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1. Constraints on the Dimensionality of Space

Author

Petway, C. A., Orlando, R. D., McNamara, A. M., Zweig, E. A., Caminada, B. C., Kincaid, E. J., Landgraf, C. V., Mohs, C. M., Schiff, M. L., and Fischbach, E.

Subjects
Physics - Classical Physics
Abstract

Complex structures can only form in a universe that allows for bound states. While this is clearly observed in three-dimensions, added degrees of freedom in a higher-dimensional space preclude the immediate assumption that binding potentials can in fact exist. In this paper, we derive a constraint on the dimensionality of a universe in the presence of an arbitrary set of forces. We then apply this constraint to systems with several example potentials. In doing so, we find that bound states in higher than 3 dimensions are in fact possible under specific circumstances which we characterize., Comment: 13 pages, 4 figures, added clarifying text and a new figure which shows an additional combination of forces

Published
2021
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2. From drug-delivery device to disease management tool: a study of preferences for enhanced features in next-generation self-injection devices

Author

Boeri M, Szegvari B, Hauber B, Mange B, Mountian I, Schiff M, and Maniadakis N

Subjects
Rheumatology, subcutaneous injection, self-administration, patient preference, discrete-choice experiment, Medicine (General), R5-920
Abstract

Marco Boeri,1 Boglarka Szegvari,2 Brett Hauber,3 Brennan Mange,3 Irina Mountian,2 Michael Schiff,4 Nikolaos Maniadakis51RTI Health Solutions, Belfast, UK; 2UCB Pharma, Brussels, Belgium; 3RTI Health Solutions, Research Triangle Park, NC, USA; 4Rheumatology Division, University of Colorado School of Medicine, Denver, CO, USA; 5Health Services Management, National School of Public Health, Athens, GreecePurpose: To quantify rheumatology patient preferences and willingness to pay (WTP) for features differentiating enhanced from standard self-injection devices and to investigate differences among subgroups.Patients and methods: Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) were recruited in the UK. A discrete-choice experiment was used to elicit preferences; respondents were presented with 10 choices between 3 different devices: a free standard disposable device, and 2 hypothetical reusable devices characterized by presence/absence of skin sensor, injection speed control, on-screen instructions, injection reminders, electronic log, and large grip. Every hypothetical device included a cost component to assess WTP for each enhanced feature. A random-parameters logit model was used to estimate preference weights and WTP.Results: Data were collected from 323 respondents by electronic survey (15/11/2017–15/02/2018; RA: 108; PsA: 103; axSpA: 112). On average, the skin sensor was the most preferred feature (£30), followed by injection speed control, injection reminders, electronic log (∼£20 each), on-screen instructions (∼£12), and a device with a small, rather than large grip (∼£7). Similar preferences for attributes were observed across condition subgroups except for grip size: axSpA patients preferred small grip (∼£27); PsA patients preferred large grip (∼£19). Overall, respondents preferred reusable devices with all enhanced features (WTP value: £85) over the standard device. RA patients exhibited a higher WTP (£145) than PsA (£102) or axSpA (£62) for the same enhanced device.Conclusion: Patients positively valued reusable self-injection devices with enhanced features, which may improve patient experience, potentially improving treatment adherence, clinical, and economic outcomes.Keywords: rheumatology, subcutaneous injection, self-administration, patient preference, discrete-choice experiment

Published
2019

3. Factors associated with contraceptive nonuse among obese and non-obese WOMEN

Author

Callegari, L, Prager, S, Schwarz, EB, and Schiff, M

Subjects
Biomedical and Clinical Sciences, Health Services and Systems, Clinical Sciences, Health Sciences, Reproductive Medicine, Paediatrics and Reproductive Medicine, Public Health and Health Services, Obstetrics & Reproductive Medicine, Clinical sciences, Reproductive medicine, Health services and systems
Published
2013

4. A novel role for the TIR domain in association with pathogen-derived elicitors

Author

Burch-Smith, TM, Schiff, M, Caplan, JL, Tsao, J, Czymmek, K, and Dinesh-Kumar, SP

Subjects
Amino Acid Sequence, Immunity, Innate, Plant Proteins, Plants, Polymerase Chain Reaction, Tobacco Mosaic Virus, Virulence, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Plant innate immunity is mediated by Resistance (R) proteins, which bear a striking resemblance to animal molecules of similar function. Tobacco N is a TIR-NB-LRR R gene that confers resistance to Tobacco mosaic virus, specifically the p50 helicase domain. An intriguing question is how plant R proteins recognize the presence of pathogen-derived Avirulence (Avr) elicitor proteins. We have used biochemical cell fraction and immunoprecipitation in addition to confocal fluorescence microscopy of living tissue to examine the association between N and p50. Surprisingly, both N and p50 are cytoplasmic and nuclear proteins, and N's nuclear localization is required for its function. We also demonstrate an in planta association between N and p50. Further, we show that N's TIR domain is critical for this association, and indeed, it alone can associate with p50. Our results differ from current models for plant innate immunity that propose detection is mediated solely through the LRR domains of these molecules. The data we present support an intricate process of pathogen elicitor recognition by R proteins involving multiple subcellular compartments and the formation of multiple protein complexes. © 2007 Burch-Smith et al.

Published
2007

5. Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

Author

Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., Wortmann, S.B., Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., and Wortmann, S.B.

Abstract

01 juni 2023, Item does not contain fulltext, PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Published
2023

6. A critical evaluation of the role of subcutaneous abatacept in the treatment of rheumatoid arthritis: patient considerations

