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The potential of antisense oligonucleotide therapies for inherited childhood lung diseases. 反义寡核苷酸疗法治疗遗传性儿童肺病的潜力。
IF 2.4 Q1 PEDIATRICS Pub Date : 2018-02-06 DOI: 10.1186/s40348-018-0081-6
Kelly M Martinovich, Nicole C Shaw, Anthony Kicic, André Schultz, Sue Fletcher, Steve D Wilton, Stephen M Stick

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism.

反义寡核苷酸是治疗已知遗传疾病的一种新兴疗法。在个性化用药时代,反义寡核苷酸有时可以设计为靶向药物,绕过或克服患者的基因突变,特别是那些影响正常前核糖核酸(pre-mRNA)加工的病变。反义寡核苷酸可通过化学和反义寡聚体设计所决定的各种机制改变基因表达。通过靶向前 mRNA,反义寡核苷酸可以改变剪接,诱导特定的剪接形式或破坏阅读框架,通过激活 RNaseH 靶向 RNA 转录本降解,阻断核糖体启动蛋白质翻译或破坏 miRNA 功能。美国食品和药物管理局最近加速批准了用于治疗杜氏肌营养不良症的 eteplirsen(更名为 Exondys 51™)和用于治疗脊髓性肌萎缩症的 nusinersen,这预示着剪接转换反义寡核苷酸应用于治疗遗传性疾病的新时代即将到来。本综述探讨了反义寡核苷酸治疗遗传性儿童肺部疾病的潜力,重点关注囊性纤维化和表面活性物质蛋白代谢紊乱。
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引用次数: 0
CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility. CISH启动子多态性对T细胞细胞因子受体信号传导和1型糖尿病易感性的影响。
Q1 PEDIATRICS Pub Date : 2018-02-06 DOI: 10.1186/s40348-018-0080-7
Julia Seyfarth, Heinz Ahlert, Joachim Rosenbauer, Christina Baechle, Michael Roden, Reinhard W Holl, Ertan Mayatepek, Thomas Meissner, Marc Jacobsen

Background: Impaired regulatory T cell immunity plays a central role in the development of type 1 diabetes (T1D). Interleukin-2 receptor (IL-2R) signaling is essential for regulatory T cells (TREG), and cytokine-inducible SH2-containing protein (CIS) regulates IL-2R signaling as a feedback inhibitor. Previous studies identified association of CISH promoter region single nucleotide polymorphisms (SNPs) with susceptibility to infectious diseases.

Methods: Here we analyzed allele frequencies of three CISH SNPs (i.e., rs809451, rs414171, rs2239751) in a study of T1D patients (n = 260, onset age < 5 years, duration > 10 years). Minor allele frequencies were compared to a control cohort of the 1000 Genomes Project. Assigned haplotypes were determined for effects on T1D manifestation and severity. Finally, the CISH haplotype influence on cytokine signaling and function was explored in T cells from healthy donors.

Results: We detected similar minor allele frequencies between T1D patients and the control cohort. T1D onset age, residual serum C-peptide level, and insulin requirement were comparable between different haplotypes. Only minor differences between the haplotypes were found for in vitro cytokine (i.e., IL-2, IL-7)-induced CIS mRNA expression. STAT5 phosphorylation was induced by IL-2 or IL-7, but no differences were found between the haplotypes. TREG purified from healthy donors with the two most common haplotypes showed similar capacity to inhibit heterologous effector T cells.

Conclusions: This study provides no evidence for an association of CISH promoter SNPs with susceptibility to T1D or severity of disease. In contrast to previous studies, no influence of different haplotypes on CIS mRNA expression or T cell-mediated functions was found.

