Regulation of ferritin: a specific role for interferon‐alpha (IFN‐α)? The acute phase response in patients treated with IFN‐α‐2b

Background Adult onset of Still’s disease is characterized by very high serum ferritin levels, in disproportion with other acute phase proteins (APPs). Because interferon‐alpha (IFN‐α) was observed to cause hyperferritinaemia in three healthy people without increase of other APPs, we hypothesized that IFN‐α stimulates specifically the synthesis of ferritin. To test this hypothesis, we studied ferritin and other APP levels in patients treated with IFN‐α. Patients and methods Fifteen patients treated with IFN‐α‐2b 3–5 times a week, as adjuvant treatment after excision of a high‐risk melanoma, were compared with six patients without adjuvant treatment (controls). Serum levels of C‐reactive protein (CRP) and secretory phospholipase A₂ (sPLA₂) were measured using ELISA. Levels of ferritin, alpha1‐acid glycoprotein (AAG) and albumin were determined by nephelometry. Results CRP was decreased significantly after 4 weeks (P < 0·01) in the patients treated with IFN‐α compared with the nontreated patients, after 6 months of treatment it was still decreased although not significantly. Ferritin increased significantly in the IFN‐α‐treated patients: 187% of pretreatment value after 4 weeks and 217% after 6 months (P < 0·01), while ferritin levels decreased in the nontreated patients. AAG increased significantly in IFN‐α‐treated patients (107, 114%) compared with the control‐patients (91, 76%) but differences were less compared with CRP and ferritin. sPLA₂ had a variable course, while albumin remained constant within the normal range in both patient groups. Conclusions IFN‐α induced a significant increase in ferritin, with a significant decrease in CRP, little increase in AAG, varying response of sPLA₂ and no change in albumin. This finding suggests a specific role for IFN‐α in the synthesis or secretion of ferritin. This mechanism may also be involved in the marked hyperferritinaemia in adult onset of Still’s disease.     

β细胞替代治疗1型糖尿病的研究进展

治疗1型糖尿病的主要目标是通过胰岛素注射控制血糖,以降低并发症发生。在胰岛素输注技术不足、有严重低血糖症或已接受肾脏移植治疗后服用免疫抑制的患者,启用β细胞替代治疗是一种安全且有效的治疗手段。其中同种异体胰岛移植是主要方法之一,肝内胰岛移植已被证实可以有效缓解上述不稳定1型糖尿病负担,有效预防糖尿病相关的急慢性并发症(包括曾进行过肾脏移植的患者)。患者的年龄、BMI、肾脏功能和心肺功能均会影响胰腺或胰岛移植的疗效,移植途径则受到胰腺细胞供者的数量和是否需要使用免疫抑制剂的限制。未来β细胞替代治疗的方法包括异种组织或人干细胞,肝外植入(例如网膜、皮下或肌内),诱导免疫耐受以及胰岛微包囊技术。     

Can β2‐adrenoceptor agonists,anticholinergic drugs,and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD?

Chronic obstructive pulmonary disease (COPD) has become a global epidemic disease with an increased morbidity and mortality in the world. Inflammatory process progresses and contributes to irreversible airflow limitation. However, there is no available therapy to better control the inflammatory progression and therefore to reduce the exacerbations and mortality. Thus, the development of efficient anti-inflammatory therapies is a priority for patients with COPD. β(2) -Adrenoceptor agonists and anticholinergic agents are widely used as first line drugs in management of COPD because of their efficient bronchodilator properties. At present, many studies in vitro and some data obtained in laboratory animals reveal the potential anti-inflammatory effects of these bronchodilators but their protective role against chronic inflammation and the development of emphysema in patients with COPD remains to be investigated. The anti-inflammatory effects of theophylline at low doses have also been identified. Beneficial interactions between glucocorticoids and bronchodilators have been reported, and signaling pathways explaining these synergistic effects begin to be understood, especially for theophylline. Recent data demonstrating interactions between anticholinergics with β(2) -adrenoceptor agonists aiming to better control the pulmonary inflammation and the development of emphysema in animal models of COPD justify the priority to investigate the interactive effects of a tritherapy associating corticoids with the two main categories of bronchodilators.     

