Showing papers by "Istanbul University published in 2013"
Radboud University Nijmegen Medical Centre1, University of Michigan2, Radboud University Nijmegen3, University of Toronto4, McGill University5, University of Basel6, University of Florence7, Auckland City Hospital8, University of Pittsburgh9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, National Health Service26, University of Colorado Denver27, Medical College of Wisconsin28, University of Alabama at Birmingham29, University of Manchester30, Rutgers University31, Thomas Jefferson University32, Amgen33, University of Toledo34, Boston University35, Medical University of South Carolina36, University of Pennsylvania37, Northwestern University38
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
2,743 citations
Radboud University Nijmegen1, University of Michigan2, University of Toronto3, McGill University4, University of Basel5, University of Florence6, Auckland City Hospital7, University of Pittsburgh8, Complutense University of Madrid9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, University of Colorado Denver26, Amgen27, Medical College of Wisconsin28, University of Alabama at Birmingham29, University of Manchester30, National Health Service31, Rutgers University32, Thomas Jefferson University33, University of Toledo34, University of Pennsylvania35, Boston University36, Medical University of South Carolina37, Northwestern University38, University of Western Ontario39
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud9s phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
1,899 citations
University of Erlangen-Nuremberg1, University College London2, University of Amsterdam3, Baylor College of Medicine4, French Institute of Health and Medical Research5, Montreal Neurological Institute and Hospital6, Bethel University7, State University of Campinas8, UCL Institute of Child Health9, Great Ormond Street Hospital for Children NHS Foundation Trust10, University of Grenoble11, University of California, Los Angeles12, York University13, Albert Einstein College of Medicine14, Istanbul University15, University of Pavia16, University of Calgary17, Carlo Besta Neurological Institute18
TL;DR: The proposed international consensus classification of hippocampal neuronal cell loss will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.
Abstract: Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug-resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well-preserved hippocampal specimens: HS International League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly in CA1 and CA4 regions, compared to CA1 predominant neuronal cell loss and gliosis (HS ILAE type 2), or CA4 predominant neuronal cell loss and gliosis (HS ILAE type 3). Surgical hippocampus specimens obtained from patients with TLE may also show normal content of neurons with reactive gliosis only (no-HS). HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control. CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control. © 2013 Wiley Periodicals, Inc.
743 citations
TL;DR: The results from one of the largest nationally representative surveys carried out so far show that diabetes has rapidly become a major public health challenge in Turkey and underscore the urgent need for national programs to prevent diabetes, to manage the illness and thus prevent complications.
Abstract: There is concern about an emerging diabetes epidemic in Turkey. We aimed to determine the prevalence of diagnosed and undiagnosed diabetes, prediabetes and their 12-year trends and to identify risk factors for diabetes in the adult Turkish population. A cross-sectional, population-based survey, ‘TURDEP-II’ included 26,499 randomly sampled adults aged ≥ 20 years (response rate: 87 %). Fasting glucose and biochemical parameters were measured in all; then a OGTT was performed to identify diabetes and prediabetes in eligible participants. The prevalence of diabetes was 16.5 % (new 7.5 %), translating to 6.5 million adults with diabetes in Turkey. It was higher in women than men (p = 0.008). The age-standardized prevalence to the TURDEP-I population (performed in 1997–98) was 13.7 % (if same diagnostic definition was applied diabetes prevalence is calculated 11.4 %). The prevalence of isolated-IFG and impaired glucose tolerance (IGT), and combined prediabetes was 14.7, 7.9, and 8.2 %, respectively; and that of obesity 36 % and hypertension 31.4 %. Compared to TURDEP-I; the rate of increase for diabetes: 90 %, IGT: 106 %, obesity: 40 % and central obesity: 35 %, but hypertension decreased by 11 % during the last 12 years. In women age, waist, body mass index (BMI), hypertension, low education, and living environment; in men age, BMI, and hypertension were independently associated with an increased prevalence of diabetes. In women current smoking, and in men being single were associated with a reduced risk. These results from one of the largest nationally representative surveys carried out so far show that diabetes has rapidly become a major public health challenge in Turkey. The figures are alarming and underscore the urgent need for national programs to prevent diabetes, to manage the illness and thus prevent complications.
