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How FGF23 shapes multiple organs in chronic kidney disease. 慢性肾脏疾病中FGF23如何影响多个器官。
Q1 PEDIATRICS Pub Date : 2021-09-18 DOI: 10.1186/s40348-021-00123-x
Maren Leifheit-Nestler, Dieter Haffner

Chronic kidney disease (CKD) is associated with distinct alterations in mineral metabolism in children and adults resulting in multiple organ dysfunctions. Children with advanced CKD often suffer from impaired bone mineralization, bone deformities and fractures, growth failure, muscle weakness, and vascular and soft tissue calcification, a complex which was recently termed CKD-mineral and bone disorder (CKD-MBD). The latter is a major contributor to the enhanced cardiovascular disease comorbidity and mortality in these patients. Elevated circulating levels of the endocrine-acting phosphaturic hormone fibroblast growth factor (FGF) 23 are the first detectable alteration of mineral metabolism and thus CKD-MBD. FGF23 is expressed and secreted from osteocytes and osteoblasts and rises, most likely due to increased phosphate load, progressively as kidney function declines in order to maintain phosphate homeostasis. Although not measured in clinical routine yet, CKD-mediated increased circulating levels of FGF23 in children are associated with pathological cardiac remodeling, vascular alterations, and increased cognitive risk. Clinical and experimental studies addressing other FGF23-mediated complications of kidney failure, such as hypertension and impaired bone mineralization, show partly conflicting results, and the causal relationships are not always entirely clear. This short review summarizes regulators of FGF23 synthesis altered in CKD and the main CKD-mediated organ dysfunctions related to high FGF23 levels.

慢性肾脏疾病(CKD)与儿童和成人矿物质代谢的明显改变相关,导致多器官功能障碍。患有晚期CKD的儿童经常遭受骨矿化受损,骨畸形和骨折,生长衰竭,肌肉无力,血管和软组织钙化,最近被称为CKD矿物质和骨骼疾病(CKD- mbd)。后者是这些患者心血管疾病合并症和死亡率增加的主要因素。循环中内分泌作用的磷酸化激素成纤维细胞生长因子(FGF) 23水平的升高是矿物质代谢的第一个可检测的改变,因此CKD-MBD。FGF23由骨细胞和成骨细胞表达和分泌,并随着肾脏功能下降以维持磷酸盐稳态而逐渐升高,这很可能是由于磷酸盐负荷增加所致。虽然尚未在临床常规中测量,但ckd介导的儿童FGF23循环水平升高与病理性心脏重构、血管改变和认知风险增加有关。针对其他fgf23介导的肾衰竭并发症(如高血压和骨矿化受损)的临床和实验研究显示,部分结果相互矛盾,而且因果关系并不总是完全清楚。这篇简短的综述总结了CKD中FGF23合成调节因子的改变以及与高FGF23水平相关的主要CKD介导的器官功能障碍。
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引用次数: 8
ESPED survey on newly diagnosed immune thrombocytopenia in childhood: how much treatment do we give? 儿童新诊断的免疫性血小板减少症的ESPED调查:我们给予多少治疗?
Q1 PEDIATRICS Pub Date : 2021-09-05 DOI: 10.1186/s40348-021-00121-z
Hannah von Lukowicz, Paul-Gerhardt Schlegel, Christoph Härtel, Henner Morbach, Imme Haubitz, Verena Wiegering

Background: Immune thrombocytopenia (ITP) is an autoimmune disease associated with isolated thrombocytopenia, which is caused by an imbalance between platelet production and platelet destruction. Petechial and mucous membrane hemorrhages are characteristic of ITP, but life-threatening bleeding rarely occurs. Depending on the bleeding symptoms, ITP can be treated with glucocorticoids (GC), intravenous immunoglobulins (IVIG), or in severe cases, platelet transfusions. Mild bleeding does not necessarily require therapy. Using the German Surveillance Unit for rare Pediatric Diseases (ESPED) we conducted a prospective survey on ITP patients in all German Children's Hospitals between September 2018 and August 2019. We collected data on ITP, including the clinical course, therapy implementation recommendations (according to the Association of German Scientific Medical Societies guidelines), outcome, and influence of treatment regimens depending on the treating physician´s experience with ITP patients.