背景:调节性T细胞免疫受损在1型糖尿病(T1D)的发展中起着核心作用。白细胞介素-2受体(IL-2R)信号传导对于调节性T细胞(TREG)至关重要,而细胞因子诱导的含sh2蛋白(CIS)作为反馈抑制剂调节IL-2R信号传导。先前的研究发现CISH启动子区域单核苷酸多态性(snp)与感染性疾病的易感性有关。方法:在一项T1D患者(n = 260,发病年龄10岁)的研究中,我们分析了三个CISH snp(即rs809451, rs414171, rs2239751)的等位基因频率。次要等位基因频率与千人基因组计划的对照队列进行比较。确定指定单倍型对T1D表现和严重程度的影响。最后,在健康供体T细胞中探讨CISH单倍型对细胞因子信号传导和功能的影响。结果:我们在T1D患者和对照组之间检测到相似的小等位基因频率。T1D发病年龄、血清剩余c肽水平和胰岛素需要量在不同单倍型之间具有可比性。在体外细胞因子(即IL-2, IL-7)诱导的CIS mRNA表达中,单倍型之间仅存在微小差异。IL-2或IL-7诱导STAT5磷酸化,但单倍型间无差异。从具有两种最常见单倍型的健康供体中纯化的TREG显示出相似的抑制异源效应T细胞的能力。结论:本研究没有提供CISH启动子snp与T1D易感性或疾病严重程度相关的证据。与以往的研究相反,未发现不同单倍型对CIS mRNA表达或T细胞介导功能的影响。
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引用次数: 1
Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis. 在因炎症性肠病或自身免疫性肝炎接受长期免疫抑制治疗的儿童中保存的体外免疫反应性
Q1 PEDIATRICS Pub Date : 2018-01-19 DOI: 10.1186/s40348-018-0079-0
Teresa Schleker, Eva-Maria Jacobsen, Benjamin Mayer, Gudrun Strauss, Klaus-Michael Debatin, Carsten Posovszky

Background: Children with inflammatory bowel disease (IBD) or autoimmune hepatitis (AIH) are at risk for severe infections. This is partially a result of their chronic disease condition but, moreover, a side effect of their immunosuppressive therapy. Currently, vaccinations with live vaccines are regarded as contraindicated under immunosuppressive therapy, mainly because of concerns about side effects and a lack of data showing an adequate immune reaction. As there is no systematic study on the individual immunoreactivity under immunosuppressive therapy in this patient group, we analyzed the lymphocyte subgroups and immunoreactivity of lymphocytes in children with IBD or AIH with and without immunosuppressive therapy in vitro.

Methods: We collected whole blood samples from 17 children with IBD or AIH on high-level immunosuppression (IS) (group 1) and 8 on low-level IS (group 2) in comparison with 6 patients without systemic IS (group 3). After Ficoll separation of peripheral mononuclear cells, the samples were analyzed by flow cytometry to determine the lymphocyte subgroups. Furthermore, we stimulated the isolated lymphocytes with phytohemagglutinin (PHA), tetanus antigen, and adenovirus antigen and measured their proliferation by incorporation of H3-thymidine detected in a beta counter. The statistical evaluation was performed by Kruskal-Wallis test and Mann-Whitney U test using a bilateral level of significance of α = 5%.

Results: Patients with low- or high-level IS showed no significant difference in the number of lymphocytes or T cells. Interestingly, IS did not influence the lymphocyte proliferation assay significantly regarding median reaction to PHA, tetanus antigen, or adenovirus antigen between the three groups. However, comparing all immunosuppressed patients to the patients without IS, there was a significant difference towards stimulation with tetanus antigen.

Conclusions: Contrary to expectations of a strong influence of IS therapy on the immunoreactivity, this study showed only minor differences between the groups with high-level, low-level, and no IS. Particularly, the in vitro reactivity to adenovirus antigen was nearly the same in all three groups. We assume that-provided a normal distribution and count of lymphocyte subgroups-patients with moderate immunosuppression might be capable of raising an effective immune response to inactivated and live vaccines.

