Objectives: To explore the pain mechanism and the origin of the pain and to evaluate a short-term pain relief treatment in women suffering from CPP persisting after childbirth in order to enable physiotherapeutic intervention. Material and methods: Thirty-six parous women with chronic pelvic pain persisting after childbirth were recruited at the Department of Physiotherapy, SundsvallHospital and by advertisements in newspapers and 29 parous women without chronic pelvic pain were recruited from an organized gynaecological screening at a midwifery surgery. All women were provoked by intra-pelvic palpation of 13 predetermined intra-pelvic landmarks. The provoked pain distribution was expressed in pain drawings and the pain intensity verbally on a Likert scale.Also, in a randomised controlled trial the 36 women with chronic pelvic pain were allocated to bilateral injection treatment with either triamcinolone or saline solutions, given once on the ischial spine with follow-up after four weeks. Results: Referred pain provoked on intra-pelvic landmarks follows a specific pattern. In general, pain provoked by palpation of the posterior intra-pelvic landmarks was mostly referred to the sacral region and pain provoked by palpation of the ischial and pubic bones was mostly referred to the groin and pubic regions. In women with chronic pelvic pain the provoked pain distribution area and pain intensity were magnified as compared to women without chronic pelvic pain. In the clinical trial decreased pain intensity, decreased distribution of pain and improved physical function was achieved among the triamcinolone treatment group as compared to the saline treatment group. Also, a positive correlation was shown between reduced pain intensity and improved function. Conclusions: Referred pain patterns provoked on intra-pelvic landmarks in women with chronic pelvic pain persisting after childbirth are consistent with sclerotomal sensory innervations and indicates allodynia and central sensitisation. This suggests that pain mapping can be used to evaluate and confirm the pain experience and contribute to diagnosis. Also, the pain intensity provoked by stimulation of the intra-pelvic landmarks is suggested to be useful to differentiate women with chronic pelvic pain from those without. Corticosteroid treatment to the ischial spine resulted in decreased pain and increased function.

Introdução: A bronquiolite aguda é a principal causa de internação de lactentes menores de um ano de idade e tem como principal agente etiológico o vírus sincicial respiratório. As principais diretrizes baseadas em evidências recomendam o tratamento de suporte com hidratação e oxigenoterapia, quando necessário e não indicam o uso rotineiro de corticosteroides, broncodilatadores e antibióticos. No entanto, estudos anteriores mostraram que o uso inadvertido dessas medicações é frequente na prática clínica. Objetivo: Analisar o tratamento aplicado a lactentes com bronquiolite viral aguda em um hospital público e compará-lo a diretrizes nacionais e internacionais. Casuística e métodos: Foi realizado um estudo observacional, transversal, descritivo e analítico que incluiu crianças menores de 2 anos, internadas no Hospital do Servidor Público Estadual durante dois anos (2012 - 2014), com primeiro episódio de sibilância e que tiveram coletado aspirado de nasofaringe, para pesquisa de vírus sincicial respiratório na admissão. Foram excluídos os lactentes com fatores de risco conhecidos para desenvolver doença grave. As informações foram coletadas dos prontuários e por contato telefônico com os responsáveis. Resultados: Dentre os 129 pacientes com resultado positivo para a pesquisa do vírus sincicial respiratório, 7 foram excluídos por apresentarem alguma comorbidade ou fator de risco prognóstico e 2 não tiveram o seus prontuários encontrados. A idade média, dos 120 estudados, foi de 6,8 meses e 51,6% foram do sexo feminino. Broncodilatadores, corticosteroides, antibióticos e inalação com solução salina hipertônica foram prescritos, durante a internação, a 90%, 72,5%, 40% e 66,7% dos casos, respectivamente. O uso dessas medicações foi excessivo e não compatível com as diretrizes, exceto o uso de solução salina hipertônica inalatória que esteve em acordo com a recomendação da Sociedade Brasileira de Pediatria. Após ajuste para confundidores, a chance de prescrição de antibióticos foi menor em menores de 3 meses (OR=0,21, p= 0,007) e também associada à presença de febre na admissão (OR=3, p = 0,013) e maior tempo de internação (OR=2,53, p= 0,003). A introdução de oxigênio suplementar apresentou associação com maior tempo de internação (OR=12,9, p < 0,001). Os lactentes com idade abaixo de 3 meses tiveram menor chance de prescrição de corticosteroides (OR=0,67, p < 0,001) que também foi associada à saturação menor que 95% no momento da admissão (OR=3,17, p= 0,037) e ao maior tempo de internação. O uso de solução salina hipertônica também foi associado ao maior tempo de internação (OR=3,07, p < 0,001). Conclusão: Em lactentes hospitalizados em um hospital público, o uso de antibióticos, corticosteroides e broncodilatadores para tratamento da bronquiolite aguda foi elevado. Essas condutas não seguiram as recomendações das principais diretrizes nacionais e internacionais. O uso de solução salina hipertônica inalatória seguiu a diretriz da Sociedade Brasileira de Pediatria / Background: Acute bronchiolitis is the main cause of hospitalization of infants under one year of age and has respiratory syncytial virus as the main etiological agent. The main evidence-based guidelines recommend hydration and oxygen therapy support when necessary and do not indicate the routine use of corticosteroids, bronchodilators and antibiotics. However, previous studies have shown that inadvertent use of these medications is common in clinical practice. Objective: To analyze the treatment of infants with acute viral bronchiolitis in a public hospital and to compare it with national and international guidelines. Patients and methods: An observational, transversal, descriptive and analytical study was