The inhibition of src kinase suppresses the production of matrix metalloproteinases in from synovial fibroblasts and inhibits mapk and stats pathways

Background/aim: The purpose of this study was to investigate the antiarthritic potentials of the inhibition of Src kinase in vivo and in vitro settings. Materials and methods: Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund’s adjuvant (collagen induced arthritis [CIA] model) in Wistar albino rats. One day after the onset of arthritis, dasatinib, a potent Src kinase inhibitor, (5 mg/kg/day) was given via oral gavage. Tissue Src, Fyn, MAPK and STAT mRNA expressions were determined by real-time polymerase chain reaction. On the other hand, fibroblast like synoviocytes (FLSs) were harvested patients with rheumatoid arthritis (RA) undergoing surgical knee joint replacement. FLSs were stimulated with cytokines and dasatinib was added in different concentrations. MMP –1, –3, and –13 levels in FLSs culture were determined by ELISA. Results: The tissue mRNA expressions of Src, Fyn, MAPK and STATs were increased in the arthritis CIA group compared to the control group. Their mRNA expressions in the CIA + dasatinib group were decreased and similar in the control group. In in vitro setting, MMP –1, –3, and –13 expressions from FLSs induced by IL-1β and TNF-α were increased, while dasatinib suppressed their productions from FLSs. Conclusion: The present study shows that the inhibition of Src kinase has antiarthritic potentials in both in vivo and in vitro settings. Src kinase inhibition may be candidate to further research in human RA

Identification of Resistance to Exogenous Thyroxine in Humans

[Background]: Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity. Dio2(−/−) mice show central resistance to exogenous T4. Patients with resistance to exogenous thyroxine (RETH) have not been described. The aim of this study was to identify hypothyroid patients with thyrotropin (TSH) unresponsiveness to levothyroxine (LT4) and to characterize the clinical, hormonal, and genetic features of human RETH.[Methods]: We investigated hypothyroid patients with elevated TSH under LT4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3, and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4, and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-β (THRB) mutations. DIO2, including the Ala92-D2 polymorphism, selenocysteine binding protein 2 (SECISBP2), and THRB were fully sequenced. [Results]: Eighteen hypothyroid patients (nine of each sex, 3–59 years) treated with LT4 showed elevated TSH (15.5 ± 4.7 mU/L; reference range [RR]: 0.4–4.5), fT4 (20.8 ± 2.4 pM; RR: 9–20.6), and TSH/fT4 ratio (0.74 ± 0.25; RR: 0.03–0.13). Despite increasing LT4 doses from 1.7 ± 1.0 to 2.4 ± 1.7 μg/kg/day, TSH remained elevated (6.9 ± 2.7 mU/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9 ± 3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2 ± 2.4, RR: 11.3–15.3 and 2.5 ± 1.4, RR: 7.5–8.5, respectively) whereas rT3/T4 was increased (0.6 ± 0.2; RR: 0.43–0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but the allele dose did not correlate with RETH.[Conclusions]: Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germline DIO2 mutations suggests that aberrant post-translational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.This work was supported by funding from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (grant PI16/00830 to J.C.M.) and by the Rare Diseases Networking Biomedical Research Centre (CIBERER)

33 Questions about Triglycerides and Cardiovascular Effects: Expert Answers

Education professionals are concerned about the dropping levels of motivation and engagement students experience as they go through schooling. Sustained low motivation across the student population leads to increased dropout rates, which in turn leads to many detrimental consequences. The literature shows clear correlations between low self-efficacy and low motivation, alongside a lack of tools to address the problem. This thesis tested a student-centered intervention composed of a goal setting instrument, an expressive writing instrument, and several coping mechanisms. Self-efficacy was tested in eight 16-year-old Finnish students before and after the intervention using a validated self-efficacy scale. A thematic analysis was conducted to assess the importance and effects of each of the components of the intervention, and to account for external variables. All the participants showed an increase in self-efficacy after the intervention, which was attributed to be the main cause. The goal setting instrument was reported to have the strongest effect on self-efficacy, followed by the expressive writing instrument. The coping mechanisms showed null effects. The results suggest that the goal setting instrument causes new appraisals of the most influential source of self-efficacy: performance attainments. Additionally, expressive writing serves as a foundational previous step to goal setting. However, further research is required to confirm the validity of these findings. The small sample size, the strong localization, and the fact that self-efficacy is not directly observable, severely limit the results of the study. In addition, a longer study should be conducted to observe the durability of the effects of the intervention