Results: Of the 287 recorded cases of children with ITP, 268 questionnaires were sent to the authors. Two hundred seventeen of the questionnaires fulfilled the inclusion criteria. ITP affected boys and girls similarly, and the median age of manifestation was 3.5 years. The main reasons for hospitalization were thrombocytopenia, bleeding signs, hematomas, and/or petechiae. Bleeding scores were ≤ 3 in 96% of children, which corresponded to a low-to-moderately low risk of bleeding. No life-threatening bleeding was documented. The most common therapies were IVIG (n = 59), GC (n = 33), or a combination of these (n = 17). Blood products (i.e., red blood cells, platelet concentrate, and fresh frozen plasma) were given to 13 patients. Compared to the established guidelines, 67 patients were over-treated, and 2 patients were under-treated.

Conclusions: Adherence to German ITP treatment guidelines is currently limited. To improve patient safety and medical care, better medical training and dissemination of the guidelines are required in line with targeted analyses of patients with serious bleeding events to identify potential risk constellations.

背景:免疫性血小板减少症(ITP)是一种与孤立性血小板减少症相关的自身免疫性疾病,它是由血小板产生和血小板破坏之间的不平衡引起的。点状和粘膜出血是ITP的特征,但危及生命的出血很少发生。根据出血症状,ITP可以用糖皮质激素(GC)、静脉注射免疫球蛋白(IVIG)治疗,或者在严重的情况下,输注血小板。轻度出血并不一定需要治疗。利用德国罕见儿科疾病监测单位(ESPED),我们对2018年9月至2019年8月期间所有德国儿童医院的ITP患者进行了前瞻性调查。我们收集了关于ITP的数据,包括临床过程、治疗实施建议(根据德国科学医学协会指南)、结果和治疗方案的影响,这取决于治疗医生对ITP患者的经验。结果:在记录的287例ITP患儿中,向作者发放了268份问卷。217份问卷符合纳入标准。ITP对男孩和女孩的影响相似,表现的中位年龄为3.5岁。住院的主要原因是血小板减少、出血症状、血肿和/或瘀点。96%的儿童出血评分≤3分,对应于低至中低出血风险。没有危及生命的出血记录。最常见的治疗方法是IVIG (n = 59)、GC (n = 33)或这些治疗方法的联合(n = 17)。13例患者给予血液制品(即红细胞、浓缩血小板和新鲜冷冻血浆)。与既定指南相比,67例患者治疗过度,2例患者治疗不足。结论:目前对德国ITP治疗指南的依从性有限。为了改善患者安全和医疗保健,需要更好地进行医疗培训和传播准则,同时对严重出血事件的患者进行有针对性的分析,以确定潜在的风险星座。
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引用次数: 0
A fresh look to the phenotype in mono-allelic likely pathogenic variants of the leptin and the leptin receptor gene. 对瘦素和瘦素受体基因的单等位基因可能致病变异的表型进行了新的观察。
Q1 PEDIATRICS Pub Date : 2021-08-26 DOI: 10.1186/s40348-021-00119-7
Ingrid Koerber-Rosso, Stephanie Brandt, Julia von Schnurbein, Pamela Fischer-Posovszky, Josef Hoegel, Hannah Rabenstein, Reiner Siebert, Martin Wabitsch

Leptin (LEP) and leptin receptor (LEPR) play a major role in energy homeostasis, metabolism, and reproductive function. While effects of biallelic likely pathogenic variants (-/-) on the phenotype are well characterized, effects of mono-allelic likely pathogenic variants (wt/-) in the LEP and LEPR gene on the phenotype compared to wild-type homozygosity (wt/wt) have not been systematically investigated. We identified in our systematic review 44 animal studies (15 on Lep, 29 on Lepr) and 39 studies in humans reporting on 130 mono-allelic likely pathogenic variant carriers with 20 distinct LEP variants and 108 heterozygous mono-allelic likely pathogenic variant carriers with 35 distinct LEPR variants. We found indications for a higher weight status in carriers of mono-allelic likely pathogenic variant in the leptin and in the leptin receptor gene compared to wt/wt, in both animal and human studies. In addition, animal studies showed higher body fat percentage in Lep and Lepr wt/- vs wt/wt. Animal studies provided indications for lower leptin levels in Lep wt/- vs. wt/wt and indications for higher leptin levels in Lepr wt/- vs wt/wt. Data on leptin levels in human studies was limited. Evidence for an impaired metabolism in mono-allelic likely pathogenic variants of the leptin and in leptin receptor gene was not conclusive (animal and human studies). Mono-allelic likely pathogenic variants in the leptin and in leptin receptor gene have phenotypic effects disposing to increased body weight and fat accumulation.