carried out, including children under 2 years of age, hospitalized between two years (2012 - 2014), with first episode of wheezing and nasopharyngeal test for respiratory syncytial virus on admission. Infants with known risk factors for developing severe disease were excluded. The information was collected from the medical records and by telephone contact with those parents. Result: Of the 129 patients with a positive test for respiratory syncytial virus, 7 were excluded because they presented some comorbidity or a prognostic risk factor, and 2 did not have their charts found. The mean age of the 120 studied was 6.8 months and 51.6% were female. Bronchodilators, corticosteroids, antibiotics and nebulised hypertonic saline were prescribed, during hospitalization, at 90%, 72.5%, 40% and 66.7% of the cases, respectively. The use of these medications was excessive and not compatible with the guidelines, except the use of nebulised hypertonic saline that was in agreement with the recommendation of the Brazilian Society of Pediatrics. After adjusting for confounders, the chance of antibiotic prescription was lower in children younger than 3 months (OR = 0.21, p = 0.007) and also associated with the presence of fever at admission (OR = 3, p = 0.013) and a longer stay (OR = 2.53, p = 0.003). The introduction of supplemental oxygen showed an association with longer hospitalization (OR = 12.9, p < 0.001). Infants less than 3 months of age had a lower chance of prescribing corticosteroids (OR = 0.67, p < 0.001), which was also associated with a saturation of less than 95% on admission (OR = 3.17, p = 0.037 ) and longer hospitalization time. The use of nebulised hypertonic saline was also associated with longer length of stay (OR = 3.07, p < 0.001). Conclusion: In infants hospitalized in a public hospital, the use of antibiotics, corticosteroids and bronchodilators to treat acute bronchiolitis was high. These conducts did not follow the recommendations of the main national and international guidelines. The use of nebulised hypertonic saline followed the guideline of the Brazilian Society of Pediatrics

PILEGGI, F.O. Análise do nível do cortisol salivar em crianças portadoras de fimose e tratadas com corticóide tópico. 2008. 60 f. Tese (Doutorado) Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 2008. O tratamento da fimose, apesar de muita controvérsia, tem como primeira escolha o uso de corticóide, topicamente e se realiza a postectomia apenas se existe falha do tratamento clínico. Os bons resultados relatados em diversos trabalhos publicados na literatura médica, desencadeou o uso indiscriminadamente, em vários ciclos, por prolongados períodos, sem orientação correta da higiene prepucial. O uso prolongado do corticóide ocasiona efeitos adversos tanto locais como sistêmicos, e a absorção desse corticóide, utilizado em pequenas dosagens, aplicado topicamente, ainda não foi bem esclarecida. Alguns trabalhos citam a ausência de efeitos adversos locais, alguns estudos mostram a absorção, mas sem estudar a supressão do eixo hipotálamo-hipófise-adrenal (H-H-A) (Kelly, Cains et al., 1991; Golubovic, Milanovic et al., 1996; Yanagisawa, Baba et al., 2000). Para analisar a absorção do corticóide, no tratamento tópico do anel fimótico, 31 crianças foram submetidas à coleta do cortisol salivar basal, às 9h, e em 10 destas crianças realizaram-se coletas às 9h e 23h, a fim de observar o ritmo circadiano e, também, para distinguir cortisol endógeno do exógeno. As dosagens do cortisol salivar variaram de 60 a 3790 ng/dl e não houve diferença (p=0,85), entre o período antes e após o tratamento, porém, apesar do teste estatístico não mostrar diferença, 2 crianças apresentaram supressão do eixo H-H-A, sugerindo que este tratamento não é inócuo. Pode-se então, concluir que o tratamento clínico da fimose, com aplicação de corticóide duas vezes ao dia, durante oito semanas é seguro, desde que a dosagem do cortisol salivar basal seja feito, para se obter um valor de referência, quando o tratamento for repetido ou prolongado por mais que duas semanas e necessitar de um controle. Palavras-chave: fimose, cortisol salivar, corticóide tópico, tratamento conservador, proprionato de clobetasol. / PILEGGI, F.O. Analysis of the level of salivary cortisol in children carryng of phimosis and treated with corticosteroid topical. 2008. 60 f. Thesis (Doctoral) Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 2008. Phimosis has always been the reason of much discussion. Currently, the use of topical steroid is a well established alternative that is indicated in great number of cases. Since good results has been showed in the literature an indiscriminate use of topical steroid has been observed with long and repeated cycles. The local absorption of low doses of topical steroid is still not well understood. Reports in the medical literature show that prolonged use of topical steroid can cause local and/or systemic adverse effects. (Kelly, Cains et al., 1991; Golubovic, Milanovic et al., 1996; Yanagisawa, Baba et al., 2000) Concerned with this, we analysed the absorption of clobetasol in the topical treatment of the phimotic ring. Thirty-one children were submitted to the dosage of salivary cortisol was done prior and after treatment at 9 oclock AM, and in 10 of these children at 9 AM and 11 PM, in order to observe the circadian rhythm and also differentiate endogenous from exogenous cortisol. Salivary cortisol values varied from 60 to 3790 ng/dl no statistical test of Wilcoxon (p=0,82). Although the values of prior and after treatment were similar we cannot state that the treatment is completely harmless due 2 children that presented dosages showing the suppression of axle hypothalamic- hypophysis- adrenal (H-H-A). In conclusion, the clinical treatment of phimosis with topical clobetasol, twice a day during 8 weeks is safe, however we suggest that dosage of cortisol should be done before and during the treatment when a prolonged treatment is proposed. Keywords: phimosis, salivary cortisol, topical corticosteroid, conservative treatment, clobetasol proprionate.

