OBJECTIVE The aim was to study the association of the use of an oral antihyperglycemic agent metformin with the presence of ocular complications in patients with type 2 diabetes (T2D). METHODS Medical records were reviewed for 234 patients with diagnosed T2D. 81.2% (n=190) patients were using metformin and 18.8% (n=44) using other oral antihyperglycemic agents. Plasma glucose concentration, glycated haemoglobin, and the presence of ocular complications in patients treated with metformin were compared to those in patients treated with other oral antihyperglycemic agents. RESULTS Ocular complications occurred in 65 patients (27.8%). Patients treated with metformin had fewer ocular complications compared to patients treated with other oral antihyperglycemic agents (χ2=19.985; p<0.0001). After adjustment for gender, age, duration of T2D, serum concentration of cholesterol, smoking, body mass index and presence of other diseases, treatment with metformin decreased the odds of both glaucoma (OR=0.14, 95% CI: 0.03-0.57, p=0.006) and diabetic retinopathy (OR=0.33, 95% CI: 0.14-0.82, p=0.017) compared with other oral antihyperglycemic agents. CONCLUSION Our results suggest that metformin may have a protective effect on ocular complications, especially glaucoma, in patients with T2D. The effects of metformin either regarding prevention of ocular complications or ocular complications already developed in patients with T2D, should be further investigated.