瘦素(LEP)和瘦素受体(LEPR)在能量稳态、代谢和生殖功能中起着重要作用。虽然双等位基因可能致病变异(-/-)对表型的影响已经得到了很好的表征,但与野生型纯合性(wt/wt)相比,LEP和LEPR基因中单等位基因可能致病变异(wt/-)对表型的影响尚未得到系统的研究。在我们的系统综述中,我们确定了44项动物研究(15项关于Lep, 29项关于Lepr)和39项人类研究,报告了130个可能的单等位基因致病变异携带者,其中20个不同的Lep变异,108个杂合的可能的单等位基因致病变异携带者,其中35个不同的Lepr变异。我们在动物和人类研究中发现,与体重/体重相比,瘦素和瘦素受体基因中可能致病的单等位基因携带者的体重状况更高。此外,动物研究表明,Lep和Lepr的体脂率比wt/- vs wt/wt更高。动物研究提供了瘦素水平较低的适应症,瘦素水平较低的适应症,瘦素水平较高的适应症,瘦素水平较低的适应症。关于人体瘦素水平的研究数据有限。瘦素和瘦素受体基因的单等位基因可能致病性变异代谢受损的证据尚无定论(动物和人类研究)。瘦素和瘦素受体基因的单等位基因可能致病变异具有导致体重增加和脂肪积累的表型效应。
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引用次数: 4
The mutual patterning between the developing nephron and its covering tissues-valid reasons to rethink the search for traces left by impaired nephrogenesis. 发育中的肾元及其覆盖组织之间的相互模式-重新考虑寻找受损肾形成留下的痕迹的正当理由。
Q1 PEDIATRICS Pub Date : 2021-08-17 DOI: 10.1186/s40348-021-00120-0
Will W Minuth

Background: The impairment of nephrogenesis can cause the termination of nephron formation in preterm and low birth weight babies. This leads to oligonephropathy with severe health consequences in later life. Although many clinical parameters are known, surprisingly little information is available regarding the initial damage on the developing nephron. Equally astounding, the first morphological data regarding the specifics of nephron formation in the nephrogenic zone of the fetal human kidney during late gestation has only been published within the past few years. In this context, it was observed that each stage of nephron anlage is surrounded by a specific set of tissues. Although highly relevant for the normal progress of nephron formation, the mutual patterning has not been systematically described.

Results: To contribute, the different stages of nephron anlage in the nephrogenic zone of the fetal human kidney during late gestation were screened by the optical microscope and documented by images. Following this, magnifications (28 × 18 cm) were produced to trace the contours of the developing nephron and its covering tissues. The resulting sketches, almost true to scale, were scanned, edited, and processed by a design program. As a base, first the individual position, size, and shape of the nephrogenic niche, pretubular aggregate, renal vesicles, comma- and S-shaped bodies are presented. Secondly, their structural relations to the renal capsule, collecting duct ampulla, perforating radiate artery, and expanding interstitium are shown. Third of all, the focus is on less considered configurations, such as site-specific approximation, local distancing, punctual adhesion, integration, separation, delamination, formation of congruent and divergent surfaces, and folding and opening of interstitial clefts.

Conclusions: The present contribution illuminates the mutual patterning between the developing nephron and its covering tissues. It is indispensable to know about the microanatomical relations, in order to identify whether the noxae impairing nephrogenesis targets only the developing nephron or also its covering tissues as interacting and controlling instances.

背景:早产儿和低出生体重儿肾发生障碍可导致肾元形成终止。这会导致少肾病,在以后的生活中造成严重的健康后果。虽然许多临床参数是已知的,但令人惊讶的是,关于发育中的肾元的初始损伤的信息很少。同样令人震惊的是,关于妊娠晚期胎儿肾脏肾原区肾元形成细节的第一个形态学数据在过去几年中才发表。在这种情况下,我们观察到肾元的每个阶段都被一组特定的组织所包围。虽然与肾元形成的正常进程高度相关,但相互模式尚未被系统地描述。结果:利用光学显微镜对妊娠晚期人胎肾肾源带不同阶段的肾元标本进行了筛选和影像记录。随后,制作了28 × 18 cm的放大镜来描绘发育中的肾元及其覆盖组织的轮廓。最终的草图,几乎是真实的比例,被扫描,编辑,并通过一个设计程序处理。作为基础,首先是肾源生态位、肾小管前聚集体、肾小泡、逗号形和s形体的个体位置、大小和形状。其次,它们与肾包膜、壶腹集管、穿透辐射动脉和扩张间质之间的结构关系。第三,重点是较少考虑的配置,例如特定位点近似,局部距离,准时粘附,整合,分离,分层,一致和分歧表面的形成,以及间隙间隙的折叠和打开。结论:本研究阐明了发育中的肾元与其覆盖组织之间的相互模式。了解它们之间的微观解剖关系是必不可少的,以便确定损害肾形成的细胞是仅以发育中的肾单位为目标,还是将其覆盖组织作为相互作用和控制的实例。
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引用次数: 3
Novel ways to monitor immunosuppression in pediatric kidney transplant recipients-underlying concepts and emerging data. 监测儿童肾移植受者免疫抑制的新方法——基本概念和新数据。
Q1 PEDIATRICS Pub Date : 2021-07-26 DOI: 10.1186/s40348-021-00118-8
Thurid Ahlenstiel-Grunow, Lars Pape