Author

Wells AF, Jodat N, and Schiff M

Subjects
Medicine (General), R5-920
Abstract

Alvin F Wells,1,2 Nicole Jodat,1 Michael Schiff3 1Rheumatology and Immunotherapy Center, Franklin, WI, USA; 2Duke University Medical Center, Durham, NC, USA; 3University of Colorado, School of Medicine, Denver, CO, USA Abstract: There are now more therapeutic options for the treatment of rheumatoid arthritis (RA) than ever before, involving a range of mechanisms of action and different routes of administration. The T-cell costimulation modulator abatacept is the first biologic therapy for RA to be available in both subcutaneous (SC) and intravenous (IV) formulations. This review evaluates the utility of SC abatacept, with a particular focus on patient-reported outcomes, including physical function, pain, fatigue, and quality of life. Practical questions relating to the clinical use of SC abatacept are also addressed, including the relevance of abatacept's mechanism of action; whether IV and SC abatacept are comparable; if patients can easily switch from IV to SC abatacept; whether an IV loading dose is needed; and if temporary treatment interruptions or lack of concomitant methotrexate can affect efficacy or safety. Topics that are of particular concern to patients when using SC biologics, such as injection-site reactions, are also discussed. Observational data from registries and meta-analyses of clinical studies suggest comparable clinical efficacy between biologic disease-modifying antirheumatic drugs; however, such analyses rarely focus on key determinants of patient quality of life such as pain, fatigue, and physical function. The head-to-head AMPLE study is one of the first studies powered to directly compare two biologics in patients with RA. Patient-reported outcomes from year 1 of the ongoing study are evaluated, demonstrating comparable improvements in physical function, pain, fatigue, Short Form-36 Health Survey, and Routine Assessment of Patient Index Data 3 scores between SC abatacept and SC adalimumab when administered with concomitant methotrexate. In summary, the data presented herein show that the SC formulation of abatacept provides a valuable addition to the range of available therapy options for patients with RA, capable of significantly improving key patient considerations such as pain, disability, loss of function, fatigue, and quality of life. Keywords: rheumatoid arthritis, abatacept, subcutaneous, biologic DMARD, patient-reported outcomes

Published
2014

7. S230: HUMAN ΒETA-DEFENSIN 2 TREATMENT MODULATES THE INTESTINAL MICROBIOME AND THE ALLOGENEIC T CELL RESPONSE TO LIMIT ACUTE GRAFT-VERSUS-HOST DISEASE

Author

Rückert, T., primary, Andrieux, G., additional, Boerries, M., additional, Woessner, N. M., additional, Minguet, S., additional, Doetsch, S., additional, Aumann, K., additional, Schiff, M, additional, Braun, L. M., additional, Haring, E., additional, Siranosian, B. A., additional, Bhatt, A. S., additional, Nordkild, P., additional, Wehkamp, J., additional, Jensen, B. A. H., additional, Duyster, J., additional, Zeiser, R., additional, and Köhler, N., additional

Published
2022
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8. Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Author

Yverneau, M., Leroux, S., Imbard, A., Gleich, F., Arion, A., Moreau, C., Nassogne, M.C., Szymanowski, M., Tardieu, M., Touati, G., Bueno, M., Chapman, K.A., Chien, Y.H., Huemer, M., Ješina, P., Janssen, M.C.H., Kölker, S., Kožich, V., Lavigne, C., Lund, A.M., Mochel, F., Morris, A., Pons, M.R., Porras-Hurtado, G.L., Benoist, J.F., Damaj, L., Schiff, M., Yverneau, M., Leroux, S., Imbard, A., Gleich, F., Arion, A., Moreau, C., Nassogne, M.C., Szymanowski, M., Tardieu, M., Touati, G., Bueno, M., Chapman, K.A., Chien, Y.H., Huemer, M., Ješina, P., Janssen, M.C.H., Kölker, S., Kožich, V., Lavigne, C., Lund, A.M., Mochel, F., Morris, A., Pons, M.R., Porras-Hurtado, G.L., Benoist, J.F., Damaj, L., and Schiff, M.

Abstract

Item does not contain fulltext, MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.

Published
2022

9. Post-authorization safety study of Betaine anhydrous

Author

Mütze U, Gleich F, Garbade SF, Plisson C, Aldámiz-Echevarría L, Arrieta F, Ballhausen D, Zielonka M, Ramadža DP, Baumgartner MR, Cano A, Jiménez MCG, Dionisi-Vici C, Ješina P, Blom HJ, Couce ML, Olivas SM, Mention K, Mochel F, Morris AAM, Mundy H, Redonnet-Vernhet I, Santra S, Schiff M, Servais A, Vitoria I, Huemer M, Kožich V, and Kölker S

Subjects
homocystinuria, post-authorization safety study, Betaine anhydrous, rare disease, orphan drug, public private partnership, E-HOD
Abstract

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate post-authorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane®), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects (E-HOD) and the marketing authorization holder (MAH). Prospective data collection, 2013-2016, in a non-interventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. 130 individuals with vitamin B(6) non-responsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B(6) non-responsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 µmoL/L to 81 ± 51 µmoL/L (P < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals older than 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Published
2022

11. Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes

Author

Husain Ra, Thomas Meitinger, Wilichowski E, Robert Kopajtich, Smirnov D, Ewa Pronicka, Christine Makowski, Elżbieta Ciara, Michael Wagner, Felix Distelmaier, René Santer, Olsen R, Wolstein T, Theresa Brunet, Muller-Felber W, Buchner B, Wolfgang Sperl, Maja Hempel, Stefan Kölker, Dominic Lenz, Sarah L. Stenton, Saskia B. Wortmann, Leiz S, Kei Murayama, Munoz-Pujol G, Konstantopoulou, Xu M, Tobias B. Haack, Tim M. Strom, Riccardo Berutti, Tsygankova P, Lim Az, Daniele Ghezzi, Robert McFarland, Deen D, Kotzaeridou U, Daniela Karall, Ardissone A, Charlotte L. Alston, Markus Schuelke, Thomas Klopstock, Peter Freisinger, Robert W. Taylor, Ban R, Verloo P, van Coster R, Shimura M, Agnès Rötig, Dariusz Rokicki, Yepez, Mandel H, Akira Ohtake, Angela Pyle, Yasushi Okazaki, Mirjana Gusic, Antonia Ribes, Costanza Lamperti, Fang F, Holger Prokisch, von Kleist-Retzow J, Ivo Barić, Julien Gagneur, Bader Alhaddad, Dorota Piekutowska-Abramczuk, Johannes A. Mayr, Michael Zech, Frederic Tort, and Schiff M

Subjects
0303 health sciences, business.industry, Mitochondrial disease, Precision medicine, medicine.disease, Bioinformatics, Phenotype, 3. Good health, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, medicine, Functional studies, business, Gene, Mitochondrial protein, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

