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DMBT1 expression and neutrophil-to-lymphocyte ratio during necrotizing enterocolitis are influenced by impaired perfusion due to cardiac anomalies. 在坏死性小肠结肠炎期间,DMBT1的表达和中性粒细胞与淋巴细胞的比例受到心脏异常引起的灌注受损的影响。
Pub Date : 2022-01-06 DOI: 10.1186/s40348-021-00133-9
Sonja Diez, Manuel Besendörfer, Veronika Weyerer, Arndt Hartmann, Julia Moosmann, Christel Weiss, Marcus Renner, Hanna Müller

Background: Deleted in malignant brain tumors 1 (DMBT1) is involved in innate immunity and epithelial differentiation. It has been proven to play a role in various states of inflammation or hypoxia of fetal gastrointestinal and pulmonary diseases. Discrimination of pathogenesis in necrotizing enterocolitis (NEC) based on cardiac status improves the understanding of NEC in different patient subgroups. We aimed at examining DMBT1 expressions regarding their association with cardiac status leading to impaired intestinal perfusion, intraoperative bacteria proof, and a fulminant course of NEC.

Methods: Twenty-eight patients with NEC were treated surgically between 2010 and 2019 at our institution. DMBT1 expression was examined in intestinal sections using immunohistochemistry to detect DMBT1 protein. Associations of clinical parameters and DMBT1 expression were analyzed.

Results: We examined DMBT1 levels in 10 patients without cardiac defects and 18 patients with persisting ductus arteriosus (PDA) and congenital heart defects (CHD). Compared to patients without cardiac malformations, DMBT1 levels tended to score higher in patients with PDA/CHD (p = 0.2113) and were negatively correlated with C-reactive protein in these infants (p = 0.0172; r = - 0.5533). The number of DMBT1-expressing macrophages was elevated in the PDA/CHD-subgroup (p = 0.0399). Ratios of neutrophils and monocytes to lymphocytes were significantly higher in infants with PDA/CHD (p = 0.0319 and 0.0493). DMBT1 expression was significantly associated with positive bacterial culture of intraoperative swabs (p = 0.0252) and DMBT1 expression of the serosa was associated with a fulminant course of NEC (p = 0.0239).

Conclusions: This study demonstrates that DMBT1 expression may be influenced by cardiac anomalies with an impaired intestinal perfusion in the neonatal intestine. NEC in PDA/CHD infants is associated with more DMBT1-positive macrophages and a significantly elevated neutrophil-to-lymphocyte ratio.

背景:恶性脑肿瘤中缺失的DMBT1参与先天免疫和上皮分化。它已被证明在胎儿胃肠道和肺部疾病的各种炎症或缺氧状态中发挥作用。基于心脏状态对坏死性小肠结肠炎(NEC)发病机制的区分提高了对不同患者亚组NEC的认识。我们的目的是研究DMBT1表达与心脏状态、肠灌注受损、术中防菌和NEC暴发性病程的关系。方法:2010年至2019年在我院接受手术治疗的28例NEC患者。采用免疫组化方法检测DMBT1蛋白在肠道组织中的表达。分析临床参数与DMBT1表达的相关性。结果:我们检测了10例无心脏缺陷患者和18例持续性动脉导管(PDA)和先天性心脏缺陷(CHD)患者的DMBT1水平。与没有心脏畸形的患者相比,PDA/CHD患者的DMBT1水平倾向于得分更高(p = 0.2113),并且这些婴儿的DMBT1水平与c反应蛋白呈负相关(p = 0.0172;R = - 0.5533)。PDA/冠心病亚组表达dmbt1的巨噬细胞数量增加(p = 0.0399)。中性粒细胞和单核细胞与淋巴细胞的比值在PDA/CHD患儿中显著升高(p = 0.0319和0.0493)。DMBT1表达与术中拭子细菌培养阳性相关(p = 0.0252),浆膜DMBT1表达与NEC的急性病程相关(p = 0.0239)。结论:本研究表明新生儿肠内灌注受损的心脏异常可能影响DMBT1的表达。PDA/CHD婴儿NEC与更多的dmbt1阳性巨噬细胞和显著升高的中性粒细胞/淋巴细胞比率相关。
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引用次数: 1
Perinatal origins of chronic lung disease: mechanisms-prevention-therapy-sphingolipid metabolism and the genetic and perinatal origins of childhood asthma. 慢性肺病的围产期起源:机制-预防-治疗-鞘脂代谢以及儿童哮喘的遗传和围产期起源。
Pub Date : 2021-12-20 DOI: 10.1186/s40348-021-00130-y
Emily Wasserman, Stefan Worgall

