Bone histology in steroid-treated children with non-azotemic nephrotic syndrome

Patients with nephrotic syndrome (NS) and normal glomerular filtration rate (GFR) frequently exhibit abnormalities of calcium and vitamin D homeostasis, mainly hypocalcemia and reduced circulating vitamin D metabolites. These abnormalities have been linked to alterations of bone histology in adults with non-azotemic NS, particularly osteomalacia and excessive bone resorption. Whether similar abnormalities of bone histology occur in children and adolescents with NS, particularly in those requiring prolonged treatment with corticosteroids, remains largely unknown. Thus, bone histomorphometry and selected bone-modulating hormones were studied in eight children (aged 2–16 years) with normal GFR (range 85–169 ml/min per 1.73 m²) and NS. All patients received corticosteroids for at least 12 months prior to bone biopsy. At the time of bone biopsy, the urine protein/creatinine ratio was elevated (2.1±3.6), while the average concentrations of parathyroid hormone (36±13 pg/ml), 25-hydroxyvitamin D [25(OH) D] (22±14 ng/ml), and 1,25(OH)₂D (59±22 pg/ml) were normal. Bone histomorphometry displayed focal osteomalacia (OM) and mild increased bone resorption in most patients. The mineralization lag time, an indicator of the degree of osteomalacia, correlated with the time elapsed since the original diagnosis of NS (r=0.93, P<0.0005). Overt hyperparathyroidism was not evident, but increased eroded perimeter and elevated bone formation rate (BFR) were evident in two patients, suggesting high-turnover bone disease. The BFR was inversely correlated with the administered dose of prednisone at the time of biopsy (r=–0.78, P<0.05) and one patient exhibited low bone turnover changes. The growth velocity standard deviation score (SDS) at time of biopsy ranged from –1.6 to 3.2, resulting in a height SDS range of –1.9 to 0.6. The height SDS at time of bone biopsy correlated inversely with the dose of administered glucocorticoid (r=–0.71, P<0.05) and with the duration of the disease (r=–0.7, P=0.05). These data, albeit preliminary, demonstrate that children with NS treated with prolonged corticosteroid therapy exhibit bone histopathological changes without a concomitant impairment in GFR. While the OM appears to be related to the disease process, the alterations of bone formation and the adynamic changes are likely the result of the corticosteroid therapy. The potential consequences of these findings on adult bone mass and ultimate height deserve further studies.     

Evidence supporting a role of glucocorticoids in short-term bone loss in burned children

Children burned 40% total body surface area suffer acute bone loss. The reason(s) for this is uncertain. In order to determine whether high endogenous glucocorticoid production can contribute to the bone loss, we sequentially studied a total of 14 pediatric burn patients for bone histomorphometry; 7 of these patients and 4 controls were studied for characteristics of corticosteroid-induced bone loss, including decreased osteoblasts and down-regulation of the glucocorticoid receptor in bone. We then studied 4 of the burn patients and three controls for a decrease in markers of osteoblast differentiation, another feature of glucocorticoid toxicity. Bone biopsies were taken from each of the 14 burn patients a mean of 3 weeks post-burn. Histomorphometry was performed on one specimen (n=7) and either glucocorticoid and mineralocorticoid receptor, collagen and alkaline phosphatase expression by RT-PCR (n=7) or marrow stromal cell culture (n=4) on the other. Patients were permitted a maximum of two biopsies for study. One biopsy was obtained intra-operatively from normal subjects during elective iliac crest alveolar bone grafting and compared with burn specimens for glucocorticoid receptors and marrow stromal cell culture. A 24-h urine specimen was obtained for free cortisol (n=7). Histomorphometry revealed low osteoblast and osteoid surfaces and few detectable osteoblasts. Resorptive surfaces were also reduced. Glucocorticoid receptor mRNA (GR) was not decreased; however, there was a trend toward inverse relationships between urine free cortisol and GR and type-1 collagen mRNA, r=–0.61 and –0.64, respectively, and a significantly lower mRNA for type-1 collagen in bone in burn vs control patients by the median test, ²=7.6 (p<0.01). Markers of osteoblast differentiation, core-binding factor (cbf)a1, bone morphogenetic protein (BMP)-2, type-I collagen, and alkaline phosphatase were reduced in burn cell cultures compared with controls (p<0.05). The eightfold elevation of urinary free cortisol excretion, low osteoblast number, decreased resorptive surface, and reduced markers of osteoblast differentiation are all consistent with an acute glucocorticoid effect on bone.     

