Decreased Tear Secretion Research Articles

Ocular Surface Changes in Patients with Thyroid Eye Disease: An Observational Clinical Study.

BackgroundThis study aimed to compare ocular surface parameter changes in active and inactive thyroid eye disease (TED) patients and controls.MethodsThis is an observational clinical study that included 60 eyes divided into three groups following clinical activity score (CAS) assessment. The first group (Group A) comprised 20 eyes with active TED (CAS score ≥3/7), while the second group (Group B) comprised 20 eyes with inactive TED (CAS score <3/7) and the third group (Group C) comprised 20 eyes of controls without dry eye manifestations. The palpebral fissure height, degree of proptosis, degree of lagophthalmos, ocular surface disease index (OSDI), Schirmer test without anesthesia, corneal fluorescein staining (CFS), non-invasive tear break-up time (NITBUT), tear meniscus height (TMH), lipid layer thickness (LLT), meiboscore, meibomian gland dysfunction (MGD), and thyroid antibodies were assessed and data were compared between study participants.ResultsThe mean OSDI was 40.0 ±5.80 in Group A, which significantly differed from Group B with a mean of 26.5 ±5.10 (p=0.02). There were significant differences between the two groups regarding palpebral fissure height (p=0.02), amount of proptosis (p=0.008), and degree of lagophthalmos (p=0.001). Similarly, active TED patients had more decreased tear secretion than inactive TED patients (p=0.012). Moreover, active TED patients showed a significant increase in Meibomian gland loss areas in both upper and lower eyelids compared with inactive TED patients (p=0.001). Corneal fluorescein staining also revealed a statistically significant difference between the studied groups (p=0.0001).ConclusionThis study showed differences regarding ocular surface parameter changes between both active and inactive TED and compared to controls. Further studies are needed to confirm these results.

Effect of Dry Eye Disease on the Kinetics of Lacrimal Gland Dendritic Cells as Visualized by Intravital Multi-Photon Microscopy

The lacrimal gland (LG) is the main source of the tear film aqueous layer and its dysfunction results in dry eye disease (DED), a chronic immune-mediated disorder of the ocular surface. The desiccating stress (DS) murine model that mimics human DED, results in LG dysfunction, immune cell infiltration, and consequently insufficient tear production. To date, the immune cell kinetics in DED are poorly understood. The purpose of this study was to develop a murine model of intravital multi-photon microscopy (IV-MPM) for the LG, and to investigate the migratory kinetics and 3D morphological properties of conventional dendritic cells (cDCs), the professional antigen presenting cells of the ocular surface, in DED. Mice were placed in a controlled environmental chamber with low humidity and increased airflow rate for 2 and 4 weeks to induce DED, while control naïve transgenic mice were housed under standard conditions. DED mice had significantly decreased tear secretion and increased fluorescein staining (p < 0.01) compared to naïve controls. Histological analysis of the LG exhibited infiltrating mononuclear and polymorphonuclear cells (p < 0.05), as well as increased LG swelling (p < 0.001) in DED mice compared to controls. Immunofluorescence staining revealed increased density of cDCs in DED mice (p < 0.001). IV-MPM of the LG demonstrated increased density of cDCs in the LGs of DED mice, compared with controls (p < 0.001). cDCs were more spherical in DED at both time points compared to controls (p < 0.001); however, differences in surface area were found at 2 weeks in DED compared with naïve controls (p < 0.001). Similarly, 3D cell volume was significantly lower at 2 weeks in DED vs. the naïve controls (p < 0.001). 3D instantaneous velocity and mean track speed were significantly higher in DED compared to naïve mice (p < 0.001). Finally, the meandering index, an index for directionality, was significant increased at 4 weeks after DED compared with controls and 2 weeks of DED (p < 0.001). Our IV-MPM study sheds light into the 3D morphological alterations and cDC kinetics in the LG during DED. While in naïve LGs, cDCs exhibit a more dendritic morphology and are less motile, they became more spherical with enhanced motility during DED. This study shows that IV-MPM represents a robust tool to study immune cell trafficking and kinetics in the LG, which might elucidate cellular alterations in immunological diseases, such as DED.

