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Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. 儿童偏色差性脑白质营养不良患者造血干细胞移植后的早期临床过程。
Pub Date : 2020-09-03 DOI: 10.1186/s40348-020-00103-7
Judith Beschle, Michaela Döring, Christiane Kehrer, Christa Raabe, Ute Bayha, Manuel Strölin, Judith Böhringer, Andrea Bevot, Nadja Kaiser, Benjamin Bender, Alexander Grimm, Peter Lang, Ingo Müller, Ingeborg Krägeloh-Mann, Samuel Groeschel

Background: Long-term outcomes of hematopoietic stem cell transplantation (HSCT) in children with juvenile metachromatic leukodystrophy (MLD) have been investigated systematically, while short-term effects of HSCT on the course of the disease remain to be elucidated.

Results: In this study, the clinical course was evaluated over the first 24 months following HSCT, conducted at our center in 12 children with juvenile MLD (mean follow-up 6.75 years, range 3-13.5) and compared with 35 non-transplanted children with juvenile MLD. Motor function (GMFM-88 and GMFC-MLD), cognitive function (FSIQ), peripheral neuropathy (tibial nerve conduction velocity), and cerebral changes (MLD-MR severity score) were tested prospectively. Seven children remained neurologically stable over a long period, five exhibited rapid disease progression over the first 12 to 18 months after transplantation. In the latter, time from first gross motor symptoms to loss of independent walking was significantly shorter compared with non-transplanted patients at the same stage of disease (p < 0.02). Positive prognostic factors were good motor function (GMFM = 100%, GMFC-MLD = 0) and a low MR severity score (≤ 17) at the time of HSCT.

Conclusions: Our results show that if disease progression occurs, this happens early on after HSCT and proceeds faster than in non-transplanted children with juvenile MLD, indicating that HSCT may trigger disease progression.

背景:造血干细胞移植(HSCT)治疗青少年色差性脑白质营养不良(MLD)的长期结果已经被系统地研究过,而HSCT对该疾病病程的短期影响仍有待阐明。结果:在本研究中,我们对12例青少年MLD儿童(平均随访6.75年,范围3-13.5年)进行了HSCT后的前24个月的临床病程进行了评估,并与35例未移植的青少年MLD儿童进行了比较。前瞻性检测运动功能(GMFM-88和GMFC-MLD)、认知功能(FSIQ)、周围神经病变(胫神经传导速度)和大脑变化(MLD-MR严重程度评分)。7名儿童长期保持神经系统稳定,5名儿童在移植后的前12至18个月内表现出疾病的快速进展。后者从出现大运动症状到丧失独立行走的时间明显短于同阶段未移植患者(p < 0.02)。阳性预后因素为HSCT时良好的运动功能(GMFM = 100%, GMFC-MLD = 0)和低MR严重程度评分(≤17)。结论:我们的研究结果表明,如果发生疾病进展,这种进展发生在HSCT后早期,并且比未移植的少年MLD儿童更快,这表明HSCT可能引发疾病进展。
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引用次数: 17
Nup133 and ERα mediate the differential effects of hyperoxia-induced damage in male and female OPCs. Nup133和ERα介导高氧损伤在雄性和雌性OPCs中的差异作用。
Pub Date : 2020-08-25 DOI: 10.1186/s40348-020-00102-8
Donna Elizabeth Sunny, Elke Hammer, Sebastian Strempel, Christy Joseph, Himanshu Manchanda, Till Ittermann, Stephanie Hübner, Frank Ulrich Weiss, Uwe Völker, Matthias Heckmann

Background: Hyperoxia is a well-known cause of cerebral white matter injury in preterm infants with male sex being an independent and critical risk factor for poor neurodevelopmental outcome. Sex is therefore being widely considered as one of the major decisive factors for prognosis and treatment of these infants. But unfortunately, we still lack a clear view of the molecular mechanisms that lead to such a profound difference. Hence, using mouse-derived primary oligodendrocyte progenitor cells (OPCs), we investigated the molecular factors and underlying mechanisms behind the differential response of male and female cells towards oxidative stress.

