Age-related macular degeneration and changes in the extracellular matrix.

Age-related macular degeneration (AMD) is the leading cause of permanent, irreversible, central blindness (scotoma in the central visual field that makes reading and writing impossible, stereoscopic vision, recognition of colors and details) in patients over the age of 50 years in European and North America countries, and an important role is attributed to disorders in the regulation of the extracellular matrix (ECM). The main aim of this article is to present the crucial processes that occur on the level of Bruch's membrane, with special consideration of the metalloproteinase substrates, metalloproteinase, and tissue inhibitor of metalloproteinase (TIMP). A comprehensive review of the literature was performed through MEDLINE and PubMed searches, covering the years 2005-2012, using the following keywords: AMD, extracellular matrix, metalloproteinases, tissue inhibitors of metalloproteinases, Bruch's membrane, collagen, elastin. In the pathogenesis of AMD, a significant role is played by collagen type I and type IV; elastin; fibulin-3, -5, and -6; matrix metalloproteinase (MMP)-2, MMP-9, MMP-14, and MMP-1; and TIMP-3. Other important mechanisms include: ARMS2 and HTR1 proteins, the complement system, the urokinase plasminogen activator system, and pro-renin receptor activation. Continuous rebuilding of the extracellular matrix occurs in both early and advanced AMD, simultaneously with the dysfunction of retinal pigment epithelium (RPE) cells and endothelial cells. The pathological degradation or accumulation of ECM structural components are caused by impairment or hyperactivity of specific MMPs/TIMPs complexes, and is also endangered by the influence of other mechanisms connected with both genetic and environmental factors.

Influence of ranibizumab treatment on the extracellular matrix in patients with neovascular age-related macular degeneration.

BACKGROUND: We know the influence of the intravitreal anti-vascular endothelial growth factor (VEGF) injections on the choroidal neovascularization in the course of exudative age-related macular degeneration (AMD). However, the influence of the ranibizumab therapy in question on the extracellular matrix (ECM) remains unknown. We aimed to estimate the influence of Lucentis intravitreal injections on the gene expression of structural components of the extracellular matrix in patients with neovascular AMD. MATERIAL AND METHODS: Patients with subfoveal localization of neovascularization in AMD, which was clinically active and observed using optical coherence tomography, were treated with ranibizumab (0.5 mg/0.05 mL) in accordance with the PrONTO scheme. Total RNA was extracted from peripheral blood mononuclear cells, and an oligonucleotide microarray technique enabled comparison of the expression level of genes encoding collagens, elastin, and laminins in AMD patients compared to control subjects. RESULTS: After 3 intravitreal injections of ranibizumab (Lucentis), COL1A1 and COL6A1 genes showed increased expression, whereas decreased expression mainly occurred for the following genes: COL4A5, COL11A1, OL4A6C, LAMB4, and LAMC2. CONCLUSIONS: Anti-VEGF local therapy influences the gene expression of structural components of the ECM as measured from blood samples. The loading dose of ranibizumab for the retina changes the expression of collagen and laminin genes, but does not influence the expression of the elastin gene.

Age-related macular degeneration in the aspect of chronic low-grade inflammation (pathophysiological parainflammation).

The products of oxidative stress trigger chronic low-grade inflammation (pathophysiological parainflammation) process in AMD patients. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, CFH, CD35, and CD46. The complement system, mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD, especially in the Y402H gene polymorphism, which causes hypofunction/lack of the protective complement factor H (CFH) and facilitates chronic inflammation mediated by C-reactive protein (CRP). Microglial activation induces photoreceptor cells injury and leads to the development of dry AMD. Many autoantibodies (antibodies against alpha beta crystallin, alpha-actinin, amyloid, C1q, chondroitin, collagen I, collagen III, collagen IV, elastin, fibronectin, heparan sulfate, histone H2A, histone H2B, hyaluronic acid, laminin, proteoglycan, vimentin, vitronectin, and aldolase C and pyruvate kinase M2) and overexpression of Fcc receptors play role in immune-mediated inflammation in AMD patients and in animal model. Macrophages infiltration of retinal/choroidal interface acts as protective factor in early AMD (M2 phenotype macrophages); however it acts as proinflammatory and proangiogenic factor in advanced AMD (M1 and M2 phenotype macrophages).