BackgroundThe spectrum of mitochondrial disease is genetically and phenotypically diverse, resulting from pathogenic variants in over 400 genes, with aerobic energy metabolism defects as a common denominator. Such heterogeneity poses a significant challenge in making an accurate diagnosis, critical for precision medicine.MethodsIn an international collaboration initiated by the European Network for Mitochondrial Diseases (GENOMIT) we recruited 2,023 pediatric patients at 11 specialist referral centers between October 2010 and January 2021, accumulating exome sequencing and HPO-encoded phenotype data. An exome-wide search for variants in known and potential novel disease genes, complemented by functional studies, followed ACMG guidelines.Results1,109 cases (55%) received a molecular diagnosis, of which one fifth have potential disease-modifying treatments (236/1,109, 21%). Functional studies enabled diagnostic uplift from 36% to 55% and discovery of 62 novel disease genes. Pathogenic variants were identified within genes encoding mitochondrial proteins or RNAs in 801 cases (72%), while, given extensive phenotype overlap, the remainder involved proteins targeted to other cellular compartments. To delineate genotype-phenotype associations, our data was complemented with registry and literature data to develop “GENOMITexplorer”, an open access resource detailing patient- (n=3,940), gene- (n=427), and variant-level (n=1,492) associations (prokischlab.github.io/GENOMITexplorer/).ConclusionsReaching a molecular diagnosis was essential for implementation of precision medicine and clinical trial eligibility, underlining the need for genome-wide screening given inability to accurately define mitochondrial diseases clinically. Key to diagnostic success were functional studies, encouraging early acquisition of patient- derived tissues and routine integration of high-throughput functional data to improve patient care by uplifting diagnostic rate.

Published
2021

12. Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea‐cycle disorders: On the basis of information from a European multicenter registry

Author

Molema, Femke, Gleich, Florian, Burgard, Peter, van der Ploeg, Ans T., Summar, Marshall L., Chapman, Kimberly A., Barić, Ivo, Lund, Allan M., Kölker, Stefan, Williams, Monique, Hörster, F., Jelsig, A.M., de Lonlay, P., Wijburg, F.A., Bosch, A., Freisinger, P., Posset, R., Augoustides‐Savvopoulou, P., Avram, P., Deleanu, C., Baumgartner, M.R., Häberle, J., Blasco‐ Alonso, J., Burlina, A.B., Rubert, L., Cazorla, A. Garcia, Saladelafont, E. Cortes i, Dionisi‐ Vici, C., Martinelli, D., Dobbelaere, D., Mention, K., Grünewald, S., Chakrapani, A., Hwu, Wuh‐Liang, Chien, Yin‐Hsiu, Lee, Ni‐Chung, Karall, D., Scholl‐Bürgi, S., Lachmann, R., De Laet, C., Matsumoto, S., de Meirleir, L., Mühlhausen, C., Schiff, M., Peña‐Quintana, L., Djordjevic, M., Sarajlija, A., Sykut‐Cegielska, J., Wisniewska, A., Leao‐Teles, E., Alves, S., Vara, R., Vives‐Pinera, I., Ortega, D.G., Morris, A., Zeman, J., Honzik, T., Chabrol, B., Arnaudo, F., Cano, A., Thompson, N., Eyskens, F., Lindner, M., Lüsebrink, N., Jalan, A., Sokal, E., Legros, V., Nassogne, M.C., Additional individual contributors from E‐IMD, Pediatrics, Paediatric Metabolic Diseases, AGEM - Inborn errors of metabolism, ARD - Amsterdam Reproduction and Development, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), and E-IMD

Subjects
Adult, Male, Ornithine, medicine.medical_specialty, Propionic Acidemia, Adolescent, organic acidurias, Protein metabolism, Ornithine transcarbamylase, amino acid mixtures, Gastroenterology, Reference Daily Intake, Young Adult, chemistry.chemical_compound, Valine, Internal medicine, Genetics, medicine, Humans, Hyperammonemia, dietary and supplemental treatment, Registries, Amino Acids, branched-chain amino acids, Child, Amino Acid Metabolism, Inborn Errors, Urea Cycle Disorders, Inborn, Genetics (clinical), Retrospective Studies, L-citrulline and L-arginine, business.industry, urea-cycle disorders, Infant, Europe, Cross-Sectional Studies, Treatment Outcome, chemistry, Methylmalonic aciduria, Child, Preschool, Urea cycle, Dietary Supplements, Feasibility Studies, Female, Human medicine, Leucine, business
Abstract

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.

Published
2019

14. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Author

Posset, R. (Roland), Garbade, S.F. (Sven), Gleich, F. (Florian), Gropman, A.L. (Andrea L.), Lonlay, P. (Pascale) de, Hoffmann, G.F. (Georg), Garcia-Cazorla, A. (Angeles), Nagamani, S.C.S. (Sandesh C. S.), Baumgartner, M.R. (Matthias), Schulze, A. (Andreas), Dobbelaere, D. (Dries), Yudkoff, M. (Marc), Kölker, S. (Stefan), Zielonka, M. (Matthias), Ah Mew, N. (Nicholas), Berry, S.A. (Susan A.), McCandless, S.E. (Shawn E.), Coughlin, C. (Curtis), Enns, G. (Gregory), Gallagher, R.C. (Renata C.), Burrage, L.C. (Lindsay C.), Seminara, J. (Jennifer), Harding, C.O. (Cary O.), Burgard, P. (Peter), Le Mons, C. (Cynthia), Merritt, J.L. (J. Lawrence), Stricker, T. (Tamar), Bedoyan, J. (Jirair), Berry, G.T. (Gerard T.), Diaz, G.A. (George A.), Wong, D. (Derek), Tuchman, M. (Mendel), Waisbren, S. (Susan), Weisfeld-Adams, J.D. (James D), Burlina, A.B. (Alberto), Leão Teles, E. (Elisa), Pedrón-Giner, C. (Consuelo), Lund, A.M. (Allan M.), Dionisi-Vici, C. (Carlo), Williams, M. (Monique), Mütze, U. (Ulrike), Karall, D. (Daniela), Blasco-Alonso, J. (Javier), Couce, M.L. (Maria L.), Sykut-Cegielska, J. (Jolanta), Augoustides-Savvopoulou, P. (Persa), Ruiz Gomez, A. (Angeles), Barić, I. (Ivo), Schiff, M. (Manuel), Chien, Y.-H. (Yin-Hsiu), Lindner, M. (Martin), Chabrol, B. (Brigitte), Skouma, A. (Anastasia), Zeman, J. (Jiri), Sokal, E. (Etienne), Santer, R. (Rene), Eyskens, F. (François), Freisinger, P. (Peter), Peña-Quintana, L. (Luis), Roland, D. (Dominique), Cortès-Saladelafont, E. (Elisenda), Djordjevic, M. (Maja), Posset, R. (Roland), Garbade, S.F. (Sven), Gleich, F. (Florian), Gropman, A.L. (Andrea L.), Lonlay, P. (Pascale) de, Hoffmann, G.F. (Georg), Garcia-Cazorla, A. (Angeles), Nagamani, S.C.S. (Sandesh C. S.), Baumgartner, M.R. (Matthias), Schulze, A. (Andreas), Dobbelaere, D. (Dries), Yudkoff, M. (Marc), Kölker, S. (Stefan), Zielonka, M. (Matthias), Ah Mew, N. (Nicholas), Berry, S.A. (Susan A.), McCandless, S.E. (Shawn E.), Coughlin, C. (Curtis), Enns, G. (Gregory), Gallagher, R.C. (Renata C.), Burrage, L.C. (Lindsay C.), Seminara, J. (Jennifer), Harding, C.O. (Cary O.), Burgard, P. (Peter), Le Mons, C. (Cynthia), Merritt, J.L. (J. Lawrence), Stricker, T. (Tamar), Bedoyan, J. (Jirair), Berry, G.T. (Gerard T.), Diaz, G.A. (George A.), Wong, D. (Derek), Tuchman, M. (Mendel), Waisbren, S. (Susan), Weisfeld-Adams, J.D. (James D), Burlina, A.B. (Alberto), Leão Teles, E. (Elisa), Pedrón-Giner, C. (Consuelo), Lund, A.M. (Allan M.), Dionisi-Vici, C. (Carlo), Williams, M. (Monique), Mütze, U. (Ulrike), Karall, D. (Daniela), Blasco-Alonso, J. (Javier), Couce, M.L. (Maria L.), Sykut-Cegielska, J. (Jolanta), Augoustides-Savvopoulou, P. (Persa), Ruiz Gomez, A. (Angeles), Barić, I. (Ivo), Schiff, M. (Manuel), Chien, Y.-H. (Yin-Hsiu), Lindner, M. (Martin), Chabrol, B. (Brigitte), Skouma, A. (Anastasia), Zeman, J. (Jiri), Sokal, E. (Etienne), Santer, R. (Rene), Eyskens, F. (François), Freisinger, P. (Peter), Peña-Quintana, L. (Luis), Roland, D. (Dominique), Cortès-Saladelafont, E. (Elisenda), and Djordjevic, M. (Maja)

