Microbial Reconstitution Improves Aging-Driven Lacrimal Gland Circadian Dysfunction.

Lacrimal glands are highly susceptible to aging and exhibit age-related structural and functional alterations. However, the mechanisms by which aging affects the lacrimal glands are not well-established. The current study explores the crosstalk between the aging process, gut microbiota, and circadian rhythm in age-associated lacrimal gland dysfunction. C57BL/6J mice were divided into young, old, and fecal microbiota transplant (FMT)-treated old groups. The gut bacterial community diversity was analyzed by 16S rRNA sequencing. Exorbital lacrimal glands (ELGs) were collected at 3-hour intervals over a 24-hour circadian cycle, and total RNA was subjected to high-throughput sequencing. Rhythmic transcriptional data were analyzed using the Jonckheere-Terpstra-Kendall algorithm and bioinformatics analysis technology. Immunostaining was used to identify lymphocytic infiltration, lipid deposition, and nerve innervation in the ELGs. Compared with young mice, old mice underwent a significant gut microbial community shift. The rhythmically transcriptomic profile was significantly reprogrammed over a 24-hour cycle in the old ELG group. Intervention with serial FMT from young donors for 1 month rejuvinated the gut microbial community of the old mice. Most alterations in rhythmic transcriptomic profiling were improved. Furthermore, chronic inflammation, lipid deposition, and aberrant neural response of the aging lacrimal glands were significantly reduced. Thus, the study shows that reconstitution of age-associated gut dysbiosis with FMTs from young donors improves aging-driven lacrimal gland circadian dysfunction.

A novel claudin-10 mutation with a unique mechanism in two unrelated families with HELIX syndrome.

HELIX syndrome, characterized by hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia due to claudin-10 (CLDN10) mutations, was recognized in 2017. Here we describe two unrelated Saudi families with this syndrome due to a novel CLDN10 mutation with a unique mechanism of CLDN10 inactivation. The two consanguineous families include 12 affected individuals (three siblings in family 1 and nine members in family 2). They presented with hypokalemia and the above-mentioned features of HELIX syndrome. The underlying mutation was detected by whole exome sequencing, confirmed by Sanger sequencing and functionally indicated by RT-PCR, electrophysiological studies and immunohistochemical staining of transfected HEK293 and MDCK C7 cells, and skin and kidney biopsy tissues. A novel biallelic single nucleotide deletion was identified in exon 5 of CLDN10 (NM_182848.3: c.647delC, p.P216Lfs∗19 for CLDN10a or NM_006984.4: c.653delC, p.P218Lfs∗21 for CLDN10b). The mutation led to frameshift and extension of the original termination codon by nine amino acids with loss of the C-terminus pdz-binding motif. Functional studies showed mRNA degradation and protein retention in intracellular compartments and that the pdz-binding motif is crucial for proper localization of claudin-10 in tight junctions. In the kidney, claudin-10 was replaced by translocation of claudin-2 (proximal tubule) and claudin-19 (thick ascending limb), and in the sweat gland by claudin-3 and occludin. However, these claudins did not functionally compensate for loss of claudin-10. Thus, this novel CLDN10 mutation identified in these two families disrupted the C-terminus pdz-binding motif of claudin-10 causing HELIX syndrome.

Transconjunctival versus Transcutaneous Injection of Botulinum Toxin into the Lacrimal Gland to Reduce Lacrimal Production: A Randomized Controlled Trial.

