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ÖZET UTİNE, G. Eda, Çocukluk Çağında Parapnömonik Plevral Efüzyonlar: Plevral Enfeksiyon Sürecinde Plevral Sıvının Biyokimyasal ve Mikrobiyolojik Özellikleri, IL-8, TNF-a ve Nitritin Enflamasyondaki Rolü. Hacettepe Üniversitesi Tıp Fakültesi, Çocuk Sağlığı ve Hastalıkları Tezi. Ankara, 2004. Çalışma plevral enfeksiyonu bulunan çocuk hastaların genel özelliklerinin, bu enfeksiyonların çocuklardaki genel seyrinin ve enflamasyon sürecinde plevral sıvının biyokimyasal özelliklerinin belirlenmesi, PCR yönteminin etkenin saptanmasındaki yerinin ve mikroorganizmalarm plevral sıvının özellikleri üzerindeki eMlerinin incelenmesi, erişkinlerde tanıda ve tedavi yaklaşımında yol gösterici olarak kullanılan değişkenlerin çocuk hastalardaki yerinin belirlenmesi amacıyla yapılmıştır. Çalışmaya klinik ve radyolojik incelemelerle plevral efüzyon tanısı alan, plevral sıvı örneklemesi yapılan 36 hasta alınmıştır. Hastalar parapnömonik ampiyem, komplike olan ve komplike olmayan parapnömonik efüzyon, malign efüzyon ve smıilanamayan efüzyon olarak 5 grupta toplanmıştır. Hastalar kanda ve plevral sıvıda lökosit sayısı, nötrofil oranı, protein, glukoz ve LDH düzeyleri, plevral sıvıdaki IL-8, TNF-a ve nitrit düzeyleri, radyolojik özellikler, tedavi yöntemleri, iyileşme süreleri, komplikasyonlar ve uzun dönemdeki sekeller açısından değerlendirilmiştir. Mikrobiyolojik olarak Gram yaymaları, plevral sıvı ve kan kültürleri dışmda S. aureus, ^.pneumonia ve H.influenzae ajanlarına yönelik PCR çalışmaları yapılmıştır. Çalışmanın sonucunda çocukluk çağı plevral efüzyonlarmda parapnömonik efüzyonlann en önemli yeri tuttuğu; en sık görülen etkenin S.pneumonia olduğu; PCR yönteminin özellikle önceden antibiyotik tedavisi almış hastalarda etkeni göstermede duyarlı bir yöntem olduğu; pediatrik hastalarda plevral sıvı lökosit sayısı, nötrofil oranı, pH ve glukoz değerleri, IL-8, TNF-a ve nitrit düzeylerinin parapnömonik efüzyonlarda daha önce açıklanan enflamasyon sürecine uygun olarak değiştiği; radyolojik ve solunum fonksiyonlarıyla ilgili rezidüel değişikliklerin klinik iyileşmeyi izleyen altı ayda kendiliğinden düzeldiği bulunmuştur. Anahtar Kelimeler: parapnömonik efüzyon, pH, IL-8, TNF-a, nitrit, PCR. iv ABSTRACT UTİNE, G. Eda. Pediatric parapneumonic pleural effusions, biochemical and microbiological properties of pleural fluid and the role of IL-8, TNF-a and nitrite during pleural inflammation. Hacettepe University Faculty of Medicine, Thesis in Pediatrics. Ankara, 2004. This study was performed in order to define the epidemiologic properties and clinical course of pediatric patients with pleural infections; to investigate the biochemical properties of the pleural fluid during the course of inflammation; the value of PCR technique on identifying the causative microorganism; and the value of some pleural biochemical markers in pediatric patients, according to which the adult patients with pleural effusions are being diagnosed and managed. The group involved 36 patients with clinical and / or radiological diagnosis of pleural effusion and from whom pleural fluid sampling was made. According to the etiology 5 groups were defined: parapneumonic empyemas, complicated and uncomplicated parapneumonic effusions, malignant effusions and unclassified effusions. Pleural fluid samples were analyzed for leukocyte counts, neutrophil ratio, protein, glucose, LDH, IL-8, TNF-a, nitrite and pH values. Blood leukocyte counts and differentials were made. The patients were also evaluated for radiological properties, management options, complications and long-term sequela. Microbiological analysis of the pleural fluid consisted of Gram smears, pleural fluid and blood cultures, and PCR analysis for S.aureus, S.pneumoniae and H. influenzae. The results revealed that parapneumonic effusions are the major etiologic group for childhood pleural effusions, for which the most commonly identified causative agent is S.pneumoniae, and PCR technique is a useful procedure in identifying the microorganism especially for patients who received antibiotics prior to pleural fluid sampling. Pleural leukocyte counts and neutrophil ratio, and pH, glucose, IL-8, TNF- a and nitrite levels in pediatric effusions are found to show similar trends of change to that of adult patients during the course of disease. The residual changes in radiographs and respiratory functions spontaneously improved in the following 6 months. Keywords: parapneumonic effusions, pH, IL-8, TNF-a, nitrite, PCR. 159

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

WOS: 000327800400004, PubMed ID: 23906836, Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies., German Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1211A, 01GM1211B]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112S398]; ERARE-ANR CraniRareFrench National Research Agency (ANR); German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01GS08167]; DFGGerman Research Foundation (DFG) [BO 1955/2-3, WU 314/6-2]; Volkswagen FoundationVolkswagen [86042]; Telethon ItalyFondazione Telethon [GTB12001], This work was part of the CRANIRARE-2 Network funded by the German Federal Ministry of Education and Research (BMBF) (01GM1211A to B. W., 01GM1211B to D. W.), the TUBITAK (112S398 to H. K.) and ERARE-ANR CraniRare to S. L. This work was also funded by a grant (MRNET) from the German Federal Ministry of Education and Research (01GS08167 to D. W.), by DFG grants (BO 1955/2-3 and WU 314/6-2 to S. B. and D. W.) and by the Volkswagen Foundation (ref 86042 to A. W.). The biobank "Cell lines and DNA bank of Rett syndrome, X linked Mental Retardation and other genetic diseases", member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, provided us with specimens.