Drops of Lactiplantibacillus plantarum CRL 759 culture supernatant attenuates eyes inflammation induced by lipopolysaccharide.

Anti-inflammatory effect of soluble secreted compounds of probiotic bacteria was widely demonstrated as therapy for different inflammatory diseases, but was not investigated in inflammatory eye disorders. The aim of this study was to determine whether Lactiplantibacillus plantarum CRL759 cell-free supernatant reduced inflammatory parameters and clinical signs in ocular inflammations. First, we evaluated the effect of L. plantarum CRL759 supernatant in vitro on human retinal cell line, ARPE-19 cells, stimulated with lipopolysaccharide (LPS). Then, we investigated in vivo its capacity to decrease inflammation by local administration on the eyes of mice with endotoxin induced inflammation. In vitro assays demonstrated that L. plantarum CRL759 supernatant reduced the production of interleukin (IL)-6, IL-8, nitric oxide and thiobarbituric acid reactive substances in LPS-stimulated ARPE-19 cells. Our in vivo data proved that L. plantarum supernatant significantly reduced the clinical score of endotoxin treated mice and diminished levels of tumour necrosis factor alpha, interferon gamma and protein concentration in aqueous humour. Histological examination showed reduction of infiltrating inflammatory cells in the posterior segment of the eyes. As far as we know, this is the first report showing that Lactobacillus spp. supernatant administered as drops reduces some parameters of ocular inflammation. This promising strategy is safe and could alleviate symptoms and signs of ocular inflammation in people that are refractories to the conventional therapies.

COVID-19: the novel coronavirus disease and its manifestations and management in ophthalmology.

Coronavirus disease 2019 (COVID-19), a newly identified acute respiratory disease caused by a strain of novel coronavirus (SARS-CoV-2), has become a worldwide pandemic. From December 2019 to present, millions of cases have been reported, bringing unprecedented pressure on both health and epidemic prevention services in every country. As frontline healthcare workers, ophthalmologists face an increased threat of viral infection, not only because of close contact with patients during examinations or operations, but also due to evidence showing that ocular fluids such as tears or conjunctival secretions may carry the virus. The risk that healthcare workers face is emphasized by the loss of our colleagues who have sacrificed themselves in combating the virus. As a result, it is necessary to have a comprehensive understanding of the threats that we face. In the first part of this review, we start by explaining the structure of SARS-CoV-2 and examining its transmission and means of infection. Next, we summarize the latest scientific advancements of epidemiology, clinical presentations, and current treatments of COVID-19. In the second half of the review, we emphasize the ocular transmission, symptomatic manifestations, and the essential knowledge in an ophthalmology clinic setting. As the pandemic of COVID-19 continues to pose a threat to global health, we hope that this review makes a contribution to combating COVID-19.

Serum Trace Elements Profile in Graves' Disease Patients with or without Orbitopathy in Northeast China.

OBJECTIVE: The purpose of the present study was to investigate serum trace elements in Graves' disease (GD) patients with or without orbitopathy in Northeast China. METHODS: Patients with newly diagnosed Graves' disease (HyGD) (n = 66), GD patients with euthyroid status or subclinical thyroidism after treatment (EUGD) (n = 55), GO patients with euthyroid status or subclinical thyroidism after treatment (GO) (n = 57), and normal controls (NC) (n = 66) were enrolled in this study. Serum trace elements were measured with ICP-MS. RESULTS: Serum selenium (Se) levels in EUGD group (median: 7.53 µg/dL), HyGD group (median: 6.76 µg/dL), and GO group (median: 7.40 µg/dL) were significantly lower than those in NC group (median: 9.20 µg/dL, all P < 0.01). Serum copper (Cu) levels in GO group (median: 95.93 µg/dL) were significantly lower than those in the NC group (median: 113.59 µg/dL, P = 0.015). After being adjusted for multivariables, thyroid-specific antibodies grade was associated with low Se levels. Hyperthyroidism and thyroid-specific antibodies grade were associated with high Cu levels. In addition, orbitopathy was associated with low Cu levels. CONCLUSIONS: Thyroid autoimmunity was associated with low Se levels. Hyperthyroidism and thyroid autoimmunity may be associated with relatively high serum Cu levels. Alternatively, ophthalmopathy may be related to low serum Cu levels.

Inflammation and immunogenicity limit the utility of the rabbit as a nonclinical species for ocular biologic therapeutics.

