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Distribution of mucins at the ocular surface.

Mucins are vital for maintenance of a healthy, wet ocular surface. Once only thought to be secreted by goblet cells, mucins are now also known to be of the membrane-associated type. Stratified ocular surface epithelia express at their apical-tear fluid surface a repertoire of membrane-associated mucins including MUC1, MUC4, MUC16. These mucins are concentrated on the tips of the microplicae, forming a dense glycocalyx at the epithelial tear film interface. A major mucin of the secretory class is the goblet-cell-derived gel-forming mucin MUC5AC. A small soluble mucin, MUC7, is expressed by the lacrimal gland acini. Our hypothesis of the role/distribution of the secreted and membrane-associated mucins at the ocular surface is that the secreted mucins are soluble in the tear fluid, and are moved about and shunted to the nasolacrimal duct and by the eyelids during blinking. Thus, in the tears, the secreted mucins act as clean-up/debris removing multimeric networks that at the same time, through their hydrophilic nature, hold fluids in place and harbor defense molecules secreted by the lacrimal gland. Membrane-associated mucins, on the other hand, form a dense barrier in the glycocalyx at the epithelial tear film interface. This barrier prevents pathogen penetrance and is a lubricating surface that allows lid epithelia to glide over the corneal epithelia without adherence. The secreted mucins move easily over the glycocalyx mucins because both have anionic character that creates repulsive forces between them. Little is known regarding regulation of expression and glycosylation of mucins by ocular surface epithelia. Since ocular surface drying diseases alter both goblet cell and mucin production, and production and glycosylation of membrane-associated mucins, studies of mucin gene regulation and glycosylation may yield treatment modalities for these diseases.

Conjunctiva↗

Significance of mucin on the ocular surface.

PURPOSE: To review the significance of mucin in the tear film and the ocular surface epithelium. METHODS: Summary of the information on how mucin derived from the corneal and conjunctival epithelia and from goblet cells plays a role in the stability of the tear film over the ocular surface. The change in mucin expression derived from the ocular surface epithelium is also discussed with reference to ocular surface disease. RESULTS: The corneal and conjunctival epithelia produce transmembrane mucins such as MUC1, MUC2, and MUC4. In contrast, goblet cells produce the gel-forming secretory mucin, MUC5AC. The lacrimal gland produces MUC7. On the ocular surface, cooperation between transmembrane mucin and secretory mucin is necessary for the stability of the tear film. The expression of mucin from the ocular surface epithelium is coordinated from the time of eyelid opening and is altered in conditions such as squamous metaplasia and dry eye. This alteration may result in instability of the tear film. CONCLU SION: The induction of mucin from the ocular surface may facilitate the stability of the tear film, and increased knowledge may lead to the development of a new modality for the treatment of dry eye.

Conjunctiva↗

Detection of sialomucin complex (MUC4) in human ocular surface epithelium and tear fluid.

PURPOSE: To evaluate human ocular surface epithelium and tear fluid for the presence of sialomucin complex (MUC4), a high-molecular-weight heterodimeric glycoprotein composed of mucin (ASGP-1) and transmembrane (ASGP-2) subunits. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis assays were used to identify sialomucin complex RNA in ocular surface epithelia. Immunoprecipitation and immunoblot analysis were used to identify immunoreactive species in human tears and in the corneal and conjunctival epithelia using antibodies specific for carbohydrate and peptide epitopes on the sialomucin complex subunits. Immunofluorescence staining was used to detect sialomucin complex in frozen sections and impression cytology specimens of human cornea and conjunctival epithelia. RESULTS: ASGP-1- and ASGP-2-specific sequences were amplified from RNA extracted from both conjunctival and corneal epithelial biopsies by RT-PCR. Sialomucin complex transcripts were also detected in these tissues by Northern blot analysis, with a greater level of RNA detected in the peripheral than the central corneal epithelium. Sialomucin complex was immunoprecipitated from tear fluid samples and both corneal and conjunctival epithelia and detected by immunoblot analysis with specific anti-ASGP-1 and anti-ASGP-2 antibodies. The ASGP-1 peptide antibody HA-1 stained the full thickness of the corneal and conjunctival epithelia. In contrast, antibody 15H10, which reacts against a carbohydrate epitope on ASGP-1, stained only the superficial epithelial layers of these tissues. No staining was observed in the conjunctival goblet cells. CONCLUSIONS: Sialomucin complex was originally identified in rat mammary adenocarcinoma cells and has recently been shown to be produced by the ocular surface epithelia of rats. Furthermore, it has been identified as the rat homologue of human MUC4 mucin. The present studies show that it is expressed in the stratified epithelium covering the surface of the human eye and is present in human tear fluid. Expression of a carbohydrate-dependent epitope on the mucin subunit (ASGP-1) of sialomucin complex occurs in a differentiation-dependent fashion. Sialomucin complex joins MUC1 as another membrane mucin produced by the human ocular surface epithelia but is also found in the tear fluid, presumably in a soluble form, as found on the rat ocular surface.