Childhood asthma derives from complex host-environment interactions occurring in the perinatal and infant period, a critical time for lung development. Sphingolipids are bioactive molecules consistently implicated in the pathogenesis of childhood asthma. Genome wide association studies (GWAS) initially identified a link between alleles within the 17q21 asthma-susceptibility locus, childhood asthma, and overexpression of the ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3), an inhibitor of de novo sphingolipid synthesis. Subsequent studies of pediatric asthma offer strong evidence that these asthma-risk alleles correlate with early-life aberrancies of sphingolipid homeostasis and asthma. Relationships between sphingolipid metabolism and asthma-related risk factors, including maternal obesity and respiratory viral infections, are currently under investigation. This review will summarize how these perinatal and early life exposures can synergize with 17q21 asthma risk alleles to exacerbate disruptions of sphingolipid homeostasis and drive asthma pathogenesis.

儿童哮喘源于围产期和婴儿期发生的复杂的宿主-环境相互作用,这是肺部发育的关键时期。鞘脂是一种生物活性分子,一直与儿童哮喘的发病机制有关。基因组全关联研究(GWAS)最初发现了17q21哮喘易感位点、儿童哮喘和ORMDL鞘脂生物合成调节因子3 (ORMDL3)过表达之间的联系,ORMDL3是一种新生鞘脂合成抑制剂。随后对儿童哮喘的研究提供了强有力的证据,表明这些哮喘风险等位基因与生命早期神经鞘脂稳态异常和哮喘相关。鞘脂代谢与哮喘相关危险因素(包括产妇肥胖和呼吸道病毒感染)之间的关系目前正在调查中。本文将总结这些围产期和生命早期暴露如何与17q21哮喘风险等位基因协同作用,加剧鞘脂稳态的破坏并驱动哮喘发病机制。
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引用次数: 2
Patho-mechanisms of the origins of bronchopulmonary dysplasia. 支气管肺发育不良起源的病理机制。
Pub Date : 2021-12-11 DOI: 10.1186/s40348-021-00129-5
Mitali Sahni, Vineet Bhandari

Bronchopulmonary dysplasia (BPD) continues to be one of the most common complications of prematurity, despite significant advancement in neonatology over the last couple of decades. The new BPD is characterized histopathologically by impaired lung alveolarization and dysregulated vascularization. With the increased survival of extremely preterm infants, the risk for the development of BPD remains high, emphasizing the continued need to understand the patho-mechanisms that play a role in the development of this disease. This brief review summarizes recent advances in our understanding of the maldevelopment of the premature lung, highlighting recent research in pathways of oxidative stress-related lung injury, the role of placental insufficiency, growth factor signaling, the extracellular matrix, and microRNAs.

支气管肺发育不良(BPD)仍然是早产最常见的并发症之一,尽管在过去的几十年里,新生儿学取得了重大进展。新的BPD在组织病理学上以肺泡化受损和血管化失调为特征。随着极早产儿存活率的增加,BPD发展的风险仍然很高,强调继续需要了解在该疾病发展中起作用的病理机制。本文简要综述了我们对早产儿肺发育不良的最新研究进展,重点介绍了氧化应激相关肺损伤途径、胎盘功能不全、生长因子信号传导、细胞外基质和microrna的作用。
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引用次数: 9
Translational research approaches to study pediatric polycystic kidney disease. 儿童多囊肾病的转化研究方法
Pub Date : 2021-12-09 DOI: 10.1186/s40348-021-00131-x
Max Christoph Liebau, Djalila Mekahli

Polycystic kidney diseases (PKD) are severe forms of genetic kidney disorders. The two main types of PKD are autosomal recessive and autosomal dominant PKD (ARPKD, ADPKD). While ARPKD typically is a disorder of early childhood, patients with ADPKD often remain pauci-symptomatic until adulthood even though formation of cysts in the kidney already begins in children. There is clinical and genetic overlap between both entities with very variable clinical courses. Subgroups of very early onset ADPKD may for example clinically resemble ARPKD. The basis of the clinical variability in both forms of PKD is not well understood and there are also limited prediction markers for disease progression for daily clinical life or surrogate endpoints for clinical trials in ARPKD or early ADPKD.As targeted therapeutic approaches to slow disease progression in PKD are emerging, it is becoming more important to reliably identify patients at risk for rapid progression as they might benefit from early therapy. Over the past years regional, national and international data collections to jointly analyze the clinical courses of PKD patients have been set up. The clinical observations are complemented by genetic studies and biorepositories as well as basic science approaches to elucidate the underlying molecular mechanisms in the PKD field. These approaches may serve as a basis for the development of novel therapeutic interventions in specific subgroups of patients. In this article we summarize some of the recent developments in the field with a focus on kidney involvement in PKD during childhood and adolescence and findings obtained in pediatric cohorts.