Introdução: A bronquiolite aguda é a principal causa de internação de lactentes menores de um ano de idade e tem como principal agente etiológico o vírus sincicial respiratório. As principais diretrizes baseadas em evidências recomendam o tratamento de suporte com hidratação e oxigenoterapia, quando necessário e não indicam o uso rotineiro de corticosteroides, broncodilatadores e antibióticos. No entanto, estudos anteriores mostraram que o uso inadvertido dessas medicações é frequente na prática clínica. Objetivo: Analisar o tratamento aplicado a lactentes com bronquiolite viral aguda em um hospital público e compará-lo a diretrizes nacionais e internacionais. Casuística e métodos: Foi realizado um estudo observacional, transversal, descritivo e analítico que incluiu crianças menores de 2 anos, internadas no Hospital do Servidor Público Estadual durante dois anos (2012 - 2014), com primeiro episódio de sibilância e que tiveram coletado aspirado de nasofaringe, para pesquisa de vírus sincicial respiratório na admissão. Foram excluídos os lactentes com fatores de risco conhecidos para desenvolver doença grave. As informações foram coletadas dos prontuários e por contato telefônico com os responsáveis. Resultados: Dentre os 129 pacientes com resultado positivo para a pesquisa do vírus sincicial respiratório, 7 foram excluídos por apresentarem alguma comorbidade ou fator de risco prognóstico e 2 não tiveram o seus prontuários encontrados. A idade média, dos 120 estudados, foi de 6,8 meses e 51,6% foram do sexo feminino. Broncodilatadores, corticosteroides, antibióticos e inalação com solução salina hipertônica foram prescritos, durante a internação, a 90%, 72,5%, 40% e 66,7% dos casos, respectivamente. O uso dessas medicações foi excessivo e não compatível com as diretrizes, exceto o uso de solução salina hipertônica inalatória que esteve em acordo com a recomendação da Sociedade Brasileira de Pediatria. Após ajuste para confundidores, a chance de prescrição de antibióticos foi menor em menores de 3 meses (OR=0,21, p= 0,007) e também associada à presença de febre na admissão (OR=3, p = 0,013) e maior tempo de internação (OR=2,53, p= 0,003). A introdução de oxigênio suplementar apresentou associação com maior tempo de internação (OR=12,9, p < 0,001). Os lactentes com idade abaixo de 3 meses tiveram menor chance de prescrição de corticosteroides (OR=0,67, p < 0,001) que também foi associada à saturação menor que 95% no momento da admissão (OR=3,17, p= 0,037) e ao maior tempo de internação. O uso de solução salina hipertônica também foi associado ao maior tempo de internação (OR=3,07, p < 0,001). Conclusão: Em lactentes hospitalizados em um hospital público, o uso de antibióticos, corticosteroides e broncodilatadores para tratamento da bronquiolite aguda foi elevado. Essas condutas não seguiram as recomendações das principais diretrizes nacionais e internacionais. O uso de solução salina hipertônica inalatória seguiu a diretriz da Sociedade Brasileira de Pediatria / Background: Acute bronchiolitis is the main cause of hospitalization of infants under one year of age and has respiratory syncytial virus as the main etiological agent. The main evidence-based guidelines recommend hydration and oxygen therapy support when necessary and do not indicate the routine use of corticosteroids, bronchodilators and antibiotics. However, previous studies have shown that inadvertent use of these medications is common in clinical practice. Objective: To analyze the treatment of infants with acute viral bronchiolitis in a public hospital and to compare it with national and international guidelines. Patients and methods: An observational, transversal, descriptive and analytical study was carried out, including children under 2 years of age, hospitalized between two years (2012 - 2014), with first episode of wheezing and nasopharyngeal test for respiratory syncytial virus on admission. Infants with known risk factors for developing severe disease were excluded. The information was collected from the medical records and by telephone contact with those parents. Result: Of the 129 patients with a positive test for respiratory syncytial virus, 7 were excluded because they presented some comorbidity or a prognostic risk factor, and 2 did not have their charts found. The mean age of the 120 studied was 6.8 months and 51.6% were female. Bronchodilators, corticosteroids, antibiotics and nebulised hypertonic saline were prescribed, during hospitalization, at 90%, 72.5%, 40% and 66.7% of the cases, respectively. The use of these medications was excessive and not compatible with the guidelines, except the use of nebulised hypertonic saline that was in agreement with the recommendation of the Brazilian Society of Pediatrics. After adjusting for confounders, the chance of antibiotic prescription was lower in children younger than 3 months (OR = 0.21, p = 0.007) and also associated with the presence of fever at admission (OR = 3, p = 0.013) and a longer stay (OR = 2.53, p = 0.003). The introduction of supplemental oxygen showed an association with longer hospitalization (OR = 12.9, p < 0.001). Infants less than 3 months of age had a lower chance of prescribing corticosteroids (OR = 0.67, p < 0.001), which was also associated with a saturation of less than 95% on admission (OR = 3.17, p = 0.037 ) and longer hospitalization time. The use of nebulised hypertonic saline was also associated with longer length of stay (OR = 3.07, p < 0.001). Conclusion: In infants hospitalized in a public hospital, the use of antibiotics, corticosteroids and bronchodilators to treat acute bronchiolitis was high. These conducts did not follow the recommendations of the main national and international guidelines. The use of nebulised hypertonic saline followed the guideline of the Brazilian Society of Pediatrics