Thyroid hormone, glucocorticoids, and prolactin at the nexus of physiology, reproduction, and toxicology

A symposium at the 2003 Annual Meeting of the Society of Toxicology brought together an expert group of endocrinologists to review how non-reproductive hormones can affect the endocrine system. This publication captures the essence of those presentations. Paul Cooke and Denise Holsberger recapitulate the evidence of how thyroid hormones affect male and female reproduction, and reproductive development. Ray Witorsch summarizes the many effects of glucocorticoids on the reproductive system. Finally, Paul Sylvester reviews the mechanism of action of prolactin, and reminds us that this ancient hormone has many functions beyond lactation.     

葡萄膜炎药物治疗中的问题分析

目的探讨葡萄膜炎临床治疗中的误区和可能原因。方法收集2000年4—10月中山大学中山眼科中心葡萄膜炎专科就诊的154例患者(268只眼)的完整资料,归纳、分析其治疗资料,尤其是糖皮质激素的给药途径、剂量和治疗时间以及抗生素应用等方面的情况。结果154例(268只眼)患者中糖皮质激素滴眼数、结膜下或球后注射眼数及全身应用例数的使用率分别为90．3％、84．0％及92．9％,而全身应用糖皮质激素的患者中静脉滴注者占85．3％。Behcet病(37例)、前葡萄膜炎(30例)及Fuchs虹膜异色性葡萄膜炎(14例)患者的既往治疗情况显示,县级、地市级和省级医院(包括省级以上医院和医学院校附属医院)的糖皮质激素应用中普遍存在着大剂量滥用或滴眼剂使用不当的现象。154例葡萄膜炎患者中抗生素滴眼数、结膜下注射眼数及全身应用例数的使用率分别为97．0％、71．6％及83．8％;仅6例(3．9％)应用了其他免疫抑制剂。结论内源性非感染性葡萄膜炎尤其是Behcet病、前葡萄膜炎及Fuchs虹膜异色性葡萄膜炎患者治疗中糖皮质激素和抗生素的滥用和误用现象相当普遍;糖皮质激素的应用途径、剂量及治疗时间应根据葡萄膜炎的类型和严重程度等而定;非感染性葡萄膜炎不需要使用抗生素。（中华眼科杂志,2004,40：679-682)     

Blunted stress responses in delayed type hypersensitivity in mice lacking the neuronal isoform of nitric oxide synthase

Nitric oxide (NO) is implicated in inflammation and hypothalamic–pituitary responses to immune stimuli; however, the specific role of NO from neurons during stress-induced immune responses remains unspecified. We measured antigen-specific delayed-type-hypersensitivity (DTH) responses in the skin of wild-type (WT) and neuronal nitric oxide synthase knockout (nNOS^−/−) mice at baseline and after 2 h of restraint. Baseline corticosterone concentrations were higher in nNOS^−/− than WT mice. However, stress-induced increases in corticosterone were dampened in nNOS^−/− mice, and restraint suppressed DTH only in WT animals. Furthermore, WT mice lost more body mass after stress, and exhibited more anxiety-like behavior in the open field, than nNOS^−/− mice. Neuronal NO appears to be involved in the neuroendocrine-immune response to stress, perhaps via glucocorticoid regulation.     