多囊肾病(PKD)是遗传性肾脏疾病的严重形式。PKD的两种主要类型是常染色体隐性和常染色体显性PKD (ARPKD, ADPKD)。虽然ARPKD通常是儿童早期的一种疾病,但患有ADPKD的患者通常直到成年都没有症状,即使儿童肾脏囊肿已经开始形成。有临床和遗传重叠之间的实体非常不同的临床过程。例如,早发性ADPKD的亚群在临床上可能与ARPKD相似。两种形式PKD的临床变异性的基础尚不清楚,而且在ARPKD或早期ADPKD的临床试验中,日常临床生活中疾病进展的预测标志物或替代终点也有限。随着减缓PKD疾病进展的靶向治疗方法的出现,可靠地识别有快速进展风险的患者变得越来越重要,因为他们可能从早期治疗中受益。在过去的几年里,已经建立了区域、国家和国际的数据收集,共同分析PKD患者的临床病程。临床观察是由遗传研究和生物库以及基础科学方法来阐明PKD领域潜在的分子机制的补充。这些方法可以作为开发针对特定亚组患者的新型治疗干预措施的基础。在这篇文章中,我们总结了该领域的一些最新进展,重点是儿童和青少年时期PKD的肾脏受累以及在儿科队列中获得的发现。
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引用次数: 1
Imaging of peripheral vascular malformations - current concepts and future perspectives. 外周血管畸形的影像学-目前的概念和未来的展望。
Pub Date : 2021-12-07 DOI: 10.1186/s40348-021-00132-w
Vanessa F Schmidt, Max Masthoff, Michael Czihal, Beatrix Cucuruz, Beate Häberle, Richard Brill, Walter A Wohlgemuth, Moritz Wildgruber

Vascular Malformations belong to the spectrum of orphan diseases and can involve all segments of the vascular tree: arteries, capillaries, and veins, and similarly the lymphatic vasculature. The classification according to the International Society for the Study of Vascular Anomalies (ISSVA) is of major importance to guide proper treatment. Imaging plays a crucial role to classify vascular malformations according to their dominant vessel type, anatomical extension, and flow pattern. Several imaging concepts including color-coded Duplex ultrasound/contrast-enhanced ultrasound (CDUS/CEUS), 4D computed tomography angiography (CTA), magnetic resonance imaging (MRI) including dynamic contrast-enhanced MR-angiography (DCE-MRA), and conventional arterial and venous angiography are established in the current clinical routine. Besides the very heterogenous phenotypes of vascular malformations, molecular and genetic profiling has recently offered an advanced understanding of the pathogenesis and progression of these lesions. As distinct molecular subtypes may be suitable for targeted therapies, capturing certain patterns by means of molecular imaging could enhance non-invasive diagnostics of vascular malformations. This review provides an overview of subtype-specific imaging and established imaging modalities, as well as future perspectives of novel functional and molecular imaging approaches. We highlight recent pioneering imaging studies including thermography, positron emission tomography (PET), and multispectral optoacoustic tomography (MSOT), which have successfully targeted specific biomarkers of vascular malformations.

血管畸形属于孤儿病谱系,可涉及血管树的所有部分:动脉、毛细血管和静脉,同样也包括淋巴血管。根据国际血管异常研究学会(ISSVA)的分类对指导正确的治疗具有重要意义。根据主要的血管类型、解剖延伸和血流模式对血管畸形进行分类,影像学起着至关重要的作用。彩色编码超声/超声造影(CDUS/CEUS)、4D计算机断层血管造影(CTA)、磁共振成像(MRI)包括动态对比增强磁共振血管造影(DCE-MRA)、常规动脉、静脉血管造影等影像学概念在目前的临床常规中得到确立。除了血管畸形的异质性表型外,分子和遗传图谱最近提供了对这些病变的发病机制和进展的深入了解。由于不同的分子亚型可能适合靶向治疗,通过分子成像捕获某些模式可以增强血管畸形的非侵入性诊断。本文综述了亚型特异性成像和已建立的成像模式,以及新型功能和分子成像方法的未来前景。我们重点介绍了最近的成像研究,包括热成像、正电子发射断层扫描(PET)和多光谱光声断层扫描(MSOT),这些研究已经成功地针对血管畸形的特定生物标志物。
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引用次数: 12
The role of the immune system in idiopathic nephrotic syndrome. 免疫系统在特发性肾病综合征中的作用。
Pub Date : 2021-11-18 DOI: 10.1186/s40348-021-00128-6
Agnes Hackl, Seif El Din Abo Zed, Paul Diefenhardt, Julia Binz-Lotter, Rasmus Ehren, Lutz Thorsten Weber

Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.

