Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual ...disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.
Autosomal recessive cutis laxa type 2 (ARCL2), a syndrome of growth and developmental delay and redundant, inelastic skin, is caused by mutations in the a2 subunit of the vesicular ATPase H+-pump ...(ATP6V0A2). The goal of this study was to define the disease mechanisms that lead to connective tissue lesions in ARCL2. In a new cohort of 17 patients, DNA sequencing of ATP6V0A2 detected either homozygous or compound heterozygous mutations. Considerable allelic and phenotypic heterogeneity was observed, with a missense mutation of a moderately conserved residue p.P87L leading to unusually mild disease. Abnormal N- and/or mucin type O-glycosylation was observed in all patients tested. Premature stop codon mutations led to decreased ATP6V0A2 mRNA levels by destabilizing the mutant mRNA via the nonsense-mediated decay pathway. Loss of ATP6V0A2 either by siRNA knockdown or in ARCL2 cells resulted in distended Golgi cisternae, accumulation of abnormal lysosomes and multivesicular bodies. Immunostaining of ARCL2 cells showed the accumulation of tropoelastin (TE) in the Golgi and in large, abnormal intracellular and extracellular aggregates. Pulse–chase studies confirmed impaired secretion and increased intracellular retention of TE, and insoluble elastin assays showed significantly reduced extracellular deposition of mature elastin. Fibrillin-1 microfibril assembly and secreted lysyl oxidase activity were normal in ARCL2 cells. TUNEL staining demonstrated increased rates of apoptosis in ARCL2 cell cultures. We conclude that loss-of-function mutations in ATP6V0A2 lead to TE aggregation in the Golgi, impaired clearance of TE aggregates and increased apoptosis of elastogenic cells.
High viral loads are observed in Torque Teno Virus (TTV) infection after hematopoietic stem cell transplantation (HSCT). We aimed to analyze the kinetics of plasma TTV-DNA load in pediatric patients ...who received immunosuppressive therapy and developed infection complications in the first 100 days after HSCT.
As a patient group; 113 plasma samples taken from 33 pediatric HSCT recipients at a time interval after transplantation and as a control group; 38 plasma samples from 38 children without known chronic disease were included in the study. Viral nucleic acid isolation was performed by using the NucliSENS easyMAG (bioMerieux, France) system. A laboratory designed quantitative polymerase chain reaction process was performed on 7300 Real-Time PCR system (Applied Biosystems, CA, USA) with the amplification mixture containing primer and probe sequences for the UTR gene region.
TTV-DNA was detected in all patient's samples and the median viral load was calculated as 7.67 Log10 copies/mL (range: 2.84–9.59). In the control group, the TTV-DNA median viral load was calculated as 5.51 Log10 copies/mL (range: 2.50–7.04), except for one negative sample. A significant difference was observed between the control group and the patient group in terms of TTV viral load levels. In nine patients, a median 2.15 Log10 copies/mL viral load increase was observed at 31–60 days post-transplant compared to the pre-transplant period.
TTV-DNA levels should be closely monitored to understand the immune status of the first 100 days after transplantation and the effects of treatment regimens on patients with HSCT.
•TTV is an immunological biomarker with the potential to improve treatment follow-up in HSCT patients.•TTV-DNA loads show fluctuations depending on the immunological status in the early period after transplantation.•Considering high viral shedding of TTV in pediatric age, cut-off values should be determined to guide follow-up in immunosuppressive patients.
Introduction: Germ cell tumors account for 2-3% of all pediatric tumors. The aim of this study was to evaluate the clinical features and treatment outcomes of pediatric patients treated and followed ...up for extragonadal MGCTs in our center. Materials and Methods: A total of 41 patients diagnosed with MGCTs in the pediatric oncology department of Akdeniz University between June 1999 and June 2019 were evaluated retrospectively. Results: Twenty-nine (71%) of the patients were girls and female dominance (p<0.001). The median age was 3.22 (0-18) years. The most patients in the less than or equal to 5 year age group (p<0.001). Nineteen (44%) of the tumors were gonadal and 22 (54%) were extragonadal. The most common histolology of MGCTs were yolk sac tumor (36%), mixed GCTs (29%), immature teratoma (20%), and dysgerminoma (15%). Twenty-five (61%) patients presented with advanced stage disease and 37 patients (90%) were treated with chemotherapy. The patients with stage I testicular and stage I ovarian germ cell tumors underwent complete tumor resection followed by a watch-and-wait approach with alpha fetoprotein monitoring without chemotherapy. Of six patients with relapse/refractory disease, two patients survived. Two patients who underwent autologous stem cell transplantation showed complete response but later died due to infection. The median follow-up period of the patients was 34.9 (4-190.6) months and the 10-year overall and disease-free survival rates were 77.1 + or - 6.8% 