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Inflammation plays a key role in dry eye disease (DED) affecting millions of people worldwide. Non-steroidal anti-inflammatory drugs (NSAIDs) can be used topically to act on the inflammatory component of DED, but their limited aqueous solubility raises formulation issues. The aim of this study was development and optimization of functional cationic nanoemulsions (NEs) for DED treatment, as a formulation approach to circumvent solubility problems, prolong drug residence at the ocular surface and stabilize the tear film. Ibuprofen was employed as the model NSAID, chitosan as the cationic agent, and lecithin as the anionic surfactant enabling chitosan incorporation. Moreover, lecithin is a mixture of phospholipids including phosphatidylcholine and phosphatidylethanolamine, two constituents of the natural tear film important for its stability. NEs were characterized in terms of droplet size, polydispersity index, zeta-potential, pH, viscosity, osmolarity, surface tension, entrapment efficiency, stability, sterilizability and in vitro release. NEs mucoadhesive properties were tested rheologically after mixing with mucin dispersion. Biocompatibility was assessed employing 3D HCE-T cell-based model and ex vivo model using porcine corneas. The results of our study pointed out the NE formulation with 0.05% (w/w) chitosan as the lead formulation with physicochemical properties adequate for ophthalmic application, mucoadhesive character and excellent biocompatibility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to investigate the effects of the concentration of two intracellular (i.e. propylene glycol and glycerol) and four extracellular (i.e. dextran, hydroxypropyl methylcellulose, polyvinylpyrolidone, trehalose) cryoprotective agents as well as the effects of freeze-thawing procedures on the corneal cryoprotection. Significance: The corneal cryopreservation may possibly become the long-term storage technique of choice for collection of animal corneas suitable for ex vivo drug testing. Methods: The integrity of corneal barrier was evaluated by measurements of transepithelial electrical resistance. Results: Under the investigated experimental conditions the best result was obtained for slow freezing (2 h at -20 °C followed by 46 h at -70 °C) and rapid thawing (0.25 h at 34 °C) procedure where 20% ( w / V ) trehalose in Krebs Ringer buffer solution was used as extracellular cryoprotective agent. Conclusions: The selection of corneal freeze-thawing protocol as well as the optimal type and concentration of a cryoprotective agent allows the cryostorage of porcine corneal tissues with suitable TEER properties (cryocornea).

