Cortisol response to traumatic stress to predict PTSD symptom development - a systematic review and meta-analysis of experimental studies.

Background: Pre-and post-traumatic hypothalamic-pituitary-adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events.Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms.Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (dSMC) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms.Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (kobservations = 25, dSMC = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = -.18 [-.35; -.01]), higher state happiness (k = 8, r = -.34 [-.59; -.03], variable inverted) and lower state anger (k = 9, r = -.14 [-.26; -.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = -.20 [-.33; -.06]) and lower state sadness (k = 17, r = -.16 [-.25; -.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]).Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms.

Experimental trauma paradigms successfully induced a cortisol response.Cortisol was predictive for single state, emotion-related symptoms, but not overall PTSD symptoms.Trauma paradigms shed light into the immediate post-trauma period that is hard to capture in real life, but the gap between experimental and naturalistic settings is difficult to overcome.

Effectiveness and safety of tacrolimus treatment for IgA nephropathy: A prospective cohort study / Efectividad y seguridad del tratamiento con tacrólimus para la nefropatía por IgA: estudio de cohorte prospectivo

Background:There is no a unified opinion in the treatment of IgA nephropathy. This prospective cohort study was to explore the effectiveness and safety of tacrolimus for treatment of IgA (Immunoglobulin A) nephropathy patients.Methods:In this study, we assigned 50 patients with biopsy-proven IgA nephropathy in a 1:1.5 ratio to receive oral tacrolimus or full-dose glucocorticoid for 6 months. All the patients had 24-h urine protein excretion≥2.0g/24h and estimated glomerular filtration rate≥50mL/min/1.73m2. Primary endpoint was rate of complete remission.Results:After 6 months of treatment, seven participants achieved complete remission in the tacrolimus group and twelve participants in the glucocorticoid group, the complete remission rate was 35% and 40%, respectively. There were not significantly differences between two groups (P=0.7). However, the serum creatinine level from baseline was an increase of 13±13.5μmol/L in the tacrolimus group and a decrease of 8.2±20μmol/L in the glucocorticoid group. When patients stopped taking tacrolimus for 3 months, creatinine level can almost fall to normal level. Thus, patients with renal insufficiency have a high incidence in the tacrolimus group.Conclusions:Tacrolimus was noninferior to full-dose glucocorticoid in inducing proteinuria remission at 6 months. This suggested that those IgA nephropathy patients who are unwilling to full-dose glucocorticoid could consider tacrolimus, but need to pay attention to the impact on renal function. (AU)

Antecedentes:No existe una opinión generalizada en el tratamiento de la nefropatía IgA. El objetivo del presente estudio fue explorar la eficacia y seguridad de tacrólimus en el tratamiento de pacientes con nefropatía por IgA.Métodos:Se incluyó a 50 pacientes con nefropatía por IgA comprobada por biopsia en una proporción de 1:1,5 para recibir tacrólimus oral o glucocorticoides en dosis completa durante 6 meses. Todos los pacientes tenían una excreción de proteínas en orina de 24 horas ≥2,0g y una tasa de filtración glomerular estimada ≥50ml/min/1,73 m2. El criterio de valoración principal fue la tasa de remisión completa.Resultados:Después de 6 meses de tratamiento, 7 pacientes lograron una remisión completa en el grupo de tacrólimus y 12 participantes en el grupo que recibió glucocorticoides; la tasa de remisión completa fue del 35% y del 40%, respectivamente (p=0,7). Sin embargo, el nivel de creatinina sérica desde el inicio aumentó 13±13,5μmol/L en el grupo de tacrólimus y disminuyó 8,2±20μmol/L en el grupo con glucocorticoides. Cuando los pacientes dejaron de tomar tacrólimus durante 3 meses, el nivel de creatinina casi descendió al nivel normal. Por consiguiente, en el grupo de tacrólimus hubo una alta incidencia de insuficiencia renal.Conclusiones:El tacrólimus no fue inferior a los glucocorticoides en dosis completa para inducir la remisión de la proteinuria a los 6 meses. Esto indica que en aquellos pacientes con nefropatía por IgA a los que no se les pueda administrar glucocorticoides en dosis completas se podría considerar el uso de tacrólimus, aunque con especial atención al posible impacto en la función renal. (AU)

p-Chloro-diphenyl diselenide modulates Nrf2/Keap1 signaling and counteracts renal oxidative stress in mice exposed to repeated dexamethasone administrations.

Dexamethasone is a synthetic glucocorticoid that has been associated with oxidative stress in central and peripheral tissues. p-Chloro-diphenyl diselenide ((p-ClPhSe)2) is an antioxidant organoselenium compound. The present study evaluated whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1) signaling contributes to the (p-ClPhSe)2 antioxidant effects in the kidney of mice exposed to dexamethasone. Adult Swiss mice received dexamethasone (intraperitoneal) at a dose of 2 mg/kg or its vehicle for 21 days. After that, mice were treated with (p-ClPhSe)2 (intragastric) (1, 5, or 10 mg/kg) for 7 days. Samples of kidneys were collected for biochemical assays. (p-ClPhSe)2 at a dose of 1 mg/kg reversed the renal reactive oxygen species (ROS) and carbonyl protein (CP) levels increased by dexamethasone. (p-ClPhSe)2 at doses of 5 and 10 mg/kg was effective against the increase of thiobarbituric acid reactive substances, ROS, and CP, as well as the decrease of δ-aminolevulinic acid dehydratase activity and nonprotein sulfhydryl levels induced by dexamethasone. At 5 mg/kg, (p-ClPhSe)2 reduced the renal levels of 4-OH-2-HNE and heme oxygenase (HO-1), as well as modulated the Nrf2/Keap-1 signaling in mice exposed to dexamethasone. The present findings revealed that (p-ClPhSe)2 antioxidant effects were associated with the modulation of Nrf2/Keap-1 signaling pathway in the kidney of mice exposed to dexamethasone.