β-arrestin2通过调控自噬水平在结肠炎中的作用

目的 研究β-抑制蛋白2 （β-arrestin2）是否通过调控自噬水平在结肠炎中发挥作用。方法 β-arrestin2野生型（WT）小鼠和β-arrestin2基因敲除（KO）小鼠各20只,随机分为4组,每组各10只,分别为β-arrestin2 WT对照组和实验组,β-arrestin2 KO对照组和实验组。实验组小鼠自由饮用3%葡聚糖硫酸钠7 d诱导急性溃疡性结肠炎,对照组给予无菌ddH₂O。观察并记录各组小鼠的疾病活动指数。收集小鼠结肠组织,免疫组织化学和蛋白免疫印迹法检测自噬相关蛋白微管相关蛋白1轻链3β（LC3B）、Beclin1的表达水平。在HCoEpiC细胞中,通过siRNA沉默β-arrestin2的表达,Earle's平衡盐溶液（EBSS）处理细胞以诱导细胞自噬的发生,检测LC3B表达水平。结果 β-arrestin2 WT实验组小鼠的结肠黏膜自噬相关蛋白表达水平上调,而β-arrestin2 KO实验组小鼠的结肠炎症程度明显改善,自噬相关蛋白LC3B-Ⅱ/Ⅰ表达水平下降（P < 0.05）,但Beclin1表达水平比较差异无统计学意义（P > 0.05）。在HCoEpiC细胞中沉默β-arrestin2的表达,EBSS处理后,LC3B-Ⅱ/Ⅰ表达水平下调。结论 在结肠炎中,β-arrestin2调控自噬水平,当β-arrestin2缺失时,可以通过抑制自噬改善结肠炎。     

血清β-CTx及TRACP-5b与多发性骨髓瘤骨病病情严重程度及预后关系

目的 探讨血清Ⅰ型胶原羧基端肽β特殊序列(β-CTx)及抗酒石酸酸性磷酸酶5b同工酶(TRACP-5b)与多发性骨髓瘤骨病(MMBD)病情严重程度及预后的关系。方法 回顾分析2016年1月-2020年1月收治的MMBD患者142例。通过诊治指南和影像学检查结果将患者按病情严重程度分为1、2、3、4级组,采用酶联免疫吸附法(ELISA)检测4组血清β-CTx、TRACP-5b水平,比较4组血清指标变化情况,以Spearman分析血清β-CTx、TRACP-5b与MMBD严重程度的相关性。所有患者根据生存情况分为生存组与死亡组,采用Cox回归分析影响预后的相关因素。结果 血清β-CTx、TRACP-5b水平随4组病情严重程度等级的增加而升高(P<0.05)。Spearman分析显示,血清β-CTx、TRACP-5b水平均与MMBD病情严重程度呈正相关(r=0.753、0.627,P<0.05)。142例患者截至随访时间生存98例,死亡44例,死亡组国际分期体系(ISS) Ⅲ期占比、MMBD严重程度4级占比、病理性骨折骨病类型占比、血清β2-MG、β-CTx及TRACP-5b水平较生存组更高(P<0.05)。β-CTx/TRACP-5b高、低水平的患者生存曲线差异具有统计学意义(P<0.05)。Cox回归分析显示,血清β-CTx、TRACP-5b、β2-MG水平、ISS Ⅲ期、MMBD严重程度4级、病理性骨折骨病类型是影响MMBD患者预后的危险因素(P<0.05)。结论 血清β-CTx、TRACP-5b水平随MMBD病情严重程度的增加而升高,且二者是影响MMBD预后的危险因素。     

7例抗γ-氨基丁酸B受体脑炎患者的护理

总结7例抗γ-氨基丁酸B受体脑炎患者出现癫痫发作、精神行为异常、意识状态改变的观察及护理。通过密切观察,连续评估,做好详实护理记录,及时与医生沟通,注重心理健康宣教,严格用药的观察与护理,患者恢复良好。     

Unwanted hydrolysis or α/β-peptide bond formation: how long should the rate-limiting coupling step take?

