[Cell technologies as a basis for the development of regenerative principles for the treatment of lacrimal gland diseases]. / Kletochnye tekhnologii kak osnova razrabotki regeneratornykh printsipov lecheniya zabolevanii sleznoi zhelezy.

The lacrimal gland (LG) is a tubuloacinar exocrine gland composed of acinar, ductal, and myoepithelial cells. Three-dimensional distribution of acinar lobules, ducts, and myoepithelial cells is necessary for the effective functioning of the organ. LG is the main organ of immune surveillance of the ocular surface system. The embryogenesis of the gland is regulated by the interaction of genetic mechanisms, internal epigenetic (enzyme systems, hormones) and exogenous factors. There is no doubt that there is a clear genetic program for the implementation of the complex process of embryonic development. The mechanisms regulating LG organogenesis initiate the work of a huge number of structural oncogenes, transcription and growth factors, etc. Studying the expression and selective activity of regulatory genes during organ development, their participation in the differentiation of different cell types is a current trend at the nexus of clinical genetics, molecular biology, embryology and immunocytochemistry. Due to its relatively simple structure and accessibility, human LG is a suitable object for potential application in regenerative medicine. Development of a universal protocol for obtaining functional differentiated secretory epithelium of LG capable of expressing tissue-specific markers is an urgent task. Determining the nature and origin of stem cells and progenitor cells will allow the isolation and multiplication of these cells in culture. After obtaining a functionally active culture of LG cells, it is possible to create a model of autoimmune diseases.

[The place of ciclosporin A cationic emulsion 0.1% in the therapy of xerophthalmia]. / Mesto kationnoi emul'sii tsiklosporina A 0,1% v terapii kseroftal'mii.

Dry eye disease (DED) is pathogenetically based on inflammation of the ocular surface. A step-by-step approach to DED treatment involves early initiation of anti-inflammatory therapy, including instillation of cyclosporine A (CsA). However, recommendations for the use of topical CsA in clinical practice are limited. This article presents an expert consensus on practical recommendations for the management of patients with DED, including indications, time of initiation and duration of CsA therapy, comparison of CsA forms currently registered in the Russian Federation, as well as issues of patient education.

[Laser Doppler flowmetry in the diagnosis of chronic mixed blepharitis]. / Lazernaya dopplerovskaya floumetriya v diagnostike khronicheskogo smeshannogo blefarita.

Chronic mixed blepharitis accounts for 51.7% of all ophthalmic diseases. The use of laser Doppler flowmetry (LDF) in the diagnosis of this disease can help establish the initial manifestations of the inflammatory process in the eyelids, which is important for the prevention of possible complications - dry eye disease. PURPOSE: This study was conducted to determine the sensitivity and specificity of the LDF method in the diagnosis of chronic mixed blepharitis based on the study of microcirculatory changes in the eyelid skin. MATERIAL AND METHODS: The study included 23 patients with chronic mixed blepharitis (mean age 67±5.8 years) and 18 healthy volunteers (mean age 63±1.1 years). LDF was performed using the LAZMA MC-1 device. ROC analysis was used to determine sensitivity and specificity. RESULTS: A typical disturbance of the eyelid skin microcirculation was revealed in chronic mixed blepharitis - ischemia - with inhibition of the intensity of the functioning of blood flow regulatory systems and moderate activation of the lymph flow. The sensitivity and specificity of the coefficient of variation (reflecting the vasomotor activity of microvessels) of blood flow was 71.43 and 71.43%, lymph flow - 65.71 and 80.00%; myogenic rhythms of blood flow - 83.33 and 85.71%, lymph flow - 66.67 and 71.43%; neurogenic rhythms of blood flow - 75.00 and 78.57%, lymph flow - 91.67 and 78.57%, respectively. CONCLUSION: Laser Doppler flowmetry of the eyelid skin in combination with clinical, functional and instrumental research methods helped reveal with high sensitivity and specificity the eyelid damage in chronic mixed blepharitis. This method allows assessment of the condition of the eyelids in individuals without diseases of the anterior segment of the eye.

[Neuropathic pain in dry eye syndrome. Part 1. Pathophysiological mechanisms of pain formation]. / Nevropaticheskaya bol' pri sindrome «sukhogo glaza¼. Chast' 1. Patofiziologicheskie mekhanizmy formirovaniya boli.