After pediatric kidney transplantation, immunosuppressive therapy is given to avoid acute and chronic rejections. However, the immunosuppression causes an increased risk of severe viral complications and bacterial infections and is associated with serious side effects. It is therefore crucial to achieve the optimal individual balance between over- and under-immunosuppression and thereby avoid unnecessary exposure to immunosuppressive drugs. In routine use, steering of immunosuppressants is performed primarily by monitoring of trough levels that mirror pharmacokinetics (although not, however, pharmacodynamics). Other diagnostic and prognostic markers to assess the individual intensity of immunosuppression are missing. Potential methods to determine immune function and grade of immunosuppression, such as analysis of the torque teno virus (TTV) load, QuantiFERON Monitor®, and ImmuKnow® as well as virus-specific T cells (Tvis), are currently being evaluated. In some studies TTV load, QuantiFERON Monitor® and ImmuKnow® were associated with the risk for post-transplant rejections and infections, but randomized controlled trials after pediatric kidney transplantation are not available. Post-transplant monitoring of Tvis levels seem to be promising because Tvis control virus replication and have been shown to correlate with virus-specific as well as general cellular immune defense, which represents the individual's susceptibility to infections. Additional Tvis-monitoring provides an innovative opportunity to personalize the antiviral management and the dosing of the immunosuppressive therapy after pediatric kidney transplantation to avoid unnecessary therapeutic interventions and identify over-immunosuppression.

小儿肾移植后,免疫抑制治疗是为了避免急性和慢性排斥反应。然而,免疫抑制导致严重病毒并发症和细菌感染的风险增加,并伴有严重的副作用。因此,在免疫抑制过度和免疫抑制不足之间实现最佳的个体平衡,从而避免不必要的免疫抑制药物暴露是至关重要的。在常规使用中,免疫抑制剂的控制主要是通过监测反映药代动力学的低谷水平来进行的(尽管不是药效学)。其他评估个体免疫抑制强度的诊断和预后标志物缺失。目前正在评估确定免疫功能和免疫抑制等级的潜在方法,例如分析转矩病毒(TTV)载量、QuantiFERON Monitor®和ImmuKnow®以及病毒特异性T细胞(Tvis)。在一些研究中,TTV负荷、QuantiFERON Monitor®和ImmuKnow®与移植后排斥反应和感染的风险相关,但没有儿童肾移植后的随机对照试验。移植后Tvis水平的监测似乎是有希望的,因为Tvis控制病毒复制,并已被证明与病毒特异性以及一般细胞免疫防御相关,这代表了个体对感染的易感性。额外的tvs监测提供了一个创新的机会,可以个性化儿童肾移植后的抗病毒管理和免疫抑制治疗的剂量,以避免不必要的治疗干预和识别过度免疫抑制。
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引用次数: 2
Aggressive infantile myofibromatosis with intestinal involvement. 侵袭性婴儿肌纤维瘤病伴肠道受累。
Q1 PEDIATRICS Pub Date : 2021-06-16 DOI: 10.1186/s40348-021-00117-9
Tristan Römer, Norbert Wagner, Till Braunschweig, Robert Meyer, Miriam Elbracht, Udo Kontny, Olga Moser

Background: Infantile myofibromatosis (IM) is the most common cause of multiple fibrous tumors in infancy. Multicentric disease can be associated with life-threatening visceral lesions. Germline gain-of-function mutations in PDGFRB have been identified as the most common molecular defect in familial IM.

Case presentation: We here describe an infant with PDGFRB-driven IM with multiple tumors at different sites, including intestinal polyposis with hematochezia, necessitating temporary chemotherapy.