Nowadays, in Solid Phase Peptide Synthesis (SPPS), being either manual, automated, continuous flow or microwave-assisted, the reaction with various coupling reagents takes place via in situ active ester formation. In this study, the formation and stability of these key active esters were investigated with time-resolved ¹H NMR by using the common PyBOP/DIEA and HOBt/DIC coupling reagents for both α- and β-amino acids. Parallel to the amide bond formation, the hydrolysis of the α/β-active esters, a side reaction that is a considerable efficacy limiting factor, was studied. Based on the chemical nature/constitution of the active esters, three amino acid categories were determined: (i) the rapidly hydrolyzing ones (t < 6 h) with smaller (Ala) or even longer side chains (Arg) holding a large protecting group; (ii) branched amino acids (Ile, Thr) with slowly hydrolyzing (6 < t < 24 h) propensities, and (iii) non-hydrolyzing ones, such as the hard-to-couple β-amino acids or β-sugar amino acid derivatives, stable for longer times (t > 24 h) in solution. The current insight into the kinetics of this key hydrolysis side reaction serves as a guide to optimize the coupling conditions of α- and β-amino acids, thereby saving time and minimizing the amounts of reagents and amino acids to be used – all key factors of more environmentally friendly chemistry.

Parallel to the amide bond formation, the hydrolysis of the active esters of α/β-amino acids, as an unwanted side reaction limiting coupling efficacy, is studied.     

“三法三穴”推拿手法对坐骨神经损伤大鼠运动功能和转化生长因子β1/Smad2通路蛋白表达的影响

目的 探讨“三法三穴”推拿手法对坐骨神经损伤大鼠后肢运动功能,施万细胞增殖、髓鞘修复以及坐骨神经中转化生长因子β1 (TGF-β1)/Smad2通路蛋白表达的影响。方法 66只雄性Sprague-Dawley大鼠随机分为假手术组(n = 22)、模型组(n = 22)和观察组(n = 22)。模型组和观察组采用夹持法制备坐骨神经损伤模型。造模后第8天,观察组每天以点法、拨法、揉法定性定量刺激大鼠术侧殷门、承山、阳陵泉。分别于干预前和干预21 d测量坐骨神经功能指数(SFI);干预前,干预7 d、14 d、21 d行斜板测试;干预21 d,免疫荧光染色观察S100、TGF-β1、Smad2的表达;干预前,干预7 d、21 d,Western blotting检测TGF-β1、Smad2和p-Smad2蛋白表达。结果 干预前,模型组和观察组SFI和斜板测试角度低于假手术组(P < 0.05);干预21 d,观察组SFI和斜板测试角度均高于模型组( P< 0.05)。免疫荧光染色显示,干预21 d,模型组坐骨神经S100表达明显低于假手术组(P < 0.01),观察组高于模型组( P < 0.05),且与假手术组比较无显著性差异( P > 0.05)。Western blotting显示,干预前和干预7 d,模型组TGF-β1、Smad2和p-Smad2表达较假手术组升高( P < 0.05);干预21 d,三组间各蛋白表达均无显著性差异( P > 0.05)。 结论 “三法三穴”推拿手法能促进施万细胞增殖,促进髓鞘恢复,改善坐骨神经损伤大鼠后肢运动功能,但该作用可能与TGF-β1/Smad2通路无关。     

Body fat distribution and their associations with cardiovascular risk,insulin resistance and β‐cell function: are there differences between men and women?