The review details the features and mechanisms of the formation of various types of pain. The emphasis is placed on the occurrence of pain syndrome in various ophthalmological diseases, particularly in dry eye syndrome. The article also presents literature data on the role of cytokines in the formation of a neuroinflammatory cascade affecting damage to corneal nerve fibers and the development of pain syndrome, which is a characteristic feature of a subtype of dry eye disease - burning eye syndrome.

[Neuropathic pain in dry eye syndrome. Part 2. Clinical picture, diagnosis and treatment]. / Nevropaticheskaya bol' pri sindrome «sukhogo glaza¼. Chast' 2. Klinicheskaya kartina, diagnostika i lechenie.

Burning eye syndrome is a chronic neuropathic pain syndrome, which is characterized by dysesthesia, spontaneous pain, allodynia and hyperalgesia. The review describes clinical features and presents available data on possible methods of diagnosis and therapy of this condition.

[The role of miRNA in the pathogenesis of diseases associated with functional dysregulation of the lacrimal gland]. / Rol' mikroRNK v patogeneze zabolevanii, svyazannykh s narusheniem funktsii sleznoi zhelezy.

At this time, the mechanism causing lacrimal gland dysfunction is not understood completely. In diseases associated with lacrimal gland involvement (Sjogren's syndrome, sarcoidosis, IgG4-associated disease, etc.) patients have been observed to experience elevated cellular apoptosis, active production of autoantibodies to glandular tissue, increased level of pro-inflammatory cytokines, functional disruption of signaling molecules leading to changes in tear production. Difficulties in differential diagnosis of lacrimal gland dysfunction in above-listed diseases are associated, on the one hand, with similarity of the clinical picture of ophthalmological manifestations, and on the other hand - with complicated morphological interpretation of changes in the glandular tissues. In this view, miRNA is a promising diagnostic and prognostic marker that would help with differential diagnosis as well as with choosing the treatment tactics. Methods of molecular profiling and identification of "molecular phenotypes" of lacrimal gland and ocular surface damage will allow the use of miRNA as biomarkers and prognostic factors for personalized treatment.

[Evolution of dry eye disease diagnostics]. / Evolyutsiya metodov diagnostiki sindroma sukhogo glaza.

This article reviews modern functional and instrumental examination methods included in the diagnostic algorithm for dry eye disease. The described methods can serve as an objective criterion for the effectiveness of the therapy.

[Features of water-electrolyte component of the tear fluid]. / Osobennosti vodno-elektrolitnogo komponenta sleznoi zhidkosti.

Tear production is a complex multi-step process that can be arbitrarily divided into three stages: «primary¼ secretion by the acinar cells of the main lacrimal glands, formation of «secondary¼ lacrimal fluid in the ducts of the main lacrimal glands, and «tertiary¼ modification of the tear composition in the conjunctival sac. This article highlights mechanisms of water and electrolytes secretion in the process of tear fluid production and describes the particularities of distribution of the membrane transport proteins in the lacrimal gland and the ocular surface.

[Predictive significance of genetic analysis of the development of dry eye disease of different origin]. / Prediktivnaya znachimost' geneticheskogo analiza razvitiya sindroma «sukhogo glaza¼ razlichnogo geneza.

One of the etiological causes of dry eye disease (DED) is systemic autoimmune diseases (AID): primary Sjögren's syndrome (PSS), rheumatoid arthritis (RA); their manifestation may begin with ophthalmic symptoms. The relationship of PSS and RA with genetic factors is proven. The contribution of polymorphic markers of the genes THBS1, MUC1, TRIM21, STAT4, PTPN22 in the development of these diseases is established, as well as their connection with the development of DED. A panel of genetic markers for evaluating the risk of developing DED in PSS and RA is developed, and its sensitivity and specificity is determined. PURPOSE: The aim of the study was to determine the prognostic significance of a panel of polymorphic gene markers in the development of dry eye syndrome in patients with primary Sjögren's syndrome and rheumatoid arthritis over a five-year follow-up period. MATERIAL AND METHODS: Patients with a verified diagnosis of PSS and RA without signs of DED were examined (n=35 and n=42, respectively). The control group included 82 volunteers without AID and DED. The observation period was 5 years. Every year all study subjects underwent an ophthalmological clinical and functional examination. RESULTS: Dry eye disease had developed in groups of patients with AID with predisposing genotypes of polymorphic markers of the genes THBS1, MUC1, TRIM21, STAT4, PTPN22. The peak of DED development in these patients was in the third year of the follow-up. As a result of ROC analysis, it was found that the sensitivity and specificity of determining the predisposing genotypes of polymorphic markers of the THBS1, MUC1, TRIM21, STAT4, PTPN22 genes was 68 and 87%, respectively (p<0.0001). CONCLUSION: Genetic research methods are essential for minimally invasive early diagnosis of dry eye disease, and can subsequently become the basis for a personalized approach to its treatment.