Abstract

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.

Published
2020
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15. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Author

Posset, R, Garbade, SF, Gleich, F, Gropman, AL, de Lonlay, P, Hoffmann, GF, Garcia-Cazorla, A, Nagamani, SCS, Baumgartner, MR, Schulze, A, Dobbelaere, D, Yudkoff, M, Kölker, S, Zielonka, M, Ah Mew, N, Berry, SA, McCandless, SE, Coughlin, C, Enns, G, Gallagher, RC, Burrage, LC, Seminara, J, Harding, CO, Burgard, P, Le Mons, C, Merritt, JL, II, Stricker, T, Bedoyan, JK, Berry, GT, Diaz, GA, Wong, D, Tuchman, M, Waisbren, S, Weisfeld-Adams, JD, Burlina, AB, Leão Teles, E, Pedrón-Giner, C, Lund, AM, Dionisi-Vici, C, Williams, Monique, Mütze, U, Karall, D, Blasco-Alonso, J, Couce, ML, Sykut-Cegielska, J, Augoustides-Savvopoulou, P, Ruiz Gomez, A, Bari?, I, Schiff, M, Chien, YH, Lindner, M, Chabrol, B, Skouma, A, Zeman, J, Sokal, E, Santer, R, Eyskens, F, Freisinger, P, Peña-Quintana, L, Roland, D, Cortès-Saladelafont, E, Djordjevic, M, Posset, R, Garbade, SF, Gleich, F, Gropman, AL, de Lonlay, P, Hoffmann, GF, Garcia-Cazorla, A, Nagamani, SCS, Baumgartner, MR, Schulze, A, Dobbelaere, D, Yudkoff, M, Kölker, S, Zielonka, M, Ah Mew, N, Berry, SA, McCandless, SE, Coughlin, C, Enns, G, Gallagher, RC, Burrage, LC, Seminara, J, Harding, CO, Burgard, P, Le Mons, C, Merritt, JL, II, Stricker, T, Bedoyan, JK, Berry, GT, Diaz, GA, Wong, D, Tuchman, M, Waisbren, S, Weisfeld-Adams, JD, Burlina, AB, Leão Teles, E, Pedrón-Giner, C, Lund, AM, Dionisi-Vici, C, Williams, Monique, Mütze, U, Karall, D, Blasco-Alonso, J, Couce, ML, Sykut-Cegielska, J, Augoustides-Savvopoulou, P, Ruiz Gomez, A, Bari?, I, Schiff, M, Chien, YH, Lindner, M, Chabrol, B, Skouma, A, Zeman, J, Sokal, E, Santer, R, Eyskens, F, Freisinger, P, Peña-Quintana, L, Roland, D, Cortès-Saladelafont, E, and Djordjevic, M

Published
2020

16. Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease‐Modifying Antirheumatic Drug Treatment

Author

Fleischmann, R., Schiff, M., Heijde, D. van der, Ramos-Remus, C., Spindler, A., Stanislav, M., Zerbini, C.A.F., Gurbuz, S., Dickson, C., Bono, S. de, Schlichting, D., Beattie, S., Kuo, W.L., Rooney, T., Macias, W., and Takeuchi, T.

Subjects
musculoskeletal diseases, Male, Sulfonamides, Rheumatoid Arthritis, Middle Aged, Arthritis, Rheumatoid, Methotrexate, Double-Blind Method, immune system diseases, Purines, Antirheumatic Agents, Azetidines, Humans, Pyrazoles, Drug Therapy, Combination, Female, skin and connective tissue diseases
Abstract

Objective We undertook this phase III study to evaluate baricitinib, an orally administered JAK‐1/JAK‐2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs. Methods A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24. Results The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment‐emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX. Conclusion Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.