Antibody Specificity↗

The impact of the onset time of atopic keratoconjunctivitis on the tear function and ocular surface findings.

PURPOSE: To investigate the tear and ocular surface findings between controls, children, and adults with atopic keratoconjunctivitis (AKC). DESIGN: Prospective comparative study. METHODS: Twenty eyes of 10 childhood-onset, 10 eyes of five adult-onset, AKC adult patients, and 12 eyes of six children with infantile-onset AKC, 14 eyes of seven normal adults and seven normal children were recruited. Corneal aesthesiometry, Schirmer test, tear film break-up time (BUT), vital staining, and conjunctival impression cytology were performed. RESULTS: The Schirmer and Rose Bengal scores in childhood-onset adult AKC patients were considerably worse than adult-onset adult AKC patients, pediatric subjects, and the controls (P < .05). The same significant relation was observed in impression cytology parameters. CONCLUSIONS: Ocular surface disease in childhood-onset adult AKC patients was characterized by greater ocular surface epithelial damage. Prolonged inflammation may be important in the evolution and progression of ocular surface disease in patients with longstanding active AKC.

Adult↗

Ocular surface management in corneal transplantation, a review.

PURPOSE: To discuss the importance of ocular surface management in corneal transplantation, especially in limbal transplantation. METHODS: Since the corneal epithelium is not completely recovered after corneal transplantation, meticulous attention should be paid to the ocular surface to prevent infection and rejection, which are the major causes of corneal transplantation failure. Preoperative evaluations of the ocular surface should be carried out, followed by appropriate surgical procedures, depending on the condition of each patient. Vigorous immunosuppressive measures should be taken after surgery. RESULTS: In both case reports presented in this study, each patient underwent successful surgery and his condition was controlled by medication suited to his needs. CONCLUSIONS: For those patients with stem cell deficiency, limbal transplantation, possibly with the use of autologous serum drops, should be considered to reconstruct and maintain the ocular surface. Ocular surface management is necessary for the success of corneal transplantation, especially for limbal transplantation.

Adult↗

Conjunctival grafting for ocular surface disease.

The procedure of transplanting healthy conjunctiva onto eyes with damaged ocular surface epithelium was first described by Thoft in 1977. Today, conjunctival autografting is widely used in pterygium surgery and has been shown to be both safe and effective in reducing pterygium recurrence. Several randomized, controlled, clinical trials have been reported in the literature, and conjunctival autografting is now recognized to have an efficacy equal to that of such adjunct therapies as beta-irradiation and mitomycin C, and yet it is safer than these treatments. Recent modifications of the conjunctival autograft include the conjunctival rotation autograft and the inferior conjunctival transposition flap, both of which have been reported to be associated with low rates of recurrence. With the discovery of the role of limbal stem cells in the maintenance and stability of the corneal surface, recent forms of ocular surface transplantation that have supplanted Thoft's conjunctival transplantation procedure include limbal autograft transplantation and limbal allograft transplantation. In addition, the adjunct use of human amniotic membrane in these ocular surface transplantation procedures has improved success and survival rates in the management of ocular surface disease, which still presents significant challenges to clinicians today.

Amnion↗

Tear function and ocular surface changes in keratoconus.

