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Item Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance(CELL PRESS, 2010-01-01) Tischfield, Max A.; Baris, Hagit N.; Wu, Chen; Rudolph, Guenther; Van Maldergem, Lionel; He, Wei; Chan, Wai-Man; Andrews, Caroline; Demer, Joseph L.; Robertson, Richard L.; Mackey, David A.; Ruddle, Jonathan B.; Bird, Thomas D.; Gottlob, Irene; Pieh, Christina; Traboulsi, Elias I.; Pomeroy, Scott L.; Hunter, David G.; Soul, Janet S.; Newlin, Anna; Sabol, Louise J.; Doherty, Edward J.; de Uzcategui, Clara E.; de Uzcategui, Nicolas; Collins, Mary Louise Z.; Sener, Emin C.; Wabbels, Bettina; Hellebrand, Heide; Meitinger, Thomas; de Berardinis, Teresa; Magli, Adriano; Schiavi, Costantino; Pastore-Trossello, Marco; Koc, Feray; Wong, Agnes M.; Levin, Alex V.; Geraghty, Michael T.; Descartes, Maria; Flaherty, Maree; Jamieson, Robyn V.; Moller, H. U.; Meuthen, Ingo; Callen, David F.; Kerwin, Janet; Lindsay, Susan; Meindl, Alfons; Gupta Jr., Mohan L.; Pellman, David; Engle, Elizabeth C.We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.Item Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation(OXFORD UNIV PRESS, 2010-01-01) Timmermann, L.; Pauls, K. A. M.; Wieland, K.; Jech, R.; Kurlemann, G.; Sharma, N.; Gill, S. S.; Haenggeli, C. A.; Hayflick, S. J.; Hogarth, P.; Leenders, K. L.; Limousin, P.; Malanga, C. J.; Moro, E.; Ostrem, J. L.; Revilla, F. J.; Santens, P.; Schnitzler, A.; Tisch, S.; Valldeoriola, F.; Vesper, J.; Volkmann, J.; Woitalla, D.; Peker, S.Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5\% at 2-6 months and 25.7\% at 9-15 months. At 9-15 months postoperatively, 66.7\% of patients showed an improvement of 20\% or more in severity of dystonia, and 31.3\% showed an improvement of 20\% or more in disability. Global quality of life ratings showed a median improvement of 83.3\% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 monthsItem Further Delineation of CANT1 Phenotypic Spectrum and Demonstration of Its Role in Proteoglycan Synthesis(WILEY-BLACKWELL, 2012-01-01) Nizon, Mathilde; Huber, Celine; De Leonardis, Fabio; Merrina, Rodolphe; Forlino, Antonella; Fradin, Melanie; Tuysuz, Beyhan; Abu-Libdeh, Bassam Y.; Alanay, Yasemin; Albrecht, Beate; Al-Gazali, Lihadh; Basaran, Sarenur Yilmaz; Clayton-Smith, Jill; Desir, Julie; Gill, Harinder; Greally, Marie T.; Koparir, Erkan; van Maarle, Merel C.; MacKay, Sara; Mortier, Geert; Morton, Jenny; Sillence, David; Vilain, Catheline; Young, Ian; Zerres, Klaus; Le Merrer, Martine; Munnich, Arnold; Le Goff, Carine; Rossi, Antonio; Cormier-Daire, ValerieDesbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of beta-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism. Hum Mutat 33:1261-1266, 2012. (c) 2012 Wiley Periodicals, Inc.Item Haploinsufficiency of a Spliceosomal GTPase Encoded by EFTUD2 Causes Mandibulofacial Dysostosis with Microcephaly(CELL PRESS, 2012-01-01) Lines, Matthew A.; Huang, Lijia; Schwartzentruber, Jeremy; Douglas, Stuart L.; Lynch, Danielle C.; Beaulieu, Chandree; Guion-Almeida, Maria Leine; Zechi-Ceide, Roseli Maria; Gener, Blanca; Gillessen-Kaesbach, Gabriele; Nava, Caroline; Baujat, Genevieve; Horn, Denise; Kini, Usha; Caliebe, Almuth; Alanay, Yasemin; Utine, Gulen Eda; Lev, Dorit; Kohlhase, Jurgen; Grix, Arthur W.; Lohmann, Dietmar R.; Hehr, Ute; Boehm, Detlef; Majewski, Jacek; Bulman, Dennis E.; Wieczorek, Dagmar; Boycott, Kym M.; Consortium, F.O.R.G.E. CanadaMandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDMItem The research agenda for general practice/family medicine and primary health care in Europe. Part 3. Results: Person centred care, comprehensive and holistic approach(TAYLOR \& FRANCIS LTD, 2010-01-01) Van Royen, Paul; Beyer, Martin; Chevallier, Patrick; Eilat-Tsanani, Sophia; Lionis, Christos; Peremans, Lieve; Petek, Davorina; Rurik, Imre; Soler, Jean Karl; Stoffers, Henri Ejh; Topsever, Pinar; Ungan, Mehmet; Hummers-Pradier, EvaThe recently published `Research Agenda for General Practice/Family Medicine and Primary Health Care in Europe' summarizes the evidence relating to the core competencies and characteristics of the Wonca Europe definition of GP/FM, and its implications for general practitioners/family doctors, researchers and policy makers. The European Journal of General Practice publishes a series of articles based on this document. In a first article, background, objectives, and methodology were discussed. In a second article, the results for the two core competencies `primary care management' and `community orientation' were presented. This article reflects on