Repeated High-Dose Vitamin A Supplements, Standard of Care for Treating Xerophthalmia, Leads to Hypervitaminosis A in Piglets.

BACKGROUND: Vitamin A (VA) deficiency and excess negatively affect development, growth, and bone health. The World Health Organization's standard of care for xerophthalmia due to VA deficiency, is 3 high-dose VA supplements of 50,000-200,000 IU, based on age, which may cause hypervitaminosis A in some individuals. OBJECTIVES: This study measured VA status following 3 VA doses in 2 piglet studies. METHODS: In Study 1, 5 groups of piglets (n = 10/group) were weaned 10 d postbirth to VA-free feed and orally administered 0; 25,000; 50,000; 100,000; or 200,000 IU VA ester on days 0, 1, and 7. On days 14 and 15, the piglets underwent the modified relative dose-response (MRDR) test for VA deficiency, and were killed. Tissues were collected for high-pressure liquid chromatography analysis. Study 2 used the same design in 3 groups (n = 13/group) weaned at 16 d and administered 0; 25,000; and 200,000 IU doses. RESULTS: In Study 1 (final weight: 3.6 ± 0.7 kg), liver VA concentration was hypervitaminotic in 40%, 90%, and 100% of 50,000; 100,000; and 200,000 IU groups, respectively. The 25,000 IU group was 100% adequate, and the placebo group was 40% deficient. In Study 2 (final weight: 8.7 ± 0.8 kg), where 200,000 IU could be prescribed to infants with a similar body weight, 31% of the piglets were hypervitaminotic, the 25,000 IU group was 100% VA adequate, and the placebo group was 100% deficient. The MRDR test measured deficiency in 50% and 70% of the placebo group in each study but had 3 false positives among hypervitaminotic piglets in Study 1. CONCLUSIONS: Repeated high-dose VA may cause hypervitaminosis, indicating dose sizes may need reduction. The MRDR resulted in false positives in a hypervitaminotic state during malnutrition and should be paired with serum retinyl ester evaluation to enhance VA status assessment in populations with overlapping interventions.

Advances in imaging of the lacrimal gland in Sjögren's syndrome: A narrative review.

Due to lymphocytic infiltration of the salivary and lacrimal glands, Sjogren's syndrome (SS), a systemic autoimmune illness that mostly affects the exocrine glands, causes dry mouth (xerostomia) and dry eyes (xerophthalmia). Additionally, SS is associated with various comorbidities such as cardiovascular diseases, infections, musculoskeletal diseases, and cancers. Among patients with SS, xerophthalmia frequently arises as a complication, leading to insufficient tear production or rapid tear evaporation, thereby causing discomfort, irritation, and a gritty sensation in the eyes. This article aims to examine recent advancements in the imaging of the lacrimal gland in Sjögren's syndrome and briefly discusses the utilization of various imaging examinations for the lacrimal gland in this particular disease.

[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.

Recognizing vitamin A deficiency: special considerations in low-prevalence areas.

PURPOSE OF REVIEW: Although vitamin A deficiency (VAD) is rare in well resourced countries, there is a growing trend of VAD in at-risk pediatric populations. Early diagnosis is critically important to prevent its associated morbidity and mortality. This review highlights key lessons for evaluation, diagnosis, and management of children with xerophthalmia in the United States. It synthesizes the latest findings from the literature on the pathophysiology, epidemiology, risk factors, evaluation, and management of VAD in low-prevalence areas. RECENT FINDINGS: Vitamin A is crucial for maintaining the functional integrity of the eye, immune system, skin, and mucous membranes. Despite the scarcity of VAD in developed countries, there are increasing reports of VAD in at-risk children, including those with autism spectrum disorder and gastrointestinal conditions. There is a broad range of manifestations of VAD, posing a diagnostic challenge. Familiarity with the variable presentations of VAD and having a high index of suspicion in at-risk populations can aid in its early diagnosis. Systemic vitamin A supplementation and a multidisciplinary approach are important components of the management of VAD. SUMMARY: Even in well resourced countries, VAD should remain on the differential in patients with risk factors who present with relevant signs and symptoms. Early diagnosis and appropriate involvement of a multidisciplinary care team can help prevent morbidity and mortality associated with VAD.

