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BackgroundMetabolic syndrome (MetS) is associated with an increased risk of incident cardiovascular diseases (CVD), but the association between the new-onset MetS at different ages and the CVD risk remain unclear.MethodsThis was a prospective study comprising a total of 72,986 participants without MetS and CVD who participated in the Kailuan study baseline survey (July 2006 to October 2007). All participants received the biennial follow-up visit until December 31, 2019. In addition, 26,411 patients with new-onset MetS were identified from follow-up, and one control participant was randomly selected for each of them as a match for age ( ± 1 year) and sex. In the end, a total of 25,125 case-control pairs were involved. Moreover, the Cox proportional hazard model was established to calculate the hazard ratios (HR) for incident CVD across the onset age groups.ResultsAccording to the median follow-up for 8.47 years, 2,319 cases of incident CVD occurred. As MetS onset age increased, CVD hazards gradually decreased after adjusting for potential confounders. Compared with non-MetS controls, the HR and the 95% confidence interval (CI) for CVD were 1.84 (1.31–2.57) in the MetS onset age ConclusionsThe relative risks of CVD differed across MetS onset age groups, and the associations was more intense in the MetS onset group at a younger age.

Introduction: Alzheimer’s disease (AD), and idiopathic Parkinson’s disease (IPD) are the neurodegenerative diseases of the central nervous system (CNS). Cognitive impairment is on the forefront in AD. However, IPD is a movement disorder. Inflammation was suggested to have an effect in the pathophysiology of these two diseases. Neutrophil–lymphocyte ratio (NLR) was shown to be a possible marker showing the peripheral inflammation. We aimed to investigate the NLR of patiens with the diagnosis of AD, and IPD, and individuals with no neurodegenerative disease. Materials and methods: A total of 100 patients with the diagnosis of IPD, and 94 with diagnosis of AD, and 61 healthy controls were included into the study. All the demographic, clinical, and laboratory data were retrospectively obtained from the hospital automated database system. Results: The NLR in the IPD group was found statistically significantly higher compared with the control group and the AD group (p < 0.001, p = 0.04, respectively). The age-adjusted values were statistically analyzed because of age difference. No statistically significant difference was detected between AD and control groups in terms of NLR (p = 0.6). The age-adjusted NLR value in the Parkinson’s group was found significantly higher compared to the control group (p = 0.02) and Alzheimer’s group (p = 0.03). Discussion: Chronic inflammation has an important role in the emergence and progression of the chronic neurodegenerative diseases of the CNS. Our results show that the inflammation in the peripheral blood in IPD was more significant compared with the inflammation in AD. © 2021, Fondazione Società Italiana di Neurologia.

Importance: Limited empirical research has examined the extent to which cohort-level prevalence of substance use is associated with the onset of drug use and transitioning into greater involvement with drug use. Objective: To use cross-national data to examine time-space variation in cohort-level drug use to assess its associations with onset and transitions across stages of drug use, abuse, dependence, and remission. Design, setting, and participants: The World Health Organization World Mental Health Surveys carried out cross-sectional general population surveys in 25 countries using a consistent research protocol and assessment instrument. Adults from representative household samples were interviewed face-to-face in the community in relation to drug use disorders. The surveys were conducted between 2001 and 2015. Data analysis was performed from July 2017 to July 2018. Main outcomes and measures: Data on timing of onset of lifetime drug use, DSM-IV drug use disorders, and remission from these disorders was assessed using the Composite International Diagnostic Interview. Associations of cohort-level alcohol prevalence and drug use prevalence were examined as factors associated with these transitions. Results: Among the 90 027 respondents (48.1% [SE, 0.2%] men; mean [SE] age, 42.1 [0.1] years), 1 in 4 (24.8% [SE, 0.2%]) reported either illicit drug use or extramedical use of prescription drugs at some point in their lifetime, but with substantial time-space variation in this prevalence. Among users, 9.1% (SE, 0.2%) met lifetime criteria for abuse, and 5.0% (SE, 0.2%) met criteria for dependence. Individuals who used 2 or more drugs had an increased risk of both abuse (odds ratio, 5.17 [95% CI, 4.66-5.73]; P < .001) and dependence (odds ratio, 5.99 [95% CI, 5.02-7.16]; P < .001) and reduced probability of remission from abuse (odds ratio, 0.86 [95% CI, 0.76-0.98]; P = .02). Birth cohort prevalence of drug use was also significantly associated with both initiation and illicit drug use transitions; for example, after controlling for individuals' experience of substance use and demographics, for each additional 10% of an individual's cohort using alcohol, a person's odds of initiating drug use increased by 28% (odds ratio, 1.28 [95% CI, 1.26-1.31]). Each 10% increase in a cohort's use of drug increased individual risk by 12% (1.12 [95% CI, 1.11-1.14]). Conclusions and relevance: Birth cohort substance use is associated with drug use involvement beyond the outcomes of individual histories of alcohol and other drug use. This has important implications for understanding pathways into and out of problematic drug use. The World Health Organization World Mental Health (WMH) Survey Initiative is supported by the United States National Institute of Mental Health (NIMH; R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the United States Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical Inc., GlaxoSmithKline, and Bristol-Myers Squibb. This work was supported by an Australian National Health and Medical Research Council (NHMRC) project grant (no. 1081984). Dr Degenhardt is supported by a NHMRC Senior Principal Research Fellowship (no. 1135991) and NIDA NIH grant R01 DA044170–02. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on data analysis. None of the funders had any role in the design, analysis, interpretation of results, or preparation of this paper. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of the World Health Organization, other sponsoring organizations, agencies, or governments. The 2007 Australian National Survey of Mental Health and Wellbeing is funded by the Australian Government Department of Health and Ageing. The Argentina survey -- Estudio Argentino de Epidemiología en Salud Mental (EASM) -- was supported by a grant from the Argentinian Ministry of Health (Ministerio de Salud de la Nación). The São Paulo Megacity Mental Health Survey is supported by the State of São Paulo Research Foundation (FAPESP) Thematic Project Grant 03/00204–3. The Bulgarian Epidemiological Study of common mental disorders EPIBUL is supported by the Ministry of Health and the National Center for Public Health Protection. The Chinese World Mental Health Survey Initiative is supported by the Pfizer Foundation. The Colombian National Study of Mental Health (NSMH) is supported by the Ministry of Social Protection. The Mental Health Study Medellín – Colombia was carried out and supported jointly by the Center for Excellence on Research in Mental Health (CES University) and the Secretary of Health of Medellín. The ESEMeD project is funded by the European Commission (Contracts QLG5–1999-01042; SANCO 2004123, and EAHC 20081308), (the Piedmont Region (Italy)), Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain (FIS 00/0028), Ministerio de Ciencia y Tecnología, Spain (SAF 2000–158-CE), Departament de Salut, Generalitat de Catalunya, Spain, DIUE de la Generalitat de Catalunya (2017 SGR 452; 2014 SGR 748), Instituto de Salud Carlos III (CIBER CB06/02/0046, RETICS Degenhardt et al. Page 12 JAMA Psychiatry. Author manuscript; available in PMC 2019 August 05. Author Manuscript Author Manuscript Author Manuscript Author Manuscript RD06/0011 REM-TAP), and other local agencies and by an unrestricted educational grant from GlaxoSmithKline. Implementation of the Iraq Mental Health Survey (IMHS) and data entry were carried out by the staff of the Iraqi MOH and MOP with direct support from the Iraqi IMHS team with funding from both the Japanese and European Funds through United Nations Development Group Iraq Trust Fund (UNDG ITF). The Israel National Health Health Services Research and the National Insurance Institute of Israel. The World Mental Health Japan (WMHJ) Survey is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13- SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013, H25-SEISHIN-IPPAN-006) from the Japan Ministry of Health, Labour and Welfare. The Lebanese Evaluation of the Burden of Ailments and Needs Of the Nation (L.E.B.A.N.O.N.) is supported by the Lebanese Ministry of Public Health, the WHO (Lebanon), National Institute of Health / Fogarty International Center (R03 TW006481–01), anonymous private donations to IDRAAC, Lebanon, and unrestricted grants from, Algorithm, AstraZeneca, Benta, Bella Pharma, Eli Lilly, Glaxo Smith Kline, Lundbeck, Novartis, OmniPharma, Pfizer, Phenicia, Servier, UPO. The Mexican National Comorbidity Survey (MNCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT-G30544- H), with supplemental support from the Pan American Health Organization (PAHO). Te Rau Hinengaro: The New Zealand Mental Health Survey (NZMHS) is supported by the New Zealand Ministry of Health, Alcohol Advisory Council, and the Health Research Council. The Nigerian Survey of Mental Health and Wellbeing (NSMHW) is supported by the WHO (Geneva), the WHO (Nigeria), and the Federal Ministry of Health, Abuja, Nigeria. The Northern Ireland Study of Mental Health was funded by the Health & Social Care Research & Development Division of the Public Health Agency. The Peruvian World Mental Health Study was funded by the National Institute of Health of the Ministry of Health of Peru. The Polish project Epidemiology of Mental Health and Access to Care –EZOP Project (PL 0256) was supported by Iceland, Liechtenstein and Norway through funding from the EEA Financial Mechanism and the Norwegian Financial Mechanism. EZOP project was co-financed by the Polish Ministry of Health. The South Africa Stress and Health Study (SASH) is supported by the US National Institute of Mental Health (R01-MH059575) and National Institute of Drug Abuse with supplemental funding from the South African Department of Health and the University of Michigan. The Psychiatric Enquiry to General Population in Southeast Spain – Murcia (PEGASUSMurcia) Project has been financed by the Regional Health Authorities of Murcia (Servicio Murciano de Salud and Consejería de Sanidad y Política Social) and Fundación para la Formación e Investigación Sanitarias (FFIS) of Murcia. The Ukraine Comorbid Mental Disorders during Periods of Social Disruption (CMDPSD) study is funded by the US National Institute of Mental Health (RO1-MH61905). The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044708), and the John W. Alden Trust. Dr Andrade is supported by the Brazilian Council for Scientific and Technological Development (CNPq Grant # 307784/2016–9). Dr Stein is supported by the Medical Research Council of South Africa (MRC). In the past three years, Dr Degenhardt has received investigator-initiated untied educational grants for studies of opioid medications in Australia from Indivior, Mundipharma and Seqirus. Dr Kessler received support for his epidemiological studies from Sanofi Aventis; was a consultant for Johnson & Johnson Wellness and Prevention, Sage Pharmaceuticals, Shire, Takeda; served on an advisory board for the Johnson & Johnson Services Inc. Lake Nona Life Project; and being a co-owner of DataStat, Inc., a market research firm that carries out healthcare research. Dr Demyttenaere has served on advisory boards for Boehringer Ingelheim, Eli Lilly, Lundbeck, Johnson&Johnson, Livanova, Servier, and has research grants from Eli Lilly, foundation ‘ga voor geluk’, Fonds voor Wetenschappelijk Onderzoek Vlaanderen. Dr Stein has received research grants and/or consultancy honoraria from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun. The views expressed in this report are those of the authors and should not be construed to represent the views or policies of the WHO, other sponsoring organisations, agencies, or governments, and do not necessarily represent the views, official policy, or position of the US. Department of Health and Human Services or any of its affiliated institutions or agencies. Dr Glantz’s role on this study is through his involvement as a Science Officer on U01- MH60220. He had no involvement in the other cited grants.