Effectiveness and safety of tacrolimus treatment for IgA nephropathy: A prospective cohort study.

BACKGROUND: There is no a unified opinion in the treatment of IgA nephropathy. This prospective cohort study was to explore the effectiveness and safety of tacrolimus for treatment of IgA (Immunoglobulin A) nephropathy patients. METHODS: In this study, we assigned 50 patients with biopsy-proven IgA nephropathy in a 1:1.5 ratio to receive oral tacrolimus or full-dose glucocorticoid for 6 months. All the patients had 24-h urine protein excretion≥2.0g/24h and estimated glomerular filtration rate≥50mL/min/1.73m2. Primary endpoint was rate of complete remission. RESULTS: After 6 months of treatment, seven participants achieved complete remission in the tacrolimus group and twelve participants in the glucocorticoid group, the complete remission rate was 35% and 40%, respectively. There were not significantly differences between two groups (P=0.7). However, the serum creatinine level from baseline was an increase of 13±13.5µmol/L in the tacrolimus group and a decrease of 8.2±20µmol/L in the glucocorticoid group. When patients stopped taking tacrolimus for 3 months, creatinine level can almost fall to normal level. Thus, patients with renal insufficiency have a high incidence in the tacrolimus group. CONCLUSIONS: Tacrolimus was noninferior to full-dose glucocorticoid in inducing proteinuria remission at 6 months. This suggested that those IgA nephropathy patients who are unwilling to full-dose glucocorticoid could consider tacrolimus, but need to pay attention to the impact on renal function.

Abordagem da hiperplasia adrenal congênita pela deficiência da enzima 21-hidroxilase em crianças e adolescentes: revisão / Management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children and adolescents: review

Objetivo: Descrever o diagnóstico e manejo clínico da deficiência da 21-hidroxilase (D-21OH), no contexto atual de inclusão da doença nos programas de triagem neonatal, bem como características genéticas, fisiopatológicas e manifestações na infância e adolescência. Fonte de Dados: Revisão integrativa realizada nas bases de dados MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science nos últimos vinte anos, em língua inglesa e portuguesa; população-alvo: crianças da primeira infância à adolescência; com o uso dos termos "triagem neonatal", "hiperplasia adrenal congênita", "deficiência da 21-hidroxilase", "glucocorticoide" e "polimorfismos do gene NR3C1". Síntese de Dados: A hiperplasia adrenal congênita (HAC) constitui um grupo de doenças caracterizadas por deficiências enzimáticas na esteroidogênese do córtex adrenal. A D-21OH é responsável por 95% dos casos e, se não tratada precocemente, pode levar ao óbito no período neonatal em sua forma clássica. A triagem neonatal para a HAC consiste na dosagem do precursor 17-hidroxiprogesterona (17OHP) no sangue de recém-nascidos, permitindo rápida confirmação diagnóstica e instituição da terapêutica. A implantação da triagem neonatal constitui um avanço, mas o controle dos pacientes pediátricos com D-21OH é complexo e deve ser sempre individualizado. Conclusão: A instituição dos programas de triagem neonatal para HAC tem trazido benefícios para o prognóstico das crianças com D-21OH. Seu manejo é multiprofissional, individualizado e ainda um desafio mesmo para o especialista. Ampla divulgação do conhecimento sobre a doença é desejável para permitir melhor condução dessas crianças, especialmente de meninas com a doença que apresentam genitália atípica.

Objective: To describe the diagnosis and clinical management of 21-hydroxylase deficiency (21OH-D), in the current context of including the disease in neonatal screening programs, as well as genetic, pathophysiological characteristics, and manifestations in childhood and adolescence. Data Source: Integrative review performed in MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science databases in the last twenty years, in English and Portuguese; target population: children from early childhood to adolescence; with the use of the terms "neonatal screening"; "congenital adrenal hyperplasia"; "21-hydroxylase deficiency"; "glucocorticoid"; "polymorphisms of the NR3C1 gene". Data Synthesis: Congenital adrenal hyperplasia (CAH) is a group of diseases characterized by enzyme deficiencies in adrenal cortex steroidogenesis. 21OH-D is responsible for 95% of cases and, if not treated early, can lead to death in the neonatal period in its classic form. Neonatal screening for CAH consists of measuring the precursor 17-hydroxyprogesterone (17OHP) in the blood of newborns, allowing rapid diagnostic confirmation and institution of therapy. The implementation of neonatal screening is an advance, but the control of pediatric patients with 21OH-D is complex and must always be individualized. Conclusion: The institution of newborn screening programs for CAH has benefits for the prognosis of children with 21OH-D. Its management is multi-professional, individualized and still a challenge even for the specialist. Wide dissemination of knowledge about the disease is desirable to allow better management of these children, especially girls with the disease who have atypical genitalia.

