目的:分析2型PI3Kδ过度活化综合征（APDS2）患儿的临床与免疫学特征。方法:回顾性分析重庆医科大学附属儿童医院收治的1例APDS2患儿临床资料、免疫相关基因测序、影像学和实验室检查结果，利用流式细胞术对患儿淋巴细胞亚群及其表型进行检测,并以正常同龄儿童或患儿父亲为对照进行对比分析。结果:患儿　女，6岁4月龄，因"面色苍白1个月余，咳嗽7 d"于2017年6月首次入院，IgA（<0.067 g/L）降低伴IgM（2.55 g/L）升高，腹部超声提示肝脏（肋下1.7 cm）和脾脏（肋下3.6 cm）肿大，基因测序显示患儿PIK3R1基因c.1425+1G>A杂合突变，予醋酸泼尼松（10 mg/次，3次/d，逐渐减量）口服治疗7个月，患儿IgM降至正常（1.72 g/L），肝脾缩小（肝肋下0 cm，脾肋下0.5 cm）。2019年7月因"面色苍黄半个月"二次入院，精细免疫分型提示初始CD4 +T细胞（0.386）和初始CD8 +T细胞（0.271）比例降低，终末分化效应记忆CD8 +T细胞（0.377）和过渡性B细胞（0.223）比例增高。患儿CD3 +T、CD4 +T、CD8 +T细胞（4 125、5 213、3 497）磷酸化蛋白激酶B（AKT）的平均荧光强度峰值高于其父亲（3 434、3 312、3 058）。患儿滤泡辅助T细胞（0.299）、Th1（0.491）和类Th1（0.438）比例高于正常儿童（0.156、0.313、0.303），而Th17（0.126）和类Th17（0.188）比例低于正常儿童（0.198，0.315）。患儿T细胞衰老指标CD57比例（0.306）高于正常儿童（0.246）。 结论:APDS2患儿体液免疫和细胞免疫均有不同程度受损，激素治疗对其淋巴组织增生和自身免疫性溶血性贫血等临床症状有一定改善。

磷脂酰肌醇3-激酶δ过度活化综合征(activated phosphoinositide 3-kinase δ syndrome，APDS)是由磷脂酰肌醇3-激酶δ(phosphoinositide 3-kinase δ，PI3Kδ)过度活化引起的原发性免疫缺陷病 [1]。APDS1是因PIK3CD基因突变引起，而APDS2是由PIK3RI基因突变引起 [2]，都导致PI3K-AKT-mTOR信号通路过度活化，造成淋巴细胞增殖和免疫抑制 [3]。现国内外报道的热点集中在c.3061G>A(E1021K)位点突变，尚未见c.1690-8C>T位点突变。现报道苏州大学附属儿童医院肾脏免疫科经基因检查确诊的2例APDS患儿，以期加深对此病的认识。

本文报道1例临床罕见的磷脂酰肌醇3-激酶δ（PI3Kδ）过度活化综合征（APDS）幼年女性患者。患儿以“间断乏力2年余”入院就诊，遗传性疾病全外显子检测提示患儿携带PIK3CD基因的杂合致病突变 c.3061G>A和SPTB基因的1个杂合意义未明突变，诊断PI3Kδ过度活化综合征。与胞兄人类白细胞抗原（HLA）配型为半相合，经异基因造血干细胞移植治疗，术后骨髓检查提示骨髓增生明显活跃，三系增生，骨髓呈完全嵌合状态。患儿定期复查评估病情稳定。

磷脂酰肌醇3激酶δ过度活化综合征(activated phosphoinositide 3-kinase-delta syndrome，APDS)是一种罕见的常染色体显性遗传的原发性免疫缺陷病。根据基因突变类型的不同分为APDS1型和APDS2型。APDS1患者较易发生支气管扩张、鼻窦炎、肝脾肿大、哮喘、自身免疫性或自身炎症性疾病，更频繁感染肺炎链球菌、流感嗜血杆菌。APDS2患者较易发生肺炎、眼部感染、淋巴结病、恶性肿瘤和神经/生长迟缓。免疫学特征中APDS1的T细胞计数显著降低，APDS2更易出现IgM水平升高。雷帕霉素治疗对APDS的两种类型都有益处，而Leniolisib在APDS1患者中的耐受性更好。该文通过对APDS1型和APDS2型临床表现、免疫学特征与治疗方面进行综述，以提高临床医生对APDS的认识。