The purpose of this study was to determine and compare the effects between injecting botulinum toxin A (BTX-A) transconjunctivally into the palpebral lobe and transcutaneously into the orbital lobe of the lacrimal gland in patients with epiphora due to lacrimal outflow obstruction. This randomized controlled study included 53 eyes of 31 patients with unilateral or bilateral epiphora. Patients were randomly allocated to receive an injection of BTX-A (3 units) either transconjunctivally (n = 15, 25 eyes) or transcutaneously (n = 16, 28 eyes). For objective assessments, the tear meniscus height and Schirmer's I test with topical anesthesia were measured at baseline and after 2, 6, 12, and 24 weeks of follow-up. Subjective evaluations were performed using the Munk score. After BTX-A injection, patients in both groups experienced significant objective and subjective reductions in tearing at all follow-up times compared to pre-injection (success rate 86.8%), and the effect lasted for a mean duration of 5.63 months. The two delivery routes showed similar clinical effectiveness for a single injected dose of BTX-A. In conclusion, injecting BTX-A via either a transconjunctival or transcutaneous route helps to reduce normal tear production and results in significant improvements in the symptoms in patients with epiphora.

Long-term Outcomes of Punctal Cauterization in the Management of Ocular Surface Diseases.

PURPOSE: To evaluate the long-term outcomes of surgical occlusion of lacrimal puncta using thermal cautery in the management of ocular surface diseases. METHODS: We reviewed medical records of 80 consecutive patients from a single academic center who underwent punctal cauterization. Patient demographics, ocular history, symptoms, and signs of ocular surface diseases pre- and post-cauterization were recorded. RESULTS: A total of 80 patients (171 puncta) were included, with an average age of 59 years and a follow-up duration of 27 months. The most common ocular morbidity was ocular graft-versus-host disease (n = 36), followed by primary keratoconjunctivitis sicca (n = 15). Indications for punctal cauterization included plug loss (n = 51), difficulty in plug fitting (n = 11), plug-related complications (n = 6), recanalization of previous cauterization (n = 7), and severe ocular surface disease requiring permanent punctal closure (n = 4). After punctal cauterization, the percentage of eyes with severe (21%) and moderate (25%) dry eye decreased significantly (8% and 19% at 3 months and 6% and 17% at 12 months, P = 0.0006). Fifty-four percent of patients reported improvement in their symptoms. The rate of recanalization was 21% during the follow-up period. The use of topical corticosteroids was associated with higher recanalization rate. Associated complications were limited to temporary pain and swelling. CONCLUSIONS: Punctal cauterization is an effective modality in treating severe ocular surface diseases in patients who repeatedly lose punctal plugs, and it can be easily performed in a clinic setting without major complications. However, cauterization may need to be repeated in up to a quarter of cases because of recanalization.

Malformation of Tear Ducts Underlies the Epiphora and Precocious Eyelid Opening in Prickle 1 Mutant Mice: Genetic Implications for Tear Duct Genesis.

Purpose: Obstruction of the tear drainage causes a range of ocular surface disorders. Hitherto, the genetics of tear duct development and obstruction has been scarcely explored, and related animal models are lacking. This study aims to study the potential role of the Wnt/PCP pathway mediated by Prickle 1 in tear duct development and diseases. Methods: A severe hypomorphic Prickle 1 mutant was generated. Histology and immunohistochemistry were performed to compare wild type, Prickle 1 hypomorphic, and null mutant tear ducts. In situ hybridization was conducted to identify the signaling components in the developing tear ducts. Three-dimensional (3D) reconstruction was used to detect the human embryonic tear duct. Results: Here, we report that a severe Prickle 1 hypomorph mouse line exhibited epiphora. This phenotype was due to the blockage of the tear drainage by incompletely formed nasolacrimal duct (NLD) and lacrimal canaliculi (LC), which also causes precocious eyelid opening. We observed a dose-dependent requirement of Prickle 1 for tear duct outgrowth. An investigation of the expression of Wnt/PCP core genes demonstrated a subset of PCP signaling components expressed in the developing tear duct. Furthermore, Prickle 1 is not required for the expression of Fgfr2/Fgf10 and p63 genes, which are associated with the NLD and LC hypoplasia in humans. Last, we showed that Prickle 1 expression in the developing tear drainage system is conserved between mice and humans. Conclusions: The study suggests that malformed tear ducts caused by disruption of Prickle 1 underlies the epiphora and precocious eyelid opening.