Overt polyautoimmunity (PolyA) corresponds to the presence of more than one well-defined autoimmune disease (AD) manifested clinically in a single patient. The current study aimed to describe the main characteristics of juvenile PolyA in a pediatric rheumatology setting and analyze the chronological aspects, index cases, familial autoimmunity, and clustering pattern. This was a cross-sectional and multicenter study in which 313 children with overt PolyA were included. Patients were systematically interviewed and their medical records reviewed using a questionnaire that sought information about demographic, clinical, immunological, and familial characteristics. A hierarchical cluster analysis was done to determine similarities between autoimmune diseases based on PolyA. PolyA occurred simultaneously in 138 (44%) patients. Multiple autoimmune syndrome was observed in 62 (19.8%) patients. There were 25 index diseases of which, systemic lupus erythematosus (SLE, n = 134, 42.8%), juvenile idiopathic arthritis (JIA, n = 40, 12.7%), Hashimoto's thyroiditis (HT, n = 24, 7.66%), immune thrombocytopenic purpura (ITP n = 20, 6.39%), antiphospholipid syndrome (APS, n = 15, 4.79%), and vitiligo (VIT, n = 15, 4.79%) were the most frequent and represented 79.23% of the total number of patients. Familial autoimmunity influenced PolyA. A high aggregation of autoimmunity was observed (λr = 3.5). Three main clusters were identified, of which SLE and APS were the most similar pair of diseases (based on the Jaccard index) followed by HT and JIA, which were related to ITP and Sjogren's syndrome. The third cluster was composed of localized scleroderma and VIT. Our findings may assist physicians to make an early diagnosis of this frequent condition. Pediatric patients with ADs should be systematically assessed for PolyA.

Autoimmune diseases (ADs) are a chronic and clinically heterogeneous group of diseases characterized by share common immunopathogenic mechanisms and risk factors (i.e., the autoimmune tautology), which explain the fact that one AD may coexist with others (i.e., polyautoimmunity - PolyA). In the present exploratory study, a mixed-cluster analysis of the most common autoimmune rheumatic diseases (ARDs) was done. A total of 187 consecutive women with established systemic lupus erythematosus (n = 70), rheumatoid arthritis (n = 51), systemic sclerosis (n = 35) and Sjögren's syndrome (n = 31) were included. A comprehensive clinical, autoantibody and cytokine assessment was simultaneously done. Total PolyA was registered in 142 (75.9%) patients. Six clusters were obtained, built mainly on autoantibodies: PolyA-I to -VI. The PolyA-III cluster showed the highest frequency of overt PolyA (p = 0.01), and the PolyA-I, -III, and -IV clusters exhibited the highest positivity for IL-12/23p40 (p = 0.015). These results provide new insights into the pathophysiology of PolyA and warrant prospective validation to enable development of a more accurate taxonomy of ARDs. © 2018 The Authors

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n=7), deficiency of adenosine deaminase 2 (n=2), mevalonate kinase deficiency (n=2), Muckle-Wells syndrome (n=1), Majeed syndrome (n=1), and STING-associated vasculopathy with onset in infancy (n=1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease. Istanbul University Scientific Research FundIstanbul University [49820, BYP-2017-22876] This study was funded by Istanbul University Scientific Research Fund (Grants: 49820 and BYP-2017-22876). WOS:000466048800017 30783801 Q3

PubMedID: 30773598 Background. Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-Termoutcome. Methods. We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. Results. Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (61.16). There was an increased prevalence of chronic kidney disease (CKD) Stage -2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. Conclusion. Long-Term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients. © The Author(s) 2018. Erciyes Üniversitesi Iran University of Medical Sciences Università degli Studi di Padova Chung Hua University American Ornithologists' Union University of Queensland 7Centre University College London Aristotle University of Thessaloniki Lunds Universitet Cairo University National Rosacea Society Heart of England NHS Foundation Trust Centre hospitalier universitaire Sainte-Justine Erasmus Universiteit Rotterdam Aristotle University of Thessaloniki 1Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK, 2Centre for Nephrology, University College London, London, UK, 3Division of Nephrology, Bambino Gesù Children’s Hospital—IRCCS, Rome, Italy, 4Pediatric Nephrology—CHU Arnaud de Villeneuve, Montpellier University Hospital, Montpellier, France, 5Ali-Asghar Clinical Research Development Center, Iran University of Medical Sciences, Tehran, Iran, 6Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland, 7Centre de référence Maladies rénales rares, Bron, France, 8ASST Niguarda, Milan, Italy, 9Department of Pediatrics, University Hospital of Cologne, Cologne, Germany, 10University Hospital Leuven, Leuven, Belgium, 11King Edward Memorial Hospital, Pune, India, 12Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt, 13Hospital Universitario Vall d’Hebron, Barcelona, Spain, 14Division of Pediatric Nephrology, NRS Medical College, Kolkata, India, 15Pediatric Nephrology, Dialysis and Transplant Unit, Azienda Ospedaliera & University of Padova, Padova, Italy, 16University Children’s Hospital, Medical School, Skopje, Macedonia, 17National Medical and Research Centre for Children’s Health, Moscow, Russia, 18Centre Hospitalier Universitaire de Toulouse, Service de Nephrologie Pediatrique, Hopital des Enfants, Centre De Reference des Maladies Rénales Rares du Sud Ouest, Toulouse, France, 19Hospital Universitario Central de Asturias, Oviedo, Spain, 20Radboud University Medical Centre, Nijmegen, The Netherlands, 21Nephrology and Dialysis Unit, Department of Woman, Child and Urological Diseases, Azienda Ospedaliero—Universitaria Sant’Orsola-Malpighi, Bologna, Italy, 22Charité Universitätsmedizin Berlin, Berlin, Germany, 23University Children’s Hospital, Münster, Germany, 24Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands, 25Centro Hospitalar de Lisboa Central, Lisbon, Portugal, 26Fourth Pediatric Department, Aristotle University, Thessaloniki, Greece, 27Lady Cilento Children’s Hospital, Brisbane, Australia, 28School of Medicine, the University of Queensland, Brisbane, Australia, 29Department of Pediatric Nephrology, Pamukkale University School of Medicine, Denizli, Turkey, 30Nephrology Unit Azienda Ospedaliera, Papa Giovani XXIII, Bergamo, Italy, 31Karolinska Institutet, Lund University,Sweden,GroupFlorenceNightingaleHospitals,Ist32· anbul, Turkey,Fondazione Policlinico A. Gemelli, Universita` Cattolica del33 Sacro Cuore, Rome, Italy, 34Pediatric Nephrology Center of Excellence and Pediatric Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, 35Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy, 36Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, Naples, Italy, 37Pediatric Department, Lillebaelt Hospital Kolding, Kolding, Denmark, 38Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Hospital of Heidelberg, Heidelberg, Germany, 39Haseki Education and Research Hospital, Istanbul, Turkey, 40Belarusian State Medical University, Minsk, Belarus, 41Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France, 42Pediatric Nephrology Unit, AOU Policlinic G Martino, Messina, Italy, 43Necker Hospital, Paris, France, 44Faculty of Medicine, Department of Pediatric Nephrology, Erciyes University, Kayseri, Turkey, 45Cukurova University, Adana, Turkey, 46Nephrology Centre, Santaros Klinikos, Vilnius University, Vilnius, Lithuania, 47University Hospital of Lille, France, 48Department of Renal Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia, 49University Hospital Centre Zagreb, Zagreb, Croatia, 50Department of Pediatrics, SMDZ in Zabrze, SUM in Katowice, Poland, 51Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany, The European dRTA Consortium consists of the authors, as well as: Amira Peco-Antic(Department of Nephrology, University Children’s Hospital, Belgrade, Serbia), Amrit Kaur (Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, UK), Antonino Paglialunga (ASP de Ragusa, Modica, Italy), Aude Servais (Department of Nephrology, Centre Hospitalier Universitaire Necker, APHP, Paris, France), Branko Lutovac (Clinical Centre of Montenegro, Institute for Children’s Disease, Podgorica, Montenegro), Ewout J. Hoorn (Erasmus Medical Center, Rotterdam, The Netherlands), Hadas Shasha-Lavsky (Galilee Medical Center, Nahariya, Israel), Jerome Harambat (Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France), Astrid Godron-Dubrasquet (Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France), Kathrin Buder (Pediatric Department, University Hospital, Carl Gustav Carus Dresden, Dresden, Germany), Lise Allard (Department of Pediatrics, Angers University Hospital, Angers, France), Ludwig Patzer (Children’s Hospital St Elisabeth and St Barbara, Halle, Germany), Marina Shumikhina (Filatov Children’s Clinical Hospital No. 13, Moscow, Russia), Matthias Hansen (KfH Centre of Paediatric Nephrology, Clementine Children’s Hospital, Frankfurt, Germany), Nikoleta Printza (First Pediatric Department, Aristotle University, Thessaloniki, Greece), Nuran Küc¸ük (Kartal Dr. Lütfi Kırdar Training and Research Hospital, İstanbul, Turkey), Ortraud Beringer (University Children’s Hospital, Ulm, Germany), Rajendra Bhimma (Inkosi Albert Luthuli, Central Hospital, Durban, South Africa), Rimante Cerkauskiene (Faculty of Medicine, Children’s Hospital, Vilnius University, Vilnius, Lithuania; Santaros Klinikos, Vilnius University Hospital, Vilnius, Lithuania), Thomas J. Neuhaus (Children’s Hospital of Lucerne, Cantonal Hospital of Lucerne, Lucerne, Switzerland), Valbona Stavileci (Pediatric Clinic, Prishtina, Kosovo), Tim Ulinski (Pediatric Nephrology Department, Armand Trousseau University Hospital, APHP, Paris, France), Nida Temizkan Dincel (Health Sciences University, Izmir Dr Behcet Uz Children’s Hospital, İzmir, Turkey) and Nilufar Mohebbi (Division of Nephrology, University Hospital Zurich, Zurich, Switzerland)

