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Expression of nerve growth factor receptors on the ocular surface in healthy subjects and during manifestation of inflammatory diseases.

PURPOSE: Recent studies have suggested the involvement of nerve growth factor (NGF) in the conjunctival inflammatory process and in corneal epithelium proliferation and differentiation. To verify the hypothesis that NGF could locally modulate the inflammatory and reparative processes, the authors evaluated the expression of NGF high-affinity receptor on the ocular surface in normal and pathologic conditions. METHODS: Ten conjunctival biopsies (obtained from three healthy subjects, five patients affected by vernal keratoconjunctivitis [VKC], and two patients with cicatricial pemphigoid [CP]) and five corneal specimens obtained from the Eye Bank of Veneto (Italy) were evaluated. All specimens were histologically stained, and immunohistochemistry was performed to identify the NGF high-affinity receptor (TrkA). RESULTS: All tissues expressed immunoreactivity for NGF receptors. In conjunctival specimens of healthy subjects, basal epithelial cells strongly expressed immunoreactivity and, in the stroma, rare cells were immunopositive for TrkA. No significant difference in immunoreactivity was observed in the conjunctival epithelium between healthy subjects and patients with inflammatory conjunctival diseases, whereas there were more immunopositive cells observed in the conjunctival stroma of VKC and CP patients than in the controls. The immunoreactivity in the cornea was confined to basal epithelial cells and endothelium. CONCLUSIONS: The NGF receptor is present on the human ocular surface. The authors' data support the possibility that NGF modulates ocular inflammation and corneal epithelial proliferation and differentiation through its receptors.

Adolescent↗

Allergy and infections: long-term improvement of vernal keratoconjunctivitis following viral conjunctivitis.

PURPOSE: Vernal keratoconjunctivitis (VKC) is a severe, chronic allergic inflammatory disease of the ocular surface poorly responsive to antiallergic treatments and possibly leading to permanent visual impairment. VKC, because of mast cell, eosinophil, and Th2-type inflammation, polyclonal IgE activation, and tissue remodeling, is considered to be a typical Th2- driven disease. Viral infection stimulates a Th1 type immune response, potentially attenuating allergen-induced inflammation. The purpose of this report is to describe the effect of viral keratoconjunctivitis in a patient with VKC. METHODS: The authors report on a patient with a severe form of VKC, poorly responsive to antiallergic treatments, who developed a viral keratoconjunctivitis. Signs, symptoms, and cytologic findings were recorded during the 5-year follow-up period. RESULTS: The authors observed a prompt and permanent improvement of signs and symptoms of the allergic condition after the viral infection. Conjunctival scraping confirms that the inhibition of the eosinophilic inflammation lasts at least for 5 years. CONCLUSIONS: In this case, the viral infection seemed to induce a clinical recovery of allergic disease, suggesting that an immune deviation induced by Th1-polarizing agents may revert an ongoing Th2 inflammation.

Child↗

Topical tretinoin treatment for severe dry-eye disorders.

Despite the diverse causes of dry-eye disorders, the ocular surface epithelia in these diseases all undergo squamous metaplasia, manifested by loss of goblet cells, mucin deficiency, and keratinization. These changes account for tearfilm instability, which leads to various ocular symptoms and corneal complications. This article reviews research in the use of topical tretinoin to treat severe dry-eye disorders. To classify squamous metaplasia into stages, a modified impression cytology technique was used to monitor the therapeutic effect of topical tretinoin ointment (0.01% or 0.1%, w/w) in 22 patients. This population had severe dry-eye disorders, including keratoconjunctivitis sicca, Stevens-Johnson syndrome, inactive ocular pemphigoid, drug-induced pseudopemphigoid, and surgery- or radiation-induced dry eyes. After treatment, clinical improvements were correlated with the reversal of squamous metaplasia as evidenced by the impression cytology technique. Tretinoin may also be effective in treating conjunctival keratinization without dry eyes, as illustrated by a case study. This may represent the first reported attempt to treat ocular surface disorders by reversing diseased epithelium.

Administration, Topical↗

Corneal topography after ocular rubbing.