Results: We demonstrate that oxidative stress severely affects cellular functions related to energy metabolism, stress response, and maturation in the male-derived OPCs, whereas the female cells remain largely unaffected. CNPase protein level was found to decline following hyperoxia in male but not in female cells. This impairment of maturation was accompanied by the downregulation of nucleoporin and nuclear lamina proteins in the male cells. We identify Nup133 as a novel target protein affected by hyperoxia, whose inverse regulation may mediate this differential response in the male and female cells. Nup133 protein level declined following hyperoxia in male but not in female cells. We show that nuclear respiratory factor 1 (Nrf1) is a direct downstream target of Nup133 and that Nrf1 mRNA declines following hyperoxia in male but not in female cells. The female cells may be rendered resistant due to synergistic protection via the estrogen receptor alpha (ERα) which was upregulated following hyperoxia in female but not in male cells. Both Nup133 and ERα regulate mitochondrial function and oxidative stress response by transcriptional regulation of Nrf1.

Conclusions: These findings from a basic cell culture model establish prominent sex-based differences and suggest a novel mechanism involved in the differential response of OPCs towards oxidative stress. It conveys a strong message supporting the need to study how complex cellular processes are regulated differently in male and female brains during development and for a better understanding of how the brain copes up with different forms of stress after preterm birth.

背景:高氧是男性早产儿脑白质损伤的一个众所周知的原因,是神经发育不良的一个独立和关键的危险因素。因此,性别被广泛认为是这些婴儿预后和治疗的主要决定性因素之一。但不幸的是,我们仍然对导致如此深刻差异的分子机制缺乏清晰的认识。因此,我们使用小鼠来源的原代少突胶质祖细胞(OPCs),研究了雄性和雌性细胞对氧化应激差异反应背后的分子因素和潜在机制。结果:我们证明氧化应激严重影响雄性来源的OPCs的能量代谢、应激反应和成熟相关的细胞功能,而雌性细胞基本不受影响。在雄性细胞中发现CNPase蛋白水平在高氧后下降,而在雌性细胞中则没有。这种成熟障碍伴随着核孔蛋白和核层蛋白在雄性细胞中的下调。我们发现Nup133是受高氧影响的一种新的靶蛋白,其反向调控可能介导了男性和女性细胞的这种差异反应。高氧后,雄性细胞中Nup133蛋白水平下降,而雌性细胞中没有。我们发现核呼吸因子1 (Nrf1)是Nup133的直接下游靶点,在男性细胞中Nrf1 mRNA在高氧后下降,而在女性细胞中则没有。雌性细胞可能由于雌激素受体α (ERα)的协同保护而产生抗性,雌激素受体α在雌性细胞高氧后上调,而在雄性细胞中没有上调。Nup133和ERα均通过Nrf1转录调控线粒体功能和氧化应激反应。结论:这些来自基本细胞培养模型的发现建立了显著的性别差异,并提示了一种涉及OPCs对氧化应激差异反应的新机制。它传达了一个强有力的信息,支持研究复杂的细胞过程在男性和女性大脑发育过程中如何受到不同的调节,以及更好地理解大脑如何应对早产后不同形式的压力。
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引用次数: 6
Osteogenesis imperfecta-pathophysiology and therapeutic options. 成骨不全:病理生理学和治疗选择。
Pub Date : 2020-08-14 DOI: 10.1186/s40348-020-00101-9
Julia Etich, Lennart Leßmeier, Mirko Rehberg, Helge Sill, Frank Zaucke, Christian Netzer, Oliver Semler

Osteogenesis imperfecta (OI) is a rare congenital disease with a wide spectrum of severity characterized by skeletal deformity and increased bone fragility as well as additional, variable extraskeletal symptoms. Here, we present an overview of the genetic heterogeneity and pathophysiological background of OI as well as OI-related bone fragility disorders and highlight current therapeutic options.The most common form of OI is caused by mutations in the two collagen type I genes. Stop mutations usually lead to reduced collagen amount resulting in a mild phenotype, while missense mutations mainly provoke structural alterations in the collagen protein and entail a more severe phenotype. Numerous other causal genes have been identified during the last decade that are involved in collagen biosynthesis, modification and secretion, the differentiation and function of osteoblasts, and the maintenance of bone homeostasis.Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation. Surgical treatment ensures pain reduction and healing without an increase of deformities. Timely remobilization and regular strengthening of the muscles by physiotherapy are crucial to improve mobility, prevent muscle wasting and avoid bone resorption caused by immobilization. Identification of the pathomechanism for SERPINF1 mutations led to the development of a tailored mechanism-based therapy using denosumab, and unraveling further pathomechanisms will likely open new avenues for innovative treatment approaches.

