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CONTEXT AND OBJECTIVE: Sepsis and septic shock are very common conditions among critically ill patients that lead to multiple organ dysfunction syndrome (MODS) and death. Our purpose was to investigate the efficacy of early administration of dexamethasone for patients with septic shock, with the aim of halting the progression towards MODS and death. DESIGN AND SETTING: Prospective, randomized, double-blind, single-center study, developed in a surgical intensive care unit at Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo. METHODS: The study involved 29 patients with septic shock. All eligible patients were prospectively randomized to receive either a dose of 0.2 mg/kg of dexamethasone (group D) or placebo (group P), given three times at intervals of 36 hours. The patients were monitored over a seven-day period by means of the sequential organ failure assessment score. RESULTS: Patients treated with dexamethasone did not require vasopressor therapy for as much time over the seven-day period as did the placebo group (p = 0.043). Seven-day mortality was 67% in group P (10 out of 15) and 21% in group D (3 out of 14) (relative risk = 0.31, 95% confidence interval 0.11 to 0.88). Dexamethasone enhanced the effects of vasopressor drugs. CONCLUSIONS: Early treatment with dexamethasone reduced the seven-day mortality among septic shock patients and showed a trend towards reduction of 28-day mortality. CONTEXTO E OBJETIVO: Sepse e choque séptico são doenças muito comuns em pacientes gravemente enfermos, evoluindo muitas vezes com síndrome de disfunção de múltiplos órgãos (SDMO) e morte. A proposta do trabalho foi investigar a eficácia da administração precoce de dexametasona a estes pacientes, tentando evitar a progressão do choque séptico para SDMO e morte. TIPO DE ESTUDO E LOCAL: Estudo prospectivo, aleatório, duplamente encoberto, monocêntrico, realizado na Unidade de Terapia Intensiva pós-operatória do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. MÉTODOS: Foram estudados 29 pacientes com choque séptico. Os participantes foram aleatoriamente divididos em dois grupos que receberam 0,2 mg/kg de dexametasona (grupo D) ou placebo (grupo P), repetidas a cada 36 horas. Os pacientes foram acompanhados durante sete dias de internação na Unidade de Terapia Intensiva através do escore SOFA (Sequential Organ Failure Assessment). RESULTADOS: Os pacientes que receberam dexametasona necessitaram de menos tempo de tratamento com vasopressores durante o período de sete dias (p = 0,043). A mortalidade em sete dias no grupo P foi de 67% (10 em 15) e no grupo D foi de 21% (3 em 14) (risco relativo = 0.31, intervalo de confiança 95% 0.11-0.88). CONCLUSÃO: O tratamento precoce com dexametasona dos pacientes com choque séptico reduziu a mortalidade em sete dias de acompanhamento e mostrou tendência de redução da mortalidade em 28 dias.

A fisiopatologia da polipose rinossinusal não é totalmente compreendida, apesar de várias hipóteses em relação ao seu processo inflamatório. OBJETIVOS: Estudo prospectivo da expressão dos genes das proteínas, anexina-1 e a galectina-1, que têm ação anti-inflamatória, e sua modulação pelo glicocorticoide. MATERIAL E MÉTODOS: Onze pacientes portadores de polipose rinossinusal tiveram biopsiados seus pólipos em dois momentos: na ausência de glicocorticoide sistêmico, e na sua presença. Nas duas amostras, foi avaliada a expressão desses genes e comparada com a expressão na mucosa nasal normal do meato médio. RESULTADOS: Verificou-se que a média de expressão dos genes que codifica a anexina-1 e galectina-1 estava predominantemente aumentada, independente do uso do glicocorticoide em relação à mucosa nasal controle. Entretanto, nos pólipos sem uso de corticoide, a média de expressão do gene da anexina-1 foi significativamente maior do que nos pólipos que estavam sob uso de glicocorticoide. Com relação à galectina-1 não houve diferença significativa entre as médias de expressão antes e após o uso de glicocorticoide sistêmico. CONCLUSÃO: Os genes apresentaram um aumento da expressão na mucosa nasal polipoide, independente do uso do glicocorticoide, porém a relação destes dois genes das proteínas anti-inflamatórias com o glicocorticoide não ocorreu da mesma maneira. Rhinosinusal polyps physiopathology is not fully understand, despite numerous hypotheses regarding its inflammatory process. AIMS: a prospective study regarding the gene expression of proteins: anexin-1 and galectin-1, which has an anti-inflammatory action and is modulated by steroids. MATERIALS AND METHODS: eleven patients with rhinosinusal polyps suffered a biopsy of their polyps at two moments: in the absence of systemic steroids and during its use. In the two samples we assessed the expression of these genes and compared it to the normal nasal mucosa in the middle meatus. RESULTS: We noticed that the mean expression of the genes which code anexin-1 and galectin-1 was predominantly increased, regardless of the use of steroids in relation to the control nasal mucosa. Notwithstanding, in polyps without the use of steroids, the mean gene expression of anexin-1 was significantly higher than in the polyps which were under the use of steroids. Regarding galectin-1, there was no significant difference between the expression mean values before and after the use of systemic steroids. CONCLUSION: The genes present an expression increase in the polyp mucosa, regardless of the use of steroids; nonetheless, the relationship of these two genes of anti-inflammatory proteins with steroids did not happen the same way.