Azelaic acid (AZA) is a dicarboxylic acid that is topically used in the treatment of acne and rosacea since it possesses antibacterial and keratolytic activity. The primary objective of this study was to develop an AZA nanocrystal suspension. It is expected that improved solubility and dissolution rate will result in advanced biopharmaceutical properties, primarily the dermal bioavailability. Furthermore, a topical nanocrystal AZA-loaded hydrogels composed of Pluronic ® F127 and hyaluronic acid mixture that are able to deliver AZA into the stratum corneum and deeper skin layers were considered. This study was conducted in order to: 1) determine the effect of non-ionic Polysorbate 60 on the stabilization and particle size of the AZA nanocrystals, as well as the effect of Pluronic ® F127, used as an in situ gelation agent, and hyaluronic acid on the viscoelastic properties and the drug release of composed hydrogels, 2) determine the relationship between the rheological properties of the gels and the penetration of AZA into the stratum corneum. The composed hydrogels revealed pseudoplastic flow behaviour. The increase in Pluronic ® F127 concentration induced a domination of elastic over viscous behaviour of the gels. The gel containing 15% of Pluronic ® F127, 1% of hyaluronic acid and lyophilised 10% nanocrystal AZA suspension was considered to be an optimal formulation, since it possessed the rheological and drug delivery properties desirable for an in situ gelling platform for dermal application., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The objective of this study was to systematically investigate the effects of surface active ophthalmic excipients on the corneal permeation of ophthalmic drugs using in vitro (HCE-T cell-based model) and ex vivo (freshly excised porcine cornea) models. The permeation of four ophthalmic drugs (i.e., timolol maleate, chloramphenicol, diclofenac sodium and dexamethasone) across in vitro and ex vivo corneal models was evaluated in the absence and presence of four commonly used surface active ophthalmic excipients (i.e., Polysorbate 80, Tyloxapol, Cremophor® EL and Pluronic® F68). The concentration and self-aggregation-dependent effects of surface active ophthalmic excipients on ophthalmic drug permeability were studied from the concentration region where only dissolved monomer molecules of surface active ophthalmic excipients exist, as well as the concentration region in which aggregates of variable size and dispersion are spontaneously formed. Neither the surface active ophthalmic excipients nor the ophthalmic drugs at all concentrations that were tested significantly affected the barrier properties of both corneal models, as assessed by transepithelial electrical resistance (TEER) monitoring during the permeability experiments. The lowest concentration of all investigated surface active ophthalmic excipients did not significantly affect the ophthalmic drug permeability across both of the corneal models that were used. For three ophthalmic drugs (i.e., chloramphenicol, diclofenac sodium and dexamethasone), depressed in vitro and ex vivo permeability were observed in the concentration range of either Polysorbate 80, Tyloxapol, Cremophor® EL or Pluronic® F68, at which self-aggregation is detected. The effect was the most pronounced for Cremophor® EL (1 and 2%, w/V) and was the least pronounced for Pluronic® F68 (1%, w/V). However, all surface active ophthalmic excipients over the entire concentration range that was tested did not significantly affect the in vitro and ex vivo permeability of timolol maleate, which is the most hydrophilic ophthalmic drug that was investigated. The results of the dynamic light scattering measurements point to the association of ophthalmic drugs with self-aggregates of surface active ophthalmic excipients as the potential mechanism of the observed permeability-depressing effect of surface active ophthalmic excipients. A strong and statistically significant correlation was observed between in vitro and ex vivo permeability of ophthalmic drugs in the presence of surface active ophthalmic excipients, which indicates that the observed permeability-altering effects of surface active ophthalmic excipients were comparable and were mediated by the same mechanism in both corneal models., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this study, we suggest the development of nanoparticle loaded in situ gelling system suitable for corticosteroid nasal delivery. We propose lipid/alginate nanoparticles (size 252.3±2.4nm, polydispersity index 0.241, zeta-potential -31.7±1.0mV, dexamethasone (Dex) content 255±7μgml -1 ) dispersed in pectin solution (5mgml -1 ) that undergoes a sol-gel phase transition triggered by Ca 2+ present in nasal mucosa. The viscoelasticity of gel obtained by mixing nanoparticle suspension in pectin continuous phase with simulated nasal fluid (1:1V/V) is characterised by a log-linear shear thinning viscosity behaviour. Observed viscosity corresponds to the range of viscosities of nasal mucus at physiological as well as under disease conditions. Nanoparticle-loaded gel was biocompatible with the selected epithelial cell model and, in comparison to dexamethasone solution, provided reduction in Dex release (t 50% 2.1h and 0.6h, respectively) and moderated transepithelial permeation in vitro (P app 7.88±0.15 and 9.73±0.57×10 -6 cms -1 , respectively). In conclusion, this study showed the potential of the proposed system to provide local therapeutic effect upon administration of a lower corticosteroid dose and minimize the possibility for adverse effects as it can be easily sprayed as solution and delivered beyond nasal valve, ensure prolonged contact time with nasal mucosa upon gelation, and moderate corticosteroid release and permeation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The most extensively characterized human-derived cell line used in transcorneal permeability studies, in terms of passive transcellular and paracellular transport, transporter expression and metabolic enzymes, is the immortalized human corneal epithelial cell line (HCE-T). The purpose of this study is to describe the changes in the HCE-T barrier phenotype in vitro when valid cultivation conditions, in accordance with the standardized HCE-T cell-based model protocol, were employed. Evaluation of the structural and functional barrier properties revealed two different HCE-T barrier phenotypes, depending on the polycarbonate membrane pore size. Model I (pore size 0.4μm) was characterized by a multilayered HCE-T epithelium at the apical side and a weak barrier function (70-115Ω×cm 2 ), whereas Model II (pore size 3μm) consisted of an apical lipophilic HCE-T monolayer and a basolateral lipophilic monolayer of migrated HCE-T cells that showed improved barrier properties (1700-2600Ω×cm 2 ) compared with Model I. Considering the permeation of ophthalmic compounds and in vitro/ex vivo correlation, Model II was better able to predict transcorneal drug permeation. This study highlights the important aspects of HCE-T barrier phenotype variability that should be continuously monitored in the routine application of HCE-T cell-based models across both academic and pharmaceutical industry research laboratories., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To evaluate the compatibility of commercially available eye drop surface tension with the tear film physiological range and to characterize commonly used ophthalmic excipients in terms of their surface activity under eye-biorelevant conditions., Significance: There are a number of quality requirements for the eye drops (e.g. tonicity, pH, viscosity, refractive index) that needs to comply with the physiological parameters of the eye surface. However, the adjustment of surface tension properties of the eye drops to the normal range of surface tension at the air/tear fluid interface (40-46 mN/m) has received rather less attention thus far. Yet, the surface tension at the air/tear fluid interface is of vital importance for the normal function of the eye surface., Methods: The surface tension compatibility of the isotonic aqueous solutions of commonly used ophthalmic excipients as well as 18 approved eye drops with the tear fluid have been evaluated using surface tension method., Results: Each ophthalmic ingredient including the preservatives, solubilizing agents and thickening agents can influence the surface tension of the final formulation. In case of complex ophthalmic formulations one should also consider the possible interactions among excipients and consequent impact on overall surface activity. Out of 18 evaluated eye drops, three samples were within, 12 samples were below and three samples were above the physiological range of the tear fluid surface tension., Conclusions: Our results provide a rationale for clinical studies aiming to assess the correlation between the eye drops surface tension and the tear film (in)stability.