Sodium hyaluronate combined with rhEGF contributes to alleviate clinical symptoms and Inflammation in patients with Xerophthalmia after cataract surgery.

BACKGROUND: To determine the effect of sodium hyaluronate combined with recombinant human epidermal growth factor (rhEGF) on clinical symptoms and inflammation in patients with newly diagnosed xerophthalmia after cataract surgery. METHODS: A total of 106 patients who underwent cataract surgery and were newly diagnosed with xerophthalmia in our hospital between June 2018 and August 2019 were enrolled. Of these, 50 patients who were treated with sodium hyaluronate (0.1%) were assigned to the monotherapy group (MG) and the remaining 56 patients who were treated with sodium hyaluronate (0.1%) combined with rhEGF (20 µg/ml) were assigned to the combination group (CG). The 2 groups were compared based on ocular surface disease index (OSDI) score, break-up time (BUT), fluorescein corneal staining level, Schirmer I test (SI) level, clinical efficacy (disappearance of typical symptoms, including eyes drying, burning sensation, foreign body sensation, etc), and interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) levels. Spearman correlation analysis was conducted to analyze the relationship between IL-1, IL-6, TNF-α and clinical efficacy. In addition, receiver operating characteristic curves were drawn to analyze the predictive value of IL-1, IL-6, and TNF-α in efficacy on xerophthalmia. RESULTS: After treatment, the CG showed reduced OSDI score compared with the MG. The CG showed increased BUT (s) and SI (mm) levels compared with MG. After treatment, the CG exhibited decreased levels of IL-1(ng/mL), IL-6 (ng/mL), and TNF-α (ng/mL) compared with the MG. Spearman correlation analysis revealed that IL-1, IL-6, and TNF-α were negatively correlated with clinical efficacy. The areas under the curves of IL-1, IL-6, and TNF-α were 0.801, 0.800, and 0.736 respectively. CONCLUSIONS: Sodium hyaluronate combined with rhEGF is helpful to alleviate clinical symptoms and inflammation in patients with xerophthalmia undergoing cataract surgery.

Defining the Role of Monocytes in Sjögren's Syndrome.

Sjögren's syndrome is one of the most prevalent autoimmune diseases after rheumatoid arthritis, with a preference for middle age, and is characterised by exocrine glandular involvement leading to xerostomia and xerophthalmia. It can have systemic implications with vascular, neurological, renal, and pulmonary involvement, and in some cases, it may evolve to non-Hodgkin's lymphoma. For a long time, B- and T-lymphocytes have been the focus of research and have been considered key players in Sjögren's syndrome pathogenesis and evolution. With the development of new technologies, including omics, more insights have been found on the different signalling pathways that lead to inflammation and activation of the immune system. New evidence indicates that a third actor linking innate and adaptive immunity plays a leading role in the Sjögren's syndrome play: the monocyte. This review summarises the recent insights from transcriptomic, proteomic, and epigenetic studies that help us to understand more about the Sjögren's syndrome pathophysiology and redefine the involvement of monocytes in this disease.

Frequency of ANA/DFS70 autoantibodies in Colombian patients with undifferentiated connective tissue disease.