Potential effect of hyaluronic acid and triamcinolone acetate, alone or combined, on chondrogenic differentiation of mesenchymal stem cells / Efecto potencial del ácido hialurónico y del acetato de triamcinolona solos o combinados sobre la diferenciación condrogénica de células-tronco mesenquimales / Efeito potencial do ácido hialurônico e triancinolona acetonida, isolados e combinados, na diferenciação condrogênica de células-tronco mensenquimais

Abstract Background: Osteoarthritis is a complex degenerative disease with several factors contributing to joint damage. Objective: To compare the potential effect of hyaluronic acid (HA) and triamcinolone acetonide (TA), alone or combined, on the in vitro chondrogenic differentiation process of mesenchymal stem cells (MSCs). Methods: MSCs were divided into four groups: Control, HA, TA, and HA/TA combined. Each treatment group was cultured for 14 days in chondrogenic differentiation medium. The chondrogenic differentiation potential was assessed by histology and immunohistochemistry. Results: The HA and HA/TA-treated MSCs presented histological characteristics similar to native chondrocytes. The extracellular matrix (ECM) of TA-treated MSCs was compact and organized. Glycosaminoglycan staining was intense in Control, moderate in TA, slight in HA/TA, and undetectable in HA. Type II collagen immunoreactivity was high in the TA-treated ECM and MSCs. Conclusions: Histological analysis shows that HA influences morphological development similar to chondrocytes of the MSCs, but with low expression of specific cartilage molecules. The TA promotes formation of a compact and organized ECM.

Resumen Antecedentes: La osteoartritis es una enfermedad degenerativa compleja en la cual varios factores contribuyen al daño articular. Objetivo: Comparar el efecto del ácido hialurónico (HA) y acetónido de triamcinolona (TA), solos o en combinación, en el proceso de diferenciación condrogénica in vitro de células madre mesenquimales (MSCs). Métodos: Las MSCs fueron divididas en cuatro grupos: Control, HA, TA y HA/TA, y cultivadas por 14 días en medio de diferenciación condrogénica para cada tratamiento. El potencial de diferenciación condrogénica fue analizado por medio de histología e inmunohistoquímica. Resultados: Las MSCs tratadas con HA y HA/TA, presentaron características histológicas similares a los condrocitos nativos, y la matriz extracelular (ECM) de MSCs tratadas con TA fue más compacta y organizada. La tinción de glicosaminoglicanos fue intensa en el Control, moderada en TA, ligera en HA/TA, y sin tinción en HA. La inmunoreactividad para colágeno tipo II fue más alta en las MSCs y ECM tratadas con TA. Conclusión: El análisis histológico muestra que el HA influencia un desarrollo morfológico similar a los condrocitos de las MSCs, pero con baja expresión de moléculas específicas de cartílago. La TA promueve la formación de una ECM compacta y organizada.

Resumo Antecedentes: A osteoartrite é uma doença degenerativa complexa, na qual vários fatores contribuem ao dano articular. Objetivo: Comparar o efeito do ácido hialurônico (HA) e Triancinolona acetonida (TA), só ou combinado no processo de diferenciação condrogênica in vitro de células tronco mesenquimais (MSCs). Métodos: MSCs foram divididas em 4 grupos: Controle, HA, TA y HA/TA e cultivadas por 14 dias com meio de diferenciação condrogênica e seus respectivos tratamentos. O potencial de diferenciação condrogênica foi acessado por meio de histologia e imunohistoquímica. Resultados: Histologicamente, MSCs tratadas com HA e HA/TA apresentaram características semelhantes de condrócitos nativos, e a matriz extracelular de MSCs tratadas com TA foi mais compacta e organizada. A coloração para glicosaminoglicanos foi intensa no Controle, moderada no TA, leve no HA/TA e sem coloração com HA. Para os grupos tratamento, a imunoreatividade para colágeno tipo II foi maior nas células e matriz extracelular tratadas com TA. Conclusão: Mediante análise histológica, o HA influenciou o desenvolvimento morfológico semelhante a condrócitos das MSCs, mas com baixa expressão de moléculas específicas de cartilagem. A TA promoveu a formação de uma matriz extracelular compacta e organizada.

Stress hormones promote DNA damage in human oral keratinocytes / Hormônios do estresse promovem dano no DNA de queratinócitos humanos de boca

O estresse crônico aumenta os níveis sistêmicos dos hormônios do estresse norepinefrina e cortisol. Assim como o carcinógeno específico do tabaco NNK (4- (metilnitrosamina)-1-(3-piridil)-1-butanona), estes hormônios podem induzir danos expressivos no DNA, o que contribui para o desenvolvimento do câncer. No entanto, é desconhecido se os hormônios do estresse possuem efeitos genotóxicos em queratinócitos de boca. Este estudo investigou os efeitos dos hormônios do estresse sobre o dano no DNA de uma linhagem celular de queratinócitos humanos de boca (NOK-SI). Células NOK-SI estimuladas com norepinefrina ou cortisol apresentaram maior dano no DNA que as células não tratadas. O dano induzido pela norepinefrina foi revertido pelo pré-tratamento das células com um beta-bloqueador. Células tratadas com NNK combinado à norepinefrina apresentaram níveis reduzidos das caspases 3 e 7. O cortisol também reduziu a atividade das enzimas pro-apoptóticas em relação às células não estimuladas. O dano no DNA promovido pelo NNK e cortisol e pela combinação de ambos levou ao acúmulo de γH2AX intracelular. Os efeitos causados pelo NNK e cortisol foram bloqueados com propranolol e com o antagonista do receptor de glicorcorticoide RU486, respectivamente. As quebras no DNA induzidas pela norepinefrina, na presença ou ausência de NNK, resultaram em maiores níveis celulares de 8OHdG. Este efeito também foi induzido via receptores beta-adrenérgicos. Os hormônios do estresse induzem danos no DNA de queratinócitos de boca e poderiam contribuir para a carcinogênese bucal(AU)