背景:患有炎症性肠病(IBD)或自身免疫性肝炎(AIH)的儿童存在严重感染的风险。这部分是由于他们的慢性疾病,但更重要的是,免疫抑制疗法的副作用。目前,活疫苗接种被认为是免疫抑制疗法的禁忌症,主要是因为担心副作用和缺乏显示充分免疫反应的数据。由于该患者组在免疫抑制治疗下的个体免疫反应性没有系统的研究,我们在体外分析了IBD或AIH患儿接受和不接受免疫抑制治疗时淋巴细胞亚群和淋巴细胞的免疫反应性。方法:收集17例高水平免疫抑制(IS)患儿(1组)和8例低水平免疫抑制患儿(2组)的全血样本,并与6例无全身性IS的患儿(3组)进行比较。外周血单核细胞Ficoll分离后,流式细胞术分析样本,确定淋巴细胞亚群。此外,我们用植物血凝素(PHA)、破伤风抗原和腺病毒抗原刺激分离淋巴细胞,并通过β计数器检测到的h3 -胸腺嘧啶的掺入来测量它们的增殖。采用Kruskal-Wallis检验和Mann-Whitney U检验,双侧显著性水平为α = 5%。结果:低水平和高水平IS患者淋巴细胞和T细胞数量无明显差异。有趣的是,IS对淋巴细胞增殖试验在三组之间对PHA、破伤风抗原或腺病毒抗原的中位反应没有显著影响。然而,将所有免疫抑制患者与非IS患者进行比较,破伤风抗原刺激有显著差异。结论:与IS治疗对免疫反应性有强烈影响的预期相反,本研究显示高水平、低水平和无IS组之间只有微小差异。特别是,在体外对腺病毒抗原的反应性在所有三组中几乎相同。我们假设-提供正态分布和淋巴细胞亚群计数-中度免疫抑制患者可能能够提高对灭活疫苗和活疫苗的有效免疫反应。
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引用次数: 4
Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone. 延长早产儿和低出生体重婴儿肾发生的治疗概念必须与肾发生区的结构-功能特性相对应。
Q1 PEDIATRICS Pub Date : 2017-12-07 DOI: 10.1186/s40348-017-0078-6
Will W Minuth

Numerous investigations are dealing with anlage of the mammalian kidney and primary development of nephrons. However, only few information is available about the last steps in kidney development leading at birth to a downregulation of morphogen activity in the nephrogenic zone and to a loss of stem cell niches aligned beyond the organ capsule. Surprisingly, these natural changes in the developmental program display similarities to processes occurring in the kidneys of preterm and low-birth-weight babies. Although those babies are born at a time with a principally intact nephrogenic zone and active niches, a high proportion of them suffers on impairment of nephrogenesis resulting in oligonephropathy, formation of atypical glomeruli, and immaturity of parenchyma. The setting points out that up to date not identified noxae in the nephrogenic zone hamper primary steps of parenchyma development. In this situation, a possible therapeutic aim is to prolong nephrogenesis by medications. However, actual data provide information that administration of drugs is problematic due to an unexpectedly complex microanatomy of the nephrogenic zone, in niches so far not considered textured extracellular matrix and peculiar contacts between mesenchymal cell projections and epithelial stem cells via tunneling nanotubes. Thus, it remains to be figured out whether disturbance of morphogen signaling altered synthesis of extracellular matrix, disturbed cell-to-cell contacts, or modified interstitial fluid impair nephrogenic activity. Due to most unanswered questions, search for eligible drugs prolonging nephrogenesis and their reliable administration is a special challenge for the future.

许多研究都涉及哺乳动物肾脏的标本和肾单位的初级发育。然而,只有很少的信息是关于肾脏发育的最后步骤,导致出生时肾源区形态原活性下调和器官被膜外排列的干细胞龛的损失。令人惊讶的是,这些发育过程中的自然变化与早产儿和低出生体重婴儿的肾脏发生的过程相似。尽管这些婴儿出生时肾源区基本完整,生态位活跃,但他们中的很大一部分患有肾生成障碍,导致少肾病、非典型肾小球的形成和实质不成熟。本研究指出,目前尚未确定的肾源区noxae阻碍了实质发育的初级步骤。在这种情况下,一个可能的治疗目标是通过药物延长肾脏形成。然而,实际数据提供的信息表明,由于肾源区出乎意料的复杂显微解剖,药物的给药是有问题的,到目前为止,还没有考虑到细胞外基质的纹理和间充质细胞突起与上皮干细胞之间通过隧道纳米管的特殊接触。因此,形态因子信号的干扰是否会改变细胞外基质的合成、细胞间接触的干扰或间质液的改变是否会损害肾形成活性,仍有待研究。由于大多数尚未解决的问题,寻找符合条件的延长肾脏发生的药物及其可靠的给药是未来的一个特殊挑战。
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引用次数: 3
Human perinatal immunity in physiological conditions and during infection. 人在生理条件和感染期间的围产期免疫。
Q1 PEDIATRICS Pub Date : 2017-12-01 Epub Date: 2017-04-21 DOI: 10.1186/s40348-017-0070-1
Gijs T J van Well, Leonie A Daalderop, Tim Wolfs, Boris W Kramer