Conclusions: PDGFRB-driven IM is clinically challenging due to its fluctuating course and multiple organ involvement in the first years of life. Early molecular genetic analysis is necessary to consider tyrosine kinase inhibitor treatment in case of aggressive visceral lesions.

背景:婴儿肌纤维瘤病(IM)是婴儿多发纤维性肿瘤最常见的病因。多中心疾病可伴有危及生命的内脏病变。PDGFRB的生殖系功能获得突变已被确定为家族性IM中最常见的分子缺陷。病例介绍:我们在这里描述了一个患有pdgfrb驱动的IM的婴儿,在不同的部位有多个肿瘤,包括肠息肉病伴便血,需要临时化疗。结论:pdgfrb驱动的IM在临床上具有挑战性,因为它的波动过程和多器官累及在生命的第一年。早期分子遗传学分析是必要的,以考虑酪氨酸激酶抑制剂治疗的情况下侵袭性内脏病变。
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引用次数: 2
Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family. 鉴定一种新的MICU1无义变异导致伊朗近亲家族锥体外系症状的肌病。
Q1 PEDIATRICS Pub Date : 2021-05-09 DOI: 10.1186/s40348-021-00116-w
Fatemeh Bitarafan, Mehrnoosh Khodaeian, Elham Amjadi Sardehaei, Fatemeh Zahra Darvishi, Navid Almadani, Yalda Nilipour, Masoud Garshasbi

Background: Ca2+ as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation, and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1), which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca2+ handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene causes a very rare neuromuscular disease, myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca2+ uptake. To date, 13 variants have been reported in MICU1 gene in 44 patients presented with the vast spectrum of symptoms.

Case presentation: Here, we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, elevated serum creatine kinase (CK), and elevated lactate dehydrogenase (LDH). We identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing (WES) and segregation analysis.

Conclusions: Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.

背景:Ca2+作为一种通用的第二信使,调节细胞周期、细胞增殖、细胞分化和细胞死亡等基本生物学功能。线粒体钙摄取蛋白MICU1被认为是钙离子的看门人,缺乏MICU1会导致线粒体Ca2+处理异常,活性氧(ROS)过量产生,以及细胞死亡增加。MICU1基因突变导致一种非常罕见的神经肌肉疾病,即锥体外系体征(MPXPS)的肌病,这是由于线粒体钙信号的原发性改变,这表明了线粒体Ca2+摄取的关键作用。迄今为止,在44名表现出广泛症状的患者中,已报告了13种MICU1基因变异。病例介绍:在这里,我们报告了一名44岁的伊朗患者,表现为学习障碍,肌肉无力,易疲劳,肌腱反射减少,共济失调,步态障碍,肝转氨酶升高,血清肌酸激酶(CK)升高,乳酸脱氢酶(LDH)升高。我们发现了一个新的无义变异c.385C>T;通过全外显子组测序(WES)和分离分析鉴定MICU1基因p.(R129*)。结论:我们的发现与先前的研究一起为MICU1致病性突变引起的疾病的临床表现提供了更多证据。发现更多的变异和扩大疾病的范围,提高了分子检测在筛查这类疾病中的诊断率,进而提高了对有风险夫妇的咨询质量,并帮助他们尽量减少生育受影响儿童的风险。
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引用次数: 7
Daratumumab therapy for post-HSCT immune-mediated cytopenia: experiences from two pediatric cases and review of literature. 达拉单抗治疗造血干细胞移植后免疫介导的细胞减少症:两个儿科病例的经验和文献综述
Q1 PEDIATRICS Pub Date : 2021-04-29 DOI: 10.1186/s40348-021-00114-y
Lina Driouk, Robert Schmitt, Anke Peters, Sabine Heine, Hermann Josef Girschick, Brigitte Strahm, Charlotte M Niemeyer, Carsten Speckmann

Background: Immune-mediated cytopenias (AIC) are challenging complications following allogeneic hematopoietic stem cell transplantation (HSCT). While broad-acting immunosuppressive agents like corticosteroids are often standard of care, several novel therapies which target specific immunological pathways have recently been developed and provide hope for patients with steroid-refractory courses and may limit long-term toxicity. The successful off-label use of the plasma cell depleting anti-CD38 antibody daratumumab was published in several case reports, suggesting efficacy, i.e., in patients with antibody-mediated AIC refractory to previous B cell depletion. We want to share our experience with two children, whom we treated with daratumumab, including one fatal course with uncontrolled disease. Given the absence of substantial data from HSCT registries or prospective trials, we furthermore provide a critical review of the literature on daratumumab treatment of AIC.