Chronic stress increases the systemic levels of stress hormones norepinephrine and cortisol. As well tobacco-specific carcinogen NNK (4-(methylnitrosamine)-1-(3- pyridyl)-1-butanone), they can induce expressive DNA damage contributing to the cancer development. However, it is unknown whether stress hormones have genotoxic effects in oral keratinocytes. This study investigated the effects of stress hormones on DNA damage in a human oral keratinocyte cell line (NOK-SI). NOK-SI cells stimulated with norepinephrine or cortisol showed higher DNA damage than untreated cells. Norepinephrine-induced DNA damage was reversed by pretreatment with beta-adrenergic blocker propranolol. Cells treated with NNK combined to norepinephrine displayed reduced levels of caspases 3 and 7. Cortisol also reduced the activity of pro-apoptotic enzymes. DNA damage promoted by NNK or cortisol and carcinogen combined to the hormone led to intracellular γH2AX accumulation. The effects caused by NNK and cortisol were abolished by propranolol and glucocorticoid receptor antagonist RU486, respectively. DNA breaks induced by norepinephrine in the presence or absence of NNK resulted in higher 8OHdG cellular levels. This effect was also induced through beta-adrenergic receptors. Stress hormones induce DNA damage of oral keratinocytes and could contribute to oral carcinogenesis(AU)

Nanoparticle drug delivery characterization for fluticasone propionate and in vitro testing 1.

Glucocorticoids, such as fluticasone propionate (FP), are used for the treatment of inflammation and alleviation of nasal symptoms and allergies, and as an antipruritic. However, both short- and long-term therapeutic use of glucocorticoids can lead to muscle weakness and atrophy. In the present study, we evaluated the feasibility of the nanodelivery of FP with poly(dl-lactide-co-glycolide) (PLGA) and tested in vitro function. FP-loaded PLGA nanoparticles were prepared via nanoprecipitation and morphological characteristics were studied via scanning electron microscopy. FP-loaded nanoparticles demonstrated an encapsulation efficiency of 68.6% ± 0.5% with a drug loading capacity of 4.6% ± 0.04%, were 128.8 ± 0.6 nm in diameter with a polydispersity index of 0.07 ± 0.008, and displayed a zeta potential of -19.4 ± 0.7. A sustained in vitro drug release pattern was observed for up to 7 days. The use of fluticasone nanoparticle decreased lipopolysaccharide (LPS)-induced lactate dehydrogenase release compared with LPS alone in C2C12 treated cells. FP also decreased expression of LPS-induced inflammatory genes in C2C12 treated cells as compared with LPS alone. Taken together, the present study demonstrates in vitro feasibility of PLGA-FP nanoparticle delivery to the skeletal muscle cells, which may be beneficial for treating inflammation.

Efficacy and safety of recombinant growth hormone treatment in children with growth retardation related to long-term glucocorticosteroid therapy.

OBJECTIVE: To evaluate safety and efficacy of recombinant human growth hormone treatment in children on long-term glucocorticoid therapy. METHODS: A 5-year prospective open-label study included children on glucocorticoid therapy with either standard deviation score (SDS)<-2 for height for chronological age (CA) if naïve to growth hormone treatment, or annual growth rate≥0 SDS for CA if currently receiving growth hormone. RESULTS: Ninety-eight patients began treatment, 63 discontinued; 59 were analyzed for safety and 58 for efficacy. There was male predominance (78.0%). Median age was 13.0 years. Median height screening was 136.0cm (range, 95.1-159.7cm). Mean SDS for height for CA in the efficacy analysis set was -2.91±1.19 (range, -7.49 to -0.96). Mean growth hormone dose was 0.4, 0.4, 0.4 and 0.3mg/kg/week at month 0, M12, M24, and M36, respectively. Primary analysis of change in SDS for height for CA from baseline to M36 showed a significant increase of 0.80±1.03. Twenty patients in the safety analysis set had≥1 treatment-emergent adverse event (TEAE) related to study treatment. Two patients experienced serious treatment-related TEAEs: 1 case of poor compliance, and 1 of mild hyperglycemia, both already observed under growth hormone treatment. CONCLUSION: This study suggests that growth hormone treatment could be effective in increasing height in children on long-term glucocorticoid treatment with a safety profile comparable to that in approved rhGH treatment indications. CLINICAL TRIAL REGISTRATION: NCT00163189.

Síndrome de deprivación glucocorticoidea. A propósito de un caso / Glucocorticoid deprivation syndrome. Case presentation

RESUMEN El síndrome de deprivación glucocorticoidea es el cuadro clínico resultante de la suspensión de la administración exógena de esteroides, aplicados por tiempo prolongado, independientemente de la vía de administración. Provoca la frenación del eje hipotálamo-hipófisis-suprarrenal y por ende disminuye la producción y secreción de corticotropina. Paciente femenina de 54 años de edad, con esteroides como tratamiento prolongado. Al retirarlo comenzó con pérdida de peso y dificultad para caminar, además de hipotensión ortostática, sufrió caída brusca al piso con pérdida de conocimiento. Fue llevada al hospital y no se constató pulsos periféricos ni tensión arterial, que no resolvió totalmente con el uso enérgico de fluidos endovenosos. Se mantuvo sin regular parámetros normales, se reevaluó como un síndrome de depravación corticoidea y se le impuso tratamiento con prednisona, mejorando paulatinamente. Los síndromes asociados a la retirada de corticoidesaparecen por el empleo de dosis altas, o retirada brusca de la corticoterapia prolongada. Al conjunto de síntomas y signos que aparecen cuando no se consigue tolerar la retirada de glucocorticoides, ante la ausencia de enfermedad subyacente para la cual fueron indicados estos medicamentos, y con un eje hipotálamo-hipófisis-suprarenal (HHS) no suprimido se le considera un síndrome de retirada de corticoides. A pesar de la gravedad, la frecuencia e importancia de este efecto secundario, en ocasiones no se repara en él, por lo que es imprescindible valorar los tratamientos indicados y reevaluar periódicamente los tratamientos crónicos indicados.

