Bilberry extract supplementation for preventing eye fatigue in video display terminal workers.

OBJECTIVES: To examine the effect of a dietary supplement containing bilberry extract (BE) on eye fatigue induced by acute video display terminal (VDT) loads. DESIGN AND SETTING: A prospective, randomized, double-blind, placebo-controlled study was performed from August 2012 to February 2013 in the Medical Corporation Jico-kai Yagi Hospital, and the Shinyokohama Shinoharaguchi Orthopedic Surgery and Dermatology Clinic, in Japan. PARTICIPANTS: Two hundred eighty-one office workers aged 20-40 years that used VDTs were screened by critical flicker fusion (CFF) and near point accommodation (NPA). INTERVENTION: The participants were randomized to either a BE (480 mg/day) or placebo (vehicle) group, and took allocated capsule, daily, for 8 weeks. MEASUREMENTS: The CFF, NPA, contrast visual acuity, functional visual acuity, keratoconjunctival epithelial damage, and fluorescein tear film break-up time were examined, and 18 subjective symptoms of eye fatigue were evaluated by questionnaire. Adverse events were reported via medical interviews. Data were collected both before and after VDT load at baseline, and 4, and 8 weeks after daily supplementation with either BE or placebo. RESULTS: Of 281 participants screened, 88 having relatively lower levels of CFF and NPA were enrolled in the study. Of these, 37 control and 43 BE group subjects completed the study. The VDT load-induced reduction in CFF was alleviated after 8 weeks of BE supplementation (95% confidence interval, 0.10-1.60; p=0.023), in contrast to placebo supplementation, while NPA variation was not. Of the subjective symptoms of eye fatigue, VDT load-induced ocular fatigue sensation, ocular pain, eye heaviness, uncomfortable sensation, and foreign body sensation were mitigated more in the BE group than in the control group, at week 8 (p<0.05). There were no severe adverse events in either group. CONCLUSIONS: BE supplementation improved some of the objective and subjective parameters of eye fatigue induced by VDT loads.

Surgical management of lacrimal punctal cauterization in chronic GVHD-related dry eye with recurrent punctal plug extrusion.

We investigated the efficacy of lacrimal punctal occlusion surgery with a cautery device in patients with chronic GVHD (cGVHD)-related dry eye, with recanalization of puncta and recurrent punctal plug extrusion. A total of 23 puncta from 14 eyes of 10 patients with chronic GVHD (cGVHD)-related dry eye underwent punctual thermal cauterization with a high-temperature disposable cautery device. All patients were refractory to conventional treatment, including artificial tear eye drops, autologous serum eye drops and vitamin A eye drops, and had a history of recanalization and recurrent punctal plug extrusion. The effect of lacrimal punctal cauterization by thermal cautery device was evaluated by changes in subjective symptom scores, corrected distance visual acuity, Schirmer's test values, fluorescein staining scores, rose bengal staining scores, and tear-film break-up time before and 3 months after the surgery. Subjective symptom scores, Schirmer's test values, fluorescein and rose bengal scores, and tear-film break-up time improved significantly 3 months after the surgery. Recanalization of puncta was not observed in all the cases (0 of 14 eyes, 0%). Lacrimal punctal cauterization was effective with no recanalization and significant improvements in subjective symptoms and the ocular surface environment in cGVHD-related dry eye patients who had been refractory to conventional treatments.

Mucosal microvilli in dry eye patients with chronic GVHD.