Ectopic lacrimal gland in the lacrimal sac mimicking tumour: literature review.

An 80-year-old man referred with repeated episode of dacryocystitis from the left lacrimal drainage system and palpable swelling. For many years, he has being presented with epiphora unilaterally with chronic dacryocystitis. Investigations with dye-test revealed subocclusion of the natural passage of the tears, and CT and MRI scans revealed solid mass in the lacrimal sac. The lacrimal sac was opened by endonasal endoscopic approach, the sacral mass was identified and completely removed. The histopathological examination showed lacrimal gland in ectopic position. Patient followed for 18 months with complete recovery of symptoms. In our differential diagnosis, the ectopic lacrimal gland is also identified, when a mass in the lacrimal sac and duct is present. Successful surgical excision required considerable multidisciplinary teamwork between ophtalmologist-ENT (Otolaryngologist) and radiologist. Endonasal endoscopic approach is perfectly safe with direct control and ensures a smooth postoperative recovery.

The Role of Nano-ophthalmology in Treating Dry Eye Disease.

Dry eye disease (DED) is a common multifactorial disease linked to the tears/ocular surface leading to eye discomfort, ocular surface damage, and visual disturbance. Antiinflammatory agents (steroids and cyclosporine A), hormonal therapy, antibiotics, nerve growth factors, essential fatty acids are used as treatment options of DED. Current therapies attempt to reduce the ocular discomfort by producing lubrication and stimulating gland/nerve(s) associated with tear production, without providing a permanent cure for dry eye. Nanocarrier systems show a great promise to revolutionize drug delivery in DED, offering many advantages such as site specific and sustained delivery of therapeutic agents. This review presents an overview, pathophysiology, prevalence and etiology of DED, with an emphasis on preclinical and clinical studies involving the use of nanocarrier systems in treating DED. Lay Summary: Dry eye disease (DED) is a multifactorial disease associated with tear deficiency or excessive tear evaporation. There are several review articles that summarize DED, disease symptoms, causes and treatment approaches. Nanocarrier systems show a great promise to revolutionize drug delivery in DED, offering many advantages such as site specific and sustained delivery of therapeutic agents. Very few review articles summarize the findings on the use of nanotherapeutics in DED. In this review, we have exclusively discussed the preclinical and clinical studies of nanotherapeutics in DED therapy. This information will be attractive to both academic and pharmaceutical industry researchers working in DED therapeutics.

An audit of 3-snip procedures performed at the Aga Khan University Hospital, Karachi, Pakistan.

OBJECTIVE: To assess the functional outcome of three-snip punctoplasty procedure for punctal stenosis at a tertiary care hospital. METHODS: The retrospective study was conducted at the Aga Khan University Hospital Karachi, and comprised medical records of all patients aged >18 years who underwent three-snip punctoplasty between January 2013 and December 2017. Data was retrieved on age, gender, diagnosis, signs and symptoms, laterality, date of procedure, resolution of symptoms post procedure, date of last eye followup, symptoms at last follow-up, functional outcome (epiphora at 1 month). SPSS 20 was used for data analysis. RESULTS: Of the 30 patients, 22(73.3%) were females. Overall mean age at the time of punctoplasty was 57.5±15.57 years. Of all the cases, 17(56.7%) had undergone bilateral puntoplasty. At one month, 20(66.7%) patients were completely symptom-free. Females had better results than males but the difference was not significant (p=0.078). CONCLUSIONS: Three-snip punctoplasty was found to be a minimally invasive procedure with good functional outcome that was comparable to other procedures.

The Immunological Basis of Dry Eye Disease and Current Topical Treatment Options.

Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making.

Establishment of a Severe Dry Eye Model Using Complete Dacryoadenectomy in Rabbits.

Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic step. Despite advances in our understanding of DED, significant knowledge gaps remain. Advances are limited in part due to the lack of informative animal models. The authors recently reported on a method of DED induced by injecting all orbital lacrimal gland (LG) tissues with the lectin concanavalin A. Here, we report a novel model of aqueous-deficient DED based on the surgical resection of all orbital LG (dacryoadenectomy) tissues. Both methods use rabbits because of their similarity to human eyes in terms of the size and structure of the ocular surface. One week after removal of the nictitating membrane, the orbital superior LG was surgically removed under anesthesia, followed by removal of the palpebral superior LG, and finally removal of the inferior LG. Dacryoadenectomy induced severe DED, evidenced by a marked reduction in the tear break up time test and the Schirmer's tear test, and significantly increased tear osmolarity and rose bengal staining. Dacryoadenectomy-induced DED lasted at least eight weeks. There were no complications and animals tolerated the procedure well. The technique can be mastered relatively easily by those with adequate surgical experience and appreciation of the relevant rabbit anatomy. Since this model recapitulates the features of human aqueous-deficient DED, it is suitable for studies of ocular surface homeostasis, DED, and candidate therapeutics.

Nanomolar Potency Aminophenyltriazine CFTR Activator Reverses Corneal Epithelial Injury in a Mouse Model of Dry Eye.

Purpose: Dry eye disorders are a major health care burden. We previously reported the identification of N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)act-K267], which activated human wild-type CFTR chloride conductance with EC50 ∼ 30 nM. Here, we report in vivo evidence for CFTRact-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. Methods: CFTR activation in mice in vivo was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTRact-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. Results: OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTRact-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTRact-K267, tear fluid CFTRact-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTRact-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. Conclusion: These studies provide in vivo evidence in mice for the efficacy of a topical, human use compatible CFTRact-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.

Human Lacrimal Drainage System Reconstruction, Recanalization, and Regeneration.

Purpose: This review examines the broad contexts of the reconstructive and recanalization strategies of the human lacrimal drainage system.Materials and methods: A PubMed search was performed using individually and combination of the terms "lacrimal," "reconstruction", "recanalization," "canaliculus," "canalicular," "stenosis," "obstruction," "block," "drainage," "disorder," "disease," "nasolacrimal duct (NLD)," "endoscopy," "dacryoendoscopy," "trauma," "laceration," "stents," "repair," "tubes," "tear," "eyelid," "Sisler," "trephine," and "trephination". Selections from these lists were the basis of examination of reconstruction and recanalization strategies of multiple lacrimal disorders and their outcomes.Results: The major focus areas of this review are obstructions of the canaliculi and the NLD, traumatic involvement of the lacrimal drainage and their reconstruction strategies, and dacryoendoscopy-guided recanalization of the NLDs. The review found evidence for lack of uniformity in accurately defining the concepts of lacrimal drainage stenosis, partial or complete obstructions. Canalicular obstructions are difficult to manage and outcomes depend on the location of the obstruction. High success rates were reported in cases of canalicular lacerations managed by repair and silicone intubation. Controversies exists in the recanalization strategies involving the NLD. In the absence of any current regenerative strategies, NLD recanalization appears to be promising, but skepticism is well justified until its long-term effects are well known.Conclusions: Reconstructive strategies in canalicular trauma are highly successful. Recanalization strategies for the lacrimal drainage system are promising and there is a need to explore stem cells and regenerative modalities to take the lacrimal drainage science a step forward.

Towards Lacrimal Gland Regeneration: Current Concepts and Experimental Approaches.