ABSTRACT The glucocorticoide deprivation symptom is the clinical symptom resulting from stoping the exogenous administration of steroids that were used for a long time, in spite of the administration way. It restrains the hypothalamus-pituitary-adrenal axis and therefore reduces corticotropine production and secretion. This is the case of a female patient, aged 54 years, with a continued steroid treatment. When stoping it, she began to lose weight and presented difficulties for walking. Besides orthostatic hypotension, she abruptly fell to the ground losing conciousness. She was carried to the hospital and there were not found periferal pulses nor arterial tension, a problem that was not solved by the active use of endovenous fluids. She kept on without regulating normal parameters, and was re-evaluated as a corticoid deprivation symptom and treated with prenisone. She gradually got better. The syndromes asociated to corticod deprivation begin due to the usage of high doses, or due to the abrupt withdrawal of a long corticotherapy. The whole of the symptoms appearing when corticoid withdrawal is not tolerated, in the absence of the underlying disease against which these medicines were indicated, and with a non-suppressed hypothalamus-pituitary-adrenal axis, is considered as a syndrome of corticoide withdrawal. In spite of its seriousness, of the frequency and importance of this secundary effect, sometimes it is not noticed; therefore it is essential to evaluate the indicated treatments and periodically reevaluate the treatments ordered for chronic diseases.

Síndrome de deprivación glucocorticoidea. A propósito de un caso / Glucocorticoid deprivation syndrome. Case presentation

RESUMEN El síndrome de deprivación glucocorticoidea es el cuadro clínico resultante de la suspensión de la administración exógena de esteroides, aplicados por tiempo prolongado, independientemente de la vía de administración. Provoca la frenación del eje hipotálamo-hipófisis-suprarrenal y por ende disminuye la producción y secreción de corticotropina. Paciente femenina de 54 años de edad, con esteroides como tratamiento prolongado. Al retirarlo comenzó con pérdida de peso y dificultad para caminar, además de hipotensión ortostática, sufrió caída brusca al piso con pérdida de conocimiento. Fue llevada al hospital y no se constató pulsos periféricos ni tensión arterial, que no resolvió totalmente con el uso enérgico de fluidos endovenosos. Se mantuvo sin regular parámetros normales, se reevaluó como un síndrome de depravación corticoidea y se le impuso tratamiento con prednisona, mejorando paulatinamente. Los síndromes asociados a la retirada de corticoidesaparecen por el empleo de dosis altas, o retirada brusca de la corticoterapia prolongada. Al conjunto de síntomas y signos que aparecen cuando no se consigue tolerar la retirada de glucocorticoides, ante la ausencia de enfermedad subyacente para la cual fueron indicados estos medicamentos, y con un eje hipotálamo-hipófisis-suprarenal (HHS) no suprimido se le considera un síndrome de retirada de corticoides. A pesar de la gravedad, la frecuencia e importancia de este efecto secundario, en ocasiones no se repara en él, por lo que es imprescindible valorar los tratamientos indicados y reevaluar periódicamente los tratamientos crónicos indicados (AU).

ABSTRACT The glucocorticoide deprivation symptom is the clinical symptom resulting from stoping the exogenous administration of steroids that were used for a long time, in spite of the administration way. It restrains the hypothalamus-pituitary-adrenal axis and therefore reduces corticotropine production and secretion. This is the case of a female patient, aged 54 years, with a continued steroid treatment. When stoping it, she began to lose weight and presented difficulties for walking. Besides orthostatic hypotension, she abruptly fell to the ground losing conciousness. She was carried to the hospital and there were not found periferal pulses nor arterial tension, a problem that was not solved by the active use of endovenous fluids. She kept on without regulating normal parameters, and was re-evaluated as a corticoid deprivation symptom and treated with prenisone. She gradually got better. The syndromes asociated to corticod deprivation begin due to the usage of high doses, or due to the abrupt withdrawal of a long corticotherapy. The whole of the symptoms appearing when corticoid withdrawal is not tolerated, in the absence of the underlying disease against which these medicines were indicated, and with a non-suppressed hypothalamus-pituitary-adrenal axis, is considered as a syndrome of corticoide withdrawal. In spite of its seriousness, of the frequency and importance of this secundary effect, sometimes it is not noticed; therefore it is essential to evaluate the indicated treatments and periodically reevaluate the treatments ordered for chronic diseases (AU).

Genomic insights into Cushing syndrome.

In the setting of Cushing syndrome, genomic analyses can be performed either in tumors responsible for endogenous Cushing, or in patients exposed to glucocorticoid excess. Genomics of tumors identified several new genes - including ZNRF3 in adrenocortical carcinomas, PRKACA in cortisol-producing adrenal adenomas, ARMC5 in primary macronodular adrenal hyperplasia and USP8 in pituitary corticotroph adenomas. These genes shed new lights on the mechanisms responsible for these tumors. Integrated genomic studies of adrenal carcinomas identified distinct molecular classes, with remarkably different prognostic outcome. Beyond the mechanistic novelties, a new generation of prognostic markers emerges, with potentially important impact on patients care. For the future, genomic efforts should be pursued, focusing on poorly characterized tumors responsible for Cushing syndrome - including endocrine tumors secreting ACTH. In addition, epigenomics is emerging as an outstanding set of tools for characterizing tumors, unraveling unprecedented aspects of tumorigenesis. Applying these tools to endocrine tumors responsible for Cushing syndrome may also lead to important discoveries. Genomics of patients exposed to glucocorticoid excess is an emerging research field. Proof of principle studies have been performed, identifying molecular markers of glucocorticoid excess in blood. Research efforts should now concentrate on markers of mild glucocorticoid excesses - endogenous or exogenous -, owing to their high prevalence in general population. In addition, markers of individual susceptibility to each type of glucocorticoid complication are needed. It remains to be determined whether genomics can identify such markers.

