Special Issue "The Molecular and Cellular Pathophysiologic Mechanisms Underlying Ocular Diseases and Emerging Therapies".

Visual impairment and ophthalmic diseases represent significant global public health concerns, and their prevalence continues to rise [...].

Pathohistological features of the aging human lacrimal gland.

AIM: To assess sex-related differences in the pathohistological features of the human lacrimal gland and to investigate age-related and sex-related differences in stereologically measured volume density of the secretory tissue, connective tissue, and fat. METHODS: We performed an observational analysis of acinar atrophy, periacinar fibrosis, periductal fibrosis, ductal dilation, ductal proliferation, fatty infiltration, and lymphocyte infiltration of hematoxylin and eosin-stained lacrimal gland samples from 81 cornea donors. Stereological analysis of the volume density of the secretory tissue, connective tissue, and fat was performed on samples from 66 donors. RESULTS: Up to 69% of all samples showed degenerative changes. Female samples had a higher frequency of all observed degenerative changes, except ductal dilation. While acinar atrophy was significantly more prevalent in women, ductal dilation was significantly more prevalent in men. Stereological analysis indicated lower portions of acini and higher portions of connective tissue and fat, as well as a more pronounced age-related progression of degenerative changes in female samples. CONCLUSION: Female lacrimal glands are more susceptible to degeneration, and this susceptibility could play an important role in the higher incidence of dry eye disease in older women. A further stereological analysis using more samples from younger age groups is needed to elucidate age-related and sex-related differences in the structure of the human lacrimal gland and their impact on dry eye disease.

Expression of Androgen and Estrogen Receptors in the Human Lacrimal Gland.

Lacrimal gland dysfunction causes dry eye disease (DED) due to decreased tear production. Aqueous-deficient DED is more prevalent in women, suggesting that sexual dimorphism of the human lacrimal gland could be a potential cause. Sex steroid hormones are a key factor in the development of sexual dimorphism. This study aimed to quantify estrogen receptor (ER) and androgen receptor (AR) expression in the human lacrimal gland and compare it between sexes. RNA was isolated from 35 human lacrimal gland tissue samples collected from 19 cornea donors. AR, ERα, and ERß mRNA was identified in all samples, and their expression was quantified using qPCR. Immunohistochemical staining was performed on selected samples to evaluate protein expression of the receptors. ERα mRNA expression was significantly higher than the expression of AR and ERß. No difference in sex steroid hormone (SSH) receptor mRNA expression was observed between sexes, and no correlation was observed with age. If ERα protein expression is found to be concordant with mRNA expression, it should be investigated further as a potential target for hormone therapy of DED. Further research is needed to elucidate the role of sex steroid hormone receptors in sex-related differences of lacrimal gland structure and disease.

Genetic and Epigenetic Features of Uveal Melanoma-An Overview and Clinical Implications.

Uveal melanoma (UM) is rare, but it is the most common primary intraocular malignancy among adults. This review represents the molecular, genetic, and immunobiological mechanisms involved in UM carcinogenesis and progression, as well as data about the association of chromosomal changes, genetic mutations, selective proteins, and biochemical biomarkers with the clinical implications of UM. Genetic analysis has the potential to identify patients with a high risk of UM metastasis, enabling management that is more effective and allowing for the follow-up of patients. Advancements in molecular characterization of UM offer opportunities to develop targeted therapeutic strategies by focusing on relevant signaling pathways. Changes in miRNA expression could be useful in the diagnosis and prognosis of UM, due to unique miRNA profiles in melanoma cells or tissue and its association with metastasis. Although liver function tests do not provide enough data on the prognosis of UM, due to the high frequency of liver metastasis, liver function tests (LFTs) might be useful indicators; however, the absence of rising LFT values cannot lead to the exclusion of liver metastases. Molecular analysis of tumor tissue will allow us to identify patients with the added benefit of new therapeutic agents and provide a better insight into melanoma pathogenesis and its biological behavior.

Vitamin D and Diabetic Retinopathy.

Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors. Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are the best-known forms of vitamin D. Calcitriol (1,25-dihydroxycholecalciferol) is the active form of vitamin D, with the sun being one of its main sources. Vitamin D is synthesized in the skin by exposure to sunlight without protective factors, but care must be taken to avoid the development of sunburn. It not only plays an important role in maintaining healthy bones and immune system but has also been highlighted in numerous studies to have an influence on various diseases, including diabetic retinopathy. A large number of people suffer from vitamin D hypovitaminosis worldwide, and diagnosis is made by measuring the concentration of 25-hydroxyvitamin D (25(OH)D) in serum. Its deficiency can cause numerous diseases and, as such, supplementation is necessary. Clinical studies have proven the effectiveness of vitamin D supplementation in the treatment of diabetic retinopathy, but with a doctor's recommendation and supervision due to possible negative side effects.