77.1 + or - 6.8%. Two relapsed refractory patients who underwent autologous transplantation survived at a mean of 33.21 months. Conclusions: The clinical features and treatment outcomes of the patients in our study were consistent with the literature. The fact that most of our patients were symptomatic at presentation and had advanced stage disease when diagnosed highlights the importance of detailed evaluation and examination. Although good outcomes are achieved in patients with early stage disease, new treatment approaches are needed for patients with advanced and relapsing disease Keywords Extracranial, malignant, germ cell tumor, child Giris: Germ hucreli tumor tum pediatrik tumorlerin %2-3'unu olusturur. Ozellikle platin bazli kemoterapi rejimlerinin uygulanmasindan sonra sag kalim oranlari %85'lerden fazladir. Malign germ hucreli tumorler (MGHT) cocuklarda oldukca heterojen bir gruptur. Bu calisma ile ekstrakraniyal MGHT tanili hastalarimizin klinik ozellikleri ve tedavi sonuclarinin degerlendirilmesi amaclandi. Gerec ve Yontem: Akdeniz Universitesi Cocuk Onkoloji Klinigi'nde 1999 -2019 Haziran tarihleri arasinda ekstrakraniyal MGHT tanisi alan 41 hasta geriye donuk olarak degerlendirildi. Bulgular: Hastalarin 29 (%71) 'i kiz olup K/E cinsiyet orani: 1,75 olup anlamli olarak kiz cinsiyet hakimdi (p<0.001). Ortanca tani yasi 3,22 yil (0-18 yas) olup hastalar agirlikli olarak (%56 hasta) less than or equal to 5 yas idi (p<0.001). Tumorlerin 19 (%44) 'u gonadal, 22 (%54) 'u ekstragonadal olup en sik ekstagonadal yerlesim yeri sakrokoksigeal bolge (%22) idi. Histolojik degerlendirmede sirasiyla yolk sak tumoru (%36), mikst GHT (%29), immatur teratom (%20) ve disgerminom (%15) saptandi. Hastalarin 25 (%61)'i ileri evre hastalik ile basvurmustu. Hastalarin 37 (%90)'ina kemoterapi verildi. Evre I testis ve evre I over GHT hastalarinda tumorun cerrahi olarak tam cikartilmasinin ardindan alphaFP degerleri takip edilerek "bekle ve izle" yaklasimi ile kemoterapi verilmedi. Tani sonrasi relaps refrakter hastalik ile seyreden 6 hastanin ikisi progresif hastaliktan kaybedildi. Otolog kok hucre nakli yapilan iki hastada nakil sonrasi kur saglanmasina ragmen enfeksiyon nedeni ile kaybedildi. Hastalarin ortanca izlem suresi 34.9 ay (4-190,6 ay), 5 ve 10 yillik genel ve hastaliksiz yasam oranlari 81.9 + or - 6.3%, 81.9 + or - 6.3% ve 77.1 + or - 6.8% 77.1 + or - 6.8 ve %77,1 + or - 6,8 olarak bulundu. Nakil yapilan iki hastanin sagkalim suresi ortalama 33.21 ay olarak hesaplandi. Sonuc: Ekstrakraniyal MIGHT lerin tedavisinde, konservatif cerrahi, evre I hastalar icin "bekle ve gor" yaklasimi ve platin bazli kemoterapi rejimleri ile basarili sonuclar alinmaktadir. Ilk basvuruda hastalarin yakinmalarinin olmasina ragmen cogu hastanin ileri evre hastalik ile basvurdugunun saptanmasi hekimlerin ayrintili degerlendirme ve muayenelerinin onemine dikkat cekmektedir. Erken evre hastalarda sonuclar basarili iken ileri evre ve relaps hastalarda yeni tedavi yaklasimlarina ihtiyac vardir. Anahtar kelimeler Ekstrakranial, malign, germ hucreli tumor, cocuk
In this study, it was aimed to investigate the factors affecting students' science achievement according to student science teachers. The survey model which is one of the quantitative research ...methods was used. The sample was consisted of total 606 student science teachers from four state universities in Turkey. The data were obtained by using the Questionnaire of Factors Affecting Students' Science Achievement (QFASSA). The data were analyzed by using the descriptive analyzing technique. The factors affecting students' science achievement were analyzed under five dimensions. The result of the study shows that the most important factors affecting student science achievement according to student science teachers are the items in the dimensions of teacher and curriculum. The results also indicates that the most important predictor of science achievement is "teaching the topics in a way that may arouse the students' curiosity" in the teacher dimension of QFASSA.
The effect of ozone treatment in experimental rat gout arthritis was investigated. Twenty adult albino male rats were divided into 4 groups: Group 1 (Control) was followed without any medication, ...Group 2 (Gout control) was injected with a single dose of 0.2 mL (10 mg) monosodium urate (MSU) intraarticulary to 1st metatarsophalangeal joint to create experimental Gouty arthritis. Group 3 (Gout + Ozone) was injected intraarticulary to 1st metatarsophalangeal joint with a single dose of 0.2 mL (10 mg) MSU to generate experimental gout, followed by ozone therapy to the rats a single dose of 1 mL (10 μg/mL) intraperitoneally daily for 3 weeks. The Group 4 (Ozone control) ozone therapy was given a single dose of 1 mL (10 μg/ mL) intraperitoneally daily for 3 weeks without gout formation. The results were recorded and compared statistically between the groups. In conclusion, the low level of inflammation in the third group (Gout + Ozone) was considered statistically significant as compared to the second group. With Ozone treatment the gout joint has been shown to have reduced acute inflammation, it has not been affected by the chronic proliferation process.
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