Neurotrophic factors and corneal nerve regeneration

The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both function and morphology using standard instruments such as corneal esthesiometer and in vivo confocal microscope. All local and systemic conditions that are associated with damage of the trigeminal nerve cause the development of neurotrophic keratitis, a rare degenerative disease. Neurotrophic keratitis is characterized by impairment of corneal sensitivity associated with development of persistent epithelial defects that may progress to corneal ulcer, melting and perforation. Current neurotrophic keratitis treatments aim at supporting corneal healing and preventing progression of corneal damage. Novel compounds able to stimulate corneal nerve recovery are in advanced development stage. Among them, nerve growth factor eye drops showed to be safe and effective in stimulating corneal healing and improving corneal sensitivity in patients with neurotrophic keratitis. Neurotrophic keratitis represents an useful model to evaluate in clinical practice novel neuro-regenerative drugs

Limbal stem cell transplantation: clinical results, limits, and perspectives

Limbal stem cell deficiency (LSCD) is a clinical condition characterized by damage of cornea limbal stem cells, which results in an impairment of corneal epithelium turnover and in an invasion of the cornea by the conjunctival epithelium. In these patients, the conjunctivalization of the cornea is associated with visual impairment and cornea transplantation has poor prognosis for recurrence of the conjunctivalization. Current treatments of LSCD are aimed at replacing the damaged corneal stem cells in order to restore a healthy corneal epithelium. The autotransplantation of limbal tissue from the healthy, fellow eye is effective in unilateral LSCD but leads to depauperation of the stem cell reservoir. In the last decades, novel techniques such as cultivated limbal epithelial transplantation (CLET) have been proposed in order to reduce the damage of the healthy fellow eye. Clinical and experimental evidence showed that CLET is effective in inducing long-term regeneration of a healthy corneal epithelium in patients with LSCD with a success rate of 70%-80%. Current limitations for the treatment of LSCD are represented by the lack of a marker able to unequivocally identify limbal stem cells and the treatment of total, bilateral LSCD which requires other sources of stem cells for ocular surface reconstruction

Sex hormones in allergic conjunctivitis: altered levels of circulating androgens and estrogens in children and adolescents with vernal keratoconjunctivitis

PURPOSE: Vernal keratoconjunctivitis (VKC) is a chronic allergic disease mainly affecting boys in prepubertal age and usually recovering after puberty. To evaluate a possible role of sex hormones in VKC, serum levels of sex hormones in children and adolescents with VKC were assessed. METHODS: 12 prepubertal and 7 early pubertal boys with active VKC and 6 male patients with VKC in remission phase at late pubertal age and 48 healthy age and sex-matched subjects were included. Serum concentration of estrone, 17 beta-estradiol, dehydroepiandrosterone-sulfate, total testosterone and free testosterone, dihydrotestosterone (DHT), cortisol, delta-4-androstenedione, follicle-stimulating hormone, luteinizing hormone, and sex-hormones binding globuline (SHBG) were evaluated. RESULTS: Serum levels of Estrone were significantly increased in all groups of patients with VKC when compared to healthy controls (P < 0.001). Prepubertal and early pubertal VKC showed a significant decrease in DHT (P = 0.007 and P = 0.028, resp.) and SHBG (P = 0.01 and P = 0.002, resp.) when compared to controls and serum levels of SHBG were increased in late pubertal VKC in remission phase (P = 0.007). CONCLUSIONS AND RELEVANCE: VKC patients have different circulating sex hormone levels in different phases of the disease and when compared to nonallergic subjects. These findings suggest a role played by sex hormones in the pathogenesis and/or activity of VKC

Diagnosis and management of iridocorneal endothelial syndrome

The iridocorneal endothelial (ICE) syndrome is a rare ocular disorder that includes a group of conditions characterized by structural and proliferative abnormalities of the corneal endothelium, the anterior chamber angle, and the iris. Common clinical features include corneal edema, secondary glaucoma, iris atrophy, and pupillary anomalies, ranging from distortion to polycoria. The main subtypes of this syndrome are the progressive iris atrophy, the Cogan-Reese syndrome, and the Chandler syndrome. ICE syndrome is usually diagnosed in women in the adult age. Clinical history and complete eye examination including tonometry and gonioscopy are necessary to reach a diagnosis. Imaging techniques, such as in vivo confocal microscopy and ultrasound biomicroscopy, are used to confirm the diagnosis by revealing the presence of "ICE-cells" on the corneal endothelium and the structural changes of the anterior chamber angle. An early diagnosis is helpful to better manage the most challenging complications such as secondary glaucoma and corneal edema. Treatment of ICE-related glaucoma often requires glaucoma filtering surgery with antifibrotic agents and the use of glaucoma drainage implants should be considered early in the management of these patients. Visual impairment and pain associated with corneal edema can be successfully managed with endothelial keratoplasty

Development and preliminary validation of a new screening questionnaire for identifying atopic children