Objectives To evaluate the relationship between age at onset of cannabis use and cannabis abuse in a sample of Portuguese cannabis users, testing the mediating role of the number of friends using cannabis and comparing these relationships between male and female subsets. Method A sample of 529 Portuguese cannabis users comprising 276 males and 244 females aged from 14 to 21 years completed a sociodemographic questionnaire, the Cannabis Abuse Screening Test (CAST), and answered four questions related to cannabis use. Data were analyzed using the PROCESS macro in SPSS version 26.0. Results Age at onset of cannabis use was negatively related to the number of friends using cannabis, while the number of friends using cannabis had a positive relationship with cannabis abuse. As predicted, the number of friends using cannabis seems to have a mediating role in the relationship between cannabis onset age use and cannabis abuse, since the indirect effect was found to be significant. The pattern of the relationships among the variables observed was found to be similar for both male and female subsets of the sample. However, males reported higher cannabis abuse than females. Conclusion The results highlight the mediating role of friends’ use of cannabis in the relationship between age at onset of cannabis use and users’ abuse. These results highlight the importance of early intervention in cannabis use. In particular, the pattern of the relationships observed among the studied variables emphasizes the need to monitor and conduct peer training interventions or interventions to promote of social skills.

BackgroundThough outcome differences between children and adults with immunoglobulin A vasculitis (IgAV) has been well documented, it remains unclear if disease features in pediatric IgAV patients vary with onset age. We aimed to explore clinical features and prognosis of pediatric IgAV stratified by onset age.MethodsWe retrospectively reviewed records of patients under 18 years old diagnosed with IgAV from January 1999 to December 2018 in one tertiary medical center in Taiwan. Patients were grouped by onset age: ≤ 6 years old, 6–12 years old (> 6, ≤ 12), and 12–18 years old (> 12, ResultsThere were 484 IgAV patients, with an onset age of 6.10 (4.72–8.58) (median (IQR)) years old. There were 234 (48.3%) patients ≤6 years old, 210 (43.4%) 6–12 years old, and 40 (8.3%) 12–18 years old. One hundred and thirty (26.9%) patients had renal involvement, which was more frequent in older children (≤ 6 years old, 18.4%; 6–12 years old, 31.0%; 12–18 years old, 55.0%;p p p ConclusionPediatric IgAV with different onset ages are associated with distinct clinical manifestations and outcomes. The risk of developing corticosteroid dependence, refractory disease and renal involvement increased with onset age.

Background The association between rheumatoid arthritis (RA) and periodontitis remains unclear. Methods We studied oral health and periodontitis in a population-based case-control study of individuals with ≥10 remaining teeth ≥61 years of age and either with, or without a diagnosis of RA. 126 dentate individuals with RA were recruited together with age-matched control individuals without RA. The control individuals were recruited from the general population from the same city (n = 249). A dental examination including a panoramic radiograph was performed on all participants. All individuals with RA were examined and medical records were reviewed by a rheumatologist. In the control group, none of the participants presented with symptoms of RA and their medical records were also negative. Results The RA group included more women (66.7% vs. 55.8%) (p p p = 0.001). Binary logistic regression analysis identified that a BMI > 25 (OR 6.2, 95% CI 3.6, 10.5, p = 0.000), periodontitis (OR 2.5 95% CI 1.5, 4.2 p = 0.000), and female gender (OR 2.3, 95% CI 1.3–4.0, p = 0.003) were associated with RA. Conclusion RA was associated a diagnosis of periodontitis.

Purpose The goal of this study was to better understand vanishing white matter (VWM) disease, which is one of the most common hereditary white matter disorders, and its relationship to radiologic features, genetic analyses, and clinical findings. Methods We performed a study on 11 patients to describe the clinical and neuroimaging features of VWM. Patients were grouped into "infantile," "early childhood," and "juvenile" based on their onset age. EIF2B1-5 genes encoding five subunits of eukaryotic translation initiation factor 2B (eIF2B) were analyzed in all patients with clinically suspected VWM disease. Results In brain magnetic resonance imaging (MRI), all patients showed white matter abnormalities with various degrees. The initial clinical presentation in five of patients was ataxia, with severe refractory epilepsy in three patients. In children with infantile-onset VWM, a rapid deterioration of motor function was detected, and the frequency of epilepsy was higher. Two patients showed manifestations of end-stage VWM disease, and one of them had chronic subdural hematoma. One of our patients and his father were diagnosed with Brugada syndrome. Sequencing of the exons and exon-intron boundaries of the EIF2B1-5 genes revealed mutations in the genes EIF2B5 (5 cases), EIF2B3 (3 cases), and EIF2B4 (2 cases). We also found a novel mutation in one patient: c.323_325delGAA in the EIF2B1 gene. Conclusions In this study, in addition to classical clinical and radiological findings, we wanted to emphasize that we may be confronted with refractory epilepsy (early infancy), cardiac problems, and intracranial complications that may occur in advanced stages. C1 [Gungor, Gulay] Pamukkale Univ, Dept Radiol, Fac Med, Denizli, Turkey. [Gungor, Olcay] Pamukkale Univ, Dept Pediat Neurol, Fac Med, TR-20100 Denizli, Turkey. [Cakmakli, Seda] Necip Fazil City Hosp, Dept Med Genet, Kahramanmaras, Turkey. [Maras Genc, Hulya] Umraniye Training & Res Hosp, Dept Pediat Neurol, Istanbul, Turkey. [Ince, Hulya] Med Pk Univ, Dept Pediat Neurol, Fac Med, Samsun, Turkey. [Yesil, Gozde] Bezmialem Vakif Univ, Dept Med Genet, Fac Med, Istanbul, Turkey. [Dilber, Cengiz] Medipol Univ, Dept Pediat Neurol, Fac Med, Istanbul, Turkey. [Aydin, Kursad] Marash Life Hosp, Dept Pediat Neurol, Kahramanmaras, Turkey.