成骨不全症(OI)是一种罕见的先天性疾病,其严重程度广泛,以骨骼畸形和骨脆性增加以及其他可变的骨骼外症状为特征。在这里,我们概述了成骨不全以及成骨不全相关的骨脆性疾病的遗传异质性和病理生理背景,并强调了当前的治疗选择。最常见的成骨不全是由两种I型胶原基因的突变引起的。停止突变通常导致胶原蛋白数量减少,导致轻度表型,而错义突变主要引起胶原蛋白的结构改变,导致更严重的表型。在过去的十年中,已经发现了许多其他的致病基因,这些基因涉及胶原蛋白的生物合成、修饰和分泌、成骨细胞的分化和功能以及骨稳态的维持。对成骨不全患者的治疗包括使用双膦酸盐作为最有希望的抑制骨吸收从而促进骨形成的治疗方法。手术治疗确保疼痛减轻和愈合,而不会增加畸形。通过物理治疗及时活动和定期加强肌肉是提高活动能力,防止肌肉萎缩和避免固定引起的骨吸收的关键。serinf1突变的病理机制的确定导致了使用denosumab的量身定制的基于机制的治疗的发展,揭示进一步的病理机制可能会为创新的治疗方法开辟新的途径。
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引用次数: 34
Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 21-羟化酶缺乏引起的非典型性先天性肾上腺增生的儿童和青少年的基因型-表型相关性。
Pub Date : 2020-07-09 DOI: 10.1186/s40348-020-00100-w
Helmuth-Günther Dörr, Nadja Schulze, Markus Bettendorf, Gerhard Binder, Walter Bonfig, Christian Denzer, Desiree Dunstheimer, Kirsten Salzgeber, Heinrich Schmidt, Karl Otfried Schwab, Egbert Voss, Martin Wabitsch, Joachim Wölfle

Background: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany.

Aims: Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation PATIENTS AND METHODOLOGY: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. RESULTS (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7).

Conclusion: Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.

背景:21-羟化酶缺乏引起的非典型性先天性肾上腺增生是由21-羟化酶活性基因(CYP21A2)突变引起的。临床症状差别很大。迄今为止,在德国还没有进行过系统的研究。目的:表型描述,诊断评估和基因型-表型相关性患者和方法:回顾性分析在巴伐利亚州和巴登-符腾堡州10个儿科内分泌中心的多中心研究中134例患者(年龄范围0.1-18.6岁)的数据。数据是现场从医疗记录中收集的。在126例患者中发现了233个CYP21A2基因突变的等位基因。突变结果的基因型-表型相关性进行了研究(C1,严重/轻度;C2,轻度/轻微的)。具有CYP21A2杂合突变的个体也包括在内(C3)。数据收集于2014 - 2015年,经埃尔兰根大学医院伦理委员会批准。结果(MW±SD): 134例患者中有117例(115例,29例)出现症状。诊断时的实足年龄(CA)为7.1±4.4岁。最常见的症状是耻骨过早(73.5%)。诊断时身高- sds为0.8±1.3,BMI-SDS为0.8±1.2。82.9%的有症状患者能确定骨龄(BA)。BA与CA的差异为1.9±1.4年。结论:大多数患者有轻度雄激素化症状。男性患者诊断不足。诊断没有标准化。突变类型之间的差异是在激素浓度上发现的,而不是在表型上。我们进一步推测,尚未明确定义的因素负责各自表型的发展。
{"title":"Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.","authors":"Helmuth-Günther Dörr,&nbsp;Nadja Schulze,&nbsp;Markus Bettendorf,&nbsp;Gerhard Binder,&nbsp;Walter Bonfig,&nbsp;Christian Denzer,&nbsp;Desiree Dunstheimer,&nbsp;Kirsten Salzgeber,&nbsp;Heinrich Schmidt,&nbsp;Karl Otfried Schwab,&nbsp;Egbert Voss,&nbsp;Martin Wabitsch,&nbsp;Joachim Wölfle","doi":"10.1186/s40348-020-00100-w","DOIUrl":"https://doi.org/10.1186/s40348-020-00100-w","url":null,"abstract":"<p><strong>Background: </strong>Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany.</p><p><strong>Aims: </strong>Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation PATIENTS AND METHODOLOGY: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. RESULTS (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7).</p><p><strong>Conclusion: </strong>Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-020-00100-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38145181","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: 6
DNA methylation biomarkers of future health outcomes in children. 儿童未来健康结局的DNA甲基化生物标志物
Pub Date : 2020-07-09 DOI: 10.1186/s40348-020-00099-0
Shivanthan Shanthikumar, Melanie R Neeland, Jovana Maksimovic, Sarath C Ranganathan, Richard Saffery