Tear Biomarkers and Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative brain disorder that represents the most common type of dementia. It poses a significant diagnostic challenge that requires timely recognition and treatment. Currently, there is no effective therapy for AD; however, certain medications may slow down its progression. The discovery of AD biomarkers, namely, magnetic resonance imaging, positron emission tomography and cerebrospinal fluid molecules (amyloid-ß and tau) has advanced our understanding of this disease and has been crucial for identifying early neuropathologic changes prior to clinical changes and cognitive decline. The close interrelationship between the eye and the brain suggests that tears could be an interesting source of biomarkers for AD; however, studies in this area are limited. The identification of biomarkers in tears will enable the development of cost-effective, non-invasive methods of screening, diagnosis and disease monitoring. In order to use tears as a standard method for early and non-invasive diagnosis of AD, future studies need to be conducted on a larger scale.

Overtraining Syndrome as a Risk Factor for Bone Stress Injuries among Paralympic Athletes.

Background and Objectives: In this review, we have explored the relationship between overtraining syndrome (OTS) and bone stress injuries among paralympic athletes. OTS is a complex condition that arises from an imbalance between training volume, nutrition, and recovery time, leading to significant negative effects on paralympic athlete's performance and overall well-being. On the other hand, bone stress injuries occur when abnormal and repetitive loading is applied to normal bone, resulting in microdamage accumulation and potential. The prevalence of overtraining syndrome and bone stress injuries among athletes highlights the need for a better understanding of their relationship and implications for prevention and management strategies. Methods: A literature review from the PubMed, Web of Science, and Google Scholar databases including the MeSH keywords "overtraining syndrome", "bone", and "paralympic athletes". Results: Studies have consistently shown that athletes engaged in endurance sports are particularly susceptible to overtraining syndrome. The multifactorial nature of this condition involves not only physical factors, but also psychological and environmental determinants. In addition, the diagnosis and management of OTS and bone stress injuries present challenges in clinical practice. Conclusions: Currently, there are no definitive biochemical markers for overtraining syndrome. The diagnosis is based on a combination of subjective measures such as questionnaires, symptoms checklists, and objective biomarkers, including hormone levels, inflammatory markers, and imaging studies. However, these diagnostic approaches have limitations regarding their specificity and sensitivity.

Transdisciplinary Approach in Type I Neurofibromatosis - Review of Psychiatric Disorders.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant a multisystem genetic disorder that primarily involves the skin and the nervous system. The incidence of the disease is 1:3000-4000 live-born children, equally in both sexes. The diagnosis of NF1 is determined individually with any two of the following clinical features: café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic glioma, distinctive bone lesions and first-degree family relative with NF1. NF1 is a disease most commonly diagnosed and treated by neuropediatricians. RESULTS: Cognitive and behavioral disorders affect between 50-80% of all children with NF1. Children with NF1 show impairments in attention, visual perception, language, executive function, academic skills, and behavior. This requires a multidisciplinary approach to the treatment s as seen in the case we present. Furthermore, NF1 is often associated with psychiatric disorders, which are more frequent in this disease than in general population, according to some studies even up to 33% patients. Psychiatric disorders are more frequent in NF1 than in the general population, particularly in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. CONCLUSIONS: We present a case of an eight-year-old boy with behavioural and learning disabilities referred for psychological and psychiatric evaluation as well as an overview of NF-related psychiatric illnesses described in the literature.

Psychiatric Disorders and Dry Eye Disease - A Transdisciplinary Approach.

Dry eye disease (DED) is a multifactorial disorder representing one of the most common ocular morbidities and a significant public health problem. It often results in eye discomfort, visual disturbances and potential damage to the corneal surface affecting quality of life (QOL). In recent years, the relationship between DED and psychiatric disorders has been gaining attention. A number of epidemiological studies have reported a possible association between dry eye and psychiatric disorders showing that the subjective symptoms of dry eye can be affected not only by changes of the tear film and ocular surface but also psychological factors such as anxiety, depression, schizophrenia, post-traumatic stress disorder (PTSP) and subjective happiness. Apart from psychiatric disorders, psychiatric medications are also considered as risk factors for DED due to their influence on the tear film status. The incidence of ocular side effects increases rapidly with the use of polypharmacy, a very common form of treatment used in psychiatry. There is often inconsistency between signs and symptoms of DED, where symptoms often are more related to non-ocular conditions including psychiatric disorders than to tear film parameters. Consequently, in many cases DED may be considered as a psychiatric as well as ophthalmological problem. Psychiatrists and ophthalmologists need to be aware of the potential influence of psychiatric disorders and medications on tear film stability. In treatment of psychiatric patients, an integrative and transdisciplinary approach will result in better functioning and higher QOL.