516 citations
TL;DR: A genome-wide association study of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behçet's disease and 1,278 controls found new associations at CCR1, STAT4 and KLRC4, and found evidence for interaction between HLA-B*51 and ERAP1.
Abstract: Individuals with Behcet's disease suffer from episodic inflammation often affecting the orogenital mucosa, skin and eyes. To discover new susceptibility loci for Behcet's disease, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behcet's disease and 1,278 controls. We identified new associations at CCR1, STAT4 and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis P < 2 × 10(-9)). We also found evidence for interaction between HLA-B*51 and ERAP1 (P = 9 × 10(-4)). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I-ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behcet's disease.
451 citations
TL;DR: This project will aid the identification and quantification of properties and mutual effects of antioxidants, bring a more rational basis to the classification of antioxidant assays with their constraints and challenges, and make the results more comparable and understandable.
Abstract: The chemical diversity of natural antioxidants (AOXs) makes it difficult to sepa- rate, detect, and quantify individual antioxidants from a complex food/biological matrix. Moreover, the total antioxidant power is often more meaningful to evaluate health beneficial effects because of the cooperative action of individual antioxidant species. Currently, there is no single antioxidant assay for food labeling because of the lack of standard quantification methods. Antioxidant assays may be broadly classified as the electron transfer (ET)- and hydrogen atom transfer (HAT)-based assays. The results obtained are hardly comparable because of the different mechanisms, redox potentials, pH and solvent dependencies, etc. of various assays. This project will aid the identification and quantification of properties and mutual effects of antioxidants, bring a more rational basis to the classification of antioxidant assays with their constraints and challenges, and make the results more comparable and understandable. In this regard, the task group members convey their own experiences in var- ious methods of antioxidants measurement.
450 citations
TL;DR: Investigating the Parkinson dataset using well-known machine learning tools, sustained vowels are found to carry more PD-discriminative information and representing the samples of a subject with central tendency and dispersion metrics improves generalization of the predictive model.
Abstract: There has been an increased interest in speech pattern analysis applications of Parkinsonism for building predictive telediagnosis and telemonitoring models. For this purpose, we have collected a wide variety of voice samples, including sustained vowels, words, and sentences compiled from a set of speaking exercises for people with Parkinson's disease. There are two main issues in learning from such a dataset that consists of multiple speech recordings per subject: 1) How predictive these various types, e.g., sustained vowels versus words, of voice samples are in Parkinson's disease (PD) diagnosis? 2) How well the central tendency and dispersion metrics serve as representatives of all sample recordings of a subject? In this paper, investigating our Parkinson dataset using well-known machine learning tools, as reported in the literature, sustained vowels are found to carry more PD-discriminative information. We have also found that rather than using each voice recording of each subject as an independent data sample, representing the samples of a subject with central tendency and dispersion metrics improves generalization of the predictive model.
445 citations
Harvard University1, Montreal Children's Hospital2, University of Tokushima3, University of Virginia4, Yale University5, Boston University6, University of Western Ontario7, United Arab Emirates University8, Istanbul University9, Riyadh Military Hospital10, Alfaisal University11, Brown University12, University of Washington13, Turkish Ministry of Health14, Center for Autism and Related Disorders15, Cornell University16, Hamad Medical Corporation17, University of New South Wales18
TL;DR: The utility of whole-exome sequencing for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs are shown.
400 citations
TL;DR: The mass determination of the exotic calcium isotopes 53Ca and 54Ca is reported, using the multi-reflection time-of-flight mass spectrometer of ISOLTRAP at CERN, to establish a prominent shell closure at neutron number N = 32, in excellent agreement with the theoretical calculations.