The intrauterine environment was long considered sterile. However, several infectious threats are already present during fetal life. This review focuses on the postnatal immunological consequences of prenatal exposure to microorganisms and related inflammatory stimuli. Both the innate and adaptive immune systems of the fetus and neonate are immature, which makes them highly susceptible to infections. There is good evidence that prenatal infections are a primary cause of preterm births. Additionally, the association between antenatal inflammation and adverse neonatal outcomes has been well established. The lung, gastrointestinal tract, and skin are exposed to amniotic fluid during pregnancy and are probable targets of infection and subsequent inflammation during pregnancy. We found a large number of studies focusing on prenatal infection and the host response. Intrauterine infection and fetal immune responses are well studied, and we describe clinical data on cellular, cytokine, and humoral responses to different microbial challenges. The link to postnatal immunological effects including immune paralysis and/or excessive immune activation, however, turned out to be much more complicated. We found studies relating prenatal infectious or inflammatory hits to well-known neonatal diseases such as respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis. Despite these data, a direct link between prenatal hits and postnatal immunological outcome could not be undisputedly established. We did however identify several unresolved topics and propose questions for further research.

长期以来,人们认为宫内环境是无菌的。然而,在胎儿时期已经存在几种传染性威胁。这篇综述的重点是产前暴露于微生物和相关炎症刺激的产后免疫后果。胎儿和新生儿的先天免疫系统和适应性免疫系统都不成熟,这使他们极易受到感染。有充分证据表明,产前感染是早产的主要原因。此外,产前炎症和新生儿不良结局之间的关联已经得到了很好的证实。妊娠期间肺、胃肠道和皮肤暴露于羊水,是妊娠期间感染和随后炎症的可能目标。我们发现大量的研究集中在产前感染和宿主反应上。宫内感染和胎儿免疫反应得到了很好的研究,我们描述了对不同微生物挑战的细胞、细胞因子和体液反应的临床数据。然而,与出生后免疫效应(包括免疫麻痹和/或过度免疫激活)的联系被证明要复杂得多。我们发现产前感染或炎症与众所周知的新生儿疾病,如呼吸窘迫综合征、支气管肺发育不良和坏死性小肠结肠炎有关。尽管有这些数据,产前撞击和产后免疫结果之间的直接联系还不能毫无争议地建立起来。然而,我们确实确定了几个未解决的主题,并提出了进一步研究的问题。
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引用次数: 55
Pediatric precursor B acute lymphoblastic leukemia: are T helper cells the missing link in the infectious etiology theory? 儿童前体B型急性淋巴细胞白血病:T辅助细胞是感染性病原学理论中缺失的一环吗?
Q1 PEDIATRICS Pub Date : 2017-12-01 Epub Date: 2017-05-16 DOI: 10.1186/s40348-017-0072-z
Simone Bürgler, David Nadal

Precursor B acute lymphoblastic leukemia (BCP-ALL), the most common childhood malignancy, arises from an expansion of malignant B cell precursors in the bone marrow. Epidemiological studies suggest that infections or immune responses to infections may promote such an expansion and thus BCP-ALL development. Nevertheless, a specific pathogen responsible for this process has not been identified. BCP-ALL cells critically depend on interactions with the bone marrow microenvironment. The bone marrow is also home to memory T helper (Th) cells that have previously expanded during an immune response in the periphery. In secondary lymphoid organs, Th cells can interact with malignant cells of mature B cell origin, while such interactions between Th cells and malignant immature B cell in the bone marrow have not been described yet. Nevertheless, literature supports a model where Th cells-expanded during an infection in early childhood-migrate to the bone marrow and support BCP-ALL cells as they support normal B cells. Further research is required to mechanistically confirm this model and to elucidate the interaction pathways between leukemia cells and cells of the tumor microenvironment. As benefit, targeting these interactions could be included in current treatment regimens to increase therapeutic efficiency and to reduce relapses.