WOS: 000505281300007, PubMed: 30680951, Objective Psoriatic arthritis (PsA) has a genetic background. Approximately 40% of patients with psoriasis or PsA have a family history of psoriasis or PsA, which may affect disease features. The aim of this study was to assess the effects of family history of psoriasis and PsA on disease phenotypes. Methods Data from 1,393 patients recruited in the longitudinal, multicenter Psoriatic Arthritis International Database were analyzed. The effects of family history of psoriasis and/or PsA on characteristics of psoriasis and PsA were investigated using logistic regression. Results A total of 444 patients (31.9%) had a family history of psoriasis and/or PsA. These patients were more frequently women, had earlier onset of psoriasis, more frequent nail disease, enthesitis, and deformities, and less frequently achieved minimal disease activity. Among 444 patients, 335 only had psoriasis in their family, 74 had PsA, and 35 patients were not certain about having PsA and psoriasis in their family, so they were excluded from further analysis. In the multivariate analysis, family history of psoriasis was associated with younger age at onset of psoriasis (odds ratio [OR] 0.976) and presence of enthesitis (OR 1.931), whereas family history of PsA was associated with lower risk of plaque psoriasis (OR 0.417) and higher risk of deformities (OR 2.557). Family history of PsA versus psoriasis showed increased risk of deformities (OR 2.143) and lower risk of plaque psoriasis (OR 0.324). Conclusion Family history of psoriasis and PsA impacts skin phenotypes, musculoskeletal features, and disease severity. The link between family history of psoriasis/PsA and pustular/plaque phenotypes may point to a different genetic background and pathogenic mechanisms in these subsets., Turkish Society for Rheumatology; Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK), Supported by the Turkish Society for Rheumatology. Dr. Bakirci's work was supported by the Scientific and Technological Research Council of Turkey and the Turkish Society for Rheumatology.

Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes. Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Despite the recognition of the usefulness of subthalamic nucleus deep brain stimulation (STN-DBS) for the treatment of Parkinson’s disease (PD), preoperative predictive factors for the long-term outcome of STN-DBS are not sufficiently established. We performed this study to determine such predictive factors. The subjects were 66 patients who were classified into two groups on the basis of their activities of daily living (ADL) evaluated five years after the STN-DBS surgery: 33 patients were assigned to the independent ADL group (group I) and the remaining 33 patients to the dependent ADL group (group D). Group I patients showed a Schwab and England (S&E) scale score of more than 70 during the off-period, indicating that these patients can maintain their independent ADL all the time. Group D patients showed a score of 70 or lower during the off-period, indicating that these patients cannot maintain their independent ADL for an entire day. We studied the differences in the preoperative state between these two groups. Statistically significant differences were noted in PD onset age, age at surgery, preoperative unified Parkinson’s disease rating scale (UPDRS) part I score, part II score, total subscore for axial symptoms in part III, mini-mental state examination (MMSE) score and S&E score. Multiple logistic regression analysis showed that the significant independent variables related to long-term independent ADL were the age at surgery, MMSE score and preoperative S&E scale score during the off-period. The PD onset age, age at surgery, preoperative high-level ADL, cognitive function, and axial symptoms are important predictive factors for the long-term outcome of STN-DBS.

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

This study using the Catalan PISCIS cohort explores risk factors of migrants’ late presentation and the impact of late presentation on their health outcomes. We analyse 9590 new HIV diagnoses enrolled in the cohort between 2004 and 2016. Univariate and multivariate logistic regression models are used to identify risk factors associated with late presentation among migrants, giving crude and adjusted odds ratios and their 95% confidence intervals. Cox regression models are estimated to identify risk factors associated with AIDS/death, and crude and adjusted hazard ratios and 95% confidence intervals are reported. Late presentation is higher in migrants than non-migrants. Among migrants, region of origin is associated with late presentation and AIDS/death during follow-up. The results highlight persisting inequalities in HIV diagnosis and care among migrants in Catalonia. Targeted interventions addressed to specific subgroups in the migrant population are needed. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

SUMMARY. Objective. The primary objective of this study was to compare the adult-onset and adolescent obsessive-compulsive disorder (OCD) patients in terms of the subthreshold autistic traits. Methods. 29 adolescent, and 45 adult-onset OCD patients were assessed by Autism-spectrum Quotient (AQ). Results. The ratio of males to females, the frequency of ritualistic compulsions, and the mean number of lifetime compulsions were significantly higher in adolescents with OCD compared to adult-onset patients. Adult-onset OCD patients had significantly higher scores on total, social skills, attention shifting, and imagination subscales of AQ than adolescent OCD patients. The mean number of compulsions, attention shifting scores of AQ, and female gender significantly predicted the distinction between adolescent and adult-onset OCD patients. In adult-onset patients, there were significant correlations between the mean number of lifetime obsessions and total, social skills, attention switching, communication, and imagination subscale scores of AQ. Conclusions. We suggest that subthreshold autistic traits may play a significant role in the occurence of obsessive-complusive symptoms (OCS) in adult-onset OCD. Autistic traits seemed to be higher and had an closer relationship with the frequency of lifetime obsessions in AO-OCD patients than in adolescent patients. © 2019 Il Pensiero Scientifico Editore s.r.l.. All rights reserved.

Background Mutations in the glucocerebrosidase (GBA) gene are an important risk factor for Parkinson's disease (PD). However, most GBA genetic studies in PD have been performed in patients of European origin and very few data are available in other populations. Methods We sequenced the entire GBA coding region in 602 PD patients and 319 controls from Colombia and Peru enrolled as part of the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD). Results We observed a significantly higher proportion of GBA mutation carriers in patients compared to healthy controls (5.5% vs 1.6%; OR = 4.3, p = 0.004). Interestingly, the frequency of mutations in Colombian patients (9.9%) was more than two-fold greater than in Peruvian patients (4.2%) and other European-derived populations reported in the literature (4–5%). This was primarily due to the presence of a population-specific mutation (p.K198E) found only in the Colombian cohort. We also observed that the age at onset was significantly earlier in GBA carriers when compared to non-carriers (47.1 ± 14.2 y vs. 55.9 ± 14.2 y; p = 0.0004). Conclusion These findings suggest that GBA mutations are strongly associated with PD risk and earlier age at onset in Peru and Colombia. The high frequency of GBA carriers among Colombian PD patients (∼10%) makes this population especially well-suited for novel therapeutic approaches that target GBA-related PD.

Background: Formal thought disorder (FTD) is considered to be a fundamental feature of schizophrenia. This study aims to analyze psychometric properties of the Turkish version of “Thought and Language Disorder Scale (TALD)” and investigate the relationship between FTD and various clinical characteristics in patients with schizophrenia. Methods: TALD was adapted into Turkish and applied to a total of 149 participants of which 114 had DSM-5 psychiatric diagnoses (schizophrenia N = 70, mania N = 20, depression N = 24) and 35 were healthy controls. Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, Young Mania Rating Scale, and Clinical Global Impression were administered to detect illness severity. Results: The principal component analyses revealed that the Turkish version of TALD (TALD-TR) consisted of four factors including the Objective Positive (OP), Subjective Negative (SN), Objective Negative (ON) and Subjective Positive (SP) symptom dimensions which were in line with the original TALD factorial structure. It was concluded that TALD-TR shows strong construct validity and high interrater reliability. The correlation analyses with TALD-TR and PANSS showed that there are positive correlations between the TALD-TR total score and the PANSS total and subscale scores. Each diagnostic group showed the distinct pattern of FTD. The mania group exhibited the highest mean total score in the OP, whereas the schizophrenia group exhibited the highest mean total score in the ON factor. In the schizophrenia group, the severity of FTD correlated positively with duration of illness and negatively with age at onset of illness. Conclusion: Adaptation of TALD into different languages seems to be possible, bringing in an international tool for research on FTD. Keywords: Formal thought disorder, Schizophrenia, Mania, Depression, Language processing

Background Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced phase disease and to describe their characteristics and outcomes. Methods Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735 ), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria. Results Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval [CI]: 66%–99%) and 74% (95% CI: 44%–89%) for patients diagnosed in CML-AP and CML-BP, respectively. Conclusion Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.