PPARγ: the dominant regulator among PPARs in dry eye lacrimal gland and diabetic lacrimal gland.

To investigate the regulatory roles of the members of the peroxisome proliferator-activated receptor (PPAR) family in lacrimal gland dysfunction under conditions of desiccating stress or diabetes. Quantitative polymerase chain reaction (qPCR) was used to examine the expression of PPARs in the cornea, conjunctiva, meibomian gland, and lacrimal gland in adult rats. The rats were divided into 3 groups: a control group, dry eye group, and diabetic group. The phenol red threads test, tear film break-up time (BUT) test and fluorescein staining were carried out to evaluate the development of dry eye. Based on bioinformatics research, qPCR was used to examine the expression level of PPARγ, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), sirtuin 1 (Sirt1), myeloid differentiation factor 88 (MyD88) and transforming growth factor-β (TGF-β) in the lacrimal glands. PPARα and PPARβ/δ were mainly expressed in the conjunctiva and the lacrimal gland, respectively. However, PPARγ was expressed in both the conjunctiva and lacrimal gland, at much higher levels than those measured for PPARα and PPARβ/δ. Dry eye rats and diabetic rats both showed decreased tear secretion, shortened BUT, and increased corneal staining. Significant changes in gene expression were observed compared with the control group. In the lacrimal glands of dry eye rats and diabetic rats, expression of PPARγ decreased (P<0.05), expression of Sirt1 also decreased (P<0.01), whereas expression of TNF-α, IL-1β, IL-6, MyD88, and TGF-β increased (P<0.05). Among PPARs, PPARγ might play a dominant role in the regulation of metabolic- and inflammatory-signaling pathways on the ocular surfaces and in lacrimal glands. Down-regulation of PPARγ is highly relevant to lacrimal gland dysfunction under desiccating-stress and diabetic conditions. PPARγ, thus, is a potential therapeutic target in the treatment of environment- or diabetes-induced dry eye diseases.

Optimization of a Rabbit Dry Eye Model Induced by Topical Instillation of Benzalkonium Chloride.

Purpose To optimize a rabbit dry eye model induced by topical instillation of benzalkonium chloride (BAC), reduce the days of instillation of the original model by increasing the concentration of BAC from 0.1% to 0.2%. Materials and Methods An experimental, prospective, and randomized study was performed on 10 male New Zealand white rabbits, divided into two groups, considering both eyes: 5 rabbits as control (n = 10) and 5 rabbits with 0.2% BAC treatment (n = 10). Saline solution (control) and 0.2% BAC were instilled for 5 consecutive days, twice daily. Tear secretion with and without anesthesia, tear breakup time, tear osmolarity, corneal staining, conjunctival hyperemia, density of goblet cells, height of mucin cloud, and transcript levels of IL-6 were measured before and after the treatment. Results After the instillation of 0.2% BAC for 5 consecutive days, there was a significant increase in tear secretion without anesthesia (P < 0.001), corneal staining (P < 0.001), conjunctival hyperemia (P < 0.001), and levels of IL-6 mRNA (P=0.005) compared to the control group. Conversely, there was a decrease in tear secretion with anesthesia (P < 0.001), tear breakup time (P=0.007), tear osmolarity (P < 0.001), density of goblet cells (P < 0.001), and height of mucin cloud (P < 0.001). Conclusions The topical instillation of 0.2% BAC for 5 consecutive days, twice daily, was a proper procedure to induce a rabbit dry eye model, reducing the number of days of instillation compared to the original model (14 days).