Case presentations: Patient 1 (P1), an 11-year-old girl with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who developed immune-mediated thrombocytopenia (AIT) from day +58 after HSCT, showed a complete response to daratumumab after the fourth of six total daratumumab doses. She remains transfusion independent for over a year of follow-up. Previously, her thrombocytopenia was refractory to corticosteroids, rituximab, intravenous immunoglobulins (IVIG), eltrombopag, cyclosporine A, and sirolimus. Patient 2 (P2), a 6-year-old boy with CD40 ligand (CD40L) deficiency, developed both AIT and hemolytic anemia (AIHA) after HSCT on days +58 and +83, respectively, and was also treated with daratumumab after being previously refractory to prednisolone, rituximab, and IVIG. Yet, he did neither respond to daratumumab nor the concomitantly administered methyprednisolone pulse, plasmapheresis, and eculizumab and succumbed due to refractory disease.

Conclusion: Reviewing the literature on the use of daratumumab for refractory AIC post-HSCT, we consider daratumumab a promising agent for this life-threatening disorder: ten of the twelve patients reached transfusion independency in the literature. However, treatment failures are likely to be underreported. Thus, controlled trials are needed to explore the safety and efficacy of daratumumab in this rare post-HSCT complication.

背景:免疫介导的细胞减少症(AIC)是同种异体造血干细胞移植(HSCT)后具有挑战性的并发症。虽然像皮质类固醇这样的广谱免疫抑制剂通常是标准的治疗方法,但最近开发了一些针对特定免疫途径的新疗法,为类固醇难治性病程的患者提供了希望,并可能限制长期毒性。血浆细胞消耗抗cd38抗体daratumumab在适应症外的成功使用已发表在几例病例报告中,表明其有效性,即抗体介导的AIC对既往B细胞消耗难治性患者。我们想与我们用达拉单抗治疗的两个孩子分享我们的经验,其中包括一个疾病无法控制的致命病程。鉴于缺乏HSCT注册或前瞻性试验的大量数据,我们进一步对daratumumab治疗AIC的文献进行了批判性回顾。病例介绍:患者1 (P1)是一名11岁的女孩,患有脂多糖反应性和米色样锚蛋白(LRBA)缺乏症,在HSCT后第58天出现免疫介导的血小板减少症(AIT),在6次达拉图单抗总剂量的第4次后显示对达拉图单抗完全缓解。在一年多的随访中,她一直没有输血。此前,她的血小板减少症对皮质类固醇、利妥昔单抗、静脉注射免疫球蛋白(IVIG)、埃曲巴格、环孢素A和西罗莫司都是难治性的。患者2 (P2),一名患有CD40配体(CD40L)缺乏症的6岁男孩,在HSCT后分别在+58天和+83天出现AIT和溶血性贫血(AIHA),并且在先前对强的松龙,利妥昔单抗和IVIG难治后也接受了daratumumab治疗。然而,他对daratumumab和同时给予的甲泼尼龙脉冲、血浆置换和eculizumab均无反应,并因难治性疾病而死亡。结论:回顾关于在hsct后使用daratumumab治疗难治性AIC的文献,我们认为daratumumab是治疗这种危及生命疾病的有希望的药物:文献中12例患者中有10例达到了输血独立。然而,治疗失败可能被低估了。因此,需要对照试验来探索达拉单抗治疗这种罕见的移植后并发症的安全性和有效性。
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引用次数: 11
Combined RT-qPCR and pyrosequencing of a Spike glycoprotein polybasic cleavage motif can uncover pediatric SARS-CoV-2 infections associated with heterogeneous presentation. 结合RT-qPCR和焦磷酸测序的Spike糖蛋白多碱性切割基序可以揭示与异质性表现相关的儿童SARS-CoV-2感染。
Q1 PEDIATRICS Pub Date : 2021-04-24 DOI: 10.1186/s40348-021-00115-x
Patrick Philipp Weil, Jacqueline Hentschel, Frank Schult, Anton Pembaur, Beniam Ghebremedhin, Olivier Mboma, Andreas Heusch, Anna-Christin Reuter, Daniel Müller, Stefan Wirth, Malik Aydin, Andreas C W Jenke, Jan Postberg