背景 PI3Kδ 过度活化综合征(APDS)采用传统治疗方案预防感染的疗效欠佳,近年来雷帕霉素被用于PIK3CD基因突变所致的APDS1 患儿的临床治疗.目的 探讨雷帕霉素治疗APDS1 的疗效和安全性.设计 病例系列报告.方法 纳入2017 年6 月至2023 年6 月在浙江大学医学院附属儿童医院经基因检测确诊为APDS1 且口服雷帕霉素治疗的连续病例.国内儿童雷帕霉素治疗APDS引起的非肿瘤性淋巴细胞增生,仍属于超说明书用药,用药前家长均充分了解用药风险并签署了知情同意书.雷帕霉素口服剂量为 1 mg·m-2·d-1.主要结局指标 ①12 个月内发生肺炎的次数;②B超评估肝、脾、淋巴结肿大情况.结果 4 例使用雷帕霉素治疗的 APDS1 患儿中,男 3 例、女 1 例,发病年龄为(35.5±17.9)月龄,确诊年龄(56.5±35.0)月龄;全外显子组测序均显示PIK3CD基因c.3061G＞A(p.E1021K)新发杂合突变;均因"反复咳嗽"就诊,均有肝、脾、淋巴结肿大;均有肺炎,反复腮腺炎 2 例,伴特异性皮炎、炎症性肠病和韦格纳肉芽肿病各1 例,生长迟缓 2 例;4 例均行支气管镜检查,3 例有支气管内膜鹅卵石样凸起;均有CD19+B细胞比例下降、CD4+/CD8+倒置,3 例 IgM升高,1 例 IgG下降.在雷帕霉素治疗前均予IVIG、抗感染、糖皮质激素等治疗,治疗后仍有反复呼吸道感染、肝脾肿大,且 3 例出现PLT减少,2 例出现贫血.4 例患儿确诊后 1～44 个月起口服雷帕霉素,疗程 12～58 个月.雷帕霉素治疗后 12 个月肺炎年均次数由 5.3 次降至 1.0 次,肝、脾和浅表淋巴结肿大均明显改善,Hb和PLT均恢复至正常水平,但免疫学指标在治疗前后比较差异均无统计学意义.随访期间未发现雷帕霉素相关不良反应,无发生肿瘤及死亡病例.结论 雷帕霉素对APSD1 有一定疗效且相对安全.

目的 总结7例PI3Kδ过度活化综合征(activated phosphoinositide 3-kinase delta syndrome,APDS)患儿的临床资料,提高对该病的认识.方法 回顾性分析2019年1月—2023年8月湖南省人民医院收治的7例APDS患儿的临床资料.结果 7例患儿(男4例,女3例)中位发病年龄为30个月,中位诊断年龄为101个月.临床表现:反复呼吸道感染、肝脾大及多部位淋巴结肿大7例,脓毒血症5例,中耳炎及多发性龋齿3例,腹泻及关节痛2例,淋巴瘤、系统性红斑狼疮各1例.4例患儿行纤维支气管镜检查,管腔内均可见大量散在的结节样突起.最常见的呼吸道病原为肺炎链球菌(4例).6例患儿为p.E1021K位点错义突变,1例为p.434-475del位点剪切突变.结论 p.E1021K是APDS患儿最常见的突变位点.对于具有反复呼吸道感染、肝脾大、多部位淋巴结肿大、中耳炎、龋齿等表现1项或多项,且纤维支气管镜下见散在结节样突起的患儿,需警惕APDS.

精神分裂症(schizophrenia,SCH)是一种主要以感知、思维、情感、行为等多方面障碍和精神活动不协调为表现的精神病,其特征为患者出现语言混乱、异常行为及自知力缺失.SCH患者可能出现的症状包括幻觉(大多以幻听的形式出现)、妄想(性质通常不合理,或感到被逼害)以及思维和言语紊乱.思维和言语紊乱的程度可从较轻微的思维不清晰至较严重的胡言乱语;患者普遍出现社交退缩、对穿衣和卫生不感兴趣,以及失去动力和判断力的情况[1].青春期晚期至成年早期是SCH发病的高峰,这亦是青壮年社会和职业发展的关键年龄[2].SCH的一线治疗方法是为患者开具处方抗精神病药物(antipsychotic drugs,APDs)如奥氮平、氯氮平、利培酮等,APDs可在约 7～14 d减轻患者阳性症状的程度,但长期服用APDs会出现不良反应[3].越来越多的研究[4-6]表明,某些种类的APDs可能对骨密度(bone mineral density,BMD)及骨代谢产生不利影响.本文旨在对长期服用APDs 的SCH患者发生骨代谢异常的流行病学及可能的危险因素和发病机制进行综述,同时归纳临床现有预防和治疗骨代谢异常的有效方案.