Submitted by Cristiane Chim (cristiane.chim@ucpel.edu.br) on 2018-09-17T11:58:26Z No. of bitstreams: 1 Esther Gonçalves de Souza e Silva Ballester.pdf: 1253998 bytes, checksum: dec0a6b4df41e79f23faed68b5338063 (MD5) / Made available in DSpace on 2018-09-17T11:58:26Z (GMT). No. of bitstreams: 1 Esther Gonçalves de Souza e Silva Ballester.pdf: 1253998 bytes, checksum: dec0a6b4df41e79f23faed68b5338063 (MD5) Previous issue date: 2018-06-19 / Introduction: Glucocorticoids have a well-known effect on fetal lung maturation and are recommended in pregnancies at risk of preterm birth. However, the application of corticoid causes immediate glycemic change and, for this reason, we must be very careful with its use in diabetic patients. Objective: The objective of this study was to compare the glycemic changes after the use of corticosteroids for fetal pulmonary maturation in diabetic and non-diabetic pregnant women. Among diabetics, compare diabetic patients with gestational diabetes. Methods: A longitudinal study was performed with pregnant women hospitalized at the School Hospital of the Federal University of Pelotas (HE-UFPel) who received two doses of betamethasone 12mg intramuscularly, with a 24-hour interval. These pregnant women were submitted to glycemic control immediately before the first dose and after, every 12 hours for 48 hours. Results: The total sample consisted of 44 pregnant women, of which 22 were diabetic, 22 were non-diabetic. The mean blood glucose was significantly higher among diabetics, with the peak being 24 hours after the first dose. Among diabetics, the mean was higher in patients with previous diabetes Conclusion: Betamethasone for fetal lung maturation causes hyperglycemia, especially in patients with previous diabetes mellitus, but this alteration can also be observed in patients without diabetes. Therefore, we suggest that all patients receiving corticotherapy for fetal pulmonary maturation should be submitted to glycemic 9 control and correction of blood glucose if necessary, reducing the risk of hyperglycemia. / Introdução: Os glicocorticoides têm sua ação bem conhecida no amadurecimento pulmonar fetal, sendo recomendados em gestações com risco de parto prematuro. No entanto, a aplicação do corticoide provoca alteração glicêmica imediata e, por este motivo, devemos ter muito cuidado com seu uso em pacientes diabéticas. Objetivo: O objetivo deste estudo foi comparar as alterações glicêmicas após o uso de corticoterapia para maturação pulmonar fetal em gestantes diabéticas e não diabéticas. Entre as diabéticas, comparar as pacientes diabéticas prévias com as diabéticas gestacionais. Métodos: Estudo longitudinal com gestantes internadas no Hospital Escola da Universidade Federal de Pelotas (HE-UFPel) que receberam duas doses de betametasona 12mg, por via intramuscular, com intervalo de 24 horas. Estas gestantes foram submetidas a controle glicêmico por hemoglicoteste (HGT) imediatamente antes da primeira dose e após, de 12 em 12 horas por 48 horas. Resultados: O total da amostra foi de 44 gestantes, sendo 22 diabéticas, 22 não diabéticas. As médias de HGT foram significativamente maiores entre as diabéticas, sendo o pico nas 24h após a primeira dose. Entre as diabéticas, a média foi maior nas diabéticas prévias. Conclusão: A betametasona realizada para amadurecimento pulmonar fetal provoca hiperglicemia, principalmente nas pacientes com diabetes mellitus prévio, porém essa alteração também pode ser observada nas pacientes sem diabetes. Sendo assim, sugere-se que todas pacientes que receberem corticoterapia para amadurecimento 7 pulmonar fetal sejam submetidas a controle glicêmico, e correção da glicemia caso necessário, diminuindo os riscos de eventual hiperglicemia.

Cortisol, the principal glucocorticoid secreted from the adrenal glands, is essential for life. Healthy cortisol levels are maintained through negative feedback on the central nervous system (CNS) – pituitary stimulatory apparatus which regulates production of adrenocorticotropin (ACTH) and contains a light–entrained intrinsic CNS driven diurnal rhythm. Cortisol participates in a regulatory mechanism where inflammatory cytokines stimulate cortisol release and cortisol in turn suppresses cytokine release. The effects of cortisol in inflammatory states include elevating blood pressure and metabolic regulation. This thesis contains three exploratory studies examining circulating cortisolaemia using the best available methodologies (total and free cortisol and corticosteroid-binding globulin (CBG)) in clinical states characterized by immune activation/ inflammation and altered blood pressure. These clinical states include: (1) septic shock, (2) hypertensive disorders of pregnancy and (3) obesity-induced hypertension. Prior to the studies described here, little was know about cortisolaemia in these common pathological states. Septic shock is a life threatening condition that complicates severe infection and is characterized by systemic inflammation and refractory hypotension. High plasma total cortisol levels and attenuated responses to synthetic ACTH stimulation are associated with increased mortality. The use of corticosteroids in septic shock has been highly controversial for decades, however recent trials have reported haemodynamic and survival benefits associated with the use of physiologic steroid replacement in patients with relative adrenal insufficiency (RAI) – currently defined as a total cortisol increment of 248 nmol/L or less following ACTH (250 μg) stimulation. However, CBG and albumin levels fall by around 50% with an increase in plasma free cortisol in critical illness. Hence, total cortisol may not reflect the biologically active free (unbound) cortisol, suggesting that standard assays for plasma cortisol (which measure total plasma cortisol) underestimate HPA axis activity. In this study, we have showed that plasma free cortisol is a better guide to circulating glucocorticoid activity in systemic infection than total cortisol. We have also validated the use of Coolens’ method in estimating free cortisol in systemic infection, using plasma total cortisol and CBG measurements as plasma free