The nonclinical safety evaluation of therapeutic drug candidates is commonly conducted in two species (rodent and non-rodent) in keeping with international health authority guidance. Biologic drugs typically have restricted species cross-reactivity, necessitating the evaluation of safety in non-human primates and thus limiting the utility of lower order species. Safety studies of cross-reactive ocular biologic drug candidates have been conducted in rabbits as a second toxicology species, despite the fact that rabbits are not a rodent species. Such studies are often confounded by the development of anti-drug antibodies and severe ocular inflammation, the latter requiring studies to be terminated prematurely for animal welfare reasons. Notably, these confounding factors preclude the interpretation of safety. Nonclinical toxicology programs should be designed with consideration of ethical animal use and 3Rs principles (Replacement, Reduction and Refinement). The experience of several pharmaceutical sponsors, demonstrating that toxicology studies of ocular (intravitreal and topical ocular) biologic drug candidates in the rabbit are of limited interpretive value, calls into question the utility of such studies in this species and indicates that such studies should not be conducted.

Neuronal Fc-epsilon receptor I contributes to antigen-evoked pruritus in a murine model of ocular allergy.

Pruritus is the major symptom of ocular allergy but currently available treatments are often ineffective. Previous studies demonstrated that subpopulations of primary sensory neurons express Fc receptors and may contribute to antigen-specific pain. We investigated the role of neuronal Fc-epsilon Receptor I (FcεRI) in allergic ocular pruritus. Ovalbumin (OVA) was used as allergen together with alum adjuvant (OVA+alum) to produce a mouse model of ocular allergy with a significant elevation in the serum levels of both antigen-specific IgE and IgG. Mice sensitized by OVA without alum only induced elevation of serum IgG but not IgE. Scratching behavior toward the eyes with the hindlimb was used as an indicator of ocular itch. Topical OVA challenging to the eye dose-dependently induced scratching toward the eye in the OVA+alum sensitized mice, but not those sensitized by OVA only. The antigen-induced scratching was largely abolished by topical application of the blocking antibody to FcεRIα, but was only partially alleviated by pretreatment of mast cell stabilizer or histamine I receptor antagonist. The expression of FcεRI was detected in subpopulations of trigeminal ganglion (TG) neurons including those expressing pruriceptive markers and innervating the conjunctiva in the naïve mice. Moreover, FcεRI was found significantly upregulated in small-sized TG neurons in the OVA+alum sensitized mice. In acutely dissociated TG neurons, IgE-immune complex (IC), but not the antibody or antigen alone, induced intracellular calcium increase. The neuronal responses to IgE-IC could be specifically blocked by pre-application of a siRNA for FcεRIα. Our results indicate that FcεRI expressed on peripheral nociceptive neurons in the TG may be directly activated by IgE-IC and contribute to allergic ocular pruritus. This study may suggest a novel mechanism for the development of pathological itch in allergic diseases.

Berberine exerts an anti-inflammatory role in ocular Behcet's disease.

Behcet's disease is a multi­system inflammatory disorder, and ocular Behcet's disease (OBD) is one of the most common causes of uveitis in China. A number of studies have indicated that Th17 cells, a subset of interleukin-17 (IL-17)-producing CD4+ T­helper cells, serve important roles in the pathogenesis of OBD. Berberine (BBR) is an isoquinoline derivative alkaloid isolated from Chinese herbs, and has been used traditionally for the treatment of gastrointestinal disorders. The aim of the present study was to investigate the effect of BBR on Th17 cell proliferation and cytokine secretion, and the expression and activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor in OBD in vitro. Blood samples were obtained from healthy controls and patients with active ocular Behcet's disease. Peripheral blood mononuclear cells (PBMCs) or CD4+ T cells were cultured for three days with or without BBR and in the presence of anti­CD3 and anti­CD28 antibodies. IL­17 expression in cell sample supernatants was determined by enzyme­linked immunosorbent assay, and cell viability was measured using the Cell Counting kit­8 assay. The number of CD4+IL­17+ cells and the expression level of phosphorylated (p)­STAT3 in CD4+ T cells was determined using flow cytometry analysis. The expression of IL­17 was increased in patients with active OBD following the activation of PBMCs and CD4+ T cells with anti­CD3 and anti­CD28 antibodies when compared with healthy controls. However, no significant difference in cell viability following exposure to BBR was observed in PBMCs derived from healthy controls or patients with OBD. Following incubation with BBR, the expression of IL­17 was reduced and the number of CD4+IL­17+ cells was decreased in patients with active OBD and healthy controls. Furthermore, the expression of p-STAT3 was significantly decreased in the presence of BBR in healthy controls. In conclusion, the results of the present study demonstrate that BBR may suppress the Th17 response in patients with OBD by reducing STAT3 phosphorylation. BBR may be a potential therapeutic agent for the treatment of OBD.

Lutein and Zeaxanthin Isomers in Eye Health and Disease.