儿童特发性肾病综合征(INS)的特点是大量蛋白尿和低白蛋白血症,通常对类固醇反应良好。然而,复发是频繁的,这可能需要多种药物治疗,有害的长期副作用。在过去的几十年里,人们对INS的分子机制提出了不同的假设,一些证据强烈表明免疫系统在非遗传性INS的发病机制中起着至关重要的作用。INS传统上被认为是一种由循环因子引发的t细胞介导的疾病,它会导致肾小球滤过屏障的损害和随后的蛋白尿。此外,Th17/Tregs和Th2/Th1之间的失衡与INS的病理机制有关。有趣的是,自从抗cd20抗体利妥昔单抗在治疗INS中表现出良好的治疗反应以来,b细胞已经引起了人们的关注。最后,最近的研究结果表明,即使足细胞也可以在炎症刺激下充当抗原呈递细胞,并在激活引起蛋白尿的细胞通路中发挥直接作用。尽管我们对INS的潜在机制的了解仍然不完整,但很明显,一个包括可溶性因子、免疫细胞和足细胞在内的多步骤控制系统是预防INS发生所必需的,而不是传统的相关细胞亚群或一个特定的分子作为INS的致病因素。这篇综述的目的是对这一主题的当前知识进行概述,因为我们对INS的免疫发病机制的理解的进展可能有助于推动新的定制治疗方法的发展。
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引用次数: 7
Does allogeneic stem cell transplantation in survivors of pediatric leukemia impact regular physical activity, pulmonary function, and exercise capacity? 同种异体干细胞移植对儿童白血病幸存者的常规身体活动、肺功能和运动能力有影响吗?
Pub Date : 2021-11-04 DOI: 10.1186/s40348-021-00127-7
Katharina Ruf, Alaa Badran, Céline Siauw, Imme Haubitz, Paul-Gerhardt Schlegel, Helge Hebestreit, Christoph Härtel, Verena Wiegering

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival in high-risk childhood leukemia but is associated with long-term sequelae such as impaired pulmonary function and reduced exercise capacity impacting quality of life.

Methods: A convenience sample of 17 patients after allo-HSCT (HSCT-12 male, age 15.7±6.7 years, time after HSCT 5.3±2.8 years) underwent pulmonary function testing, echocardiography, and an incremental exercise test on a bike. Physical activity and health-related quality of life were assessed by questionnaires (7-day physical activity recall, PEDS-QL). Seventeen healthy age- and gender-matched controls served as control group (CG) for results of pulmonary function and exercise testing.

Results: HSCT showed reduced pulmonary function (HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7%pred; FVC 88.4±19.3 vs. 107.6±6.9%pred, DLCO 75.3±23.6 vs. 104.9±12.8%pred) and exercise capacity (VO2peak 89±30.8%pred, CG 98±17.5%pred; Wmax 84±21.7%pred, CG 115±22.8%pred), but no relevant cardiac dysfunction and a good quality of life (PEDS-QL mean overall score 83.3±10.7). Differences in peak oxygen uptake between groups were mostly explained by 5 adolescent patients who underwent total body irradiation for conditioning. They showed significantly reduced diffusion capacity and reduced peak oxygen uptake. Patients reported a mean time of inactivity of 777±159min/day, moderate activity of 110±107 min/day, hard activity of 35±36 min/day, and very hard activity of 23±22 min/day. A higher amount of inactivity was associated with a lower peak oxygen uptake (correlation coefficient tau -0.48, p=0.023).

Conclusions: This pilot study shows that although patients after allo-HSCT reported a good quality of life, regular physical activity and exercise capacity are reduced in survivors of stem cell transplantation, especially in adolescents who are treated with total body irradiation for conditioning. Factors hindering regular physical activity need to be identified and exercise counseling should be part of follow-up visits in these patients.