cortisol is not performed in clinical laboratories. Free cortisol measurement allows better categorization of RAI and non-RAI groups with a free cortisol increment of 110 nmol/L as cut-off. Moreover, we have shown that survivors of RAI have normal adrenocortical function on follow-up testing suggesting a lack of functional adrenal reserve rather than adrenal damage during critical illness. Larger randomized controlled trials will be required to redefine RAI using free cortisol measurements and relate that to clinical outcomes and responses to corticosteroid therapy. Nitric oxide (NO) is normally produced in the endothelium by the constitutive form of the NO synthase and this physiologic production is important for blood pressure regulation and blood flow distribution. Studies have shown that an overproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Clinical studies of non-selective inhibitors of the L-arginine nitric oxide pathway showed increased mortality from cardiovascular complications. However, glucocorticoids, which improve vasopressor sensitivity, may act by partially suppressing NO synthesis through selective direct inhibition of iNOS, and suppression of inflammatory cytokine synthesis. Hence, plasma nitrate/ nitrite (NOx) levels may provide a titratable end point to individualize glucocorticoid therapy in sepsis. The NOx study in this thesis showed that cortisol (total and free), CBG and NOx correlated to illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx levels, predicted septic shock. NOx levels were characteristically stable within individuals but inter-individual differences were only partly accounted for by illness severity or renal dysfunction. NOx levels correlated weakly with cortisol, did not relate to the need for vasopressors and were not suppressed by hydrocortisone treatment. Thus, NOx is not a suitable target for glucocorticoid therapy in septic shock. Pregnancy is the only sustained physiologic state of hypercortisolism in humans. A large body of data suggests that excessive foetal and prenatal glucocorticoid exposure leads to reduced birth weight and adverse health in offspring such as elevated blood pressure and insulin resistance. Pre-eclampsia and gamete donor pregnancies are associated with immune activation, elevated inflammatory cytokines as well as elevated blood pressure. Prior to the study described in this thesis however, there was no prospective data on maternal cortisolaemia in these complicated pregnancies. My study has demonstrated for the first time that there was a substantial fall in plasma CBG levels in the last few weeks of gestation with a corresponding rise in free cortisol in normal pregnancy, a finding obscured for methodological reasons in past studies. This free cortisol elevation in late pregnancy may facilitate organ maturation in the foetus and perhaps prepare the mother for the metabolic demands of labour. In pre-eclampsia and gestational hypertension, plasma CBG, total and free cortisol levels were lower in late third trimester; and in IUGR, plasma CBG levels were suppressed from 28 weeks gestation until delivery but with no significant difference in plasma total and free cortisol. Women with assisted reproduction using donor gametes/ embryos had significantly lower plasma CBG, total and free cortisol levels even in those with normal pregnancy outcomes. Low CBG may be due to reduced synthesis or enhanced inflammation-driven degradation. Low maternal cortisol may be due to a lack of placental corticotropin-releasing hormone, or reduced maternal ACTH, driving cortisol production. This unanticipated maternal hypocortisolism in complicated pregnancies may trigger precocious activation of the foetal HPA axis and could have implications for postnatal and adult health. Speculatively, since excess prenatal GCs increase HPA axis activity, we proposed that maternal hypocortisolism may predispose to the hypocortisolaemic state characterized by fatigue, pain and stress sensitivity, in offspring. The third state of immune/ inflammatory activation associated with blood pressure dysregulation studied in this thesis is obesity. The epidemiologic relationship between obesity and hypertension is widely recognised. Central obesity in particular has been associated with exaggerated HPA responses to stimuli. Studies of severe dieting and starvation resulted in hypercortisolism and a significant decrease in CBG. The HPA axis and the renin-angiotensin-aldosterone system (RAAS) have been implicated in the pathophysiology of obesity-induced hypertension. However, there is little data on the effect of moderate weight loss (30% caloric restriction) on adrenocortical function, and the relation of adrenal hormones to altered blood pressure with weight loss. In this study, measures of HPA axis and RAAS and blood pressure monitoring were performed in twenty-five obese subjects before and after a 12-week diet program (6000kJ/day). Short-term, moderate weight loss (mean 8.5 kg) was associated with a small reduction in blood pressure (mean arterial pressure 6 mmHg) and significantly reduced levels of aldosterone and renin but not cortisol levels. These findings suggest that aldosterone may have an important role in the blood pressure reduction with weight loss via a renin mediated mechanism, perhaps involving renal sympathetic tone. In contrast to severe caloric restriction, HPA axis activation does not occur with moderate weight loss. This suggests a threshold effect of weight loss on the HPA axis where greater caloric restriction is required for HPA stimulation, or a counterbalancing of central and direct adrenal effects on HPA axis function. Overall, these three exploratory studies have provided novel data on HPA axis function in systemic infection, pregnancy and in diet-induced weight loss. Each study offers a basis for further studies of HPA axis function in these disorders. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1289330 / Thesis(Ph.D.)-- School of Medicine, 2007.

