Screening practices for paediatric asymptomatic adrenal suppression in Canada: Are we addressing this important risk?

BackgroundChildren with adrenal suppression (AS), a potential side effect of glucocorticoids (GCs) may be asymptomatic, present with nonspecific signs and symptoms or with adrenal crisis. Asymptomatic AS (AAS) can only be diagnosed through screening. Identifying and treating asymptomatic patients before symptoms develop may reduce morbidity. Screening guidelines for AS are lacking. Consequently, screening practices are highly variable.ObjectiveTo assess (1) the screening practices for and recognition of paediatric AAS among clinicians in Canada and (2) the educational impact of a 2-year surveillance program of symptomatic AS cases.MethodsBefore and after a 2-year Canadian Paediatric Surveillance Program (CPSP) study of symptomatic AS, participants were surveyed through the CPSP. The prestudy survey was sent to 2,548 participants in March 2010 and the poststudy survey was sent to 2,465 participants in April 2013.ResultsResponse rates were 32% for the prestudy survey and 21% for the poststudy survey. Between the pre- and poststudy surveys, the percentage of physicians who reported routinely screening patients on GCs for AS increased from 10% to 21% and the percentage who reported having a screening policy in their office/centre increased from 6% to 11%. There was no significant change in the percentage of physicians who had diagnosed a child/youth with AAS in the preceding year.ConclusionFrequency of screening for AAS increased following the 2-year study but remains low. Development of a clinical practice guideline should increase both awareness of asymptomatic AS among Canadian paediatricians and the identification of AAS, before symptoms develop.     

激素对股骨头微血管及组织细胞的影响

目的通过建立激素性股骨头缺血性坏死动物模型,研究股骨头微血管密度(microvas-culardensity,MVD)和股骨头组织细胞超微结构的变化,探讨长期大剂量使用糖皮质激素引起股骨头缺血性坏死的机制。方法健康日本白兔40只,1.86～2.21kg,平均2.06kg。随机分为两组,实验组31只,对照组9只。实验组每周皮下注射醋酸氢化泼尼松8mg/kg,对照组每周皮下注射生理盐水0.32ml/kg。在实验的第4、8和12周分别对实验组和对照组的股骨头行微血管墨汁灌注,研究股骨头MVD的变化;制作半薄切片,在透射电镜下分别观察实验组和对照组的股骨头组织细胞的超微结构。拍摄兔耳背微血管网观察用药前后的变化。结果实验组双侧股骨头松质骨和密质骨的单位面积内MVD与对照组相比在用药3个月后明显下降(P<0.01)。兔耳背微血管网随用药时间的延长逐渐变稀疏。股骨头各系组织细胞内均发现有脂质堆积;骨细胞核膜失去连续性、碎裂,染色质溶解;血管内皮细胞内出现脂滴,胞膜结构不完整,可见明显的裂隙,线粒体肿胀、变圆,结构不清;脂肪细胞异常肥大,核内出现脂滴,并压迫小静脉,管腔变窄;小静脉内可见红细胞相互重叠呈“缗线状”。结论骨内压升高是激素性骨坏死病理过程中的一个表现,与肥大的脂肪细胞压迫小静脉有关。长期大剂量使用糖皮质激素可抑制     

Randomized Trial of Basiliximab Induction versus Steroid Therapy in Pediatric Liver Allograft Recipients Under Tacrolimus Immunosuppression

Avoidance of corticosteroids could be beneficial after pediatric liver transplantation (LTx). To test this hypothesis, we performed a randomized prospective study to compare immunosuppression with tacrolimus (TAC) and steroids versus TAC and basiliximab (BAS) after pediatric LTx. Seventy-two patients were recruited, 36 receiving TAC and steroids and 36 TAC and BAS. The primary endpoint was the occurrence of the first rejection episode. Secondary endpoints were the cumulative incidence and severity of rejection, patient and graft survival, and incidence of adverse events. Overall 1-year patient and graft survival rates were 91.4% and 85.5% in the steroid group, and 88.6% and 80% in the BAS group (p = NS). Patients free from rejection were 87.7% in the BAS group and 67.7% in the steroid group (p = 0.036). The use of BAS was associated with a 63.6% reduction in incidence of acute rejection episodes. Overall incidence of infection was 72.3% in the steroid group and 50% in the BAS group (p = 0.035). We conclude that the combination of TAC with BAS is an alternative to TAC and steroid immunosuppression in pediatric LTx, which allows for a significant reduction in the incidence of acute rejection and infectious complications.     