[Modern possibilities of studying the composition of meibomian glands secretion]. / Sovremennye vozmozhnosti issledovaniya sostava sekreta meibomievykh zhelez.

As the main source of various lipids, the meibomian glands are involved in the formation of lipid layer of the tear film and the maintenance of homeostasis of the ocular surface. This process is directly dependent on the chemical composition and thickness of the lipid layer. In addition to lipid components, the meibum also contains various proteins that affect the properties of the tear film. The introduction of various modifications of mass spectrometry into clinical practice is a new diagnostic approach that allows obtaining information about the composition of meibomian glands secretion and tears.

[Association of polymorphic markers rs7947461 of the TRIM21 gene and rs33996649 of the PTPN22 gene with the risk of developing exogenous dry eye syndrome]. / Assotsiatsiya polimorfnykh markerov rs7947461 gena TRIM21 i rs33996649 gena PTPN22 s riskom razvitiya sindroma sukhogo glaza ekzogennoi etiologii.

In this age of technological advancement, an increasing number of people is being exposed to external risk factors of damaging their ocular surface (wearing contact lenses, electromagnetic radiation from computers, mobile devices, etc.). However, the presence of external factors does not lead to a 100% risk of developing the dry eye disease (DED). The trigger mechanism in the development of autoimmune lesions of the ocular environment in some systemic diseases is known to be associated with molecular genetic factors. The search for molecular genetic disorders is based on the analysis of polymorphic markers of a number of genes responsible for the state of the eye surface. PURPOSE: To study the relationship of polymorphic markers rs7947461 of the TRIM21 gene and rs33996649 of the PTPN22 gene with the risk of developing dry eye syndrome of exogenous etiology. MATERIAL AND METHODS: The study included 57 people with exogenous risk factors for DED development. The control group included volunteers without a history of ophthalmic pathologies (n=75). Genotyping was done by real-time polymerase chain reaction followed by melting curve analysis. Statistical processing of data was done using the Statistica 6.1 RUS software for statistical analysis. RESULTS: In the course of the study, 31 patients of the main group were diagnosed with DED and separated into the 1st subgroup; DED diagnosis was not confirmed in 26 patients, who were put into the 2nd subgroup. The 1st subgroup showed a significant increase in the frequency of predisposing genotypes of the TRIM21 and PTPN22 genes. The relative risk of developing DED turned out to be 2.5 and 4.86 times higher, respectively. In the 2nd subgroup, no statistically significant data was found on the presence of predisposing genotypes of polymorphic markers of the TRIM21 and PTPN22 genes (p=0.3). CONCLUSION: The revealed association of polymorphic markers rs7947461 of the TRIM21 gene and rs33996649 of the PTPN22 gene with the risk of developing DED of exogenous etiology puts these loci as possible markers for diagnosing this pathology.

[Experimental investigation of the safety of terahertz radiation in corneal hydration assessment]. / Eksperimental'noe obosnovanie bezopasnosti primeneniya teragertsovogo izlucheniya dlya analiza izmenenii gidratatsii rogovitsy.

Application of terahertz (THz) radiation in novel non-invasive biomedical technologies has recently received considerable attention. However, experimental data about the safety of exposure to THz radiation for biological objects (including eye structures in vivo) are limited. To our knowledge, the safety of THz reflectometry (frequency range of 0.30-0.40 THz) has not been closely examined in an animal model with subsequent morphological assessment of corneal tissues. PURPOSE: To assess the safety of pulsed THz radiation with various parameters (time, power, and frequency) for the cornea in a rabbit model. MATERIAL AND METHODS: The sample for the current study consisted of 18 Chinchilla rabbits (18 eyes). Corneal imaging and epithelial cell density before and after the exposure were evaluated using confocal laser scanning microscopy (CLSM). The histological study for objective assessment of the cornea state (day 1 and day 14) was performed after experiment termination. RESULTS: Single and multiple exposures of laser radiation at a frequency below 0.1 THz and power density below 30 nW/cm2 do not cause visible structural changes in any layers of the rabbit cornea. The results obtained in the long-term period showed insignificant reversible morphological changes only within the epithelium. CONCLUSION: The described parameters of terahertz and subterahertz radiation can be considered safe for assessing changes in corneal epithelium hydration level using non-invasive methods based on THz reflectometry.

