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Garces S.,Instituto Gulbenkian Of Ciencia | Antunes M.,University of Lisbon | Benito-Garcia E.,Clinical and Translational Research Center | Benito-Garcia E.,Assessment Technology Group | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Introduction Clinical remission is today the treatment goal for rheumatoid arthritis (RA), which requires fast and assertive therapeutic decisions for a tight control of disease activity. Few objective parameters are available to guide clinical decisions, particularly in switcher patients. We designed a preliminary algorithm introducing immunogenicity assessment in the current approach to patients with RA receiving tumour necrosis factor inhibitors (TNFi). Objective To evaluate the concordance between the new algorithm and current clinical practice, comparing the effectiveness of 'immunogenicity-based' versus 'empirical-based' switches in a cohort of patients with established RA receiving biologics. Methods: EULAR therapeutic response was evaluated in 105 patients with RA (naive or switchers) over one year, through generalised estimation equation (GEE) analyses. Serum drug trough levels were assessed by ELISA and antidrug antibodies (ADAb) by Bridging ELISA. Results: During follow-up, 48.6% of patients had therapeutic decisions concordant with the proposed algorithm (Group A), and 51.4% had discordant decisions (Group B). One year after the therapeutic decision, patients from Group A had a higher probability of achieving response (OR=7.91, p<0.001, 95% CI 3.27 to 19.13) and low disease activity (OR=9.77, p<0.001, 95% CI 4.69 to 20.37) than patients in Group B. Conclusions: Immunogenicity assessment might help to optimise therapeutic decisions, leading to a better control of disease activity with significantly better clinical outcomes in patients with RA receiving TNFi.

Huang Y.,Tongji University | Zhang Q.,Tongji University | Song N.-N.,Tongji University | Zhang L.,Tongji University | And 7 more authors.
Molecular Brain | Year: 2016

Background: The cerebellum is responsible for coordinating motor functions and has a unique laminated architecture. Purkinje cells are inhibitory neurons and represent the only output from the cerebellar cortex. Tyrosine hydroxylase (TH) is the key enzyme for the synthesis of catecholamines, including dopamine and noradrenaline, and it is normally not expressed in cerebellar neurons. Results: We report here that the low-density lipoprotein receptors (Lrp) 5 and 6, Wnt co-receptors, are required for the development of the cerebellum and for suppressing ectopic TH expression in Purkinje cells. Simultaneous inactivation of Lrp 5 and 6 by Nestin-Cre results in defective lamination and foliation of the cerebellum during postnatal development. Surprisingly, TH is ectopically expressed by Purkinje cells, although they still keep its other neurochemical characteristics. These phenotypes are also observed in the cerebellum of GFAP-Cre;β-cateninflox/flox mice, and AAV2-Cre-mediated gene deletion leads to ectopic TH expression in Purkinje cells of β-cateninflox/flox mice as well. Conclusions: Our results revealed a new role of the canonical Lrp5/6-β-catenin pathway in regulating the morphogenesis of the cerebellum during postnatal development. © 2016 Huang et al.

Grimberg A.,Childrens Hospital of Philadelphia | Grimberg A.,University of Pennsylvania | Cousounis P.,Childrens Hospital of Philadelphia | Cucchiara A.J.,Clinical and Translational Research Center | And 4 more authors.
Hormone Research in Paediatrics | Year: 2015

To examine parental concerns about child growth and factors that drive parents' decisions whether to intervene medically with their child's height. Methods: Parents of 9-to 14-year-old pediatric primary care patients of various heights, oversampled for those with short stature, participated in exploratory focus groups and nominal group technique sessions. Growth concerns expressed by the groups were incorporated into a survey, completed by 1,820 parents, and rated for their degree of impact on medical decision-making. Ordinal logistic regression modeled concern scores against parent traits. Explanatory focus groups clarified the survey results. Results: Research team consensus and factor analysis organized the 22 distinct concerns expressed by the parent groups into 7 categories. Categories rated as having the greatest influence on parental decisionmaking involved: treatment efficacy and side effects, child health and psychosocial function. Level of concern was highly associated with parental education and parenting style. Conclusion: Psychosocial issues are influential, but parental decision-making is most impacted by concerns about treatment and child health. By discussing the real risks and benefits of hormone treatment and addressing parents' perceptions of what is needed for physical and psychosocial health, clinicians can be highly effective educators to assure that treatment is used only as medically indicated. © 2015 S. Karger AG, Basel.

Adams J.S.,University of California at Los Angeles | Rafison B.,University of California at Los Angeles | Witzel S.,Clinical and Translational Research Center | Chun R.,University of California at Los Angeles | And 3 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-β, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN-γ-promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled 'Vitamin D Workshop'. © 2014 Elsevier Ltd.

Murphy T.F.,Clinical and Translational Research Center | Brauer A.L.,Clinical and Translational Research Center | Kirkham C.,Clinical and Translational Research Center | Johnson A.,Clinical and Translational Research Center | And 2 more authors.
Infection and Immunity | Year: 2013

Moraxella catarrhalis is a human respiratory tract pathogen that causes otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease. We have identified and characterized a zinc uptake ABC transporter that is present in all strains of M. catarrhalis tested. A mutant in which the znu gene cluster is knocked out shows markedly impaired growth compared to the wild type in medium that contains trace zinc; growth is restored to wild-type levels by supplementing medium with zinc but not with other divalent cations. Thermal-shift assays showed that the purified recombinant substrate binding protein ZnuA binds zinc but does not bind other divalent cations. Invasion assays with human respiratory epithelial cells demonstrated that the zinc ABC transporter of M. catarrhalis is critical for invasion of respiratory epithelial cells, an observation that is especially relevant because an intracellular reservoir of M. catarrhalis is present in the human respiratory tract and this reservoir is important for persistence. The znu knockout mutant showed marked impairment in its capacity to persist in the respiratory tract compared to the wild type in a mouse pulmonary clearance model. We conclude that the zinc uptake ABC transporter mediates uptake of zinc in environments with very low zinc concentrations and is critical for full virulence of M. catarrhalis in the respiratory tract in facilitating intracellular invasion of epithelial cells and persistence in the respiratory tract. © 2013, American Society for Microbiology.

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