Cortisol, the principal glucocorticoid secreted from the adrenal glands, is essential for life. Healthy cortisol levels are maintained through negative feedback on the central nervous system (CNS) – pituitary stimulatory apparatus which regulates production of adrenocorticotropin (ACTH) and contains a light–entrained intrinsic CNS driven diurnal rhythm. Cortisol participates in a regulatory mechanism where inflammatory cytokines stimulate cortisol release and cortisol in turn suppresses cytokine release. The effects of cortisol in inflammatory states include elevating blood pressure and metabolic regulation. This thesis contains three exploratory studies examining circulating cortisolaemia using the best available methodologies (total and free cortisol and corticosteroid-binding globulin (CBG)) in clinical states characterized by immune activation/ inflammation and altered blood pressure. These clinical states include: (1) septic shock, (2) hypertensive disorders of pregnancy and (3) obesity-induced hypertension. Prior to the studies described here, little was know about cortisolaemia in these common pathological states. Septic shock is a life threatening condition that complicates severe infection and is characterized by systemic inflammation and refractory hypotension. High plasma total cortisol levels and attenuated responses to synthetic ACTH stimulation are associated with increased mortality. The use of corticosteroids in septic shock has been highly controversial for decades, however recent trials have reported haemodynamic and survival benefits associated with the use of physiologic steroid replacement in patients with relative adrenal insufficiency (RAI) – currently defined as a total cortisol increment of 248 nmol/L or less following ACTH (250 μg) stimulation. However, CBG and albumin levels fall by around 50% with an increase in plasma free cortisol in critical illness. Hence, total cortisol may not reflect the biologically active free (unbound) cortisol, suggesting that standard assays for plasma cortisol (which measure total plasma cortisol) underestimate HPA axis activity. In this study, we have showed that plasma free cortisol is a better guide to circulating glucocorticoid activity in systemic infection than total cortisol. We have also validated the use of Coolens’ method in estimating free cortisol in systemic infection, using plasma total cortisol and CBG measurements as plasma free cortisol is not performed in clinical laboratories. Free cortisol measurement allows better categorization of RAI and non-RAI groups with a free cortisol increment of 110 nmol/L as cut-off. Moreover, we have shown that survivors of RAI have normal adrenocortical function on follow-up testing suggesting a lack of functional adrenal reserve rather than adrenal damage during critical illness. Larger randomized controlled trials will be required to redefine RAI using free cortisol measurements and relate that to clinical outcomes and responses to corticosteroid therapy. Nitric oxide (NO) is normally produced in the endothelium by the constitutive form of the NO synthase and this physiologic production is important for blood pressure regulation and blood flow distribution. Studies have shown that an overproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Clinical studies of non-selective inhibitors of the L-arginine nitric oxide pathway showed increased mortality from cardiovascular complications. However, glucocorticoids, which improve vasopressor sensitivity, may act by partially suppressing NO synthesis through selective direct inhibition of iNOS, and suppression of inflammatory cytokine synthesis. Hence, plasma nitrate/ nitrite (NOx) levels may provide a titratable end point to individualize glucocorticoid therapy in sepsis. The NOx study in this thesis showed that cortisol (total and free), CBG and NOx correlated to illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx levels, predicted septic shock. NOx levels were characteristically stable within individuals but inter-individual differences were only partly accounted for by illness severity or renal dysfunction. NOx levels correlated weakly with cortisol, did not relate to the need for vasopressors and were not suppressed by hydrocortisone treatment. Thus, NOx is not a suitable target for glucocorticoid therapy in septic shock. Pregnancy is the only sustained physiologic state of hypercortisolism in humans. A large body of data suggests that excessive foetal and prenatal glucocorticoid exposure leads to reduced birth weight and adverse health in offspring such as elevated blood pressure and insulin resistance. Pre-eclampsia and gamete donor pregnancies are associated with immune activation, elevated inflammatory cytokines as well as elevated blood pressure. Prior to the study described in this thesis however, there was no prospective data on maternal cortisolaemia in these complicated pregnancies. My study has demonstrated for the first time that there was a substantial fall in plasma CBG levels in the last few weeks of gestation with a corresponding rise in free cortisol in normal pregnancy, a finding obscured for methodological reasons in past studies. This free cortisol elevation in late pregnancy may facilitate organ maturation in the foetus and perhaps prepare the mother for the metabolic demands of labour. In pre-eclampsia and gestational hypertension, plasma CBG, total and free cortisol levels were lower in late third trimester; and in IUGR, plasma CBG levels were suppressed from 28 weeks gestation until delivery but with no significant difference in plasma total and free cortisol. Women with assisted reproduction using donor gametes/ embryos had significantly lower plasma CBG, total and free cortisol levels even in those with normal pregnancy outcomes. Low CBG may be due to reduced synthesis or enhanced inflammation-driven degradation. Low maternal cortisol may be due to a lack of placental corticotropin-releasing hormone, or reduced maternal ACTH, driving cortisol production. This unanticipated maternal hypocortisolism in complicated pregnancies may trigger precocious activation of the foetal HPA axis and could have implications for postnatal and adult health. Speculatively, since excess prenatal GCs increase HPA axis activity, we proposed that maternal hypocortisolism may predispose to the hypocortisolaemic state characterized by fatigue, pain and stress sensitivity, in offspring. The third state of immune/ inflammatory activation associated with blood pressure dysregulation studied in this thesis is obesity. The epidemiologic relationship between obesity and hypertension is widely recognised. Central obesity in particular has been associated with exaggerated HPA responses to stimuli. Studies of severe dieting and starvation resulted in hypercortisolism and a significant decrease in CBG. The HPA axis and the renin-angiotensin-aldosterone system (RAAS) have been implicated in the pathophysiology of obesity-induced hypertension. However, there is little data on the effect of moderate weight loss (30% caloric restriction) on adrenocortical function, and the relation of adrenal hormones to altered blood pressure with weight loss. In this study, measures of HPA axis and RAAS and blood pressure monitoring were performed in twenty-five obese subjects before and after a 12-week diet program (6000kJ/day). Short-term, moderate weight loss (mean 8.5 kg) was associated with a small reduction in blood pressure (mean arterial pressure 6 mmHg) and significantly reduced levels of aldosterone and renin but not cortisol levels. These findings suggest that aldosterone may have an important role in the blood pressure reduction with weight loss via a renin mediated mechanism, perhaps involving renal sympathetic tone. In contrast to severe caloric restriction, HPA axis activation does not occur with moderate weight loss. This suggests a threshold effect of weight loss on the HPA axis where greater caloric restriction is required for HPA stimulation, or a counterbalancing of central and direct adrenal effects on HPA axis function. Overall, these three exploratory studies have provided novel data on HPA axis function in systemic infection, pregnancy and in diet-induced weight loss. Each study offers a basis for further studies of HPA axis function in these disorders. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1289330 / Thesis(Ph.D.)-- School of Medicine, 2007.