Background: Allergic diseases represent a frequent and increasing condition affecting children. A screening questionnaire allowing an easy identification of children with symptoms of allergic diseases may improve management and clinical outcome. The aim of this study was to develop and validate an easy-to-use screening questionnaire to detect children requiring further allergological evaluations. Methods: A 10-item questionnaire, evaluating the presence and the history of the most frequent allergic conditions affecting children, including allergic asthma, allergic rhinitis and conjunctivitis, food allergy, and atopic dermatitis, was developed and administered to 214 parents of children from 5 to 10 years of age (163 with allergic disease and 51 healthy, nonallergic children). Validation was performed by Pearson's correlation between the clinical diagnosis and the responses to the questionnaire. Internal consistency was computed by Cronbach's alpha correlation coefficient. Sensitivity and specificity of the novel questionnaire were assessed by the receiver operating characteristic (ROC) curve. Results: Validation analysis of the new children atopy (ChAt) questionnaire showed good internal consistency with a Cronbach's alpha of 0.757. Responses to the items evaluating the presence of individual allergic conditions significantly correlated with the clinical diagnosis (p&lt;0.001). The ROC curve showed an area of 0.956 and identified a cutoff value &gt;2 of the ChAt questionnaire total score for detection of allergy (sensitivity =0.92 and specificity =0.902). Conclusion: The novel ChAt questionnaire represents a simple tool able to detect the presence of all major allergic diseases in a pediatric population allowing an early identification of allergic multimorbidity and potentially facilitating clinical management

Tear ferning test and pathological effects on ocular surface before and after topical cyclosporine in vernal keratoconjunctivitis patients

Background: Vernal keratoconjunctivitis (VKC) is a rare ocular surface inflammatory disease that affects mainly boys in the first decade of life. Clinical observations show that it generally regresses spontaneously with the onset of puberty, but therapeutic measures must be taken before then to control the course of the disease. Purpose: To evaluate the role of the lacrimal mucous component in VKC patients and compare tear ferning test (TFT) modifications, MUC5AC levels in tears, and density of conjunctival goblet cells to clinical characteristics before and after treatment with cyclosporine A (CY) in eye drops. Methods: Forty-seven patients affected by VKC and 30 healthy subjects aged between 3 and 16 years of life were enrolled. All individuals were submitted to complete eye examination and skin prick test (SPT) for the most common allergens. Then, they were subjected to collection of the tears and to impression cytology to evaluate TFT, MUC5AC levels, and conjunctival goblet cell density, before and after treatment with CY in eye drops. Results: Comparing the VKC group vs. the control group at baseline, a significant alteration in the degree of the ferns was found, indicating a pathological condition of the lacrimal mucous layer. In addition, an increased number of goblet cells were observed in the patients. The concentration of lacrimal secretory mucins (MUC5AC) did not show significant differences between the 2 groups. Patients treated with CY have reported improvements of some signs and symptoms of disease activity, including TFT, and a tendency of conjunctival goblet cell density to normalise. Conclusions: The results obtained demonstrated for the first time a significant alteration of the lacrimal mucin component evaluated in the VKC group, and an improvement of the latter after CY therapy

Human umbilical cord blood-borne fibroblasts contain marrow niche precursors that form a bone/marrow organoid in vivo

Human umbilical cord blood (CB) has attracted much attention as a reservoir for functional hematopoietic stem and progenitor cells, and, recently, as a source of blood-borne fibroblasts (CB-BFs). Previously, we demonstrated that bone marrow stromal cell (BMSC) and CB-BF pellet cultures make cartilage in vitro. Furthermore, upon in vivo transplantation, BMSC pellets remodelled into miniature bone/marrow organoids. Using this in vivo model, we asked whether CB-BF populations that express characteristics of the hematopoietic stem cell (HSC) niche contain precursors that reform the niche. CB ossicles were regularly observed upon transplantation. Compared with BM ossicles, CB ossicles showed a predominance of red marrow over yellow marrow, as demonstrated by histomorphological analyses and the number of hematopoietic cells isolated within ossicles. Marrow cavities from CB and BM ossicles included donor-derived CD146-expressing osteoprogenitors and host-derived mature hematopoietic cells, clonogenic lineage-committed progenitors and HSCs. Furthermore, human CD34+ cells transplanted into ossicle-bearing mice engrafted and maintained human HSCs in the niche. Our data indicate that CB- BFs are able to recapitulate the conditions by which the bone marrow microenvironment is formed and establish complete HSC niches, which are functionally supportive of hematopoietic tissue

Review Article SLC4A11 and the Pathophysiology of Congenital Hereditary Endothelial Dystrophy

Congenital hereditary endothelial dystrophy (CHED) is a rare autosomal recessive disorder of the corneal endothelium characterized by nonprogressive bilateral corneal edema and opacification present at birth. Here we review the current knowledge on the role of the SLC4A11 gene, protein, and its mutations in the pathophysiology and clinical presentation of CHED. Individuals with CHED have mutations in SLC4A11 which encodes a transmembrane protein in the SLC4 family of bicarbonate transporters. The expression of SLC4A11 in the corneal endothelium and inner ear patterns the deficits seen in CHED with corneal edema and hearing loss (Harboyan syndrome). slc4a11-null-mouse models recapitulate the CHED disease phenotype, thus establishing a functional role for SLC4A11 in CHED. However, the transport function of SLC4A11 remains unsettled. Some of the roles that have been attributed to SLC4A11 include H + and NH 4 + permeation, electrogenic Na + -H + exchange, and water transport. Future studies of the consequences of SLC4A11 dysfunction as well as further understanding of corneal endothelial ion transport will help clarify the involvement of SLC4A11 in the pathophysiology of CHED

Tear levels of neuropeptides increase after specific allergen challenge in allergic conjunctivitis

Growing evidence is showing a role of neurogenic inflammation in allergic reactions, with sensory and autonomic nerve fibers releasing neuromediators, which may actively participate in the allergic inflammatory cascade. Although the cornea is the most densely innervated tissue of the human body, little is known on the role of neuromediators at the ocular surface. In this study, we aimed at evaluating the role of substance P (SP), calcitonine gene related peptide (CGRP), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) in allergic reactions of the ocular surface

Establishment of bone marrow and hematopoietic niches in vivo by reversion of chondrocyte differentiation of human bone marrow stromal cells

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