Abstract: The properties of exotic nuclei on the verge of existence play a fundamental part in our understanding of nuclear interactions. Exceedingly neutron-rich nuclei become sensitive to new aspects of nuclear forces. Calcium, with its doubly magic isotopes (40)Ca and (48)Ca, is an ideal test for nuclear shell evolution, from the valley of stability to the limits of existence. With a closed proton shell, the calcium isotopes mark the frontier for calculations with three-nucleon forces from chiral effective field theory. Whereas predictions for the masses of (51)Ca and (52)Ca have been validated by direct measurements, it is an open question as to how nuclear masses evolve for heavier calcium isotopes. Here we report the mass determination of the exotic calcium isotopes (53)Ca and (54)Ca, using the multi-reflection time-of-flight mass spectrometer of ISOLTRAP at CERN. The measured masses unambiguously establish a prominent shell closure at neutron number N = 32, in excellent agreement with our theoretical calculations. These results increase our understanding of neutron-rich matter and pin down the subtle components of nuclear forces that are at the forefront of theoretical developments constrained by quantum chromodynamics.
369 citations
TL;DR: This work discusses childhood cancer in relation to global development and proposes strategies that could result in improved survival and education of the public, more and better-trained health professionals, strengthened cancer services, locally relevant research, regional hospital networks, international collaboration, and health insurance are all essential components of an enhanced model of care.
Abstract: Summary Patterns of cancer incidence across the world have undergone substantial changes as a result of industrialisation and economic development. However, the economies of most countries remain at an early or intermediate stage of development—these stages are characterised by poverty, too few health-care providers, weak health systems, and poor access to education, modern technology, and health care because of scattered rural populations. Low-income and middle-income countries also have younger populations and therefore a larger proportion of children with cancer than high-income countries. Most of these children die from the disease. Chronic infections, which remain the most common causes of disease-related death in all except high-income countries, can also be major risk factors for childhood cancer in poorer regions. We discuss childhood cancer in relation to global development and propose strategies that could result in improved survival. Education of the public, more and better-trained health professionals, strengthened cancer services, locally relevant research, regional hospital networks, international collaboration, and health insurance are all essential components of an enhanced model of care.
309 citations
TL;DR: The MCL-001 study demonstrated durable efficacy of lenalidomide with a predictable safety profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were refractory to bortezomib.
Abstract: Purpose Although dose-intensive strategies or high-dose therapy induction followed by autologous stem-cell transplantation have improved the outcome for patients with mantle-cell lymphoma (MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bortezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE) trial is a global, multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had relapsed or were refractory to bortezomib. Patients and Methods Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease progression or intolerance. Primary end points were overall response rate (ORR) and duration of response (DOR); secondary end points included complete response (CR) rate, progression-free survival (PFS), overall surv...
TL;DR: In this paper, ultrasound assisted extraction of polyphenols from agricultural and industrial waste of olive oil and table oil productions, olive tree (Olea europaea) leaves were investigated.
TL;DR: The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant immunosuppressive medication (ISM) in patients with noninfectious uveitis.
TL;DR: Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo.
Abstract: Summary Background Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. Methods VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m 2 intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0–1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 Findings Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29–41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3–24·1) in the aflibercept group and 21·2 months (19·6–23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82–1·08; p=0·38). We recorded a higher incidence of grade 3–4 gastrointestinal disorders (182 [30%] vs 48 [8·0%]), haemorrhagic events (32 [5·2%] vs ten [1·7%]), hypertension (81 [13%] vs 20 [3·3%]), fatigue (97 [16%] vs 46 [7·7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3·4%] vs nine [1·5%]) in the aflibercept group than in the placebo group. Interpretation Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy. Funding Sanofi and Regeneron Pharmaceuticals Inc.
TL;DR: In this paper, the authors investigated low and high temperature thermoelectric properties by measuring the electrical conductivity, Seebeck coefficient, thermal conductivity and Hall coefficient between 2 K and 900 K.