Chronic inflammation increases the risk of lung cancer. Macrophages (MO) are important players in inflammation, with regulatory and executive functions. Eicosanoids and exosomes can be both triggers and mediators of these functions. Cysteinyl leukotrienes (CysLTs) are the most potent mediators of broncho-constriction in the lungs, a function exerted via CysLT1 receptor. Their function in asthma is well described, but little is known about CysLTs and lung cancer. In the first study we investigated how the interaction between pulmonary epithelium and leukocytes affects CysLTs formation. Monocytic cells and eosinophils formed LTC4, which was exported and promptly converted to LTD4 by pulmonary epithelial cells in a transcellular manner. The lung cancer cell line A549 expressing γ-glutamyl transpeptidase 1 (GGT-1) showed a high activity. Exosomes released by A549 cells also contained GGT-1 and efficiently converted LTC4 to LTD4. On the other hand, healthy bronchial epithelial cells (PBEC) expressing GGT-5 formed LTD4 12 times more slowly. The results highlight an active role for epithelial cells and their exosomes in biosynthesis of LTD4, which may be of particular relevance in the lung, given that LTD4 is the most potent agonist of CysLT1. MOs can be differentiated from blood monocytes with GM-CSF and M-CSF, resulting in cells primed toward the inflammatory M1and resolving M2-states. A comprehensive analysis of eicosanoid formation in these two in vitro models is missing and our second study focused on this gap. By LC-MS analysis, we observed that both MO phenotypes released pro-resolving lipid mediators (PGE metabolite, LXA4) in resting conditions. When the same cells were incubated (30 min) with bacterial stimuli, there was a shift to pro-inflammatory eicosanoids: M-CSF MOs produced high amounts of LTC4, relevant for M2 functions in asthma. GM-CSF cells expressed the highest levels of cPLA2, 5-LO and FLAP; and in ionophore incubations these cells also produced the highest levels of 5-HETE. However, MCSF MO formed more products apparently due to a better response to bacterial stimuli, demonstrated by enhanced mobilization and activation of cPLA2 and 5-LO. In conclusion, GM-CSF and M-CSF can regulate specific pathways in MOs, and it appears that eicosanoid biosynthesis primarily reflect the cellular response and activation mechanisms, rather than the protein expression profile. In colon cancer a pro-tumorigenic effect of LTD4 but not LTC4 has been demonstrated. A pro-tumorigenic effect has been shown also for exosomes. To extend the findings of our first study, we used pleura exudates from lung cancer patients to isolate primary cancer cells and exosomes. Both cells and exosomes metabolized LTC4 to LTD4, and we also found that exosomes stimulated CysLTs formation in the cancer cells. Cancer cells from all patients expressed CysLT1, and exosomes promoted their migration and survival in a CysLT1 dependent manner, as demonstrated by the inhibition by montelukast (MK) treatment, a CysLT1 antagonist used to treat asthma. In cancer, interactions between the transformed cancer cells and other recruited cell types in the tumor are important. Tumor associated macrophages (TAMs) provide cancer cells with a suitable low-grade inflammation milieu including growth promoting factors. Taken together, the results in this thesis suggest a novel pro-tumorigenic mechanism based on this theme, driven by the exosomes/CysLT1 cascade: TAMs provide LTC4 that lung cancer cells and their exosomes convert to LTD4. Via CysLT1 receptor this promotes survival and migration of the cancer cells. A protective effect in lung cancer has been previously described for MK and our results suggest a possible mechanism for this, driven by the exosomes/ CysLT1 cascade, further encouraging the use of this drug in lung cancer treatment. LIST OF SCIENTIFIC PAPERS I. Lukic, A., Ji, J., Idborg, H., Samuelsson, B., Palmberg, L., Gabrielsson, S., & Rådmark, O. (2016). Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4. Journal of lipid research, 57(9), 1659-1669 II. Lukic, A., Larssen, P., Fauland, A., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., & Radmark, O. (2017). GM-CSF–and M-CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures. The FASEB Journal, 31(10), 4370-4381. III. Lukic, A., Wahlund, C., Gomez, C., Brodin, D., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., & Radmark, O. Exosomes and malignant cells from lung cancer pleura exudates form LTD4, promoting cell migration and survival in a CysLT1 dependent mechanism. Manuscript Publications not included in this thesis: I. Torregrosa Paredes, P., Esser, J., Admyre, C., Nord, M., Rahman, Q. K., Lukic, A., ... & Scheynius, A. (2012). Bronchoalveolar lavage fluid exosomes contribute to cytokine and leukotriene production in allergic asthma. Allergy, 67(7), 911-919. II. Basavarajappa, D., Wan, M., Lukic, A., Steinhilber, D., Samuelsson, B., & Rådmark, O. (2014). Roles of coactosin-like protein (CLP) and 5-lipoxygenase-activating protein (FLAP) in cellular leukotriene biosynthesis. Proceedings of the National Academy of Sciences, 111(31), 11371-11376. III. Martinez-Bravo, M. J., Wahlund, C. J., Qazi, K. R., Moulder, R., Lukic, A., Rådmark, O., ... & Gabrielsson, S. (2017). Pulmonary sarcoidosis is associated with exosomal vitamin D–binding protein and inflammatory molecules. Journal of Allergy and Clinical Immunology, 139(4), 1186-1194. LIST OF ABBREVIATIONS AA AERD BAL BEC BLT CD COPD COX cPLA2 CYP CysLT DHA DiHET DiHOME EDP EET EGFR EMT EP EPA EpOME ESCRT FLAP fMLP GGT GM-CSF Arachidonic acid Aspiring exacerbated respiratory disease Bronco-alveolar lavage Bronchial epithelial cells Leukotriene B4 receptor Cluster of differentiation Chronic obstructive pulmonary disease Cyclooxygenase Cytosolic phospholipase A2 Cytochrome P450 Cysteinyl leukotriene Docosahexaenois acid Dihydroxyeicosatrienoic acids Dihydroxyoctadecenoic acid Epoxydocosapentaenoic acid Epoxyeicosatrienoic acid Epithelial growth factor receptor Epithelial to mesothelial transition Prostaglandin E2 receptor Epoxydocosapentaenoic acid Epoxyoctadecenoic acid Endosomal complex required for transport Five lipoxygenase activating protein N-formylmethionyl-leucyl-phenylalanine Gamma-glutamyl transpeptidase Granulocyte macrophage-colony stimulating factor M-CSF GSH GTP HDoHE HETE HODE HpETE HPLC IL IFN-γ LA LC-MS LO LPS Macrophage-colony stimulating factor Glutathione Guanosine Triphosphate Hydroxydocosahexaenoic acid Hydroxyeicosatetraenoic acid Hydroxyoctadecadienoic acid Hydroperoxy eicosatetraenoic acid High-performance liquid chromatography Interleukin Interferon γ Linoleic acid Liquid chromatography-mass spectrometry Lipoxygenase Lipopolysaccharide LT LTC4s LTB4h LX MDSC MHC miRNA MK MM6 mPGES MSC MVB NSCLC PBEC PBMC Leukotriene LTC4 synthase LTB4 hydrolase Lipoxin Myeloid derived suppressor cells Major histocompatibility complex Micro RNA Montelukast Mono Mac 6 Microsomal prostaglandin E2 synthase Mesenchymal stem cells Multivesicular bodies Non-small cell lung cancer Primary BEC Peripheral blood mononuclear cells PE PG PGN PMN PTGIS PUFA RvE/RvD TLR SBC sEH SPM TAM Th TME TNFα Treg TXAS VEGF Pleural exudate Prostaglandin Peptidoglycan Polymorphonuclear neutrophils PGI2 synthase Polyunsaturated fatty acids Resolvins E/D series Toll like receptor Serine Borate Complex soluble Epoxide Hydrolase Specialized proresolving mediators Tumor associated macrophages T helper cell Tumor micro-environment Tumor necrosis factor alpha Regulatory T cell Thromboxane A synthase 1 Vascular endothelial growth factor

