平野 耕治

Purpose: To classify secondary corneal amyloidosis (SCA) by its clinical appearance, to analyze the demographics of the patients, and to determine the involvement of lactoferrin. Design: Retrospective, observational, noncomparative, multicenter study. Participants: Twenty-nine eyes of 29 patients diagnosed with SCA by corneal specialists at 9 ophthalmologic institutions in Japan were studied. Methods: The clinical appearance of SCA was determined by slit-lamp biomicroscopy and was classified into 3 types. The demographics of the patients, for example, age, gender, and the duration of the basic disease (trichiasis, keratoconus, and unknown), were determined for each clinical type. Surgically excised tissues were stained with Congo red and antilactoferrin antibody. The postoperative prognosis also was determined. Main Outcome Measures: Clinical appearance of the 3 types of SCA, along with the gender, age, and duration of the basic diseases were determined. Results: Classification of SCA into 3 types based on clinical appearance found 21 cases with gelatinous drop-like dystrophy (GDLD)-like appearance (GDLD type), 3 cases with lattice corneal dystrophy (LCD)-like appearance (LCD type), and 5 cases with the combined type. Patients with the GDLD type were younger (average age: 40.9 years for the GDLD type, 74.3 years for the LCD type, and 46.8 years for the combined type), predominantly women (85.7% for the GDLD type, 33.3% for the LCD type, and 60% for the combined type), and had the basic disease over a longer time (average duration: 22.1 years for the GDLD type, 14.0 for the LCD type, and 11.4 for the combined type). The distribution of the basic diseases (trichiasis vs. keratoconus vs. unknown) was not significantly different for each type. Surgical treatments, for example, phototherapeutic keratectomy, lamellar keratoplasty, and simple keratectomy, resulted in a good resolution in all surgically treated cases. One subject dropped out of the study. Spontaneous resolution was seen in one subject after epilation of the cilia. Amorphous materials in the excised tissues showed positive staining results by Congo red and by antilactoferrin antibody. Conclusions: Secondary corneal amyloidosis can be classified into 3 clinical types based on its clinical appearance. Larger numbers of females and lactoferrin expression were seen in all 3 types. (C) 2013 by the American Academy of Ophthalmology.

Objective: To investigate the dose-dependent efficacy and safety of diquafosol ophthalmic solution for the treatment of dry eye syndrome. Design: Randomized, double-masked, multicenter, parallel-group, placebo-controlled trial. Participants: A total of 286 Japanese patients with dry eye who were prescribed topical diquafosol (1%, n = 96; 3%, n = 96) or placebo ophthalmic solution (n = 94). Methods: After a washout period of 2 weeks, qualified subjects were randomized to receive a single drop of 1% or 3% diquafosol or placebo ophthalmic solutions 6 times per day for 6 weeks. Main Outcome Measures: The primary outcome measure was fluorescein corneal staining score assessment. The secondary outcome measures were Rose Bengal corneal and conjunctival staining scores, tear break-up time (BUT), and subjective symptom assessment. Safety measures were clinical blood and urine examination and recording of adverse events. Results: Fluorescein corneal staining scores significantly improved with both 1% and 3% topical diquafosol compared with placebo at 4 weeks, respectively (P = 0.037, P = 0.002). There was a dose-dependent effect among the groups. Rose Bengal corneal and conjunctival staining scores also improved significantly with both 1% and 3% diquafosol compared with placebo (P = 0.007 and P = 0.004, respectively). Subjective dry eye symptom scores significantly improved with both diquafosol ophthalmic solutions (P < 0.033), although there were no significant differences in BUT compared with placebo. No significant differences between the treatment groups were observed in relation to the occurrence of adverse events. Conclusions: Both 1% and 3% diquafosol ophthalmic solutions are considered effective and safe for the treatment of dry eye syndrome. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012;119:1954-1960 (C) 2012 by the American Academy of Ophthalmology.