Current evidence suggests lutein and its isomers play important roles in ocular development in utero and throughout the life span, in vision performance in young and later adulthood, and in lowering risk for the development of common age-related eye diseases in older age. These xanthophyll (oxygen-containing) carotenoids are found in a wide variety of vegetables and fruits, and they are present in especially high concentrations in leafy green vegetables. Additionally, egg yolks and human milk appear to be bioavailable sources. The prevalence of lutein, zeaxanthin, and meso-zeaxanthin in supplements is increasing. Setting optimal and safe ranges of intake requires additional research, particularly in pregnant and lactating women. Accumulating evidence about variable interindividual response to dietary intake of these carotenoids, based on genetic or metabolic influences, suggests that there may be subgroups that benefit from higher levels of intake and/or alternate strategies to improve lutein and zeaxanthin status.

[Correlation of the microbiota and intestinal mucosa in the pathophysiology and treatment of irritable bowel, irritable eye, and irritable mind syndrome]. / A mikroflóra és a bélnyálkahártya kölcsönhatása az irritábilis bél, irritábilis szem és irritábilis elme szindróma kórtanában és kezelésében.

Accumulating clinical evidence supports co-morbidity of irritable bowel, irritable eye and irritable mind symptoms. Furthermore, perturbation of the microbiota-host symbiosis (dysbiosis) is considered a common pathogenic mechanism connecting gastrointestinal, ocular and neuropsychiatric symptoms. Consequently, maintaining or restoring microbiota-host symbiosis represents a new approach to treat these symptoms or to prevent their relapses. Current treatment approach assigned a primary role to live probiotics alone or in combination with prebiotics to enhance colonization of beneficial bacteria and to strengthen the symbiosis. However, several papers showed major benefits of heat-killed probiotics as compared to their live counterparts on both intestinal and systemic symptoms. Recently, in addition to killing probiotics, in a proof of concept study lysates (fragments) of probiotics in combination with vitamins A, B, D and omega 3 fatty acids were successfully tested. These findings suggested a conceptual change in the approach addressed to both the microbiota and host as targets for intervention.

Biotherapies in inflammatory ocular disorders: Interferons, immunoglobulins, monoclonal antibodies.

Biotherapies used in clinical practice for the treatment of ophthalmologic manifestations of systemic diseases include interferons (IFN), intravenous immunoglobulins (IVIG) and monoclonal antibodies (anti-TNF, anakinra, tocilizumab and rituximab). Several open prospective studies have shown the effectiveness of IFN-α (78 to 98% complete remission) for the treatment of severe uveitis in Behcet's disease. IFN is capable of inducing prolonged remission and continued after his arrest, in 20-40% of patients. Side effects (flu-like, psychological effects) limit its use in practice. Anti-TNFα (infliximab and adalimumab) represents an attractive alternative therapeutic in severe uveitis refractory to immunosuppressants, especially in Behcet's disease. They are almost always (>90% of cases) and rapidly effective but their action is often suspensive. Anti-TNFα requires an extended prescription or takes over from another immunosuppressant once ocular inflammation has been controlled. IVIG are used for the treatment of Kawasaki disease and Birdshot disease. Several open or retrospective studies showed their effectiveness for the treatment of severe and refractory cicatricial pemphigoid. Tolerance of IVIG is good but their efficacy is transient. Rituximab showed an efficacy in few observations of various inflammatory eye diseases (uveitis, scleritis and idiopathic inflammatory pseudo-tumors or associated with granulomatosis with polyangiitis) and cicatricial pemphigoid. The risk of infection associated with this biotherapy limits its use in refractory diseases to conventional therapy. Anakinra (a soluble antagonist of IL-1R) showed interesting results in terms of efficiency in one small open study in Behcet's disease. Its safety profile is good and with a quick action that could be interesting for the treatment of severe uveitis.

A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency.

This review looks at the critical role of vitamin D in improving barrier function, production of antimicrobial peptides including cathelicidin and some defensins, and immune modulation. The function of vitamin D in the innate immune system and in the epithelial cells of the oral cavity, lung, gastrointestinal system, genito-urinary system, skin and surface of the eye is discussed. Clinical conditions are reviewed where vitamin D may play a role in the prevention of infections or where it may be used as primary or adjuvant treatment for viral, bacterial and fungal infections. Several conditions such as tuberculosis, psoriasis, eczema, Crohn's disease, chest infections, wound infections, influenza, urinary tract infections, eye infections and wound healing may benefit from adequate circulating 25(OH)D as substrate. Clinical diseases are presented in which optimization of 25(OH)D levels may benefit or cause harm according to present day knowledge. The safety of using larger doses of vitamin D in various clinical settings is discussed.

Association for Research in Vision and Ophthalmology (ARVO)--2010 Annual Meeting. For Sight: The Future of Eye and Vision Research--part 1.