Nodal cytotoxic molecule (CM)‐positive peripheral T‐cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein‐Barr virus (EBV)‐negative CTL to 48 patients with EBV‐positive CTL. The two groups did not differ in histopathology, T‐cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV‐negative CTL less frequently showed hepatic involvement (P = .007), B symptoms (P = .020), hemophagocytosis (P = .024), and detectable CD4 (P = .002) and CD5 (P = .009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age

Işıkay S, Işıkay N, Per H, Çarman KB, Kocamaz H. Restless leg syndrome in children with celiac disease. Turk J Pediatr 2018; 60: 70-75. Celiac disease (CD) is an immune-mediated enteropathy triggered by ingestion of dietary gluten in genetically predisposed individuals. The aim of the study was to determine the prevalence of restless leg syndrome (RLS) in children with CD and to investigate the associated factors for RLS. Totally 494 children with the ages ranging between 11-18 years were included. Among those, 226 were under follow-up with CD and constituted the study group while other 268 children did not have any symptoms or signs associated with CD and established the control group. The demographic data, educational status and routine laboratory data of children including complete blood count, ferritin, vitamin B12, foliate and 25 (OH) vitamin D levels were recorded. The RLS prevalence and associated symptoms of children were defined with a questionnaire. There was no statistically significant difference between the 2 groups regarding the age and gender. Moreover, RLS prevalence was also similar in both groups (3.5% vs 3.0% in CD and control groups, respectively, p=0.98). However, interestingly, in CD group, the mean age of the patients at the onset of RLS symptoms was statistically significantly younger (p=0.02) and the disease was more severe (p=0.026) than the control group. In correlation analysis in CD group, the RLS severity significantly negatively correlated with serum ferritin, folic acid or 25 (OH) vitamin D levels in Celiac disease group. In this study we did not determine an increased prevalence of RLS in children with CD. However, in CD group, the age at the onset of RLS symptoms was significantly younger and the disease was more severe in CD group compared with the control cases.

"Çalışmada 57 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır.” Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers. Federal Ministry of Education & Research (BMBF) - IFB/CCI: 01EO1303 - E:med/SysInflame: 012X1306F - DZIF: 8000805-3 German Research Foundation (DFG) - FR 2821/6-1

Objective Assess reported risk of suicide attempts by patients with bipolar disorder (BD). Method Systematic searching yielded 101 reports from 22 countries (79 937 subjects). We analyzed for risk (%) and incidence rates (%/year) of attempts, comparing sex and diagnostic types, including by meta-analysis. Results Attempt risk averaged 31.1% [CI: 27.9–34.3] of subjects, or 4.24 [3.78–4.70]%/year. In BD-I (43 studies) and BD-II subjects (30 studies), risks (29.9%, 31.4%) and incidence rates (4.01, 4.11%/year) were similar and not different by meta-analysis. Among women vs. men, risks (33.7% vs. 25.5%) and incidence (4.50 vs. 3.21%/year) were greater (also supported by meta-analysis: RR = 1.35 [CI: 1.25–1.45], P men). Future studies should routinely include exposure times and incidence rates by diagnostic type and sex for those who attempt suicide or not.

Although there is a significant association between preexisting depression and later onset of chronic headache, the extent to which other preexisting mental disorders are associated with subsequent onset of headache in the general population is not known. Also unknown is the extent to which these associations vary by gender or by life course. We report global data from the WHO's World Mental Health surveys (n = 52,095), in which, by means of the Composite International Diagnostic Interview–3.0, 16 mental disorders from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition , were retrospectively assessed in terms of lifetime prevalence and age of onset. Frequent or severe headaches were assessed using self-reports. After adjustment for covariates, survival models showed a moderate but consistent association between preexisting mood (odds ratios [ORs] = 1.3–1.4), anxiety (ORs = 1.2–1.7), and impulse-control disorders (ORs = 1.7–1.9) and the subsequent onset of headache. We also found a dose-response relationship between the number of preexisting mental disorders and subsequent headache onset (OR ranging from 1.9 for 1 preexisting mental disorder to 3.4 for ≥5 preexisting mental disorders). Our findings suggest a consistent and pervasive relationship between a wide range of preexisting mental disorders and the subsequent onset of headaches. This highlights the importance of assessing a broad range of mental disorders, not just depression, as specific risk factors for the subsequent onset of frequent or severe headaches. Perspective This study shows that there is a temporal association between a broad range of preexisting mental disorders and the subsequent onset of severe or frequent headaches in general population samples across the world.

Background: Late onset cases of Huntington disease (HD), with onset ≥60 years, account for up to 20% of HD cases worldwide. Clinical features include mild motor dysfunction with slow progression and cognitive impairment, frequent absence of family history and low number of CAG repeats. The clinical and molecular features of late onset HD is still understudied in Latin America. Objectives: To describe the clinical and molecular characteristics of late onset HD in a Peruvian cohort. Methods: An observational study was carried out by reviewing the HD registry at the Neurogenetics Research Center-INCN from 2000 to 2014. Genotyping of HTT gene was confirmed using standard PCR and PAGE in accordance to protocols previously established. Results: Thirty-one late onset HD cases from 27 pedigrees were identified (9.42% of total HD cases, n = 329), 51.61% were male. Mean age at onset was 64.1 ± 4.2 and CAG repeats mean was 42.5 ± 2.5. We did not find significant correlation between age at onset and CAG repeats. 33.3% of cases were traced back to Cañete valley. Twenty-two cases had a positive family history, 14 of them with paternal transmission. Choreic movements and cognitive impairment were the main existing manifestations reported in this cohort, with lower frequency of psychiatric disturbances. Conclusions: This report of late onset HD affected individuals shows a mild phenotype expression of the disease, associated with low range of CAG repeats and up to 30% of cases with absence of clear family history. Cañete valley remains the region with more cases.

Predictive genetic model for levodopa-induced dyskinesia in patients with Parkinson's disease S.A. Ivanova(1), V.M. Alifirova(2), M.B. Freidin(3), I.V. Pozhidaev(4), O.Y. Fedorenko(4), N.A. Bokhan(4), I.A. Zhukova(5), N.G. Zhukova(5), B. Wilffert(6), A.J.M. Loonen(6) (1)Mental Health Research Institute, Molecular Genetics and Biochemistry Laboratory, Tomsk, Russia (2)Siberian State Medical University, Department of Neurology and Neurosurgery, Tomk, Russia (3)Tomsk National Research Medical Center of the Russian Academy of Sciences, Research Institute of Medical Genetics, Tomsk, Russia (4)Tomsk National Research Medical Center of the Russian Academy of Sciences, Mental Health Research Institute, Tomsk, Russia (5)Siberian State Medical University, Department of Neurology and Neurosurgery, Tomsk, Russia (6)University of Groningen, Groningen Research Institute of Pharmacy, Groningen, The Netherlands Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with levodopa (L-DOPA). The use of this drug, however, is severely limited by adverse effects. Levodopa-induced dyskinesia (LID) is one of these and characterized by involuntary muscle movements that occur as a consequence of chronic levodopa treatment. LID is a substantial barrier to effective symptomatic management of PD as up to 45% of L-DOPA users develop LID within 5 years [1]. Clinical heterogeneity of LID suggests a significant role of endogenous factors in determining their prevalence. Some evidences suggest a relationship between LID and specific genetic variants, such as polymorphisms in the genes controlling enzymes responsible for drug and monoamine metabolism, neurotransmitter receptors and proteins involved in oxidative stress or antioxidant function [2–4]. Objective: To investigate a contribution of polymorphic variants of neurotransmitter receptors and cytochrome genes in the development of LID in PD patients. Methods: A total of 212 PD patients who received L-DOPA therapy were studied. Dyskinesia was assessed by using the Abnormal Involuntary Movement Scale (AIMS). DNA extraction and genotyping were conducted according to standard protocols and blind to the clinical status of the subjects. Genotyping was carried out for 72 SNPs of DRD1, DRD2, DRD2/ANKK1, DRD3, DRD4, HTR2C, HTR3A, HTR3B, HTR6, HTR2A, HTR1A, HTR1B, CYP1A2*1F, CYP2D6*3, CYP2D6*4, CYP2C19*3, CYP2C19*17, CYP2C19*2, and GSTP1 genes using MassARRAY® Analyzer 4 (Agena Bioscience™) and the set SEQUENOM Consumables iPLEX Gold 384. Discriminant analysis and receiver operating curve (ROC)-analysis were carried out to build a genetic predictive model for dyskinesia. Results: Group of PD patients consists of 149 females and 83 males (age ranging from 40 to 86 years, average age 68.7 ± 7.6 years). The mean age of onset is 60.04 ± 9.46 years, average disease duration is 9.79 ± 5.57 years. Dyskinesia was reported in 57 (26.9%) patients. The best discriminant model was obtained with the following predictors: rs11721264, rs165774, rs3758653, rs4245147, rs6313, rs1364043, rs2734849, rs324035, rs6311, rs11246226 and rs4244285. These polymorphisms are localized in the following genes: DRD3 (rs11721264, rs324035), DRD4 (rs3758653, rs11246226), DRD2 (rs4245147, rs2734849), HTR2A (rs6313, rs6311), HTR1A (rs1364043). The discriminant model using this set of SNPs gives the error of classification about 13% and the AUC 0.795. Depending on the anticipated frequency of LID, positive and negative predictor values varied between 0.745–0.834 and 0.864–0.916, respectively. We hypothesized in our previous studies that the pathological basis of LID might be degeneration of indirect pathway medium spiny neurons [5]. These indirect pathway medium spiny neurons carry type 2 family dopamine receptors (DRD2, DRD3, DRD4), and HTR2A receptors. Moreover, dopamine release may be promoted by inhibiting serotonergic neurotransmission. Hence, the current findings are well in line with this hypothesis. Conclusion: The resulting panel of 11 SNPs provides a sufficiently high accuracy of LID prediction. The use of this panel in a prospective study will clarify the prospects for its application in clinical practice for predicting risk of LID in patients with PD. References [1] Rascol, O., Brooks, D.J., Korczyn, A.D., et al., 2000. Study Group: A five–year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or L–DOPA. N Engl J Med 342, 1484–1491. [2] Ivanova, S.A., Fedorenko, O.Yu., Freidin, M.B., et al., 2016. Dissimilar mechanistic background of peripheral and orofacial hyperkinesia in patients with Parkinson's disease and levodopa-induced dyskinesia. Physiology and Pharmacology 19, 216–221. [3] Kaplan, N., Vituri, A., Korczyn, A.D., et al., 2014. Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopa-induced dyskinesias in Parkinson's disease. J Mol Neurosci 53 (2), 183–188. [4] Loonen, A.J.M., Ivanova, S.A., 2016. Role of 5-HT2C receptors in dyskinesia. International Journal of Pharmacy and Pharmaceutical Sciences 8 (1), 5–10. [5] Loonen, A.J., Ivanova, S.A., 2013. New insights into the mechanism of drug-induced dyskinesia. CNS Spectr 18, 15–20. Keywords: Genetics / Molecular genetics Parkinson's disease levodopa-induced dyskinesia