背景:同种异体造血干细胞移植(Allogeneic hematopoietic stem cell transplantation, alloo - hsct)可提高高危儿童白血病患者的生存率,但也存在长期后遗症,如肺功能受损和运动能力下降,影响生活质量。方法:选取17例同种异体造血干细胞移植后患者(HSCT-12例男性,年龄15.7±6.7岁,HSCT后时间5.3±2.8年)进行肺功能检查、超声心动图检查和自行车增量运动试验。通过问卷(7天体力活动回忆,ped - ql)评估体力活动和健康相关生活质量。17名年龄和性别匹配的健康对照组(CG)作为肺功能和运动测试结果的对照组。结果:HSCT显示肺功能降低(HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7%;FVC 88.4±19.3 vs. 107.6±6.9%pred, DLCO 75.3±23.6 vs. 104.9±12.8%pred)和运动能力(vo2峰值89±30.8%pred, CG 98±17.5%pred;Wmax 84±21.7%pred, CG 115±22.8%pred),但无相关心功能障碍和良好的生活质量(PEDS-QL平均总评分83.3±10.7)。两组之间的峰值摄氧量差异主要由5名接受全身照射的青少年患者来解释。它们的扩散能力和峰值摄氧量明显降低。患者报告平均不活动时间为777±159min/天,中等活动时间为110±107 min/天,剧烈活动时间为35±36 min/天,剧烈活动时间为23±22 min/天。不活动的时间越长,吸氧峰值越低(相关系数tau -0.48, p=0.023)。结论:这项初步研究表明,尽管同种异体造血干细胞移植后的患者报告了良好的生活质量,但干细胞移植幸存者的常规体力活动和运动能力下降,特别是在接受全身照射治疗的青少年中。需要确定妨碍定期身体活动的因素,并在这些患者的随访中提供运动咨询。
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引用次数: 0
Bacterial metabolites and cardiovascular risk in children with chronic kidney disease. 慢性肾病儿童的细菌代谢物与心血管风险
Pub Date : 2021-10-22 DOI: 10.1186/s40348-021-00126-8
Julia Schlender, Felix Behrens, Victoria McParland, Dominik Müller, Nicola Wilck, Hendrik Bartolomaeus, Johannes Holle

Cardiovascular complications are the major cause of the marked morbidity and mortality associated with chronic kidney disease (CKD). The classical cardiovascular risk factors such as diabetes and hypertension undoubtedly play a role in the development of cardiovascular disease (CVD) in adult CKD patients; however, CVD is just as prominent in children with CKD who do not have these risk factors. Hence, the CKD-specific pathophysiology of CVD remains incompletely understood. In light of this, studying children with CKD presents a unique opportunity to analyze CKD-associated mechanisms of CVD more specifically and could help to unveil novel therapeutic targets.Here, we comprehensively review the interaction of the human gut microbiome and the microbial metabolism of nutrients with host immunity and cardiovascular end-organ damage. The human gut microbiome is evolutionary conditioned and modified throughout life by endogenous factors as well as environmental factors. Chronic diseases, such as CKD, cause significant disruption to the composition and function of the gut microbiome and lead to disease-associated dysbiosis. This dysbiosis and the accompanying loss of biochemical homeostasis in the epithelial cells of the colon can be the result of poor diet (e.g., low-fiber intake), medications, and underlying disease. As a result of dysbiosis, bacteria promoting proteolytic fermentation increase and those for saccharolytic fermentation decrease and the integrity of the gut barrier is perturbed (leaky gut). These changes disrupt local metabolite homeostasis in the gut and decrease productions of the beneficial short-chain fatty acids (SCFAs). Moreover, the enhanced proteolytic fermentation generates unhealthy levels of microbially derived toxic metabolites, which further accumulate in the systemic circulation as a consequence of impaired kidney function. We describe possible mechanisms involved in the increased systemic inflammation in CKD that is associated with the combined effect of SCFA deficiency and accumulation of uremic toxins. In the future, a more comprehensive and mechanistic understanding of the gut-kidney-heart interaction, mediated largely by immune dysregulation and inflammation, might allow us to target the gut microbiome more specifically in order to attenuate CKD-associated comorbidities.