Biomarkers which predict future health outcomes are key to the goals of precision health. Such biomarkers do not have to be involved in the causal pathway of a disease, and their performance is best assessed using statistical tests of clinical performance and evaluation of net health impact. DNA methylation is the most commonly studied epigenetic process and represents a potential biomarker of future health outcomes. We review 25 studies in non-oncological paediatric conditions where DNA methylation biomarkers of future health outcomes are assessed. Whilst a number of positive findings have been described, the body of evidence is severely limited by issues with outcome measures, tissue-specific samples, accounting for sample cell type heterogeneity, lack of appropriate statistical testing, small effect sizes, limited validation, and no assessment of net health impact. Future studies should concentrate on careful study design to overcome these issues, and integration of DNA methylation data with other 'omic', clinical, and environmental data to generate the most clinically useful biomarkers of paediatric disease.

预测未来健康结果的生物标志物是实现精准健康目标的关键。这些生物标志物不必参与疾病的因果途径,它们的性能最好通过临床性能的统计测试和净健康影响评估来评估。DNA甲基化是最常研究的表观遗传过程,代表了未来健康结果的潜在生物标志物。我们回顾了25项非肿瘤性儿科疾病的研究,其中评估了DNA甲基化生物标志物对未来健康结果的影响。虽然已经描述了一些积极的发现,但由于结果测量、组织特异性样本、考虑样本细胞类型异质性、缺乏适当的统计测试、效应量小、验证有限以及未评估净健康影响等问题,证据体受到严重限制。未来的研究应该集中在仔细的研究设计上,以克服这些问题,并将DNA甲基化数据与其他“组学”、临床和环境数据相结合,以产生临床上最有用的儿科疾病生物标志物。
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引用次数: 6
Infant formula with cow's milk fat and prebiotics affects intestinal flora, but not the incidence of infections during infancy in a double-blind randomized controlled trial. 在一项双盲随机对照试验中,含有乳脂和益生元的婴儿配方奶粉会影响肠道菌群,但不会影响婴儿期感染的发生率。
Pub Date : 2020-07-02 DOI: 10.1186/s40348-020-00098-1
Antonia Nomayo, Andreas Schwiertz, Rainer Rossi, Katharina Timme, Janine Foster, Richard Zelenka, Josef Tvrdik, Frank Jochum

Background: The postnatal intestinal colonization of human milk-fed and formula-fed infants differs substantially, as does the susceptibility to infectious diseases during infancy. Specific ingredients in human milk, such as prebiotic human milk oligosaccharides and a specifically structured fat composition with high proportion of beta-palmitic acid (beta-PA) promote the growth of intestinal bifidobacteria, which are associated with favorable effects on infants' health. The present study investigates whether addition of prebiotic galactooligosaccharides (GOS) in combination with higher amounts of beta-PA from cow's milk fat in infant formula positively affects gut microbiota and the incidence of infections in formula-fed infants.

Methods: In a double-blind controlled trial, formula-fed infants were randomly assigned to either receive an experimental formula containing a higher proportion of beta-PA (20-25%) from natural cow's milk fat, and a prebiotic supplement (0.5 g GOS/100 ml), or a standard infant formula with low beta-PA (< 10%), without prebiotics. A breast-fed reference group was also enrolled. After 12 weeks, fecal samples were collected to determine the proportion of fecal bifidobacteria. The number of infections during the first year of life was recorded.

Results: After 12 weeks, the proportion of fecal bifidobacteria was significantly higher in infants receiving formula with high beta-PA and GOS compared to control, and was similar to the breast-fed group (medians 8.8%, 2.5%, and 5.0% respectively; p < 0.001). The incidence of gastrointestinal or other infections during the first year of life did not differ between groups.

Conclusions: The combination of higher amounts of beta-PA plus GOS increased significantly the proportion of fecal bifidobacteria in formula-fed infants, but did not affect the incidence of infections.

Trial registration: The study protocol was registered with Clinical Trials (Protocol Registration and Results System Trial ID: NCT01603719 ) on 05/15/2012 (retrospectively registered).