PILEGGI, F.O. Análise do nível do cortisol salivar em crianças portadoras de fimose e tratadas com corticóide tópico. 2008. 60 f. Tese (Doutorado) Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 2008. O tratamento da fimose, apesar de muita controvérsia, tem como primeira escolha o uso de corticóide, topicamente e se realiza a postectomia apenas se existe falha do tratamento clínico. Os bons resultados relatados em diversos trabalhos publicados na literatura médica, desencadeou o uso indiscriminadamente, em vários ciclos, por prolongados períodos, sem orientação correta da higiene prepucial. O uso prolongado do corticóide ocasiona efeitos adversos tanto locais como sistêmicos, e a absorção desse corticóide, utilizado em pequenas dosagens, aplicado topicamente, ainda não foi bem esclarecida. Alguns trabalhos citam a ausência de efeitos adversos locais, alguns estudos mostram a absorção, mas sem estudar a supressão do eixo hipotálamo-hipófise-adrenal (H-H-A) (Kelly, Cains et al., 1991; Golubovic, Milanovic et al., 1996; Yanagisawa, Baba et al., 2000). Para analisar a absorção do corticóide, no tratamento tópico do anel fimótico, 31 crianças foram submetidas à coleta do cortisol salivar basal, às 9h, e em 10 destas crianças realizaram-se coletas às 9h e 23h, a fim de observar o ritmo circadiano e, também, para distinguir cortisol endógeno do exógeno. As dosagens do cortisol salivar variaram de 60 a 3790 ng/dl e não houve diferença (p=0,85), entre o período antes e após o tratamento, porém, apesar do teste estatístico não mostrar diferença, 2 crianças apresentaram supressão do eixo H-H-A, sugerindo que este tratamento não é inócuo. Pode-se então, concluir que o tratamento clínico da fimose, com aplicação de corticóide duas vezes ao dia, durante oito semanas é seguro, desde que a dosagem do cortisol salivar basal seja feito, para se obter um valor de referência, quando o tratamento for repetido ou prolongado por mais que duas semanas e necessitar de um controle. Palavras-chave: fimose, cortisol salivar, corticóide tópico, tratamento conservador, proprionato de clobetasol. / PILEGGI, F.O. Analysis of the level of salivary cortisol in children carryng of phimosis and treated with corticosteroid topical. 2008. 60 f. Thesis (Doctoral) Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 2008. Phimosis has always been the reason of much discussion. Currently, the use of topical steroid is a well established alternative that is indicated in great number of cases. Since good results has been showed in the literature an indiscriminate use of topical steroid has been observed with long and repeated cycles. The local absorption of low doses of topical steroid is still not well understood. Reports in the medical literature show that prolonged use of topical steroid can cause local and/or systemic adverse effects. (Kelly, Cains et al., 1991; Golubovic, Milanovic et al., 1996; Yanagisawa, Baba et al., 2000) Concerned with this, we analysed the absorption of clobetasol in the topical treatment of the phimotic ring. Thirty-one children were submitted to the dosage of salivary cortisol was done prior and after treatment at 9 oclock AM, and in 10 of these children at 9 AM and 11 PM, in order to observe the circadian rhythm and also differentiate endogenous from exogenous cortisol. Salivary cortisol values varied from 60 to 3790 ng/dl no statistical test of Wilcoxon (p=0,82). Although the values of prior and after treatment were similar we cannot state that the treatment is completely harmless due 2 children that presented dosages showing the suppression of axle hypothalamic- hypophysis- adrenal (H-H-A). In conclusion, the clinical treatment of phimosis with topical clobetasol, twice a day during 8 weeks is safe, however we suggest that dosage of cortisol should be done before and during the treatment when a prolonged treatment is proposed. Keywords: phimosis, salivary cortisol, topical corticosteroid, conservative treatment, clobetasol proprionate.