心血管并发症是慢性肾脏疾病(CKD)显著发病率和死亡率的主要原因。糖尿病和高血压等经典心血管危险因素无疑在成人CKD患者心血管疾病(CVD)的发展中起着重要作用;然而,心血管疾病在没有这些危险因素的CKD患儿中同样突出。因此,CVD的ckd特异性病理生理机制仍不完全清楚。鉴于此,研究儿童CKD提供了一个独特的机会,可以更具体地分析CKD相关的CVD机制,并有助于揭示新的治疗靶点。在这里,我们全面回顾了人类肠道微生物群和营养物质微生物代谢与宿主免疫和心血管终末器官损伤的相互作用。人类肠道微生物群在整个生命过程中受到内源性因素和环境因素的进化制约和修饰。慢性疾病,如慢性肾病,会对肠道微生物群的组成和功能造成严重破坏,并导致疾病相关的生态失调。这种生态失调和伴随的结肠上皮细胞生化稳态的丧失可能是不良饮食(如低纤维摄入)、药物和潜在疾病的结果。由于生态失调,促进蛋白水解发酵的细菌增加,而促进糖水解发酵的细菌减少,肠道屏障的完整性受到干扰(漏肠)。这些变化破坏了肠道内局部代谢物的稳态,减少了有益的短链脂肪酸(SCFAs)的产生。此外,增强的蛋白质水解发酵产生不健康水平的微生物衍生的有毒代谢物,这些代谢物进一步积聚在体循环中,导致肾功能受损。我们描述了CKD中全身性炎症增加的可能机制,这与SCFA缺乏和尿毒症毒素积累的联合作用有关。在未来,对主要由免疫失调和炎症介导的肠-肾-心相互作用的更全面和机制的理解,可能使我们能够更有针对性地靶向肠道微生物群,以减轻ckd相关的合共病。
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引用次数: 2
Proceedings of the 9th International Symposium on MDS and SAA in Childhood : Athens, Greece. 30 September-2 October 2021. 第九届儿童MDS和SAA国际研讨会论文集:希腊雅典,2021年9月30日至10月2日。
Pub Date : 2021-10-11 DOI: 10.1186/s40348-021-00125-9
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引用次数: 1
Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis. 外显子组测序提示常染色体显性下尿路功能障碍和轻度遗传性痉挛性截瘫中DSTYK的一种新的杂合错义变异。
Pub Date : 2021-10-04 DOI: 10.1186/s40348-021-00122-y
Clara Vidic, Marcin Zaniew, Szymon Jurga, Holger Thiele, Heiko Reutter, Alina C Hilger

Introduction: DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures.

Materials and methods: Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome.

Results: Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family.

Conclusion: To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.

DSTYK编码双丝氨酸/苏氨酸和酪氨酸蛋白激酶。DSTYK与常染色体显性先天性肾脏和尿路异常以及常染色体隐性遗传性痉挛性截瘫23型有关。在这里,我们报告了一位父亲和他的两个异卵双胞胎儿子,他们携带一种新的DSTYK杂合错义变异,由于排尿功能障碍而出现早发性下尿路功能障碍。此外,在疾病的后期,两个儿子都表现为双侧下肢痉挛,反射快,失神发作。材料和方法:对患病父亲及其患病儿子进行外显子组测序。儿子临床表现为排尿犹豫,排尿功能障碍,夜间尿失禁,直到青春期,而父亲报告排尿困难。在男孩中,膀胱镜检查排除了尿道瓣膜,发现膀胱颈肥大和膀胱小梁。此外,两个儿子都在儿童早期被诊断为缺乏性癫痫。外显子组数据的过滤主要集中在罕见的(MAF < 0.01%),常染色体显性变异,预测是有害的,位于外显子组的高度保守区域。结果:外显子组分析鉴定出一种新的杂合错义变异(c.271C> a (p.Leu91Met))在DSTYK中与疾病分离。计算机预测分析一致认为该变异是有害的,表明该变异在家族中是致病的。结论:据我们所知,这是首次报道与DSTYK中一种新的杂合显性错义变异相关的早发性排尿功能障碍、癫痫发作和双侧下肢痉挛。
{"title":"Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis.","authors":"Clara Vidic,&nbsp;Marcin Zaniew,&nbsp;Szymon Jurga,&nbsp;Holger Thiele,&nbsp;Heiko Reutter,&nbsp;Alina C Hilger","doi":"10.1186/s40348-021-00122-y","DOIUrl":"https://doi.org/10.1186/s40348-021-00122-y","url":null,"abstract":"<p><strong>Introduction: </strong>DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures.</p><p><strong>Materials and methods: </strong>Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome.</p><p><strong>Results: </strong>Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family.</p><p><strong>Conclusion: </strong>To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39485753","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: 1
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Molecular and cellular pediatrics
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