the three core competencies, which deal with person related aspects of GP/FM, i.e. `person centred care', `comprehensive approach' and `holistic approach'. Though there is an important body of opinion papers and (non-systematic) reviews, all person related aspects remain poorly defined and researched. Validated instruments to measure these competencies are lacking. Concerning patient-centredness, most research examined patient and doctor preferences and experiences. Studies on comprehensiveness mostly focus on prevention/care of specific diseases. For all domains, there has been limited research conducted on its implications or outcomes.Item Series: The research agenda for general practice/family medicine and primary health care in Europe. Part 6: Reaction on commentaries - how to continue with the Research Agenda?(TAYLOR \& FRANCIS LTD, 2011-01-01) Van Royen, Paul; Beyer, Martin; Chevallier, Patrick; Eilat-Tsanani, Sophia; Lionis, Christos; Peremans, Lieve; Petek, Davorina; Rurik, Imre; Soler, Jean Karl; Stoffers, Henri Ejh; Topsever, Pinar; Ungan, Mehmet; Hummers-Pradier, EvaThe Research Agenda should be used as a key reference point to which new research should relate its usefulness and added value. Primary care evolves towards more interdisciplinary care, and research should focus more on the core competency of person-centred team care. There is an urgent need to develop clear definitions and appropriate research instruments for this domain. It will be a particular challenge to study comprehensive approaches in primary-care patients with multi-morbidity. The Research Agenda and the commentaries on it show future directions for primary care research. There are challenges related to a changing society, the shared responsibility and guidance of research by professionals and citizens (patients), and the need to fully integrate research as part of primary healthcare provision. There will be a need for a prioritization of spearheads to guide primary care research for the next decade: translational research, research on equity and health differences, on chronic disease and health systems research. This can not be realized without the development and maintenance of a solid research infrastructure: easily maintained and accessed observational databases, helpful information technology, strategies and techniques for patient involvement, advanced research training possibilities, and the development and validation of appropriate research instruments and outcome measures to capture the different challenges. Worldwide, primary care not only is a priority for health care policy, but it needs to become a research priority as well.Item DNA Fragmentation Simulation Method (FSM) and Fragment Size Matching Improve aCGH Performance of FFPE Tissues(PUBLIC LIBRARY SCIENCE, 2012-01-01) Craig, Justin M.; Vena, Natalie; Ramkissoon, Shakti; Idbaih, Ahmed; Fouse, Shaun D.; Ozek, Memet; Sav, Aydin; Hill, D. Ashley; Margraf, Linda R.; Eberhart, Charles G.; Kieran, Mark W.; Norden, Andrew D.; Wen, Patrick Y.; Loda, Massimo; Santagata, Sandro; Ligon, Keith L.; Ligon, Azra H.Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice.Item Assessment of cardiovascular risk in paediatric peritoneal dialysis patients: a Turkish Pediatric Peritoneal Dialysis Study Group (TUPEPD) report(OXFORD UNIV PRESS, 2009-01-01) Bakkaloglu, Sevcan A.; Saygili, Arda; Sever, Lale; Noyan, Aytul; Akman, Sema; Ekim, Mesiha; Aksu, Nejat; Doganay, Beyza; Yildiz, Nurdan; Duzova, Ali; Soylu, Alper; Alpay, Harika; Sonmez, Ferah; Civilibal, Mahmut; Erdem, Sevcan; Kardelen, FiratMethods. We aimed to clarify arteriosclerotic risk and to document possible relationships between cardiovascular risk factors and echocardiographic parameters in paediatric peritoneal dialysis (PD) patients. M-mode/Doppler/tissue Doppler echocardiographic studies and lipid/lipoproteins, homocysteine, high-sensitivity C-reactive protein (HS-CRP) levels and carotid intima-media thickness (CIMT) were determined in 59 patients (age: 14.2 +/- 4.5 years) and in 36 healthy subjects. Results. Structural and functional cardiac abnormalities were observed in patients on maintenance dialysis. Increased left ventricular mass index (LVMI, P = 0.000), relative wall thickness (P = 0.000), myocardial performance index (MPI, P = 0.000) were documented in the patients. Lipoprotein (a) (P = 0.000), homocysteine (P = 0.001), HS-CRP (P = 0.000) and CIMT (P = 0.000) were significantly elevated in the patients. Left ventricular hypertrophy (LVH) was prevalent in 68\% of the patients. Patients with LVH had higher levels of