Identification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gait

Ankara : The Department of Molecular Biology and Genetics and the Graduate School of Engineering and Science of Bilkent University, 2012.Thesis (Ph. D.) -- Bilkent University, 2012.Includes bibliographical references leaves 138-153.Cerebellar ataxia, mental retardation, and dysequilibrium syndrome is a rare and heterogeneous neurodevelopmental disorder characterized by cerebellar atrophy, dysarthric speech, and quadrupedal locomotion. Here, a consanguineous family with four affected individuals which suggest an autosomal recessive inheritance was investigated. Homozygosity mapping analysis using high-resolution genotyping arrays in two affected individuals revealed four shared homozygous regions on 13q12, 19p13.3, 19q13.2, and 20q12. Target enrichment and next-generation sequencing of these regions in an affected individual was uncovered 11 novel protein altering variants which were filtered against dbSNP132 and 1000 genomes databases. Further population filtering using personal genome databases and previous exome sequencing datasets, segregation analysis, geographically-matched population screening, and prediction approaches revealed a novel missense mutation, p.I376M, in ATP8A2 segregated with the phenotype in the family. The mutation resides in a highly conserved C-terminal transmembrane region of E1-E2 ATPase domain. ATP8A2 is mainly expressed in brain, in particular with the highest levels at cerebellum which is a crucial organ for motor coordination. Mice deficient with Atp8a2 revealed impaired axonal transport in the motor neurons associated with severe cerebellar ataxia and body tremors. Recently, an unrelated individual with a de novo t(10;13) balanced translocation whose one of the ATP8A2 allele was disrupted has been identified. This patient shares similar neurological phenotypes including severe mental retardation and hypotonia. These findings suggest a role for ATP8A2 in the neurodevelopment, especially in the development of cerebro-cerebellar structures required for posture and gait in humans.Onat, Onur EmrePh.D

In silico identification of candidate MECP2 targets and quantitative analysis in rett syndrome

Cataloged from PDF version of article.Rett syndrome (RTT) is an X-linked neuro-developmental disorder seen exclusively girls in the childhood. It is one of the most common causes of mental retardation with an incidence rate of 1/10,000-1/15,000. Mutations in MECP2 gene was described as a common cause of RTT. MECP2 is a transcriptional repressor that regulates gene expression. It is not fully understood which MECP2 targets are affected in RTT and therefore contribute to disease pathogenesis. Researchers approached the problem in two directions: a) Global expression profile analysis and b) Candidate gene analysis. Global expression profile analysis revealed which a limited number of genes including those on the X-chromosome are de-regulated. Candidate gene analysis studies showed that loss of imprinting as exemplified by DLX5 could also contribute to disease pathogenesis. We hypothesize that Xchromosome inactivation (XCI) is an important physiological epigenetic mechanism that could be involved in Rett pathogenesis. We predicted a MECP2 binding motif by a distinctive bioinformatic approach. Using this algorithm we searched for the candidate MECP2 target genes on the X-chromosome and whole genome. The genes FHL1 and MPP1, whose interaction with MECP2 were heuristically displayed were predicted by our algorithm. We identified more than 100 genes which are on the Xchromosome. 10 genes from the list were selected according to their MECP2 binding homology score and X-inactivation status. In order to test this hypothesis we analyzed these genes with quantitative RT-PCR .We expect to identify the key genes that potentially contribute to RTT pathogenesis via disturbances in X-chromosome inactivation.Onat, Onur EmrePh.D

The Influence of Counsellor Trainee Support on Public Speaking and Foreign Language Speaking Anxiety in the Class Setting

This mixed methods study examined the influence of cognitive behavioral approach based counsellor trainee support on prospective English teachers’ public speaking anxiety and foreign language speaking anxiety in the class setting. The participants of the study included sixteen third year prospective English teachers studying at Trakya University. Both quantitative and qualitative data analysis revealed that the participants benefited from the counselling procedure. The study aims to trigger more interest on different forms of anxiety experienced by prospective teachers and motivate researchers to design interventions that will psychologically assist prospective teachers in their transition to the teaching profession

