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Characterization of adolescents with functional respiratory disorders and prior history of SARS-CoV-2. 青少年功能性呼吸障碍和既往SARS-CoV-2病史的特征分析
Q1 PEDIATRICS Pub Date : 2023-09-12 DOI: 10.1186/s40348-023-00165-3
Sebastian Felix Nepomuk Bode, Anja Schwender, Monika Toth, Christine Kaeppler-Schorn, Ute Siebeneich, Joachim Freihorst, Ales Janda, Dorit Fabricius

Background: The SARS-CoV-2 pandemic has caused significant pulmonary morbidity and mortality in the adult population. Children and adolescents typically show milder symptoms; however, a relevant proportion of them report persistent pulmonary symptoms even after mild SARS-CoV-2 infection. Functional respiratory disorders may be relevant differential diagnoses of persistent dyspnea. This study aims at characterizing functional respiratory disorders that may arise after SARS-CoV-2 infection regarding their clinical presentation and pulmonary function tests as well as gaining insights into the clinical course after initiation of appropriate therapy.

Methods: This study retrospectively identified all patients referred to an outpatient clinic for pediatric pulmonology with functional respiratory disorders manifesting after proven SARS-CoV-2 infection between January 1, 2022, and October 31, 2022. Clinical history, thorough clinical examination regarding breathing patterns, and pulmonary function tests (PFTs) were taken into consideration to diagnose functional respiratory disorders.

Results: Twenty-five patients (44% female) with mean (m) age = 12.73 years (SD ± 1.86) who showed distinctive features of functional respiratory disorders after SARS-CoV-2 infection (onset at m = 4.15 (± 4.24) weeks after infection) were identified. Eleven patients showed thoracic dominant breathing with insufficient ventilation, and 4 patients mainly had symptoms of inducible laryngeal obstruction. The rest (n = 10) showed overlap of these two etiologies. Most patients had a flattened inspiratory curve on spirometry and slightly elevated residual volume on body plethysmography, but values of PFTs were normal before and after standardized treadmill exercise testing. Patients were educated about the benign nature of the condition and were offered rebreathing training. All patients with follow-up (n = 5) showed normalization of the breathing pattern within 3 months.

Conclusions: Functional respiratory disorders are important differential diagnoses in persisting post-SARS-CoV-2 dyspnea in adolescents. A combination of clinical history, detailed examination of breathing patterns, and pulmonary function tests are helpful to correctly diagnose these conditions. Reassurance and rebreathing training are the mainstay of the therapy. The clinical course is favorable.

背景:SARS-CoV-2大流行已在成人人群中引起显著的肺部发病率和死亡率。儿童和青少年通常表现出较轻的症状;然而,他们中有相当比例的人报告即使在轻度SARS-CoV-2感染后也存在持续的肺部症状。功能性呼吸障碍可能是持续性呼吸困难的相关鉴别诊断。本研究旨在了解SARS-CoV-2感染后可能出现的功能性呼吸系统疾病的临床表现和肺功能测试,并了解开始适当治疗后的临床过程。方法:本研究回顾性分析了2022年1月1日至2022年10月31日期间在儿科肺科门诊就诊的所有确诊为SARS-CoV-2感染后出现功能性呼吸障碍的患者。在诊断功能性呼吸障碍时,考虑了临床病史、有关呼吸模式的全面临床检查和肺功能测试(pft)。结果:25例患者(44%为女性),平均年龄(m) = 12.73岁(SD±1.86),在感染后(m = 4.15(±4.24)周发病)表现出明显的功能性呼吸障碍特征。11例患者表现为胸腔优势呼吸伴通气不足,4例患者主要表现为诱导性喉梗阻。其余(n = 10)显示这两种病因重叠。大多数患者肺活量计吸气曲线变平,体体积描记仪残余体积略有升高,但pft值在标准化跑步机运动测试前后均正常。患者被告知病情的良性,并接受了再呼吸训练。所有患者(n = 5)均在3个月内呼吸方式恢复正常。结论:功能性呼吸障碍是青少年持续sars - cov -2后呼吸困难的重要鉴别诊断。结合临床病史、详细的呼吸模式检查和肺功能检查有助于正确诊断这些疾病。安慰和再呼吸训练是治疗的主要内容。临床过程良好。
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引用次数: 0
Childhood asthma phenotypes and endotypes: a glance into the mosaic. 儿童哮喘表型和内型:一瞥进入马赛克。
Q1 PEDIATRICS Pub Date : 2023-08-30 DOI: 10.1186/s40348-023-00159-1
Francesco Foppiano, Bianca Schaub

Background: Asthma is an inflammatory lung disease that constitutes the most common noncommunicable chronic disease in childhood. Childhood asthma shows large heterogeneity regarding onset of disease, symptoms, severity, prognosis, and response to therapy.