Pathophysiology of Glucocorticoid Signaling.

Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9ß) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients.

Presentación de tres casos y revisión en la literatura: Síndrome de Cushing / Presentation of three cases and review in the literature: Cushing's syndrome

El hipercortisolismo es una enfermedad rara, con afección de múltiples sistemas, asociada a elevada morbilidad y mortalidad sino es tratada a tiempo. El sistema cardiovascular es uno de los que más se afecta en esta enfermedad. El pronóstico de la enfermedad se ve afectado principalmente por las dificultades en el diagnóstico y el tratamiento, los cuales siguen siendo un desafío actualmente. El síndrome de Cushing se clasifica como dependiente o independiente de hormona adrenocorticotrópica (ACTH). Los ACTH dependientes son los más comunes. Los ACTH independientes corresponden a menos de 15% de los casos y son causados por enfermedades suprarrenales.A continuación, describimos los casos de los tres pacientes, a quienes se les estableció el diagnóstico de síndrome de Cushing de origen adrenal y se realiza una revisión acerca de los tópicos principales en este tema..(AU)

Hypercortisolims is an infrequent disease with multi-systemic compromise and increases morbility and mortality. Cardiovascular disease is one of the most common complica-tions associaded with Cushing syndrome. The prognosis of this disease is affected by the difficulties associated with its diagnosis and treatment. Clearly, Cushing syndrome is still a clinical challenge. Cushing syndrome can be classified in ACTH dependent or ACTH independent. ACTH-dependent causes are more frequent, however, CTHindependent causes are responsible of less than 15% of Cushing`s syndrome and are secondary to adrenal tumors. Three cases of adrenal Cushing are reported with a review of the main clinical points of Cushing syndrome..(AU)

Pythiosis cutaneous in horses treated with triamcinolone acetonide. Part 2. Histological and histochemical description / Pythiosis cutánea en equinos tratados con acetonida de triamcinolona. Parte 2. Descripción histológica e histoquímica

ABSTRACT Objective. The study aimed to evaluate the histomorphometry tissue recovery process of the skin granuloma of skin pythiosis in horses treated with triamcinolone acetonide. Materials and methods. We conducted a descriptive study, not probabilistic in convenience animals with cutaneous pythiosis. 24 horses were used with cutaneous pythiosis, a group of 12 animals was administered 50 mg of intramuscular injection of triamcinolone acetonide (TG) and the other group was not applied any treatment (CG). Are tissue biopsies performed for histological and histochemical evaluation and stained with hematoxylin eosin (HE), Gomori trichrome (GT), picrosirius red polarization (PR/P), Grocott methenamine silver (GMS) and periodic acid-Schiff (PAS). Results. It is noted that in TG inflammation was gradually decreasing, as evidenced in decreased fibrin layer leukocyte, PMN and phenomena Splendore Hoepli, also in increased angiogenesis, epiteliogénesis, and increasing the overall amount of fibroblasts and collagen fibers, anyway in the progressive replacement of collagen type III to type I collagen at the end of the process, and that the presence of intralesional pseudo-hyphae of Pythium insidiosum reduces it to the second week. Neither of the animals in the CG showed improvement in histological and histochemical characteristics of pythiosis and maintained equal to the first day throughout the study. Conclusions. The use of triamcinolone acetonide is a good therapeutic alternative for the treatment of granulomatous pythiosis wounds in horses with 100% clinical recovery and demonstrated with histological and histochemical findings.

RESUMEN Objetivo. El objetivo del estudio fue realizar una descripción histológica e histoquímica del proceso de cicatrización de la pythiosis cutánea en equinos tratados con acetonida de triamcinolona. Materiales y métodos. Se Realizó un estudio de tipo descriptivo, no probabilístico en animales de conveniencia con pythiosis cutánea. Fueron utilizados 24 equinos con pythiosis, siendo aplicado 50 mg de acetonida de triamcinolona vía intramuscular a un grupo de 12 animales (GT) y en otro grupo no fue aplicado tratamiento (GC). Se realizaron biopsias de tejidos para evaluación histológica e histoquímica, en las coloraciones de hematoxilina eosina (H&E), tricrómico de Gómori (TG), picrosirius red/polarization (PR/P) y plata metanamina de Grocott (GMS). Resultados. Se observó que en el GT el proceso inflamatorio fue disminuyendo progresivamente, evidenciado en la disminución de la capa fibrino leucocitaria, PMN y de los fenómenos de Splendore Hoepli, así como mayor angiogénesis, epiteliogénesis y aumento de la cantidad de fibroblastos y fibras colágenas generales, así mismo en el cambio progresivo de colágeno tipo III a colágeno tipo I al final del proceso, además de que la presencia de hifas intralesionales de Pythium insidiosum disminuyó a la segunda semana. Ninguno de los animales del GC presentó mejoría en las características histológicas e histoquímicas de la pythiosis y se mantuvieron iguales al primer día durante todo el estudio. Conclusiones. La acetonida de triamcinolona es una buena alternativa terapéutica en el tratamiento de las heridas granulomatosas por pythiosis en equinos con 100% de recuperación clínica y demostrada con las constataciones histológicas e histoquímicas.

Topical ocular dexamethasone decreases intraocular pressure and body weight in rats.

