sensitivity. The mechanisms responsible for this relative glucocorticoid resistance remain unknown but may involve expression of genes encoding glucocorticoid receptor (GR) and/or inflammatory molecules of nuclear factor kappa B1 (NFkB1) signaling pathway and cytokines. This study aimed to determine the impact of prolonged physical training on the expression of genes involved in glucocorticoid action and inflammatory response. Methods: Normal sedentary male cadets of the Brazilian Air Force Academy were submitted to 6 weeks of standardized physical training. Eighteen of 29 initially selected cadets were able to fully complete the training program. Fasting glucose, insulin and cortisol levels, cytokine concentration and the expression of genes encoding GR, NFkB1, inhibitor of NFkB1 and IkB kinase A were determined before and after the training period. Results: Prolonged physical exercise reduced the basal cortisol levels and the percent cortisol reduction after dexamethasone. These findings were associated with a significant reduction in the mRNA levels of GR (6.3%), NFkB1 (63%), inhibitor of NFkB1 (25%) and IkB kinase A (46%) with concomitant reduction in cytokine concentrations (ELISA). Conclusions: Prolonged physical training decreases the glucocorticoid sensitivity and the mRNA levels of the GR gene combined with decreased mRNA of genes related to the NFkB pathway. Copyright (C) 2010 S. Karger AG, Basel

Métodos diagnóstico de Hiperadrenocorticismo canina

The Hyperadrenocorticism is a disease that occur in dogs between mead to old age, is associated with the higher level of glucocorticoid that result in a corporal reaction. To make a diagnostic of this disease is necessary have a good history and physical examination, the principals complains of the proprietary are polyuria, polydipsia and polyphagia, in some times abdominal enlargement and lethargy. In the physical examination is observed this abdominal enlargement, hepatomegaly, alopecia, in some cases pyoderma and difficult respiratory. From this documents is possible determinate the differential diagnostics and with the tests find the diagnostic of the disease that the animal have. The base methods are hemogram, biochemical, urinalysis, radiographs and ultrasonography it’s possible do tomography and magnetic resonance too. There are confirmation methods too, they are very important, because the others not have documents necessary for the final diagnostic. Those are Urine cortisol to creatinine ratio, dexamethasone suppression test with high dose or low dose and ACTH stimulation test. Despite those tests have high sensibility and specificity, they can result in false positive or false negative, this is one of the causes to do the base methods and together make the veterinary doctor find the solution of the diagnostic and do the adequate treatment

Hiperadrenocorticismo em cães: revisão

Hyperadrenocorticism is a relatively common endocrinopathy in dogs, which is associated to an excessive production or administration of cortisol. The most affected breeds are Poodles, Teckels, Boxers, Boston Terriers and Beagles. The clinical signs most commonly observed are polyuria, polydipsia, polyfagia, panting, distended abdomen, endocrine alopecia, muscular weakness and lethargy. Laboratorial abnormalities include stress leukogram, increase in alkaline phosphatase and alanine aminotransferase activities, hypercholesterolemia, lipemia, hyperglycemia and hyposthenuria. The preferred essay to evaluate adrenal gland function is the low-dose dexamethasone suppression test, whereas the most used treatments include mitotane and trilostane. The objective of this paper is to review hyperadrenocorticism in dogs, because this disease is relatively common in small animal clinics and has many long-term complications.

Plasma cortisol in first episode drug-naive mania: Differential levels in euphoric versus irritable mood