Main body: Evidence suggests that this variability is due to distinct pathophysiological mechanisms, which has led to an exhaustive research effort to understand and characterize these distinct entities currently designated as "endotypes." Initially, studies focused on identifying specific groups using clinical variables yielding different "clinical phenotypes." In addition, the identification of specific patterns based on inflammatory cell counts and cytokine data has resulted in "inflammatory endotypes." More recently, an increasing number of molecular data from high-throughput technology ("omics" data) have allowed to investigate more complex "molecular endotypes."

Conclusion: A better definition and comprehension of childhood asthma heterogeneity is key for improving diagnosis and treatment. This review aims at summarizing the current knowledge on this topic and discusses some limitations in their application as well as recommendations for future studies.

背景:哮喘是一种炎症性肺部疾病,是儿童时期最常见的非传染性慢性疾病。儿童哮喘在发病、症状、严重程度、预后和治疗反应方面表现出很大的异质性。正文:有证据表明,这种可变性是由于不同的病理生理机制,这导致了详尽的研究努力来理解和表征这些不同的实体,目前被称为“内源性”。最初,研究集中于使用产生不同“临床表型”的临床变量来识别特定的群体。此外,基于炎症细胞计数和细胞因子数据的特定模式的识别导致了“炎症内型”。最近,越来越多来自高通量技术的分子数据(“组学”数据)允许研究更复杂的“分子内型”。结论:更好地定义和理解儿童哮喘异质性是提高诊断和治疗水平的关键。本文综述了目前关于这一课题的知识,并讨论了其应用中的一些局限性以及对未来研究的建议。
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引用次数: 0
Sex differences in long-term kidney fibrosis following neonatal nephron loss during ongoing nephrogenesis. 正在进行的肾脏形成过程中新生儿肾元丢失后长期肾纤维化的性别差异。
Q1 PEDIATRICS Pub Date : 2023-08-25 DOI: 10.1186/s40348-023-00164-4
Carlos Menendez-Castro, Nada Cordasic, Fabian B Fahlbusch, Joachim Woelfle, Karl F Hilgers, Andrea Hartner

Background: Clinical studies suggest that female sex plays a protective role in the development and progression of kidney disease. Recent experimental studies indicate that in male rats early nephron loss under ongoing nephrogenesis is accompanied by severe long-term sequelae. In humans, nephron formation occurs mainly in the third trimester, ceasing with 36 weeks of gestation. Due to perinatal complications, preterm infants delivered during this vulnerable period may undergo acute nephron loss. In rats nephrogenesis persists until postnatal day 10, reflecting the situation of human preterms with persisting nephrogenesis. In our animal model of neonatal uninephrectomy, female and male rats were uninephrectomized at day 1 of life. Hypothesizing sex-dependent differences, long-term renal outcome was assessed after 1 year.

Results: In both sexes, neonatal uninephrectomy was not followed by arterial hypertension at 1 year of age. Compensatory weight gain and glomerular hypertrophy of the remaining kidney occurred in uninephrectomized female and male animals. Selected markers of interstitial inflammation and fibrosis were regulated sex-dependently. The expression of monocyte chemoattractant protein-1 was increased in females, while tubulointerstitial infiltration by M1 macrophages was significantly higher in males after neonatal uninephrectomy. Neonatally uninephrectomized male rats had more glomerulosclerosis and podocyte damage compared to females, which was assessed by a semiquantitative score and desmin staining. RT-PCR revealed that after neonatal uninephrectomy in the remaining contralateral kidney of female rats the expression of candidate genes of renal development and function, i.e., wt-1, nephrin, synaptopodin, gdnf, and itga8 was higher than in males.

Conclusions: Based on these observations we conclude that female sex is protective in the long-term response of the kidney to acute nephron loss under active nephrogenesis.