PURPOSE: To examine the immediate effect of ocular rubbing on corneal topography. METHODS: Corneal topography and analysis were performed before, immediately after, and 5 minutes after eyelid rubbing in 29 volunteers without ocular disease. RESULTS: The surface regularity index increased from a baseline of 0.24 to 0.91 ( p< 0.0001) immediately after rubbing and returned to baseline after 5 minutes. The surface asymmetry index increased from 0.27 to 0.89 ( p= 0.0018) immediately after rubbing. There was a small amount of astigmatism induced immediately by rubbing (0.5 diopter) ( p= 0.01). CONCLUSIONS: Ocular rubbing should be avoided prior to standard corneal topography. The increased surface regularity index may reflect the alterations of the tear film and/or the molding of the corneal surface.

Adult↗

Differential expression of thymus- and activation-regulated chemokine (CCL17) and macrophage-derived chemokine (CCL22) by human fibroblasts from cornea, skin, and lung.

BACKGROUND: Allergic diseases of the ocular surface, skin, and lung are triggered by T(H)2 cells, which are recruited by thymus- and activation-regulated chemokine (TARC; CCL17) and macrophage-derived chemokine (MDC; CCL22). Resident fibroblasts are thought to contribute to inflammatory cell infiltration through chemokine production. OBJECTIVE: We sought to provide insight into the clinical differences apparent among these allergic diseases of the eye, skin, and lung, and we compared the abilities of corneal, dermal, and lung fibroblasts to produce TARC and MDC. METHODS: The amounts of chemokines released into the culture supernatant were determined by means of ELISA, and the intracellular abundance of chemokine mRNAs was quantitated by means of reverse transcription and real-time PCR analysis. RESULTS: Neither TNF-alpha, IFN-gamma, IL-4, nor IL-13 alone induced the release of TARC from or affected the amount of TARC mRNA in corneal, dermal, or lung fibroblasts. The combination of TNF-alpha with either IL-4 or IL-13, however, markedly increased both TARC release and the abundance of TARC mRNA in corneal and dermal fibroblasts, but not in lung fibroblasts. Neither MDC release nor MDC mRNA was detected in any of the 3 types of fibroblasts stimulated with any of the cytokines examined. CONCLUSION: These results indicate that cytokine regulation of TARC expression differs among fibroblasts derived from the cornea, skin, or lung. Corneal and dermal fibroblasts might thus be important sources of TARC during allergic inflammation.

Cells, Cultured↗

Epidermal growth factor in human tear fluid: a minireview.

This minireview deals with the presence of epidermal growth factor (EGF) in human tear fluid. It explains the occurrence of EGF in tear fluid, the origin of EGF and its dependency on tear fluid dynamics. The alterations in tear fluid EGF concentrations that occur during diseases of the ocular surface are described and discussed in the context of the current knowledge about the interaction between EGF and EGF receptors. The possible clinical implications of topical treatment with EGF are considered.

Epidermal Growth Factor↗

Penetrating keratoplasty for corneal scarring due to herpes zoster ophthalmicus.

We retrospectively studied the postoperative results in nine patients with corneal scarring due to herpes zoster ophthalmicus who underwent penetrating keratoplasty. This was a highly selected group that satisfied all of the following criteria: (a) absence of active disease of the ocular surface and eyelids, (b) intraocular pressure under control, and (c) absence of active keratouveitis. Penetrating keratoplasty after herpes zoster ophthalmicus may do well in patients with long preoperative quiescent periods in whom these restrictive preoperative criteria are observed.

Aged↗

Tear cytokines in acute and chronic ocular allergic inflammation.