Dry eye disease (DED) is a complex and multifactorial disease resulting in a continual cycle of tear hyperosmolarity and inflammation. Patients suffering from DED experience severe pain and visual impairments leading to a reduced quality of life. Aqueous-deficient dry eye (ADDE), mainly caused through a loss of functional lacrimal gland tissue, results in the most severe forms of DED. Despite a high prevalence, the current treatments remain palliative and may be insufficient to alleviate the symptoms. Consequently, investigations on experimental approaches for in situ lacrimal gland regeneration are of great clinical interest. This article reviews the current knowledge about processes involved in lacrimal gland regeneration, about lacrimal gland resident stem cells, and offers deductions about possible concepts for in situ lacrimal gland regeneration. Promising starting points might be the utilization of therapeutic proteins, such as bone morphogenetic protein 7, mesenchymal stem cells (MSC) or MSC-based treatments such as conditioned medium, lyophilized cell extracts or adult acinar cells. This review further summarizes current experimental approaches for the treatment of ADDE in animal models and patients. Approaches investigating side population stem cells, epithelial progenitor cells and MSC showed that the transplantation of these cells had therapeutic effects on ADDE. However, the most promising and best-studied experimental approach is the use of MSC for induction/enhancement of in situ lacrimal gland regeneration. Their immunomodulatory effects, low immunogenicity, promotion of tissue regeneration and involvement during spontaneous lacrimal regeneration are favorable traits for clinical applications. In addition, the efficacy and safety of allogeneic MSC transplantation have already been demonstrated in a small patient cohort.

[Clinical and pathological study on IgG4-related ophthalmic disease involving the lacrimal gland].

Objective: To summarize the clinical and pathological characteristics of IgG4-related ophthalmic disease (IgG4-ROD) involving the lacrimal gland. Methods: A retrospective case series study. Forty cases (56 eyes) of lacrimal gland lesions were collected in Tianjin Eye Hospital from January 2003 to January 2018 and confirmed by histopathology as lymphocyte and plasma cell infiltration with fibrosis of lacrimal gland tissue, excluding lymphoma, epithelial tumor, mesenchymal tumor and metastasis tumor. The clinical manifestations, serological and imaging examination of the patients were analyzed. Meanwhile, HE staining and immunohistochemical staining of IgG and IgG4 were performed on the pathological specimens. According to the diagnostic criteria, the cases were divided into the IgG4-ROD group and the non-IgG4-ROD group. The clinical and pathological characteristics of the two groups were statistically analyzed by Pearson chi-square and signed-rank test. Results: In the 40 cases (56 eyes), there were 15 cases (25 eyes) of IgG4-ROD and 25 cases (31 eyes) of non-IgG4-ROD. Statistically significant differences were observed between the two groups in the clinical and pathological characteristics (all P<0.05). About the distribution of eyes position, there were 10 binocular cases and 5 monocular cases in the IgG4-ROD group, and 6 binocular cases and 19 monocular cases in non-IgG4-ROD group (χ2=7.111).There were 21 eyes in the IgG4-ROD group and 5 eyes in the non-IgG4-ROD group about ptosis (χ2=25.631), 4 eyes in the IgG4-ROD group and 21 eyes in the non-IgG4-ROD group about ocular protrusion (χ2=14.992), 23 eyes in the IgG4-ROD group and 15 eyes in the non-IgG4-ROD group about the clear boundary of the tumor (χ2=12.069), 4 eyes in the IgG4-ROD group and 18 eyes in the non-IgG4-ROD group about the involvement of other orbital tissues (χ2=10.266) and 7 cases in the IgG4-ROD group and 3 cases in the non-IgG4-ROD group about the association with other systemic diseases (χ2=6.009). Compared with the non-IgG4-ROD group, the IgG4-ROD group had a heavier lymphocyte and plasma cell infiltration (+++,++,+; 10, 4, 1 vs. 6, 5, 12 eyes, Z=-3.153), and more lymphoid follicles (+++,++,+; 3, 6, 4 vs. 1, 2, 7 eyes, Z=-3.339), interstitial fibrosis was mostly striate (10 vs. 5 eyes, χ2=8.711), and there were a large number of IgG4+ plasma cells [96 (67, 135) vs. 4 (0, 12) cells per high power field, Z=-5.271] and ratio of IgG4+ plasma cells/IgG+ plasma cells [0.570 (0.500, 0.754) vs. 0.046 (0.000, 0.143), Z=-5.268, all P<0.05). Among the 10 cases of IgG4-ROD with serological examination, 9 cases showed elevated serum in IgG and IgG4. The ultrasonography and CT findings showed the lacrimal gland lesions in the IgG4-ROD group were mostly spindle or kidney shaped with clear boundaries, while the lesions in non-IgG4-ROD were mostly round or irregular with unclear boundaries. Conclusions: The lacrimal gland lesions of IgG4-ROD are characterized by bilaterally spindle or kidney shaped enlargement with clear boundaries. They are more associates with other systemic diseases. The pathological characteristics are a large number of IgG4+ plasma cells infiltration among the lacrimal gland tissue, interstitial striate fibrosis and a large number of lymphoid follicles. (Chin J Ophthalmol, 2019, 55: 834-841).