背景:母乳喂养和配方奶粉喂养的婴儿出生后肠道定植有很大的不同,婴儿对传染病的易感性也有很大的不同。母乳中的特定成分,如益生元母乳低聚糖和含有高比例β -棕榈酸(β -pa)的特殊结构脂肪成分,可以促进肠道双歧杆菌的生长,这对婴儿的健康有良好的影响。本研究探讨了在婴儿配方奶粉中添加益生元低聚半乳糖(GOS)和大量从牛奶脂肪中提取的β - pa是否会对配方奶粉喂养的婴儿的肠道微生物群和感染发生率产生积极影响。方法:在双盲对照试验中,配方奶喂养的婴儿随机分为两组,一组服用天然牛乳脂肪中β - pa含量较高(20-25%)的实验配方奶粉,另一组服用益生元补充剂(0.5 g GOS/100 ml),另一组服用低β - pa含量(< 10%)的标准婴儿配方奶粉,不含益生元。一个母乳喂养参照组也被纳入研究。12周后,收集粪便样本,测定粪便双歧杆菌比例。记录了生命第一年的感染人数。结果:12周后,接受高- pa和GOS配方奶粉的婴儿粪便双歧杆菌比例显著高于对照组,与母乳喂养组相似(中位数分别为8.8%、2.5%和5.0%;P < 0.001)。在生命的第一年,胃肠道或其他感染的发生率在两组之间没有差异。结论:高剂量β - pa + GOS联合使用可显著提高配方奶喂养婴儿粪便双歧杆菌比例,但不影响感染发生率。试验注册:研究方案于2012年5月15日在临床试验(方案注册和结果系统试验ID: NCT01603719)注册(回顾性注册)。
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引用次数: 7
Pro-inflammatory cytokine ratios determine the clinical course of febrile neutropenia in children receiving chemotherapy. 促炎细胞因子比率决定接受化疗的儿童发热性中性粒细胞减少症的临床病程。
Pub Date : 2020-06-09 DOI: 10.1186/s40348-020-00097-2
Mira Siegmund, Julia Pagel, Tasja Scholz, Jan Rupp, Christoph Härtel, Melchior Lauten

Background: Febrile neutropenia is a common and serious complication during treatment of childhood cancer. Empirical broad-spectrum antibiotics are usually administered until neutrophil cell count recovery. It was the aim of this study to investigate cytokine profiles as potential biomarkers using in-vitro sepsis models to differentiate between distinct clinical courses of febrile neutropenia (FN).

Methods: We conducted an observational study in FN episodes of pediatric oncology patients. Courses of neutropenia were defined as severe in case of proven blood stream infection or clinical evidence of complicated infection. We collected blood samples at various time points from the onset of FN and stimulated ex vivo with lipopolysaccharide (LPS) and Staphylococcus epidermidis (SE) for 24 h. Twenty-seven cytokine levels were measured in the whole blood culture supernatants by a multiplex immunoassay system.

Results: Forty-seven FN episodes from 33 children were investigated. IL-8, IL-1β, and MCP-1 expression increased significantly over time. IL-8, MIP-1α, MIP-1β, MCP-1, and TNF-α showed significantly lower concentration in patients with a clinically severe course of the FN.

Conclusions: Distinct patterns of cytokine profiles seem to be able to determine infectious FN and to predict the severity of its clinical course. If these data can be verified in a multi-centre setting, this may finally lead to an individualized treatment strategy facilitating antibiotic stewardship in these patients.

背景:发热性中性粒细胞减少症是儿童癌症治疗过程中常见且严重的并发症。经验广谱抗生素通常使用,直到中性粒细胞计数恢复。本研究的目的是利用体外脓毒症模型来研究细胞因子谱作为潜在的生物标志物,以区分发热性中性粒细胞减少症(FN)的不同临床病程。方法:我们对小儿肿瘤患者FN发作进行了一项观察性研究。中性粒细胞减少的病程被定义为严重的情况下,证实血流感染或临床证据的复杂感染。我们在FN发作后的不同时间点采集血液样本,并用脂多糖(LPS)和表皮葡萄球菌(SE)刺激体外24小时。通过多重免疫分析系统测量全血培养上清中27种细胞因子的水平。结果:调查了33例儿童47例FN发作。随着时间的推移,IL-8、IL-1β和MCP-1的表达显著增加。IL-8、MIP-1α、MIP-1β、MCP-1和TNF-α浓度在FN临床严重病程患者中显著降低。结论:细胞因子谱的不同模式似乎能够确定感染性FN并预测其临床病程的严重程度。如果这些数据可以在多中心环境中得到验证,这可能最终导致个性化的治疗策略,促进这些患者的抗生素管理。
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引用次数: 0
Modulation of CYP2E1 metabolic activity in a cohort of confirmed caffeine ingesting pregnant women with preterm offspring. CYP2E1代谢活性的调节在证实咖啡因摄入的早产孕妇队列中。
Pub Date : 2020-06-01 DOI: 10.1186/s40348-020-00096-3
M R Alcorta-García, C N López-Villaseñor, G Sánchez-Ferrer, H Flores-Mendoza, F Castorena-Torres, M A Aguilar-Torres, C M Sepúlveda-Treviño, J A Hernández-Hernández, R C López-Sánchez, V J Lara-Díaz

Background: To ascertain interactions of caffeine ingestion, food, medications, and environmental exposures during preterm human gestation, under informed consent, we studied a cohort of Mexican women with further preterm offspring born at ≤ 34 completed weeks. At birth, blood samples were taken from mothers and umbilical cords to determine caffeine and metabolites concentrations and CYP1A2 (rs762551) and CYP2E1 (rs2031920, rs3813867) polymorphisms involved in caffeine metabolism.

Results: In 90 pregnant women who gave birth to 98 preterm neonates, self-informed caffeine ingestion rate was 97%, laboratory confirmed rate was 93 %. Theobromine was the predominant metabolite found. Consumption of acetaminophen correlated significantly with changes in caffeine metabolism (acetaminophen R2 = 0.637, p = 0.01) due to activation of CYP2E1 alternate pathways. The main caffeine source was cola soft drinks.

Conclusion: Environmental exposures, especially acetaminophen ingestion during human preterm pregnancy, can modulate CYP2E1 metabolic activity.

背景:为了确定咖啡因摄入、食物、药物和环境暴露在人类早产妊娠期间的相互作用,在知情同意的情况下,我们研究了一组墨西哥妇女,她们的后代在≤34周出生。出生时,从母亲和脐带采集血液样本,以确定咖啡因和代谢物浓度以及参与咖啡因代谢的CYP1A2 (rs762551)和CYP2E1 (rs2031920, rs3813867)多态性。结果:90例分娩98例早产儿的孕妇中,自知咖啡因摄入率为97%,实验室确证率为93%。可可碱是主要代谢物。由于CYP2E1替代通路的激活,对乙酰氨基酚的摄入与咖啡因代谢的变化显著相关(对乙酰氨基酚R2 = 0.637, p = 0.01)。主要的咖啡因来源是可乐软饮料。结论:环境暴露,尤其是早产儿对乙酰氨基酚的摄入可调节CYP2E1的代谢活性。
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引用次数: 0
Shedding light on pediatric diseases: multispectral optoacoustic tomography at the doorway to clinical applications. 揭示儿科疾病:多光谱光声断层扫描在临床应用的门口。
Pub Date : 2020-03-04 DOI: 10.1186/s40348-020-00095-4
Adrian P Regensburger, Alexandra L Wagner, Jing Claussen, Maximilian J Waldner, Ferdinand Knieling

Optoacoustic imaging (OAI), or photoacoustic imaging (PAI), has fundamentally influenced basic science by providing high-resolution visualization of biological mechanisms. With the introduction of multispectral optoacoustic tomography (MSOT), these technologies have now moved closer to clinical applications. MSOT utilizes short-pulsed near-infrared laser light to induce thermoelastic expansion in targeted tissues. This results in acoustic pressure waves, which are used to resolve specific endo- and exogenous chromophores. Especially in the pediatric population, this non-invasive imaging approach might hold fundamental advantages compared to conventional cross-sectional imaging modalities. As this technology allows the visualization of quantitative molecular tissue composition at high spatial resolution non-invasively in sufficient penetration depth, it paves the way to personalized medicine in pediatric diseases.