Comparison of the Schein and Osdi Questionnaire as Indicator of Tear Film Stability in Patients with Schizophrenia.

BACKGROUND: The aim of this research was to determine which of two chosen questionnaires for subjective symptoms of dry eye (Ocular Surface Disease Index and Schein questionnaire) is more reliable in the assessment of dry eye in patients with schizophrenia. SUBJECTS AND METHODS: Our research included 80 patients (160 eyes) of both sexes with schizophrenia ranging between the age of 25 and 55 who have been taking one of three antipsychotic drugs namely clozapin, olanzapin, quetiapin for five or more years and were in a stable phase of the disease or remission. All participants were required to satisfy all included and excluded criteria. They all filled out the Schein and OSDI questionnaires for assessment of subjective symptoms. Tear break-up time test (TBUT) for objective evaluation of tear film stability was also performed. In order to determine the correlation between two subjective and objective tests we calculated Spearmans correlation coefficients. RESULTS: Obtained results of the correlation between OSDI questionnaire and TBUT test for the right eye was r=-0.73; p<0.01 and for the left eye was r=-0.72; p<0.01. Results of the correlation between Schein questionnaire and TBUT test for the right eye was r=-0.62; p<0.01 and for the left eye was r=-0.60; p<0.01. A detailed analysis shows that there are no statistically significant differences between the correlations. Both subjective questionnaires are statistically significantly and negatively related to the TBUT test, showing that an increase in the results on the OSDI and Schein's questionnaires led to the decreases in the results on the TBUT test. CONCLUSION: In patients with schizophrenia the OSDI and Schein questionnaires are equally reliable in the assessment of subjective symptoms of Dry eye disease. Considering that, OSDI is more common in clinical practice and includes questions regarding quality of life, it would have certain advantages and it is recommended for use in patients with schizophrenia.

Mental Disorders as Influencing Factors for Discordances in the Signs and Symptoms of Dry Eye Disease.

Dry eye disease (DED) is a multifactorial disease of the tear film and ocular surface representing one of the most common problems in ophthalmological practice. Characteristic symptoms of DED include gritty, sandy foreign body sensation as well as visual disturbances that have a negative impact on the patient's daily activities and social life. It is often assumed that the symptoms of dry eye are the main features of this disease, however, the symptoms do not always coincide with the signs and the results of diagnostic tests and the cause of this discordance in perception is still unclear. Numerous studies have been conducted in order to determine the cause of these discrepancies. Mental health disorders may be one of considerable contributing factors for dry eye symptoms and undiagnosed mental health conditions can be an influencing element for unexplained levels of DED symptoms. Depression, anxiety, stress, hypochondriasis, neuroticism, sleep and mood disorders may be associated with the exacerbation of symptoms to degrees that are not consistent with the objective signs related to tear dysfunction as well as changes in the anterior surface of the eye. Thus, a detailed medical history, thorough ophthalmological examination and referral to a psychologist or psychiatrist may be essential in the treatment of patients whose symptoms do not correlate with objective evidence of DED.

Prevalence of diabetic retinopathy in the Dubrovnik-Neretva County.

OBJECTIVE: Diabetic retinopathy is one of the leading causes of blindness. We estimated the prevalence of diabetic retinopathy among a diabetic population in the Dubrovnik-Neretva County in the Republic of Croatia and searched for potential risk factors. METHODS: A prospective study was performed with 600 diabetic patients from different parts of the Dubrovnik-Neretva County who attended regular medical and ophthalmological check-ups at the General Hospital Dubrovnik from September 2014 to September 2015. Patients underwent a complete medical assessment by two ophthalmologists. Retinal examination included evaluation of the presence of diabetic retinopathy. Any retinopathy present was graded as mild non-proliferative retinopathy, moderate-severe non proliferative retinopathy or proliferative retinopathy. RESULTS: Retinopathy was present in 44.5% of the study sample. 20.7% had the mild form of diabetic retinopathy, 18.8% had the moderate-severe form, and 5.0% had proliferative diabetic retinopathy. The mean duration of diabetes was 12.94 years ± 6.85; 12.89 years ± 9.18 in men, 12.94 ± 6.54 in women. The mean BMI was 27.14 ± 2.98; for diabetics without diabetic retinopathy 26.19 ± 2.75; for those with the mild form 28.06 ± 3.01; for those with the moderate-severe form 28.49 ± 2.54; for those with proliferative diabetic retinopathy 28.79 ± 3.16. 168 (28%) patients were treated by laser and 22 (3.7%) by vitrectomy. CONCLUSION: The prevalence of diabetic retinopathy in the Dubrovnik-Neretva County is 44.5%. Regular screening to detect diabetic retinopathy is highly recommended as timely intervention can prevent most diabetic causes of blindness.