The ocular surface is a frequent target tissue of mucosal chronic GVHD (cGVHD). We investigated the histopathological features of the conjunctival microvilli in patients with cGVHD. Conjunctival tissue specimens from patients with cGVHD or Sjögren's syndrome (SS) or from healthy individuals were examined by light microscopy and EM, impression cytology, and immunohistochemistry. The cGVHD conjunctivae showed significantly more metaplasia and fewer goblet cells than the SS and normal conjunctivae. Abundant CD8(+) T cells infiltrated the basal epithelia in the cGVHD conjunctiva. The microvilli per standard epithelial unit and the secretory vesicles were counted by analyzing electron micrographs. The mean number of mucosal microvilli was significantly lower in the cGVHD than that in the SS or normal specimens, and the microvilli were significantly shorter, with a smaller height-width ratio. The mean number of secretory vesicles was also significantly lower, and the membrane-spanning mucin thinner, in the cGVHD compared with the SS and normal specimens. Thus, the conjunctival mucosal microvilli of cGVHD patients were significantly different in number and morphology from those of SS and normal subjects. These may be important factors affecting the stability of the tear-film layer and its contribution to cGVHD-related dry eye.

Donor-recipient gender difference affects severity of dry eye after hematopoietic stem cell transplantation.

PURPOSE: To determine whether the incidence rate and severity of dry eye after hematopoietic stem cell transplantation varies with donor vs recipient gender. METHODS: We limited this study to patients received bone marrow transplantation (BMT). In all, 172 patients received BMT at Keio University School of Medicine between January 2000 and May 2007. Of them, 136 recipients who survived at least 70 days were studied prospectively. We classified the 136 patients according to the gender of the donor and the recipient (group I: female to female; group II: male to male; group III: male to female; group IV: female to male). The incidence and severity of chronic graft-vs-host disease-associated dry eye were determined for each group. The donor gender was masked when we assessed dry eye and calculate the incidence. RESULTS: The incidence of dry eye was 47.4% for group I, 37.5% for group II, 58.6% for group III, and 42.9% for group IV. The percentage of patients with severe dry eye was 44.4, 50.0, 35.3, and 77.8% respectively. There was a significant difference between the percent severe dry eye/total dry eye incidences in groups III and IV (P=0.0375) (odds ratio, 7.6; 95% confidence interval, 1.00-101.01). CONCLUSIONS: Close attention must be paid to the development of dry eye in cases of female to male BMTs, because the ratio of severe/total dry eye is more common in cases of female to male BMTs than in other gender combination.

Baseline profiles of ocular surface and tear dynamics after allogeneic hematopoietic stem cell transplantation in patients with or without chronic GVHD-related dry eye.

We evaluated ocular surface alterations in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with or without chronic GVHD-related dry eye in a prospective study. Fifty eyes of 25 post-HSCT patients and 28 eyes of 14 age-matched healthy controls were included. Meibomian gland (MG) obstruction, tear evaporation rate, corneal sensitivity (CS), Schirmer test-I, tear break-up time (BUT) and ocular surface vital staining were examined. Conjunctival impression and brush cytology specimens were collected to evaluate the goblet cell density (GCD) and the inflammatory cell numbers. Obvious MG obstruction, decreased CS and enhanced tear evaporation rate were found in post-HSCT patients compared with normal controls. In addition, decreased conjunctival GCD, increased conjunctival squamous metaplasia and inflammatory cells were noted in cGVHD-related dry eyes compared with normal controls and post-HSCT without dry eye subjects. Furthermore, the conjunctival inflammatory cells were significantly higher in severe dry eyes compared with mild dry eyes (P=0.03). We found comprehensive ocular surface alteration in post-HSCT patients, regardless of whether they had cGVHD-related dry eye or not. The results suggest that the extent of inflammatory process seems to have a pivotal role in the outcome of the cGVHD-related dry eye.

Topical tranilast for treatment of the early stage of mild dry eye associated with chronic GVHD.