Background: Dysregulation of HPA axis has been widely described in subjects with bipolar disorder (BD), including changes in cortisol levels during mood episodes and euthymia. However, most of the studies were done with medicated BD patients with variable length of illness, which was shown to interfere on peripheral cortisol levels. Therefore, the present study aims to evaluate plasma cortisol levels in drug-naive BD subjects during the first manic episode, as well as investigate the relationship between plasma cortisol levels and manic symptomatology. Methods: Twenty-six drug-naive patients were enrolled meeting criteria for a first manic episode in bipolar I disorder. Severity of mania was assessed using the Young Mania Rating Scale (YMRS). The control group included 27 healthy subjects matched by age and gender. Cortisol was quantified using a direct radioimmunoassay. Results: Plasma cortisol levels were decreased during first manic episode compared to healthy controls. Higher cortisol levels were positively associated with the presence of irritability (dysphoria), while elated mania showed lower cortisol levels compared to controls. Limitation: Data including larger samples are lacking. Conclusion: Higher cortisol in dysphoric mania compared to predominantly elated/euphoric mania may indicate a clinical and neurobiological polymorphic phenomenon, potentially involving a higher biological sensitivity to stress in the presence of irritable mood. The present findings highlight the importance to add a dimensional approach to the traditional categorical diagnosis for future neurobiological studies in BD. (C) 2011 Elsevier B.V. All rights reserved.

Glucocorticoid receptor polymorphisms and post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is reported in some studies to be associated with increased glucocorticoid (GC) sensitivity. Two common glucocorticoid receptor (GR) potymorphisms (N363S and 8cll) appear to contribute to the population variance in GC sensitivity. There is some evidence that there may be a genetic predisposition to PTSD. Hence we studied 118 Vietnam war veterans with PTSD for (i) GR polymorphisms, particularly the N363S and the Bcll polymorphisms which are thought to be GC sensitising, and (ii) two measures of GC sensitivity, the tow-dose 0.25 mg dexamethasone suppression test (LD-DST) and the dermal vasoconstrictor assay (DVVA). The DST and GR polymorphisms were also performed in 42 combat exposed Vietnam war veterans without PTSD. Basal plasma cortisol levels were not significantly different in PTSD (399.5 +/- 19.2 nmol/L, N=75) and controls (348.6 +/- 23.0 nmol/L, N = 33) and the LD-DST resulted in similar cortisol suppression in both groups (45.6 +/- 3.2 vs. 40.8 +/- 4.1%). The cortisol suppression in PTSD patients does not correlate with Clinician Administered PTSD Scores (CAPS), however there was a significant association between the Bcll GG genotype and low basal cortisol levels in PTSD (P=0.048). The response to the DVVA was similar to controls (945 +/- 122, N = 106 vs. 730 +/- 236, N = 28, P = 0.42). PTSD patients with the GG genotype, however, tended to be more responsive to DVVA and in this group the DVVA correlated with higher CAPS scores. The only exon 2 GR polymorphisms detected were the R23K and N363S. Heterozygosity for the N363S variant in PTSD, at 5.1% was not more prevalent than in other population studies of the N363S polymorphism in Caucasians (6.0-14.8%). The GG genotype of the Bcll polymorphism found to be associated with increased GC sensitivity in many studies showed a tendency towards increased response with DVVA and correlated with higher CAPS scores. In conclusion, the N363S and Bcll GR polymorphisms were not more frequent in PTSD patients than controls and reported population frequencies. Our PTSD group did not display GC hypersensitivity, as measured by the LD-DST and DVVA. In a subset of PTSD patients with the Bcll GG genotype, CAPS scores and basal cortisol Levels were negatively correlated. (C) 2004 Elsevier Ltd. All rights reserved.

Caracterização clínica, metabólica e hormonal de portadores de lipodistrofia parcial familiar

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2015.

Suppression of cell proliferation and programmed cell death by dexamethasone during postnatal lung development

Prematurely born babies are often treated with glucocorticoids. We studied the consequences of an early postnatal and short dexamethasone treatment (0.1-0.01 microg/g, days 1-4) on lung development in rats, focusing on its influence on peaks of cell proliferation around day 4 and of programmed cell death at days 19-21. By morphological criteria, we observed a dexamethasone-induced premature maturation of the septa (day 4), followed by a transient septal immatureness and delayed alveolarization leading to complete rescue of the structural changes. The numbers of proliferating (anti-Ki67) and dying cells (TdT-mediated dUTP nick end labeling) were determined and compared with controls. In dexamethasone-treated animals, both the peak of cell proliferation and the peak of programmed cell death were reduced to baseline, whereas the expression of tissue transglutaminase (transglutaminase-C), another marker for postnatal lung maturation, was not significantly altered. We hypothesize that a short neonatal course of dexamethasone leads to severe but transient structural changes of the lung parenchyma and influences the balance between cell proliferation and cell death even in later stages of lung maturation.

Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder

Objective: To evaluate cortisol suppression following 0.5 mg of dexamethasone (DEX) in trauma survivors (N = 52),with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), both, or neither disorder, and in subjects never exposed to trauma (N = 10), in order to examine interactions between diagnosis and trauma history on cortisol negative feedback inhibition. Method: Lifetime trauma exposure and psychiatric diagnoses were assessed and blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of DEX at 11:00 p.m. and blood samples for determination of cortisol and DEX were obtained at 8:00 a.m. the following day. Results: PTSD was associated with enhanced cortisol suppression in response to DEX Among trauma survivors, the presence of a traumatic event prior to the "focal" trauma had a substantial impact on cortisol suppression in subjects with MDD. Such subjects were more likely to show cortisol alterations similar to those associated with PTSD, whereas subjects with MDD with no prior trauma were more likely to show alterations in the opposite direction, i.e. relative non-suppression. Conclusions: Cortisol hypersuppression in PTSD appears not to be dependent on the presence of traumatic events prior to the focal trauma. However, prior trauma exposure may affect cortisol suppression in MDD. This finding may have implications for understanding why only some depressed patients show non-suppression on the DST. Published by Elsevier Ltd.

The ACTH response to dexamethasone in PTSD

Objective: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSID). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSID. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSID relative to healthy comparison subjects. Method: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSID and 19 subjects (14 men and five women) without psychiatric disorder. Results: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. Conclusions: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.

Evaluation of Adrenal Reserve in Children with Acute Lymphocytic Leukemia Treated with Prednisone or Dexamethasone

Background/Aims: The purpose of this study was to compare adrenal gland reserve in acute lymphocytic leukemia (ALL) patients 8 weeks after treatment with either prednisone (PRED) or dexamethasone (DEX) during the induction phase of therapy. Methods: A double-blind comparative study of patients treated with PRED and DEX was performed. Sixteen patients received PRED (40 mg/m(2)/day) and 13 patients received DEX (6 mg/m(2)/day), both for 28 days. A low-dose adrenocorticotropic hormone test (1.0 mu g/m(2), IV) was performed before and weekly for 8 weeks after abrupt cessation of glucocorticoid therapy. Sixteen children without ALL were used as controls to determine the cutoff peak cortisol level (14.2 mu g/dl). Results: Both groups (PRED and DEX) displayed similar mean peak cortisol levels before treatment and during the 8 weeks of evaluation (p = 0.652). No relationship was observed between the incidence of infection/stress and peak cortisol level within each group, nor was there a difference in the frequency of infection/stress between groups (p = 0.359). Although the patients presented variations in peak cortisol during the study period, no signs or symptoms of adrenal insufficiency were observed. Conclusion: Patients who received PRED or DEX for 4 weeks showed similar adrenal reserves and infection rates for 8 weeks after abruptly stopping glucocorticoid therapy, suggesting that DEX, which is a better antileukemic drug than PRED, has similar adrenal suppression and recovery rates. Copyright (c) 2012 S. Karger AG, Basel

Induktion tolerogener dendritischer Zellen zur Suppression von experimenteller autoimmuner Enzephalomyelitis und Kontaktallergie

