Comparison of efficacy and safety of accelerated trans-epithelial crosslinking for keratoconus patients with corneas thicker and thinner than 380µm.

PURPOSE: Accelerated trans-epithelial cross-linking (ATE-CXL), a therapy to halt keratoconus progression, has the merit of widening the indications for thinner corneas (<380 µm). Since a hypotonic solution affects the swollen cornea, corneas of <380 µm thickness at preoperative measurement can be an indication for ATE-CXL. The aim of this retrospective study was to compare the efficacy and safety of ATE-CXL for keratoconus between corneas with thicknesses <380 µm and ≥380 µm. MATERIALS AND METHODS: Thirty-four eyes of 27 patients who underwent ATE-CXL (30 mW/cm2; 3 minutes) with completion of a 24-month follow-up, were enrolled and divided into two groups: Group 1, thinnest corneal thickness (TCT), <380 µm (n = 10) and Group 2, TCT, ≥380 µm (n = 24). A hypotonic solution was administered to Group 1 until the corneal thickness increased by >380 µm before UV-A irradiation. We measured uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), maximum and average keratometric values (Kmax and AveK), central corneal thickness (CCT), TCT by anterior segment optical coherence tomography, and corneal endothelial cell density (ECD) using specular microscopy. The changes from baseline to 24 months postoperatively between the two groups were compared accordingly. RESULTS: The changes in Kmax and AveK from baseline to 24 months in Group 1 (ΔKmax: -7.8 ± 7.7 D, ΔAveK: -4.3 ± 6.1 D) showed significant decreases compared to those in Group 2 (ΔKmax: 0.2 ± 3.0 D, ΔAveK: 0.6 ± 2.7 D) (p = .004 and p = .001), and there were no significant changes from baseline to 24 months postoperatively in UCVA, BCVA, CCT, TCT, and ECD in both groups. CONCLUSION: ATE-CXL is effective and safe for keratoconic corneas in both groups. The effect of reducing keratometric values was greater in the group with thinner corneas.

Relationship between total tear and serum IgE in allergic conjunctivitis.

BACKGROUND: Recently, a new commercial test for total tear IgE based on immunochromatography (Allerwatch®) was developed. We examined the relationship between total tear and serum IgE levels with the Allerwatch test. METHODS: A nonrandomized cross-sectional study was conducted in 40 patients with allergic conjunctivitis, 35 age- and sex-matched healthy control subjects, and 6 patients with epidemic keratoconjunctivitis (EKC). The total tear IgE score was determined with the Allerwatch test (0, 1 and 2), and the serum total IgE level was measured by solid-phase immunoassay (Phadezym PRIST) in all subjects. RESULTS: Total tear IgE was assayed within 10 min of collection in all samples. The total tear IgE-positive rate was significantly higher in the allergic group than in the control and EKC groups (92.5 vs. 0.0 vs. 0.0%; p < 0.00001). Sensitivity and specificity were 0.925 and 1.000, respectively. The total IgE score and log (total serum IgE) were also higher in the allergic group than in the control and EKC groups [total IgE score: 1.48 ± 0.63 vs. 0.00 ± 0.00 vs. 0.00 ± 0.00, p < 0.00001; log (serum total IgE): 2.23 ± 0.50 vs. 0.80 ± 0.31 vs. 0.79 ± 0.37, p < 0.00001]. The total tear IgE score was significantly correlated with log (total serum IgE) in the allergic group (r = 0.712, p < 0.00001). CONCLUSIONS: These results show that this rapid test for the measurement of total tear IgE is easy to perform on an outpatient basis and may be helpful in the management of ocular allergy.

Immunochromatographic assay for measurement of total IgE in tears, nasal mucus, and saliva of patients with allergic rhinoconjunctivitis.