Fibrosis and excessive extracellular matrix production are characteristic features of lacrimal gland chronic GVHD (cGVHD). Tranilast (n-[3,4-anthoranilic acid]), used for fibrotic skin disease, inhibits transforming growth factor-beta-induced matrix production. We conducted a non-randomized study comparing 8 patients (five men, three women; median age, 47 years) given topical tranilast with 10 patients (three men, seven women; median age, 37 years) receiving therapy with topical artificial tears, sodium hyaluronate and vitamin A for mild ocular cGVHD. The tranilast group instilled topical tranilast and artificial tears q.i.d., beginning the day of dry eye diagnosis. The ocular surface and tear dynamics of each patient were evaluated before hematopoietic stem cell transplant, at the onset of dry eye and after 3 months of treatment. At 3 months, the scores of the Rose Bengal test and Schirmer test with nasal stimulation had significantly improved in the tranilast group compared with that in the control group (P<0.05). Furthermore, although five control patients (50%) developed severe dry eye within the treatment period, only one tranilast-treated patient (12.5%) did; the rest still had mild dry eye (P<0.05). These results suggest the hypothesis that topical tranilast may effectively retard the progression of mild dry eye associated with cGVHD.

Tear function and lipid layer alterations in dry eye patients with chronic graft-vs-host disease.

PURPOSE: To investigate the changes in the tear film lipid layer in haematopoietic stem cell transplantation (HSCT) patients with dry eye (DE) associated with chronic graft-vs-host disease (cGVHD) and compare with HSCT recipients without DE. METHODS: We performed a prospective study in 10 HSCT patients with DE associated with cGVHD and 11 HSCT recipients without DE. We performed Schirmer's test, tear film break up time examinations, ocular surface dye staining and meibum expressibility test and DR-1 tear film lipid layer interferometry. DR-1 interferometry images of the tear film surface were assigned a 'DR-1 grade' according to the Yokoi severity grading system. The DR-1 grades were analysed according to the presence or absence of DE, conjunctival fibrosis and systemic cGVHD. RESULTS: The mean DR-1 severity grade in patients with DE related to cGVHD (DE/cGVHD group; 3.9+/-0.9) was significantly higher than in patients without DE after HSCT (non-DE/non-cGVHD group; 1.3+/-0.6; P<0.05). The DR-1 grade for HSCT recipients with conjunctival fibrosis was significantly higher than in patients without conjunctival fibrosis (P<0.05). When DE severity was graded according to the recommendation of the 2007 Dry Eye Workshop Report, our results showed a correlation between the severity of DE and DR-1 grades (r=0.8812, P<0.0001). CONCLUSION: DR-1 interferometry may be applicable to diagnosing DE and evaluating its progression subsequent to HSCT.

Measurement of fornix depth and area: a novel method of determining the severity of fornix shortening.

PURPOSE: To measure the depth and area of the fornix in normal adults and patients with symblepharon. METHODS: The fornix depth of normal eyes (n=20) and patients with symblepharon (Stevens-Johnson syndrome, n=4) was measured at six locations in each eye using non-invasive, dull-edged stainless steel metric scale. Before and after conjunctival reconstruction surgery, the depths of fornix were also measured by the same method. The overall area was assessed from those fornix depth at six points. RESULTS: The mean depths of the superior nasal and temporal, inferior nasal and temporal, fornices as well as mean depths of medial nasal and temporal canthi fornices in normal eyes were 14.1+/-2.5, 14.1+/-2.5, 10.0+/-2.1, 10.4+/-1.8, 3.0+/-0.9, and 5.2+/-1.2 mm, respectively. The mean overall area of the conjunctival fornix in normal subjects was 909.6+/-162.2 mm(2). All these parameters were significantly lower in the eyes of patients. Both depth and area after surgery were significantly deeper and larger than before. CONCLUSIONS: This estimation may prove useful when evaluating the severity of symblepharon and determining the post-surgical prognosis.

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders.

BACKGROUND: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. OBJECTIVE: To determine the differences between IgG(4)-related disorders including MD and SS. METHODS: A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. RESULTS: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement. CONCLUSION: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.

Reduced efficacy of topical corticosteroid in preventing cytarabine-induced kerato-conjunctivitis in patients receiving high-dose cytarabine and total body irradiation for allogeneic hematopoietic stem cell transplantation.