Dendritische Zellen (DC) spielen als professionelle antigenpräsentierende Zellen (APC) eine zentrale Rolle in der Aktivierung und Regulierung antigenspezifischer Immunantworten. Aus diesem Grund wird der therapeutische Einsatz von DC zur Behandlung von Autoimmunerkrankungen und Allergien sowie zur Tumorbekämpfung erforscht. Im ersten Teil der vorliegenden Arbeit untersuchten wir das Potenzial einer biolistischen DNA-Vakzinierung zur Induktion tolerogener DC in vivo. Im Tiermodell der Myelin-Oligodendrozyten-Glykoprotein Peptid 35-55 (MOGp35-55) induzierten experimentellen autoimmunen Enzephalomyelitis (EAE) sollte mittels präventiver biolistischer Kovakzinierung von Plasmid-DNA kodierend für MOG und die immunregulatorischen Zytokine TGFβ oder IL-10 eine protektive Immunität induziert werden. Die MOG-Expression stand dabei entweder unter der Kontrolle des ubiquitär aktiven CMV-Promotors oder des murinen Fascin-Promotors, um eine ektopische MOG-Expression spezifisch in dermalen DC und Langerhanszellen zu erreichen. Dass MOGp35-55-präsentierende DC nach biolistischer DNA-Vakzinierung von der Haut in die drainierenden Lymphknoten migrieren und dort T-Zellen aktivieren, konnte im Vorfeld anhand einer substanziellen Proliferation von MOGp35-55-reaktiven 2D2 T-Zellen nachgewiesen werden. Im präventiven Ansatz der MOGp35-55-induzierten EAE zeigten Mäuse, die mit MOG-kodierenden Plasmiden biolistisch transfiziert wurden, eine leicht reduzierte EAE-Symptomatik. Die Kotransfektion von MOG und TGFβ führte zu einer Verstärkung der EAE-Suppression – unabhängig davon, ob die MOG-Expression unter der Kontrolle des CMV- oder des Fascin-Promotors stand. Interessanterweise resultierte die Koapplikation von MOG- und IL-10-kodierender Plasmid-DNA nur bei DC-fokussierter MOG-Expression zu reduzierter EAE-Symptomatik. Für biolistische DNA-Vakzinierungen stellt somit der Fascin-Promotor eine potente Alternative zu viralen Promotoren dar. Entsprechend der milderen EAE-Symptome beobachteten wir bei behandelten EAE-Mäusen einen geringeren Grad an Demyelinisierung sowie eine reduzierte Infiltration des ZNS mit IFNγ-produzierenden CD4+ Th1- und IL-17-produzierenden CD4+ Th17-Zellen. Desweiteren zeigten Milzzellen ex vivo nach MOGp35-55-Restimulation eine inhibierte Proliferation und eine signifikant reduzierte IFNγ- und IL-17-Zytokinproduktion. Überraschenderweise ging die antigenspezifische Immunsuppression nicht mit der Expansion von Foxp3+ regulatorischen T-Zellen einher. Da die Milzen aber erhöhte Mengen an CD8+IFNγ+ T-Zellen aufweisen, könnte ein zytotoxisch-suppressiver Mechanismus für die Inhibition der Th1- und Th17-Immunantwort verantwortlich sein. Nachfolgende Untersuchungen sind notwendig, um die induzierten immunologischen Mechansimen mittels biolistischer DNA-Vakzinierung aufzuklären. Der zweite Teil der Arbeit befasst sich mit der Generierung von tolerogenen DC in vitro. Dafür wurden murine Knochenmarkszellen unter DC-differenzierenden Bedingungen in Gegenwart des synthetischen Glucocorticoids Dexamethason (DEX) kultiviert. Die DEX-Zugabe führte zur Differenzierung von APC mit geringer CD11c-Expression. DEX-APC waren in vitro weitestgehend gegen LPS stimulierungsresistent und zeigten eine reduzierte Expression von MHC-II und den kostimulatorischen Molekülen CD80, CD86 und CD40. Ihrem tolerogenen Phänotyp entsprechend besaßen DEX-APC ein geringeres syngenes T-Zellstimulierungspotenzial als unbehandelte BM-DC. Anhand der erhöhten Oberflächenexpression von CD11b, GR1 und F4/80 besteht eine phänotypische Ähnlichkeit zu myeloiden Suppressorzellen. Die Fähigkeit von DEX-APC in vivo antigenspezifische Toleranz zu induzieren, wurde durch einen therapeutischen Ansatz im murinen Krankheitsmodell der Kontaktallergie überprüft. Die therapeutische Applikation von DEX-APC führte hierbei im Vergleich zur Applikation von PBS oder unbehandelten BM-DC zu einer signifikant reduzierten Ohrschwellungsreaktion. Zusammenfassend demonstrieren die Ergebnisse dieser Arbeit, dass potente tolerogene DC sowohl in vivo als auch in vitro induziert werden können. Dass diese Zellpopulation effektiv antigenspezifische Immunreaktionen supprimieren kann, macht sie zu einem vielversprechenden Werkzeug in der Behandlung von Autoimmunerkrankungen und Allergien.rn