PURPOSE: To describe the ocular surface disorder in patients with keratoconus. DESIGN: A prospective, case-controlled study. PARTICIPANTS: Seventy-five eyes of 38 patients with keratoconus seen at Uludag University School of Medicine, Department of Ophthalmology, from March 2000 through April 2001, and 80 eyes of 40 normal control subjects were studied. INTERVENTION: The subjects underwent routine ophthalmic examinations, corneal sensitivity measurements, Schirmer test, tear film breakup time (BUT), fluorescein and rose bengal staining of the ocular surface, and conjunctival impression cytology. MAIN OUTCOME MEASURES: Patients and control subjects were compared for corneal sensitivity, tear function, ocular surface staining parameters, goblet cell density, and squamous metaplasia grade. The relation of these parameters to the severity of keratoconus progression was also investigated. RESULTS: The mean corneal sensitivity was significantly lower in keratoconus patients compared with control subjects (P < 0.001). The BUT values were also significantly lower in the keratoconus group. Patients with keratoconus had significantly higher fluorescein and rose bengal staining scores (P < 0.001). Corneal sensitivity and tear function changes seemed to get worse with advanced stages of keratoconus. Impression cytology showed goblet cell loss and conjunctival squamous metaplasia, both of which again related to the extent of progression of keratoconus. CONCLUSIONS: The ocular surface disease in keratoconus is characterized by disorder of tear quality, squamous metaplasia, and goblet cell loss, all of which seem to relate to the extent of keratoconus progression.

Adolescent↗

The role of nitric oxide in ocular surface cells.

The role of nitric oxide (NO) in the ocular surface remains unknown. We investigated the conditions leading to an increase of NO generation in tear and the main sources of NO in ocular surface tissue. We evaluated the dual action (cell survival or cell death) of NO depending on its amount. We measured the concentration of nitrite plus nitrate in the tears of ocular surface diseases and examined the main source of nitric oxide synthase (NOS). When cultured human corneal fibroblast were treated with NO producing donor with or without serum, the viabilities of cells was studied. We found that the main sources of NO in ocular surface tissue were corneal epithelium, fibroblast, endothelium, and inflammatory cells. Three forms of NOS (eNOS, bNOS, and iNOS) were expressed in experimentally induced inflammation. In the fibroblast culture system, the NO donor (SNAP, S-nitroso-N-acetyl-D, L-penicillamine) prevented the death of corneal fibroblast cells caused by serum deprivation in a dose dependent manner up to 500 micrometer SNAP, but a higher dose decreased cell viability. This study suggested that NO might act as a double-edged sword in ocular surface diseases depending on the degree of inflammation related with NO concentration.

Animals↗

[The local immune system of ocular surface].

Local immunity on the ocular surface was observed in guinea pigs immunized with horseradish peroxidase (HRP) by determining the activity of a specific antibody in local sites of the conjunctiva by the enzyme-antigen method, which enables a specific antibody to be stained. In addition, immunohistochemical study of the localization of IgA was performed by the enzyme-labelled antibody method. The enzyme-antigen method revealed a number of positive cells in the subconjunctival tissue and the parafollicular area of conjunctival-associated lymphoid tissue. These cells were identified as plasma cells by electron microscopy. The mirror section technique revealed that the cells positive for the enzyme-antigen method were consistent with anti-IgA-positive cells at many sites. Thus the distribution of plasma cells secreting IgA-specific antibody responsible for local immunity on the ocular surface was observed immunohistochemically. The results suggest that immunocytes in the conjunctival-associated lymphoid tissue differentiate and mature into specific antibody-producing plasma cells.

Animals↗

Host-defense mechanism of the ocular surfaces.

The defense of the ocular surfaces presents an unique challenge in that not only must integrity be maintained against microbial, inflammatory and physical assault, but it must be done while minimizing the risk of loss of corneal transparency. This puts severe limitations on the degree to which scarring or neovascularization can occur in the cornea secondary to any infectious, inflammatory, immunological or wound healing process. Moreover, this defense system must be equally effective under two extremes of conditions: those found in the open eye and the closed eye environments. It is our contention that these constraints have resulted in the evolution of a highly complex fail-safe defense system that utilizes distinctly different strategies in open and closed eye conditions. The extraordinary effectiveness of this system is evidenced by the fact that despite continued exposure to a microbe rich environment, the external ocular surfaces maintain a very low microbial titer and are highly resistant to breaching by all but a few pathogens. It is the intent of this review to provide a working model of this defense system as it operates under both open and closed eye conditions, to provide evidence in support of this model as well as highlight some of the many areas of uncertainty.

Anti-Infective Agents↗

[Principles of treatment in ocular burns regarding the ocular surface and limbal stem cells].