Glucocorticoids are involved in the long-term effects of a single immobilization stress on the hypothalamic-pituitary-adrenal axis

We have previously observed that a single exposure to a severe stressor such as immobilization (IMO) induces long-lasting desensitization of the responsiveness of the hypothalamic–pituitary–adrenal (HPA) axis to the same stressor that enhances rather than dissipates with time (days). As this desensitization of the HPA axis was not observed in response to a novel stressor, we suggested this might be a particular type of learning linked to severe stressful situations. Taking into account the evidence that glucocorticoids are involved in learning and memory, the present study addresses the role of glucocorticoids in the induction of long-term effects of an acute exposure to IMO. Three different experimental approaches were used: (i) blockade of stress-induced corticosterone release by using adrenalectomized rats supplemented with a low dose of corticosterone in the drinking saline (ADX+B); (ii) blockade of corticosterone synthesis during the first exposure to IMO with the 11-β-hydroxylase inhibitor metyrapone (200 mg/kg); and (iii) administration of the glucocorticoid receptor antagonist RU486 (100 mg/kg). Previous exposure to IMO resulted in an enhanced post-stress recovery of the HPA response to the same stressor 1 week later. These long-term effects of IMO were blocked in ADX+B rats, were partially reduced in metyrapone-treated rats and only modestly affected by RU486 administration. These data suggest that glucocorticoids play a partial role in the induction of long-term effects of IMO on the HPA responsiveness to the same stressor, although the weak effect of RU486 suggests that non-classical corticosteroid receptors may be involved. The role of glucocorticoids in the expression of the phenomenon is suggested by the full blockade of the phenomenon in ADX+B rats, but further studies are needed. As blockade of corticosterone synthesis only partially blunted the long-term effect of IMO, it appears that full induction of the long-term effects of acute exposure to IMO on the HPA axis is only achieved by the concerted action of several endocrine (or neurochemical) factors.     

糖皮质激素对大鼠先天性膈疝模型肺发育保护作用及其机制研究

目的对胎鼠膈疝模型进行产前糖皮质激素干预，探讨其作用机制。方法孕9．5dSD大鼠橄榄油灌胃为对照组（C组，n=3），异草醚（nitrofen）橄榄油溶液灌胃为实验组，孕18．5d分为：Nitrofen模型组（N组，n=5）、Nitrofen＋生理盐水组（N＋S组，n=2）、Nitrofen＋低剂量激素组（N＋DEX组，n=4）、Nitrofen＋大剂量激素组（N＋4DEX组，n=4）。检测各组肺泡、支气管和肺小动脉发育的相关病理指标：双侧肺重／体重（Lw／Bw）、平均终末支气管密度（MTBD）、轴向腺泡计数（RAC）、肺泡面积百分比（SN）、血管计数、血管外径（ED）、血管内径（ID）、中膜厚度百分比（MT％）。电镜观测膈疝发生时II型肺泡细胞分布、肺泡间隔厚度等的改变。应用免疫组织化学及实时荧光定量PCR检测甲状腺转录因子（TTF-1）、转化生长因子β1（TGF-β1，）的表达。结果N组Lw／Bw、RAC、sN较C组明显减少，MTBD增加（P〈0．05），MT％显著增高。N＋DEX组Lw／Bw、RAC、s0A较N组升高，N＋4DEX组升高更显著，MTBD亦出现明显下降（P〈0．05）。MT％在N＋DEX组略少于N组，但N＋4DEX组明显减少（P〈0．05）。TTF-1免疫组织化学阳性染色区域面积比N＋4DEX组明显高于N组（P〈0．05）。实时荧光定量RT-PCR检测，TTF-1 mRNA表达在N组显著下降（P〈0．05），大剂量激素使用后出现回升（P〈0．05）。结论糖皮质激素可改善大鼠先天性膈疝模型肺泡、支气管、肺小动脉发育不良，TTF-1是其改善肺发育的一个下游因子。     

