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Introduction: Gliomas are difficult to treat primary brain tumours classified into grades I-IV by the WHO. One problem is the development of multiple drug resistance (MDR) in response to repeated cycles of chemotherapy. MDR occurs through the increased expression of ATP-binding cassette transporters (ABC transporters). Several ABC transporters are linked to drug resistance in human tumours and include MDR1/P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and the multiple drug resistance proteins, ABCC1 and ABCC2. Cyclooxygenase2 (COX-2) can cause up-regulation of ABCB1 and a correlation exists between COX-2 and ABCB1 in breast cancer. Considering the fact that gliomas can develop MDR and express high levels of COX-2, the aim of the study was to investigate the importance of COX-1 and COX-2 to the expression and activity of the ABC transporters ABCB1 and ABCC1-5 in the absence or presence of vincristine-induced MDR. Materials and Methods: The human glioma cell lines A172, T98G, U87MG, U138MG and U251MG were used. mRNA and protein expression of COX-1, COX-2, microsomal ­prostaglandin E synthase 1, 2 and cytosolic prostaglandin E synthase (mPGES1, mPGES2 and cPGES), ABCB1 and ABCC1-5 were determined by qPCR and Western blotting in the absence or presence of COX-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or gamma-linolenic acid (GLA). ABC transporter activity was determined using fluorescent probes. The response of vincristine-resistant cells was studied as vincristine is used in gliomas in PCV (procarbazine, CCNU, vincristine) treatment and is a known substrate for the ABC transporters ABCB1 and ABCC2. Tumour samples from grade II-IV gliomas were also analysed for ABCB1 and ABCC1-4 expression by immunohistochemical staining and compared with COX1, COX2, mPGES1, mPGES2 and cPGES expression. Results: The results showed constitutive expression of COX-1 and COX-2 in the panel of human glioma cells as well as the expression of all the ABC transporters studied, although considerable variations in expression were found among the different cell lines. Inhibition of COX-1 and COX-2 caused a decrease in the expression and activity of several ABC transporters. The presence of GLA also led to changes in COX-1, COX-2 and ABC transporter expression in the glioma cell lines. Vincristine-resistant cells showed an increase in expression of both COX enzymes and ABC transporters which was altered by COX inhibition. Patient samples had variable expression of COX enzymes and ABC transporters. Conclusions: The potential for altering the expression profile and activity of ABC transporters through the manipulation of COX-2 and/or prostaglandin metabolism may lead to improved tumour response to chemotherapy in the future. Financial support: FAPESP (15/08777-0), CNPq, CAPES.

Background The role of vascular risk factors in glaucoma is still being debated. To assess the importance of vascular risk factors in patients with primary open-angle glaucoma (POAG), data from the medical history of 2,879 POAG patients and 973 age-matched controls were collected and analyzed. Methods Design: observational survey. Setting: 35 Italian academic centers. Study population: POAG patients and age-matched controls. In order to reduce bias consecutive patients were included. Observation procedures: data concerning vascular risk factors were collected for all patients with a detailed questionnaire. A complete ophthalmological examination with assessment of intraocular pressure (IOP), visual field, optic disc, and systemic blood pressure was performed. Main outcome measures: the ESH-ESC (European Society of Hypertension-European Society of Cardiology) guidelines were used to calculate the level of cardiovascular risk. Crude and adjusted estimates of the odds ratios (OR) were calculated for all cardiovascular risk factors in POAG and controls. Results The study included 2,879 POAG patients and 973 controls. POAG cases had a significantly higher systolic and diastolic blood pressure (p=0.001) and systolic perfusion pressure (p=0.02) as compared with controls. Also mean IOP was significantly higher in the POAG group (p=0.01), while diastolic perfusion pressure was not significantly different in the two groups. Myopia was more prevalent in the POAG group (23 vs 18%, p=0.005) as well as a positive family history for glaucoma (26 vs 12%, p= 0.004). POAG patients tended to have a higher cardiovascular risk than controls: 63% of glaucoma cases vs 55% of controls (OR: 1.38, p=0.005) had a “high” or “very high” cardiovascular risk. Conclusions The level of cardiovascular risk was significantly higher in glaucoma patients than in controls.

Aim: To investigate and compare the effects of topical benzalkonium chloride-preserved prostaglandins (PGAs) on the ocular surface in patients with primary open-angle glaucoma before and after 3 months of treatment with additional 0.5% preservative-free tamarind seed polysaccharide single-dose eyedrops (TSP®, Oftagen, Pisa, Italy). Methods: This was a prospective, longitudinal, multicenter study. From 5 different Italian glaucoma centers, 10 glaucomatous patients were recruited in each center. All the patients were treated with a PGA with preservative for at least 1 year. Preservative-free artificial tears 3 times per day were prescribed. The participants were subjected to clinical and instrumental evaluation at baseline, after 1 month and after 3 months of treatment. All patients were examined with a digital corneal confocal laser scanning microscope (HRT II Rostock Cornea Module). Results: After 3 months of TSP 0.5% treatment, an improvement of some ocular signs and symptoms was found. The percentage of conjunctival hyperemia decreased from 67 to 13%. Schirmer's test and breakup time significantly changed from the baseline after 3 months. Confocal microscopy showed a significant increase in conjunctival goblet cells. Conclusion: Artificial substitutes, in particular TSP 0.5%, might protect the ocular surface hence giving higher compliance, adherence and quality of life to the patients.