Herein, we propose an innovative approach to improving wound healing. Our strategy is to deliver melatonin locally at the wound site by means of lecithin/chitosan nanoparticles. We used four types of chitosan that differed in terms of molecular weight and/or deacetylation degree. Melatonin encapsulation efficiency, nanoparticle size, zeta potential, biocompatibility and in vitro drug release were studied as a function of the type of chitosan used in preparation. The nanoparticles were evaluated in terms of their potential to promote wound epithelialisation via an in vitro scratch assay using a human keratinocyte (HaCaT) monolayer. The model wounds were treated with nanoparticle suspensions at a chitosan concentration of 5μgml(-1), which was based on preceding cell biocompatibility studies. Nanoparticles prepared with different types of chitosan showed similar effect on the keratinocyte proliferation/migration. Nanoparticle-mediated interplay of chitosan and melatonin was shown to be crucial for improved wound epithelialisation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In this study, two types of nanosystems, namely lecithin/chitosan nanoparticles and Pluronic® F127/chitosan micelles, have been prepared and evaluated for their potential for the ocular delivery of melatonin, which is known to exert an ocular hypotensive effect. The melatonin content, particle size, zeta potential and in vitro drug release properties were studied as a function of the presence of chitosan in the nanosystem. Lecithin/chitosan nanoparticles were evaluated in terms of the mucoadhesive properties by a newly established method based on HCE-T cells, also used in in vitro biocompatibility and permeability studies. Lecithin/chitosan nanoparticles were significantly larger than the corresponding F127/chitosan micelles (mean diameter of 241.8 vs. 20.7nm, respectively) and characterised by a higher surface charge (22.7 vs. 4.3mV, respectively). The HCE-T cell viability assay did not show significant toxic effects of nanosystems investigated at the (relevant) chitosan concentration tested. The permeability study results confirmed the permeation enhancing effect of F127, which was hindered in the presence of chitosan. Lecithin/chitosan nanoparticles were characterised by prominent mucoadhesive properties and prolonged melatonin release, which was shown to control melatonin permeation across an in vitro corneal epithelial model. Such properties demonstrate the potential for nanoparticles to provide an extended pre-corneal residence time of melatonin, ensuring higher eye-related bioavailability and extended intraocular pressure reduction compared to melatonin in both aqueous and micelle solutions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: Osteopontin (OPN) is non-collagenous extracellular matrix protein involved in various physiological and pathological events, including tumor progression. The aim of this study was to analyze the expression of OPN in normal oral mucosa and oral squamous cell carcinoma (OSCC) and to assess its prognostic significance., Methods: The expression of OPN was immunohistochemicaly analyzed in 86 OSCC and compared with clinicopathological variable such as tumor size, nodal stage, WHO clinical stage, Ki-67 proliferation index, and patients' outcome. OPN mRNA was analyzed using quantitative real-time PCR and compared with protein OPN expression and clinical outcome in 18 OSCC samples., Results: The expression of OPN protein was found in OSCC tumor cells (t-OPN) and various stromal cells (s-OPN). High level of t-OPN expression was associated with higher nodal stage (P = 0.045), higher WHO clinical stage (P = 0.033), and poor clinical outcome (P = 0.022). In multivariate analysis, t-OPN emerged as an adverse independent factor for survival (P = 0.049). Although correlated with t-OPN (P = 0.005), s-OPN was not significantly associated with clinical parameters, including patients' outcome. Also, there was no association between OPN and clinical parameters at the mRNA level., Conclusion: OPN is upregulated in tumor and stromal OSCC cells. Tumor cell-derived OPN is involved in tumor progression and can independently predict the clinical outcome. Stromal-derived OPN probably has a different function compared with OPN secreted from tumor cells., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Locked-in syndrome (LIS) is an entity that usually occur a consequence of the lesion of ventral part of pons. Etiology of locked-in syndrome can be vascular and nonvascular origin. Locked-in syndrome usually occurs as a consequence of thrombosis of intermedial segment of basilar artery that induces bilateral infarction of the ventrobasal part of the pons. Additionally, LIS can be caused by trauma which often leads to posttraumatic thrombosis of basilar artery. The incidence of locked-in syndrome is still unknown. The basic clinical features of locked-in syndrome are: quadriplegia (a consequence of disruption of corticospinal pathways located in ventral part of pons), different stages of paralysis of mimic musculature, paralysis of pharynx, tongue and palate with mutism and anarthria. The patient can not move, but is conscious and can communicate only by eye movements. Two patients with locked-in syndrome were present in this article. In the first case, the patient had classic locked-in syndrome that was first described by Plum and Posner. Other patient had incomplete form of locket-in syndrome which was first described by Bauer. In these two patients locked-in syndrome occurred as a consequence of trauma. In the first patient locked-in syndrome was caused by direct contusion of ventral part of pons while in other patient locked-in syndrome was a consequence of posttraumatic thrombosis of vertebrobasilar artery. The introduction of anticoagulant therapy, besides the other measures of intensive therapy, has shown complete justification in the second patient. The gradual partial recovery of neurologic deficit has developed in the second patient without any additional complications.