糖皮质激素治疗急性呼吸窘迫综合征58例临床分析

目的 评价糖皮质激素在急性呼吸窘迫综合征（ARDS）救治中的作用。方法 回顾性分析我院1992年8月－2001年5月58例临床确诊为ARDS患的临床资料，其中肺内型ARDS组（ARDSp）18例，肺外型ARDS组（ARDSexp)40例。各组再以使用地塞米松情况分为：≥30mg/d组，＜30mg/d组和非激素治疗组。结果 各组病情程度相当，组间APACHE Ⅱ评分比较差异无显性（P＞0．05）。激素用量≥30mg/d组与＜30mg/d组及非激素治疗组比较，病情改善天数及使用呼吸机治疗天数均明显缩短，差异有显性（P＜0．01）。58例患总病死率为20．7％，ARDSp组，ARDSexp组中激素用量≥30mg/d组的病死率分别为14．3％，11．5％，均低于ARDSp与ARDSexp组的平均病死率（分别为22．2％，20．0％）。所有病例未见感染扩散或加重。结论 早期，足量，适当疗程应用糖皮质激素治疗ARDS可及时逆转过度失控的炎症反应，缓解病情，降低病死率。     

Glucocorticoids Decrease Hippocampal and Prefrontal Activation during Declarative Memory Retrieval in Young Men

Glucocorticoids (GCs, cortisol in human) are associated with impairments in declarative memory retrieval. Brain regions hypothesized to mediate these effects are the hippocampus and prefrontal cortex (PFC). Our aim was to use fMRI in localizing the effects of GCs during declarative memory retrieval. Therefore, we tested memory retrieval in 21 young healthy males in a randomized placebo-controlled crossover design. Participants encoded word lists containing neutral and emotional words 1 h prior to ingestion of 20 mg hydrocortisone. Memory retrieval was tested using an old/new recognition paradigm in a rapid event-related design. It was found that hydrocortisone decreased brain activity in both the hippocampus and PFC during successful retrieval of neutral words. These observations are consistent with previous animal and human studies suggesting that glucocorticoids modulate both hippocampal and prefrontal brain regions that are crucially involved in memory processing. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

糖皮质激素受体高、低亲和力位点在急性淋巴细胞性白血病治疗中的意义

研究了１０例正常人和２９例急性淋巴细胞性白血病（急淋）患者外周血糖皮质激素受体高、低亲和力结合位，或（ＧＣＲＨ、ＧＣＲＬ），利用Ｒｕ３８４８６对ＧＣＲＬ进行封闭，对部分患者ＧＣＲＨ、ＧＣＲＬ在激素联合化疗前后水平的变化进行了动态观察。结果表明，正常对照组ＧＣＲＨ、ＧＣＲＬ分别为４６０８±１８８９位点／细胞和１３５２３８±８８５０９位点／细胞，两者相关良好。急淋患者ＧＣＲＨ、ＧＣＲＬ分别为６０５２±３８８８位点／细胞和１２６４０５±１０２１３３位点／细胞，经过糖皮质激素药物联合化疗后，其水平分别为３６１６±１９６２位点／细胞和１４３５９７±１１２２８９位点／细胞，ＧＣＲＨ下降明显（Ｐ＜０．０１），下降率为４０．３％；而ＧＣＲＬ化疗前后差异不显著（Ｐ＞０．０５）。提示ＧＣＲＬ在介导糖皮质激素联合化疗疗效的维持中起重要的作用。     

Interactions between growth hormone and dexamethasone in skeletal growth and bone structure of the young mouse