[Morphofunctional substantiation of repeated invasive treatment of chronic blepharitis]. / Morfofunktsional'noe obosnovanie provedeniya povtornykh kursov invazivnogo lecheniya khronicheskogo blefarita.

The expanding range of diagnostic instrumental methods allows an in-depth study of the morphological and functional state of the eyelids, which is the basis for determining the strategy for the treatment of chronic blepharitis and subsequent timely supplementation and altering of its algorithm. PURPOSE: To substantiate the repeated courses of invasive treatment of chronic blepharitis based on morphological and functional studies. MATERIAL AND METHODS: The study included 45 patients (90 eyes) with chronic mixed blepharitis. Instrumental research methods - laser Doppler flowmetry, laser scanning confocal microscopy (LSCM), tiascopy, and optical coherence tomography - were used to assess the morphological and functional state of the eyelids during meibomian gland probing (MGP) and eyelid massage course. The therapy effectiveness was evaluated after 1 week, 1, 3 and 6 months. RESULTS: Using a complex of diagnostic methods for assessing the morphological and functional state of the eyelids, surgical invasive treatment for mixed chronic blepharitis was proved to have a significant positive clinical effect compared with the eyelid massage traditionally used in polyclinic practice. After 6 months from the start of treatment, in the absence of changes in the clinical picture in both groups, functional changes in the control group were recorded that were expressed as a decrease in the values of the Norn test, confirmed by the data of tiascopy, and the number of functioning meibomian glands. The indicators of lacrimal meniscus depth in both groups corresponded to the values of the monitoring stage after 3 months. According to LSCM, the control group had higher inflammatory activity: the heterogeneity of the interstitium and the walls of the acini of the meibomian glands increased, the acinar area decreased in comparison with the main group. Deterioration of the blood flow microcirculation in both groups was manifested as a decrease in neurogenic rhythms. Additionally, a 3.05% decrease in myogenic rhythms was recorded in the main group. The study of the microcirculation of lymph flow showed a decrease in neurogenic rhythms in the main group by 4.79%. CONCLUSION: The analysis of the morphological and functional state of the eyelids after MGP has shown that its results persisted for 6 months, and repeated probing was justified, while the interval before repeated course of eyelid massage averaged 1.5 months.

The Role of Polymorphic Markers rs1478604, rs2292305, and rs2228262 in THBS1 Gene in the Development of Autoimmune Dry Eye Syndrome.

An association of polymorphic marker rs2228262 in the THBS1 gene with the risk of developing dry eye in Sjögren syndrome was revealed. Confocal microscopy data suggest that this polymorphic marker is responsible for the high probability of corneal nerve fiber lesion in Sjögren syndrome even in the absence of clinical and functional signs of dry eye syndrome. A significant correlation was established between polymorphic markers rs1478604, rs2228262 in THBS1 gene and the coefficients of anisotropy and orientation symmetry of corneal nerve fibers. These results allow considering these polymorphic markers as a genetic factor of predisposition to dry eye syndrome in patients with Sjögren syndrome.

[Treatment of chronic posterior blepharitis after allogeneic hematopoietic stem cell transplantation (a case report)]. / Lechenie khronicheskogo zadnego blefarita posle allogennoi transplantatsii gematopoeticheskikh stvolovykh kletok (klinicheskoe nablyudenie).

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), various eye diseases are detected in 30-60% of patients, with chronic graft-versus-host reaction - in 50-90% of patients. Among the complications, the most frequent is damage to the eye surface and eyelids. The article presents a clinical case of successful minimally invasive treatment of chronic posterior blepharitis in a patient who has undergone allogeneic hematopoietic stem cell transplantation. Normalization of the outflow of meibomian gland secretion after the medical procedure was a prerequisite for improving the quantitative and qualitative composition of the lipid layer of the tear film and a factor contributing to a decrease in the amplitude of inflammation, which is reflected in the clinical and functional results.

[Treatment of chronic blepharitis]. / Lechenie khronicheskikh blefaritov.

The most effective method of treating chronic blepharitis - a disease with multifactorial pathogenesis requiring an individual approach - is a combination of remedial measures that addresses eyelids hygiene and includes medicated and device therapy.

[The relationship between Sjogren's syndrome, systemic sclerosis and lymphoproliferative diseases].

Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature. AIM: To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogrens syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkins lymphomas (NHL), developing in patients with these rheumatic diseases (RDs). MATERIALS AND METHODS: In 19982018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkins lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD. RESULTS: Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands 7, disseminated MALT lymphoma 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) 1]. RDs debuted with Raynauds phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score 4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies 60%, antibodies to ribonucleoprotease III 30%, Pm/Scl 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La 70%, RF (rheumatoid factor) 90%), were detected in patients with a combination of these RDs. CONCLUSION: pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.