OBJECTIVE: Measurement of total immunoglobulin E (IgE) is clinically important for the diagnosis of allergic diseases. The total serum IgE level is normally measured because of its widespread use and convenience, but little attention has been paid to the measurement of local IgE concentrations. We evaluated whether the measurement of local production of IgE in tears, saliva, and nasal mucus was useful for the diagnosis of allergic rhinoconjunctivitis. METHODS: A prospective, nonrandomized, cross-sectional study was conducted in 33 consecutive patients with seasonal allergic rhinoconjunctivitis (allergic group) and in 30 age- and sex-matched healthy control subjects (control group). The total IgE level was measured in tears, saliva, and nasal mucus from all subjects. Using a 4- or 5-point scale, symptoms (sneezing, rhinorrhea, nasal obstruction, ocular itching, and lacrimation) were assessed in each subject along with the activities of daily living (ADL) score and total symptom score for allergic conjunctivitis. RESULTS: Total IgE could be assayed within 10 minutes of collection in all samples. The scores for all symptoms were higher in the allergic group than in the control group (p < .00001). The IgE scores for tear fluid samples (p < .00001) and undiluted saliva (p = .00003) were significantly higher in the allergic group than in the control group. The total IgE score of tear fluid samples was strongly correlated with the severity of symptoms of allergic conjunctivitis, including ocular itching (r = 0.769, p < .00001), tearing (r = 0.560, p = .00035), and ocular symptom score (r = 0.329, p = .03452). On the contrary, the total IgE scores for both saliva and nasal mucus were correlated with the severity of rhinitis-related symptoms, including sneezing (saliva r = 0.897, p < .00001; nasal mucus r = 0.871, p = .00024), nose blowing (saliva r = 0.764, p < .00001; nasal mucus r = 0.829, p = .00080), and nasal obstruction (saliva r = 0.519, p = .00099; nasal mucus r = 0.745, p = .00429). The ADL score was correlated with the total IgE level in each specimen (tear r = 0.705, p < .00001; saliva r = 0.468, p = .00301; nasal mucus r = 0.479, p = .06816). CONCLUSIONS: These results suggest that local production of IgE is closely correlated with local allergic symptoms. This rapid test for the measurement of local IgE is easy to perform on an outpatient basis and may be helpful in the diagnosis of allergic rhinitis and conjunctivitis.

Disruption of GM2/GD2 synthase gene resulted in overt expression of 9-O-acetyl GD3 irrespective of Tis21.

GM2/GD2 synthase gene knockout mice lack all complex gangliosides, which are abundantly expressed in the nervous systems of vertebrates. In turn, they have increased precursor structures GM3 and GD3, probably replacing the roles of the depleted complex gangliosides. In this study, we found that 9-O-acetyl GD3 is also highly expressed as one of the major glycosphingolipids accumulating in the nervous tissues of the mutant mice. The identity of the novel component was confirmed by neuraminidase treatment, thin layer chromatography-immunostaining, two-dimensional thin layer chromatography with base treatment, and mass spectrometry. All candidate factors reported to be possible inducer of 9-O- acetylation, such as bitamine D binding protein, acetyl CoA transporter, or O-acetyl ganglioside synthase were not up-regulated. Tis21 which had been reported to be a 9-O-acetylation inducer was partially down-regulated in the null mutants, suggesting that Tis21 is not involved in the induction of 9-O-acetyl-GD3 and that accumulated high amount of GD3 might be the main factor for the dramatic increase of 9-O-acetyl GD3. The ability to acetylate exogenously added GD3 in the normal mouse astrocytes was examined, showing that the wild-type brain might be able to synthesize very low levels of 9-O-acetyl GD3. Increased 9-O-acetyl GD3, in addition to GM3 and GD3, may play an important role in the compensation for deleted complex gangliosides in the mutant mice.

Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate.

Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient's age, which is usually not eligible for transplantation. Comprehensive analysis of CMML pathophysiology and the development of therapeutic agents have been limited partly due to the lack of cell lines in CMML and the limited developments of mouse models. After successfully establishing patient's derived disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with CMML, we utilized these CMML-iPSCs to achieve hematopoietic re-differentiation in vitro, created a humanized CMML mouse model via teratomas, and developed a drug-testing system. The clinical characteristics of CMML were recapitulated following hematopoietic re-differentiation in vitro and a humanized CMML mouse model in vivo. The drug-testing system using CMML-iPSCs identified a MEK inhibitor, a Ras inhibitor, and liposomal clodronate as potential drugs for treating CMML. Clodronate is a drug commonly used as a bisphosphonate for osteoporosis. In this study, the liposomalization of clodronate enhanced its effectiveness in these assays, suggesting that this variation of clodronate may be adopted as a repositioned drug for CMML therapy.

Accelerated transepithelial corneal cross-linking for progressive keratoconus: a prospective study of 12†months.

BACKGROUND/AIMS: To evaluate the clinical results of accelerated transepithelial corneal cross-linking (CXL) in Japanese patients with progressive keratoconus (KCN). METHODS: Thirty eyes of 19 patients (16 male, 3 female patients) with progressive KCN were included. The mean age was 24.9±7.0 (range 16-38) years. All patients received ultraviolet A radiation for 3 min at an irradiance of 30 mW/cm2. Patients were followed up on the first day, at 1 week and 2 weeks, and at 1 month, 3 months, 6 months and 12 months postoperatively. Clinical examinations included measures of uncorrected visual acuity, best corrected visual acuity (BCVA), average keratometry (AveK), maximum keratometry (Kmax), central corneal thickness, thinnest corneal thickness (TCT), endothelial cell density, intraocular pressure and non-mydriatic indirect fundus examination. Patients were asked to report any pain or discomfort at each visit. RESULTS: There were no intraoperative or postoperative complications. All 30 eyes finished the follow-up. After 12 months, there was a significant decrease in Kmax (p<0.0001), AveK (p=0.003) and TCT (p=0.002), and a significant improvement in BCVA (p=0.001). There were no other significant changes. Pain or foreign-body sensation following CXL appeared in the first 2 days, but lasted no more than 1 week in all cases. CONCLUSIONS: There were no complications associated with accelerated transepithelial corneal CXL, and the clinical outcomes were appraisable in a 12-month follow-up. TRIAL REGISTRATION NUMBER: UMIN000009372.