Abstract: Cu2Se, Cu2Te and Ag-overstoichiometric compounds Cu1.98Ag0.2Se and Cu1.98Ag0.2Te were prepared by melting, annealing, followed by spark plasma sintering compaction. Low and high temperature thermoelectric properties were investigated by measuring the electrical conductivity, Seebeck coefficient, thermal conductivity and Hall coefficient between 2 K and 900 K. Structural analyses were performed by PXRD and SEM-EDX analyses. The Hall and Seebeck coefficients show that holes are the dominant carrier in all compounds. High temperature α–β phase transition in Cu2Se and Cu1.98Ag0.2Se between 350 and 400 K and multiple phase transitions (α–β, β–γ, γ–δ, δ–∈) in Cu2Te and Cu1.98Ag0.2Te between 350 K and 900 K were observed in measurements of heat capacity, temperature dependent PXRD data, and transport coefficients. Low temperature transport measurements (Hall coefficient, electrical conductivity, carrier mobility) strongly suggest the presence of yet another phase transition in Cu2Se, Cu1.98Ag0.2Se, and Cu1.98Ag0.2Te compounds at temperatures between 85 K and 115 K, reported here for the first time. Based on the transport data and structural analysis we conclude that doping Cu2Se and Cu2Te by Ag reduces the density of holes and strongly suppresses the thermal conductivity not only due to a smaller electronic contribution but also due to enhanced point defect scattering of phonons that reduces the lattice portion of the thermal conductivity. Moreover, the phase transition temperature is shifted to lower temperatures upon doping with Ag. The presence of Ag enhances thermoelectric performance of Cu2Te at all temperatures and Cu2Se benefits from Ag doping over a broad range of temperatures up to 700 K. The maximum ZT value of 1.2 at 900 K; 0.52 at 650 K; 0.29 at 900 K; and 1.0 at 900 K were achieved for Cu2Se, Cu1.98Ag0.2Se, Cu2Te and Cu1.98Ag0.2Te, respectively, between 2 K and 900 K.
TL;DR: The role of the thymus is still obscure in MG defined by antibodies against the agrin receptor LRP4 and in MG without all of the above autoantibdies (triple sero-negative MG) since these MG subtypes have been described only recently and thymectomy has been their standard treatment.
TL;DR: The finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.
Abstract: We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated β-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.
TL;DR: Analysis of BAs in foods were reviewed from 2007 to present, and high-performance liquid chromatography, gas chromatography and capillary electrophoresis techniques were used.
TL;DR: Patients with RRMS do not inevitably develop a progressive disease course, and onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course.
Abstract: Background:It is unclear if all patients with relapsing–remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disea...
TL;DR: A critical assessment of the available evidence concerning cognitive enhancing properties of noninvasive brain stimulation in neuropsychiatry is provided and suggestions to guide future efforts are provided.
TL;DR: The south-western Black Sea Coast seems to receive foreign litter from two main sources: land-based debris from the neighboring countries and seaborne debris due to international shipping.
University of Cologne1, Technical University of Dortmund2, Acıbadem University3, Boston Children's Hospital4, Istanbul University5, University of Duisburg-Essen6, Leiden University Medical Center7, Ludwig Maximilian University of Munich8, University of Kiel9, Katholieke Universiteit Leuven10, University of Siena11, Marmara University12, Haukeland University Hospital13, Necker-Enfants Malades Hospital14, University of Bordeaux15, Ege University16, University of Zurich17, Dresden University of Technology18, University of Erlangen-Nuremberg19
TL;DR: It is shown that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations, and proposed genotype-phenotype correlations are important for molecular screening strategies.
Abstract: Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant 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.
TL;DR: This study aimed to document traditional uses of medicinal plants in the Marmaris district of south-west Anatolia and to compare this information with the current knowledge of plant medicine in Turkey and the Mediterranean countries.
TL;DR: This analysis suggests that the young age, advanced stage, intraabdominal involvement and unfavorable histological features may predict poor prognosis, and surgery is the most effective treatment modality and adjuvant radiotherapy has no significant effect on overall survival of patients.
Abstract: Dendritic cell tumors are extremely rare and current knowledge on these tumors is limited. The characteristics of three dendritic cell sarcoma subtypes and their optimal treatment approaches are not fully clarified. We aimed to make a systematic review of the literature and enrich the current data with five new cases. Pooled analysis of 462 reported cases revealed that the tumor had no age, gender or racial predilection. Our analysis suggests that the young age, advanced stage, intraabdominal involvement and unfavorable histological features (i.e. large tumor size, absence of lymphoplasmacytic infiltration, coagulative necrosis, high mitotic count) may predict poor prognosis. Subtypes of this tumor have different clinical behaviors with interdigitating dendritic cell sarcoma being the most aggressive form. In general, surgery is the most effective treatment modality and adjuvant radiotherapy has no significant effect on overall survival of patients. The role of chemotherapy for the management of advanced disease is controversial.
