Molecular and cellular pediatrics最新文献

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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
Molecular and cellular 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
{"title":"The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.","authors":"Kelly M Martinovich, Nicole C Shaw, Anthony Kicic, André Schultz, Sue Fletcher, Steve D Wilton, Stephen M Stick","doi":"10.1186/s40348-018-0081-6","DOIUrl":"10.1186/s40348-018-0081-6","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"3"},"PeriodicalIF":2.4,"publicationDate":"2018-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35803345","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
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。
Molecular and cellular 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
{"title":"CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility.","authors":"Julia Seyfarth,&nbsp;Heinz Ahlert,&nbsp;Joachim Rosenbauer,&nbsp;Christina Baechle,&nbsp;Michael Roden,&nbsp;Reinhard W Holl,&nbsp;Ertan Mayatepek,&nbsp;Thomas Meissner,&nbsp;Marc Jacobsen","doi":"10.1186/s40348-018-0080-7","DOIUrl":"https://doi.org/10.1186/s40348-018-0080-7","url":null,"abstract":"<p><strong>Background: </strong>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 (T<sub>REG</sub>), 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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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. T<sub>REG</sub> purified from healthy donors with the two most common haplotypes showed similar capacity to inhibit heterologous effector T cells.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2018-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0080-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35803273","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
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
Molecular and cellular 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
{"title":"Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis.","authors":"Teresa Schleker,&nbsp;Eva-Maria Jacobsen,&nbsp;Benjamin Mayer,&nbsp;Gudrun Strauss,&nbsp;Klaus-Michael Debatin,&nbsp;Carsten Posovszky","doi":"10.1186/s40348-018-0079-0","DOIUrl":"https://doi.org/10.1186/s40348-018-0079-0","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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 H<sub>3</sub>-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%.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2018-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0079-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35752286","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: 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。
Molecular and cellular pediatrics Pub Date : 2017-12-07 DOI: 10.1186/s40348-017-0078-6
Will W Minuth
{"title":"Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone.","authors":"Will W Minuth","doi":"10.1186/s40348-017-0078-6","DOIUrl":"https://doi.org/10.1186/s40348-017-0078-6","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2017-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0078-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35232154","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: 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。
Molecular and cellular 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
{"title":"Human perinatal immunity in physiological conditions and during infection.","authors":"Gijs T J van Well, Leonie A Daalderop, Tim Wolfs, Boris W Kramer","doi":"10.1186/s40348-017-0070-1","DOIUrl":"10.1186/s40348-017-0070-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0070-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34933272","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: 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?
Molecular and cellular pediatrics Pub Date : 2017-12-01 Epub Date: 2017-05-16 DOI: 10.1186/s40348-017-0072-z
Simone Bürgler, David Nadal
{"title":"Pediatric precursor B acute lymphoblastic leukemia: are T helper cells the missing link in the infectious etiology theory?","authors":"Simone Bürgler,&nbsp;David Nadal","doi":"10.1186/s40348-017-0072-z","DOIUrl":"https://doi.org/10.1186/s40348-017-0072-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0072-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35000138","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: 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。
Molecular and cellular 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
{"title":"The molecular pathophysiology of chronic non-bacterial osteomyelitis (CNO)-a systematic review.","authors":"Sigrun Ruth Hofmann, Franz Kapplusch, Katrin Mäbert, Christian Michael Hedrich","doi":"10.1186/s40348-017-0073-y","DOIUrl":"10.1186/s40348-017-0073-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0073-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35148576","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: 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
Molecular and cellular pediatrics Pub Date : 2017-11-07 DOI: 10.1186/s40348-017-0076-8
Prajakta Oak, Anne Hilgendorff
{"title":"The BPD trio? Interaction of dysregulated PDGF, VEGF, and TGF signaling in neonatal chronic lung disease.","authors":"Prajakta Oak, Anne Hilgendorff","doi":"10.1186/s40348-017-0076-8","DOIUrl":"10.1186/s40348-017-0076-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2017-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0076-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35235376","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: 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。
Molecular and cellular 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
{"title":"Estimated prevalence of potentially damaging variants in the leptin gene.","authors":"Adriana Nunziata,&nbsp;Guntram Borck,&nbsp;Jan-Bernd Funcke,&nbsp;Katja Kohlsdorf,&nbsp;Stephanie Brandt,&nbsp;Anke Hinney,&nbsp;Barbara Moepps,&nbsp;Peter Gierschik,&nbsp;Klaus-Michael Debatin,&nbsp;Pamela Fischer-Posovszky,&nbsp;Martin Wabitsch","doi":"10.1186/s40348-017-0074-x","DOIUrl":"https://doi.org/10.1186/s40348-017-0074-x","url":null,"abstract":"<p><strong>Background: </strong>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 ).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"10"},"PeriodicalIF":0.0,"publicationDate":"2017-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0074-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35520858","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: 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)。
Molecular and cellular pediatrics Pub Date : 2017-11-03 DOI: 10.1186/s40348-017-0077-7
Roman Scheidmann, Thomas Paul, Matthias Sigler
{"title":"Transcatheter atrial septal defect closure in an infant (body weight 6.4 kg) using the GORE CARDIOFORM septal occluder (GCSO).","authors":"Roman Scheidmann,&nbsp;Thomas Paul,&nbsp;Matthias Sigler","doi":"10.1186/s40348-017-0077-7","DOIUrl":"https://doi.org/10.1186/s40348-017-0077-7","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Case description: </strong>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.</p><p><strong>Discussion, evaluation and conclusion: </strong>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.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"9"},"PeriodicalIF":0.0,"publicationDate":"2017-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0077-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35571086","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: 4
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