Imaging Findings of the Morel-Lavellée Lesion

Introduction: This study aims to evaluate the magnetic resonance imaging (MRI) findings of the Morel-Lavellée lesion (MLL),which described as degloving injury of the subcutaneous fatty tissue.Methods: MRI features of fifteen patients in whom the diagnosis of MLL was established by clinically or surgery retrospec-tively analyzed.Results: All the lesions were located in the lower extremities, and 86.6% (n=13) were located at the knee level or above. Alllesions had an anatomic relationship with deep fascia. The majority of the lesions were in either fusiform or crescentic form.60% (n=9) of the lesions showed a well-defined smooth contour. Pseudocapsules were observed in nine patients (60%).46.6% (n=7) of the lesions had a homogeneous signal property. The intralesional hemorrhagic signal was observed in 26.6%(n=4) of the lesions and intra-lesional fat signal in 46.6% (n=7). One patient had fluid-fluid leveling. In two cases, muscleinjury were accompanied by the MLL. In all cases, no associated bone lesion was noted.Discussion and Conclusion: MLL should be considered if a well-circumscribed, crescentic or fusiform subcutaneous masslesion in association with the deep fascia is present, especially in the presence of a history of previous trauma

The effect of placental angiogenic and anti-angiogenic factors on pregnancy outcome in patients with early onset preeclampsia

Objective: The aim was to evaluate the possible effects of anti-angiogenic factors including soluble endoglin (sEng), placental growth factor (Pgf), and soluble fms-like tyrosine kinase 1 (sFlt-1) in both normotensive pregnant patients and preeclampsia (PE) patients. Material and Methods: The study was carried out at the Departments of Gynecology and Obstetrics and Biochemistry of Yozgat Bozok University Training and Research Hospital. Eighteen women with PE who were pregnant for at least 20 weeks comprised the study group. The control group consisted of 33 pregnant women with no complications and with similar demographic features. In the study, laboratory parameters, demographic characteristics, sEng, sFlt-1, and Pgf levels, delivery type, APGAR scores of the infants, and birthweight were determined and a comparison was made between the groups. Results: It was found that the sEng level was significantly lower in the PE group compared to the control group (p<0.05). In addition, the Pgf, birthweight, and 1st and 5th-minute APGAR scores were significantly lower in the PE group compared to the control group (p[removed

Sexual function and depression in polycystic ovary syndrome: Is it associated with inflammation and neuromodulators?

Numerous studies have been carried out on depression and sexual dysfunction concomitant with polycystic ovary syndrome (PCOS). Increasing evidence has revealed the importance of inflammation in the etiology of PCOS. In addition, it has been known that some neuromodulators affect depression and sexual function. However, their effects on PCOS are not known. This study aimed to evaluate the relationship of depression and sexual function with cytokines and neuromodulators in PCOS patients. The present study included 20 fertile and 30 infertile patients diagnosed with PCOS and 30 healthy volunteers. Metabolic and endocrine parameters, interleukin (IL)-1β, IL-6, TNFα, γ-aminobutyric acid (GABA), Glutamate, Brain-derived neurotrophic factor (BDNF) serum levels, Beck Depression Index (BDI) and Female Sexual Function Index (FSFI) scores of the patients were compared between the groups. TNFα, IL-1β, IL-6, glutamate, GABA, and BDI scores were found to be significantly higher (p 0.05). Multivariate logistic regression analysis was conducted with potential factors that may affect sexual dysfunction. The results indicated that high waist-to-hip ratio (WHR) (> 0.80) with an odds ratio of 1.81 in PCOS patients, and body mass index (BMI) with an odds ratio of 2.3 and high WHR (> 0.80) with an odds ratio of 1.97 in all patients were found to be independent risk factors affecting sexual dysfunction. The results of the present study suggested that chronic low-dose inflammation seen in PCOS may interact with some neuromodulators, leading to the development of depression. However, no relationship was found between these parameters and sexual function. © 2020 Elsevier Lt

The relationship between oxidative stress and preeclampsia. The serum Ischemia-modified albumin levels and thiol/disulfide homeostasis