The objective was to describe the clinical characteristics and the frequency of the ANA/DFS70 autoantibodies in patients affected by undifferentiated connective tissue disease (UCTD) in a tertiary hospital in Colombia. This descriptive cross-sectional study enrolled patients who fulfilled the classification criteria for UCTD. ANAHEp- 2 test and the modified assay for ANA/DFS70 autoantibodies were performed through the indirect immunofluorescence technique. Erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and the antibodies to anti-extractable nuclear antigens, DNA, phospholipids (IgG, IgM, IgA), and cyclic citrullinated peptide were also evaluated. Fifty-three patients were studied; 42/53 (79%) tested positive for ANA and 5/42 (11.9%) for ANA/DFS70 antibodies with a dense fine speckled fluorescent pattern (AC-2) in ANA HEp-2 test that was confirmed by a modified HEp-2-DFS70 assay. Patients had arthralgia (87%, n=47), non-erosive arthritis (66%, n=34), xerostomia (64%, n=34), xerophthalmia (42%, n=22), and Raynaud's phenomenon (17%, n=9). Arthralgia, xerophthalmia, xeroderma, and absence of disease evolution to a specific disease over five years were more frequent in patients with a positive result for the anti-DFS70 antibodies. The ANA/DFS70 autoantibodies were more frequent in patients with UCTD compared to other rheumatic diseases for which they were initially evaluated. More studies are required to support the predictive role of this antibody to the absence of progression to a well-defined connective tissue disease.

An Accidental Nutritionist.

My career as an accidental nutritionist began with my immersion in cholera control, a cyclone disaster, a smallpox epidemic, and formal training in ophthalmology and epidemiology. Interest in blindness prevention inexplicably led me to (re)pioneer the effects, treatment, and prevention of vitamin A deficiency, while faced with intense criticism by many leading scientists in the nutrition community. The resulting efforts by the World Health Organization and UNICEF in support of programs for the global control of vitamin A deficiency still face vocal opposition by some senior scientists, despite having been estimated to have saved tens of millions of children from unnecessary death and blindness. This entire journey was largely an accident!

Application of classification criteria of Sjogren syndrome in patients with sicca symptoms: Real-world experience at a medical center.

BACKGROUND: Patients who have symptoms of sicca, such as dry eyes and mouth, may have Sjögren's syndrome (SS). However, the conservative culture makes patients hesitate to undergo an invasive biopsy, which contributes to the difficulty of confirming a diagnosis. We aimed to identify the characteristics of patients with sicca symptoms to develop a better predictive value for each item included in the three different diagnostic criteria for SS and clarify the best diagnostic tools for the local population. METHODS: This is a single-center retrospective case-control study from January 2016 to December 2017. Patients who underwent sialoscintigraphy because of clinical symptoms of xerostomia and xerophthalmia at one medical center were reviewed via the patients' electronic medical records. RESULTS: Of 515 patients enrolled, the severity of results for sialoscintigraphy and Schirmer's test was correlated with a diagnosis of SS and generated receiver operator characteristic curve. The area under curve (AUC) was 0.603 for positive Schirmer's test, 0.687 for positive anti-Ro/La results, 0.893 for a positive salivary gland biopsy. The AUC was 0.626 and 0.602 for Schirmer's test which is redefined as <10 mm/5 minutes in either eye and according to 2016 the American College of Rheumatology/ European League Against Rheumatism criteria, respectively. CONCLUSION: Our results indicate the cut-off point for defining a positive test result in the Schirmer's test is worth modified to <10 mm/5 minutes in either eye.

Case Report: Vitamin A Deficiency and Nyctalopia in a Patient with Chronic Pancreatitis.

SIGNIFICANCE: Vitamin A deficiency is a known concern in developing countries, but it is often overlooked in developed regions. A history of conditions causing alimentary malabsorption should be considered when patients present with complaints of nyctalopia. PURPOSE: A case of vitamin A deficiency with nyctalopia in a patient with chronic pancreatitis including pertinent diagnostic testing, treatment, and management is presented. The intent is to draw attention to the condition as a differential diagnosis for nyctalopia due to increased prevalence of conditions causing malabsorption. CASE REPORT: A patient with a history of chronic pancreatitis and pancreatic tumor presented with symptoms of nyctalopia and xerophthalmia. Given his systemic history, testing was ordered to determine serum vitamin A levels and retinal function. After results had confirmed depleted vitamin A levels and diminished retinal function, treatment with both oral and intramuscular vitamin A supplementation was initiated to normalize vitamin A levels and improve retinal photoreceptor function. Subjective improvement in symptoms was reported shortly after beginning supplementation, and ultimately, vitamin A levels and retinal function showed improvement after intramuscular treatment. CONCLUSIONS: Detailed case history and a careful review of systems along with serum vitamin A testing and, if available, electroretinography to assess retinal function can help to make a definitive diagnosis. With appropriate comanagement with the patient's primary care physician, it is possible for those with nyctalopia to begin vitamin A supplementation and regain retinal function.