BACKGROUND: Recently, topical dexamethasone-induced ocular hypertension and a consequent loss of retinal ganglion cells (RGCs) have been described in mice. This has been proposed as a model of steroid-induced glaucoma. In this study, we set up and evaluated a similar model in rats. RESULTS: Ten-week old Sprague Dawley (SD) rats (N = 12) were used to evaluate the effect of topical 0.1% dexamethasone (50 µl) administered 3 times daily for 4 weeks. Sodium chloride (0.9%) was used in another group of rats (N = 12) that served as the controls. After 1 week, we observed a progressive decrease in body weight in the dexamethasone-treated rats compared both to the pre-treatment baseline and the vehicle-treated rats. In contrast to earlier work that showed elevated Intraocular pressure (IOP) following dexamethasone instillation in mice, IOP in the rats unexpectedly fell to 11.3 ± 1.3 mmHg in the treated eyes, compared to 14.8 ± 2.4 mmHg in the untreated eyes, after 3 weeks of topical dexamethasone (P = 0.032). Blood tests performed after 4 weeks of treatment showed a 3.3-fold increase in both plasma cholesterol (P < 0.001) and alanine transaminase (P = 0.019) in the dexamethasone-treated rats compared to the control rats. Meanwhile, topical steroid did not induce changes in either plasma blood glucose or glycated hemoglobin (HbA1c). We also did not detect changes in the expression of RGC markers (with real-time PCR) following the treatment. CONCLUSIONS: In contrast to mice, which previously showed increased IOP following the topical administration of dexamethasone, the rats displayed a paradoxical reduction in IOP following a similar treatment. This was accompanied by a loss of body weight without affecting the level of blood glucose.

Primary hypoadrenocorticism in a dog / Hipoadrenocorticismo primário em um cão / Hipoadrenocorticismo primario en un perro

This report describes the clinical and laboratorial findings as well as the therapeutic protocol performed in a three-year-old mongrel female intact dog, referred to the Veterinary Hospital of FAMEZ/UFMS. The animal had a previous history of recurrent gastrointestinal signs (such as lethargy, vomiting, loss of appetite, melena and abdominal pain), acute crisis episodes, bradycardia, hypotension, hypothermia and increase of capillary refill time, recognized as addisonian crisis due to primary hypoadrenocorticism. Laboratorial findings included anemia, eosinophilia, neutrophilia, lymphocytosis, sodium-potassium ratio of 14,02 mEq/L and prerenal azotemia. Based on that, it was confirmed the diagnosis of primary hypoadrenocorcitism. Thus, it was recommended supplementation therapy with mineralocorticoid (aldosterone) and glucocorticoid (cortisol) corresponding respectively, fludrocortisone acetate of 0.2 mg per kg of BW, by mouth, once daily and prednisone 0.2 mg per kg of BW, by mouth, twice daily until further recommendations. The prognostic was excellent, since the animal significantly improved body condition, andclinical signs disappeared after therapy which lead the sodium-potassium ratio to 35.11 mEq/L. Thus, the clinician must always suspect of primary hypoadrenocorticism in dogs with intermittent nonspecific signs that get better with support therapy. Presumably, hypoarenocorticism must be under diagnosed in veterinary medicine, reinforcing the need to require specific exams in patients that show this wax and wane feature of clinical signs.

O presente relato descreve os achados clínicos, laboratoriais e conduta terapêutica de um animal da espécie canina, fêmea, com três anos de idade, inteiro, sem raça definida, diagnosticado com hipoadrenocorticismo primário atendido no Hospital Veterinário da FAMEZ/UFMS. O animal apresentou histórico de recidivas de sinais gastrintestinais (letargia, vômitos, perda de apetite, melena e dor abdominal), crise adrenal aguda, bradicardia, hipotensão, hipotermia e aumento do tempo de preenchimento capilar. As alterações laboratoriais compreenderam linfocitose, anemia, eosinofilia, neutrofilia, densidade urinária < 1.030, relação sódio: potássio 14,02 mEq/L e azotemia pré-renal. Baseado nos achados clínicos-laboratoriais confirmou-se o hipoadrenocorticismo primário. Em seguida, foi instituído terapia de suplementação de mineralocorticoide (aldosterona) e glicocorticoide (cortisol), correspondendo respectivamente ao acetato de fludrocortisona na dose de 0,2 mg/kg por via oral uma vez ao dia e prednisona 0,2 mg/kg por via oral duas vezes por dia até novas recomendações. O prognóstico foi excelente para este caso, já que houve melhora significativa do animal, com o desaparecimento dos sinais clínicos e com nova relação sódio: potássio de 35,11 mEq/L. Assim, deve-se sempre suspeitar de hipoadrenocorticismo primário canino em pacientes com o curso de aparecimento e desaparecimento com sinais inespecíficos que melhorem com terapia de suporte. Presume-se que o hipoadrenocorticismo primário em cães seja subdiagnosticado na medicina veterinária, por isso a importância dos clínicos em suspeitar e solicitar exames específicos em pacientes que apresentam esse curso da doença.