Biosignals modulated by tumor-associated carbohydrate antigens: novel targets for cancer therapy.

Based on the remodeling of glycosphingolipids on the human tumor cell lines with manipulation of glycosyltransferase genes, roles of sugar moieties in tumor-associated carbohydrate antigens have been analyzed. Two main topics, that is, the roles of ganglioside GD3 in human malignant melanomas and those of GD2 in small cell lung cancer (SCLC) were reported. GD3 enhances tyrosine phosphorylation of two adaptor molecules, p130Cas and paxillin, resulting in the increased cell growth and invasion in melanoma cells. GD2 also enhances the proliferation and invasion of SCLC cells. GD2 also mediates apoptosis with anti-GD2 monoclonal antibodies (mAbs) via dephosphorylation of the focal adhesion kinase. These approaches have promoted further understanding of mechanisms by which gangliosides modulate malignant properties of human cancer, and the results obtained here propose novel targets for cancer therapy.

Relation between total tear IgE and specific serum IgE in seasonal allergic conjunctivitis.

PURPOSE: Recently, a new commercial test for total tear immunoglobulin E (IgE), based on immunochromatography (Allerwatch), was developed. We examined the relation between the total IgE level in tears and specific serum IgE. METHODS: A prospective, nonrandomized, cross-sectional study was conducted in 35 patients with allergic conjunctivitis (allergic group), 30 age- and sex-matched healthy control subjects (control group), and 8 patients with epidemic keratoconjunctivitis. In all subjects, the total tear IgE score was determined with the Allerwatch test (0, 1, and 2), and serum levels of total IgE and specific IgE for 12 inhaled allergens were measured with the Phadezym PRIST and CAP-RAST systems, respectively. RESULTS: The total tear IgE-positive rate was significantly higher in the allergic group than in the control and epidemic keratoconjunctivitis groups (100.0% vs. 0.0% vs. 0.0%; P < 0.00001). In the allergic group, the total tear IgE score was significantly correlated with the log-transformed total serum IgE level (r = 0.61) and with the serum levels of IgE for cedar pollen (r = 0.35), house dust (r = 0.46), Dermatophagoides pteronyssinus (r = 0.49), and acarus (r = 0.36). Multivariate logistic regression analysis showed that the log-transformed total serum IgE level was the only significant predictor of the total tear IgE score (odds ratio = 1.85, P = 0.00008). CONCLUSIONS: The total tear IgE score, determined with the Allerwatch test, was correlated with the total and specific serum IgE levels. This rapid test is easy to perform, sensitive, and highly specific for the detection of ocular allergy on an outpatient basis.

Mechanisms for the apoptosis of small cell lung cancer cells induced by anti-GD2 monoclonal antibodies: roles of anoikis.

Anti-GD2 ganglioside antibodies could be a promising, novel therapeutic approach to the eradication of human small cell lung cancers, as anti-GD2 monoclonal antibodies (mAbs) induced apoptosis of small cell lung cancer cells in culture. In this study, we analyzed the mechanisms for the apoptosis of these cells by anti-GD2 mAbs and elucidated the mechanisms by which apoptosis signals were transduced via reduction in the phosphorylation levels of focal adhesion kinase (FAK) and the activation of a MAPK family member, p38, upon the antibody binding. Knock down of FAK resulted in apoptosis and p38 activation. The inhibition of p38 activity blocked antibody-induced apoptosis, indicating that p38 is involved in this process. Immunoprecipitation-immunoblotting analysis of immune precipitates with anti-FAK or anti-integrin antibodies using an anti-GD2 mAb revealed that GD2 could be precipitated with integrin and/or FAK. These results suggested that GD2, integrin, and FAK form a huge molecular complex across the plasma membrane. Taken together with the fact that GD2+ cells showed marked detachment from the plate during apoptosis, GD2+ small cell lung cancer cells seemed to undergo anoikis through the conformational changes of integrin molecules and subsequent FAK dephosphorylation.