Clinical features and risk factors of neurological involvement in Sjögren's syndrome.

BACKGROUND: To investigated distinct manifestations of Sjögren's syndrome (SS) patients with neurological complications and the potential risk factors associated with neurological complications in SS, and to produce a disease evaluation and neurological involvement prediction for SS. METHODS: 566 patients who fulfilled the 2002 classification criteria for SS from the Rheumatology Department of the First Affiliated Hospital of Wenzhou Medical University were included in the cross-sectional study. Clinical, immunological and histological characteristics were surveyed, and potential risk factors for neurological complications were examined by multivariate analysis. RESULTS: Among 566 SS patients, 184 (32.5%) patients had neurological involvement, with more than 10% got limbs pain, limbs numbness and cerebral infarction, respectively. Of these 184 SS patients with neurological complications, secondary SS (sSS) patients had a higher prevalence of peripheral nervous system (PNS) involvement than primary SS (pSS) patients (31.1 vs. 19%). And sSS patients showed higher total ESSPRI score and higher prevalence of xerostomia and low C3, C4 levels with more liver, articular involvement and saliva gland atrophy, and more severe lymphocyte infiltration in salivary glands than pSS patients. As for the specific factors associated with neurological involvement, low C3 level were found to be significant in pSS or sSS patients who were younger 50 year old, and ANA positivity, cardiac involvement, saliva gland atrophy were demonstrated to be associated in elder pSS patients. And xerophthalmia was found to be associated in sSS patients. CONCLUSION: Low complement (C3) levels, xerophthalmia, ANA positive, cardiac involvement and labial salivary gland histological result were good ways to predict neurological complications in different subgroups of SS, which might provide insight into better clinical decision-making, especially at early stages of the disease.

Microvascular abnormalities in dry eye patients.

This study was conducted to evaluate conjunctival blood flow velocities and microvascular network density in patients with dry eye disease (DED). Twenty-five patients with DED and 25 healthy controls were recruited. The microvasculature and microcirculation of the temporal bulbar conjunctiva of the right eyes were assessed using a functional slit-lamp biomicroscope. Vascular variables included blood flow velocity (BFV), blood flow rate (BFR), microvascular network density and vessel diameter. A fractal analysis was performed using the box counting method to measure the fractal dimension (Dbox) representing the vessel density. The bulbar BFV was 0.59 ±â€¯0.09 mm/s in the DED group and 0.47 ±â€¯0.12 in the control group (P < 0.001). BFR was 169.5 ±â€¯1.8 in the DED group compared to the control group (107.2 ±â€¯49.6) (P < 0.001). Dbox was higher in DED patients (1.65 ±â€¯0.04) than controls (1.60 ±â€¯0.07, P < 0.05). Moreover, the vessel diameter was larger in the DED group (21.8 ±â€¯1.8 µm) compared with controls (17.9 ±â€¯2.2 µm, P < 0.001). Dbox was positively related with ocular surface disease index (OSDI) in patients with DED (r = 0.54, P = 0.008). Microvascular alterations were found in the bulbar conjunctiva of DED patients, including increased blood flow velocity, higher vessel density and larger vessel diameter.

Pilocarpine and artificial saliva for the treatment of xerostomia and xerophthalmia in Sjögren syndrome: a double-blind randomized controlled trial.