Identification of Lacrimal Gland Postganglionic Innervation and Its Regulation of Tear Secretion

Tear fluid secreted from the exocrine lacrimal gland (LG) has an essential role in maintaining a homeostatic environment for a healthy ocular surface. Tear secretion is regulated by the sympathetic and parasympathetic components of the autonomic nervous system, although the contribution of each component is not fully understood. To investigate LG innervation, we identified sympathetic and parasympathetic postganglionic nerves, specifically innervating the mouse LG, by injecting a retrograde neuronal tracer into the LG. Interruption of neural stimuli to the LG by the denervation of these postganglionic nerves immediately and chronically decreased tear secretion, leading to LG atrophy along with destruction of the lobular structure. This investigation also found that parasympathetic, but not sympathetic, innervation was involved in these alterations.

Dynamic changes of ocular surface tissue of diabetic dry eye in mice

Objective To explore the occurring and developing characteristics of dry eye syndrome in type 1 diabetic mouse model induced with streptozotocin (STZ)-intraperitoneal injection. Methods Completely randomized design method was performed.Sixty SPF degree male C57BL/6 mice (6-8 weeks old) was randomly divided into diabetic group and control group, which were intraperitoneally injected with citrate buffer and STZ-citrate buffer (50 mg/kg per day), respectively.The average weight, blood glucose level and lacrimal gland weight were examined before injection and 1 month, 2 months, 4 months after the last injection; meanwhile, phenol cotton thread and rose bengal staining methods were used to check tear formation and ocular surface condition; corneal perception meter was used to test corneal sensitivity; periodic acid-schiff (PAS) staining method was used to test the density of conjunctival goblet cells; histopathological staining and Masson staining methods were used to test the tissue changes of lacrimal gland. Results Compared with before injections, the body weight and lacrimal gland weight in diabetic group were not significantly changed 1 month, 2 months and 4 months after injection (all at P>0.05), but these measurements in diabetic group 1 month, 2 months and 4 months after injection were significantly lower than those in control group at corresponding time points (all at P<0.05). Compared with before injections and control group at corresponding time points, the blood glucose level were dramatically higher and the tear formation were significantly decreased in diabetic group at 1 month, 2 months, 4 months after injection (all at P<0.05). The ocular surface of diabetic model mice showed positive rose bengal staining 2 months after STZ injections.The corneal sensitivities were significantly lower in diabetic model mice 2 months and 4 months after injection than those before injection and in control group at corresponding time points (all at P<0.05). The density of conjunctival goblet cells in diabetic group 4 months after injection was significantly decreased than those before injection in diabetic group and 4 months after injection in control group (all at P<0.05). The apparent collagen fibrosis and inflammatory cell infiltration were observed at lacrimal gland in diabetic model mice 4 months after injection. Conclusions The major early stage manifestations of STZ induced type 1 diabetes mice include retarded growth of lacrimal gland and decreased tear secretion volume, which gradually develop along the course of diabetes; in the later stage, the manifestations include decreased corneal sensitivity, ocular structural damage, structural changes of lacrimal gland and decreased conjunctival goblet cell density. Key words: Diabetes mellitus; Dry eye; Tear formation; Lacrimal gland; Corneal sensitivity

Enriched environment alleviates stress-induced dry-eye through the BDNF axis

The number of patients with dry eye disease (DED) is increasing, and DED has become an urgent public health problem. A comorbidity of mental disorders has been reported in DED patients. We hypothesized that physical and psychological stressors impair tear secretion. To examine the relationship between stress loading and decreased tear secretion, we established a stress-induced DED mouse model, which permitted us to address the underlying mechanism of pathogenesis and resilience. Enriched environment (EE) was an effective intervention to prevent and alleviate stress-induced decreased tear secretion. Because stress loading resulted in decreased brain-derived neurotrophic factor (BDNF) expression while EE resulted in increased expression, we focused on the role of BDNF in tear secretion. Using two distinct Bdnf gene knockdown mice, we evaluated whether BDNF was a deterministic factor in regulating tear secretion in healthy and stressed conditions. Bdnf knockdown mice showed decreased basal tear secretion and loss of stress tolerance by EE for tear secretion. These results suggest that BDNF expression is related to tear secretion and to the pathology of DED.

Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-κB Pathway.