Aconitine(ACO),a main active ingredient of Aconitum,is well-known for its cardiotoxicity.However,the mechanisms of toxic action of ACO remain unclear.In the current study,we investigated the cardiac effects of ACO and mesaconitine(MACO),a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs.We showed that intravenous administration of ACO or MACO(25 μg/kg)to guinea pigs caused various types of arrhythmias in electrocardiogram(ECG)recording,including ventricular premature beats(VPB),atrioventricular blockade(AVB),ventricular tachycardia(VT),and ventricular fibrillation(VF).MACO displayed more potent arrhythmogenic effect than ACO.We conducted whole-cell patch-clamp recording in isolated guinea pig ventricular myocytes,and observed that treatment with ACO(0.3,3 μM)or MACO(0.1,0.3 μM)depolarized the resting membrane potential(RMP)and reduced the action potential amplitude(APA)and durations(APDs)in a concentration-dependent manner.The ACO-and MACO-induced AP remodeling was largely abolished by an lNa blocker tetrodotoxin(2 μM)and partly abolished by a specific Na+/K+pump(NKP)blocker ouabain(0.1 μM).Furthermore,we observed that treatment with ACO or MACO attenuated NKP current(INa/c)and increased peak lNa by accelerating the sodium channel activation with the EC50 of 8.36 ±1.89 and 1.33 ± 0.16 μM,respectively.Incubation of ventricular myocytes with ACO or MACO concentration-dependently increased intracellular Na+and Ca2+concentrations.In conclusion,the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak tNa via accelerating sodium channel activation and inhibiting the INa/c.These results may help to improve our understanding of cardiotoxic mechanisms of ACO and MACO,and identify potential novel therapeutic targets for Aconitum poisoning.

目的 探讨PIK3CD基因突变所致PI3Kδ过度活化综合征(APDS)的临床特征、免疫学特征及基因突变特点.方法 回顾性分析2017年7月深圳市儿童医院收治的APDS家系中2例患儿临床资料及全外显子基因测序结果,并总结复习文献.结果 2例女性患儿,就诊年龄分别为9岁4月龄和6岁2月龄,均以大便带血为首发症状,伴反复呼吸道感染.病原学检查提示巨细胞病毒和(或)EB病毒感染.免疫学表型显示初始CD4+T细胞及初始CD8T细胞数量减少,记忆B细胞减少,总IgG正常,IgG2显著降低,例1同时伴IgA水平降低及IgM升高.胸部影像学检查提示肺实变及支气管扩张.纤维支气管镜及消化内镜下分别见呼吸道和消化道黏膜滤泡样增生性病变.外周血基因测序结果显示2例患儿均存在PIK3CD基因c.3061G＞A(E1021K)杂合突变,其父母均未见该基因位点变异.结论 APDS1主要表现为反复呼吸道感染、血便、淋巴增殖、联合免疫缺陷及PIK3CD基因致病性杂合突变.

Interleukin-17A(IL-17),a potent proinflammatory cytokine,has been shown to participate in cardiac electrical disorders.Diabetes mellitus is an independent risk factor for ventricular arrhythmia.In this study,we investigated the role of IL-17 in ventricular arrhythmia of diabetic mice.Diabetes was induced in both wild-type and IL-17 knockout mice by intraperitoneal injection of streptozotocin(STZ).High-frequency electrical stimuli were delivered into the right ventricle to induce ventricular arrhythmias.We showed that the occurrence rate of ventricular tachycardia was significantly increased in diabetic mice,which was attenuated by IL-17 knockout.We conducted optical mapping on perfused mouse hearts and found that cardiac conduction velocity(CV)was significantly decreased,and action potential duration(APD)was prolonged in diabetic mice,which were mitigated by IL-17 knockout.We performed whole-cell patch clamp recordings from isolated ventricular myocytes,and found that the densities of Ito,INa and ICa,L were reduced,the APDs at 50％and 90％repolarization were increased,and early afterdepolarization(EAD)was markedly increased in diabetic mice.These alterations were alleviated by the knockout of IL-17.Moreover,knockout of IL-17 alleviated the downregulation of Nav1.5(the pore forming subunit of INa),Cav1.2(the main component subunit of ICa,L)and KChIP2(potassium voltage-gated channel interacting protein 2,the regulatory subunit of Ito)in the hearts of diabetic mice.The expression of NF-κB was significantly upregulated in the hearts of diabetic mice,which was suppressed by IL-17 knockout.In neonatal mouse ventricular myocytes,knockdown of NF-κB significantly increased the expression of Nav1.5,Cav1.2 and KChIP2.These results imply that IL-17 may represent a potential target for the development of agents against diabetes-related ventricular arrhythmias.