Abstract The aim of this work was to describe the clinical features and clinical course of Henoch-Schönlein purpura (HSP) in a prospective setting, to compare the efficacy of cyclosporine A (CyA) and methylprednisolone (MP) pulses for the treatment of severe HSP nephritis (HSN) and to study the effect of prophylactic prednisone treatment given at disease onset on the long-term outcome. A total of 223 children with newly diagnosed HSP were followed up prospectively for 6 months. Patients with severe HSN also had extrarenal symptoms more frequently during this time. Protein loss via the intestine was more common than previously described, occurring in 3% of the patients. HSN developed in the early course of the disease. The results suggest that weekly urine dipstick tests are indicated for 2 months after HSP onset and individually for over 6 months in cases of HSN or HSP recurrences. Prednisone did not affect the frequency or timing of the appearance of HSN. The efficacy of CyA and MP treatments was evaluated in a trial with a mean follow-up time of 6 years involving 24 paediatric patients (11 CyA, 13 MP), 15 of whom were randomized and 9 were treated according to the given protocol without randomization. Oral CyA was not inferior to intravenous MP pulses and proved to be an efficient, safe steroid-sparing treatment for severe HSN. All the CyA-treated patients achieved remission of nephrotic-range proteinuria within 3 months, while remission was achieved more slowly in the MP group and only in 6/13 (46%) with the initial treatment. There was no difference in the renal biopsy findings two years after initiation of the therapy. The 8-year outcome of HSP was assessed by means of a health questionnaire in 160 (94%) of the 171 former patients in the randomized placebo-controlled prednisone trial and in 138 (81%) with urine analysis and measurement of blood pressure. HSP carried a good prognosis, although skin relapses occurred up to a decade after the initial onset and could be accompanied by late-onset nephritis. Hypertension and/or renal abnormalities were recorded in 13% of the patients, being more frequent in those with an initial occurrence of HSN (OR 4.3, p=0.009, 95% CI 1.4–14.0) and warranting long-term follow-up of HSN patients. Early prednisone treatment did not affect the long-term outcome of HSP and should not be routinely used. / Tiivistelmä Väitöskirjan tarkoituksena oli kuvata Henoch-Schönleinin purppuran (HSP) oireita ja taudinkulkua, verrata siklosporiini A:n (CyA) ja metyyliprednisolonipulssihoidon (MP-pulssihoidon) tehoa vaikean HSP-nefriitin (HSN) hoidossa ja selvittää taudin alussa annetun prednisonihoidon vaikutusta pitkäaikaisennusteeseen. Taudinkulkua seurattiin prospektiivisesti 6 kuukauden ajan diagnoosista 223 lapsipotilaan aineistossa. Potilailla, joilla oli vaikea HSN, esiintyi myös muita oireita pitempään. Proteiinin menetystä suolistoon esiintyi 3 %:lla, mikä on aiemmin kuvattua yleisempää. HSN ilmaantui taudin alkuvaiheessa. Tutkimustulosten perusteella viikoittainen virtsanäytteiden seuranta riittää 2 kuukauden ajan taudin alusta. Seuranta-aikaa tulee pidentää yksilöllisesti yli 6 kuukauden, jos potilaalla todetaan HSN tai HSP uusiutuu. Prednisonilla ei todettu olevan vaikutusta HSN:n yleisyyteen tai ilmaantumisaikaan. CyA- ja MP-hoitojen tehoa vaikeaan HSN:n seurattiin 24 lapsipotilaan aineistossa (11 CyA, 13 MP) 6 vuoden ajan. Potilaista 15 satunnaistettiin hoitoryhmiin ja 9 hoidettiin tutkimussuunnitelman mukaan ilman satunnaistamista. Suun kautta otettu CyA vaikutti hoidoista tehokkaammalta, sillä kaikilla potilailla nefroottistasoinen valkuaisvirtsaisuus hävisi kolmessa kuukaudessa. MP-hoitoa saaneista vain 6/13 (46 %) pääsi remissioon MP-hoidolla ja hekin CyA-hoidettuja hitaammin. Kaksi vuotta tutkimuksen alusta otettujen munuaisbiopsioiden histologisissa löydöksissä ei ollut eroa ryhmien välillä. Varhaisen kortisonihoidon pitkäaikaisvaikutuksia arvioitiin 8 vuotta lumekontrolloidun prednisonihoitotutkimuksen jälkeen, jolloin aiemman tutkimuksen 171 potilaasta 160 (94 %) vastasi terveyskyselyyn ja 138 (81 %) osallistui virtsa-analyysin ja verenpaineen mittauksen sisältäneeseen seurantatutkimukseen. HSP:n ennuste oli hyvä, vaikka taudin iho-oireet saattoivat uusia jopa 10 vuoden ajan ja taudin uusiutumisen yhteydessä saattoi ilmaantua myöhäinen HSN. Kohonnut verenpaine ja/tai valkuais-/verivirtsaisuus todettiin 13 %:lla. Ne olivat yleisempiä potilailla, joilla oli ollut HSN taudin alkuvaiheessa (OR 4.3, p=0.009, 95 % CI 1.4–14.0). Siten HSN-potilaiden pitkäaikaisseuranta on tarpeen. Varhaisella kortisonihoidolla ei ollut vaikutusta taudin ennusteeseen, minkä vuoksi kortisonia tulee käyttää HSP-potilaiden hoidossa vain harkiten.

© 2017, © 2017 American Federation for Medical Research. A middle-aged man presents with acute pancreatitis of unknown etiology and is found to have a presentation consistent with the diagnosis of type 2 autoimmune pancreatitis (AIP). AIP is a group of rare heterogeneous diseases that are challenging to diagnose. There are 2 types of AIP. Type 1 disease is the more common worldwide than type 2 AIP. While type 1 AIP is associated with IgG4-positive antibodies, type 2 AIP is IgG4 antibody negative. Both types of AIP are responsive to corticosteroid treatment. Although type 1 AIP has more extrapancreatic manifestations and more commonly relapses, this is a case of a patient with type 2 AIP with inflammatory bowel disease and relapsing course.