Our study aimed to evaluate the side effects of selective serotonin reuptake inhibitors (SSRIs) on the ocular surface. Twenty patients with depression and dry eye disease (DED) were randomly picked to receive SSRI treatment, whereas another 20 patients received placebo treatment. The serotonin, inflammatory cytokine, and proapoptotic protein levels were determined by using protein chip, qRT-PCR, and ELISA analyses. A rat depression model was established, and SSRIs were applied for 3 or 6 weeks. Tear production and corneal epithelial barrier function were evaluated. The serotonin and inflammatory cytokine levels were analyzed by qRT-PCR, immunohistochemical staining, and ELISA. Human corneal epithelial cells were subjected to serotonin, a HTR antagonist, and/or an NF-κB signaling inhibitor. The inflammatory cytokine and proapoptotic protein levels were determined by qRT-PCR, Western blot analysis, and ELISA. The cell apoptosis rate was assessed by using flow cytometry. The SSRI group had higher tear serotonin levels and more serious inflammation and cell apoptosis on the ocular surface. In the rat depression model, depression decreased tear secretion and increased IL-1β and TNF-α production, whereas the serotonin, TLR2, and TLR4 levels were not increased. SSRI aggravated DED, disrupted the corneal epithelial barrier, and promoted an inflammatory response on the ocular surface by increasing the tear serotonin levels. In addition, serotonin induced an inflammatory response and cell apoptosis in corneal epithelial cells by activating NF-κB signaling. SSRIs aggravate depression-associated DED via activating the NF-κB pathway. The antagonist of HTRs or the inhibitor of NF-κB signaling presents a potential therapeutic strategy for depression-associated DED. (Trial registration number, ChiCTR1800015592).

Approach to Dry Eye in Video Display Terminal Workers (Basic Science).

The use of video display terminals (VDT) and staring at screens of technologic devices, including desktops, laptops, tablets, and smartphones have become ubiquitous in a wide range of age groups because of the rapid advance of network culture-mediated communications. The incidence of dry eye is particularly high in workers that work with VDT. To facilitate an understanding of the mechanisms of VDT-associated dry eye, as well as to develop novel treatment approaches, a VDT worker dry eye model was created. The procedure involved placing rats on a swing in combination with exposure to an evaporative environment. This animal model reveals that the blink frequency was reduced to one-third of the nonswing riding levels, which is similar to the results that have been reported by VDT users. Pathologic analysis of the lacrimal gland in this dry eye model showed that the decrease in tear secretion was accompanied by a decrease in the acinar cell number, and an enlargement of acinar cells was accompanied by filling with an increased volume of secretory vesicles and a loss of intracellular cell structure, suggesting the involvement of lacrimal hypofunction. An interventional study using this dry eye model showed that oral supplementation of some natural ingredients is a possible therapy for relieving symptoms of VDT-associated dry eye. Further investigations for the establishment of VDT use-associated dry eye models that may be used to evaluate ocular discomfort that mimic the condition in humans are needed to understand and modify this type of dry eye.

Ocular Surface and Tear Film Characteristics in a Sclerodermatous Chronic Graft-Versus-Host Disease Mouse Model.

To report the characteristics of the ocular surface in a previously established sclerodermatous chronic graft-versus-host disease (cGVHD) mouse model. The ocular surface features and tear film parameters of the mouse model were assessed by histopathology, immunohistochemistry, electron microscopy, quantitative polymerase chain reaction, and flow cytometry. The mice exhibited loss of body weight and decreased tear secretion (P < 0.001), mimicking the clinical features of patients with cGVHD. Ocular examination demonstrated significant corneal epithelial staining, conjunctival (P < 0.001), and eyelid (P = 0.015) fibrosis compared with the control mice. The density of both goblet cells (P = 0.043) and microvilli was lower (P < 0.001), and the microvilli were shorter (P = 0.007) in the conjunctiva of cGVHD mice than those of the controls. The immunohistochemical studies demonstrated greater expression of CD45, CD4, and CD8 cells in the conjunctiva and eyelid tissues compared with the controls (P < 0.05 for all). In addition, reduced Forkhead box P3 (Foxp3)+ cells were found in both the peripheral blood (P < 0.001) and conjunctiva (P = 0.042) of cGVHD mice compared with the controls. The constellation of these findings suggests that the sclerodermatous cGVHD mouse model well recapitulates ocular manifestations of cGVHD in humans. This model can be used to study the mechanisms involved in the pathogenesis and treatment of chronic ocular graft-versus-host disease.

