Evaluation of objective and subjective binocular ocular refraction with looking in type.

BACKGROUND: This study aimed to compare the results of the Chronos binocular/monocular refraction system, that measures objective and subjective ocular refraction in one unit, to objective findings obtained from a conventional autorefractometer and a conventional subjective ocular refraction using a trial-frame in real space. METHODS: Twenty-eight healthy volunteers (21.2 ± 1.5 years old) were included in this study. Objective ocular refraction was measured using two tests: the Chronos binocular/monocular refraction system under binocular conditions and a conventional autorefractometer under monocular conditions. Subjective ocular refraction was measured using three tests: Chronos binocular/monocular refraction system under binocular, monocular conditions, and trial-frame in the real space under monocular conditions. The measurement distance was set to 5.0 m for each test. All ocular refractions were converted into spherical equivalents (SEs). RESULTS: The objective SE was significantly more negative with Chronos binocular/monocular refraction system under binocular condition (- 4.08 ± 2.76 D) than with the conventional autorefractometer under monocular condition (- 3.85 ± 2.66 D) (P = 0.002). Although, the subjective SE was significantly more negative with Chronos binocular/monocular refraction system under binocular condition (- 3.55 ± 2.67 D) than with the trial-frame in the real space under monocular condition (- 3.33 ± 2.75 D) (P = 0.002), Chronos binocular/monocular refraction system under monocular condition (- 3.17 ± 2.57 D) was not significantly different from that in trial-frame in real space under monocular condition (P = 0.33). CONCLUSION: These findings suggest that the Chronos binocular/monocular refraction system, which can complete both objective and subjective ocular refraction tests in a single unit, is suitable for screening ocular refraction, although it produces slightly more myopic results. Furthermore, subjective ocular refraction testing accuracy in Chronos binocular/monocular refraction system can be equivalent to trial-frame in real-space testing by switching from binocular to monocular condition.

Objective evaluation of visual fatigue in patients with intermittent exotropia.

PURPOSE: The purpose of this study was to evaluate the degree of visual fatigue in patients with intermittent exotropia (IXT) using the binocular fusion maintenance (BFM) test. METHODS: Fourteen patients with IXT (32.1 ± 16.4 years) and 15 age-matched healthy volunteers (31.2 ± 9.3 years) participated in the study. BFM was assessed by measuring the transmittance of liquid crystals placed in front of the subject's nondominant eye at the instance when binocular fusion was broken and vergence eye movement was induced. A questionnaire on subjective symptoms was administered to the subjects before and after the visual task. The visual task consisted of a reciprocal movement between 67 and 40 cm. RESULTS: The change [post-pre] of BFM was significantly lower in the IXT group (-0.185 ± 0.187) than in the control group (-0.030 ± 0.070) (P = 0.010). The change of total subjective eye symptom score was significantly greater in the IXT group (2.28 ± 1.43) than in the control group (0.93 ± 1.27) (P = 0.018). The reduction in BFM rate with increasing total subjective eye symptom score was significantly greater in the IXT group (-0.106 ± 0.017) than in the control group (-0.030 ± 0.013) (P = 0.006). CONCLUSION: The present findings objectively showed that patients with IXT are at a greater risk of visual fatigue in comparison with healthy individuals.

Comparison of visual fatigue caused by head-mounted display for virtual reality and two-dimensional display using objective and subjective evaluation.

This study aimed to evaluate objective and subjective visual fatigue experienced before and after performing a visual task while using a head-mounted display for virtual reality (VR-HMD) and two-dimensional (2D) display. Binocular fusion maintenance (BFM) was measured using a binocular open-view Shack-Hartmann wavefront aberrometer equipped with liquid crystal shutters. Twelve healthy subjects performed the BFM test and completed a questionnaire regarding subjective symptoms before and after performing a visual task that induces low visually induced motion sickness (VIMS). BFM (p = .87) and total subjective eye symptom scores (p = .38) were not significantly different between both groups, although these values were significantly lower after the visual task than before the task within both groups (p < .05). These findings suggest that visual fatigue after using a VR-HMD is not significantly different from that after using a 2D display in the presence of low-VIMS VR content. Practitioner summary: Objective and subjective evaluation of visual fatigue were not significantly different with the use of a head-mounted display for virtual reality (VR-HMD) and two-dimensional display. These results should be valuable not only to engineers developing VR content but also to researchers involved in the evaluation of visual fatigue using VR-HMD. Abbreviations: VR: virtual reality; VR-HMD: head-mounted display for virtual reality; BFM: binocular fusion maintenance; BWFA: binocular open-view Shack-Hartmann wavefront aberrometer.