Suppression of adenovirus E1A-induced apoptosis by mutated p53 is overcome by coexpression with Id proteins

The rat 3Y1 derivative cell lines, EId10 and EId23, established by introducing the adenovirus E1A12S, Id-1H, and Id-2H cDNAs linked to the hormone-inducible promoter, express these proteins upon treatment with dexamethasone and elicit apoptosis, although these cell lines express mutated p53. The E1A mutants containing a deletion in either the N terminus or the conserved region 1 were unable to induce apoptosis in cooperation with Ids. Western blot analysis of the immunoprecipitates prepared from the dexamethasone-treated EId10 cell extract showed that Id-2H preferentially binds to E1A and E2A (E12/E47) helix–loop–helix transcription factors in vivo, but scarcely to the retinoblastoma protein. After induction of E1A and Ids, EId10 and EId23 cells began to accumulate in S phase and undergo apoptosis before entering G2 phase, suggesting that abnormal synthesis of DNA induced by coexpression of E1A, Id-1H, and Id-2H results in the induction of apoptosis. Apoptosis also is induced in mouse A40 (p53−/−) cells by E1A alone or E1A plus Ids after transient transfection of the expression vectors. The induction of apoptosis is stimulated by coexpression with wild-type p53; however, apoptosis induced by E1A alone was suppressed completely by coexpression with mutated p53, whereas apoptosis induced by E1A plus Ids was stimulated by the mutated p53 as done by wild-type p53. These results suggest that the suppressive function of mutated p53 is overcome by Ids.

Differential suppression by protease inhibitors and cytokines of apoptosis induced by wild-type p53 and cytotoxic agents.

Apoptosis induced in myeloid leukemic cells by wild-type p53 was suppressed by different cleavage-site directed protease inhibitors, which inhibit interleukin-1 beta-converting enzyme-like, granzyme B and cathepsins B and L proteases. Apoptosis was also suppressed by the serine and cysteine protease inhibitor N-tosyl-L-phenylalanine chloromethylketone (TPCK) [corrected], but not by other serine or cysteine protease inhibitors including N alpha-p-tosyl-L-lysine chloromethylketone (TLCK), E64, pepstatin A, or chymostatin. Protease inhibitors suppressed induction of apoptosis by gamma-irradiation and cycloheximide but not by doxorubicin, vincristine, or withdrawal of interleukin 3 from interleukin 3-dependent 32D non-malignant myeloid cells. Induction of apoptosis in normal thymocytes by gamma-irradiation or dexamethasone was also suppressed by the cleavage-site directed protease inhibitors, but in contrast to the myeloid leukemic cells apoptosis in thymocytes was suppressed by TLCK but not by TPCK. The results indicate that (i) inhibitors of interleukin-1 beta-converting enzyme-like proteases and some other protease inhibitors suppressed induction of apoptosis by wild-type p53 and certain p53-independent pathways of apoptosis; (ii) the protease inhibitors together with the cytokines interleukin 6 and interferon-gamma or the antioxidant butylated hydroxyanisole gave a cooperative protection against apoptosis; (iii) these protease inhibitors did not suppress induction of apoptosis by some cytotoxic agents or by viability-factor withdrawal from 32D cells, whereas these pathways of apoptosis were suppressed by cytokines; (iv) there are cell type differences in the proteases involved in apoptosis; and (v) there are multiple pathways leading to apoptosis that can be selectively induced and suppressed by different agents.