Leiden University1, Radboud University Nijmegen2, Conwy & Denbighshire NHS Trust3, Boston Children's Hospital4, St Mary's Hospital5, University of Amsterdam6, Hamad Medical Corporation7, Instituto Gulbenkian de Ciência8, University of Ferrara9, Lille University of Science and Technology10, Northwick Park Hospital11, University of Manchester12, Princess Anne Hospital13, University of Genoa14, Churchill Hospital15, Charité16, Guy's and St Thomas' NHS Foundation Trust17, Maulana Azad Medical College18, Cedars-Sinai Medical Center19, Erasmus University Rotterdam20, Belfast Health and Social Care Trust21, Amrita Vishwa Vidyapeetham22, St. Michael's Hospital23, National Health Service24, Pompeu Fabra University25, University of Otago26, University of Bordeaux27, University of Turin28, Wrocław Medical University29, University of Southampton30, Istanbul University31, Utrecht University32, University College London33, Bezmialem Foundation University34
TL;DR: The emerging phenotype–genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay, and the variability in phenotype seems most marked in ARIDs1A and ARID1B patients.
Abstract: De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype-genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.
Istanbul University1, Helsinki University Central Hospital2, University of Bergen3, National and Kapodistrian University of Athens4, University Hospital of Lausanne5, University of Debrecen6, University Hospital of Basel7, Heidelberg University8, Medical University of Vienna9, Radboud University Nijmegen10, University of Milan11, Semmelweis University12
TL;DR: These features were compared based on individual patient data from 15 European stroke centers and found that gender‐specific differences by stroke etiology are scare.
Abstract: BACKGROUND AND PURPOSE: Risk factors for IS in young adults differ between genders and evolve with age, but data on the age- and gender-specific differences by stroke etiology are scare. These features were compared based on individual patient data from 15 European stroke centers. METHODS: Stroke etiology was reported in detail for 3331 patients aged 15-49 years with first-ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large-artery atherosclerosis (LAA), cardioembolism (CE), small-vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low- and high-risk sources. Other determined group was divided into dissection and other non-dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity. RESULTS: Etiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high-risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high-risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe. CONCLUSIONS: The etiology of IS in young adults has clear gender-specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria.
University of Marburg1, Sigmund Freud University Vienna2, University of Erlangen-Nuremberg3, French Institute of Health and Medical Research4, Case Western Reserve University5, University of California, Los Angeles6, Istanbul University7, University of Eastern Finland8, University of Florida9, University of São Paulo10, University of Duisburg-Essen11, UCL Institute of Neurology12
TL;DR: Prospective trials are needed to determine when and how surgery should be done and to define the relations of the hemosiderin rim to the epileptogenic zone, and recommendations regarding the diagnostic evaluation and etiology‐specific management of patients with CRE are made.
Abstract: Cerebral cavernous malformations (CCMs) are well-defined, mostly singular lesions present in 0.4-0.9% of the population. Epileptic seizures are the most frequent symptom in patients with CCMs and have a great impact on social function and quality of life. However, patients with CCM-related epilepsy (CRE) who undergo surgical resection achieve postoperative seizure freedom in only about 75% of cases. This is frequently because insufficient efforts are made to adequately define and resect the epileptogenic zone. The Surgical Task Force of the Commission on Therapeutics of the International League Against Epilepsy (ILAE) and invited experts reviewed the pertinent literature on CRE. Definitions of definitive and probable CRE are suggested, and recommendations regarding the diagnostic evaluation and etiology-specific management of patients with CRE are made. Prospective trials are needed to determine when and how surgery should be done and to define the relations of the hemosiderin rim to the epileptogenic zone.
TL;DR: Evidence is found that Autosomal-recessive CLCN2 mutations cause a leukoencephalopathy that belongs to an emerging group of disorders affecting brain ion and water homoeostasis and characterised by intramyelinic oedema, substantiate the concept that ClC-2 is involved in brain ionand water homOEostasis.