The aim of this study was to determine the salivary concentrations of tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6) in patients with premalignant and malignant lesions. The study involved 57 patients who were examined between 2008 and 2010 at the Department of Oral Medicine and Department of Oral and Maxillofacial Surgery of the Medical Faculty, University of Rijeka, Croatia. They were divided into three groups: 19 patients with oral premalignant lesions, 19 with oral squamous cell carcinoma and 19 healthy control volunteers. Whole saliva was collected and investigated for the presence of TNF-α and IL-6 by enzyme immunoassay at the Department of Dentistry and Maxillofacial Surgery, Medical Faculty, University of Graz, Austria. All groups had statistically significant differences in values of TNF-α and IL-6 (P < 0.001). The results suggest that these proinflammatory cytokines are elevated in the saliva of patients with oral squamous cell carcinoma and oral premalignant lesions as compared to controls, which may have diagnostic and/or prognostic significance.

Patient underwent mandibular resection due to surgical therapy of oropharingeal malignoma. Facial asymmetry and cosmetic distortion are frequent consequences of such interventions, which may also include deviation and intrusion of the mandible, motor and sensory disorders, abnormal intermaxillary relations and malocclusion. Implant-supported prosthesis could be an optimal solution to prosthodontic treatment of such patients. However, there is a problem in determination of stable (interocclusal) intermaxillary relations. This article describes the choice of therapy and procedures undertaken in prosthetic rehabilitation of a patient who underwent mandibular resection and radiotherapy with supported prosthesis retained with four implants.

The effects of psychological factors in alcoholics with malignant tumor of the oral cavity and oropharynx are scarcely explored. The aim of the research was to examine early family relations and investigate differences in the use of defense mechanisms in alcohol dependent patients suffering from malignant tumor of the oral cavity and oropharynx compared to alcohol dependent persons without malignant tumors and healthy controls. The research included 51 alcohol dependent patients treated for malignant tumor of the oral cavity and oropharynx at the University Hospital Center Rijeka from 2005 to 2009. The control groups corresponded to the experimental group in age, sex and education level. The research used a general demographic questionnaire, the Mini International Neuropsychiatric Interview and the Revised Questionnaire of Life Style and Defense Mechanisms. The research groups showed significant differences in difficult childhood (p < 0.001) including abuse (p = 0.004). The alcohol dependent persons suffering from malignant tumors of the oral cavity and oropharynx significantly less frequently used primitive defense mechanisms of regression (p = 0.004) and displacement (p = 0.013) compared to alcoholics without malignant tumors who significantly more often used neurotic defense mechanisms - compensation (p = 0.005) and intellectualization (p < 0.001). The earliest emotional experiences and quality of family relations affect the development of defense mechanisms. These are the psychological factors in the development of oropharyngeal cancer in alcohol addicts.