Objective: The objective was to examine the independent and gender‐specific effects of WC and BMI on CVD risk factors, insulin resistance and β‐cell function. Design: A cross‐sectional study of 2931 adults aged 20–79 years was carried out in Fujian province by multi‐stratified sampling from July 2007 to May 2008. Gender‐specific differences of WC and BMI on CVD risk factors, insulin resistance and β‐cell function were displayed jointly by WC and BMI tertiles. The homeostasis model assessment of insulin resistance (HOMA‐IR) index and the quantitative insulin‐sensitivity check index (QUICKI): l/(log G0 ± log I0) were used to estimate insulin sensitivity; insulin secretion was assessed using the HOMA‐β index; β‐cell function was quantified as the ratio of the incremental insulin to glucose responses over the first 30 min during the OGTT (△I30/△G30). The oral disposition index (DIo) was calculated as ΔI₃₀/ΔG₃₀ × 1/fasting insulin. The Matsuda index is defined as 10,000/sqrt (FBG × FPI × [G × I]) where FPG is fasting glucose, FPI is fasting insulin, G is mean glucose during the OGTT (calculated from glucose samples at 0, 30, and 120 min), and I is mean insulin during the OGTT (calculated from insulin samples at 0, 30, and 120 min). Results: Waist circumference and BMI correlated with each other in both men (0.756, p < 0.001) and women (0.728, p < 0.001). The two indexes were independently associated with CVD risk factors (such as hypertension, metabolic syndrome, and dyslipidaemia) in both men and women. BMI was better than WC in assessing the risk of diabetes in men (p = 0.003 for BMI, and p = 0.234 for WC), while WC was better than BMI in predicting diabetes in women (p < 0.001 for WC, and p = 0.831 for BMI). There were significant associations between BMI and insulin resistance or β‐cell function even after adjustment for WC except for DIo in male subjects, but WC only associated with HOMA‐IR positively or the Matsuda index and QUICKI negatively after adjustment for BMI. For women, associations between WC and insulin resistance or β‐cell function remained strong even after adjustment for BMI besides DIo. However, there were no independent relations of BMI to insulin resistance and β‐cell function except for Matsuda index with a significant negative association after adjustment for WC in women. Conclusion: Body mass index and WC were independently associated with CVD risk factors. There were differences in the gender‐specific relevance of measures of body fat distribution in assessing the insulin resistance, β‐cell function and thus the risk of diabetes. Therefore, WC should be measured in addition to BMI to assess CVD risk accurately and implement efficient treatment strategies.     

Wnt/β-catenin信号通路相关环状RNA在肺癌中的研究进展

环状RNA（circRNA）是转录组中普遍存在的一种封闭成环RNA分子,参与癌症在内的多种疾病进展。Wnt/β-连环蛋白（β-catenin）信号通路控制着许多驱动癌症发展的细胞过程,circRNA的异常表达可通过包括Wnt/β-catenin信号通路在内的多种特定信号通路促进癌症的发生和发展。近年来多项研究表明Wnt/β-catenin信号通路相关circRNA在肺癌中作为新的生物标志物和治疗靶点的潜能。该文就Wnt/β-catenin信号通路相关circRNA对肺癌的影响做一综述,以期为肺癌诊治研究提供新的思路。     

