Clinical study on the application of dexamethasone and cyclosporine/dimethyl sulfoxide combination eye drops in the initial therapy of chronic superficial keratitis in dogs.

PURPOSE: To assess the initial therapy of chronic superficial keratitis (CSK) in dogs with the use of dexamethasone and cyclosporine/ dimethyl sulfoxide combination eye drops. METHODS: The study was conducted on 41 dogs - 16 males and 25 females, aged 2 to 9 years, diagnosed with CSK. The disease was treated with two kinds of eye drops containing 0.1% dexamethasone and 0.75% cyclosporine in combination with 30% DMSO, administered three times a day. Prior to the treatment and after 5 weeks of therapy, depigmentation of the third eyelid margin, corneal neovascularization and pigmentation were assessed. The percentage of the corneal surface afflicted with inflammatory processes was calculated with the use of IsoCalc.com's Get Area software for CorelDRAW12. RESULTS: The administered therapy resulted in a significant decrease in the mean number of quadrants affected by corneal neovascularization in the right eye from 2.63 prior to treatment to 0.24 after treatment (p⟨0.001), and the left eye from 2.66 to 0.59 (p⟨0.001), respectively. Mean corneal surface afflicted with inflammatory processes was statistically significantly reduced from 53.5% to 26.3% (p⟨0.001) in the case of right corneas, and from 54.5% to 30.2% (p⟨0.001) in the case of left corneas. Of 77 corneas diagnosed with pigmentation, pigmentation reduction was observed in 54 and pigmentation increase in 27. CONCLUSIONS: Using dexamethasone and cyclosporine/DMSO combination eye drops proved to be a viable initial therapy against CSK, which facilitates reduction of inflammatory processes and neovascularization atrophy, but in many cases does not inhibit the progress of pigmentation.

Enhanced contractility of intraparenchymal arterioles after global cerebral ischaemia in rat - new insights into the development of delayed cerebral hypoperfusion.

AIM: Delayed cerebral hypoperfusion is a secondary complication found in the days after transient global cerebral ischaemia that worsens the ischaemic damage inflicted by the initial transient episode of global cerebral ischaemia. A recent study demonstrated increased cerebral vasoconstriction in the large arteries on the brain surface (pial arteries) after global cerebral ischaemia. However, smaller arterioles inside the brain (parenchymal arterioles) are equally important in the regulation of cerebral blood flow and yet their pathophysiology after global cerebral ischaemia is largely unknown. Therefore, we investigated whether increased contractility occurs in the intraparenchymal arterioles. METHODS: Global cerebral ischaemia was induced in male Wistar rats by bilateral common carotid occlusion for 15 min combined with hypovolaemia. Regional cerebral blood flow was determined by quantitative autoradiography. Intraparenchymal arterioles were isolated and pressurized, and concentration-response curves to endothelin-1 with and without the endothelin B receptor-selective antagonist BQ788 was generated. Endothelin B receptor expression was investigated by quantitative flow cytometry and immunohistochemistry. RESULTS: We observed increased endothelin-1-mediated contractility of parenchymal arterioles correlating with reduced cerebral blood flow of the cortex, hippocampus and caudate nucleus 48 h after global cerebral ischaemia. The increased endothelin-1-mediated contractility was abolished by BQ788, and the vascular smooth muscle cell-specific expression of endothelin B receptors was significantly increased after global cerebral ischaemia. CONCLUSION: Increased endothelin-1-mediated contractility and expression of endothelin B receptors in the intraparenchymal vasculature contributes to the development of delayed cerebral hypoperfusion after global cerebral ischaemia in combination with vascular changes of the pial vasculature.

Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs: mechanisms and implications for chemoresistance.

BACKGROUND AND PURPOSE: Cancer cells grow without the restraints of feedback control mechanisms, leading to increased cancer cell survival. The treatment of cancer is often complicated by the lack of response to chemotherapy leading to chemoresistance and persistent survival of tumour cells. In this work we studied the role of platelets in chemotherapy-induced cancer cell death and survival. EXPERIMENTAL APPROACH: Human adenocarcinoma cells, colonic (Caco-2) and ovarian (59 M) cells, were incubated with 5-fluorouracil (1-300 µg·mL(-1) ) or paclitaxel (1-200 µg·mL(-1) ) in the presence or absence of platelets (1.5 × 10(8) mL(-1) ) for 1, 24 or 72 h. Following incubation, cancer cells were harvested and cell survival/death was assayed using flow cytometry, Western blotting, real-time PCR, TaqMan® Gene Expression Assays and proteomics. KEY RESULTS: Human platelets increased the survival of colonic and ovarian adenocarcinoma cells treated with two standard anticancer drugs, 5-fluorouracil and paclitaxel. In the presence of platelets, cancer cells up-regulated anti-apoptotic and down-regulated pro-apoptotic genes, increased the number of cells in the synthesis of DNA and decreased the number in the quiescent phase, increased expression of cyclins, DNA repair proteins and MAPKs. The analysis of platelet-Caco-2 secretome demonstrated the release of the chemokine RANTES, thrombospondin-1, TGF-ß and clusterin. Finally, human recombinant RANTES and thrombospondin-1 improved survival of Caco-2 cells challenged with paclitaxel. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that platelets increase adenocarcinoma cells survival, proliferation and chemoresistance to standard anticancer drugs. Modulating cancer cell-platelet interactions may offer a new strategy to improve the efficacy of chemotherapy.