Quantitative analysis of SOD2, ALDH1A1 and MGST1 messenger ribonucleic acid in anterior lens epithelium of patients with pseudoexfoliation syndrome.

PURPOSE: The aim of the study was to investigate the expression of selected genes encoding enzymes involved in the antioxidant defense system (superoxide dismutase 2, SOD2; aldehyde dehydrogenase 1, ALDH1A1; microsomal glutathione S-transferase 1, MGST1) in fragments of anterior lens capsules of patients with pseudoexfoliation syndrome (PEX). The specificity and sensitivity of these molecular markers for PEX development were also assessed. METHODS: The study group consisted of 20 patients (9 women and 11 men) with diagnosed PEX and cataract. The control group included 23 patients (8 women and 15 men) who needed cataract surgery but did not have PEX. Quantification of SOD2, ALDH1A1, and MGST1 messenger ribonucleic acid (mRNA) was performed with quantitative real-time PCR. RESULTS: SOD2, ALDH1A1, and MGST1 mRNAs were detected in all studied samples. The examined genes had statistically significant higher expression in the group of patients with PEX than in the control group (SOD2, p=0.0015; ALDH1A1, p=0.0001; MGST1, p=0.0001, Mann-Whitney U test). The areas under the curve (AUC) of SOD2, MGST1, and ALDH1A1 were 0.766, 0.818, and 0.957, respectively. CONCLUSIONS: Differential expression of SOD2, ALDH1A1, and MGST1 genes in the anterior lens capsules of patients with PEX suggest that diseased tissue appears to respond to the previously reported oxidative stress. A possible role of ALDH1A1 mRNA level as a risk factor or marker for PEX needs further confirmation.

Antioxidative Role of Heterophagy, Autophagy, and Mitophagy in the Retina and Their Association with the Age-Related Macular Degeneration (AMD) Etiopathogenesis.

Age-related macular degeneration (AMD), an oxidative stress-linked neurodegenerative disease, leads to irreversible damage of the central retina and severe visual impairment. Advanced age and the long-standing influence of oxidative stress and oxidative cellular damage play crucial roles in AMD etiopathogenesis. Many authors emphasize the role of heterophagy, autophagy, and mitophagy in maintaining homeostasis in the retina. Relevantly modifying the activity of both macroautophagy and mitophagy pathways represents one of the new therapeutic strategies in AMD. Our review provides an overview of the antioxidative roles of heterophagy, autophagy, and mitophagy and presents associations between dysregulations of these molecular mechanisms and AMD etiopathogenesis. The authors performed an extensive analysis of the literature, employing PubMed and Google Scholar, complying with the 2013-2023 period, and using the following keywords: age-related macular degeneration, RPE cells, reactive oxygen species, oxidative stress, heterophagy, autophagy, and mitophagy. Heterophagy, autophagy, and mitophagy play antioxidative roles in the retina; however, they become sluggish and dysregulated with age and contribute to AMD development and progression. In the retina, antioxidative roles also play in RPE cells, NFE2L2 and PGC-1α proteins, NFE2L2/PGC-1α/ARE signaling cascade, Nrf2 factor, p62/SQSTM1/Keap1-Nrf2/ARE pathway, circulating miRNAs, and Yttrium oxide nanoparticles performed experimentally in animal studies.

Substantial light woodland and open vegetation characterized the temperate forest biome before Homo sapiens.

The extent of vegetation openness in past European landscapes is widely debated. In particular, the temperate forest biome has traditionally been defined as dense, closed-canopy forest; however, some argue that large herbivores maintained greater openness or even wood-pasture conditions. Here, we address this question for the Last Interglacial period (129,000-116,000 years ago), before Homo sapiens-linked megafauna declines and anthropogenic landscape transformation. We applied the vegetation reconstruction method REVEALS to 96 Last Interglacial pollen records. We found that light woodland and open vegetation represented, on average, more than 50% cover during this period. The degree of openness was highly variable and only partially linked to climatic factors, indicating the importance of natural disturbance regimes. Our results show that the temperate forest biome was historically heterogeneous rather than uniformly dense, which is consistent with the dependency of much of contemporary European biodiversity on open vegetation and light woodland.