Dopamine receptors genes polymorphisms in Parkinson patients with levodopa-induced dyskinesia I. Pozhidaev(1), V.M. Alifirova(2), M.B. Freidin(3), I.A. Zhukova(2), O.Y. Fedorenko(1), D.Z. Osmanova(1), Y.S. Mironova(2), B. Wilffert(4), S.A. Ivanova(1), A.J.M. Loonen(5) (1)Mental Health Research Institute, Molecular Genetics and Biochemistry, Tomsk, Russia (2)Siberian State Medical University, Neurology and Neurosurgery, Tomsk, Russia (3)Research Institute for Medical Genetics, Laboratory of Population Genetics, Tomsk, Russia (4)Groningen Research Institute of Pharmacy, Pharmacotherapy and Clinical Pharmacology, Groningen, The Netherlands (5)Groningen Research Institute of Pharmacy, Pharmacotherapy in Psychiatric Patients, Groningen, The Netherlands Introduction: Long-term levodopa treatment of Parkinson's disease (PD) is frequently complicated by spontaneously occurring involuntary muscle movements called levodopa-induced dyskinesia (LID). LID are a substantial barrier to effective symptomatic management of Parkinson's disease (PD), as up to 45% of L-DOPA users develop LID within 5 years [1]. The exact pathological mechanism of this complication has not yet been elucidated. A lot of studies nowadays which approved complex genetic nature of LID. And these genes are involved not only for oxidative stress, but in drug metabolism too [2–4]. Objective: This study aimed to investigate a possible contribution of polymorphic variants of DRD1, DRD2, DRD2/ANKK1, DRD3, DRD4 genes in the development of LID in PD patients. Methods: 212 patients with Parkinson's disease on levodopa therapy were investigated. Dyskinesia was measured by using Abnormal Involuntary Movement Scale (AIMS). DNA extraction and fluorogenic 5′-exonuclease TaqMan genotyping assays were conducted according to standard protocols and blind to clinical status of the subjects. Genotyping was carried out on 28 SNPs of dopamine receptors (rs4532, rs936461, rs6275, rs1801028, rs4245147, rs134655, rs6277, rs1076560, rs2283265, rs179997, rs6279, rs1076562, rs2734842, rs2734849, rs11721264, rs167770, rs3773678, rs963468, rs7633291, rs2134655, rs9817063, rs324035, rs1800828, rs167771, rs6280, rs1587756, rs3758653, rs11246226) on the MassARRAY® Analyzer 4 (Agena Bioscience™) using the set SEQUENOM Consumables iPLEX Gold 384. SPSS software was used for statistical analysis. Statistical significance of the association testing was established using permutations. P-value

PubMedID: 28830306 Background and aim: The effect of epigenetic modifications in the genes related to Parkinson’s disease (PD) is still unclear. In the present study, we investigated methylation status of SNCA and PARK2 genes in patients with early-onset Parkinson’s disease (EOPD). Materials and methods: The promoter region methylation status of SNCA and PARK2 genes was evaluated by methylation specific-PCR (MSP) in 91 patients with EOPD and 52 healthy individuals. Results: The methylation of SNCA and PARK2 promoter regions were significantly lower in EOPD patients compared to the control group (P = 0.013 and P = 0.03, respectively). We also found that the methylation status of the SNCA might be associated with positive family history of PD (P = 0.042). Conclusion: Although it should be supported by further analysis, based on the results of the present study, the methylation status of SNCA and PARK2 genes might contribute to EOPD pathogenesis. © 2017 Informa UK Limited, trading as Taylor & Francis Group. Firat University Scientific Research Projects Management Unit This work was supported by a grant from the Scientific Research Projects Foundation of the Uludag University, Bursa, Turkey [Project No. KUAP(T)-2013/43].

Annual European Congress of Rheumatology -- JUN 14-17, 2017 -- Madrid, SPAIN, WOS: 000413181404260

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer’s disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)—control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5–41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD. © 2017, The Author(s).

Introduction: Colchicine is the mainstay for the treatment of FMF, which is an auto-inflammatory disease mainly with relapsing polyserositis. Despite daily doses of 2 mg ormore each day, approximately 5% to 10% of the patients continue to suffer from its attacks. In this study, we aimed to investigate the depression and attack features in patients withFMF who have colchicine resistance (CR).Patients e Methods: CR was defined for FMF patients with 2 or more attacks within the last6 months period while using 2 mg/day colchicine. Eighteen patients (9 Female/9 Male) wereenrolled into the CR group and 41 patients were enrolled into the control group (12 Male/29Female). Demographic, clinical e laboratory findings, treatment adherence, and the BeckDepression Inventory (BDI) scores were evaluated. Results: The age of onset of FMF was significantly lower in the CR group (12.3 yrs vs. 16.9 yrs, P = 0.03). Disease duration was longer in the CR group (P = 0.01). Abdominal and leg pain dueto exercise were significantly more frequent in the CR group versus controls (83% vs. 51%;P = 0.02 e 88% vs. 60%; P = 0.04, respectively). Patients with BDI scores over 17 points weremore frequent in the CR group compared to controls (50% vs. 34.1%; P < 0.001).Discussion: We found that: (1) the age of disease onset was lower and (2) the disease durationwas longer in CR group. Pleuritic attacks, hematuria e proteinuria were more frequent in CRpatients. We propose that depression is an important factor to consider in the susceptibilityto CR. © 2014 Elsevier Editora Ltda.

Objective: Pathogenesis of Henoch-Schönlein purpura (HSP) is not clearly defined. The present study was conducted to investigate the alterations in erythrocyte deformability and oxidative stress in HSP and to examine the possible relationship between erythrocyte deformability and organ involvement in this disease. Methods: Plasma malondialdehyde (MDA) levels, total antioxidant status (TAS), erythrocyte deformability and aggregation were measured in 21 children with HSP at the disease onset and during the remission period in comparison with healthy subjects. Findings: HSP patients at the active stage had significantly higher MDA and lower TAS levels (P0.05). Conclusion: The present findings emphasize the association between impaired erythrocyte deformability and organ involvement in HSP. © 2014 by Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, All rights reserved.

Background We have previously reported using two-step cluster analysis to classify myasthenia gravis (MG) patients into the following five subtypes: ocular MG; thymoma-associated MG; MG with thymic hyperplasia; anti-acetylcholine receptor antibody (AChR-Ab)-negative MG; and AChR-Ab-positive MG without thymic abnormalities. The objectives of the present study were to examine the reproducibility of this five-subtype classification using a new data set of MG patients and to identify additional characteristics of these subtypes, particularly in regard to response to treatment. Methods A total of 923 consecutive MG patients underwent two-step cluster analysis for the classification of subtypes. The variables used for classification were sex, age of onset, disease duration, presence of thymoma or thymic hyperplasia, positivity for AChR-Ab or anti–muscle-specific tyrosine kinase antibody, positivity for other concurrent autoantibodies, and disease condition at worst and current. The period from the start of treatment until the achievement of minimal manifestation status (early-stage response) was determined and then compared between subtypes using Kaplan-Meier analysis and the log-rank test. In addition, between subtypes, the rate of the number of patients who maintained minimal manifestations during the study period/that of patients who only achieved the status once (stability of improved status) was compared. Results As a result of two-step cluster analysis, 923 MG patients were classified into five subtypes as follows: ocular MG (AChR-Ab-positivity, 77%; histogram of onset age, skewed to older age); thymoma-associated MG (100%; normal distribution); MG with thymic hyperplasia (89%; skewed to younger age); AChR-Ab-negative MG (0%; normal distribution); and AChR-Ab-positive MG without thymic abnormalities (100%, skewed to older age). Furthermore, patients classified as ocular MG showed the best early-stage response to treatment and stability of improved status, followed by those classified as thymoma-associated MG and AChR-Ab-positive MG without thymic abnormalities; by contrast, those classified as AChR-Ab-negative MG showed the worst early-stage response to treatment and stability of improved status. Conclusions Differences were seen between the five subtypes in demographic characteristics, clinical severity, and therapeutic response. Our five-subtype classification approach would be beneficial not only to elucidate disease subtypes, but also to plan treatment strategies for individual MG patients.

