Effect of PRX-1 Downregulation in the Type 1 Diabetes Microenvironment

Type 1 diabetes (T1D) is caused by dysregulation of the immune system in the pancreatic islets, which eventually leads to insulin-producing pancreatic β-cell death and destabilization of glucose homeostasis. One of the major characteristics of T1D pathogenesis is the production of inflammatory mediators by macrophages that result in destruction or damage of pancreatic β-cells. In this study the inflammatory microenvironment of T1D was simulated with RAW264.7 cells and MIN6 cells, acting as macrophages and pancreatic β-cells respectably. In this setting, peroxiredoxin-1, an anti-oxidant enzyme was knocked down to observe its functions in the pathogenesis of T1D. RAW264.7 cells were primed with lipopolysaccharide and co-cultured with MIN6 cells while PRX-1 was knocked down in one or both cell types. Our results suggest that hindrance of PRX-1 activity or the deficiency of this enzyme in inflammatory conditions negatively affects pancreatic β-cell survival. The observed decrease in viability of MIN6 cells seems to be caused by nitric oxide production. Additionally, it seems that PRX-1 affects previously reported protective activity of IL-6 in pancreatic β cells as well. These results signify new, undiscovered roles for PRX-1 in inflammatory conditions and may contribute toward our understanding of autoimmunity.     

CTLA-4-Tg/CD-28-KO Mice Exhibit Reduced T Cell Proliferation in vivo Compared to CD-28-KO Mice in a Graft-versus-host Disease Model

Activated T cells express inhibitory receptors such as CTLA-4 that can downregulate immune responses. Blockade of or genetic deficiency in CTLA-4 can result in autoimmunity. Therefore, strategies to increase the inhibitory function of CTLA-4 may be attractive in settings of undesirable T cell responses such as autoimmunity or transplant rejection. We have tested the hypothesis that transgenic constitutive expression of CTLA-4 can further attenuate immune responses when compared with normal inducible expression. Our results indicate that transgenic expression of CTLA-4 in mouse T cells (CTLA-4-Tg T cells) results in reduced cell cycle progression and increased apoptosis of TCR-stimulated T cells. CTLA-4-Tg T cells display reduced T cell proliferation in an in vivo model of graft versus host disease (GVHD). These results further our understanding of how CTLA-4 can be manipulated to inhibit immune responses and may help development of new therapeutic strategies for clinical settings of autoimmunity and transplantation.     

Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors: correlation between changes in covariates and imatinib exposure

A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (C(min)) during long-term treatment. Follow-up (FU) imatinib C(min) was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5-24.0 months) and 13.0 months (range, 9.6-17.9 months), respectively. Mean inter- and intra-subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib C(min) (1,370 ± 661 ng/mL) was significantly higher than mean initial C(min) (1,171 ± 573 ng/mL; p = 0.003). Compared with initial C(min), FU C(min) was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib C(min) and that of albumin (r = -0.39, p = 0.003). During long-term treatment, imatinib C(min) did not decrease significantly but remained stable or increased in most patients. Changes in imatinib C(min) were associated with changes in albumin concentration. Monitoring of imatinib C(min) only for concerns about time-dependent increases in imatinib clearance is not necessary.     

Protective Effects of Korean Red Ginseng on Radiation-Induced Oral Mucositis in a Preclinical Rat Model

Numerous studies' attempts to improve radiation-induced oral mucositis have not produced a qualified treatment yet. Our aim was to investigate the effectiveness of Korean red ginseng (KRG) on radiation-induced damage in an in vivo rat model. After 20 Gy of irradiation, rats were divided randomly into the following 4 groups: control, KRG only, radiotherapy (RT) only, and RT + KRG group. The rats were monitored in terms of survival rate, activity, mucositis grade, oral intake, and body weight. The tongue, buccal mucosa, and submandibular gland (SMG) were harvested, and the weight of the SMG was analyzed. The samples then underwent hematoxylin and eosin, TUNEL, and immunohistochemical staining. Radiation-induced severe oral mucositis and SMG injury led to poor oral intake and delayed healing, resulting in the death of some rats. We found that survival rate, oral intake, and body weight increased. Moreover, rats treated with KRG showed less severe mucositis and decreased histologic changes of the oral mucosa and SMG. Furthermore, we showed that the protective effects of KRG were caused by inhibition of the apoptotic signal transduction pathway linked to caspase-3. In conclusion, KRG protects the oral mucosa and SMG from radiation-induced damage by inhibiting caspase-mediated apoptosis in rats.     

Therapeutic effects of strengthening exercise on gait function of cerebral palsy

Purpose. To assess the effectiveness of strengthening exercises of the lower limbs on improvement of muscle strength and gait function.

Method. Those included were diagnosed as spastic diplegic or hemiplegic type of cerebral palsy (CP) and verified as grade 2 or 3 of the Gross Motor Function Classification System (GMFCS). Participants were divided into an experimental group (n = 9) or a control group (n = 8). The experimental group completed a 5-week strengthening program and the control group took part in conventional physical therapy. Muscle tone and strength of lower limb, Gross Motor Function Measure, lateral step up, squat to stand, and three dimensional gait analysis were tested at pre-training, post-training, and 6 week follow up.

Results. Maximal hip extensor strength, and number of squat to stand were significantly increased at post-training and 6 weeks follow up in the experimental group compared with the control group. GMFM score D and E significantly improved in the experimental group at post-training. The experimental group demonstrated significant increase of gait speed and stride length and decrease of double support phase at post-training and 6 weeks follow up.

Conclusions. Strengthening exercises could be a useful method to improve gait function of patients with spastic CP.