Novel Insight Into the Role of CFTR in Lacrimal Gland Duct Function in Mice

PurposeThe role of cystic fibrosis transmembrane conductance regulator (CFTR) in lacrimal gland (LG) function has only recently received some attention, mainly from our group. In the present study, we investigated the potential changes of LG pathology, tear secretion, ocular surface integrity, and fluid secretion in isolated LG ducts from CFTR knockout (KO) mice.MethodsTear production and ocular surface integrity were investigated in anesthetized wild-type (WT) and KO mice using cotton threads and fluorescein staining, respectively. Immunofluorescence was used to localize CFTR protein in the LGs. Ductal fluid secretions evoked by forskolin (10 μM); cell-permeable cAMP analogue (8-bromo cAMP, 100 μM); or carbachol (100 μM) were measured in isolated LG ducts using video-microscopy. Intracellular Ca2+ homeostasis underlying carbachol stimulation was investigated with microfluorometry.ResultsSignificant decrease in tear secretion and impaired ocular surface integrity were observed in KO mice. Immunofluorescence demonstrated the predominant presence of CFTR protein in the apical membranes of the duct cells from WT mice. Continuous fluid secretion was evoked by forskolin and 8-bromo cAMP in LG ducts from WT mice, while no secretory response was observed in ducts from KO mice. Carbachol caused similar secretory responses in ducts from WT and KO animals without significant differences in cytosolic Ca2+ signaling.ConclusionsOur results suggest the important role of CFTR in LG ductal secretion and in the maintenance of ocular surface integrity, suggesting that CFTR may be a promising target of novel therapeutic approaches in the treatment of dry eye.

The Semaphorin 3A inhibitor SM-345431 preserves corneal nerve and epithelial integrity in a murine dry eye model

Dry eye disease (DED) is a common disorder causing discomfort and ocular fatigue. Corneal nerves are compromised in DED, which may further cause loss of corneal sensation and decreased tear secretion. Semaphorin 3A (Sema3A) is expressed by the corneal epithelium under stress, and is known as an inhibitor of axonal regeneration. Using a murine dry eye model, we found that topical SM-345431, a selective Sema3A inhibitor, preserved corneal sensitivity (2.3 ± 0.3 mm versus 1.4 ± 0.1 mm in vehicle control, p = 0.004) and tear volume (1.1 ± 0.1 mm versus 0.3 ± 0.1 mm in vehicle control, p < 0.001). Fluorescein staining area of the cornea due to damage to barrier function was also reduced (4.1 ± 0.9% in SM-345431 group versus 12.9 ± 2.2% in vehicle control, p < 0.001). The incidence of corneal epithelial erosions was significantly suppressed by SM-345431 (none in SM-345431 group versus six (21%) in vehicle control, p = 0.01). Furthermore, sub-epithelial corneal nerve density and intraepithelial expression of transient receptor potential vanilloid receptor 1 (TRPV1) were significantly preserved with SM-345431. Our results suggest that inhibition of Sema3A may be an effective therapy for DED.