前体B急性淋巴细胞白血病(BCP-ALL)是最常见的儿童恶性肿瘤,起源于骨髓中恶性B细胞前体的扩增。流行病学研究表明,感染或对感染的免疫反应可能促进这种扩张,从而促进BCP-ALL的发展。然而,导致这一过程的特定病原体尚未被确定。BCP-ALL细胞严重依赖于与骨髓微环境的相互作用。骨髓也是记忆T辅助细胞(Th)的家园,这些T辅助细胞之前在外周免疫反应中扩增。在次级淋巴器官中,Th细胞可以与成熟B细胞来源的恶性细胞相互作用,而骨髓中Th细胞与恶性未成熟B细胞之间的相互作用尚未被描述。然而,文献支持一种模型,即在儿童早期感染期间扩增的Th细胞迁移到骨髓并像支持正常B细胞一样支持BCP-ALL细胞。进一步的研究需要从机制上证实这一模型,并阐明白血病细胞与肿瘤微环境细胞之间的相互作用途径。作为益处,针对这些相互作用可以包括在当前的治疗方案中,以提高治疗效率和减少复发。
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引用次数: 10
The molecular pathophysiology of chronic non-bacterial osteomyelitis (CNO)-a systematic review. 慢性非细菌性骨髓炎(CNO)的分子病理生理——系统综述。
Q1 PEDIATRICS Pub Date : 2017-12-01 Epub Date: 2017-07-06 DOI: 10.1186/s40348-017-0073-y
Sigrun Ruth Hofmann, Franz Kapplusch, Katrin Mäbert, Christian Michael Hedrich

Chronic non-bacterial osteomyelitis (CNO) belongs to the growing spectrum of autoinflammatory diseases and primarily affects the skeletal system. Peak onset ranges between 7 and 12 years of age. The clinical spectrum of CNO covers sometimes asymptomatic inflammation of single bones at the one end and chronically active or recurrent multifocal osteitis at the other.Despite the intense scientific efforts, the exact molecular mechanisms of CNO remain unknown. Recent data suggest CNO as a genetically complex disorder with dysregulated TLR4/MAPK/inflammasome signaling cascades resulting in an imbalance between pro- and anti-inflammatory cytokine expression, leading to osteoclast activation and osteolytic lesions.In this manuscript, the current understanding of molecular patho-mechanisms in CNO will be discussed.

慢性非细菌性骨髓炎(CNO)是一种自身炎症性疾病,主要影响骨骼系统。发病高峰在7至12岁之间。CNO的临床谱有时包括一端单骨无症状炎症和另一端慢性活动性或复发性多灶性骨炎。尽管进行了大量的科学研究,但CNO的确切分子机制仍不清楚。最近的数据表明,CNO是一种遗传复杂的疾病,TLR4/MAPK/炎性小体信号级联失调,导致促炎性和抗炎性细胞因子表达不平衡,导致破骨细胞活化和溶骨病变。在这篇文章中,将讨论目前对CNO分子病理机制的理解。
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引用次数: 40
The BPD trio? Interaction of dysregulated PDGF, VEGF, and TGF signaling in neonatal chronic lung disease. BPD三人组?PDGF、VEGF和TGF信号失调在新生儿慢性肺病中的相互作用
Q1 PEDIATRICS Pub Date : 2017-11-07 DOI: 10.1186/s40348-017-0076-8
Prajakta Oak, Anne Hilgendorff

The development of neonatal chronic lung disease (nCLD), i.e., bronchopulmonary dysplasia (BPD) in preterm infants, significantly determines long-term outcome in this patient population. Risk factors include mechanical ventilation and oxygen toxicity impacting on the immature lung resulting in impaired alveolarization and vascularization. Disease development is characterized by inflammation, extracellular matrix remodeling, and apoptosis, closely intertwined with the dysregulation of growth factor signaling. This review focuses on the causes and consequences of altered signaling in central pathways like transforming growth factor (TGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) driving these above indicated processes, i.e., inflammation, matrix remodeling, and vascular development. We emphasize the shared and distinct role of these pathways as well as their interconnection in disease initiation and progression, generating important knowledge for the development of future treatment strategies.