[Punctal and canalicular plugs: Indications, efficacy and safety (French translation of the article)]. / Les bouchons lacrymaux : indications, efficacité et tolérance.

Lacrimal occlusion with punctal or canalicular plugs have been used to treat dry eye disease for more than 40 years. Indeed, punctal plugs constitute a safe and effective tool to retain the natural tear film and prolong the effect of tear substitutes. A wide variety of plugs is available, differing in their design, location (punctal versus canalicular) and their resorbability. There indications have increasingly broadened, and they are now one of the treatment options for numerous ocular surface diseases. Current research focuses on using punctal plugs for extended delivery of drugs to the ocular surface. This review addresses physiology of lacrimal drainage, available models of punctal plugs, their indications, practical details of prescribing and placing punctal and canalicular plugs, and possible complications.

Surfactant proteins: Role in lacrimal drainage disorders.

Surfactants are complex mixtures of phospholipids and proteins produced by type II alveolar cells of the lungs and play a crucial role in pulmonary physiology. Six types of surfactant proteins (SP) are known; SP-A, SP-B, SP-C, SP-D, SP-G and SP-H. The major role of SP is in reducing surface tension and various immunological functions. SP-A, SP-B, SP-C and SP-D have been demonstrated in the tear film and the epithelium of the lacrimal sac (LS) and nasolacrimal ducts (NLD). All surfactant proteins except SP-G were also isolated from the canalicular tissues. The authors hypothesize that surfactant proteins play a significant role in the pathogenesis of lacrimal drainage disorders; functional nasolacrimal duct obstruction (FNLDO) and infective dacryocystitis.

Tears and ocular surface disorders: Usefulness of biomarkers.

INTRODUCTION: Corroborating data suggest that the analysis of tear fluid might represent an additional tool in the ophthalmological practice. AREAS COVERED: The purpose of this review was to sum up the tear protein profiles in healthy and diseased ocular surface and to highlight biomarker usefulness in the early diagnosis as well as at follow-up. This analysis encompasses a deep examination of the protein profile expression under physiological and pathological conditions. Tear protein profile analysis will allow in the near future discriminating between different grades of inflammation, from acute trauma toward immune-, endocrine-, and nervous-related disorders of the ocular surface. CONCLUDING REMARKS: The review provides an overview of old and recent findings about inflammatory mediators identified at the ocular surface, under physiological and pathological conditions. To date, the analysis of tear fluid represents a new additional approach for diagnosis and management of ocular surface diseases. Understanding the pathophysiological mechanism could also offer significant advantages to develop strategies addressed to better clarify some complex ocular surface disorders. To sum up, the possibility to provide selective biomarkers as a future target of specific diseases should be considered for supporting diagnosis and management of ocular surface diseases.

An experimental study of amniotic lacrimal duct stents in the treatment of perimenopausal female rabbits with dry eye.