Background: Reverse transcription of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (+)RNA genome and subgenomic RNAs (sgRNAs) and subsequent quantitative polymerase chain reaction (RT-qPCR) is the reliable diagnostic gold standard for COVID-19 diagnosis and the identification of potential spreaders. Apart from clinical relevance and containment, for specific questions, it might be of interest to (re)investigate cases with low SARS-CoV-2 load, where RT-qPCR alone can deliver conflicting results, even though these cases might neither be clinically relevant nor significant for containment measures, because they might probably not be infectious. In order to expand the diagnostic bandwidth for non-routine questions, particularly for the reliable discrimination between negative and false-negative specimens associated with high CT values, we combined the RT-qPCR workflow with subsequent pyrosequencing of a S-gene amplicon. This expansion can help to confirm SARS-CoV-2 infections without the demand of confirmative antibody testing, which requires to summon patients again for blood sampling few to several weeks after symptom onset.

Results: We successfully established a combined RT-qPCR and S-gene pyrosequencing method which can be optionally exploited after routine diagnostics. This allows a reliable interpretation of RT-qPCR results in specimens with relatively low viral loads and close to the detection limits of qPCR. After laboratory implementation, we tested the combined method in a large pediatric cohort from two German medical centers (n=769). Pyrosequencing after RT-qPCR enabled us to uncover 5 previously unrecognized cases of pediatric SARS-CoV-2-associated diseases, mainly exhibiting mild and heterogeneous presentation-apart from a single case of multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, who was hospitalized in the course of the study.

Conclusions: The proposed protocol allows a specific and sensitive confirmation of SARS-CoV-2 infections close to the detection limits of RT-qPCR. The tested biotinylated primers do not negatively affect the RT-qPCR pipeline and thus can be optionally applied to enable deeper inspection of RT-qPCR results by subsequent pyrosequencing. Moreover, due to the incremental transmission of SARS-CoV-2 variants of concern, we note that the used strategy can uncover (Spike) P681H allowing the pre-selection of SARS-CoV-2 B.1.1.7 candidate specimens for deep sequencing.

背景:严重急性呼吸综合征冠状病毒2 (SARS-CoV-2) (+)RNA基因组和亚基因组RNA (sgRNAs)逆转录及随后的定量聚合酶链反应(RT-qPCR)是诊断COVID-19和鉴定潜在传播者的可靠诊断金标准。除了临床相关性和遏制外,对于具体问题,可能有兴趣(重新)调查低SARS-CoV-2载量的病例,其中单独使用RT-qPCR可能会产生相互矛盾的结果,即使这些病例可能既不具有临床相关性,也不重要,因为它们可能不具有传染性。为了扩大非常规问题的诊断带宽,特别是对于与高CT值相关的阴性和假阴性标本的可靠区分,我们将RT-qPCR工作流程与随后的s基因扩增子焦磷酸测序相结合。这种扩大可以帮助确认SARS-CoV-2感染,而无需进行确认抗体检测,这需要在症状出现后几周到几周再次召唤患者进行血液采样。结果:成功建立了RT-qPCR与s基因焦磷酸测序相结合的方法,该方法可在常规诊断后选择性使用。这允许在病毒载量相对较低且接近qPCR检测限的标本中可靠地解释RT-qPCR结果。在实验室实施后,我们在来自两个德国医学中心的大型儿科队列中测试了联合方法(n=769)。RT-qPCR后的焦氧测序使我们发现了5例以前未被识别的儿童SARS-CoV-2相关疾病,主要表现为轻度和异质性,除了一例与SARS-CoV-2相关的儿童多系统炎症综合征(MIS-C),该病例在研究过程中住院。结论:该方案可对SARS-CoV-2感染进行特异性和敏感性确认,接近RT-qPCR的检测限。所测试的生物素化引物不会对RT-qPCR管道产生负面影响,因此可以选择性地应用于通过随后的焦磷酸测序对RT-qPCR结果进行更深入的检查。此外,由于关注SARS-CoV-2变体的增量传播,我们注意到所使用的策略可以发现(Spike) P681H,从而可以预先选择SARS-CoV-2 B.1.1.7候选样本进行深度测序。
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引用次数: 1
Relationship between adiponectin, TNFα, and SHBG in prepubertal children with obesity. 青春期前肥胖症儿童体内脂肪连接素、TNFα和SHBG之间的关系。
IF 2.4 Q1 PEDIATRICS Pub Date : 2021-03-10 DOI: 10.1186/s40348-021-00113-z
Marta Ramon-Krauel, María Jesús Leal-Witt, Óscar Osorio-Conles, Montse Amat-Bou, Carles Lerin, David M Selva

Background: Sex hormone-binding globulin (SHBG) levels are low in adult subjects with obesity when compared to normal-weight individuals. Obesity is associated with higher tumor necrosis factor alpha (TNFα) plasma levels and lower adiponectin levels. Moreover, we have recently elucidated the molecular mechanisms by which TNFα and adiponectin regulate hepatic SHBG production.