This study aimed to retrospectively evaluate the incidence of kerato-conjunctivitis in patients receiving TBI followed by high-dose cytarabine, and to clarify how effectively topical corticosteroid eye drops prevent kerato-conjunctivitis in these patients. Fifty-three patients who received cytarabine at a dose of 3 g/m2 every 12 h for 4 days after receiving TBI (12 Gy) as a conditioning for allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated. For the prophylaxis of kerato-conjunctivitis, all patients received betamethasone sodium phosphate eye drops every 6 h, starting 1 day before the first dose of cytarabine and continuing until 1 day after the last dose of cytarabine or the complete resolution of ocular symptoms. For grading of kerato-conjuncitivitis, the National Cancer Institute-Common Toxicity Criteria were used. Among the 53 patients, the grades of kerato-conjunctivitis were grade 0 in 13 patients, grade 1 in 6 patients (11.3%), grade 2 in 10 patients (18.9%) and grade 3 in 25 patients (47.2%). These results strongly suggest that topical corticosteroid eye drops could not effectively prevent the development of cytarabine-induced kerato-conjunctivitis in HSCT recipients who receive high-dose cytarabine following TBI. Further investigation into a more effective prophylaxis for cytarabine-induced kerato-conjunctivitis in this setting is required.

Alterations of the tear film and ocular surface health in chronic smokers.

OBJECTIVE: To investigate the effects of chronic smoking on ocular surface and tear functions. METHODS: Fifteen right eyes of 15 healthy chronic smokers (9 men, 6 women; age range: 36-47 years) who smoked 20 cigarettes per day for 20 years and 20 eyes of 20 control non-smokers (12 men, 8 women; age range: 38-43 years) were included in this prospective study. All subjects underwent measurements of breath and haemoglobin CO concentration, tear lipid layer interferometry, evaporimetry, tear film break-up time (TBUT), Schirmer's I test, corneal fluorescein staining, conjunctival impression, and brush cytology. RESULTS: The mean Hb CO level was significantly higher in smokers compared to non-smokers. TBUT was also significantly shorter in smokers. Tear lipid layer showed significant slowing in spread over the tear film with a concomitant significant increase in tear evaporation rate. Conjunctival impression cytology revealed significant loss of goblet cells and squamous metaplasia in smokers. Brush cytology showed significant conjunctival neutrophil infiltration in smoker subjects. CONCLUSION: Chronic smoking induced distinctive quantitative and qualitative disturbances on the ocular surface health.

Ocular surface and tear functions after topical cyclosporine treatment in dry eye patients with chronic graft-versus-host disease.

We investigated the effect of 0.05% topical cyclosporine (Cys) on the ocular surface and tear functions in dry eye patients with chronic GVHD (cGVHD) in a prospective comparative study. Thirty eyes of 15 patients refractory to baseline treatment were recruited and the patients assigned for topical Cys treatment group (14 eyes of 7 patients) and control group (12 eyes of 6 patients) respectively. Two patients dropped out because of intolerable irritation while using topical Cys eye drops. Visual analog scale symptom scores, corneal sensitivity, Schirmer I test value, tear film break-up time (TBUT), tear evaporation rate and ocular surface vital staining scores were recorded at baseline and at the end of the following one month. Conjunctival impression and brush cytology were performed before and after the treatment. After topical Cys treatment, significant improvements were found in symptom scores, corneal sensitivity, tear evaporation rate, TBUT, vital staining scores, goblet cells density, conjunctival squamous metaplasia grade, inflammatory cell numbers and the MUC5AC expression. Our study suggests that 0.05% topical Cys may be an effective treatment for dry eye patients with cGVHD. The improvements in the ocular surface and tear functions resulted presumably from the decreased inflammation, increased goblet cell density and MUC5AC mRNA expression. Bone Marrow Transplantation (2008) 41, 293-302; doi:10.1038/sj.bmt.1705900; published online 5 November 2007.