[Association of polymorphisms of the TRIM21 gene with the severity of dry keratoconjunctivitis in rheumatoid arthritis and Sjogren's disease]. / Vzaimosviaz' polimorfizmov gena TRIM21 s tiazhest'iu sukhogo keratokon''iunktivita pri revmatoidnom artrite i bolezni Shegrena.

Ophthalmologic manifestation of Sjogren's disease (SD) and rheumatoid arthritis (RA) is dry keratoconjunctivitis (dry eye disease; DED). PURPOSE: To study the relationship of polymorphic markers rs7947461 (C/T), rs915956 (C/T), rs4144331 (C/A) of the TRIM21 gene with the severity of DED in patients with RA and SD. MATERIAL AND METHODS: The study included 70 patients with RA (n=27) and SD (n=43). The control group consisted of volunteers without a history of RA or SD (n=35). Alleles of the polymorphic marker C660T rs7947461 of the TRIM21 gene were identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method; alleles of the polymorphic marker rs915956 (C/T) and rs4144331 (C/A) of the TRIM21 gene were identified by analyzing DNA melting curves. RESULTS: An association was found between the predisposing genotype (TT) of rs7947461 polymorphic marker and the risk of developing severe DED. The AA genotype of rs4144331 polymorphic marker was found only in severe DED (c2=7.74; OR=17.46, CI95%=1.96-318.38, p=0.02). CONCLUSION: An association was established between rs7947461 (rs660) and rs4144331 and the risk of developing severe DED.

[Inflammatory granuloma after intracanalicular punctal plug migration (a clinical case)]. / Vospalitel'naia granulema pri vnutrikanal'tsevoi migratsii okkliudera sleznoi tochki (sluchai iz praktiki).

At present, installation of punctal plugs (tear duct occluders) draws attention of ophthalmologists, but this method of treating dry eye syndrome (DES) is not without complications. Considering the rise of DES occurrence - the tendency anticipated to continue - as well as expansion of indications for installation of tear duct occluders, their usage can be expected to rise. The article describes a relatively rare clinical case that involved intracanalicular migration of silicone punctal plug. A female patient of 36 years old sought medical help in Research Institute of Eye Diseases (Moscow) to treat a lump in the area of lower lacrimal punctum in the left eye that was growing in size; the lump had appeared around 2 months prior to the visit. Patient's medical history read that around 2 years ago she had a silicone occluder installed in the lower lacrimal punctum of the left eye. On examination, in the area of lower lacrimal punctum, a body with a nutrient vascular pedicle deriving from lower lacrimal duct could be found. The occluder was absent in the opening of the lacrimal punctum. A revision of lower tear duct cavity was performed to remove its contents. The body filling tear duct opening was removed with forceps. Substance was then sent for histological examination. Tear duct was scraped out, the silicone occluder removed and sent to laboratory for scanning electron microscopy. The patient had no complaints 6 months after the procedure. CONCLUSION: The study showed that the forming body was granuloma resulting from aseptic inflammation. Surface of the silicone occluder in retention of lacrimal pathways remained unchanged. Described surgical tactic is suitable for treating patients with intracanalicular punctal plug migration.

[Polymorphic markers of certain genes in the development of dry keratoconjunctivitis in patients with rheumatoid arthritis and Sjogren's syndrome]. / Polimorfnye markery nekotorykh genov v razvitii sukhogo keratokon''iunktivita u patsientov s revmatoidnym artritom i sindromom Shegrena.

The article reviews literature on relationships between polymorphic variants of the genes THBS1, GTF2I, MUC1, TRIM21, STAT4, PTPN22 with clinical features of dry keratoconjunctivitis in rheumatoid arthritis and Sjogren's syndrome. The development and implementation of a method for analyzing polymorphic gene variants used to diagnose dry keratoconjunctivitis in rheumatoid arthritis and Sjogren's syndrome will allow assessment of the possibility of developing dry keratoconjunctivitis and/or its progression in patients with autoimmune diseases or in people at risk. Determination of clinical and morphological regularities of dry keratoconjunctivitis in accordance with the revealed molecular and genetic changes will contribute to better understanding of the etiology and pathogenesis of ophthalmological manifestations of autoimmune diseases, and will also help improve the diagnostics and prognosis of dry keratoconjunctivitis.