ASXL1 and SETBP1 mutations promote leukaemogenesis by repressing TGFß pathway genes through histone deacetylation.

Mutations in ASXL1 and SETBP1 genes have been frequently detected and often coexist in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). We previously showed that coexpression of mutant ASXL1 and SETBP1 in hematopoietic progenitor cells induced downregulation of TGFß pathway genes and promoted the development of MDS/AML in a mouse model of bone marrow transplantation. However, whether the repression of TGFß pathway in fact contributes to leukaemogenesis remains unclear. Moreover, mechanisms for the repression of TGFß pathway genes in ASXL1/SETBP1-mutated MDS/AML cells have not been fully understood. In this study, we showed that expression of a constitutively active TGFß type I receptor (ALK5-TD) inhibited leukaemic proliferation of MDS/AML cells expressing mutant ASXL1/SETBP1. We also found aberrantly reduced acetylation of several lysine residues on histone H3 and H4 around the promoter regions of multiple TGFß pathway genes. The histone deacetylase (HDAC) inhibitor vorinostat reversed histone acetylation at these promoter regions, and induced transcriptional derepression of the TGFß pathway genes. Furthermore, vorinostat showed robust growth-inhibitory effect in cells expressing mutant ASXL1, whereas it showed only a marginal effect in normal bone marrow cells. These data indicate that HDAC inhibitors will be promising therapeutic drugs for MDS and AML with ASXL1 and SETBP1 mutations.

Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation.

Additional sex combs like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.

Objective Evaluation of Visual Fatigue Using Binocular Fusion Maintenance.

PURPOSE: In this study, we investigated whether an individual's visual fatigue can be evaluated objectively and quantitatively from their ability to maintain binocular fusion. METHODS: Binocular fusion maintenance (BFM) was measured using a custom-made binocular open-view Shack-Hartmann wavefront aberrometer equipped with liquid crystal shutters, wherein eye movements and wavefront aberrations were measured simultaneously. Transmittance in the liquid crystal shutter in front of the subject's nondominant eye was reduced linearly, and BFM was determined from the transmittance at the point when binocular fusion was broken and vergence eye movement was induced. In total, 40 healthy subjects underwent the BFM test and completed a questionnaire regarding subjective symptoms before and after a visual task lasting 30 minutes. RESULTS: BFM was significantly reduced after the visual task (P < 0.001) and was negatively correlated with the total subjective eye symptom score (adjusted R2 = 0.752, P < 0.001). Furthermore, the diagnostic accuracy for visual fatigue was significantly higher in BFM than in the conventional test results (aggregated fusional vergence range, near point of convergence, and the high-frequency component of accommodative microfluctuations; P = 0.007). CONCLUSIONS: These results suggest that BFM can be used as an indicator for evaluating visual fatigue. TRANSLATIONAL RELEVANCE: BFM can be used to evaluate the visual fatigue caused by the new visual devices, such as head-mount display, objectively.

A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies.

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription.

[Clinical analysis of chronic myeloid leukemia patients complicated with chronic kidney impairment during treatment with tyrosine kinase inhibitors].

Since the long-term safety profile of tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) therapy has not been well characterized, we investigated renal impairment in 50 CML patients treated with TKI in our institute. During the median follow up period of 63 months, 29% of patients developed chronic kidney disease (CKD). Although the glomerular filtration rate (GFR) gradually declined, it dropped most markedly in the first 2 years after starting TKI. The CKD incidence was higher in patients older than 40 years or with decreased GFR, hypertension, or dyslipidemia at baseline. These findings highlight the necessity of careful monitoring of renal function in TKI-treated CML patients with these risk factors.

Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD).

Recent progress in high-speed sequencing technology has revealed that tumors harbor novel mutations in a variety of genes including those for molecules involved in epigenetics and splicing, some of which were not categorized to previously thought malignancy-related genes. However, despite thorough identification of mutations in solid tumors and hematological malignancies, how these mutations induce cell transformation still remains elusive. In addition, each tumor usually contains multiple mutations or sometimes consists of multiple clones, which makes functional analysis difficult. Fifteen years ago, it was proposed that combination of two types of mutations induce acute leukemia; Class I mutations induce cell growth or inhibit apoptosis while class II mutations block differentiation, co-operating in inducing acute leukemia. This notion has been proven using a variety of mouse models, however most of recently found mutations are not typical class I/II mutations. Although some novel mutations have been found to functionally work as class I or II mutation in leukemogenesis, the classical class I/II theory seems to be too simple to explain the whole story. We here overview the molecular basis of hematological malignancies based on clinical and experimental results, and propose a new working hypothesis for leukemogenesis.

Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels.

Recent progress in deep sequencing technologies has revealed many novel mutations in a variety of genes in patients with myelodysplastic syndromes (MDS). Most of these mutations are thought to be loss-of-function mutations, with some exceptions, such as the gain-of-function IDH1/2 and SRSF2 mutations. Among the mutations, ASXL1 mutations attract much attention; the ASXL1 mutations are identified in a variety of hematologic malignancies and always predicts poor prognosis. It was found that the C-terminal truncating mutants of the ASXL1 or ASXL1 deletion induced MDS-like diseases in mouse. In addition, it has recently been reported that ASXL1 mutations are frequently found in clonal hematopoiesis in healthy elderly people, who frequently progress to hematologic malignancies. However, the underlying molecular mechanisms by which ASXL1 mutations induce hematologic malignancies are not fully understood. Moreover, whether ASXL1 mutations are loss-of-function mutations or dominant-negative or gain-of-function mutations remains a matter of controversy. We here present solid evidence indicating that the C-terminal truncating ASXL1 protein is indeed expressed in cells harboring homozygous mutations of ASXL1, indicating the ASXL1 mutations are dominant-negative or gain-of-function mutations; for the first time, we detected the truncated ASXL1 proteins in two cell lines lacking the intact ASXL1 gene by mass spectrometry and Western blot analyses. Thus, together with our previous results, the present results indicate that the truncating ASXL1 mutant is indeed expressed in MDS cells and may play a role in MDS pathogenesis not previously considered.

[Autoimmune hemolytic anemia with normal serum lactate dehydrogenase level].

We herein report two cases of AIHA (autoimmune hemolytic anemia), a 25-year-old woman and a 77-year-old man, who presented with normal serum LDH values. Though in these two cases, low hemoglobin and haptoglobin, high total bilirubin and positive direct Coombs' test results led to the diagnosis of AIHA, both patients had normal LDH levels (218 and 187 IU/l). Both cases were successfully treated with prednisone. In the diagnosis of AIHA, elevated LDH is usually used as a marker of hemolysis. However, medical records of 24 AIHA patients collected in our institute from January 2001 to August 2012 revealed LDH levels to have been normal in 25% of these cases. This report indicates the importance of obtaining complete information about the blood testing of patients and taking these data into account when considering the diagnosis of AIHA.

The molecular basis of myeloid malignancies.

Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis.

Evaluation of actual retinal images produced by misaligned aspheric intraocular lenses in a model eye.

PURPOSE: To examine the effect of misalignment (decentration and tilt) of intraocular lenses (IOLs) on retinal image quality using a water-immersed model eye with corneal spherical aberration adjusted to the values found in normal human eyes (spherical aberration 0.25 µm; pupil diameter 6 mm). METHODS: Three types of IOL holders were prepared. The first was without decentration or tilt, the second had a decentration of 0.5 mm, and the third had a tilt of 5.0°. One spherical IOL and three aspherical IOLs, each with a power of +20 D, were set in the holders and their optical properties (wave front aberration, defocused modulation transfer function, defocused point spread function, and Landolt ring simulations) were compared. RESULTS: Coma aberrations generated by misaligned IOLs were related to the spherical aberration corrective power of the IOLs. Landolt ring simulations show that the depth of focus increased as spherical aberration increased and that the retinal image quality was degraded by increases in coma aberration. CONCLUSION: Coma aberration was generated by IOLs with a large degree of spherical aberration correction, leading to reduced retinal image quality when the IOL was misaligned. This suggests that, in a clinical setting, the quality of vision might be improved by reducing the degree of coma aberration using IOLs that retain, or minimally correct, spherical aberration.

Pregnancy and delivery in a PNH patient treated with eculizumab.

We report a 37-year-old pregnant woman with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab. She had been diagnosed with PNH-aplastic anemia at age 19 years, and started to receive eculizumab at age 35 years. Thereafter, she had no hemolytic attacks. She became pregnant 2 years later, and treatment with eculizumab was continued. During her pregnancy, she showed no exacerbation of hemolysis. She delivered a girl by Caesarean section at 37 weeks and 3 days of gestation. Postpartum, anticoagulant therapy was started. Although mild hemolysis and a rise in FDP/Ddimer were seen, she had no symptoms of thrombosis. Ten days after delivery, she and her baby were discharged. Eculizumab was present in the first breast milk and cord blood but was below detectable levels. The cord blood showed blockage of hemolysis.