Main objective of this study was to evaluate the usefulness and accuracy of fine needle aspiration cytology (FNAC) diagnosis of parotid masses to distinguish reliably between benign and malignant lesions. In the period of 5 years, 214 parotid glands were resected at the Rijeka University Hospital Center (Croatia), but 176 patients had cytopathological and histopathological diagnoses and therefore fulfilled the criteria for study. The results of the FNAC were analyzed and compared to the corresponding histopathological diagnosis obtained from the surgical specimen. Histological evaluation revealed 17malignant and 159 benign lesions. There were 13 true positive, 147 true negative, 3 false negative, and 13 false positive. Sensitivity of FNAC was 81%, and specificity was 98%. FNAC results provide useful predictive preoperative information and better preparation the surgeon and patient for surgical procedure.

Number of researches dealing with the influence of the ABO blood group antigens on the development of the oral cancer have hypothesized that people who do not secrete these substances in the saliva are more prone to suffer from this disease. The objective of this research is to examine this hypothesis. In total 114 subjects were examined, half of which suffered from oral cancer, while the other half was the healthy control group. All examinees were subjected to clinical examinations and the experimental group to pathohistological examination. An analysis of the secretor status was carried out using the Wiener agglutination test. The experimental group consisted of 78.95% of secretors, while the control group consisted of 82.46% of secretors. This difference is not statistically significant. The starting hypothesis that non-secretors are more prone to the development of oral cancer was not confirmed.

Frontobasal injuries and some other diseases of frontal sinuses sometimes require radical surgery with the obliteration of the sinus. A cosmetic correction of the forehead and supraorbital arches has to be performed after such a procedure. Nowadays, there is a wide choice of alloplastic materials on the market. We tried polymethyl methacrylate implants in correction of the exterior appearance of the forehead and supraorbital arches and followed the behaviour of the implants up to 25 years after surgery. The result was 18 (94.7%) successful implantations and one failure (5.3%) with a mild sagging of the borders of the implant. Polymethyl-methacrylate proved pliable for work and modelling, not invasive for the organism and stable. In conclusion, the cure of some frontobasal injuries and diseases with the first surgical step followed by cosmetic correction of the forehead and supraorbital arches (2nd surgical step) using this alloplastic material provides a safe, durable and aesthetically satisfactory solution for the patient.

Seventy-six patients with oroantral communications after tooth extraction and chronic maxillary sinusitis were treated as follows: bacterial cultures were taken in all of them and maxillary sinuses were irrigated with an antibiotic from the cephalosporin group. Then, in 36 patients, drainage using the Caldwell Luc procedure was performed, including a naso-antral window. In all patients operations were completed by closing oroantral communications with flaps of the mucosa of the alveolar process close to the fistula. Antibiotics according to antibiogram were administered to all patients at least 10 days after surgery. Retrospective comparison between the results obtained in the first group and those in the second group 1, 3 and 6 months after operation was based on objective findings (condition of the oroantral communication, maxillary sinusitis), side effects (pain, numbness of the operated area, headache) and control radiographs (clear maxillary sinus or with mucosal thickening). The study suggests that transnasal drainage is not required in maxillary sinus surgery and in the closure of oroantral communications. Equally good results are achieved by treating with antibiotics and without drainage of the maxillary sinus into the nose.

In this paper we have presented 38 cases of wounded persons who had sustained war injuries in maxillo-facial and neck region. All of them were injured in Croatia during the war period of 1991 and 1992, and treated at the Maxillo-Facial Surgery Department of the Clinical Hospital of Rijeka. The wounded persons were observed and monitored from the moment of their injury through the first aid on the spot, up to the surgical treatment of the wounds, subsequent primary and secondary reconstruction, and the final medical treatment. This paper describes for wounded persons with injuries of bones and soft tissue of the face. In two thirds of the wounded persons with the primary medical treatment and reconstruction, the cure terminated, while in one third it was necessary to provide for a secondary reconstructive operation. At the end of the treatment, all the wounded persons were successfully cured, functionally and aesthetically restored, so they were able to leave the Clinic to return to their everyday life and work. Such result has been particularly gratifying because they were mostly young men.