Published
2017

17. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up

Author

Altassan, R., Peanne, R., Jaeken, J., Barone, R., Bidet, M., Borgel, D., Brasil, S., Cassiman, D., Cechova, A., Coman, D., Corral, J., Correia, J., Morena-Barrio, M.E. de la, Lonlay, P. de, Reis, V. Dos, Ferreira, C.R., Fiumara, A., Francisco, R., Freeze, H., Funke, S., Gardeitchik, T., Gert, M., Girad, M., Giros, M., Grunewald, S., Hernandez-Caselles, T., Honzik, T., Hutter, M., Krasnewich, D., Lam, C., Lee, J., Lefeber, D.J., Marques-de-Silva, D., Martinez, A.F., Moravej, H., Ounap, K., Pascoal, C., Pascreau, T., Patterson, M., Quelhas, D., Raymond, K., Sarkhail, P., Schiff, M., Seroczynska, M., Serrano, M., Seta, N., Sykut-Cegielska, J., Thiel, C, Tort, F., Vals, M.A., Videira, P., Witters, P., Zeevaert, R., Morava, E., Altassan, R., Peanne, R., Jaeken, J., Barone, R., Bidet, M., Borgel, D., Brasil, S., Cassiman, D., Cechova, A., Coman, D., Corral, J., Correia, J., Morena-Barrio, M.E. de la, Lonlay, P. de, Reis, V. Dos, Ferreira, C.R., Fiumara, A., Francisco, R., Freeze, H., Funke, S., Gardeitchik, T., Gert, M., Girad, M., Giros, M., Grunewald, S., Hernandez-Caselles, T., Honzik, T., Hutter, M., Krasnewich, D., Lam, C., Lee, J., Lefeber, D.J., Marques-de-Silva, D., Martinez, A.F., Moravej, H., Ounap, K., Pascoal, C., Pascreau, T., Patterson, M., Quelhas, D., Raymond, K., Sarkhail, P., Schiff, M., Seroczynska, M., Serrano, M., Seta, N., Sykut-Cegielska, J., Thiel, C, Tort, F., Vals, M.A., Videira, P., Witters, P., Zeevaert, R., and Morava, E.

Abstract

Contains fulltext : 203022.pdf (publisher's version ) (Closed access), Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.

Published
2019

19. Inferring the long duration response to levodopa in Parkinson's disease.

Author

Clissold B.G., Kempster P.A., Schiff M., Reardon K.A., Nagao K., McColl C.D., Ding C., Ganga G., Alty J.E., Clissold B.G., Kempster P.A., Schiff M., Reardon K.A., Nagao K., McColl C.D., Ding C., Ganga G., and Alty J.E.

Abstract

Introduction: The long duration response to levodopa in Parkinson's disease outlasts drug elimination by days to weeks. Though a substantive part of anti-parkinsonian motor benefit, it cannot easily be observed. Objective(s): To infer the magnitude of the long duration response during the first decade of Parkinson's disease and identify factors that influence it. Method(s): Serial practically defined off scores of 24 patients from a longitudinal study of levodopa short duration response were used to establish their rate of motor progression. A line of notional untreated disability (as if drug treatment had never been given) with the same progression gradient was the basis for calculation of the long duration response. Predictors of mean long duration response amplitude were identified using a multiple linear regression model. Result(s): Over a mean treatment period of 16.6 +/- 4.4 years, annual increase in motor disability was 2.3% of the maximum score. The long duration response composed 49% of total levodopa response during the first decade of treatment, and this proportion was significantly higher soon after commencing levodopa (p = 0.001). Higher pre-treatment motor score (r = 0.60) and lower MMSE (r = 0.60) were the main predictors of a larger long duration response. There was little correlation between long and short duration responses. Conclusion(s): Long duration responses contribute almost half of the total levodopa benefit during the first decade of treatment. An appreciation of both long and short duration components of drug symptomatic effects is important in clinical trial design to investigate possible neuroprotective treatments.Copyright © 2018 Elsevier Ltd

Published
2019

25. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry

Author

Huemer, M. Diodato, D. Martinelli, D. Olivieri, G. Blom, H. Gleich, F. Kölker, S. Kožich, V. Morris, A.A. Seifert, B. Froese, D.S. Baumgartner, M.R. Dionisi-Vici, C. Martin, C.A. Baethmann, M. Ballhausen, D. Blasco-Alonso, J. Boy, N. Bueno, M. Burgos Peláez, R. Cerone, R. Chabrol, B. Chapman, K.A. Couce, M.L. Crushell, E. Dalmau Serra, J. Diogo, L. Ficicioglu, C. García Jimenez, M.C. García Silva, M.T. Gaspar, A.M. Gautschi, M. González-Lamuño, D. Gouveia, S. Grünewald, S. Hendriksz, C. Janssen, M.C.H. Jesina, P. Koch, J. Konstantopoulou, V. Lavigne, C. Lund, A.M. Martins, E.G. Meavilla Olivas, S. Mention, K. Mochel, F. Mundy, H. Murphy, E. Paquay, S. Pedrón-Giner, C. Ruiz Gómez, M.A. Santra, S. Schiff, M. Schwartz, I.V. Scholl-Bürgi, S. Servais, A. Skouma, A. Tran, C. Vives Piñera, I. Walter, J. Weisfeld-Adams, J. the EHOD consortium

Abstract

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design. © 2018 SSIEM

Published
2018

28. Dicken, Paul. Getting science wrong: why the philosophy of science matters

Author

Schiff, M.

Subjects
Getting Science Wrong: Why the Philosophy of Science Matters (Nonfiction work) -- Dicken, Paul -- Book reviews, Library and information science, Literature/writing
Abstract

Dicken, Paul. Getting science wrong: why the philosophy of science matters. Bloomsbury, 2018. 202p bibl index ISBN 9781350007277 cloth, $68.00; ISBN 9781350007284 pbk, $22.95; ISBN 9781350007291 ebook, contact publisher for [...]

Published
2018

30. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Author

Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), Wortmann, S.B. (S.), Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), and Wortmann, S.B. (S.)