The term ocular surface emphasizes the functional interdependence of the nonkeratinizing epithelium of cornea and conjunctiva. The limbal stem cells are responsible for replacement of corneal epithelium following ocular surface injuries. Over the past decades important advances in the management of chemical injury have occurred based on the application of theories on ocular surface and limbal stem cells.

Burns, Chemical↗

Ocular surface changes in pterygium.

PURPOSE: To evaluate ocular surface abnormalities in eyes with pterygium. METHODS: Impression cytology was performed on 56 pterygia in 50 eyes with primary or recurrent pterygium. Superior, inferior, nasal, and temporal bulbar conjunctivae were evaluated. RESULTS: The ocular surface morphology directly over the pterygium was found to be abnormal in 100% of cases. This was significant compared with abnormalities in 2.4% in the superior bulbar conjunctiva, 54.5% in the inferior bulbar conjunctiva, and 58.1% in the clinically unaffected interpalpebral conjunctiva. The epithelial cells in pterygium demonstrated squamous metaplasia in 73.2% of cases, with marked enlargement and elongation of the cells and pyknotic changes in the nuclei. Squamous metaplasia was also seen in the inferior conjunctiva (31.7%) and the clinically unaffected interpalpebral conjunctiva (54.8%) but without the advanced changes seen over the pterygium (p < 0.001). A low cellular yield was obtained over the pterygium in 98.2% of cases but only 22.7% in the inferior conjunctiva and 22.6% in the clinically unaffected interpalpebral conjunctiva (p < 0.001). Mucinous hyperplasia signifying increased goblet cell density was observed over the surface of the pterygium in 87.5% compared with 2.4% in the superior conjunctiva, 15.9% in the inferior conjunctiva, and 12.9% in the clinically unaffected interpalpebral conjunctiva (p < 0.001). CONCLUSION: The cytology of surface cells in pterygium exhibits squamous metaplasia with increased goblet cell density. A graded series of ocular surface changes exists throughout the bulbar conjunctiva in eyes with pterygium, with the most advanced changes occurring directly over the pterygium surface.

Adult↗

Epithelial transplantation for the management of severe ocular surface disease.

PURPOSE: First, to present a new classification of epithelial transplantation procedures for ocular surface disease; second, to present our experience with a keratolimbal allograft procedure for limbal stem cell deficiency; and third, to make recommendations for the indications and postoperative management of epithelial transplantation procedures. METHODS: A review of all epithelial transplantation procedures was performed. A classification of these procedures based on the source of donor tissue and the tissue transplanted was proposed. In addition, a review of 25 eyes of 21 patients who underwent a keratolimbal allograft was completed. Ocular surface stability, improvement of visual acuity, success of subsequent keratoplasties, and preoperative risk factors were evaluated. Results were compared with those of other epithelial transplantation procedures for ocular surface disease. On the basis of the results of published studies, as well as ours, a recommendation for the indication of the various procedures was made. RESULTS: Epithelial transplantation for ocular surface disease can be classified as one of the following procedures: conjunctival autograft (CAU), conjunctival allograft (CAL), conjunctival limbal autograft (CLAU), cadaveric conjunctival limbal allograft (c-CLAL), living related conjunctival limbal allograft (lr-CLAL), or keratolimbal allograft (KLAL). Evaluation of our keratolimbal allograft patients revealed that 18 of 25 eyes (72%) developed a stable ocular surface. Fifteen eyes (60%) demonstrated a significant improvement in visual acuity. Persistent epithelial defects and symblephara were successfully managed with this procedure. Six of 13 (46%) subsequent keratoplasties were successful. Patients with limbal deficiency due to Stevens-Johnson syndrome had a significantly worse outcome. Patients with preoperative conjunctival keratinization also had a significantly worse outcome. Indications for epithelial transplantation are as follows: For patients with unilateral cicatrizing conjunctival disease, the first option should be CAU. For patients with unilateral limbal deficiency, CLAU is the procedure of choice. For patients with bilateral disease Ir-CLAL should be considered first. If this procedure is not available, then consideration of KLAL is warranted. CONCLUSIONS: Classification of the various epithelial transplantation procedures based on anatomy is useful for an accurate comparison and discussion of the procedures. KLAL is a useful technique in the management of severe ocular surface disease due to limbal deficiency. However, patients with preoperative conjunctival keratinization have a poor prognosis. Consideration of a CLAU or a Ir-CLAL should be made for ocular surface disease on the basis of whether the disease is unilateral or bilateral. The importance of HLA and ABO typing, as well as the protocol for immunosuppression in the allograft procedures for limbal deficiency, needs further study.