HS-CRP (P = 0.001) and CIMT (P = 0.028) than those without LVH. Haemoglobin was an independent predictor of LVMI (beta: -8.9, P = 0.001), while residual diuresis and CIMT were independent predictors of diastolic dysfunction (beta: -0.45, P = 0.034 and beta: 5.90, P = 0.008, respectively). Albumin (beta: -0.72, P = 0.018) and Kt/V urea (beta: -0.48, P = 0.012) were significant predictors of CIMT. There were positive correlations between LVMI and CIMT. HS-CRP was positively correlated with LVMI as well as CIMT. Conclusions. Elevated levels of atherosclerotic/inflammatory risk factors, low haemoglobin levels and loss of residual renal function and their negative effects on heart are of remarkable importance in paediatric patients on maintenance peritoneal dialysis. Achieving recommended targets for haemoglobin, blood pressure and Kt/V urea, preserving residual renal function as well as managing inflammation and subsequent arteriosclerosis is obviously essential to improve the patients' prognosis.Item Clinical and Radiographic Features of the Autosomal Recessive form of Brachyolmia Caused by PAPSS2 Mutations(WILEY, 2013-01-01) Iida, Aritoshi; Simsek-Kiper, Pelin Ozlem; Mizumoto, Shuji; Hoshino, Touma; Elcioglu, Nursel; Horemuzova, Eva; Geiberger, Stefan; Yesil, Gozde; Kayserili, Hulya; Utine, Gulen Eda; Boduroglu, Koray; Watanabe, Shigehiko; Ohashi, Hirofumi; Alanay, Yasemin; Sugahara, Kazuyuki; Nishimura, Gen; Ikegawa, ShiroBrachyolmia is a heterogeneous skeletal dysplasia characterized by generalized platyspondyly without significant long-bone abnormalities. Based on the mode of inheritance and radiographic features, at least three types of brachyolmia have been postulated. We recently identified an autosomal recessive form of brachyolmia that is caused by loss-of-function mutations of PAPSS2, the gene encoding PAPS (3-phosphoadenosine 5-phosphosulfate) synthase 2. To understand brachyolmia caused by PAPSS2 mutations (PAPSS2-brachyolmia), we extended our PAPSS2 mutation analysis to 13 patients from 10 families and identified homozygous or compound heterozygous mutations in all. Nine different mutations were found: three splice donor-site mutations, three missense mutations, and three insertion or deletion mutations within coding regions. In vitro enzyme assays showed that the missense mutations were also loss-of-function mutations. Phenotypic characteristics of PAPSS2-brachyolmia include short-trunk short stature, normal intelligence and facies, spinal deformity, and broad proximal interphalangeal joints. Radiographic features include platyspondyly with rectangular vertebral bodies and irregular end plates, broad ilia, metaphyseal changes of the proximal femur, including short femoral neck and striation, and dysplasia of the short tubular bones. PAPSS2-brachyolmia includes phenotypes of the conventional clinical concept of brachyolmia, the Hobaek and Toledo types, and is associated with abnormal androgen metabolism. (C) 2013 Wiley Periodicals, Inc.Item Treatment results and prognostic factors in primary thyroid lymphoma patients: a Rare Cancer Network study(OXFORD UNIV PRESS, 2011-01-01) Onal, C.; Li, Y. X.; Miller, R. C.; Poortmans, P.; Constantinou, N.; Weber, D. C.; Atasoy, B. M.; Igdem, S.; Ozsahin, M.; Ozyar, E.Background: This study analyzed prognostic factors and treatment outcomes of primary thyroid lymphoma. Patients and Methods: Data were retrospectively collected for 87 patients (53 stage I and 34 stage II) with median age 65 years. Fifty-two patients were treated with single modality (31 with chemotherapy alone and 21 with radiotherapy alone) and 35 with combined modality treatment. Median follow-up was 51 months. Results: Sixty patients had aggressive lymphoma and 27 had indolent lymphoma. The 5- and 10-year overall survival (OS) rates were 74\% and 71\%, respectively, and the disease-free survival (DFS) rates were 68\% and 64\%. Univariate analysis revealed that age, tumor size, stage, lymph node involvement, B symptoms, and treatment modality were prognostic factors for OS, DFS, and local control (LC). Patients with thyroiditis had significantly better LC rates. In multivariate analysis, OS was influenced by age, B symptoms, lymph node involvement, and tumor size, whereas DFS and LC were influenced by B symptoms and tumor size. Compared with single modality treatment, patients treated with combined modality had better 5-year OS, DFS, and LC. Conclusions: Combined modality leads to an excellent prognosis for patients with aggressive lymphoma but does not improve OS and LC in patients with indolent lymphoma.