Aims To compare the efficacy and safety of 3% diquafosol ophthalmic solution with those of 0.1% sodium hyaluronate ophthalmic solution in dry eye patients, using mean changes in fluorescein and rose bengal staining scores as endpoints. Trial design and methods In this multicenter, randomised, double-masked, parallel study of 286 dry eye patients with fluorescein and rose bengal staining scores of >= 3 were randomised to the treatment groups in a 1:1 ratio. Efficacy and safety were evaluated after drop-wise instillation of the study drug, six times daily for 4 weeks. Results After 4 weeks, the intergroup difference in the mean change from baseline in fluorescein staining score was -0.03; this verified the non-inferiority of diquafosol. The mean change from baseline in rose bengal staining score was significantly lower in the diquafosol group (p=0.010), thus verifying its superiority. The incidence of adverse events was 26.4% and 18.9% in the diquafosol and sodium hyaluronate groups, respectively, with no significant difference. Conclusions Diquafosol (3%) and sodium hyaluronate (0.1%) exhibit similar efficacy in improving fluorescein staining scores of dry eye patients, whereas, diquafosol exhibits superior efficacy in improving rose bengal staining scores. Diquafosol has high clinical efficacy and is well tolerated with a good safety profile.

Stem/progenitor cells of the human corneal epithelium are present in the human corneal limbus, and several corneal epithelial stem/progenitor cell markers have been reported. Recently, the neurotrophin family receptors were reported to be useful markers of corneal epithelial stem/progenitor cells. Therefore, we examined an enzymatic separation method for obtaining corneal epithelial stem/progenitor cells and measuring the change in the expression of low-affinity neurotrophin receptor p75 (p75(NTR)), a receptor belonging to the neurotrophin family. As a result, it was found that our separation method preserved cell viability. Furthermore, p75(NTR) was mainly observed in epithelial basal cells as were the corneal epithelial stem/progenitor markers p63 and integrin beta 1. p75(NTR) was also observed in the cultured cells, but its frequency decreased with passage. In conclusion, we propose that our culture method will enable the culture of corneal stem cells and that it is a useful tool for elucidating the molecular basis of the niche that is necessary for the maintenance of epithelial stem cells in the corneal limbus. Furthermore, we conclude that p75(NTR) is a useful cell marker for evaluating the characteristics of stem/progenitor cells in culture.

This article reviews our data on secondary localized corneal amyloidosis after chronic ocular inflammation including trichiasis and keratoconus. Previous findings have suggested that lactoferrin is a precursor protein in secondary corneal amyloidosis. The clinical finding that amyloidosis is frequently observed in female patients also supports a role for lactoferrin as a precursor protein. However, among the whole population with chronic corneal inflammation, the incidence of secondary amyloidosis is low. In this regard, we have identified a genetic polymorphism (Glu561Asp) on the lactoferrin gene in secondary amyloidosis associated with trichiasis. Structural changes may destabilize the local hydrophobic cluster, resulting in exposure of the amyloidogenic region and amyloid fibril formation. On the other hand, this polymorphism was not detected in secondary amyloidosis associated with keratoconus. A different mechanism such as enzymatic digestion might contribute to lactoferrin aggregation. We histochemically analyzed 13 keratoconus specimens obtained at keratoplasty and found lactoferrin protein at corneal epithelial basal cells before amyloid deposition in 3 cases. In some other cases, amyloid was present coincidentally with lactoferrin deposits between basal cells and Bowman membrane. These results suggest that lactoferrin is derived from corneal basal cells. By immunostaining and reverse transcription-polymerase chain reaction, we have shown that human corneal epithelial cells are a putative source of lactoferrin.

細隙灯顕微鏡検査でアミロイド沈着が疑われ、続発性角膜アミロイドーシスと診断された6施設20例(男4例・女16例・平均44.5歳)の臨床像をまとめた。全例片眼性で、基礎疾患は睫毛乱生12例(A群)、円錐角膜5例(B群)、不明3例(C群)、罹病期間1〜35年であった。細隙灯顕微鏡で膠様滴状を示す隆起型が15例、線状の格子状型が5例で、格子状型3例は隆起型病変を合併していた。病変の部位は、A群では全例睫毛との接触部位、角膜下方に位置していた。B群では全例コンタクトレンズを使用しており、4例はその接触部位である中央部に病変を認めた。残り1例は円錐角膜に対する全層角膜移植術後で、角膜下方に病変を認めた。C群の病変は中央部に位置していた。9例には表層角膜切除を行い、術後平均39.6ヵ月で6例に上皮の再生と表面の平坦化を認め、2例は再発し、1例は不明である。切除組織の病理所見ではエオジン好性の無構造な沈着物を認め、コンゴ赤染色で橙赤色に染まった。