Ophthalmic transplantology: posterior segment of the eye--part II.

BACKGROUND: Transplants of the retina are among the new strategies being used in the treatment of genetic and degenerative macular diseases. Moreover, various cell cultures are being tested to treat retinal disorders. MATERIAL/METHODS: Literature dated from 2004 to 2011 was comprehensively examined via Medline and PubMed searches for the following terms: auto-, homo-, heterologous transplantation, retina, stem cells, cultivated cells. RESULTS: Tissue and cell therapy of retinal diseases are reviewed, including full-thickness retina/retinal pigment epithelium (RPE)/choroid graft; full and partial thickness RPE/choroid complex grafts; RPE/Bruch membrane complex graft; and RPE, iris pigment epithelium and stem cell grafts. Recommendations for transplants, as well as the benefits and weaknesses of specific techniques in retina transplants, are discussed. CONCLUSIONS: Auto- and allogenic transplants of a full or partial thickness retina/RPE/ Bruch membrane/choroid complex represent an alternative treatment offered to patients with some macular diseases. Stem cell transplantation to reconstruct and regenerate the macula requires further biomolecular and animal research studies.

Ophthalmic transplantology: anterior segment of the eye - part I.

BACKGROUND: Transplantology is a quickly developing field of ophthalmology. It currently is able to treat many inherited, degenerative, inflammatory, traumatic, and cancerous diseases. This review outlines recent concepts and methods of treating ocular diseases with tissue and cell grafts. Ocular transplants related to the anterior part of the eye, including the conjunctiva and the cornea, are reviewed in Part 1. MATERIAL/METHODS: The scientific literature dated from January 2005 to July 2011 was thoroughly searched using Medline and PubMed. Publications dated 2009, 2010, and 2011 were analyzed in detail. Search terms were as follows: auto-, homo-, heterologous transplantation, eyeball, ocular adnexa, anterior segment of the eye, cornea, lamellar keratoplasty, stem cells, cultured cells. Further data were found at the website of the Eye Bank Association of America. RESULTS: Nearly all tissues of the anterior segment of the eye (the conjunctiva, sclera, eye muscles, and cornea) are transplanted. Because of the recent significant progress in the field, cornea transplantation was analyzed in more detail, specifically procedures such as limbus grafts and anterior and posterior lamellar keratoplasty. Indications, advantages, and drawbacks of the transplant techniques were also reviewed. CONCLUSIONS: Recent progress in the field of cornea transplants allows treatment at the level of the endothelium and the use of cultured limbal epithelial stem cell grafts. However, compared with previous techniques, modern and multilayered transplant techniques of the cornea require much more expertise and longer training of the surgeon, as well as expensive and technologically advanced equipment. The availability of donor tissue is still the main limitation affecting all transplants. Therefore, cell culturing techniques such as stem cells, as well as artificial cornea projects, seem to be very promising.

Holocene environmental changes in a prehistoric mining and metallurgical region in the light of paleobotanical studies of the bogs of the Brynica river drainage basin (southern Poland).

The analyses of human-environment interactions in prehistoric and medieval mining and metallurgical centres in Europe result in various assessments of the environmental impact of early metal ore mining and metallurgy. In some mining and metallurgical sites or areas, such as the prehistoric basin on the Greek island of Kythnos or the later Morvan and Mont Lozère areas in France as well as Tjursbosjön in Sweden, the impact was significant and lasting. In others, such as: Cors Fochno in Wales, the Falkenstein region in Austria, or the Northern Vosges Mountains in France, the environmental changes were limited and reversible. The results of palaeobotanical research (pollen analysis and analysis of plant macroremains) in peat cores from southern Poland enabled the Holocene vegetation transformations in one of the oldest mining regions in Central Europe to be reconstructed. They also provided new data, used to assess the impact of settlements as well as the development of metallurgy on the environment in the region and changes in bog ecosystems. The first changes in vegetation caused by human activity were observed at the boundary between the Neolithic and Bronze Ages. They are documented by pollen indicating shepherding activity and single grains of cereal pollen. The greatest intensity of change, reflected in sediment as a maximum concentration of charcoal, was recorded at the end of the Bronze Age and attributed to the Lusatian culture. The changes in the vegetation under the impact of human activity until the early Middle Ages were reversible and had a local scope. The intensification of slash-and-burn agriculture was indicated as the most probable and important cause.