新生儿慢性肺病(nCLD)的发展,即早产儿支气管肺发育不良(BPD),在很大程度上决定了这一患者群体的长期预后。危险因素包括机械通气和氧毒性对未成熟肺的影响,导致肺泡和血管形成受损。疾病的发展以炎症、细胞外基质重塑和细胞凋亡为特征,与生长因子信号的失调密切相关。本文主要综述了转化生长因子(TGF)、血小板衍生生长因子(PDGF)和血管内皮生长因子(VEGF)等中心通路信号改变的原因和后果,这些信号通路驱动上述过程,即炎症、基质重塑和血管发育。我们强调这些通路的共同和独特的作用,以及它们在疾病发生和进展中的相互联系,为未来治疗策略的发展提供重要的知识。
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引用次数: 27
Estimated prevalence of potentially damaging variants in the leptin gene. 估计瘦素基因中潜在破坏性变异的流行程度。
Q1 PEDIATRICS Pub Date : 2017-11-03 DOI: 10.1186/s40348-017-0074-x
Adriana Nunziata, Guntram Borck, Jan-Bernd Funcke, Katja Kohlsdorf, Stephanie Brandt, Anke Hinney, Barbara Moepps, Peter Gierschik, Klaus-Michael Debatin, Pamela Fischer-Posovszky, Martin Wabitsch

Background: Mutations in the leptin gene (LEP) can alter the secretion or interaction of leptin with its receptor, leading to extreme early-onset obesity. The purpose of this work was to estimate the prevalence of heterozygous and homozygous mutations in the leptin gene with the help of the Exome Aggregation Consortium (ExAC) database ( http://exac.broadinstitute.org/about ).

Results: The ExAC database encompasses exome sequencing data from 60,706 individuals. We searched for listed leptin variants and identified 36 missense, 1 in-frame deletion, and 3 loss-of-function variants. The functional relevance of these variants was assessed by the in silico prediction tools PolyPhen-2, Sorting Intolerant from Tolerant (SIFT), and Loss-Of-Function Transcript Effect Estimator (LOFTEE). PolyPhen-2 predicted 7 of the missense variants to be probably damaging and 10 to be possibly damaging. SIFT predicted 7 of the missense variants to be deleterious. Three loss-of-function variants were predicted by LOFTEE. Excluding double counts, we can summarize 21 variants as potentially damaging. Considering the allele count, we identified 31 heterozygous but no homozygous subjects with at least probably damaging variants. In the ExAC population, the estimated prevalence of heterozygous carriers of these potentially damaging variants was 1:2000. The probability of homozygosity was 1:15,000,000. We furthermore tried to assess the functionality of ExAC-listed leptin variants by applying a knowledge-driven approach. By this approach, additional 6 of the ExAC-listed variants were considered potentially damaging, increasing the number of heterozygous subjects to 58, the prevalence of heterozygosity to 1:1050, and the probability of homozygosity to 1:4,400,000.

Conclusion: Using exome sequencing data from ExAC, in silico prediction tools and by applying a knowledge-driven approach, we identified 27 probably damaging variants in the leptin gene of 58 heterozygous subjects. With this information, we estimate the prevalence for heterozygosity at 1:1050 corresponding to an incidence of homozygosity of 1:4,400,000 in this large pluriethnic cohort.