A Survey of Current Prophylactic Treatment for Ophthalmia Neonatorum in Croatia and a Review of International Preventive Practices.

BACKGROUND Ophthalmia neonatorum, or neonatal conjunctivitis, is an acute infection that occurs within the first 28 days of life. This aim of this survey was to evaluate the current methods of preventive treatment for ophthalmia neonatorum in maternity hospitals in Croatia. MATERIAL AND METHODS The annual hospital birth rate in Croatia is approximately 40,000. A clinical survey was undertaken with data collected using questionnaires sent to all 32 maternity hospitals in Croatia. There was a 100% response rate to the questionnaires. RESULTS Preventive treatment for ophthalmia neonatorum was administrated to all newborns in 75% (24/32) of Croatian maternity hospitals. In 45.8% of maternity hospitals, (11/32) these procedures were performed within the first hour after birth. In 54.2% of maternity hospitals (13/32), preventive treatment for ophthalmia neonatorum was administrated to all newborns from one to three hours after birth. The main treatment agent was tobramycin (83.3%). Other topical prophylactic treatments included povidone-iodine (8.3%), erythromycin (4.2%), and silver nitrate (4.2%). In 25% of obstetric units, prophylaxis for ophthalmia neonatorum was not used routinely, but in cases of diagnosed neonatal conjunctivitis, antibiotic treatment with tobramycin was mainly used. CONCLUSIONS A survey of all 32 maternity hospitals in Croatia showed variation in the prevalence of preventive treatment for ophthalmia neonatorum and the methods used. These findings support the need to implement standardized preventive measures that both conform to international clinical guidelines and recognize treatment availability in Croatia, where topical povidone-iodine is currently preferred for the prevention of ophthalmia neonatorum.

Dry eye in contact lens wearers as a growing public health problem.

BACKGROUND: The aim of this study is to analyze the relationship between the self-reported symptoms and objective signs of dry eye disease in long-term rigid gas-permeable (RGP) or soft contact lens (SCL) wearers. SUBJECTS AND METHODS: The study included 84 eyes of Caucasian RGP and SCL wearers between the age of 15 and 71 who wore contact lenses on a continuous daily basis for more than 1 year. Symptoms were assessed according to the Ocular Surface Disease Index (OSDI). Clinical assessments included corneal fluorescein staining according to the National Eye Institute (NEI) staining grid and tear film break-up time (TBUT). RESULTS: There were more female (76.19%) than male (23.81%) persons with a higher proportion of RGP wearers among the females (88.89% vs. 11.11%). The mean duration of daily lens wear was 7.71±2.72 hours. No RGP wearer in this study had a NEI corneal staining grid score higher than 2. A weak negative correlation was found between daily lens wear duration and TBUT (Pearson's coefficient, r=-0.1467). A strong negative correlation was found between TBUT and OSDI values (r=-0.844). CONCLUSION: The results of the study emphasize the importance of early and accurate diagnosis of dry eye disease for successful long term RGP and SCL contact lens wear. This will hopefully motivate future larger scale investigations on dry eye related problems in contact lens wearers.

The Influence of Tear Film Quality on Visual Function.

BACKGROUND: The prevalence of dry eye disease (DED) is increasing globally, resulting in a variety of eye symptoms characterized by discomfort and visual disturbances. The accurate diagnosis of the disease is often challenging and complex, requiring specialized diagnostic tools. This study aimed to investigate the impact of tear film instability on visual function and to evaluate the value of post-blink blur time (PBBT) as an alternative method for assessing tear film stability. METHODS: The study included 62 subjects: 31 with subjective symptoms of DED (Group A) and a control group consisting of 31 healthy participants (Group B). Symptoms were assessed using the standard Schein questionnaire, supplemented with additional questions. PBBT was measured using standard Snellen charts to investigate a potential association between PBBT and tear film dysfunction. Additional clinical assessments included tear film break-up time (TBUT). RESULTS: Statistically significant differences were observed in the average values of PBBT and TBUT between the examined groups. The average PBBT was 8.95 ± 5.38 s in the group with DED and 14.66 ± 10.50 s in the control group, p < 0.001. Group A exhibited an average TBUT of 4.77 ± 2.37 s, while Group B had a TBUT of 7.63 ± 3.25 s, p < 0.001. Additionally, a strong positive correlation was identified between PBBT and TBUT values (r = 0.455; p < 0.001). CONCLUSIONS: The research confirms that tear film stability has an important role in the refraction of light and the maintenance of optical quality of vision. PBBT could potentially function as an objective and clinically significant screening test for DED.