Abstract: BACKGROUND: Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confirmed in human beings. We aimed to define novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifically interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis. METHODS: In this observational analytical study, we recruited patients with leukoencephalopathies characterised by MRI signal abnormalities in the posterior limbs of the internal capsules, midbrain cerebral peduncles, and middle cerebellar peduncles from our databases of patients with leukoencephalopathies of unknown origin. We used exome sequencing to identify the gene involved. We screened the candidate gene in additional patients by Sanger sequencing and mRNA analysis, and investigated the functional effects of the mutations. We assessed the localisation of ClC-2 with immunohistochemistry and electron microscopy in post-mortem human brains of individuals without neurological disorders. FINDINGS: Seven patients met our inclusion criteria, three with adult-onset disease and four with childhood-onset disease. We identified homozygous or compound-heterozygous mutations in CLCN2 in three adult and three paediatric patients. We found evidence that the CLCN2 mutations result in loss of function of ClC-2. The remaining paediatric patient had an X-linked family history and a mutation in GJB1, encoding connexin 32. Clinical features were variable and included cerebellar ataxia, spasticity, chorioretinopathy with visual field defects, optic neuropathy, cognitive defects, and headaches. MRI showed restricted diffusion suggesting myelin vacuolation that was confined to the specified white matter structures in adult patients, and more diffusely involved the brain white matter in paediatric patients. We detected ClC-2 in all components of the panglial syncytium, enriched in astrocytic endfeet at the perivascular basal lamina, in the glia limitans, and in ependymal cells. INTERPRETATION: Our observations substantiate the concept that ClC-2 is involved in brain ion and water homoeostasis. Autosomal-recessive CLCN2 mutations cause a leukoencephalopathy that belongs to an emerging group of disorders affecting brain ion and water homoeostasis and characterised by intramyelinic oedema. FUNDING: European Leukodystrophies Association, INSERM and Assistance Publique-Hopitaux de Paris, Dutch Organisation for Scientific Research (ZonMw), E-Rare, Hersenstichting, Optimix Foundation for Scientific Research, Myelin Disorders Bioregistry Project, National Institute of Neurological Disorders and Stroke, and Genetic and Epigenetic Networks in Cognitive Dysfunction (GENCODYS) Project (funded by the European Union Framework Programme 7).
TL;DR: Several genes involved in enamel formation appear to contribute to molar-incisor hypomineralization (MIH), and allele and genotype frequencies between cases with MIH and controls were compared.
TL;DR: The protein misfolding, the inflammatory response, and decreased neurotrophic factor synthesis are all suggested to be related to AD type brain pathology, and results indicate these alterations might be traced from serum samples.
Abstract: Identifying early-detection biomarkers have become an increasingly important approach in the treatment and prevention of Alzheimer's disease (AD). In this study, we investigated the potential of brain-derived neurotrophic factor (BDNF), complement factor H (CFH), tumor necrosis factor-α (TNFα), interleukin 10 (IL-10), and heat shock protein 90 (Hsp90) as serum biomarkers for AD in a cohort of the Turkish population because they have been suggested to be associated with AD. Serum BDNF, CFH, TNFα, IL-10, and Hsp90 levels in three groups of patients, early-onset AD (EOAD; age of onset 65; n = 54), and mild cognitive impairment (MCI) (n = 30), were compared with age-matched healthy controls (age 65; n = 32) using ELISA. The serum BDNF levels significantly decreased and TNFα levels significantly increased in the EOAD and LOAD groups compared to the age-matched healthy controls. There was a correlation between serum TNFα and IL-10 levels in the LOAD and healthy control groups. Serum CFH levels in the LOAD and MCI patients were significantly decreased compared with controls. Serum Hsp90 levels in the EOAD, LOAD, and MCI patients were significantly decreased compared with controls. The protein misfolding, the inflammatory response, and decreased neurotrophic factor synthesis are all suggested to be related to AD type brain pathology, and our results indicate these alterations might be traced from serum samples. For accurate early diagnosis of AD, it is important to determine a profile of alterations in multiple biomarkers in large-scale population studies.