Effect of trospium chloride therapy on intraocular pressure and tear secretion in overactive bladder patients

Purpose: To investigate the effect of trospium chloride, which has an anticholinergic effect, used in overactive bladder (OAB) treatment on the intraocular pressure (IOP) and tear secretion after 12 weeks of treatment.Materials and methods: This prospective study was performed at a single center between October 2014 and January 2016. A detailed history was obtained from the female OAB patients at the eye outpatient department. After checking the exclusion criteria, oral trospium chloride 30 mg bd was started. The patients were followed-up in terms of drug effectiveness and ophthalmic and other side effects at the 4th and 12th weeks. All procedures were repeated at both of these time-points.Results: The mean age of the patients was 48.98 ± 11.98 years (range 19–75). The data of 80 OAB patients were evaluated in the study. Trospium chloride did not cause any significant change in the OAB patients regarding their 4th week and 12th week IOP measurements (p = 0.251, p = 0.340, respectively). It was found to decrease tear secretion significantly at both time-points (p = 0.020, p = 0.001, respectively). Trospium chloride treatment of one patient (1.25%) was discontinued due to dry eye.Conclusions: Trospium chloride decreases the symptoms in female OAB patients. Trospium chloride can be safely used in female OAB patients with normal IOP and no comorbidity as regards IOP changes as it did not cause a significant change in IOP in these patients. Pre-treatment and post-treatment dry eye symptoms of OAB patients about to start using trospium chloride should be queried beforehand as it can cause a statistically significant decrease in tear secretion. We concluded that it would be appropriate to refer the patients to an ophthalmologist before starting the drug if relevant symptoms are present.

Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea.

The corneal epithelium consists of stratified epithelial cells, sparsely interspersed with dendritic cells (DCs) and a dense layer of sensory axons. We sought to assess the structural and functional correlation of DCs and sensory nerves. Two morphologically different DCs, dendriform and round-shaped, were detected in the corneal epithelium. The dendriform DCs were located at the sub-basal space where the nerve plexus resides, with DC dendrites crossing several nerve endings. The round-shaped DCs were closely associated with nerve fiber branching points, penetrating the basement membrane and reaching into the stroma. Phenotypically, the round-shaped DCs were CD86 positive. Trigeminal denervation resulted in epithelial defects with or without total tarsorrhaphy, decreased tear secretion, and the loss of dendriform DCs at the ocular surface. Local DC depletion resulted in a significant decrease in corneal sensitivity, an increase in epithelial defects, and a reduced density of nerve endings at the center of the cornea. Post-wound nerve regeneration was also delayed in the DC-depleted corneas. Taken together, our data show that DCs and sensory nerves are located in close proximity. DCs may play a role in epithelium innervation by accompanying the sensory nerve fibers in crossing the basement membrane and branching into nerve endings.

Corneal Sensitivity and Dry Eye Symptoms in Patients with Keratoconus.

PurposeTo investigate corneal sensitivity to selective mechanical, chemical, and thermal stimulation and to evaluate their relation to dry eye symptoms in patients with keratoconus.MethodsCorneal sensitivity to mechanical, chemical, and thermal thresholds were determined using a gas esthesiometer in 19 patients with keratoconus (KC group) and in 20 age-matched healthy subjects (control group). Tear film dynamics was assessed by Schirmer I test and by the non-invasive tear film breakup time (NI-BUT). All eyes were examined with a rotating Scheimpflug camera to assess keratoconus severity.ResultsKC patients had significatly decreased tear secretion and significantly higher ocular surface disease index (OSDI) scores compared to controls (5.3±2.2 vs. 13.2±2.0 mm and 26.8±15.8 vs. 8.1±2.3; p<0.001). There was no significant difference in NI-BUT between the two groups (KC: 9.8±4.8 vs. control: 10.7±3.8; p>0.05). The mean threshold for selective mechanical (KC: 139.2±25.8 vs. control: 109.1±24.0 ml/min), chemical (KC: 39.4±3.9 vs. control: 35.2±1.9%CO2), heat (KC: 0.91±0.32 vs. control: 0.54±0.26 Δ°C) and cold (KC: 1.28±0.27 vs. control: 0.98±0.25 Δ°C) stimulation in the KC patients were significantly higher than in the control subjects (p<0.001, for all parameters). No correlation was found between age and mechanical, chemical, heat or cold thresholds in the patients with KC (p>0.05), whereas in the control subjects both mechanical (r = 0.52, p = 0.02), chemical (r = 0.47, p = 0.04), heat (r = 0.26, p = 0.04) and cold threshold (r = 0.40, p = 0.03) increased with age. In the KC group, neither corneal thickness nor tear flow, NI-BUT or OSDI correlated significantly with mechanical, chemical, heat or cold thresholds (p>0.05 for all variables).ConclusionsCorneal sensitivity to different types of stimuli is decreased in patients with keratoconus independently of age and disease severity. The reduction of the sensory input from corneal nerves may contribute to the onset of unpleasant sensations in these patients and might lead to the impaired tear film dynamics.