鼻用糖皮质激素治疗慢性鼻窦炎的鼻窦CT观察

目的采用影像学方法评价鼻用糖皮质激素治疗慢性鼻窦炎（不合并鼻息肉）的疗效。方法慢性鼻窦炎患者24例（42侧），其中青少年患者11例（20侧），平均（x^-±s，下同）年龄（11．8±3．2）岁；成年患者13例（22侧），平均（36．7±11．0）岁。患者接受鼻用糖皮质激素（布地奈德鼻喷雾剂）治疗，成年和青少年患者的药物剂量分别为256μg／d和128μg／d，平均疗程分别为（7．5±3．2）周和（7．0±3．4）周。采用Lund-Mackay评分方法，在治疗前后分别对患者鼻窦CT进行评分（Lund得分），同时记录患者主诉鼻部症状改善情况。结果①治疗后，成年患者的平均Lund得分为6．5±7．5，显著低于治疗前（12．2±5．7，t=3．82，P〈0．01）；青少年患者的平均Lund得分治疗后为2．6±3．7，显著低于治疗前（10．3±5．7，t=5．08，P〈0．01）。成年患者中5例（38％）达到影像学治愈标准，好转7例（54％），无效1例（8％）；青少年患者中8例（73％）达到影像学治愈标准，好转3例（27％），两组疗效差异无统计学意义（P〉0．05）。②鼻用糖皮质激素对成年慢性前组筛窦炎治愈率最高（47％），对慢性后组筛窦炎治愈率最低（38％）；药物对青少年慢性前、后组筛窦炎和慢性蝶窦炎的疗效优于成年患者。③成年患者的主观疗效与治疗前Lund得分呈正相关关系（r=0．676．P〈0．05），即治疗前Lund得分越高，主观疗效越差。青少年患者的主观疗效，与治疗前Lund得分无相关关系（P〉0．05）。结论鼻用糖皮质激素可有效治疗慢性鼻窦炎，部分患者可以达到影像学上的治愈标准。     

大鼠局灶性脑外伤后脑组织糖皮质激素受体表达变化的实验研究

目的 探讨脑外伤后早期脑组织GR及其mRNA表达变化的时相特点.评价脑外伤治疗过程中应用GC的合理性.方法 采用Feeney'S脑损伤模型,致伤方式制作大鼠局灶性脑损伤模型,应用免疫组化和RT-PCR观察外伤后早期不同时段GR及其mRNA在脑组织中表达情况.结果 与对照组相比外伤后GR及其mRNA在脑组织表达均明显降低(P＜0.05).结论 脑外伤后早期脑组织GR呈低表达,本研究结果不支持在脑外伤治疗过程中使用激素.     

Clinical analysis of osteonecrosis of the femoral head induced by steroids

Objective: To explore the clinical characteristics of osteonecrosis of the femoral head (ONFH) induced by steroids. Methods: From January 2000 to October 2009, 497 hips in 270 cases of ONFH induced by steroids were studied. A questionnaire was administered when the patients were admitted; the questions concerned the underlying disease, duration of steroid usage, total dosage of steroid, incubation period (time interval between commencement of steroid therapy and onset of pain), severity of pain, location of initial complaint, primary diagnosis, time lag from onset of pain to final diagnosis and physical signs when admitted. The correlations between pain and Association Research Circulation Osseous (ARCO) stage, bone marrow edema (BME) and lesion size were analyzed. Results: The median of time between commencing steroid medication and developing ONFH for the 269 cases was 18 months (range, 2–384 months). 78.82% cases presented with pain within three years of steroid initiation, only 10.41% patients first complained of pain six or more years after commencing steroid therapy. Fifty‐six cases (20.82%) were misdiagnosed, lumbar disorders being the most frequent misdiagnoses. 79.29% of symptomatic hips presented with abnormal physical tests. Of 420 symptomatic hips, 166 hips were type C1, 223 hips type C2; 299 hips had collapsed; and there was BME in 209 hips. Conclusion: Most patients with ONFH induced by steroids complained of pain within 3 years of commencing steroid therapy. Pain was associated with lesion size, collapse and BME. Atypical location of pain, failure to perform a physical examination and MRI findings were the main causes of misdiagnoses.