沙利度胺治疗β-地中海贫血外周血miR-223-3p水平变化及临床价值

目的 探讨输血依赖型β-地中海贫血患者沙利度胺治疗前后外周血单个核细胞中miR-223-3p表达水平的变化,并分析与患者血红蛋白浓度(Hb)及胎儿血红蛋白(HbF)水平的关系。方法 收集8例输血依赖型β-地中海贫血患者及8例健康人的外周静脉血5ml,分离外周血单个核细胞,提取细胞总RNA,应用实时定量PCR的方法,检测口服沙利度胺有效的β-地中海贫血患者外周血单个核细胞的miR-223-3p表达水平,分析miR-223-3p与血红蛋白浓度及HbF、红细胞(RBC)、红细胞比容 (Hct)、平均红细胞体积 (MCV)、平均红细胞血红蛋白量(MCH)、血小板(PLT)的相关性。结果 在β-地中海贫血患者外周血单个核细胞中miR-223-3p相对表达量为0.191±0.089,显著高于对照组0.053±0.039(P=0.003),口服沙利度胺后miR-223-3p相对表达量为0.106±0.047(P=0.047),表达量下降,miR-223-3p表达水平与Hb(r=-0.488,P=0.015)、HCT(r=-0.420,P=0.004)水平呈显著负相关。结论 miR-223-3p在输血依赖型β-地中海贫血患者中高表达,口服沙利度胺后miR-223-3p 表达水平下降,沙利度胺可能通过靶向调节miR-223-3p而改善贫血。     

Amide conjugates of the DO3A‐N‐(α‐amino)propionate ligand: leads for stable,high relaxivity contrast agents for MRI?

A novel synthetic methodology for preparing amide conjugates of the DO3A‐N‐(α‐amino)propionate chelator is described, using the synthesis of the DO3A‐N‐(α‐benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A‐N‐(α‐benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn²⁺. The Gd[DO3A‐N‐(α‐benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A‐N‐(α‐amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents. Copyright © 2012 John Wiley & Sons, Ltd.     

TGF-β1–induced endothelial-mesenchymal transition: a potential contributor to fibrotic remodeling in atrial fibrillation?

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources. These important findings extend our understanding of the origin, biology, and function of fibroblasts and offer possibilities for therapeutic targeting of fibrosis in AF.     

约翰·霍普金斯大学护理硕士研究生教育特点及启示

目的 分析总结约翰·霍普金斯大学护理硕士研究生教育的特点,为我国护理硕士研究生教育改革发展提供参考。方法 通过登录约翰·霍普金斯大学护理学院官方网站、寻求国外硕士留学生帮助、购买相关书籍及文献回顾等收集资料,分析其护理硕士项目类型、入学条件、课程设置和教学方法等。结果 霍普金斯大学护理硕士研究生教育的特点概括为：项目目标具体明确,项目实施注重合作;入学条件灵活,资料审查全面;课程设置注重学科交叉,重视“学”和“用”的结合;多种教学方法相结合,重视高质量的在线护理教育。结论 对我国护理硕士研究生教育的启示包括：开设统一规范的专业方向,拓展合作项目;设置综合全面的入学条件,明确审核内容;加强课程设置的针对性,强调理论与实践相融合;综合使用多种教学方法,提高对在线教育的重视程度。     

免疫治疗桥接二次非血缘外周血干细胞移植治疗重型β地中海贫血一例

造血干细胞移植是目前唯一能治愈重型β地中海贫血的方法,但移植难度大,移植失败后再次移植风险更大,如何改进预处理方案提高移植成功率尚无定论,该文报道了1例接受非血缘HLA全相合供者造血干细胞移植术后发生原发排斥并接受二次移植成功患儿。该例患儿被确诊为Pesaron分度Ⅲ度的重型β地中海贫血,首次接受非血缘HLA全相合供者造血干细胞移植术,移植失败,原发排斥,自身造血恢复后1年再次接受另一非血缘HLA全相合供者外周血干细胞移植术。二次移植前30 d予氟达拉滨联合地塞米松免疫抑制治疗,调整预处理方案,并输注骨髓间充质干细胞促进植入。二次移植后患儿获得稳定植入,完全脱离输血状态至35个月,发生肺炎1次,无其他并发症。该例治疗结果提示,移植前予氟达拉滨联合地塞米松抑制受者T淋巴细胞功能可促进植入。减低强度预处理方案,辅助输注骨髓间充质干细胞促进造血重建,可以克服非血缘外周血干细胞移植治疗重型β地中海贫血的原发排斥,促进二次移植成功。