背景:临床研究表明,女性在肾脏疾病的发生和发展中起保护作用。最近的实验研究表明,在正在进行的肾脏形成过程中,雄性大鼠早期肾元丢失伴随着严重的长期后遗症。在人类中,肾元的形成主要发生在妊娠晚期,在妊娠36周时停止。由于围产期并发症,早产婴儿在这一脆弱时期分娩可能发生急性肾元损失。大鼠肾形成持续到出生后第10天,反映了人类早产儿肾形成持续的情况。在我们的新生儿不切除肾动物模型中,雌性和雄性大鼠在出生第1天不切除肾。假设性别依赖性差异,1年后评估长期肾脏预后。结果:在两性中,新生儿肾切除术后在1岁时没有出现动脉高血压。未切除肾的雌性和雄性动物均出现代偿性体重增加和剩余肾脏的肾小球肥大。间质炎症和纤维化的选定标记物受性别依赖性调节。新生儿肾切除术后,雌性小鼠单核细胞趋化蛋白-1表达增加,而雄性小鼠肾小管间质M1巨噬细胞浸润明显增加。通过半定量评分和desmin染色来评估,未切除肾脏的新生雄性大鼠比雌性大鼠有更多的肾小球硬化和足细胞损伤。RT-PCR结果显示,雌性大鼠新生期单肾切除后对侧剩余肾脏wt-1、nephrin、synaptopodin、gdnf、itga8等肾脏发育和功能的候选基因表达高于雄性大鼠。结论:基于这些观察,我们得出结论,女性对活动性肾形成下急性肾单位损失的肾脏长期反应具有保护作用。
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引用次数: 0
Real-world evidence study on tolerance and growth in infants fed an infant formula with two human milk oligosaccharides vs mixed fed and exclusively breastfed infants. 用两种人乳低聚糖配方奶粉喂养的婴儿与混合喂养和纯母乳喂养的婴儿的耐受性和生长的真实证据研究。
Q1 PEDIATRICS Pub Date : 2023-08-19 DOI: 10.1186/s40348-023-00162-6
Frank Jochum, Martina Meyer-Krott, Tina Hübler, Maja Lorenz, Raffi Bedikian, Joseph Zakarian, Anja Litzka, Guido Judex, Holger Hertzberg, Daniela Klee, Lothar Maurer, Martin Schacht, Adnan Al-Radhi, Jan Maier, Alexander Kröckel, Christian Faustmann, Luca Lavalle, Samir Dahbane

Introduction: Human milk oligosaccharides (HMOs) are important components of human milk having diverse functions in the development of infants. Randomized controlled trials (RCTs) have demonstrated that infant formulas with the HMOs 2'-fucosyllactose (2'FL) and lacto-N-neotetraose (LNnT) are safe, well-tolerated, and support normal growth. This study aimed to generate real-world evidence (RWE) on growth and gastrointestinal (GI) tolerance in infants consuming a formula with 1 g/L 2'FL and 0.5 g/L LNnT, including a mixed feeding group not studied before in RCTs.

Participants and methods: This 8-week open-label prospective multicenter study was conducted in Germany and Austria, and included groups of healthy, exclusively breastfed infants (BF), exclusively formula-fed infants (FF) who received the HMO-formula, and infants mixed fed with both HMO formula and human milk (MF). Co-primary outcomes were anthropometry and gastrointestinal tolerance via validated Infant Gastrointestinal Symptom Questionnaire (IGSQ). Secondary outcomes included formula satisfaction and adverse events (AEs).

Results: One-hundred six infants completed the study (46 FF, 22 MF, and 38 BF). Mean anthropometric z-scores were comparable between groups and generally within ± 0.5 of WHO medians at week 8. IGSQ composite scores demonstrated good GI tolerance in all groups with no significant group differences at week 4 or 8. IGSQ composite scores in FF improved during the course of the study and parents provided high satisfaction ratings for the HMO-formula. Four potentially product-related AEs were reported in FF (no in MF).

Conclusions: In this RWE study examining an infant formula with HMOs, growth and GI tolerance outcomes were confirming the good tolerance and safety of this early feeding option previously reported in RCTs.