Our experience of Restasis® use in patients with “dry eye” syndrome occurring against the context of graft versus host reaction after bone marrow allografting

Restasis® is the only ophthalmic medication containing cyclosporine A that is registered in the Russian Federation. According to prescribing information, it is indicated in keratoconjunctivitis sicca with decreased tear secretion. However, there are several similar conditions, in particular ophthalmic forms of graft versus host reaction, in which its use may be appropriate and of high practical interest. We observed 20 patients with ophthalmic forms of graft versus host reaction after bone marrow allografting. All patients were treated by Restasis® b.i.d., there were no side-effects. In one month of treatment tear breakup time test results improved, as well as the corneal epithelium status.

The pathophysiology, diagnosis, and treatment of dry eye disease.

Dry eye disease (DED) is common; its prevalence around the world varies from 5% to 34%. Its putative pathogenetic mechanisms include hyperosmolarity of the tear film and inflammation of the ocular surface and lacrimal gland. Dry eye is clinically subdivided into two subtypes: one with decreased tear secretion (aqueous-deficient DED), and one with increased tear evaporation (hyperevaporative DED). This review is based on pertinent publications retrieved by a selective PubMed search and on the authors' own clinical and scientific experience. The diagnostic evaluation of dry eye disease should include a detailed patient history, thorough split-lamp examination, and additional tests as indicated. Few randomized controlled therapeutic trials for dry eye have been published to date. Artificial tears of various kinds are recommended if the symptoms are mild. Lid hygiene is helpful in the treatment of hyperevaporative dry eye, while collagen or silicon plugs can be used for partial occlusion of the efferent lacrimal ducts to treat severe hyposecretory dry eye. The benefit of long-term topical anti-inflammatory treatment of moderate or severe dry eye disease with corticosteroids or cyclosporine A eye drops has been documented in clinical trials on a high evidence level. Orally administered tetraycycline derivatives and omega-3 or omega-6 fatty acids are also used. The treatment of dry eye has evolved from tear substitution alone to a rationally based therapeutic algorithm. Current research focuses on pathophysiology, new diagnostic techniques, and novel therapies including secretagogues, topical androgens, and new anti- inflammatory drugs.

Vascular Endothelial Growth Factor in Tear Samples of Patients with Systemic Sclerosis.

Background. Systemic sclerosis is an autoimmune disease, characterized by widespread small vessel vasculopathy, immune dysregulation with production of autoantibodies, and progressive fibrosis. Changes in levels of proangiogenic cytokines had already been determined largely in serum. Our aim was to assess the levels of VEGF in human tears of patients with SSC. Patients and methods. Forty-three patients (40 female and 3 men, mean (SD) age 61 (48–74) years) with SSc and 27 healthy controls were enrolled in this study. Basal tear sample collection and tear velocity investigations were carried out followed by an ophthalmological examination. Total protein concentrations and VEGF levels were determined in tear samples. Results. The average collected tear fluid volume developed 10.4 μL (1.6–31.2) in patients and 15.63 μL (3.68–34.5) in control subjects. The average total protein level was 6.9 μg/μL (1.8–12.3) in tears of patients and control tears contained an average of 4.132 μg/μL (0.1–14.1) protein. In patients with SSc the average concentration of VEGF was 4.9 pg/μL (3.5–8.1) and 6.15 pg/μL (3.84–12.3) in healthy samples. Conclusions. Total protein production was increased because of the smaller tear volume. Decreased VEGF in tear of SSc patients can be explained also by the decreased tear secretion of patients.