Abstract

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and s

Published
2018
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31. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Author

Repp, B, Mastantuono, E, Alston, C, Schiff, M, Haack, T, Rötig, A, Ardissone, A, Lombès, A, Catarino, C, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Wenhong, D, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, H, Wittig, I, Scurr, I, De Coo, I, Moroni, I, Smet, J, Mayr, J, Dai, L, De Meirleir, L, Schuelke, M, Zeviani, M, Morscher, R, Mcfarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, T, Herberg, U, Ahting, U, Sperl, W, Nassogne, M, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, R, Häberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, Birgit M., Mastantuono, Elisa, Alston, Charlotte L., Schiff, Manuel, Haack, Tobias B., Rötig, Agnes, Ardissone, Anna, Lombès, Anne, Catarino, Claudia B., Diodato, Daria, Schottmann, Gudrun, Poulton, Joanna, Burlina, Alberto, Jonckheere, An, Munnich, Arnold, Rolinski, Boris, Ghezzi, Daniele, Rokicki, Dariusz, Wellesley, Diana, Martinelli, Diego, Wenhong, Ding, Lamantea, Eleonora, Ostergaard, Elsebet, Pronicka, Ewa, Pierre, Germaine, Smeets, Hubert J. M., Wittig, Ilka, Scurr, Ingrid, De Coo, Irenaeus F. M., Moroni, Isabella, Smet, Joél, Mayr, Johannes A., Dai, Lifang, De Meirleir, Linda, Schuelke, Markus, Zeviani, Massimo, Morscher, Raphael J., McFarland, Robert, Seneca, Sara, Klopstock, Thomas, Meitinger, Thomas, Wieland, Thomas, Strom, Tim M., Herberg, Ulrike, Ahting, Uwe, Sperl, Wolfgang, Nassogne, Marie-Cecile, Ling, Han, Fang, Fang, Freisinger, Peter, Van Coster, Rudy, Strecker, Valentina, Taylor, Robert W., Häberle, Johannes, Vockley, Jerry, Prokisch, Holger, Wortmann, Saskia, Repp, B, Mastantuono, E, Alston, C, Schiff, M, Haack, T, Rötig, A, Ardissone, A, Lombès, A, Catarino, C, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Wenhong, D, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, H, Wittig, I, Scurr, I, De Coo, I, Moroni, I, Smet, J, Mayr, J, Dai, L, De Meirleir, L, Schuelke, M, Zeviani, M, Morscher, R, Mcfarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, T, Herberg, U, Ahting, U, Sperl, W, Nassogne, M, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, R, Häberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, Birgit M., Mastantuono, Elisa, Alston, Charlotte L., Schiff, Manuel, Haack, Tobias B., Rötig, Agnes, Ardissone, Anna, Lombès, Anne, Catarino, Claudia B., Diodato, Daria, Schottmann, Gudrun, Poulton, Joanna, Burlina, Alberto, Jonckheere, An, Munnich, Arnold, Rolinski, Boris, Ghezzi, Daniele, Rokicki, Dariusz, Wellesley, Diana, Martinelli, Diego, Wenhong, Ding, Lamantea, Eleonora, Ostergaard, Elsebet, Pronicka, Ewa, Pierre, Germaine, Smeets, Hubert J. M., Wittig, Ilka, Scurr, Ingrid, De Coo, Irenaeus F. M., Moroni, Isabella, Smet, Joél, Mayr, Johannes A., Dai, Lifang, De Meirleir, Linda, Schuelke, Markus, Zeviani, Massimo, Morscher, Raphael J., McFarland, Robert, Seneca, Sara, Klopstock, Thomas, Meitinger, Thomas, Wieland, Thomas, Strom, Tim M., Herberg, Ulrike, Ahting, Uwe, Sperl, Wolfgang, Nassogne, Marie-Cecile, Ling, Han, Fang, Fang, Freisinger, Peter, Van Coster, Rudy, Strecker, Valentina, Taylor, Robert W., Häberle, Johannes, Vockley, Jerry, Prokisch, Holger, and Wortmann, Saskia

Abstract

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.

Published
2018

32. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Author

Repp, BM, Mastantuono, E, Alston, CL, Schiff, M, Haack, TB, Rotig, A, Ardissone, A, Lombes, A, Catarino, CB, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Ding, WH, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, HJM, Wittig, I, Scurr, I, Coo, IFM, Moroni, I, Smet, J, Mayr, JA, Dai, LF, de Meirleir, L, Schuelke, M, Zeviani, M, Morscher, RJ, McFarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, TM, Herberg, U, Ahting, U, Sperl, W, Nassogne, MC, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, RW, Haberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, BM, Mastantuono, E, Alston, CL, Schiff, M, Haack, TB, Rotig, A, Ardissone, A, Lombes, A, Catarino, CB, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Ding, WH, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, HJM, Wittig, I, Scurr, I, Coo, IFM, Moroni, I, Smet, J, Mayr, JA, Dai, LF, de Meirleir, L, Schuelke, M, Zeviani, M, Morscher, RJ, McFarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, TM, Herberg, U, Ahting, U, Sperl, W, Nassogne, MC, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, RW, Haberle, J, Vockley, J, Prokisch, H, and Wortmann, S

Published
2018

33. Ekeberg, Bjorn. Metaphysical experiments: physics and the invention of the universe

Author

Schiff, M.

Subjects
Metaphysical Experiments: Physics and the Invention of the Universe (Textbook) -- Ekeberg, Bjorn -- Book reviews, Library and information science, Literature/writing
Abstract

Ekeberg, Bjorn. Metaphysical experiments: physics and the invention of the universe. Minnesota, 2019. 198p bibl index (Posthumanities, 49) ISBN 9781517905699 cloth, $100.00; ISBN 9781517905705 pbk, $25.00; ISBN 9781452959504 ebook, contact [...]

Published
2019

34. Feke, Jacqueline. Ptolemy's philosophy: mathematics as a way of life

Author

Schiff, M.

Subjects
Ptolemy's Philosophy: Mathematics as a Way of Life (Nonfiction work) -- Feke, Jacqueline -- Book reviews, Library and information science, Literature/writing
Abstract

Feke, Jacqueline. Ptolemy's philosophy: mathematics as a way of life. Princeton, 2018. 234p bibl index ISBN 9780691179582 cloth, $39.50; ISBN 9780691184036 ebook, contact publisher for price 56-2760 QA8 MARC Claudius [...]

Published
2019

36. Correction to: Impact of age at onset and newborn screening on outcome in organic acidurias

Author

Heringer, J. (Jana), Valayannopoulos, V. (Vassili), Lund, A.M. (Allan), Wijburg, F.A. (Frits), Freisinger, P. (Peter), Barić, I. (Ivo), Baumgartner, M.R. (Matthias), Burgard, P. (Peter), Burlina, A.B. (Alberto), Chapman, K. (Kimberly), Cortès i Saladelafont, E. (Elisenda), Karall, D. (Daniela), Mühlhausen, C. (Chris), Riches, V. (Victoria), Schiff, M. (Manuel), Sykut-Cegielska, J. (Jolanta), Walter, J.H. (John), Zeman, J. (Jiri), Chabrol, B. (Brigitte), Kölker, S. (Stefan), Heringer, J. (Jana), Valayannopoulos, V. (Vassili), Lund, A.M. (Allan), Wijburg, F.A. (Frits), Freisinger, P. (Peter), Barić, I. (Ivo), Baumgartner, M.R. (Matthias), Burgard, P. (Peter), Burlina, A.B. (Alberto), Chapman, K. (Kimberly), Cortès i Saladelafont, E. (Elisenda), Karall, D. (Daniela), Mühlhausen, C. (Chris), Riches, V. (Victoria), Schiff, M. (Manuel), Sykut-Cegielska, J. (Jolanta), Walter, J.H. (John), Zeman, J. (Jiri), Chabrol, B. (Brigitte), and Kölker, S. (Stefan)

Abstract

Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.