Objective: Preeclampsia (PE) is a dangerous complication of pregnancy and still a major cause of maternal-fetal morbidity and mortality. Its etiology remains largely unknown, but researchers have suggested oxidative stress-mediated inflammation for the same. The purpose of this study is to investigate the relationship between oxidative stress and PE as well as the usability of oxidative stress indicators such as serum ischemia-modified albumin (IMA) levels and thiol/disulfide balance in the prediction of PE. Materials and Methods: The study included 47 pregnant women with PE and 57 healthy pregnant women. We measured their serum IMA, native thiol, total thiol, and disulfide levels. Additionally, we determined the optimal cutoff values via the receiver operating characteristic curve analysis. Results: There were no differences between the two groups with respect to the maternal age, body mass index, gravida, and parity. The native and total thiol levels were found to be low when the disulfide and IMA levels were high in the patients with PE (p<0.05). When the IMA level was corrected by the albumin level (IMAR), the significant difference between the two groups disappeared. We also found that the native and total thiol concentrations were correlated with the systolic and diastolic blood pressures. The optimal cut-off values calculated for the prediction of PE were as follows: 178.45 µmol/L (with sensitivity of 72% and specificity of 83%) for native thiol, 232.55 µmol/L (with a sensitivity of 75% and specificity of 85%) for total thiol, and 29.05 µmol/L (with sensitivity of 65% and specificity of 72%) for disulfide. Conclusion: The balance of thiol/disulfide may play a role in the pathogenesis of PE and could be used as a biological marker for PE. © 2020 by Turkish Society of Obstetrics and Gynecology Turkish Journal of Obstetrics and Gynecology published by Galenos Publishing House

The Value of Cervical Length Measurement at 10-15 and 20-25 Weeks to Predict Preterm Birth

Amaç: Düşük riskli gebelerde, 10-15. haftalar ve 20-25. haftalar arasında ölçülen serviks uzunluğu ile preterm doğum ilişkisini belirlemek amaçlanmıştır. Yöntemler: İstanbul Eğitim ve Araştırma Hastanesi Gebe Polikliniğine Nisan 2008- Ocak 2009 tarihleri arasında rutin antenatal takip amacıyla başvuran, çalışma kriterlerine uyan 118 gebe ile çalışma grubumuz oluşturuldu. Çoğul gebelikler, daha önce preterm doğum yapanlar, kronik hastalığı olanlar, bilinen uterin anomalisi olanlar ve fetal anomalili gebelikler çalışma dışı tutuldu. 37. gebelik haftasından önceki doğumlar preterm doğum grubunu, 37. gebelik haftasından sonraki doğumlar term doğum grubunu oluşturdu. Bulgular: Çalışma kapsamındaki gebelerin %88,99'u 37. gebelik haftasının üzerinde, %11,01'i 37. gebelik haftasının altında doğum yaptı. Term grupta 10-15. ve 20-25. haftalardaki servikal uzunluk değerleri, preterm gruba göre anlamlı derecede fazla bulunmuştur (p<0,01, p<0,001). Preterm doğum için eşik değer 10-15 hafta servikal uzunluk ölçümleri için 41,4 bulunurken, 20-25 hafta için 33,7 bulundu. Sonuç: Asemptomatik gebelerin taranmasında ve riskli olguların belirlenmesinde 20-25. haftada yapılan transvaginal ulatrasonografi etkili görülmektedir. Erken doğum açısından kötü obstetrik öyküye sahip olan ve risk altında olan gebelerin taranmasına daha erken başlanıp başlanmayacağı konusunda daha ileri çalışmalara ihtiyaç vardır.Objective: We aimed to predict the risks of preterm labor by measuring the cervical length between 10 and 15 weeks gestation and between 20 and 25 weeks gestation, in low risk pregnants. Methods: Our study group was formed in the outpatient clinic of the Ministry of Health Istanbul Education and Research Hospital with 118 pregnants who fulfilled the inclusion criteria and wished to attend our study during routine antenatal screening. Delivery before 37 weeks gestation constituted the preterm labor group, delivery after 37 weeks gestation constituted the term group. Multiple pregnancies, previous preterm delivery, chronic diseases, history of preterm labor, previously diagnosed uterine abnormalities and fetal anomalies were stated as exclusion criteria. Results: In our study pregnant patients who delivered after 37 weeks gestation constituted 88.99% (n: 105) of the study group, whereas 11.01% (n: 13) pregnant patients delivered before 37 weeks gestation. Cervical length measurements in both 10-15 weeks and 20-25 weeks were significantly higher in the term group (p&lt;0.01, p&lt;0.001). Cut off value of cervical length for preterm labor was found as 41.4 among 10 to 15 gestation weeks and 33.7 among 20 to 25 gestation weeks. Conclusion: Transvaginal sonography performed at 20 to 25 gestational weeks has an impressive role when screening asymptomatic pregnants and defining the risks. We need more studies to decide whether to begin earlier screening or not for preterm labor when an individual has a poor obstetric history and is under such risks

The genetic structure of the Turkish population reveals high levels of variation and admixture

The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe