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

Strategic Planning and Design of Supply Chains: a Literature Review

In this paper, a literature review of the mathematical models for supply chain design is proposed. The research is based on the study and analysis of publications of the last twelve years from the most widespread international journal about operations management and logistics. The aim of the work lies in identifying tendencies in the literature and related open issues about the strategic decisions, economic parameters, constraints and model features considered in the strategic planning and design of supply chains. After a description of the review methodology, comparison parameters and paper exhaustiveness, some guidelines are given in order to support future works in this field

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

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

A Multi-parameter Model for Effective Configuration of Supply Chains

In this paper, a mathematical model for the strategic planning and design of supply chains in the globalization context is proposed. A multi-objective function is used to address decisions about capacity sizing, sourcing, and facility location, with the scope of maximizing supply chain profits. The model is dynamic and is applied to a multiechelon, multi-facility and multi-product supply chain in hypotheses of delocalization. The model is characterized by the specific attention given to cost, revenue and financial factor modelling, which has been obtained by means of an activity-based approach and the inclusion of two drivers that are usually neglected in the literature: energy and labour. The model’s applicability and flexibility have been proved via a scenario analysis in which 12 different scenarios were implemented to reproduce the behaviour of major industries

Neuronavigational approach for orbital neurofibroma excision: a case report

Orbital neurofibromas are uncommon in adults, accounting for approximately 1%-3% of all space occupying lesions of the orbit. The complex anatomy of the orbital region, with the pronounced vulnerability of its neurovascular structures, requires particular surgical precautions. Neuronavigation, as a high-tech device for intraoperative safety, represents a valuable option for the confined orbital space. However, the application of neuronavigation in orbital surgery has been rarely reported. The authors present a case report of a 32-year-old female with an isolated localized neurofibroma surgically approached by intraoperative navigation and a review of the literature

NGF and NGF-receptor expression of cultured immortalized human corneal endothelial cells

Several growth factors, including nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), play an important role in the homeostasis of the ocular surface. The involvement of both these growth factors in the pathophysiology of intraocular tissues has been extensively investigated. Despite the expression of NGF receptors by corneal endothelium, to date the role of NGF on the endothelial cell remains to be determined. Using a clonal cell line of human corneal endothelial cells, the aim of this study was to investigate the expression of the NGF-receptor and the potential partnership of NGF and VEGF in maintaining cell viability in vitro

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

NGF modulates trkANGFR/p75NTR in αsMA-expressing conjunctival fibroblasts from human ocular cicatricial pemphigoid (OCP)

OBJECTIVE: In a previous study, we reported the upregulation of Nerve Growth Factor (NGF) and trkANGFR expression in Ocular Cicatricial Pemphigoid (OCP), an inflammatory and remodeling eye disease. Herein, we hypothesize a potential NGF-driven mechanism on fibroblasts (FBs) during OCP remodeling events. To verify, human derived OCP-FBs were isolated and characterized either at baseline or after NGF exposure. MATERIALS AND METHODS: Conjunctival biopsies were obtained from 7 patients having OCP and 6 control subjects (cataract surgery). Both conjunctivas and primary FB cultures were characterised for αSMA, NGF and trkANGFR/p75NTR expression. Subcultures were exposed to NGF and evaluated for αSMA, NGF, trkANGFR/p75NTR expression as well as TGFβ1/IL4 release. For analysis, early and advanced subgroups were defined according to clinical parameters. RESULTS: OCP-conjunctivas showed αSMA-expressing FBs and high NGF levels. Advanced OCP-FBs showed higher αSMA expression associated with higher p75NTR and lower trkANGFR expression, as compared to early counterparts. αSMA expression was in keeping with disease severity and correlated to p75NTR. NGF exposure did not affect trkANGFR levels in early OCP-FBs while decreased both αSMA/p75NTR expression and TGFβ1/IL4 release. These effects were not observed in advanced OCP-FBs. CONCLUSIONS: Taken together, these data are suggestive for a NGF/p75NTR task in the potential modulation of OCP fibrosis and encourages further studies to fully understand the underlying mechanism occurring in fibrosis. NGF/p75NTR might be viewed as a potential therapeutic target