Published
2017
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37. Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases

Author

Maas, RR, Iwanicka-Pronicka, K, Ucar, SK, Alhaddad, B, AlSayed, M, Al-Owain, MA, Al-Zaidan, HI, Balasubramaniam, S, Baric, I, Bubshait, DK, Burlina, A, Christodoulou, J, Chung, WK, Colombo, R, Darin, N, Freisinger, P, Garcia Silva, MT, Grunewald, S, Haack, TB, van Hasselt, PM, Hikmat, O, Hoerster, F, Isohanni, P, Ramzan, K, Kovacs-Nagy, R, Krumina, Z, Martin-Hernandez, E, Mayr, JA, McClean, P, De Meirleir, L, Naess, K, Ngu, LH, Pajdowska, M, Rahman, S, Riordan, G, Riley, L, Roeben, B, Rutsch, F, Santer, R, Schiff, M, Seders, M, Sequeira, S, Sperl, W, Staufner, C, Synofzik, M, Taylor, RW, Trubicka, J, Tsiakas, K, Unal, O, Wassmer, E, Wedatilake, Y, Wolff, T, Prokisch, H, Morava, E, Pronicka, E, Wevers, RA, de Brouwer, AP, Wortmann, SB, Maas, RR, Iwanicka-Pronicka, K, Ucar, SK, Alhaddad, B, AlSayed, M, Al-Owain, MA, Al-Zaidan, HI, Balasubramaniam, S, Baric, I, Bubshait, DK, Burlina, A, Christodoulou, J, Chung, WK, Colombo, R, Darin, N, Freisinger, P, Garcia Silva, MT, Grunewald, S, Haack, TB, van Hasselt, PM, Hikmat, O, Hoerster, F, Isohanni, P, Ramzan, K, Kovacs-Nagy, R, Krumina, Z, Martin-Hernandez, E, Mayr, JA, McClean, P, De Meirleir, L, Naess, K, Ngu, LH, Pajdowska, M, Rahman, S, Riordan, G, Riley, L, Roeben, B, Rutsch, F, Santer, R, Schiff, M, Seders, M, Sequeira, S, Sperl, W, Staufner, C, Synofzik, M, Taylor, RW, Trubicka, J, Tsiakas, K, Unal, O, Wassmer, E, Wedatilake, Y, Wolff, T, Prokisch, H, Morava, E, Pronicka, E, Wevers, RA, de Brouwer, AP, and Wortmann, SB

Abstract

OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.

Published
2017

39. Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency

Author

Olsen, R. K., Konarikova, E., Giancaspero, T. A., Mosegaard, S., Boczonadi, V., Matakovic, L., Veauville-Merllie, A., Terrile, C., Schwarzmayr, T., Haack, T. B., Auranen, M., Leone, P., Galluccio, M., Imbard, A., Gutierrez-Rios, P., Palmfeldt, J., Graf, E., Vianey-Saban, Christine, Oppenheim, M., Schiff, M., Pichard, S., Rigal, O., Pyle, A., Chinnery, P. F., Konstantopoulou, V., Moslinger, D., Feichtinger, R. G., Talim, B., Topaloglu, H., Coskun, T., Gucer, S., Botta, A., Pegoraro, E., Malena, A., Vergani, L., Mazza, D., Zollino, M., Ghezzi, D., Acquaviva, C., Tyni, T., Boneh, A., Meitinger, T., Strom, T. M., Gregersen, N., Mayr, J. A., Horvath, R., Barile, M., Prokisch, H., Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Clinicum, Neurologian yksikkö, Children's Hospital, Lastenneurologian yksikkö, HUS Children and Adolescents, and Pillet, Lauriane

Subjects
Male, Mitochondrial Diseases, Genetics, Genetics (clinical), Riboflavin, [SDV]Life Sciences [q-bio], Messenger, Settore MED/03 - GENETICA MEDICA, DISEASE, FUNCTIONAL-CHARACTERIZATION, MITOCHONDRIA, Site-Directed, Genetics(clinical), heterocyclic compounds, Frameshift Mutation, Multiple Acyl Coenzyme A Dehydrogenase Deficiency, Cells, Cultured, Skin, Cultured, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Skeletal, Nucleotidyltransferases, [SDV] Life Sciences [q-bio], Liver, ESCHERICHIA-COLI, Adult, Blotting, Western, Case-Control Studies, Electron Transport, Female, Fibroblasts, Flavin-Adenine Dinucleotide, Gene Expression Profiling, Humans, Infant, Infant, Newborn, Muscle, Skeletal, Mutagenesis, Site-Directed, Protein Binding, RNA, Messenger, Real-Time Polymerase Chain Reaction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Vitamin B Complex, Young Adult, Muscle, Western, Cells, Article, VIALETTO-VAN LAERE, Matrix-Assisted Laser Desorption-Ionization, COFACTORS, Spectrometry, ISOFORM 2, Mass, Newborn, ELECTRON-TRANSFER FLAVOPROTEIN, OVER-EXPRESSION, enzymes and coenzymes (carbohydrates), Mutagenesis, RNA, bacteria, 3111 Biomedicine, SYNTHETASE
Abstract

International audience; Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.