El informe describe los hallazgos clínicos, de laboratorio y manejo terapéutico de un perro, hembra, con tres años de edad, entera, mestizo, con diagnóstico de hipoadrenocorticismo primario atendido en el Hospital Veterinario de la FAMEZ/UFMS. El animal tuvo un historial de signos gastrointestinales recurrentes (letargia, vómitos, pérdida de apetito, melena y dolor abdominal), crisis renal aguda, bradicardia, hipotensión, hipotermia y un aumento del tiempo de llenado capilar. Las alteraciones de laboratorio presentaron linfocitosis, anemia, eosinofilia, neutrofilia, densidad de la orina < 1,030, relación sodio: potasio 14,02 mEq/L y azotemia prerrenal. Con base en los hallazgos clínicos y de laboratorio, se confirmó el hipoadrenocorticismo primario. A continuación, se introdujo terapia con administración de mineralocorticoide (aldosterona) y glucocorticoide (cortisol), que correspondieron respectivamente al acetato de fludrocortisona a una dosis de 0,2mg/kg por vía oral una vez al día y prednisona 0,2 mg/kg por vía oral dos veces al día hasta nuevas recomendaciones. El pronóstico fue excelente para este caso, ya que hubo mejora significativa del animal, desapareciendo los signos clínicos y con una nueva relación sodio: potasio de 35,11 mEq/L. Por lo tanto, siempre se debe sospechar del hipoadrenocorticismo primario canino en pacientes con el curso de aparecimiento y desaparecimiento con signos inespecíficos que mejoran con terapia de soporte. Es posible que el hipoadrenocorticismo primario en perros sea diagnosticado en la medicina veterinaria, así la importancia de los clínicos en sospechar y solicitar exámenes específicos en pacientes que presentan ese curso de la enfermedad.

Self-perceived health status of patients with adrenal insufficiency receiving glucocorticoid replacement therapy - French data from a worldwide patient survey.

An international survey was undertaken to investigate current practices in glucocorticoid replacement therapy and self-perceived health status of patients with adrenal insufficiency, using a 39-item questionnaire. Results were published in 2012. We analyzed data from French patients, extracted from the database. Participants were recruited via a patient advocacy group to respond anonymously to a questionnaire developed by clinical experts. Ninety-four patients participated (primary adrenal insufficiency 79% and secondary adrenal insufficiency 16%). They were treated mainly with hydrocortisone (97.5%). Dosing regimens were once daily (8%), twice daily (38%), thrice daily (30%) or other (24%). Nearly 80% of the participants considered their affection to have an impact on their physical activity, work, family or social life and 38% reported absence from work/school in the last 3 months. Fatigue in the morning or during the day was a problem for 57% and 69% of respondents respectively. Eighty percent were concerned about long-term side effects of therapy, mainly osteoporosis (79%), fatigue (57%) and obesity (43%). Despite obvious biases in the survey, we should be alerted by the high number of patients' complaints and the clear signs of quality of life impairment in this population, and think about strategies to improve their management.

Pro-inflammatory mediators increase levels of the noncoding RNA GAS5 in airway smooth muscle and epithelial cells.

The long noncoding RNA (lncRNA) GAS5 has been found to act as a decoy for the glucocorticoid receptor (GR), thus implicating GAS5 as a potential regulator of glucocorticoid sensitivity and resistance. Airway smooth muscle (ASM) cells and airway epithelial cells (AEC) play an important role in the pathogenesis and persistence of asthma and other chronic airways diseases. These airway structural cell types are also important cellular targets of the anti-inflammatory actions of glucocorticoids. In this study, we sought to examine the relevance of GAS5 to glucocorticoid sensitivity and resistance in ASM and AEC. We provide the first evidence that pro-inflammatory mediators up-regulate GAS5 levels in both airway epithelial and smooth muscle cells, and that decreasing GAS5 levels can enhance glucocorticoid action in AEC.

Histiocitoma de Células de Langerhans en canino: reporte de caso en Colombia / Langerhans Cell Histiocytoma in canine: a case report in Colombia / Histiocitoma das células de Langerhans em caninos: relato de caso na Colômbia

Resumen Se reporta el caso clínico de un paciente canino de 10 años de edad, macho, mestizo y esterilizado, que llega a la Clínica veterinaria de Antioquia, Medellín Colombia, con una masa de 5 cms de diámetro en la región lateral del prepucio. La masa de forma circular y de consistencia firme, a la evaluación histopatológica correspondió a un histiocitoma de las células de Langerhans. El paciente fue sometido a resección quirúrgica de la masa y tratado posteriormente con cefalexina 25 mg/kg cada 12 horas oral por 1 semana, prednisolona por 20 días y desinfección de la zona con clorhexidina cada 12 horas, además se aplica en la zona dimetilsulfóxido tópico cada 12 horas por 3 semanas. Debido a lo poco descrito este tipo de histiocitoma en dermatología, se considera de valor científico su reporte.

Abstract A 10–year-old crossbred neutered dog was submitted to Clínica Veterinaria de Antioquia (Medellín, Colombia) presenting a firm and circular mass of 5 cm in diameter in the lateral region of the foreskin. After histopathological evaluation, the mass corresponded to a Langerhans cell histiocytoma. The patient underwent surgical resection of the mass and was then treated with cephalexin (25 mg/kg every 12 hours, orally, for 1 week), prednisolone (20 days), disinfection of the area (every 12 hours using chlorhexidine), and applying dimethyl sulfoxide on the area (every 12 hours for 3 weeks). We consider this report has a scientific value because this type of histiocytoma is rarely described in dermatology.

Resumo Relatar o caso clínico de um paciente canino de 10 anos de idade, macho, mestiço e esterilizado, que chegou a Clínica Veterinária de Antioquia, Medellín, Colômbia, com uma massa de 5 cm de diâmetro na região lateral do prepúcio, a massa era de forma circular e de consistência firme, na avaliação histopatológica revelou-se um histiocitoma das células de Langerhans, o paciente foi submetido a resseção cirúrgica da massa e tratado posteriormente com cefalexina 25 mg/kg a cada 12 horas oral durante uma semana, prednisolona por 20 dias e desinfecção da região com clorexidina a cada 12 horas, além disto, se aplicou na região afetada dimetilsulfóxido tópico a cada 12 horas durante três semanas. Devido as poucas referencias escritas deste tipo de histiocitoma em dermatologia, considera-se de valor cientifico seu relato.