摘要:人乳寡糖(HMOs)是人乳中的重要成分,在婴儿发育过程中具有多种功能。随机对照试验(RCTs)表明,含有HMOs 2′-聚焦乳糖(2′fl)和乳酸-n -新四糖(LNnT)的婴儿配方奶粉是安全的,耐受性良好,并支持正常生长。本研究旨在为食用含有1 g/L 2'FL和0.5 g/L LNnT的配方奶粉的婴儿的生长和胃肠道耐受性提供真实证据(RWE),包括之前未在随机对照试验中研究的混合喂养组。参与者和方法:这项为期8周的开放标签前瞻性多中心研究在德国和奥地利进行,包括健康的纯母乳喂养婴儿(BF),接受HMO配方奶粉的纯配方喂养婴儿(FF),以及HMO配方奶粉和母乳混合喂养的婴儿(MF)。通过婴儿胃肠症状问卷(IGSQ)进行人体测量和胃肠耐受性测试。次要结局包括配方满意度和不良事件(ae)。结果:106名婴儿完成了研究(46名FF, 22名MF, 38名BF)。各组间的平均人体测量z分数具有可比性,通常在第8周时WHO中位数的±0.5范围内。IGSQ综合评分在所有组中显示良好的胃肠道耐受性,在第4周或第8周没有显著的组间差异。在研究过程中,FF的IGSQ综合得分有所提高,家长对HMO-formula的满意度较高。FF中报告了4例可能与产品相关的不良反应(MF中没有)。结论:在这项RWE研究中,研究了一种含有HMOs的婴儿配方奶粉,生长和胃肠道耐受性结果证实了这种早期喂养选择的良好耐受性和安全性,这是之前在随机对照试验中报道的。
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引用次数: 0
Metamizole-induced agranulocytosis (MIA): a mini review. metamizole诱导的粒细胞缺乏症(MIA):一个小回顾。
Q1 PEDIATRICS Pub Date : 2023-08-17 DOI: 10.1186/s40348-023-00160-8
Markos K Tomidis Chatzimanouil, Ines Goppelt, Yvonne Zeissig, Ulrich J Sachs, Martin W Laass

Metamizole is an analgesic, antipyretic, and spasmolytic drug in Germany only approved for the treatment of severe pain or high fever that does not respond to other measures. In recent years, an increased use has been described among both adults and children, often against the approved indication. The most important side effect of metamizole is the development of agranulocytosis (neutrophil count < 500/µL). Incidence of metamizole-induced agranulocytosis (MIA) ranges depending on the study from 0.96 cases per million per year to 1:1602 per patient and metamizole prescription. The risk of agranulocytosis in children remains unclear, but is probably lower than in adults. Female gender and older age are associated with higher incidence, reflecting prescription distribution. MIA is dose-independent and risk seems to increase with duration of intake. In patients with past exposure, re-exposure may lead to rapid onset. MIA is believed to be induced either through immunologic or toxic mechanisms. MIA presents with fever, sore throat, fatigue, and mucosal inflammation, up to ulceration. Even in the case of suspected MIA, treatment with metamizole should be immediately paused and an examination of the blood cell count is required. In case of local or systemic infections, empirical therapy with broad-spectrum antibiotics should be administered. G-CSF therapy should be limited to patients with poor prognostic factors. The patient should be monitored closely until the neutrophil count returns to normal. Re-exposure to metamizole must be avoided.

在德国,Metamizole是一种镇痛、解热和解痉药,仅被批准用于治疗其他措施无效的严重疼痛或高热。近年来,在成人和儿童中有越来越多的使用,经常违反批准的适应症。甲硝唑最重要的副作用是粒细胞缺乏症(中性粒细胞计数)
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引用次数: 1
Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus (jSLE). 青少年发病的系统性红斑狼疮(jSLE)的神经精神参与。
IF 2.4 Q1 PEDIATRICS Pub Date : 2023-08-09 DOI: 10.1186/s40348-023-00161-7
Valentina Natoli, Amandine Charras, Gabriele Hahn, Christian M Hedrich

Systemic lupus erythematosus (SLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Approximately 15-20% of SLE patients develop the disease during childhood or adolescence (juvenile-onset SLE/jSLE). Patients with jSLE exhibit more variable and severe disease when compared to patients with disease-onset during adulthood. Neuropsychiatric (NP) involvement is a clinically heterogenous and potentially severe complication. Published reports on the incidence and prevalence of NP-jSLE are scarce, and the exact pathophysiology is poorly understood.This manuscript provides a review of the existing literature, suggesting NP involvement in 13.5-51% of jSLE patients. Among patients with NP-jSLE affecting the CNS, we propose two main subgroups: (i) a chronic progressive, predominantly type 1 interferon-driven form that poorly responds to currently used treatments, and (ii) an acutely aggressive form that usually presents early during the disease that may be primarily mediated by auto-reactive effector lymphocytes. While this hypothesis requires to be tested in large collaborative international cohort studies, it may offer future patient stratification and individualised care.