BACKGROUND: Sjögren syndrome (SS) is associated with xerostomia and xerophthalmia. Pilocarpine has been shown to stimulate the secretion of saliva. OBJECTIVES: To investigate and compare the efficacy of pilocarpine and artificial saliva as symptomatic treatments for xerostomia and xerophthalmia in patients with SS. METHODS: A double-blind randomized controlled study was performed. A total of 72 patients with SS were assigned randomly to receive 10 drops of pilocarpine (5 mg) or 10 drops of artificial saliva orally, three times daily for 12 weeks. Whole saliva and tear flow were evaluated at baseline and periodically throughout the study to provide a global assessment of dryness and to report any adverse effects. RESULTS: Patients receiving pilocarpine had a statistically significant improvement in their salivary flow (P < 0·001), lacrimal flow (P < 0·001) and their subjective global assessment (P < 0·001), compared with patients who received artificial saliva. The most common side-effects were sialorrhoea and nausea. CONCLUSIONS: Pilocarpine is more effective than artificial saliva for enhancing salivary and lacrimal secretion in patients with SS. This is the first study to compare the efficacy of pilocarpine and artificial saliva for the treatment of xerostomia and xerophthalmia in SS.

Discrepancy between subjective symptoms, objective measures and disease activity indexes: the lesson of primary Sjögren's syndrome.

Mucosal dryness is a key clinical feature in primary Sjögren's syndrome (pSS) and its assessment relies on both objective measurement of residual secretion and subjective symptoms reported by patients. However, while the objective assessment and grading of glandular dysfunction can be easily performed, the spectrum of clinical symptoms encompassed by the terms 'dry eye' and 'dry mouth' is wide and heterogeneous. Therefore, patient reported outcomes (PROs) for dryness in pSS poorly correlate with the amount of glandular secretion. In addition, subjective dryness is not correlated with the severity of systemic disease and severely affects the patient quality of life even in presence of active extraglandular manifestations. The purpose of this review article is to provide an overview of glandular dysfunction in pSS as well as the impact of discrepancy between objective assessment, subjective symptom and extraglandular disease activity on disease management.

Proprotein convertase enzyme FURIN is upregulated in primary Sjögren's syndrome.

OBJECTIVES: The proprotein convertase enzyme FURIN is a critical regulator of the anti-inflammatory TGFß-1 cytokine and peripheral immune tolerance. In T cells, FURIN is co-regulated with IFN-γ and thus highly expressed in T helper 1 type cells. Previous studies have demonstrated that FURIN is upregulated in inflammatory conditions, including atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus. Here, we evaluated the levels of FURIN in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with primary Sjögren's syndrome (pSS) and in healthy controls. METHODS: FURIN plasma levels were determined by ELISA, and the mRNA expression in PBMCs was quantitated using qPCR. FURIN levels in the plasma were correlated with the clinical and demographic characteristics of the patients. RESULTS: FURIN was found to be significantly upregulated at both the protein and mRNA level in pSS patients compared to healthy controls. In pSS patients, high FURIN protein levels were significantly associated with elevated IFN-γ levels in the plasma as well as a longer duration of sicca symptoms in the eyes. pSS patients with high FURIN levels in their plasma showed a trend towards lower levels of serum beta-2 microglobulin, ESR and a lower systemic disease activity index ESSDAI. CONCLUSIONS: The proprotein convertase FURIN is significantly upregulated in pSS. Elevated FURIN levels associate with high levels of the Th1 type cytokine IFN-γ and long duration of dry eye symptoms. Patients with high FURIN levels show signs of lower disease activity suggesting that FURIN might have a protective role in pSS.

Epidermal Fatty Acid-Binding Protein: A Novel Marker in the Diagnosis of Dry Eye Disease in Sjögren Syndrome.