OBJECTIVE To evaluate and compare the water sorption of three luting cements in three different solutions: distilled water and artificial saliva with different pH values (7.4 and 3.0). MATERIALS AND METHODS Resin-modified glass-ionomer cement (GC Fuji Plus) and two resin cements (Multilink Automix and Variolink II) were used. A total of 45 specimens - 15 specimens (15x1 mm) for each cement were prepared according to ISO standard 4049:2009. The water sorptions of the cements were calculated by weighing the specimens before and after immersion and desiccation. RESULTS . Nonparametric statistic methods were applied. GC Fuji Plus cement showed significantly higher values of water sorption in all three solutions of both resin cements (p<0.009) and significantly higher values of sorption in artificial saliva pH 3.0. Multilink Automix showed significantly higher values of water sorption compared with Variolink II in artificial saliva pH 7.4, and higher values of sorption in this solution compared with pH value 3.0. CONCLUSION Water sorption values are mainly influenced by the proportion of hydrophilic matrix, the type and composition of filler, and the pH value of solutions.

Drawing from the mental ability framework and information processing theory, two studies embedded within the B2C retail setting investigate the role of the sales manager's ability-to-perceive-emotions in the complex non-linear relationships between salespeople's customer and selling orientations on one side, and its outcomes (sales performance and customer re-purchase intention) on the other. Using multilevel data from salespeople and their managers, Study 1 tests a theoretical model of salesperson orientation and performance, while Study 2 further verifies the results of Study 1 from the customer's perspective. Both studies find strong empirical support for a curvilinear, inverted U-shaped effect of a salesperson's customer orientation on sales performance and customer re-purchase intention. This effect is, however, reversed for the link between selling orientation and performance/re-purchase intention, where results indicate a U-shaped curvilinear relationship. Furthermore, we show that the sales manager's ability to perceive emotions facilitates the effect of salespeople's customer orientation on sales performance.

The aim of this study was to research the relation between exposure to maltreatment in childhood and working memory capacity in adulthood. A survey among 376 females in the age between 16 and 67 was administered. Exposure to maltreatment in childhood (sexual, physical and psychological abuse, neglect and witnessing family violence) was assessed retrospectively using the Child Maltreatment Questionnaire (Karlović, Buljan-Flander, & Vranić, 2001), whilst the Working Memory Questionnaire (Vallat-Azouvi, Pradat-Diehl, & Azouvi, 2012) was used to assess working memory capacity (recalling verbal information, numerical information, attention ability and executive functioning). The results suggest a significantly greater prevalence of physical abuse and witnessing family violence in comparison to other forms of maltreatment in childhood. Psychological abuse and witnessing family violence have shown themselves to be statistically significant predictors for deficits in total working memory capacity, verbal recall and attention ability. The results suggest that traumatic experiences during childhood, such as abuse, may trigger particular cognitive changes which may be reflected in adulthood. It is, therefore, exceedingly important to conduct further research in order to contribute to the understanding of the correlation between cognitive difficulties and maltreatment in childhood.

Introduction : A method for age estimation, based on measurements of projections of open apices and heights of developing permanent teeth on orthopantomograms (OPTs), was presented by Cameriere in 2006 and adopted European formula was presented in 2007. Aim : This cross-sectional study tested the accuracy of Cameriere’s European formula on a sample from the City of Sarajevo, Bosnia and Herzegovina. Materials and methods : A final sample of 560 OPTs of 305 girls and 255 boys aged 8 to 14 years was obtained. The sample was collected at the Department of Orthodontics, School of Dental Medicine at the University of Sarajevo (SFUNSA). Dental age was compared to chronological age and mean absolute error (MAE) was calculated. Intra-rater and inter-rater agreement of the evaluated variables were calculated. Results : The dental age was underestimated when compared to chronological age, precisely, mean underestimation was -0.14 years in girls and -0.17 years in boys. The values of MAE were 0.62 years in girls and 0.56 years in boys. The greatest error was found for the 14-year old group; DA was -1.04 years and -0.70 years in girls and boys respectively. Conclusion : Our results showed that Cameriere’s European formula might be a useful tool for age estimation in children from Bosnia and Herzegovina under the age of 14 years.