Supposedly, prostaglandin analogs (PGA) could reduce the central corneal thickness (CCT), while topical carbonic anhydrase inhibitors (TCAI) could increase CCT. The aim of the study was to evaluate clinically significant CCT effects in patients treated with PGA or TCAI.At least 50 glaucomatous patients were saved on the Italian Glaucoma Register from 16 different glaucoma centers. About 816 glaucomatous patients were found in the register; of these, 316 were recruited in this study because they were treated with PGA or TCAI. The diagnosis of glaucoma was based on visual field examination, optic nerve head analysis, intraocular pressure (IOP) measurements, and gonioscopy. Two age-matched subgroups were created: one treated with PGA and the other with TCAI. CCT, ophthalmoscopic cup/disc ratio (CDR), mean deviation (MD), pattern standard deviation (PSD), and IOP were considered for both eyes of each patient. Student t-test was used to compare the 2 subgroups.The mean age of the PGA group was 66.35±12.17 years, while 65.17±12.52 years was for the TCAI group. No significant difference was found for CCT (543.75±35 μm and 544±35 μm, respectively), CDR (0.55±0.2 and 0.53±0.2, respectively), MD (-4.5±4.9 dB and -5.4±6.4 dB, respectively), PSD (4.6±3.4 and 4.6±4.9, respectively), and IOP (15.9±3.3 mmHg and 15.7±2.9 mmHg, respectively) between the 2 subgroups. A significant (P0.001) correlation was found between CCT and CDR and between CCT and IOP.No significant difference in CCT was found between patients treated with PGA and TCAI, suggesting that these topical medications did not statistically and clinically change the CCT.

To evaluate whether a difference in central corneal thickness (CCT) between the paired eyes could be associated to worse glaucoma in the thinner cornea eye.From 16 different glaucoma centres, at least 50 glaucomatous patients were saved on the Italian Glaucoma Register. Eight hundred and sixteen glaucomatous patients were found in the register. CCT, ophthalmoscopic cup/disc ratio, mean deviation (MD), pattern SD (PSD), and intraocular pressure (IOP). The difference (Δ) between the paired eyes was calculated for all the considered parameters and two subgroups were created on the basis of ΔCCT. Because the difference between the two eyes could be positive or negative, the absolute value of Δ was considered for all the measurements. Three different ΔCCT cutoffs were selected: 10, 15, and 20 μm. Student's t-test was used to compare the subgroups.When the entire group was divided in two subgroups using 20 μm as ΔCCT cutoff, no significant difference was found for ΔIOP (-0.38 ± 2.53 (mean ± SD) mm Hg and -0.07 ± 2.35 mm Hg, respectively) between the two subgroups. Significant (P0.001) difference was found for ΔMD (6.58 ± 7.30 and 3.14 ± 4.22 dB, respectively), ΔPSD (3.92 ± 4.01 and 2.16 ± 2.57, respectively), and ΔC/D (0.11 ± 0.14 and 0.08 ± 0.11, respectively) between the two subgroups. No significant correlation was found between ΔCCT and the other parameters.The ΔCCT between the two eyes could be associated to a worse glaucoma in the thinner cornea eye.

To investigate and compare the diagnostic accuracy of the Heidelberg Retinal Tomograph 3 (HRT3) diagnostic algorithms and establish whether they are affected by optic disc size and glaucoma severity.Multicenter cross-sectional evaluation of diagnostic tests.Two hundred forty-two eyes from 139 normal subjects and 103 glaucomatous patients classified by the presence of a repeatable visual field (VF) defect.Eyes were imaged by the HRT3. The diagnostic accuracies of Moorfields regression analysis (MRA) and the glaucoma probability score (GPS) was explored by sensitivity and specificity and area under the receiver operating characteristics curves (AUC). The analysis was performed globally and by optic disc size quartiles and by 3 VF severity groups.Sensitivity, specificity, and AUC.The GPS showed a sensitivity (80% vs. 77%) similar to and a specificity (57% vs. 67%) lower than that of MRA Result. It showed a higher specificity in small discs than MRA Result (77% vs. 68%) but a low to very low specificity in medium to very large discs (medium, 61%; large, 50%; very large, 26%). Moorfields regression analysis Global showed the highest sensitivity and specificity (68% and 78%) in very large discs. R. Burke linear discriminant function (RB-LDF) and cup shape measure (CSM) showed the best and least variable AUC across optic nerve head sizes and glaucoma stages. The sensitivity of both MRA and the GPS decreased at the earlier glaucoma stages. The MRA and GPS agreement was moderate throughout the entire population and in small discs and early stage, whereas it was weaker among the other disc size and glaucoma stage subgroups.HRT3 diagnostic algorithms' accuracy is moderate. The GPS is less specific and more influenced by disc size than MRA. Cup shape measure and the RB-LDF offer the best and less variable performances across different disc sizes and glaucoma stages.