PURPOSE OF REVIEW: Elevated levels of inflammatory cytokines have been reported in tears from ocular allergic disease states. The purpose of this review is to assimilate recent research contrasting tear cytokine concentrations in non-allergic subjects versus subjects with acute (seasonal allergic conjunctivitis) and chronic (giant papillary conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis) ocular allergic inflammation to discover whether the cytokine profiles could provide useful insight into disease mechanisms and therapeutic targets. RECENT FINDINGS: Recent studies have revealed distinct differences in the cytokine/chemokine concentrations in tears between the various manifestations of ocular allergy. The acute (seasonal allergic conjunctivitis) and iatrogenic (giant papillary conjunctivitis) forms of ocular allergic inflammation are characterized by an overall lack of significant cytokine changes in tears compared with chronic disease (vernal keratoconjunctivitis, atopic keratoconjunctivitis). Chronic ocular allergic inflammation produces increased concentrations of T helper 1 and 2, and proinflammatory cytokines as well as chemokines. However, vernal and atopic keratoconjunctivitis portray distinct differences in the patterns of tear cytokines/chemokines expressed. SUMMARY: The plethora of increased cytokines and chemokines in vernal and atopic keratoconjunctivitis compared with non-allergic, seasonal allergic conjunctivitis and giant papillary conjunctivitis provides a new perspective into the complex inflammatory processes occurring on the ocular surface in chronic disease. The ability to measure multiple cytokines in tears, combined with knowledge obtained from in-vitro analysis of the individual and combined effects of these cytokines on various conjunctival cells (i.e. mast cells, epithelial cells, fibroblasts) has facilitated further understanding of specific processes contributing to maintenance of inflammation and progression of vision-threatening disease and paved the way toward new therapeutic targets.

Acute Disease↗

Diquafosol tetrasodium: a novel dry eye therapy.

The ophthalmic formulation of diquafosol tetrasodium (INS365), a P2Y2 receptor agonist, is targeted to treat dry eye disease through rehydration of the ocular surface. Existing pharmacological therapies for dry eye disease are limited, therefore, approval of this medication is anticipated. This review summarises key findings during development and in clinical trials including clinical effectiveness and safety. The relevance of P2Y2 receptor technology to dry eye disease and the disease process is discussed.

Biological Availability↗

Conjunctival cytology in asymptomatic wearers of soft contact lenses.

Conjunctival epithelium was systematically investigated with impression cytology in clinically asymptomatic wearers of soft contact lenses who had been using their lenses for several years. Severe abnormalities were observed, which had so far only been seen in diseases of the ocular surface mainly in dry eye syndromes. All patients showed evidence of squamous metaplasia with distinctly enlarged, flattened cells without evidence of keratinization. They also showed frequent nuclear abnormalities, primarily a high percentage of snakelike-appearing condensations of nuclear chromatin (snakes). The goblet cell density observed was relatively low. Snakes were for the first time detected outside the known localization (upper bulbar conjunctiva, 12 o'clock position) and could be demonstrated throughout the whole bulbar conjunctival epithelium. It is suggested that the changes observed are due to chronic mechanical irritation by the contact lens, as indicated by their topographical distribution and as proven by their reversibility after omission of contact lens wear.

Adult↗

Corneal epithelial adhesion abnormalities associated with LASIK.

PURPOSE: To assess the clinical characteristics, incidence, and pathologic correlation of corneal epithelial adhesion abnormalities encountered during LASIK. DESIGN: Prospective noncomparative interventional case series. PARTICIPANTS: Five hundred consecutive eyes of 268 patients undergoing primary LASIK procedures by one surgeon utilizing the Moria LSK One microkeratome and VISX Star S-2 excimer laser. METHODS: Corneal epithelial adhesion was assessed immediately preoperatively using a cellulose surgical sponge (adhesion test), and the incidence, extent, and location of epithelial defects occurring during the microkeratome incision of the corneal flap were recorded. Epithelial specimens from 7 corneas requiring debridement of dysadhesive epithelium were examined by transmission electron microscopy. MAIN OUTCOME MEASURES: The characteristics of the study population (age, gender, contact lens use, relevant ocular surface or systemic disease, refractive error, keratometry, pachymetry) and the microkeratome-related variables (head selection and vacuum level) were compared with the results of the preoperative epithelial adhesion test, the development of intraoperative epithelial effects (size and location), and the postoperative outcome. RESULTS: Epithelial defects were sustained by 51 corneas (10.2%), and among these, 31 (6.2%) were microdefects and 20 (4.0%) were macrodefects. The adhesion test was positive (indicative of compromised adhesion of epithelium to stroma) in 20 (64.5%) corneas with microdefects, but false negatives (epithelial defect despite negative adhesion test) occurred in 11 cases (35.4%). The adhesion test was positive in 16 (80%) of corneas having macrodefects, with 4 (20%) false negatives. Thus, the overall positive predictive value of the adhesion test was 59%, and the percentage of positive prediction was 92% (Bayes' theorem). Among all other outcome measures assessed, only corneal flap thickness seemed a potential risk factor, as 40 (78.4%) epithelial defects were associated with the creation of a 180- micro m-thick flap, whereas 10 (19.6%) were associated with a 160- micro m-thick flap and only 1 (2%) occurred with a 130- micro m flap. These trends were not, however, statistically significant (P = 0.15, Fisher exact test). Transmission electron microscopy of all epithelial debridement specimens disclosed consistent abnormality of the basement membrane adhesion complex, as thickened and multilaminated basement membrane remained adherent to the intact epithelial sheet. CONCLUSIONS: : Corneal epithelial dysadhesion and defects occurring in the course of LASIK surgery may be associated with an intrinsic compromise of the basement membrane adhesion complex, as evidenced clinically by the adhesion test and demonstrated pathologically by duplicated basement membrane.

