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1.
Rheumatology (Oxford) ; 59(7): 1505-1513, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31628482

RESUMEN

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Proteína C-Reactiva/inmunología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lovastatina/uso terapéutico , Adulto , Anticuerpos Antiproteína Citrulinada/inmunología , Artritis Reumatoide/inmunología , Artritis Reumatoide/fisiopatología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factor Reumatoide/inmunología , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
2.
J Immunol ; 189(9): 4305-12, 2012 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-23024275

RESUMEN

Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies, whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed H chain transgene 3H9. Serum anti-dsDNA Abs appeared in males at 12 wk, and most had high-titer IgG anti-dsDNA and anti-cardiolipin Abs and developed >300 mg/dl proteinuria by 8 mo. Females had only low-titer IgG anti-cardiolipin Abs, and none developed proteinuria by 1 y. Males had a smaller marginal zone than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of marginal zone B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, which were rare in the naive repertoire, were markedly overrepresented in the germinal center repertoire of both males and females, but the VJ junctions differed between males and females with higher-affinity autoreactive B cells being selected into the germinal centers of males. Administration of IFN-α to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, which includes an extra copy of Tlr7, or administration of exogenous IFN-α relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the Ag-driven B cell repertoire.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Diferenciación Celular/inmunología , Sitios Genéticos/inmunología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Interferón-alfa/fisiología , Lupus Eritematoso Sistémico/inmunología , Animales , Autoanticuerpos/biosíntesis , Autoanticuerpos/metabolismo , Subgrupos de Linfocitos B/patología , Sitios de Unión de Anticuerpos , Femenino , Centro Germinal/patología , Inmunofenotipificación , Interferón-alfa/administración & dosificación , Interferón-alfa/antagonistas & inhibidores , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos MRL lpr , Ratones Endogámicos NZB , Ratones Mutantes , Transducción de Señal/inmunología , Receptor Toll-Like 7/antagonistas & inhibidores , Receptor Toll-Like 7/fisiología
3.
Cureus ; 14(6): e26280, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35911308

RESUMEN

BACKGROUND/OBJECTIVE: To examine rates of counseling on driving for individuals with osteoarthritis (OA) and/or rheumatoid arthritis (RA) and evaluate the Health Assessment Questionnaire Disability Index (HAQ-DI) as a screening tool for further driving evaluation. METHODS: A cross-sectional survey was completed by individuals recruited via ResearchMatch (a national web-based recruitment tool) between March 5 and April 20, 2020. Individuals with a current US driver's license, ≥18 years old, with self-reported OA and/or RA diagnosis were surveyed about driving difficulty and vehicle modification and completed a HAQ-DI assessment. Respondents were dichotomized based on reporting vehicle modification(s) due to arthritis versus no modification(s) for univariate and multivariate analyses. RESULTS: Of 4,435 recruited patients, 304 (6.9%) met inclusion/exclusion criteria and completed the surveys. Of all respondents, 259 (85.2%) reported at least some difficulty with one or more driving activities, but only 47 (15.5%) reported discussion with a physician and/or healthcare professional. A total of 184 (60.5%) respondents had HAQ-DI ≥ 1 and were more likely to report vehicle modification(s) compared to respondents with HAQ-DI score < 1 (OR = 5.00, 95% CI = 2.69-9.32, p < 0.011) after controlling for age, gender, type of arthritis, and driving behaviors. CONCLUSION: Few respondents report discussion of driving difficulties with healthcare providers, although many report driving-related impairments, particularly those with HAQ-DI scores ≥ 1. Our data suggest a strong association between HAQ-DI scores and vehicle modification. The HAQ-DI may serve as a screening tool to predict a patient's need for driving evaluation and vehicle modification(s).

4.
Cell Tissue Res ; 341(3): 453-64, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20694478

RESUMEN

Spermatogenesis is a complex series of processes that involves (1) the maintenance of a renewable pool of diploid stem cells within a niche, (2) the mitotic expansion of a subpopulation of stem cells committed to the spermatogenic pathway, and (3) the differentiation of diploid cells into highly specialized, haploid spermatozoa through meiotic and post-meiotic cellular transformations. Drosophila melanogaster is a desirable model for studying spermatogenesis, as similarities exist between mammalian and fly spermatogenesis. Like mammals, flies maintain a spermatogenic stem cell niche; the steps involved in mammalian spermatogenesis are mimicked in flies, with the main difference being that fly sperm develop within cysts rather than an epithelial cell layer. Here, we report a reliable robust system for culturing whole testes and individual spermatogenic cysts obtained from mid- to late-pupal stages of Drosophila pseudoobscura. D. pseudoobscura testes can be easily distinguished in later pupal stages because of their intense red pigmentation and are easily handled because of their simple ellipsoidal morphology. Cultured cysts are comparable in length to cysts obtained from adult flies, and motility is consistently achieved in vitro. This system not only offers a method for dissecting the mechanisms involved in meiotic and post-meiotic cellular transformations, but also can be used for the study of signaling during spermatogenesis.


Asunto(s)
Drosophila , Espermatozoides/citología , Espermatozoides/fisiología , Nicho de Células Madre/citología , Testículo/citología , Animales , Técnicas de Cultivo de Célula , Proliferación Celular , Células Cultivadas , Disección , Drosophila/fisiología , Masculino , Modelos Biológicos , Técnicas de Cultivo de Órganos , Espermatogénesis/fisiología , Esferoides Celulares/citología , Esferoides Celulares/fisiología , Coloración y Etiquetado , Testículo/cirugía
5.
Spermatogenesis ; 1(2): 159-171, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22319665

RESUMEN

Spermatogenesis is a series of cellular processes that leads to the development of motile, elongate sperm cells. Mitotic expansion of spermatogenic stem cells is followed by two meiotic cell divisions that yield haploid round spermatids which then transform from a spherical form into an elongate, highly polarized form. In Drosophila, spermatogenesis takes place within encapsulating cysts that contain spermatogenic cells. Spermatogenic cysts were isolated and grown in culture over the course of 96 hours. Cultures were treated with buthionine sulfoximine (BSO), glutathione (GSH), insulin and GSH+insulin in order to test the effects of these agents on cyst viability. The addition of glutathione and exogenous insulin to cultured spermatogenic cysts each appeared to have a positive effect on early spermatogenic cyst survival in vitro at some timepoints. The addition of GSH+insulin together had no significant effect on early spermatogenic cyst survival in vitro. Oxidative stress induced by BSO resulted in a significant decrease and/or complete loss of specific early spermatogenic cyst types and the abnormal development of elongating cysts in culture. This culture system offers the opportunity for high-resolution analysis of spermatogenic processes not previously possible.

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