Interplay between reactive oxygen species and autophagy in the course of age-related macular degeneration.

Pathological biomolecules such as lipofuscin, methylglyoxal-modified proteins (the major precursors of advanced glycationend products), misfolding protein deposits and dysfunctional mitochondria are source of oxidative stress and act as strong autophagic stimulators in age-related macular degeneration. Disturbed autophagy accelerates progression of the disease, since it leads to retinal cells' death and activates inflammation by the interplay with the NLRP3 inflammasome complex. Vascular dysfunction and hypoxia, as well as circulating autoantibodies against autophagy regulators (anti-S100A9, anti-ANXA5, and anti-HSPA8, A9 and B4) compromise an autophagy-mediated mechanism as well. Metformin, the autophagic stimulator, may act as a senostatic drug to inhibit the senescent phenotype in the age-related macular degeneration. PGC-1α , Sirt1 and AMPK represent new therapeutic targets for interventions in this disease.

[Phacoemulsification of subluxated lens with capsular tension ring implantation]. / Wyniki fakoemulsyfikacji podwichnietej zacmy z implantacjl pierscienia dotorebkowego.

PURPOSE: To evaluate long term results of phacoemulsification with PC IOL and capsular tension ring (CTR) implantation in lens subluxation. MATERIAL AND METHODS: The study comprised of 134 patients--146 eyes with subluxated lens. In all cases phacoemulsification with PC IOL and CTR implantation was performed. RESULTS: No intaroperative complications has occured. Postoperative complications included: inflammation in the anterior chamber in 3 eyes (2.1%), retinal detachment in 2 eyes (1.4%). In all cases there was no PC IOL decentration. CONCLUSIONS: (1) CTR facilitates phacoemulsification with PC IOL implantation in lens subluxation. (2) Phacoemulsification of subluxated lens with PC IOL and CTR implantation seems to be safe and effective procedure.

Smoking and Eye Pathologies. A Systemic Review. Part II. Retina Diseases, Uveitis, Optic Neuropathies, Thyroid-Associated Orbitopathy.

BACKGROUND: Tobacco smoking has detrimental influence on human health. AIM: The analysis of influence of tobacco smoking on retina diseases, uveitis, optic neuropathies, and thyroidassociated orbitopathy in adults and children. METHODS: A comprehensive review of the literature performed through MEDLINE and PubMed searches, covering the years 2000-2016. RESULTS: In adults, tobacco smoking is a strong risk factor for age-related macular degeneration, polypoidal choroidal vasculopathy, uveitis and inflamed cystoid macular edema as well as Grave`s ophthalmopathy. Tobacco smoking reduces thickness of the retina and choroid, plays a role in episcleritis, sclerits, tobacco optic neuropathy, and Leber's hereditary optic neuropathy. In children, maternal smoking is a significant risk factor for stages 3 and 4 retinopathy of prematurity, optic nerve hypoplasia among babies with a birth weight over 2500 g and thinner retinal nerve fiber layer. CONCLUSION: Tobacco smoking plays an important role in the pathogenesis of many posterior eye segment diseases leading to blindness in adults and children.

Smoking and Eye Pathologies. A Systemic Review. Part I. Anterior Eye Segment Pathologies.