Aim: The main objective of this study was to assess if the adult associations between TNFα, adiponectin, and SHBG are present in prepubertal children.

Methods: We determined several morphometric and biochemical parameters in normal-weight (n=15) and obese prepubertal (n=51) children, as well as quantified plasma SHBG, TNFα receptor 1 (TNFα-R1), and adiponectin levels.

Results: Our results showed that prepubertal children with obesity had decreased plasma SHBG levels compared to normal-weight controls (67 nmol/L vs 172 nmol/L). Importantly, SHBG plasma levels correlated significantly (P < 0.05) with TNFα (negatively, ßstd= - 0.31) and adiponectin (positively, ßstd= 0.58) suggesting an important role of these two cytokines in determining plasma SHBG levels in prepubertal children.

Conclusions: Our results suggest that plasma adiponectin levels may play a more important role than TNFα in influencing plasma SHBG levels in our prepubertal population with obesity.

背景:与正常体重的人相比,成年肥胖症患者的性激素结合球蛋白(SHBG)水平较低。肥胖与肿瘤坏死因子α(TNFα)血浆水平升高和脂肪连素水平降低有关。此外,我们最近还阐明了 TNFα 和脂肪连通素调节肝脏 SHBG 生成的分子机制:方法:我们测定了体重正常儿童(n=15)和青春期前肥胖儿童(n=51)的多项形态计量和生化指标,并量化了血浆SHBG、TNFα受体1(TNFα-R1)和脂肪连接蛋白的水平:结果表明:与体重正常的对照组相比,青春期前肥胖症儿童的血浆SHBG水平降低(67 nmol/L vs 172 nmol/L)。重要的是,SHBG血浆水平与TNFα(负相关,ßstd= - 0.31)和脂肪连素(正相关,ßstd= 0.58)显著相关(P<0.05),这表明这两种细胞因子在决定青春期前儿童血浆SHBG水平方面起着重要作用:我们的研究结果表明,在青春期前肥胖症人群中,血浆脂肪连素水平对血浆SHBG水平的影响可能比TNFα更重要。
{"title":"Relationship between adiponectin, TNFα, and SHBG in prepubertal children with obesity.","authors":"Marta Ramon-Krauel, María Jesús Leal-Witt, Óscar Osorio-Conles, Montse Amat-Bou, Carles Lerin, David M Selva","doi":"10.1186/s40348-021-00113-z","DOIUrl":"10.1186/s40348-021-00113-z","url":null,"abstract":"<p><strong>Background: </strong>Sex hormone-binding globulin (SHBG) levels are low in adult subjects with obesity when compared to normal-weight individuals. Obesity is associated with higher tumor necrosis factor alpha (TNFα) plasma levels and lower adiponectin levels. Moreover, we have recently elucidated the molecular mechanisms by which TNFα and adiponectin regulate hepatic SHBG production.</p><p><strong>Aim: </strong>The main objective of this study was to assess if the adult associations between TNFα, adiponectin, and SHBG are present in prepubertal children.</p><p><strong>Methods: </strong>We determined several morphometric and biochemical parameters in normal-weight (n=15) and obese prepubertal (n=51) children, as well as quantified plasma SHBG, TNFα receptor 1 (TNFα-R1), and adiponectin levels.</p><p><strong>Results: </strong>Our results showed that prepubertal children with obesity had decreased plasma SHBG levels compared to normal-weight controls (67 nmol/L vs 172 nmol/L). Importantly, SHBG plasma levels correlated significantly (P < 0.05) with TNFα (negatively, ßstd= - 0.31) and adiponectin (positively, ßstd= 0.58) suggesting an important role of these two cytokines in determining plasma SHBG levels in prepubertal children.</p><p><strong>Conclusions: </strong>Our results suggest that plasma adiponectin levels may play a more important role than TNFα in influencing plasma SHBG levels in our prepubertal population with obesity.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"8 1","pages":"3"},"PeriodicalIF":2.4,"publicationDate":"2021-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25451964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Molecular and cellular pediatrics
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