Objectives: The heterogeneity of schizophrenia mainly results from variations in clinical expressions of the disease, such as age at onset, gender differences in onset of illness, symptoms and response to antipsychotic treatment. Enhanced sensitisation of dopamine pathways in males, having consistently an earlier onset, might be implicated as disease modifiers for schizophrenia in males.Methods: In this study, we performed a case (n = 87)-control (n = 100) association study between the DBH5′-ins/del and DBH-444g/a polymorphisms of the DBH gene and also compared the level of psychotic symptoms between patients with different DBH genotypes/haplotypes with respect to antipsychotic therapeutic response and gender difference.Results: No significant differences between allele and genotype and haplotype frequencies at either groups (p < 0.05). When the age is considered in patient group, a significant difference was observed between patients with ID genotype and with II genotype (p = 0.018). Patients with ID genotype have been diagnosed as schizophrenics in early ages when compared to II genotype carriers. We also found a significant difference between II and ID genotype (p = 0.007) when the gender had taken into account, showing that the ID genotype carriers had an early onset to schizophrenia.Conclusions: This association was more significant in male schizophrenia patients than females. Thus, this finding may constitute a novel biological support for the prior finding that onset of schizophrenia varies with gender. The results also showed that critical genetic vulnerability may be associated with the presence or absence of the ID genotype of DBH5′-ins/del.

WOS: 000380854200011, PubMed ID: 26834222, Objective. To assess the performance of the new 2012 provisional European League Against Rheumatism (EULAR)/ American College of Rheumatology (ACR) polymyalgia rheumatica (PMR) clinical classification criteria in discriminating PMR from other mimicking conditions compared with the previous 5 diagnostic criteria in a multicenter prospective study. Methods. Patients older than 50 years, presenting with new-onset bilateral shoulder pain with elevated acute-phase reactants (APR), were assessed for the fulfillment of the new and old classification/diagnostic criteria sets for PMR. At the end of the 1-year followup, 133 patients were diagnosed with PMR (expert opinion) and 142 with non-PMR conditions [69 rheumatoid arthritis (RA)]. Discriminating capacity, sensitivity, and specificity of the criteria sets were estimated. Results. Discriminating capacity of the new clinical criteria for PMR from non-PMR conditions and RA as estimated by area under the curve (AUC) were good with AUC of 0.736 and 0.781, respectively. The new criteria had a sensitivity of 89.5% and a specificity of 57.7% when tested against all non-PMR cases. When tested against all RA, seropositive RA, seronegative RA, and non-RA control patients, specificity changed to 66.7%, 100%, 20.7%, and 49.3%, respectively. Except for the Bird criteria, the 4 previous criteria had lower sensitivity and higher specificity (ranging from 83%-93%) compared with the new clinical criteria in discriminating PMR from all other controls. Conclusion. The new 2012 EULAR/ ACR clinical classification criteria for PMR is highly sensitive; however, its ability to discriminate PMR from other inflammatory/noninflammatory shoulder conditions, especially from seronegative RA, is not adequate. Imaging and other modifications such as cutoff values for APR might increase the specificity of the criteria.

Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c. IVS3ds + 1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future. Türk Pediatrik Endokrinoloji Araştırma Bursu- UPE-2014-2 Wellcome Trust/European Commission - 098513/Z/12/Z National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London European Commission - PIEF-GA-2012-328959

WOS: 000377212700036, PubMed ID: 26523528, Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c. IVS3ds + 1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future., Turkish Pediatric Endocrinology Research Grant [UPE-2014-2]; Wellcome TrustWellcome Trust [098513/Z/12/Z]; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London; European CommunityEuropean Community (EC) [PIEF-GA-2012-328959], This work was supported by Turkish Pediatric Endocrinology Research Grant UPE-2014-2. J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (Grant 098513/Z/12/Z), with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. T.G. is a European Community, Marie-Curie research fellow (Grant PIEF-GA-2012-328959).

Objective American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. Methods A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). Results The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P less than 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P less than 0.0001). American Indian ancestry protected against photosensitivity (P less than 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P less than 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P less than 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. Conclusion In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age. Copyright © 2012 by the American College of Rheumatology.

Background: Psoriasis is an inflammatory disease characterized by increased squamous cell proliferation and impaired differentiation. Vitamin D, Calcitriol, and its analogues are successfully used for psoriasis therapy. However, it is unknown why some psoriasis patients are resistant to Vitamin D therapy. Vitamin D mediates its activity by a nuclear receptor. It is suggested that polymorphisms and haplotypes in the VDR gene may explain the differences in response to vitamin D therapy. Material/Methods: In this study, 102 psoriasis patients and 102 healthy controls were studied for VDR gene polymorphisms. The Fok I, Bsm I, Apa I and Taq I polymorphisms were examined by PCR-RFLP, and 50 subjects received vitamin D therapy to evaluate the association between VDR gene polymorphisms and response to vitamin D therapy. Existence of cutting site is shown by capital letters, and lack was shown by lower case. The haplotypes were analysed by CHAPLIN. Results: There was significant difference in allele frequency of T and genotype frequency of Tt between cases and controls (p values 0.038 and 0.04, respectively). The Aa and bb genotypes were significantly higher in early onset than late onset psoriasis (p values 0.008 and 0.04, respectively). The genotypes Ff, ff and TT are significantly different between vitamin D3 therapy responders and non-responders (p values 0.04, 0.0001, 0.009, respectively). To the best of our knowledge, this is the first report showing importance of VDR gene haplotypes in psoriasis, the significance of the Wald and LR (Likelihood Ratio) statistics (p=0,0042) suggest that FfBbAatt is a disease-susceptibility haplotype. Conclusions: Haplotype analysis is a recent and commonly used method in genetic association studies. Our results reveal a previously unidentified susceptibility haplotype and indicate that certain haplotypes are important in the resistance to vitamin D3 therapy and the onset of psoriasis. The haplotypes can give valuable data where genotypes unable to do. © Med Sci Monit.

Objectives: To determine factors influencing the age at onset of rheumatoid arthritis (RA). Methods: A sample of 152 Colombian patients was investigated. Hazard ratios (HRs) that measured the effect size of risk factors on the age at RA onset were computed by using Cox regression models. Results: Positive anti-CCP antibodies were associated with an increased risk of early RA onset (HR=1.60; 95% confidence interval, [1.06, 2.4]), whereas the presence of the protective 70DERAA74 sequence was associated with a delayed onset (HR=0.55; [0.33, 0.92]). After controlling for both anti-CCP antibodies and the 70DERAA74 sequence, the following variables did not influence significantly the age at RA onset: gender, ever cigarette smoking, family RA history, the TNF-308 A polymorphism, HLA shared epitope, and the presence of rheumatoid factor. Conclusion: Anti-CCP antibodies and the HLA-DRB1 70DERAA74 sequence influence the age at onset of RA. © 2010 Société française de rhumatologie.

The typical clinical presentation of dopa‐responsive dystonia, which is also called Segawa disease, is a young age of onset, with predominance in females, diurnal fluctuation of lower limb dystonia, and fair response to low‐dose levodopa. This disease has both autosomal dominant and autosomal recessive inheritance. Autosomal dominant Segawa disease is caused by GCH1 mutation on chromosome 14q22.1‐q22.2. Here, we report the case of a male patient with genetically confirmed Segawa disease and atypical presentations including no diurnal symptom fluctuation and insufficient response to levodopa. The patient's father who had the same mutation presented parkinsonism in old age. We also review the literature to address the broad clinical heterogeneity of Segawa disease and the influence of onset age on clinical presentation.