Background The microenvironment and stress factors like glucocorticoids have a strong influence on breast cancer progression but their role in the first stages of breast cancer and, particularly, in myoepithelial cell regulation remains unclear. Consequently, we investigated the role of glucocorticoids in ductal carcinoma in situ (DCIS) in breast cancer, focusing specially on myoepithelial cells. Methods To clarify the role of glucocorticoids at breast cancer onset, we evaluated the effects of cortisol and corticosterone on epithelial and myoepithelial cells using 2D and 3D in vitro and in vivo approaches and human samples. Results Glucocorticoids induce a reduction in laminin levels and favour the disruption of the basement membrane by promotion of myoepithelial cell apoptosis in vitro. In an in vivo stress murine model, increased corticosterone levels fostered the transition from DCIS to invasive ductal carcinoma (IDC) via myoepithelial cell apoptosis and disappearance of the basement membrane. RU486 is able to partially block the effects of cortisol in vitro and in vivo. We found that myoepithelial cell apoptosis is more frequent in patients with DCIS+IDC than in patients with DCIS. Conclusions Our findings show that physiological stress, through increased glucocorticoid blood levels, promotes the transition from DCIS to IDC, particularly by inducing myoepithelial cell apoptosis. Since this would be a prerequisite for invasive features in patients with DCIS breast cancer, its clinical management could help to prevent breast cancer progression to IDC. Electronic supplementary material The online version of this article (10.1186/s13058-018-0977-z) contains supplementary material, which is available to authorized users.

The quality of sleep has recently come to the forefront of public health concerns in industrialized nations. Indeed, voluntary sleep curtailment is widespread, sleep disorders are increasingly recognized and both correlate with the current epidemiology of diabetes and obesity (Van Cauter and Knutson, 2008). Sleep fragmentation (SF) is a periodic disruption found in highly prevalent sleep-related breathing and movement disorders, where the sleeper might be aroused several hundred times per night. By roughly summing the prevalence of obstructive sleep apnea (OSA) syndromes and periodic limb movement disorders, two of the most common sleep disorders, we predict a total prevalence for SF of nearly 15% in the European active population. Overlooked cases and insufficient concern for the problematic bear a major socioeconomic burden because of the broad impact of excessive daytime sleepiness on productivity (Hossain and Shapiro, 2002), motor vehicle accidents (Aldrich, 1989) and medical complications (Spiegel et al., 2009). Recurrent interference with the natural architecture of sleep leads to sleepiness, difficulty in concentration and cognitive impairments such as decreased reaction times and poor working memory equivalent to a full night of sleep deprivation in severe cases (Bonnet, 1985, 1989; Stepanski, 2002). In addition, recent experimental evidence in humans has unraveled the unprecedented link between sleep of poor quality and dramatic endocrine imbalances such as deregulation of appetite controlling hormones, glucocorticoids and increase in sympathetic tone, ultimately leading to the development of insulin resistance (Spiegel et al., 2009; Stamatakis and Punjabi, 2010). Current animal models for the study of sleep pathology mostly involve short intervention often biased by stress induction and usually involving a complete period of sleep deprivation. These models do not tightly reflect the most common clinical pattern characterized by sleep perturbation over long periods of time. Therefore, paying attention to maximally avoid methodological stress, we designed a new device aiming at performing instrumental SF for fourteen days in mice. Our model mimics SF observed in sleep disorders since it has no major impact on circadian timing and total amount of sleep but clearly shortens individual sleep episodes. With this method, we approached three problematics that were insufficiently addressed in the literature. In our first study, we addressed the question of whether SF could trigger electrophysiological and molecular sleep homeostasis mechanisms in the short-term and whether these effects could be maintained in the long-term. We showed that SF leads to an anticipated homeostatic regulation of Slow Wave Activity (SWA), the sleep EEG hallmark of sleep homeostasis. Furthermore, EEG spectral analysis revealed an unexpected power increase in 4-40 Hz frequencies during sleep with a clear increase in the amplitude of slow waves and spindles. We concluded that sustained sleep pressure in SF leads to a global increase in cortical synchronization. We next explored whether these electrophysiological changes could impact on the expression of transcripts known to be regulated by sleep homeostasis (immediate early genes, clock-genes and heat shock proteins). Only heat shock proteins showed a consistent induction after one day but normalized after fourteen days of SF. These results point to the fact that electrophysiological and molecular aspects of sleep homeostasis are dissociable and that long-term sleep pressure triggers allostatic cellular processes of adaptation. In our second study, we explored the effects of long-term SF on general metabolism. We showed that SF led to a general imbalance in energy intake and expenditure, possibly through a slight elevation of brain temperature at rest. We also observed that glucocorticoids were slightly elevated at given circadian points and were accompanied by glucose intolerance. Altogether, this study brings evidence for the participation of SF in addition to intermittent hypoxia in the development of a metabolic syndrome in OSA patients. In the third study, we combined our chronic model with a spatial learning task spanning over several days (Morris Water Maze) in order to study the impact of SF on memory and metabolic plasticity. We showed that SF impaired proper memory consolidation supporting the idea that continuous sleep is required for specific mechanisms of memory trace post-processing. We also provide preliminary evidence that brain energy metabolism is not optimally responsive to neural activation after SF and that this effect might underlie the observed cognitive impairment. In conclusion, we showed that our animal SF model is suitable for studying the specific mechanisms underlying cognitive impairments and metabolic imbalance observed in sleep medicine. Our results underscore the existence of a global allostatic load in a wide range of systems during SF. Sensitization of the population to the prevalence of SF and its stealthy mode of presentation might improve its detection. Increased recognition of the problematic would be especially beneficial to cognitive development in school children with sleep apnea and might reduce accidents related to sleepiness. More specifically, we propose that screening sleep quality and effective correction of SF in patients with endocrine disorders has the potential to improve glucose metabolism and energy balance.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.