A New Nonhuman Primate Model of Severe Dry Eye

The aim of this study was to establish a new rhesus monkey model of severe dry eye. A total of 8 rhesus monkeys were used for the study. Four monkeys had their main lacrimal gland and nictitating membrane surgically removed (group 1). Another 4 monkeys had a similar surgery with further application of 50% trichloroacetic acid on the bulbar conjunctiva (group 2). The ocular surface was evaluated before and after the surgery (1, 4, 8, 12, and 24 weeks) using Schirmer-1 test, corneal fluorescein staining, and the lissamine green test. Conjunctival impression cytology was also performed before and 24 weeks after the surgery. Finally, the cornea and the conjunctiva were evaluated using light microscopy. A significant decrease in tear secretion was observed in all operated eyes. Schirmer test data measured were ≤4 mm in all the operated eyes. Slit-lamp examination also revealed abnormal staining in all the operated eyes that remained stable until the end of the experiment. In group 2, corneal fluorescein staining and lissamine green test values were always ≥5 (max 12) and ≥4 (max 9), respectively. Impression cytology specimens of both the treated groups showed conjunctival squamous metaplasia and a decreased number of goblet cells. Under light microscopy, the corneal epithelium appeared irregular with edematous basal epithelial cells. The conjunctiva showed a decreased goblet cell density with infiltration of inflammatory cells. Complete removal of the principal lacrimal gland and nictitating membrane associated with the application of 50% trichloroacetic acid on the conjunctiva could induce severe dry eye in rhesus monkeys.

A Case of Juvenile Sjögren's Syndrome with Interstitial Nephritis

Primary Sjögren's syndrome (SS) is a rare autoimmune disease, especially in children. Juvenile primary SS with interstitial nephritis is rare in Japan. We report on a 12-year-old girl in whom salivary gland swelling had recurred from the age of 5 years, SS was diagnosed at the age of 10 years, and interstitial nephritis developed at the age of 12 years. The patient presented with a chief complaint of swelling of both parotid glands. The patient had a history of recurrent parotitis from 5 years of age, with episodes recurring 5 to 6 times a year and resolving within 3 days each time. However, at the age of 11 years, the patient had continuous mild swelling of the parotid glands. Examination on admission showed bilateral nontender parotid gland swelling; mild swelling of the lower extremities, xerostomia, and xerophthalmia but no exanthem. Laboratory findings were as follows: serum protein, 10.1 g/dL; immunoglobulin (Ig) G, 3,828 mg/dL; antinuclear antibodies, 1,280-fold; anti-Ro/SS-A antibody, 512-fold; anti-Ro/SS-B antibody, 4-fold; creatinine, 0.45 mg/dL; blood β2-microglobulin, 2.2 mg/L (slightly elevated); and cystatin C, 0.86 mg/L. Urinalysis showed proteinuria and a β2-microglobulin concentration of 11,265 mg/L. Thus, this patient had low molecular weight proteinuria. Schirmer's test showed decreased tear secretion (5 mm), and fluorescein staining showed marked bilateral superficial punctate keratitis. A lip biopsy showed infiltration by small round cells (mild to moderate), interstitial fibrosis, loss of salivary gland parenchyma, and atrophy, with no obvious epimyoepithelial islands, leading to a diagnosis of SS. Light microscopic examination of the renal biopsy specimens showed expansion of mononuclear cell infiltration in the renal interstitium, inflammatory cell infiltration of interstitial areas with edema and mild fibrosis, and tubulitis and mononuclear cell infiltration that included many lymphocytes and plasma cells. There were no pathological findings of glomerulonephritis. Small arteries showed no obvious abnormalities. Immunofluorescent staining showed slight, nonspecific deposition of IgM, but no deposition of IgG, complement 1q, 3, or 4. On the basis of the renal biopsy showing nonspecific chronic interstitial nephritis, renal tubular atrophy, and interstitial enlargement, tubulointerstitial nephritis associated with SS was diagnosed.