背景:瘦素基因(LEP)突变可改变瘦素的分泌或与其受体的相互作用,导致极端早发性肥胖。这项工作的目的是在ExAC数据库(http://exac.broadinstitute.org/about)的帮助下估计瘦素基因杂合和纯合突变的患病率。结果:ExAC数据库包含60,706个人的外显子组测序数据。我们搜索了列出的瘦素变体,并确定了36个错义,1个帧内缺失和3个功能缺失变体。这些变异的功能相关性通过计算机预测工具polyphen2、从耐受性中筛选不耐受性(SIFT)和功能缺失转录效应估计器(LOFTEE)进行评估。polyphen2预测7个错义变异可能具有破坏性,10个可能具有破坏性。SIFT预测其中7个错义变异是有害的。LOFTEE预测了三种功能丧失变体。排除重复计算,我们可以总结出21种具有潜在破坏性的变异。考虑到等位基因数量,我们确定了31个杂合但没有纯合的受试者,至少可能具有破坏性的变异。在ExAC人群中,这些潜在破坏性变异的杂合携带者的估计患病率为1:2000。纯合概率为1:15 000 000。此外,我们试图通过应用知识驱动的方法来评估exacl列出的瘦素变体的功能。通过这种方法,另外6个列出的基因变体被认为具有潜在的破坏性,将杂合受试者的数量增加到58个,杂合患病率增加到1:1050,纯合概率增加到1:44万。结论:利用ExAC的外显子组测序数据、计算机预测工具和应用知识驱动的方法,我们在58名杂合受试者中确定了27个可能有害的瘦素基因变异。根据这些信息,我们估计在这个大型多民族队列中,杂合度的发生率为1:10 050,对应于纯合度的发生率为1:44 000。
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引用次数: 17
Transcatheter atrial septal defect closure in an infant (body weight 6.4 kg) using the GORE CARDIOFORM septal occluder (GCSO). 使用GORE CARDIOFORM房间隔封堵器(GCSO)经导管房间隔缺损闭合1例婴儿(体重6.4 kg)。
Q1 PEDIATRICS Pub Date : 2017-11-03 DOI: 10.1186/s40348-017-0077-7
Roman Scheidmann, Thomas Paul, Matthias Sigler

Introduction: Transcatheter closure has become the treatment of choice for secundum atrial septal defects (ASD II), but particularly in small children, there is concern regarding procedure-related complications.

Case description: We report on a 10-month-old infant, body weight of 6.4 kg, with a large ASD who was referred for failure to thrive and dyspnea on exertion. Echocardiography showed two neighboring ASDs centrally located within an atrial septum with a length of 27 mm resulting in significant left-to-right shunting. During cardiac catheterization, hemodynamic significance of the defect as well as normal pulmonary vascular resistance was demonstrated. Balloon sizing of the central ASD showed a stretched defect diameter of 12 × 11 mm. A 20-mm GORE CARDIOFORM septal occluder (GCSO; Goremedical, W. L. Gore & Associates, Inc., Newark, DE, USA) was implanted without any complications. Initial trivial residual shunting resolved during 4 months of follow-up. Right ventricular dimensions declined significantly, and the boy gained body weight properly.

Discussion, evaluation and conclusion: As demonstrated in our report, even large ASDs can be closed safely by catheter intervention in small infants. Selection of implant device and optimal sizing is of paramount importance. The size of the delivery sheath (11 French in our patient) is a potential limitation for the GCSO in smaller infants.

导论:经导管闭合术已成为治疗继发性房间隔缺损(ASD II)的首选方法,但特别是在幼儿中,存在手术相关并发症的担忧。病例描述:我们报告了一个10个月大的婴儿,体重6.4 kg,患有严重的ASD,因发育不全和用力呼吸困难而被转诊。超声心动图显示两个相邻的asd位于房间隔中心,长度为27mm,导致明显的左向右分流。在心导管术中,证实了缺损的血流动力学意义以及正常的肺血管阻力。中心ASD的球囊大小显示拉伸缺陷直径为12 × 11 mm。20mm GORE心型间隔闭塞器(GCSO;Goremedical, W. L. Gore & Associates, Inc. Newark, DE, USA)植入无任何并发症。最初轻微的残余分流在4个月的随访中得到解决。右心室尺寸明显减小,男孩体重正常增加。讨论、评价和结论:在我们的报告中,即使是大的asd也可以通过导管介入在小婴儿中安全地闭合。选择植入装置和最佳尺寸是至关重要的。分娩鞘的大小(在本例患者中为11 French)是小婴儿GCSO的潜在限制因素。
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引用次数: 4
期刊
Molecular and cellular pediatrics
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