Adult↗

Electron microscopy of impression-acquired conjunctival epithelial cells.

The authors describe a technique with which one can perform electron microscopy on conjunctival epithelial cells acquired by impression cytology. With adjacent excisional and impression biopsies of conjunctival epithelium in patients having mucopolysaccharidoses (MPS), typical fibrillo-granular inclusions are shown. This noninvasive procedure has potential for the study of subcellular, cellular, and intercellular morphology in diseases of the ocular surface.

Biopsy↗

[Effect of acupuncture in keratoconjunctivitis sicca].

BACKGROUND: Conjunctivitis sicca is a chronic disease of the ocular surface. The substitution of tear deficiency with artificial tears is not satisfying in many patients. In a series of patients successfully treated with acupuncture we observed very different effects on each patient. In this study we evaluate the correlation between the effect of acupuncture and the etiology of the dry eyes treated. PATIENTS AND METHODS: 102 patients (87 women, 15 men) with dry-eye syndrome have been needed 10 sessions, once per week, for 30 minutes. We recorded causal factors according to the traditional chinese medicine (TCM): external and internal factors. External factors were: toxic, allergic, drug-induced, ocular surface inflammation and infection, contact lens and generally external irritations. Internal factors were disorders of hormones, immune system, psychic, and vitamin-A deficiency. Ophthalmologic observation included the slit-lamp examination, Schirmers test II, break-up time of tear film (BUT) and a drop-frequency protocol--before and 1 week after acupuncture treatment. RESULTS: There was a statistically significant difference (p < 0.001) in Schirmers test, BUT and drop frequency between before and after acupuncture. There was no significant difference between internal and external factors, but the effect on external induced sicca was better. The best effect of acupuncture was found in external factors after inflammation and in patients with imbalance of the autonomic nervous system, the least effects in Sjögren Syndrome. The effect was better in younger then in patients over 50 years. CONCLUSION: The study demonstrate, according DeLa Fuye that the best effect of acupuncture is seen on functionally disorders.

Acupuncture Therapy↗

[Clinical study of the effectiveness of a new preservative-free polyvidon preparation in therapy of dry-eye disorders].

BACKGROUND: Diseases of the ocular surface very frequently seen are related to irregularities of wetting. Patients often have complaints and feeling of ill-health, although under symptomatic therapy. Tolerability of the tear substitutes plays a key role in these cases. It is improved with unpreserved medication. METHOD: 59 patients with 'dry eye condition' of various etiology were enrolled in an open multicentre study and treated 8 weeks with a new preservative-free tear substitute. All patients had a history of previous ineffective treatment with artificial tears. The product was formulated with polyvidone and electrolytes in a composition which resembles natural tears. The therapeutic effect was evaluated by ratings of patients' self assessment of their complaints, tear film break up time (BUT), Schirmer I test, visual acuity, biomicroscopic examination and physicians' assessment. RESULTS: Based on the key criteria patients's self assessment and BUT, the new agent (Oculotect fluid sine) improved symptoms and reduced discomfort significantly compared with the previous treatment (paired t test, two-sided, level of significance p < or = 0.05). The improved condition was confirmed by the other findings taken. CONCLUSION: In 4/5 of patients, as typically met in ophthalmologists' offices, whose complaints were insufficiently relieved by previously applied tear substitutes, treatment with the new preservative-free product resulted in a distinct improvement of their condition. The lack of preservatives contributed to better tolerability and acceptance of tear substitution.