系统性红斑狼疮(SLE)是一种罕见的自身免疫性/炎症性疾病,发病率和死亡率很高。大约15-20%的SLE患者在儿童期或青春期发病(少年型SLE/jSLE)。与成年期发病的患者相比,jSLE患者表现出更多的变异性和严重的疾病。神经精神(NP)受累是一种临床异质性和潜在的严重并发症。关于NP-jSLE发病率和患病率的报道很少,确切的病理生理机制也知之甚少。本文对现有文献进行了回顾,表明13.5-51%的jSLE患者有NP参与。在影响中枢神经系统的NP-jSLE患者中,我们提出了两个主要的亚组:(i)慢性进行性,主要是1型干扰素驱动型,对目前使用的治疗反应较差;(ii)急性侵袭型,通常在疾病早期出现,可能主要由自身反应性效应淋巴细胞介导。虽然这一假设需要在大型国际合作队列研究中进行验证,但它可能为未来的患者分层和个性化护理提供帮助。
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引用次数: 0
Perinatal origins of bronchopulmonary dysplasia-deciphering normal and impaired lung development cell by cell. 支气管肺发育不良的围产期起源——逐个细胞解读正常和受损的肺发育。
Q1 PEDIATRICS Pub Date : 2023-04-18 DOI: 10.1186/s40348-023-00158-2
I Mižíková, B Thébaud

Bronchopulmonary dysplasia (BPD) is a multifactorial disease occurring as a consequence of premature birth, as well as antenatal and postnatal injury to the developing lung. BPD morbidity and severity depend on a complex interplay between prenatal and postnatal inflammation, mechanical ventilation, and oxygen therapy as well as associated prematurity-related complications. These initial hits result in ill-explored aberrant immune and reparative response, activation of pro-fibrotic and anti-angiogenic factors, which further perpetuate the injury. Histologically, the disease presents primarily by impaired lung development and an arrest in lung microvascular maturation. Consequently, BPD leads to respiratory complications beyond the neonatal period and may result in premature aging of the lung. While the numerous prenatal and postnatal stimuli contributing to BPD pathogenesis are relatively well known, the specific cell populations driving the injury, as well as underlying mechanisms are still not well understood. Recently, an effort to gain a more detailed insight into the cellular composition of the developing lung and its progenitor populations has unfold. Here, we provide an overview of the current knowledge regarding perinatal origin of BPD and discuss underlying mechanisms, as well as novel approaches to study the perturbed lung development.

支气管肺发育不良(BPD)是一种多因素疾病,由于早产以及产前和产后对发育中的肺的损伤而发生。BPD的发病率和严重程度取决于产前和产后炎症、机械通气、氧疗以及相关的早产相关并发症之间的复杂相互作用。这些最初的撞击导致未被充分探索的异常免疫和修复反应,促纤维化和抗血管生成因子的激活,进一步使损伤永久化。组织学上,该病主要表现为肺发育受损和肺微血管成熟停止。因此,BPD会导致新生儿期以后的呼吸系统并发症,并可能导致肺部过早衰老。虽然许多产前和产后刺激对BPD发病机制的影响相对已知,但驱动损伤的特定细胞群及其潜在机制仍未得到很好的理解。最近,一项努力,以获得更详细的洞察细胞组成的发展中的肺和它的祖先群体已经展开。在这里,我们概述了目前关于BPD围产期起源的知识,并讨论了潜在的机制,以及研究肺发育紊乱的新方法。
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引用次数: 2
New insights into the immune functions of podocytes: the role of complement. 足细胞免疫功能的新认识:补体的作用。
Q1 PEDIATRICS Pub Date : 2023-04-15 DOI: 10.1186/s40348-023-00157-3
Valentina Bruno, Anne Katrin Mühlig, Jun Oh, Christoph Licht