BACKGROUND: Tobacco smoking has detrimental influence on human health and is one of the leading causes of preventable mortality worldwide, associated with lung cancer, chronic obstructive lung disease and cardiovascular disease. AIM: The analysis of the influence of tobacco smoking on pathology of the anterior segment of the eye in adults and children. METHODS: A comprehensive review of the literature performed through MEDLINE and PubMed searches, was published during the period 2000-2016. RESULTS: In adults, tobacco smoking is associated with hyperopia, delayed corneal epithelial healing and progression of Fuchs' endothelial corneal dystrophy. Smoking is a strong risk factor for age-related nuclear cataract. However, smoking is not associated with pterygium, and its influence on dry eye symptoms, central corneal thickness and progression of primary open glaucoma remains controversial. Smoking during pregnancy increases risk of convergent or divergent strabismus or poor stereo acuity, however, its influence on anophtalmia, microphtalmia, amblyopia and hyperopic refractive error is controversial. CONCLUSION: Tobacco smoking plays an important role in the pathogenesis of many diseases of anterior eye segment leading to visual impairment in adults and children.

Gene expression levels of the insulin-like growth factor family in patients with AMD before and after ranibizumab intravitreal injections.

PURPOSE: The present study focused on the assessment of the mRNA levels of the insulin-like growth factor (IGF) family in patients with the exudative form of age-related macular degeneration (AMD) before and after ranibizumab intravitreal injections. PATIENTS AND METHODS: An analysis of the expression profile of the IGF family of genes in patients with AMD was carried out using the oligonucleotide microarray and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) methods. RESULTS: In the peripheral blood mononuclear cells (PBMCs) obtained from AMD group receiving ranibizumab compared to the peripheral blood mononuclear cells from AMD group before ranibizumab treatment using oligonucleotide microarray technique, six statistically significant differentially expressed transcripts related to the IGF family were detected (unpaired t-test, p<0.05, fold change >1.5). Moreover, analysis using the real-time RT-qPCR technique revealed statistically significant differences in the IGF2 and IGF2R mRNA levels (Mann-Whitney U test, p<0.05) between the two groups that were studied. Statistical analyses of both oligonucleotide microarray and real-time RT-qPCR results demonstrated a significant decreased expression only for IGF2 mRNA. CONCLUSION: Our results revealed a changed expression of IGF2 mRNA after ranibizumab treatment.

The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults.

The reactive oxygen species (ROS) form under normal physiological conditions and may have both beneficial and harmful role. We search the literature and current knowledge in the aspect of ROS participation in the pathogenesis of anterior and posterior eye segment diseases in adults. ROS take part in the pathogenesis of keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, stimulating apoptosis of corneal cells. ROS play a role in the pathogenesis of glaucoma stimulating apoptotic and inflammatory pathways on the level of the trabecular meshwork and promoting retinal ganglion cells apoptosis and glial dysfunction in the posterior eye segment. ROS play a role in the pathogenesis of Leber's hereditary optic neuropathy and traumatic optic neuropathy. ROS induce apoptosis of human lens epithelial cells. ROS promote apoptosis of vascular and neuronal cells and stimulate inflammation and pathological angiogenesis in the course of diabetic retinopathy. ROS are associated with the pathophysiological parainflammation and autophagy process in the course of the age-related macular degeneration.

Leprosy in the Bible.

For many years, the biblical term tzaraat has referred to leprosy. In fact, the disease or diseases described under this name have no relationship to leprosy, as it was known in the Middle Ages or today; moreover, the term referred not only to skin disease, but also to the state of the ritual impurity and punishment for the sins. Although the real nature of tzaraat remains unknown, the differential diagnosis might include the following: Psoriasis, seborrheic dermatitis, favus, dermatophyte infections, nummular dermatitis, atopic dermatitis, pityriasis rosea, crusted scabies, syphilis, impetigo, sycosis barbae, alopecia areata, furuncles, scabies, neurodermatitis, scarlet fever, lupus erythematosus, lichen sclerosus et atrophicus, folliculitis decalvans, morphea, sarcoidosis, and lichen planopilaris. Leprosy became interchangeable with the biblical leprosy due to two inaccurate translations: The Hebrew tzaraat was first translated into Greek as leprosy in the sixth century, and later, the word leprosy was translated into Arabic as lepra in the ninth century.

Leprosy: Social implications from antiquity to the present.