The 2010 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), held in Fort Lauderdale, FL, USA, included topics covering new therapeutic developments in the field of eye and vision research. This conference report highlights selected presentations on the development of FOV-2304 (Fovea Pharmaceuticals SA) for the potential treatment of diabetic macular edema; PHA-666859 (Pfizer Inc) for diabetic retinopathy; GTx-878 (GTx Inc) and FCFD-4514S (Genentech Inc) for age-related macular degeneration; SYL-040012 (Sylentis Sau) for ocular hypertension associated with open-angle glaucoma; PEG-PLA-TNP-470 (Harvard Medical School) for ocular neovascularization; recombinant galectin-3 (Senju Pharmaceutical Co Ltd) for corneal injury; and CellBead Neuro (CellMed Inc) for neurological trauma and neurodegeneration.

Review of complementary and alternative medicine in treatment of ocular allergies.

PURPOSE OF REVIEW: Ocular allergy is a common complaint of allergy sufferers, many of whom may choose to use complementary and alternative medicine in the treatment of these symptoms. In this review major complementary and alternative medicine modalities including herbal therapies, acupuncture, homeopathy, alternative immunotherapy and behavior modification are assessed for evidence of their effectiveness in the treatment of ocular allergy symptoms. RECENT FINDINGS: Certain herbs including Euphrasia officinalis, Petasites hybridus and Argemone mexicana have been evaluated in control studies in the treatment of ocular allergy. Honey is no more effective than placebo in the treatment of ocular allergy. Acupuncture used regularly has demonstrated some positive trends in ocular allergy sufferers. Homeopathy has shown conflicting results in the treatment of ocular allergy, while alternative forms of immunotherapy have been shown to develop immunologic tolerogenic effects in the control of the condition. SUMMARY: Several forms of complementary and alternative medicine have been studied for their effectiveness in treatment of ocular allergy symptoms. Further research is needed to assess mechanisms of action and to establish practice guidelines for the use of these modalities

Human ocular mast cells.

PURPOSE OF REVIEW: Seasonal allergic conjunctivitis is a common and clinically significant type I hypersensitivity response, in which the mast cell is considered to play a pivotal role in causing the signs and symptoms, including ocular itching, hyperaemia, lacrimation and chemosis. This review focuses on the biology of the human mast cell, particularly that of the human conjunctiva. RECENT FINDINGS: The ocular mast cell not only releases histamine and eicosanoids into the extravascular environment when activated, but also synthesizes the cytokines IL-4 and TNF-alpha. The number of IL-4 messenger RNA-positive mast cells found in the conjunctival submucosa increases threefold in seasonal allergic conjunctivitis 'in season' compared with 'out of season', suggesting a role in disease. Treatment of the eye with 2% nedocromil sodium eye drops twice a day for 2 weeks reduced the tear concentrations of both histamine and prostaglandin D(2) by more than 70% at 30 min after challenge (both <0.05) illustrating an effective mast cell stabilizing effect in the conjunctiva. SUMMARY: Mast cells are a heterogeneous family of cells that are pivotal in initiating the signs and symptoms of seasonal allergic conjunctivitis. The expression of cytokines also endows them with the ability to initiate the inflammatory cascade, resulting in eosinophil accumulation associated with vernal conjunctivitis. Drug modulation of mast cell activity, although reducing the acute symptoms of active disease, also reduces the cytokine stimulus for the development of chronic allergic inflammation.

Early and late phases of ocular anaphylaxis in actively immunized guinea pigs.

A model of ocular anaphylaxis with distinct early- and late-phase components was studied in actively immunized guinea pigs. Twenty guinea pigs were injected with dinitrophenylated (DNP) bovine gamma globulin emulsified in Freund's complete adjuvant and challenged topically with di-DNP-lysine. Clinical signs were monitored over a 48 h period. An early-phase reaction (EPR) characterized by conjunctival edema, conjunctival erythema, lid swelling, and lid redness was observed. This reaction peaked at 0.5 h after challenge and subsided to a low point at 3-4 h. Subsequently, a second episode of lid swelling and lid redness was observed at 4-8 h. All animals in both groups exhibited an EPR. In addition, 75% of the animals underwent an EPR and an LPR. No animals exhibited an isolated LPR. Of the animals that underwent a dual response, 47% were biphasic, 6% were prolonged and 47% were multiphasic. The development of an active model of ocular anaphylaxis exhibiting both EPR and LPR components will enable studies of mechanisms which regulate the frequency and magnitude of these ocular allergic responses.

Diagnosis and treatment of ocular rosacea.

Eighteen patients with ocular rosacea were treated with oral tetracycline which resulted in marked improvement in all patients. Approximately one half of the patients were able to taper and stop the medication without recurrence of symptoms. The remaining have tapered their medication but could not stop without recurrence of symptoms. The majority of the patients in the series had Staphylococcus aureus on their conjunctiva and lids before and after surgery.