Effect of topical application of 5-FU on the corneoscleral limbus of rabbits

• Aim: To observe the effects of topical application of 5-fluorouracil (5-FU) on the rabbits corneal limbus. • Methods: 5-FU was applied topically to the corneoscleral region of rabbits eyes. The animals were sacrificed immediately or 7, 15, 30 and 60 days later, and tissues were submitted to histological examination. • Results: All animals presented corneoscleral deepithelization close to the site of application during the immediate post-operative period, whereas on the 4th postoperative day ulceration was no longer present. Histological examination showed absence of epithelium and slight edema. After one week (G2), 2 animals presented epithelial defects, thickened epithelium with larger basal cells and loose chromatin, and slight subepithelial edema. The remaining groups showed no alterations. • Conclusion: The 5-FU topically on the corneoscleral limbus postpone the epitelization.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Lyprinol : is it a useful anti-inflammatory agent?

The New Zealand green lipped mussel preparation Lyprinol is available without a prescription from a supermarket, pharmacy or Web. The Food and Drug Administration have recently warned Lyprinol USA about their extravagant anti-inflammatory claims for Lyprinol appearing on the web. These claims are put to thorough review. Lyprinol does have anti-inflammatory mechanisms, and has anti-inflammatory effects in some animal models of inflammation. Lyprinol may have benefits in dogs with arthritis. There are design problems with the clinical trials of Lyprinol in humans as an anti-inflammatory agent in osteoarthritis and rheumatoid arthritis, making it difficult to give a definite answer to how effective Lyprinol is in these conditions, but any benefit is small. Lyprinol also has a small benefit in atopic allergy. As anti-inflammatory agents, there is little to choose between Lyprinol and fish oil. No adverse effects have been reported with Lyprinol. Thus, although it is difficult to conclude whether Lyprinol does much good, it can be concluded that Lyprinol probably does no major harm.

Load–frequency control : a GA-based multi-agent reinforcement learning

The load–frequency control (LFC) problem has been one of the major subjects in a power system. In practice, LFC systems use proportional–integral (PI) controllers. However since these controllers are designed using a linear model, the non-linearities of the system are not accounted for and they are incapable of gaining good dynamical performance for a wide range of operating conditions in a multi-area power system. A strategy for solving this problem because of the distributed nature of a multi-area power system is presented by using a multi-agent reinforcement learning (MARL) approach. It consists of two agents in each power area; the estimator agent provides the area control error (ACE) signal based on the frequency bias estimation and the controller agent uses reinforcement learning to control the power system in which genetic algorithm optimisation is used to tune its parameters. This method does not depend on any knowledge of the system and it admits considerable flexibility in defining the control objective. Also, by finding the ACE signal based on the frequency bias estimation the LFC performance is improved and by using the MARL parallel, computation is realised, leading to a high degree of scalability. Here, to illustrate the accuracy of the proposed approach, a three-area power system example is given with two scenarios.