One of the most important dermatologic diseases from the sociologic viewpoint has been leprosy. Those with leprosy were isolated, excluded from society, and stigmatized. Such a stigma indicates the strong feeling that a leprosy patient is shameful and should not be accepted by society. During the first millennium, leprosy was rapidly inscribed in the system of religious prohibitions-the disease was a punishment by God for wrongdoing, and the disease was associated with the lower spheres of the society. Social perception of leprosy gradually changed during the time of Crusades. The care for lepers became a Christian obligation, and celebrating Holy Masses as for the dead was forsaken. The sick were forced to stay at leprosaria, particularly from the 14th through the 19th centuries when fear of leprosy was at a high point. Admission to a leprosarium was mandatory not only for patients with leprosy but also even those suspected of having the disease.

Ocular changes induced by drugs commonly used in dermatology.

The use of many drugs in dermatologic diseases may cause ocular side effects. Some may regress after discontinuation of the therapy, but others persist or progress even after the cessation of treatment. This review presents four groups of commonly prescribed drugs-antimalarial medicines, glucocorticoids, retinoids, and psoralens + ultraviolet A (UVA) therapy-and discusses their possible ocular side effects. The most significant complication of antimalarial drugs is retinopathy with the risk of permanent visual impairment. There are different recommendations for screening for this drug-related retinopathy. The most important ocular manifestations of steroid management are irreversible optic nerve damage in "steroid responders" (steroid glaucoma) and cataract. Some other side effects may disappear after discontinuation of the therapy. Retinoid-induced ocular side effects include ocular surface disease as well as retinal dysfunction. It is recommended to modify the therapy when night blindness occurs or after the decrease of color vision. Protective eyewear is sufficient to avoid ocular surface problems during psoralen + UVA therapy. The knowledge of screening schemes and closer cooperation between physicians may decrease the risk of serious or irreversible ocular side effects.

Effects of intravitreal ranibizumab on the untreated eye and systemic gene expression profile in age-related macular degeneration.

The purpose of this study was to evaluate the systemic effects of intravitreal ranibizumab (Lucentis) treatment in patients with neovascular age-related macular degeneration (AMD). The impact of intravitreal ranibizumab injections on central retinal thickness (CRT) of treated and contralateral untreated eyes, and differences in gene expression patterns in the peripheral blood mononuclear cells were analyzed. The study included 29 patients aged 50 years old and over with diagnosed neovascular AMD. The treatment was defined as 0.5 mg of ranibizumab injected intravitreally in the form of one injection every month during the period of 3 months. CRT was measured by optical coherence tomography. The gene expression profile was assigned using oligonucleotide microarrays of Affymetrix HG-U133A. Studies have shown that there was a change of CRT between treated and untreated eyes, and there were differences in CRT at baseline and after 1, 2, and 3 months of ranibizumab treatment. Three months after intravitreal injection, mean CRT was reduced in the treated eyes from 331.97±123.62 to 254.31±58.75 µm, while mean CRT in the untreated fellow eyes reduced from 251.07±40.29 to 235.45±36.21 µm at the same time. Furthermore, the research has shown that among all transcripts, 3,097 expresses change after the ranibizumab treatment in relation to controls. Among these transcripts, 1,339 were up-regulated, whereas 1,758 were down-regulated. Our results show the potential systemic effects of anti-VEGF therapy for AMD. Moreover, our study indicated different gene expression in peripheral blood mononuclear cells before and after intravitreal ranibizumab treatment.

Ocular leprosy.

Ocular involvement in leprosy is estimated to be 70-75%, about 10-50% of leprosy patients suffer from severe ocular symptoms, and blindness occurs in about 5% of patients. The disease leads to many ophthalmologic symptoms and signs in the range of the eyeball itself, as well as of the bulb adnexa, ie, eyebrows, eyelids with eyelashes, and lacrimal drainage system. Especially dangerous are complications of lagophthalmos and corneal hypoanesthesia, neurotrophic or infectious keratitis, and iridocyclitis and cataract formation, which may lead to significant decrease of visual acuity or even blindness. Multidrug treatment rapidly interrupts transmission of Mycobacterium leprae by infectious patients, but even after being completed, it does not guarantee the withholding of ocular complications.