The aim of the present study was to investigate the effects of an amniotic membrane lacrimal stent in the treatment of dry eye syndrome in a perimenopausal rabbit model. In total, 48 healthy female rabbits were randomly divided into four groups (12 rabbits/group): Group A, sham­operated group; group B, negative control group; group C, sham­implantation group; and group D, implantation with amniotic membrane lacrimal stents. A Schirmer I test (SIT), corneal fluorescein staining, optical coherence tomography angiography and corneal confocal microscopy were conducted and the biomechanical properties of the amniotic membrane were measured prior to and 2, 4 and 6 weeks after the operations. There were marked differences in the amount of tear secretion and the SIT following the operation compared with prior to the operation. The amount of tear secretion of group B and C was significantly reduced (F=8.894; P=0.0017). Compared with groups A, B and C, group D demonstrated a significant increase in the amount of tear secretion and a significant reduction in SIT (P<0.05). However, there was no statistical difference between the tear secretion of the A, B and C groups (P>0.05). The cornea epithelial of groups A and D was significantly thinner compared with groups B and C. The superior part [superior temporal (ST)5, superior (S)5, superior nasal (SN)5, ST6, S6 and SN6] was significantly thinner compared with the central part of the cornea epithelium. The corneal epithelia of all groups were thin in the center and thick at the edge. At 6 weeks after the operation, group D exhibited a markedly decreased number of anterior stromal luminescent cells, compared with groups A, B and C. Furthermore, the bending degree of corneal stromal neural trunks was significantly improved, and the density, branches and curvature of corneal epithelium sub­basal nerves ameliorated to a certain extent (P<0.05). Amniotic membrane lacrimal stents demonstrated specific therapeutic effects on dry eye in perimenopausal female rabbits.

The role of endocrine disruptors in ocular surface diseases.

Endocrine disruptors are a group of compounds that occur in increasing amounts in the environment. These compounds change the hormone homeostasis of the target organs regulated by those hormones, mostly by binding to their receptors and affecting their signaling pathways. Among the hormones altered by endocrine disruptors are sex hormones, thyroid hormones, and insulin. Studies have documented abnormalities in the reproductive and metabolic systems of various animal species exposed to endocrine disruptors. Endocrine disruptors can play a significant role in ocular diseases once hormone deficiency or excess are involved in the mechanism of that disease. Cataracts, dry eye disease and retinal diseases, such as macular hole and diabetic retinopathy, are some of the frequent problems where hormones have been implicated. We found that some compounds function as endocrine disruptors in the metabolism of body organs and systems. The increasing frequency of dry eye and other ocular diseases indicates the need to better investigate the potential relationships beyond the isolated associations mentioned by patients and documented as rare case reports. The evidence from case-control studies and experimental assays can provide the information necessary to confirm the endocrine effects of these chemicals in the pathophysiology of dry eye disease. We hypothesize that endocrine disruptors may contribute to the increase of ocular diseases, such as dry eye disease, in recent years.

Immune Response Targeting Sjögren's Syndrome Antigen Ro52 Suppresses Tear Production in Female Mice.

Autoantibodies reactive against Ro52 are present in 70% of Sjögren's syndrome patients and are associated with higher disease severity. However, their role in causing aqueous deficient dry eye, a major cause for morbidity in Sjögren's syndrome, is unclear. To investigate whether immune responses targeting Ro52 contribute towards the dry eye, male and female NZM2758 mice were immunized with recombinant Ro52. Tear production was measured by the phenol red thread test. Sera were analyzed for anti-Ro52 levels by immunoprecipitation. Lacrimal glands were evaluated for inflammatory foci and IgG deposits. Our results showed that, although all mice generated anti-Ro52 antibodies, only females developed a significant drop in tear production. None of the mice developed severe lacrimal gland inflammation, and female mice with anti-Ro52 showed higher levels of IgG deposits within their glands. Passive transfer of anti-Ro52 sera caused reduced tear production in female mice, but not in males. This study demonstrates for the first time that immune responses initiated by Ro52 induce aqueous dry eye, and this may be driven by anti-Ro52 antibodies. Furthermore, the sexual dimorphism in glandular dysfunction suggests that the lacrimal glands in females are more susceptible to autoantibody-mediated injury.