Podocytes are differentiated epithelial cells which play an essential role to ensure a normal function of the glomerular filtration barrier (GFB). In addition to their adhesive properties in maintaining the integrity of the filtration barrier, they have other functions, such as synthesis of components of the glomerular basement membrane (GBM), production of vascular endothelial growth factor (VEGF), release of inflammatory proteins, and expression of complement components. They also participate in the glomerular crosstalk through multiple signalling pathways, including endothelin-1, VEGF, transforming growth factor β (TGFβ), bone morphogenetic protein 7 (BMP-7), latent transforming growth factor β-binding protein 1 (LTBP1), and extracellular vesicles.Growing literature suggests that podocytes share many properties of innate and adaptive immunity, supporting a multifunctional role ensuring a healthy glomerulus. As consequence, the "immune podocyte" dysfunction is thought to be involved in the pathogenesis of several glomerular diseases, referred to as "podocytopathies." Multiple factors like mechanical, oxidative, and/or immunologic stressors can induce cell injury. The complement system, as part of both innate and adaptive immunity, can also define podocyte damage by several mechanisms, such as reactive oxygen species (ROS) generation, cytokine production, and endoplasmic reticulum stress, ultimately affecting the integrity of the cytoskeleton, with subsequent podocyte detachment from the GBM and onset of proteinuria.Interestingly, podocytes are found to be both source and target of complement-mediated injury. Podocytes express complement proteins which contribute to local complement activation. At the same time, they rely on several protective mechanisms to escape this damage. Podocytes express complement factor H (CFH), one of the main regulators of the complement cascade, as well as membrane-bound complement regulators like CD46 or membrane cofactor protein (MCP), CD55 or decay-accelerating factor (DAF), and CD59 or defensin. Further mechanisms, like autophagy or actin-based endocytosis, are also involved to ensure podocyte homeostasis and protection against injury.This review will provide an overview of the immune functions of podocytes and their response to immune-mediated injury, focusing on the pathogenic link between complement and podocyte damage.

足细胞是一种分化的上皮细胞,对确保肾小球滤过屏障(GFB)的正常功能起着至关重要的作用。除了具有维持滤过屏障完整性的粘附特性外,它们还有其他功能,如合成肾小球基底膜(GBM)成分、产生血管内皮生长因子(VEGF)、释放炎症蛋白和表达补体成分。它们还通过内皮素-1、VEGF、转化生长因子β (TGFβ)、骨形态发生蛋白7 (BMP-7)、潜伏转化生长因子β结合蛋白1 (LTBP1)和细胞外囊泡等多种信号通路参与肾小球串音。越来越多的文献表明足细胞具有先天免疫和适应性免疫的许多特性,支持确保健康肾小球的多功能作用。因此,“免疫足细胞”功能障碍被认为与几种肾小球疾病(称为“足细胞病”)的发病机制有关。机械性、氧化性和/或免疫应激等多种因素可诱导细胞损伤。作为先天免疫和适应性免疫的一部分,补体系统也可以通过多种机制定义足细胞损伤,如活性氧(ROS)的产生、细胞因子的产生和内质网应激,最终影响细胞骨架的完整性,导致足细胞脱离GBM和蛋白尿的发生。有趣的是,足细胞被发现是补体介导的损伤的来源和目标。足细胞表达补体蛋白,促进局部补体活化。同时,它们依靠几种保护机制来逃避这种伤害。足细胞表达补体因子H (CFH),补体级联的主要调节因子之一,以及膜结合的补体调节因子如CD46或膜辅助因子蛋白(MCP), CD55或衰变加速因子(DAF), CD59或防御素。进一步的机制,如自噬或基于动作蛋白的内吞作用,也参与确保足细胞稳态和保护免受损伤。本文将对足细胞的免疫功能及其对免疫介导损伤的反应进行综述,重点讨论补体与足细胞损伤之间的致病关系。
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引用次数: 1
Modelling human lower urinary tract malformations in zebrafish. 用斑马鱼模拟人类下尿路畸形。
Q1 PEDIATRICS Pub Date : 2023-03-29 DOI: 10.1186/s40348-023-00156-4
Caroline M Kolvenbach, Gabriel C Dworschak, Johanna M Rieke, Adrian S Woolf, Heiko Reutter, Benjamin Odermatt, Alina C Hilger