Adult↗

Guidelines for the treatment of chronic dry eye disease.

Keratoconjunctivitis sicca (KCS), also known as dry eye syndrome, dry eye disease, chronic dry eye disease, or keratitis sicca, refers to disorders of the tear film caused by reduced tear production, poor tear quality, or excessive tear evaporation. These disorders are associated with such symptoms of ocular discomfort as irritation, foreign body sensation, or redness, and may cause disease of the ocular surface.

Clinical Laboratory Techniques↗

Induction of conjunctival epithelial alterations by contact lens wearing. A prospective study.

In a prospective clinical study, contact lenses were applied to 14 wearers of glasses with clinically and cytologically normal conjunctiva. The alterations of conjunctival cytology after the start of contact lens wearing were recorded with the technique of impression cytology over a period of 6 months. Within the first few weeks after application of the contact lenses, the patients developed a rapidly increasing alteration of cell size and nuclear morphology. Enlargement of the cell diameter with flattening of the cell body was seen together with numerous different nuclear alterations, in particular snakes (condensations of the nuclear chromatin into a sticklike or snakelike shape, centrally arranged in the nucleus). After this very rapid onset, the alterations increased more slowly towards a possible saturation point (and it seemed that the ultimate changes might possibly not be reached within the investigated period). At about 3-6 months, the patients reached a degree of cytological alteration which was seen in long-time contact lens wearers in our previous study and before this, except for the lack of keratinization, only observed in diseases of the ocular surface. There was a distinct squamous metaplasia of major parts of the conjunctival epithelium which normally is columnar and a decrease of goblet cell density. Squamous metaplasia and nuclear alterations increased with the length of time which had elapsed since the application of contact lenses and with extending the daily wearing time but were always restricted to the contact lens excursion zone on the eye and disappeared after contact lens omission, as seen before. Even patients with major cytological alterations remained free of symptoms, and the conjunctiva was still clinically normal.

Cell Count↗

Keratoconjunctivitis sicca and corneal ulcers.

We reviewed the records of 56 patients (109 eyes) who satisfied our criteria for keratoconjunctivitis sicca (KCS) to determine factors associated with the development of sterile corneal ulcers. The patient's age, sex, and associated local ocular surface and/or systemic disease were studied. We found a statistically significant association between the development of corneal ulceration and the presence of an underlying condition or disease state, especially chronic rheumatoid arthritis. Patient sex and age were not significantly associated with the development of corneal ulceration. We present three case histories that illustrate the complications that arise in managing KCS plus an associated disease and methods of management.

Adult↗

Impression cytology in atopic dermatitis.

PURPOSE: This study aimed to describe the ocular surface disorder in patients with atopic dermatitis (AD). DESIGN: A prospective case-controlled study. PARTICIPANTS: A total of 44 patients with active AD seen at Kobe University School of Medicine, Department of Ophthalmology, during 1994 through 1996 and 22 normal control subjects were studied. INTERVENTION: The subjects underwent routine ophthalmic examinations, tear film break-up time (BUT), Schirmer test, and conjunctival impression cytology. MAIN OUTCOME MEASURES: Patients and control subjects were compared for tear function parameters, goblet cell density, and conjunctival squamous metaplasia grade. The relation of duration and recurrences of AD to the ocular surface disorder also was looked for. RESULTS: The duration of atopic disease ranged from 18 to 32 years (mean, 22.8 years). The average for exacerbations was 4.5 times. Chronic allergic conjunctivitis with superficial punctate keratitis was the most frequent clinical presentation. The BUT and Schirmer test values were significantly lower in patients with AD compared with those of the control subjects. Impression cytology showed goblet cell loss and conjunctival squamous metaplasia, both of which related to the number of recurrences of AD rather than the duration of disease. Facial atopy and allergic keratoconjunctivitis (AKC) related to the metaplasia of the ocular surface (P < 0.001). Patients with reduced goblet cell density also showed low BUT levels (P < 0.001). CONCLUSION: Ocular surface disorder of AD characterized by goblet cell loss and conjunctival squamous metaplasia seemed to evolve independently of the duration of disease but worsen with increased number of flare-ups. Direct epithelial damage by the allergic reaction, disorder of tear quality, and quantity may be important in the genesis of the atopic ocular surface disease.

Adolescent↗