Adolescent↗

Differential regulation of membrane-associated mucins in the human ocular surface epithelium.

PURPOSE: Membrane-associated mucins present in the apical cells of the ocular surface epithelium (MUC1, -4, and -16) are believed to contribute to the maintenance of a hydrated and wet-surfaced epithelial phenotype. Serum and retinoic acid (RA) have been used to treat drying ocular surface diseases. The goal of this study was to determine whether serum or RA regulates the production of membrane-associated mucins in human conjunctival epithelial cells. METHODS: A telomerase-immortalized human conjunctival epithelial cell line (HCjE) was used. Cells were cultured in serum-free medium to confluence and then cultured with either 10% calf serum or with 100 nM RA for 0 to 72 hours. Conventional RT-PCR was used to determine the expression of retinoic acid receptors (RARs) and quantitative real-time PCR was used to investigate the mRNA expression of MUC1, -4, and -16. Protein levels were assayed by immunoblot analysis, using the antibodies HMFG-2, 1G8, or OC125, which are specific to MUC1, -4 and -16, respectively. To determine whether RA-associated MUC4 mRNA induction is a direct or indirect effect, HCjE cells were treated with RA and the protein synthesis inhibitor cycloheximide (1.0 microg/mL) for 12 hours. RESULTS: MUC1 and -16, but not -4, mRNAs were detectable in HCjE cells grown in serum-free medium. Real-time PCR revealed that MUC4 mRNA was significantly induced by serum 3 hours after its addition, and that MUC1 and MUC16 mRNA levels were significantly upregulated at 72 hours. Western blot analysis demonstrated that the MUC1, -4, and -16 proteins increased over time after addition of serum. Conventional RT-PCR analysis demonstrated that RAR-alpha and -gamma mRNA were expressed in native human conjunctival tissue as well as in the HCjE cells. Treatment with RA upregulated the expression of both MUC4 and -16 mRNA and protein, but MUC1 was unaffected. Because the protein synthesis inhibitor cycloheximide did not prevent the RA-associated induction of MUC4 mRNA, the action of RA on the MUC4 promoter may be direct. CONCLUSIONS: The membrane-associated mucins of the ocular surface epithelia, MUC1, -4, and -16, are differentially regulated by serum and RA in the telomerase-immortalized human conjunctival epithelial cell line. Serum derived from vessels in the conjunctiva may play an important role in mucin regulation in the ocular surface epithelia. These data also support the clinical efficacy of autologous serum and RA application in patients with ocular surface diseases. Furthermore, the data suggest that MUC4 and -16 are particularly important hydrophilic molecules involved in maintenance of a healthy ocular surface.

Blood↗

New perspectives in ocular surface disorders. An integrated approach for diagnosis and management.

The cornea, conjuctiva and the limbus comprise the tissues at the ocular surface. All of them are covered by stratified, squamous, non-keratinizing epithelium and a stable tear film. The ocular surface health is ensured by intimate relationship between ocular surface epithelia and the preocular team film. There are two types of ocular surface failure. The first one is characterized by squamous metaplasia and loss of goblet cells and mucin expression. This is consistent with unstable tear film which is the hallmark of various dry-eye disorders. The second type of ocular surface failure is characterized by the replacement of the normal corneal epithelium in a process called limbal stem cell deficiency. It is essential to establish accurate diagnosis for appropriate management of complex ocular surface disorders. There has been considerable advancement in the understanding of the pathophysiology of ocular surface disease. Management has improved with introduction of the limbal stem cell concept and use of amniotic membrane transplantation.

Amnion↗

Blinking is controlled primarily by ocular surface conditions.