光声成像(OAI)或光声成像(PAI)通过提供生物机制的高分辨率可视化,从根本上影响了基础科学。随着多光谱光声断层扫描(MSOT)的引入,这些技术现在已经接近临床应用。MSOT利用短脉冲近红外激光诱导靶组织的热弹性膨胀。这就产生了声压波,用于分辨特定的内和外源性发色团。特别是在儿科人群中,与传统的横断面成像方式相比,这种非侵入性成像方法可能具有根本优势。由于该技术可以在足够的穿透深度下以高空间分辨率无创地可视化定量分子组织组成,为儿科疾病的个性化医疗铺平了道路。
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引用次数: 12
Random X chromosome inactivation in patients with Klinefelter syndrome. Klinefelter综合征患者随机X染色体失活。
Pub Date : 2020-01-24 DOI: 10.1186/s40348-020-0093-x
Kenichi Kinjo, Tomoko Yoshida, Yoshitomo Kobori, Hiroshi Okada, Erina Suzuki, Tsutomu Ogata, Mami Miyado, Maki Fukami

Background: X chromosome inactivation (XCI) is an indispensable process in the development of human female embryos. Reportedly, XCI occurs when a blastocyst contains 10-12 embryonic progenitor cells. To date, it remains unclear whether XCI ratios are normally preserved in Klinefelter syndrome (KS) patients with 47,XXY karyotype.

Methods: We examined XCI ratios in 18 KS patients through DNA methylation analysis for the polymorphic trinucleotide locus in the AR gene. The results of the KS patients were compared to previous data from healthy young women.

Results: XCI ratios in KS patients followed a normal distribution. Skewed XCI was observed in two patients, one of whom exhibited extremely skewed XCI. The frequencies of skewed and extremely skewed XCI in the KS cohort were comparable to those in healthy women.

Conclusion: This study confirmed the rarity of skewed XCI in KS patients. These results indicate that the presence of a supernumerary X chromosome during the cleavage and early blastocyst stages does not affect the developmental tempo of embryos. Our data deserve further validation.

背景:X染色体失活(XCI)是人类女性胚胎发育过程中不可缺少的过程。据报道,当囊胚含有10-12个胚胎祖细胞时,XCI就会发生。迄今为止,仍不清楚XCI比率是否正常保存在Klinefelter综合征(KS)患者的47xxy核型。方法:通过对AR基因多态三核苷酸位点的DNA甲基化分析,检测18例KS患者的XCI比率。将KS患者的结果与之前健康年轻女性的数据进行比较。结果:KS患者XCI比值服从正态分布。在2例患者中观察到偏斜的XCI,其中1例表现为极端偏斜的XCI。KS队列中XCI偏斜和极度偏斜的频率与健康女性相当。结论:本研究证实了KS患者XCI偏斜的罕见性。这些结果表明,在卵裂期和囊胚早期存在多余的X染色体并不影响胚胎的发育速度。我们的数据值得进一步验证。
{"title":"Random X chromosome inactivation in patients with Klinefelter syndrome.","authors":"Kenichi Kinjo,&nbsp;Tomoko Yoshida,&nbsp;Yoshitomo Kobori,&nbsp;Hiroshi Okada,&nbsp;Erina Suzuki,&nbsp;Tsutomu Ogata,&nbsp;Mami Miyado,&nbsp;Maki Fukami","doi":"10.1186/s40348-020-0093-x","DOIUrl":"https://doi.org/10.1186/s40348-020-0093-x","url":null,"abstract":"<p><strong>Background: </strong>X chromosome inactivation (XCI) is an indispensable process in the development of human female embryos. Reportedly, XCI occurs when a blastocyst contains 10-12 embryonic progenitor cells. To date, it remains unclear whether XCI ratios are normally preserved in Klinefelter syndrome (KS) patients with 47,XXY karyotype.</p><p><strong>Methods: </strong>We examined XCI ratios in 18 KS patients through DNA methylation analysis for the polymorphic trinucleotide locus in the AR gene. The results of the KS patients were compared to previous data from healthy young women.</p><p><strong>Results: </strong>XCI ratios in KS patients followed a normal distribution. Skewed XCI was observed in two patients, one of whom exhibited extremely skewed XCI. The frequencies of skewed and extremely skewed XCI in the KS cohort were comparable to those in healthy women.</p><p><strong>Conclusion: </strong>This study confirmed the rarity of skewed XCI in KS patients. These results indicate that the presence of a supernumerary X chromosome during the cleavage and early blastocyst stages does not affect the developmental tempo of embryos. Our data deserve further validation.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-020-0093-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37573993","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: 7
期刊
Molecular and cellular pediatrics
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