Advances in molecular biology are improving our understanding of the genetic causes underlying human congenital lower urinary tract (i.e., bladder and urethral) malformations. This has recently led to the identification of the first disease-causing variants in the gene BNC2 for isolated lower urinary tract anatomical obstruction (LUTO), and of WNT3 and SLC20A1 as genes implicated in the pathogenesis of the group of conditions called bladder-exstrophy-epispadias complex (BEEC). Implicating candidate genes from human genetic data requires evidence of their influence on lower urinary tract development and evidence of the found genetic variants' pathogenicity. The zebrafish (Danio rerio) has many advantages for use as a vertebrate model organism for the lower urinary tract. Rapid reproduction with numerous offspring, comparable anatomical kidney and lower urinary tract homology, and easy genetic manipulability by Morpholino®-based knockdown or CRISPR/Cas editing are among its advantages. In addition, established marker staining for well-known molecules involved in urinary tract development using whole-mount in situ hybridization (WISH) and the usage of transgenic lines expressing fluorescent protein under a tissue-specific promoter allow easy visualization of phenotypic abnormalities of genetically modified zebrafish. Assays to examine the functionality of the excretory organs can also be modeled in vivo with the zebrafish. The approach of using these multiple techniques in zebrafish not only enables rapid and efficient investigation of candidate genes for lower urinary tract malformations derived from human data, but also cautiously allows transferability of causality from a non-mammalian vertebrate to humans.

分子生物学的进步使我们对人类先天性下尿路(即膀胱和尿道)畸形的遗传原因有了更深入的了解。最近,我们首次发现了导致孤立性下尿路解剖性梗阻(LUTO)的 BNC2 基因中的致病变体,并发现了 WNT3 和 SLC20A1 基因与膀胱萎缩-尿道外翻综合征(BEEC)的发病机制有关。要从人类基因数据中推断出候选基因,需要有证据证明它们对下尿路发育的影响,并证明所发现的基因变异具有致病性。斑马鱼(Danio rerio)作为下尿路的脊椎动物模型有很多优点。斑马鱼繁殖速度快,后代数量多,肾脏和下尿路解剖结构相似,而且易于通过基于 Morpholino® 的基因敲除或 CRISPR/Cas 编辑进行遗传操作,这些都是它的优势。此外,利用全贴片原位杂交(WISH)对参与尿路发育的知名分子进行标记染色,以及使用在组织特异性启动子下表达荧光蛋白的转基因品系,可以方便地观察转基因斑马鱼的表型异常。检查排泄器官功能的试验也可以用斑马鱼在体内模拟。在斑马鱼身上使用这些多种技术的方法不仅能快速有效地研究从人类数据中得出的下尿路畸形候选基因,还能谨慎地将非哺乳类脊椎动物的因果关系转移到人类身上。
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引用次数: 0
Umbilical catheter placement aided by coronary guidewires. 在冠状动脉导丝辅助下放置脐带导管。
Q1 PEDIATRICS Pub Date : 2023-03-14 DOI: 10.1186/s40348-023-00155-5
Katarzyna Gendera, Stanimir Georgiev, Peter Ewert, Stefan Eckstein, Christoph Fusch, Niels Rochow

Catheterization of the umbilical vessels has proven to be an effective and relatively rapid method for gaining central vascular access in neonates. However, it can be technically difficult, the procedure may last 30 min or longer, and it can be associated with complications in some patients. We suggest using a coronary guidewire during catheterization of umbilical vessels to support the placement of umbilical catheters and significantly reduce a risk for complications. We tested the proposed technique in 6 successful ex vivo bench tests of catheterization of the umbilical vessels in stillborn piglets immediately after birth. We are confident that using coronary guidewire as a guiding tool during catheterization of the umbilical vessels is a rapid and safe method. We expect that it allows to obtain a vascular access with lower risk for dangerous procedural complications, which could be a lifesaving in critically ill patients. However, the approach needs to be validated in a comparative study in neonates.

脐带血管导管已被证明是一种有效和相对快速的方法,以获得中央血管通路在新生儿。然而,这在技术上可能很困难,手术可能持续30分钟或更长时间,并且在一些患者中可能伴有并发症。我们建议在脐带血管置管时使用冠状动脉导丝,以支持脐带导管的放置,并显著降低并发症的风险。我们在6个成功的死产仔猪出生后脐带血管插管离体实验中测试了所提出的技术。我们相信使用冠状动脉导丝作为引导工具在脐带血管置管过程中是一种快速和安全的方法。我们希望它能在降低手术并发症风险的情况下获得血管通路,这可能是危重病人的救命之恩。然而,该方法需要在新生儿的比较研究中得到验证。
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Molecular and cellular pediatrics
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