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Martinelli D Häberle J Rubio V Giunta C Hausser I Carrozzo R Gougeard N Marco-Marín C Goffredo BM Meschini MC Bevivino E Boenzi S Colafati GS Brancati F Baumgartner MR Dionisi-Vici C 《Journal of inherited metabolic disease》2012,35(5):761-776
Δ(1)-Pyrroline-5-carboxylate synthetase (P5CS) catalyzes the first two steps of ornithine/proline biosynthesis. P5CS deficiency has been reported in three families, with patients presenting with cutis/joint laxity, cataracts, and neurodevelopmental delay. Only one family exhibited metabolic changes consistent with P5CS deficiency (low proline/ornithine/citrulline/arginine; fasting hyperammonemia). Here we report a new P5CS-deficient patient presenting the complete clinical/metabolic phenotype and carrying p.G93R and p.T299I substitutions in the γ-glutamyl kinase (γGK) component of P5CS. The effects of these substitutions are (1) tested in mutagenesis/functional studies with E.coli γGK, (2) rationalized by structural modelling, and (3) reflected in decreased P5CS protein in patient fibroblasts (shown by immunofluorescence). Using optical/electron microscopy on skin biopsy, we show collagen/elastin fiber alterations that may contribute to connective tissue laxity and are compatible with our angio-MRI finding of kinky brain vessels in the patient. MR spectroscopy revealed decreased brain creatine, which normalized after sustained arginine supplementation, with improvement of neurodevelopmental and metabolic parameters, suggesting a pathogenic role of brain creatine decrease and the value of arginine therapy. Morphological and functional studies of fibroblast mitochondria show that P5CS deficiency is not associated with the mitochondrial alterations observed in Δ(1)-pyrroline-5-carboxylate reductase deficiency (another proline biosynthesis defect presenting cutis laxa and neurological alterations). 相似文献
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Kleinert S Tony HP Krause A Feuchtenberger M Wassenberg S Richter C Röther E Spieler W Gnann H Wittig BM 《Rheumatology international》2012,32(9):2759-2767
The objective of this study was to use data from a noninterventional study to evaluate the effectiveness of adalimumab in rheumatoid arthritis (RA) patients during routine clinical practice and to explore the potential impact of patient and disease characteristics in response to adalimumab therapy. A total of 2,625 RA patients with specified data at baseline (prior to initiating adalimumab treatment) and 12 months entered this study between April 2003 and March 2009. We evaluated response to adalimumab therapy and conducted stepwise regression and subgroup analyses of factors influencing therapeutic response. During the 1-year adalimumab treatment period, disease activity decreased from a baseline mean disease activity score-28 joints (DAS28) of 5.9-3.9, while functional capacity improved from 59.0 to 68.4 Funktionsfragebogen Hannover (FFbH) percentage points. In multivariate regression models, high baseline DAS28 was the strongest positive predictor for decrease in disease activity, and high baseline functional capacity was associated with reduced gains in functional capacity. Male gender was a positive predictor of therapeutic response for both disease activity and functional capacity, while older age and multiple previous biologics were associated with a reduced therapeutic response. Subset analyses provided further support for the impact of baseline DAS28, FFbH, and prior biologic therapy on therapeutic response during treatment. We conclude that treatment with adalimumab leads to decreased disease activity and improved function during routine clinical practice. Patients with high disease activity and low functional capacity are particularly benefitted by adalimumab therapy. 相似文献
996.
Leblanc CM Lang B Bencivenga A Chetaille AL Dancey P Dent P Miettunen P Oen K Rosenberg A Roth J Scuccimarri R Tse SM Benseler S Cabral DA Campillo S Chédeville G Duffy CM Duffy KW Haddad E Huber AM Laxer R Levy D Johnson N Ramsey S Shiff N Schmeling H Schneider R Stringer E Yeung RS Tucker LB 《The Journal of rheumatology》2012,39(9):1875-1879
997.
The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclini... 相似文献
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Rebeca Kawahara Gabriela V. Meirelles Henry Heberle Romênia R. Domingues Daniela C. Granato Sami Yokoo Rafael R. Canevarolo Flavia V. Winck Ana Carolina P. Ribeiro Thaís Bianca Brand?o Paulo R. Filgueiras Karen S. P. Cruz José Alexandre Barbuto Ronei J. Poppi Rosane Minghim Guilherme P. Telles Felipe Paiva Fonseca Jay W. Fox Alan R. Santos-Silva Ricardo D. Coletta Nicholas E. Sherman Adriana F. Paes Leme 《Oncotarget》2015,6(41):43635-43652
Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. 相似文献
999.
The Basic Documentation for Psycho‐Oncology Short Form (PO‐Bado SF)—an expert rating scale for distress screening: development and psychometric properties
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1000.
Tract‐based spatial statistics analysis of diffusion‐tensor imaging data in pediatric‐ and adult‐onset multiple sclerosis
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Rachel Aliotta Jennifer L. Cox Katelyn Donohue Bianca Weinstock‐Guttman E. Ann Yeh Paul Polak Michael G. Dwyer Robert Zivadinov 《Human brain mapping》2014,35(1):53-60
Background: White matter (WM) microstructure may vary significantly in pediatric‐onset (PO) and adult‐onset (AO) patients with multiple sclerosis (MS), a difference that could be explained by the effects of an inherent plasticity in the affected pediatric brains early in the disease, and a phenomenon that does not occur later in life. This hypothesis would support the observation that disease progression is much slower in POMS compared to AOMS patients. Objectives: To examine WM microstructure in the brain of adults with POMS and AOMS, using tract based spatial statistics (TBSS) analysis of diffusion‐tensor imaging (DTI). Methods: Adults with relapsing‐remitting (RR) POMS, who were diagnosed before age of 18 years (n = 16), were compared with age‐matched (AOA, n = 23) and disease duration‐matched (AOD, n = 22) RR patients who developed MS after the age of 18 years. Scans were analyzed using the FSL software package (Oxford, UK) and statistics were performed using TBSS to evaluate WM microstructure between groups based on the mean fractional anisotropy (FA) values obtained from the DTI. Results: Widespread cortical and deep WM area differences characterized by increased FA values were seen in the AOAMS compared with POMS group (P < 0.05, TFCE corrected). Significantly increased FA values of posterior WM areas were detected in the AODMS compared with POMS group (P < 0.05, TFCE corrected). Conclusion: Increased FA values in WM areas of the AOMS compared with the POMS patients suggest that diffuse WM microstructure changes are more attributable to age of onset than a simple function of disease duration and age. Hum Brain Mapp 35:53–60, 2014. © 2012 Wiley Periodicals, Inc. 相似文献