PURPOSE: To investigate the relation between blinking and ocular surface conditions and to introduce and examine a new index, the maximum blink interval. METHODS: In a prospective study, the blink rate of subjects under relaxed conditions was determined from a video recording taken by a hidden observer. The maximum blink interval was defined as the longest time subjects can avoid blinking without feeling uncomfortable. RESULTS: Significant changes in the blink rate and maximum blink interval were induced by factors that directly or indirectly affect the ocular surface: topical anesthesia, changing exposed ocular surface area, and wind. Moreover, the blink rate and maximum blink interval were significantly different in dry eye patients compared with healthy volunteers, with the values of the former approaching the values of the latter after use of artificial tears. The maximum blink interval was decreased by the same factors that increased the blink rate, and there was a significant inverse correlation between blink rate and maximum blink interval. Use of video display terminals was associated with decreased maximum blink interval and, hence, the development of dry eye symptoms. CONCLUSIONS: There was an important association among blink rate, maximum blink interval, and ocular surface conditions. The blink rate and our newly introduced measurement, the maximum blink interval, should prove useful in assessing factors that cause dry eye. This prospective study should contribute to the understanding and treatment of dry eyes.

Administration, Topical↗

[Transdifferentiation of conjunctival epithelium after ocular surface rehabilitation through deep lamellar sclerokeratoplasty].

PURPOSE: The quality of the postoperative corneal epithelia of patients with severe ocular surface disorders, whose ocular surface had been reconstructed through deep lamellar sclerokeratoplasty (DLSKP) using allografts, was examined. PATIENTS AND METHODS: Six eyes with ocular surface disorders in 6 patients who had received DLSKP were observed for periods of 2 years or longer (average: 3 years and 10 months). The rehabilitated corneal epithelium cells of some of these patients were analyzed with impression cytology and fluorescence in situ hybridization (FISH) analysis methods. RESULTS: All 3 cases analyzed using the impression cytology method showed normal corneal epithelium cell forms. In the 2 cases analyzed also with the FISH analysis method, in which the hosts and donors were of the opposite gender, the cells were host-derived (99.3% and 98.8%). CONCLUSION: It is considered that rehabilitation of severe ocular surface disorders using allograft epithelial transplantation procedures, including DL-SKP, is eventually concluded by transdifferentiation of the conjunctival epithelium cells derived from the host.

Adult↗

Tear function and ocular surface findings in premature and term babies.

OBJECTIVE: To describe the ocular surface and tear function findings in premature and term babies. DESIGN: Prospective, case-control study. PARTICIPANTS: Forty-eight eyes of 24 premature babies seen at the Department of Ophthalmology of Uludag University School of Medicine, Bursa, Turkey, from March 2002 through September 2002 and 50 eyes of 25 healthy term babies were studied. INTERVENTION: The subjects underwent routine ophthalmic examinations; corneal sensitivity measurements; Schirmer test with anesthesia, with and without nasal stimulation; primary Jones test; fluorescein staining of the ocular surface; and conjunctival impression cytology. MAIN OUTCOME MEASURES: Premature and term babies were compared for corneal sensitivity, lacrimal drainage system patency, tear function and ocular surface staining parameters, goblet cell density, and squamous metaplasia grade. The relation of these parameters to the status of the ocular surface was also investigated. RESULTS: Mean corneal sensitivity scores were 45+/-5.0 mm and 55+/-4.5 mm in the premature and term babies, respectively (P<0.001). Premature babies had a mean corneal fluorescein staining score of 1.5+/-0.25 points, compared with 0.22+/-0.28 points in the term babies (P<0.001). The mean Schirmer test scores without and with stimulation were 1.5+/-2.5 mm and 4.15+/-2.5 mm in the premature babies, respectively, compared with 15+/-3.5 mm and 18.75+/-4.5 mm in the term babies. The intragroup and intergroup Schirmer test scores were statistically significant (P<0.001). The primary Jones test was positive in 20.8% of the eyes in the premature babies, whereas it was positive in 84% of eyes in the term babies. The premature babies with positive primary Jones test results all had corneal epithelial defects or severe superficial punctuate keratopathy. Mean conjunctival impression cytology squamous metaplasia scores were 1.86+/-1.2 in the premature babies and 0.86+/-0.47 in the term babies (P<0.001). Mean goblet cell densities were 393+/-484 cells/mm(2) and 739+/-503 cells/mm(2) in the premature and term babies, respectively (P<0.001). CONCLUSION: Decreased corneal sensitivity, reduced tearing, and lacrimal drainage patency are important determinants of ocular surface disease in premature infants. Premature newborns with low Schirmer test scores and a patent lacrimal system may experience corneal and conjunctival epithelial problems and should be carefully checked for the presence of dry eye complications.

Case-Control Studies↗