The differences of tear function and ocular surface findings in patients with atopic keratoconjunctivitis and vernal keratoconjunctivitis.

BACKGROUND: The pathogenesis of the ocular surface disease in atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC) has not been fully understood. We tried to clarify the differences in the ocular surface status in patients with AKC, VKC, and healthy control subjects. METHODS: Twenty-four eyes of 12 AKC patients, 12 eyes of six VKC patients, and 20 eyes of 10 normal control subjects were studied. The subjects underwent corneal sensitivity measurements, Schirmer test, tear film break-up time (BUT), vital staining of the ocular surface, conjunctival impression and brush cytology. Impression cytology samples underwent periodic acid Schiff staining for goblet cell density, squamous metaplasia grading, and immunohistochemical staining for MUC1, 2, 4, and 5AC. Brush cytology specimens underwent staining for inflammatory cell counting and Real Time PCR for MUC1, 2, 4, and 5AC mRNA expression. RESULTS: The mean BUT, corneal sensitivity, and conjunctival goblet cell density values in AKC patients were significantly lower compared with VKC patients and control subjects. The squamous metaplasia grades in eyes with AKC were significantly higher compared to eyes with VKC and controls. The inflammatory cell response in brush cytology specimens was different between patients with AKC and VKC. Eyes with AKC showed significantly higher MUC1, 2 and 4 and lower MUC5AC mRNA expression compared to eyes with VKC. CONCLUSIONS: Differences of the infiltrates, higher level of tear instability, lower corneal sensitivity, up-regulation of MUC1, 2, and 4, and down regulation of MUC5AC were important differential features of the ocular surface disease in AKC compared with VKC.

Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice.

Regulation of the adhesion of mononuclear cells to endothelial cells is considered to be a critical step for the treatment of inflammatory diseases, including autoimmune diseases. K-13182 was identified as a novel inhibitor for these adhesions. K-13182 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) on human umbilical vein endothelial cells (HUVECs) and on mouse vascular endothelial cell line (MAECs) induced by tumour necrosis factor (TNF)-alpha. K-13182 also inhibited the adhesion of mononuclear cells to these HUVECs and MAECs, indicating that K-13182 suppressed these adhesions mediated by cellular adhesion molecules including VCAM-1. To evaluate the therapeutic effect in autoimmune disease model mice, K-13182 was orally administered to non-obese diabetic (NOD) mice as Sjögren's syndrome (SS) model mice. Severe destructive inflammatory lesions were observed in the lacrimal glands of vehicle-treated control mice; however, 8-week administration of K-13182 inhibited the mononuclear cell infiltration into the inflammatory lesions of the lacrimal glands. In K-13182-treated mice, the decrease in tear secretion was also prevented compared to the control mice. In addition, the apoptosis and the expression of FasL (CD178), perforin, and granzyme A was suppressed in the lacrimal glands of K-13182-treated mice. Therefore, K-13182 demonstrated the possibility of therapeutic efficacy for the inflammatory region of autoimmune disease model mice. These data reveal that VCAM-1 is a promising target molecule for the treatment of autoimmune diseases as a therapeutic strategy and that K-13182 has the potential as a new anti-inflammatory drug for SS.

Foregut cyst of the oesophageal wall in a cynomolgus monkey (Macaca fascicularis).

Congenital oesophageal cysts of foregut origin are rare in animals and human beings. This report describes a case in a 4-year-old cynomolgus monkey with no clinical symptoms. The cyst, which was located within the oesophageal submucosal tissue near the mid-point of the oesophagus, was lined with pseudostratified ciliated epithelium and had a thin layer of submucosal tissue. The cyst was surrounded by a smooth muscle layer which was partly intermingled with the circular muscle layer of the oesophagus. The muscularis mucosae of the oesophagus was not shared with the cyst wall. Simple tubular glands were present, opening into the cyst lumen. No communication between the cyst lumen and the oesophagus was observed. Cartilaginous tissue, which is a diagnostic feature of bronchogenic cysts, was not identified in the cyst wall. On the basis of the histopathological features, a foregut cyst of the oesophagus was diagnosed.