Summary The present study investigated the interactions of growth hormone (GH) and glucocorticoid on skeletal growth and bone structure in young mice. The purpose of this study was to examine the possible prevention by GH of the damage inflicted by dexamethasone (Dex) at sites of skeletal growth and ossification. Dex (1 mg/kg) with or without rat GH (rGH) or bovine GH (bGH), 1 mg/kg, was given for 4 weeks, from age 3–7 weeks, to female ICR mice. Tibiae, humerus, and vertebrae were analyzed morphometrically and biochemically. Growth, as determined by the mouse weight, tibial length, and humerus protein content was found to be compromised by dexamethasone. This was prevented by rGH or bGH. The epiphyseal growth plate width, trabecular bone volume, cortical bone width, mineral bone content, and alkaline and acid phosphatase activity were decreased by dexamethasone. These were prevented by rGH or by bGH. The findings of the present study suggest that in the mouse, GH can decrease or even avoid some of the pathological features in growing bones inflicted by high-dose glucocorticoid treatment.     

Linomide,a novel immunomodulator that prevents death in four models of septic shock

Intravenous injections of 50 μ.g Staphylococcus aureus enterotoxin B (SEB) or bacterial lipopolysaccharide (LPS) are lethal, provided that mice are simultaneously sensitized with either N-galactosamine (GalN) or the anti-glucocorticoid RU-38486. Similar to the synthetic glucocorticoid (GC) receptor agonist dexamethasone, pharmacological doses of the immunomodulator linomide (quinoline-3-carboxamide) prevent death in all four models of lethal septic shock (LPS + GalN, LPS + RU-38486, SEB + GalN, and SEB + RU-38486) and inhibit the secretion of tumor necrosis factor, one of the major intermediate effector molecules of SEB and LPS toxicity. In this system, cyclosporine A (CsA), although effective in suppressing SEB toxicity, fails to counteract the lethal effect of LPS. This observation, together with the fact that linomide acts in the presence of excess amounts of GC receptor antagonist, indicates that linomide functions in a different way to that of known immunosuppressive agents like CsA and GC.     

Chronic social stress: effects on limbic brain structures

Different types of stressors are known to activate distinct neuronal circuits in the brain. Acute physiological stimuli that are life threatening and require immediate reactions lead to a rapid stimulation of brainstem and hypothalamus to activate efferent visceral pathways. In contrast, psychological stressors activate higher-order brain structures for further interpretations of the perceived endangerment. Common to the later multimodal stressors is that they need cortical processing and, depending on previous experience or ongoing activation, the information is assembled within limbic circuits connecting, e.g., the hippocampus, amygdala and prefrontal cortex to induce neuroendocrine and behavioral responses. In view of the fact that stressful life events often contribute to the etiology of psychopathologies such as depressive episodes, several animal models have been developed to study central nervous mechanisms that are induced by stress. The present review summarizes observations made in the tree shrew chronic psychosocial stress paradigm with particular focus on neurotransmitter systems and structural changes in limbic brain regions.     

Glucocorticoids down-regulate dendritic cell function in vitro and in vivo

Exogenous glucocorticoid hormones are widely used as therapeutical agents, whereas endogenous glucocorticoids may act as physiological immunosuppressants involved in the control of immune and inflammatory responses. The optimal activation of T lymphocytes requires two distinct signals: the major histocompatibility complex-restricted presentation of the antigen and an additional co-stimulatory signal provided by the antigen-presenting cells. There is ample evidence that, among the cells able to present the antigen, the dendritic cells (DC) have the unique property to activate antigen-specific, naive T cells in vitro and in vivo, and are therefore required for the induction of primary immune responses. In this work, we tested whether glucocorticoids affected the capacity of DC to sensitize naive T cells. Our data show that, in vitro, the steroid hormone analog dexamethasone (Dex) affects the viability of DC, selectively downregulates the expression of co-stimulatory molecules on viable DC, and strongly reduces their immunostimulatory properties. In vivo, a single injection of Dex results in impaired antigen presenting function, a finding which correlates with reduced numbers of splenic DC. These results show that glucocorticoids regulate DC maturation and immune function in vitro and in vivo and suggest that this mechanism may play a role in preventing overstimulation of the immune system.