Published
2016

40. Impact of age at onset and newborn screening on outcome in organic acidurias

Author

Heringer, J, Valayannopoulos, V, Lund, AM, Wijburg, FA, Freisinger, P, Baric, I, Baumgartner, MR, Burgard, P, Burlina, AB, Chapman, K A, Saladelafont, ECI, Karall, D, Muhlhausen, C, Riches, V, Schiff, M, Sykut-Cegielska, J, Walter, JH, Zeman, J, Williams, Monique, Chabrol, B, Kolker, S, Pediatrics, Paediatric Metabolic Diseases, Reproduction and Genetics, Neurogenetics, and Clinical sciences

Subjects
0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Methylmalonic acid, Late onset, Glutaric aciduria type 1, 030105 genetics & heredity, Asymptomatic, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Neonatal Screening, Metabolic Diseases, Intellectual Disability, Genetics, Journal Article, Medicine, Humans, Young adult, Age of Onset, Child, Amino Acid Metabolism, Inborn Errors, Genetics (clinical), Newborn screening, Glutaryl-CoA Dehydrogenase, business.industry, Brain Diseases, Metabolic, Infant, Newborn, Brain Diseases, Metabolic, Inborn, Infant, food and beverages, Odds ratio, Middle Aged, medicine.disease, Vitamin B 12, chemistry, Child, Preschool, Female, Amino Acid Transport Disorders, Inborn, Age of onset, medicine.symptom, business, 030217 neurology & neurosurgery, Methylmalonic Acid
Abstract

BACKGROUND AND AIM: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. METHODS: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). RESULTS: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p

Published
2016

41. Angine

Author

Alexandre, J., Balian, A., Bensoussan, L., Chaïb, A., Gridel, G., Kinugawa, K., Lamazou, F., Lim-Sabbah, I., Mink, V., Planquette, B., Rouprêt, M., Rousseau, M.-A., Roze, E., Salama, S., Schiff, M., Simon, D., Skurnik, D., and Soria, A.

Subjects
Article
Published
2011

42. Reid, Thomas. Thomas Reid on mathematics and natural philosophy

Author

Schiff, M.

Subjects
Thomas Reid on Mathematics and Natural Philosophy, ed. by Paul Wood (Collection) -- Reid, Thomas -- Wood, Paul -- Book reviews, Library and information science, Literature/writing
Abstract

Reid, Thomas. Thomas Reid on mathematics and natural philosophy, ed. by Paul Wood. Pennsylvania State, 2017. 318p bibl indexes (The Edinburgh edition of Thomas Reid, 9) ISBN 9780271078496 cloth, $199.95 [...]

Published
2018

43. Baricitinib, Methotrexate, or Baricitinib Plus Methotrexate in Patients with Early Rheumatoid Arthritis Who Had Received Limited or No Treatment with Disease-Modifying Anti-Rheumatic Drugs (DMARDs): Phase 3 Trial Results

Author

Fleischmann, R, Takeuchi, T, Schlichting, D, Macias, W, Rooney, T, Gurbuz, S, Stoykov, I, Beattie, S, Kuo, WL, Schiff, M, Kekow, J, Fleischmann, R, Takeuchi, T, Schlichting, D, Macias, W, Rooney, T, Gurbuz, S, Stoykov, I, Beattie, S, Kuo, WL, Schiff, M, and Kekow, J

Published
2016

44. Study of levodopa response in Parkinson's disease: Observations on rates of motor progression

Author

Ding, C, Ganesvaran, G, Alty, JE, Clissold, BG, McColl, CD, Reardon, KA, Schiff, M, Srikanth, V, Kempster, PA, Ding, C, Ganesvaran, G, Alty, JE, Clissold, BG, McColl, CD, Reardon, KA, Schiff, M, Srikanth, V, and Kempster, PA

Abstract

INTRODUCTION: It is important to understand how the rate of motor progression in PD relates to dopaminergic treatment. METHODS: The methods for this study comprised prospective defined off state measurements of the levodopa response at 3-year intervals over a mean 13.3-year period in 34 patients enrolled before treatment initiation. RESULTS: Despite worsening of on and off scores, the magnitude of the l-dopa short-duration response is maintained as the disease progresses. A linear mixed-effects regression analysis of off phase motor scores showed a yearly deterioration of 2.3% of the maximum disability score. Greater motor disability at the commencement of treatment was an independent predictor of faster progression. Demented patients had worse motor function than those without dementia (P = 0.02), and motor deficit appeared to accelerate toward the end of the disease course in patients who had died. CONCLUSIONS: These observations should inform clinical trial design for drugs with possible neuroprotective properties.

Published
2016

45. Association of radiographic outcomes with low disease activity and remission, and sustainability of response with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial

Author

Fleischmann, R, Schiff, M, Weinblatt, M, Maldonado, M, Massarotti, E, Fay, J, and Yazici, Y

Subjects
musculoskeletal diseases, abatacept, ddc: 610, 610 Medical sciences, Medicine, radiographic outcomes
Abstract

Background: Remission and low disease activity (LDA) are now more achievable goals in RA. Data from the AMPLE trial showed comparable rates of remission and LDA for patients treated with subcutaneous (SC) abatacept or adalimumab [ref:1], [ref:2]. We evaluated the relationship of [for full text, please go to the a.m. URL], 42. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 28. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 24. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Published
2014
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46. The limits of science: an analysis from 'barriers' to 'confines'

Author

Schiff, M.

Subjects
The Limits of Science: An Analysis from 'Barriers' to 'Confines' (Essay collection) -- Gonzalez, Wenceslao J. -- Book reviews, Library and information science, Literature/writing
Abstract

54-3709 Q175 2016-28031 CIP The limits of science: an analysis from 'barriers' to 'confines,' ed. by Wenceslao J. Gonzalez. Brill Rodopl, 2016. 216p bibl indexes afp (Poznan studies in the [...]

Published
2017

48. Eyes on MEGDEL: Distinctive Basal Ganglia Involvement in Dystonia Deafness Syndrome

Author

Wortmann, S.B., Hasselt, P.M. van, Baric, I., Burlina, A., Darin, N., Horster, F., Coker, M., Ucar, S. Kalkan, Krumina, Z., Naess, K., Ngu, L.H., Pronicka, E., Riordan, G., Santer, R., Wassmer, E., Zschocke, J., Schiff, M., Meirleir, L. de, Alowain, M.A., Smeitink, J.A.M., Morava, E., Kozicz, L.T., Wevers, R.A., Wolf, N.I., Willemsen, M.A., Wortmann, S.B., Hasselt, P.M. van, Baric, I., Burlina, A., Darin, N., Horster, F., Coker, M., Ucar, S. Kalkan, Krumina, Z., Naess, K., Ngu, L.H., Pronicka, E., Riordan, G., Santer, R., Wassmer, E., Zschocke, J., Schiff, M., Meirleir, L. de, Alowain, M.A., Smeitink, J.A.M., Morava, E., Kozicz, L.T., Wevers, R.A., Wolf, N.I., and Willemsen, M.A.

Abstract

Contains fulltext : 155252.pdf (publisher's version ) (Closed access), Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.

Published
2015

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