Increased percentage of L-selectin+ and ICAM-1+ peripheral blood CD4+/CD8+ T cells in active Graves' ophthalmopathy.

The purpose of the study was to evaluate the percentage of CD4+/CD8+ peripheral T cells expressing CD62L+ and CD54+ in patients with Graves' disease and to assess if these estimations could be helpful as markers of active ophthalmopathy. The study was carried out in 25 patients with Graves' disease (GD) divided into 3 groups: 1/ 8 patients with active Graves' ophthalmopathy (GO) (CAS 3-6, GO complaints pound 1 year), 2/ 9 patients with hyperthyroid GD without symptoms of ophthalmopathy (GDtox) and 3/ 8 patients with euthyroid GD with no GO symptoms (GDeu). The control group consisted of 15 healthy volunteers age and sex matched to groups 1-3. The expression of lymphocyte adhesion molecules was evaluated by using three-color flow cytometry. In GO group the percentage of CD8+CD54+, CD8+CD62L+, CD4+CD54+ and CD4+CD62L+ T cells was significantly higher as compared to controls (p<0.001, p<0.05, p<0.01, p<0.001 respectively). The percentage of CD8+CD54+ T lymphocytes was also elevated in GO group in comparison to hyperthyroid GD patients (p< 0.05). CD4+CD62L+ and CD8+CD54+ percentages were also increased in GDtox and GDeu as compared to controls. We found a positive correlation between the TSHRab concentration and the percentage of CD8+CD62L+ T cells in all studied groups (r= 0.39, p<0.05) and between the TSHRab level and CAS (r= 0.77, p<0.05). The increased percentage of CD8+CD54+ and CD8+CD62L+ T cells in patients with Graves' ophthalmopathy may be used as a marker of immune inflammation activity

Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions

A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg−1 of body weight) or over 300 min (0, 5, 10 or 51 μmol kg−1 of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M1) inhibited the formation of R and the last compartment (MN) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC50, of NiAc was 45 nmol L−1, the fractional turnover rate kout was 0.41 L mmol−1 min−1 and the turnover rate of moderator ktol was 0.027 min−1. A lower physiological limit of NEFA was modeled as a NiAc-independent release (kcap) of NEFA into plasma and was estimated to 0.032 mmol L−1 min−1. This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues

Quercetin Inhibits IL-1β-Induced Inflammation, Hyaluronan Production and Adipogenesis in Orbital Fibroblasts from Graves' Orbitopathy

Management of Graves' orbitopathy (GO) is challenging, as no reliable, specific, and safe medical therapeutic agents have yet been developed. We investigated the effect of quercetin in primary cultured orbital fibroblasts from GO, targeting pathways of inflammation, aberrant accumulation of extracellular matrix macromolecules, and adipose tissue expansion. Quercetin significantly attenuated intercellular adhesion molecule-1 (ICAM-1), interleukin (IL) -6, IL-8, and cyclooxygenase (COX) -2 mRNA expression, and inhibited IL-1β-induced increases in ICAM-1, IL-6, and IL-8 mRNA. Increased hyaluronan production induced by IL-1β or tumor necrosis factor-α was suppressed by quercetin in a dose- and time-dependent manner. Treatment with noncytotoxic doses of quercetin inhibited accumulation of intracytoplasmic lipid droplets and resulted in a dose-dependent decrease in expression of peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein (C/EBP) α, and C/EBPβ proteins. In conclusion, inhibition of inflammation, hyaluronan production, and adipogenesis by the natural plant product quercetin in vitro provides the basis for further study of its potential use in the treatment of GO

A Flexible Nonlinear Feedback System That Captures Diverse Patterns of Adaptation and Rebound

An important approach to modeling tolerance and adaptation employs feedback mechanisms in which the response to the drug generates a counter-regulating action which affects the response. In this paper we analyze a family of nonlinear feedback models which has recently proved effective in modeling tolerance phenomena such as have been observed with SSRI’s. We use dynamical systems methods to exhibit typical properties of the response-time course of these nonlinear models, such as overshoot and rebound, establish quantitive bounds and explore how these properties depend on the system and drug parameters. Our analysis is anchored in three specific in vivo data sets which involve different levels of pharmacokinetic complexity. Initial estimates for system (kin, kout, ktol ) and drug (EC50/IC50, Emax/Imax, n ) parameters are obtained on the basis of specific properties of the response-time course, identified in the context of exploratory (graphical) data analysis. Our analysis and the application of its results to the three concrete examples demonstrates the flexibility and potential of this family of feedback models

Differential profiling of lacrimal cytokines in patients suffering from thyroid-associated orbitopathy.

The aim was to investigate the levels of cytokines and soluble IL-6R in the tears of patients with thyroid-associated orbitopathy (TAO) disease. Schirmer's test was adopted to collect tears from TAO patients (N = 20, 17 women, mean age (±SD): 46.0 years (±13.4)) and healthy subjects (N = 18, 10 women, 45.4 years (±18.7)). Lacrimal cytokines and soluble IL-6R (sIL-6R) were measured using a 10-plex panel (Meso Scale Discovery Company) and Invitrogen Human sIL-6R Elisa kit, respectively. Tear levels of IL-10, IL-12p70, IL-13, IL-6 and TNF-α appeared significantly higher in TAO patients than in healthy subjects. Interestingly, IL-10, IL-12p70 and IL-8 levels increased in tears whatever the form of TAO whereas IL-13, IL-6 and TNF-α levels were significantly elevated in inflammatory TAO patients, meaning with a clinical score activity (CAS) ≥ 3, compared to controls. Furthermore, only 3 cytokines were strongly positively correlated with CAS (IL-13 Spearman coeff. r: 0.703, p = 0.0005; IL-6 r: 0.553, p = 0.011; IL-8 r: 0.618, p = 0.004, respectively). Finally, tobacco use disturbed the levels of several cytokines, especially in patient suffering of TAO. The differential profile of lacrimal cytokines could be useful for the diagnosis of TAO patients. Nevertheless, the tobacco use of these patients should be taken into account in the interpretation of the cytokine levels