Background: Familial amyloidotic polyneuropathy (FAP) TTR Val30Met is a lethal autosomal dominant sensorimotor and autonomic neuropathy due to a substitution of methionine for valine at position 30 of the transthyretin (TTR) gene. Amyloid, composed of mutated TTR, is deposited in the peripheral nervous system, myocardium and kidneys. Considerable variability in the age of onset and penetrance of the disease occurs in different countries. Penetrance in Sweden, Cyprus and Portugal is 2%, 28% and 80% respectively. Environmental and genetic factors are believed to contribute to this variability. So far, no single modifier gene has been unequivocally associated with age of onset or penetrance. Methods: Candidate modifier genes were chosen from among those coding for chaperone proteins co-localized with TTR deposits in peripheral nerves. Seventy one TTRVal30Met carriers, 51 affected and 20 asymptomatic, belonging to 22 unrelated Greek-Cypriot families, and 59 normal controls were recruited for this study. Sequencing of the coding regions of TTR, serum amyloid P (APCS) and complement C1Q (A, B and C) genes was performed and APOE genotypes were determined. We searched for correlations between various polymorphisms of chaperone proteins and age of disease onset. Results: Four new and 4 previously described single nucleotide substitutions were identified. One polymorphic site in C1QA (rs172378) and one in C1QC (rs9434) as well as the ε2 allele correlated with age of onset (p < 0.05). Conclusions: Our study has identified polymorphisms which may influence the FAP-TTR Val30Met phenotype. Identifying modifier genes and their protein products may contribute to therapeutic advances. © 2009 Elsevier B.V. All rights reserved. 284 1-2 158 162 Cited By :16

To study the prevalence of early adversities in schizophrenia and unipolar depression, 2 groups of consecutive adult-onset inpatients with DSM-IV diagnoses of schizophrenia (n = 173) and unipolar depression (n = 305) were compared with an unscreened control group of volunteers from the general population (n = 310), with respect to their association with 4 types of childhood abuse and with early parental adversities (discord, separation, death, psychiatric caseness). Compared with general population, most types of early adversities (except sexual abuse and parental death) were significantly associated with both clinical groups. Compared with depression, all early adversities with the same 2 exceptions were significantly associated with schizophrenia; both frequency of abuse and number of types of abuse increased the risk of schizophrenia in a dose-response pattern, suggesting causality. These findings stress the role of social developmental factors in the etiology of schizophrenia.

Purpose: To investigate neuronal dysfunction in the thalami of juvenile myoclonic epilepsy (JME) by using proton magnetic resonance spectroscopy (MRS). Methods: We performed single-voxel proton MRS over the right and the left thalami of 15 consecutive patients (10 women, 5 men) with JME (mean age 20.3 years) and 16 healthy volunteers (10 women, 6 men) (mean age 24.5 years). All patients had seizure onset in late childhood-teenage, normal neurologic examination, typical electroencephalogram (EEG) of JME and normal magnetic resonance imaging (MRI). We determined N-acetylaspartate (NAA) values and NAA over creatine-phosphocreatine (Cr) values. Mann-Whitney U-test was used to evaluate group differences. Results: Group analysis showed that echo time (TE) 270 integral value of NAA over left thalamus were significantly decreased in JME patients as compared with controls (34.6033 +/- 15.8386; 48.0362 +/- 22.2407, respectively, P = 0.019). Also group analysis showed that thalami NAA/Cr ratios were significantly decreased in JME patients (right side, 2.21 +/- 1.07; left side 2.00 +/- 0.72) as compared with controls (right side, 3.45 +/- 1.50; left side, 3.08. +/- 1.60; P = 0.011 and P = 0.030, respectively). Conclusion: In the previous studies, NAA values inpatients with JME found that they were not statistically lower in thalami than control group. But, in our study, NAA value was found tow as well. It has been known that NAA is a neuronal marker and hence it is a valuable metabolite in the neuron physiopathology. As a result, in the patients with JME we tried to support the theory that the underlying mechanism of the generalized seizures was the abnormal thalamocortical circuity, determining the thalamic neuronal dysfunction in MRS statistically.

Objective Variations in PARK genes ( PRKN , PINK1 , DJ-1, and SNCA ) cause early-onset Parkinson's disease (EOPD) in different populations. In the current study, we aimed to evaluate the frequencies of variations in PARK genes and the effects of these variations on the phenotypes of Turkish EOPD patients. Methods All coding regions and exon-intron boundaries of the PRKN, PINK1, DJ-1, and SNCA genes were screened by heteroduplex analysis followed by direct sequencing of the detected variants in 50 Turkish EOPD patients. These variants were evaluated using SIFT, PolyPhen, HSF, and LOVD web-based programs. Results The frequency of EOPD-associated variations in the PRKN gene was 34%. Among these variations, p.A82E in exon 3 and p.Q409X in exon 11 was determined to be pathogenic. We also defined previously unknown cryptic variations, including c.872-35 G>A and c.872-28T>G in exon 8 of PRKN and c.252+30 T>G and c.322+4 A>G in exons 4 and 5 of DJ1 , respectively, that were associated with EOPD. Although no significant association was observed between the PARK gene mutations and clinical features (P>0.05), the alterations were related to the clinical symptoms in each patient. Conclusion An increasing number of studies report that PRKN , PINK1 , DJ1 and SNCA mutations are associated with early-onset Parkinson's disease; however, a limited number of studies have been conducted in Turkey. Additionally, our study is the first to evaluate the frequency of SNCA mutations in a Turkish population. The aim of this study was determine the frequency distributions of the PRKN , PINK1 , DJ1, and SNCA gene mutations and to analyze the relationships between these genetic variations and the clinical phenotype of EOPD in Turkish patients.

Objective: To evaluate the prevalence and factors associated with non-erosive rheumatoid arthritis (RA). Methods: First, a cross-sectional analytical study was performed. Non-erosive disease, defined as the absence of any erosion on X-rays after 5 years of RA, was evaluated in 500 patients. Further and additional evaluations including ultrasonography (US) and computed tomography (CT) were performed in those patients meeting the eligibility criteria. The Spearman correlation coefficient, kappa analysis, and Kendall[U+05F3]s W test were used to analyze the data. Second, a systematic literature review (SLR) was performed following the PRISMA guidelines. Results: Of a total of 40 patients meeting the eligibility criteria for non-erosive RA, eight patients were confirmed to have non-erosive RA by the three methods. A positive correlation between non-erosive RA and shorter disease duration, antinuclear antibodies positivity, lower rheumatoid factor (RF) and C-reactive protein titers, lower global visual analog scale values, toxic exposures, and lower disease activity-(RAPID3) was found. In addition, an inverse correlation with anticyclic citrullinated peptide antibodies (ACPA) positivity and medication use was observed. From the SLR, it was corroborated that factors associated with this subphenotype were shorter disease duration, younger disease onset, negative ACPA and RF titers, low cytokine levels, and some genetic markers. Conclusion: Non-erosive RA is rare, occurring in less than 2% of cases. These findings improve on the understanding of RA patients who present without erosions and are likely to have less severe disease. © 2014 Elsevier Inc.

Objectives To determine the prevalence and the predictive factors of autoimmune hypothyroidism (AH) within a systemic lupus erythematosus (SLE) cohort and to analyse the current information concerning the prevalence and impact of autoimmune thyroid disease (AITD) and thyroid autoimmunity in patients with SLE. Methods A total of 376 patients with SLE were assessed for the presence of the following: (i) confirmed AH, (ii) positive thy-roperoxidase/thyroglobulin antibodies [TPOAb/TgAb] without hypothyroidism, (iii) nonautoimmune hypothyroidism and (iv) SLE patients with neither. Multivariate analysis and a classification and regression tree model were used to analyse data. The current information was discussed through a systematic literature review (SLR). Results In our cohort, the prevalence of confirmed AH was 12%. However, in euthyroid patients with SLE, TPOAb and TgAb were observed in 21% and 10%, respectively. Patients with confirmed AH were significantly older and had later age at onset of the disease. Smoking (adjusted odds ratio (AOR) 6·93, 95% CI 1·98-28·54, P = 0·004), Sjögren's Syndrome (SS) (AOR 23·2, 95% CI 1·89-359·53, P = 0·015) and positivity for anticyclic citrullinated peptide (anti-CCP) (AOR 10·35, 95% CI 1·04-121·26, P = 0·047) were associated with AH-SLE, regardless of gender and duration of the disease. Smoking and SS were confirmed as predictors of AH-SLE. In the SLR, the prevalence of AITD ranged from 1% to 60%. The factors associated with this polyautoimmunity were female gender, older age, smoking, certain autoantibodies, SS, and cutaneous and articular involvement. Conclusions AITD is frequent in SLE and does not affect the severity of SLE. Identified risk factors will assist clinicians in the search for AITD. Our results encourage smoke-free policies in patients with SLE. © 2014 John Wiley and Sons Ltd.

Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed ?-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall ?-secretase activity levels, and therefore, loss of overall (endopeptidase) ?-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (?-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like ?-secretase activity with ?-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase- like ?-secretase activities. However and interestingly, a few SAD patient samples display ?-secretase dysfunction, suggesting that ?-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-ß (Aß) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aß products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations. © 2015 Szaruga et al.

Studies documenting increased risk of developing autoimmune diseases (ADs) have shown that these conditions share several immunogenetic mechanisms (i.e., the autoimmune tautology). This report explored familial aggregation and segregation of AD, polyautoimmunity, and multiple autoimmune syndrome (MAS) in 210 families. Familial aggregation was examined for first-degree relatives. Segregation analysis was implemented as in S.A.G.E. release 6.3. Data showed differences between late- and early-onset families regarding their age, age of onset, and sex. Familial aggregation of AD in late- and early-onset families was observed. For polyautoimmunity as a trait, only aggregation was observed between sibling pairs in late-onset families. No aggregation was observed for MAS. Segregation analyses for AD suggested major gene(s) with no clear discernible classical known Mendelian transmission in late-onset families, while for polyautoimmunity and MAS no model was implied. Data suggest that polyautoimmunity and MAS are not independent traits and that gender, age, and age of onset are interrelated factors influencing autoimmunity. © 2015 John Castiblanco et al.