Microkeratome assisted deep lamellar keratoprosthesis.

AIMS: To establish a keratoprosthesis (Kpro) surgical technique that maintains an intact superficial corneal layer. METHODS: A manual microkeratome (Moria LSK-1) was used to create a 130 mum flap of approximately 10 mm diameter in the right eye of Japanese white rabbits. The stoma beneath the flap area was dissected before the removal of a 5.0 mm stromal disc. A 5.0 mm collagen I immobilised poly(vinyl alcohol) (COL-PVA) disc was placed on the exposed posterior stroma close to Descemet's membrane. The flap was repositioned and fixed using 10-0 nylon sutures, which were removed 2 days following surgery. The corneas were followed clinically by slit lamp microscopy and photographs. Rabbits were sacrificed after 6 months, and the transplanted corneas were examined histologically by haematoxylin and eosin staining and immunohistochemistry against vimentin and alpha-smooth muscle actin (alpha-SMA). RESULTS: The transplanted COL-PVA discs remained transparent throughout the study, with no complications related to the flap or overlying epithelium. The interface between COL-PVA and Descemet's membrane remained clear without signs of opacification caused by scarring or cellular deposition. Pathology revealed the intact COL-PVA polymer in the posterior stroma, with minimal cellular infiltration along the anterior and posterior interfaces. Immunohistology shows vimentin and alpha-SMA staining at levels comparable to lamellar keratoplasty control. CONCLUSIONS: Microkeratome assisted deep lamellar keratoprosthesis may be a safe technique for the transplantation of artificial hydrogels for therapeutic purposes.

Elucidation of apoptosis induced by serum deprivation in cultured conjunctival epithelial cells.

BACKGROUND/AIMS: The conjunctival epithelial cell line, CCL20.2 (CCL), requires the presence of 10% fetal calf serum (FCS) in the medium to survive. To elucidate the molecular mechanism underlying such cell death, including the death signal for these cells, the activities of several caspases in the CCL were measured, and the effects of caspase inhibitors and serum components on cell death were examined. METHODS: CCL was grown in Medium 199 containing 10% FCS, and the medium was changed to Medium 199 with or without 10% FCS, or medium without 10% FCS but containing caspase inhibitors or serum components. After 24 hours' incubation, the enzyme activities of caspases 1, 3, 8, and 9 in the culture supernatants were measured, and the effects of caspase inhibitors and serum components-for example, growth factors, lactoferrin, retinoic acid, were investigated. RESULTS: DNA fragmentation was induced by serum deprivation, confirming that serum deprivation induces apoptosis in CCL. While the activities of caspases 3 and 8 were found to be increased, those of caspases 1 and 9 were not detected in the apoptotic cells. Z-VAD completely suppressed the caspase 3 activation, and specific inhibitors of caspases 1, 8, and 9 partially suppressed the activation. Serum deprivation induced a decrease in the cellular viability, which, however, partially recovered in the presence of caspase inhibitors, epidermal growth factor and retinoic acid. CONCLUSION: These results suggest that the apoptosis induced by serum deprivation involves caspases 1, 3, 8, and 9, and is suppressed by caspase inhibitors. EGF and retinoic acid have a key role in the maintenance of the ocular surface.

Preliminary repair of eyelids for the treatment of opaque corneas caused by burns.

The treatment of opaque cornea as a result of a burn is challenging, because the cornea often re-opacifies even after transplantation. One of the main risk factors is the deformity of the eyelids, and we have developed a new treatment for this. Preliminary repair of the lower eyelid is done by an auricular composite graft before transplantation, so that the grafted materials can be safely protected by the eyelids. The results of treatment since have greatly improved. Preliminary repair of the eyelid is an effective way to secure successful transplantation.