PURPOSE: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease of the lacrimal and salivary glands. This study compared the concentrations of epidermal fatty-acid binding protein (E-FABP) in the saliva, serum, and tears of SS patients with dry eye and dry mouth, with those of healthy adults to investigate the usefulness of E-FABP as a diagnostic marker for SS. DESIGN: Prospective, observational case series. PARTICIPANTS: The subjects were 11 new patients with untreated Sjogren syndrome and 12 healthy control individuals. METHODS: The diagnosis of SS was in accordance with the Ministry of Health, Labour and Welfare (Japan) Diagnostic Criteria (1999). Saliva, serum, and tear specimens were collected during internal medicine, dental, and ophthalmological examinations. The ophthalmological tests included the Dry Eye-related Quality of life Score (DEQS), tear break-up time (BUT), vital staining with fluorescein (FS) and lissamine green (LG), and the Schirmer test-1. The E-FABP concentration in the tears, saliva, and serum was measured by enzyme-linked immunosorbent assay (ELISA). MAIN OUTCOME MEASURE: The E-FABP concentrations were compared between patients and controls. RESULTS: There were significant differences between the patient and healthy control groups in all ophthalmological test results. There were no significant differences between the groups in the E-FABP concentrations in the saliva (p = 0.1513) or the serum (p = 0.4799), but the E-FABP concentration in the tears significantly differed between groups. The E-FABP concentration in tears tended to be significantly lower in patients with SS (mean, 323.5 ± 325.6 pg/mL) than healthy control subjects (mean, 4076 pg/mL; p = 0.0136). The E-FABP concentration in tears significantly correlated with the results of dry eye parameters. CONCLUSION: The E-FABP concentration in tears appears to be related to ocular surface epithelial damage and tear stability and may be a promising novel biomarker in the diagnosis of SS.

Aucuba japonica Extract and Aucubin Prevent Desiccating Stress-Induced Corneal Epithelial Cell Injury and Improve Tear Secretion in a Mouse Model of Dry Eye Disease.

Dry eye disease is affected by a broad range of causes such as age, lifestyle, environment, medication and autoimmune diseases. These causes induce tear instability that activates immune cells and promotes expression of inflammatory molecules. In this study, we investigated the therapeutic effects of an ethanolic extract of Aucuba japonica (AJE) and its bioactive compound, aucubin, on dry eye disease. The human corneal cells were exposed to desiccation stress induced by exposing cells to air, so that viability was decreased. On the other hand, pre-treatment of AJE and aucubin restored cell survival rate depending on the dose under the dry condition. This result was confirmed again by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The mRNA expression of inflammatory molecules was reduced by the pretreatment of AJE and aucubin under the dry state. The therapeutic effects of AJE and aucubin were examined in the animal model for dry eye induced by unilateral excision of the exorbital lacrimal gland. Declined tear volumes and corneal irregularity in the dry eye group were fully recovered by the administration of AJE and aucubin. The apoptotic cells on the cornea were also decreased by AJE and aucubin. Therefore, this study suggests that administration of AJE can be a novel therapeutic for dry eye disease and that the pharmacological activities of AJE may be in part due to its bioactive compound, aucubin.

A Comparison of the Effects of Benzalkonium Chloride on Ocular Surfaces between C57BL/6 and BALB/c Mice.

Models of benzalkonium chloride (BAC)-induced ocular disruption have been created and are widely used in various animals. This study aimed to compare the effects of BAC on the ocular surfaces of C57BL/6 and BALB/c mice. C57BL/6 and BALB/c mice were treated separately with BAC eye-drops at different concentrations. Eyes were evaluated by scoring epithelial disruption, corneal opacity and neovascularization in vivo, and by histological assays with hematoxylin/eosin (H/E) and periodic acid-Schiff stainings and by determining the expression of inflammatory factors in vitro on Days 7 and 14. The in vivo corneal epithelial disruption, corneal edema/opacity and neovascularization, which were in accordance with the results of the H/E staining and peaked at Day 7, were observed in a dose-dependent manner in the BAC-treated mice, with more severe signs in the C57BL/6 mice than the BALB/c mice. The loss of conjunctival goblet cells in the conjunctivas and the increasing expression of monocyte chemoattractant protein 1 (MCP-1), growth-regulated protein alpha (GROa) and macrophage inflammatory protein-1 alpha (MIP-1a) in the corneas were found in a dose-dependent manner in both strains of mice. Topical application of BAC can dramatically disrupt the ocular surfaces of C57BL/6 and BALB/c mice, and the disruptions were much more severe in the C57BL/6 mice that received high doses of BAC.