Higher-order aberrations of anterior and posterior corneal surfaces in patients with keratectasia after LASIK.

PURPOSE: We investigated higher-order aberrations (HOAs) of the anterior and posterior corneal surfaces in patients with keratectasia after LASIK. METHODS: The subjects comprised four groups: 12 eyes with keratectasia after LASIK, 30 eyes following LASIK without keratectasia, 30 keratoconic eyes, and 30 normal eyes. Corneal HOAs due to the anterior and posterior corneal surfaces for 6-mm pupils (root mean square [µm]) were obtained using a Scheimpflug-based corneal tomographer and compared among the four groups. RESULTS: There were significant differences in total HOAs of the anterior and posterior corneal surfaces (mean ± SD) in the keratectasia (2.49 ± 1.37 and 0.83 ± 0.57), keratoconus (4.50 ± 2.57 and 1.18 ± 0.65), LASIK (0.84 ± 0.25 and 0.14 ± 0.04), and normal (0.52 ± 0.15 and 0.17 ± 0.06) groups except for between keratoconus and keratectasia at the posterior surface. Keratectasia and keratoconus showed similar coma-dominant patterns at both surfaces, and there were no significant differences in the Zernike terms between both groups except for the total HOAs and coma aberration at the anterior surface. CONCLUSIONS: Although flap creation and laser ablation were supposed to center on the primary line of sight in LASIK, keratectasia after LASIK showed coma-dominant HOAs at both corneal surfaces. This suggests that the cornea in keratectasia has optical properties similar to those in keratoconus.

Four discriminant models for detecting keratoconus pattern using Zernike coefficients of corneal aberrations.

PURPOSE: We compared the ability of four discriminant models to detect keratoconus (KC) using Zernike coefficients of corneal aberrations. METHODS: We studied 51 eyes with KC, 46 with KC suspect, 50 after laser in situ keratomileusis, and 65 normal eyes. Four statistical discriminant analyses-linear discriminant analysis, k-nearest neighbor algorithm, Mahalanobis distance method, and neural network method-were performed using Zernike coefficients of corneal aberrations obtained by a Placido-based topographer. The detection scheme was constructed using a training set of data from one half of the randomly selected study participants, and performance was evaluated by a validation set in the other half. RESULTS: Performance of the four models was different when <12 explanatory variables were included. Performance using the 2nd- to 4th-order Zernike terms did not differ significantly among models; average accuracy was 79 %. CONCLUSIONS: Determining explanatory variables of Zernike expansion coefficients of the corneal topography in discriminant models may contribute to improving accuracy of KC detection over the discriminant model, as appropriate selection of explanatory variables gave similar results despite different discriminant models.

Characteristic higher-order aberrations of the anterior and posterior corneal surfaces in 3 corneal transplantation techniques.

PURPOSE: To investigate the corneal higher-order aberrations (HOAs) of the anterior and posterior corneal surfaces in eyes that underwent penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK), and Descemet stripping automated endothelial keratoplasty (DSAEK). DESIGN: Retrospective, case-control study. METHODS: study population: Twenty-four eyes underwent PK, 28 eyes underwent DALK, and 19 eyes underwent DSAEK; 29 normal eyes served as controls. observation procedures: The anterior and posterior corneal heights and pachymetric data were obtained with a Scheimpflug-based corneal topographer. Corneal HOAs for 4-mm pupils were calculated from the height data and were expanded with normalized Zernike polynomials. The HOAs resulting from the anterior and posterior corneal surfaces were compared among the procedures. main outcome measures: Anterior and posterior corneal HOAs (root mean square). RESULTS: Control eyes had significantly lower total HOAs and Zernike vector terms of the anterior and posterior surfaces than the other groups, except for spherical aberration. The mean anterior corneal surface total HOAs in the PK, DALK, DSAEK, and control groups were 1.38 ± 0.67 µm, 1.19 ± 0.57 µm, 0.61 ± 0.33 µm, and 0.21 ± 0.07 µm, respectively. The anterior corneal HOAs in the DSAEK group were significantly less than those in the PK group (P < .001) and DALK group (P < .001). The mean posterior corneal surface total HOAs were, respectively, 0.20 ± 0.09 µm, 0.24 ± 0.11 µm, 0.27 ± 0.15 µm, and 0.07 ± 0.02 µm. There were no significant differences in the posterior corneal HOAs among the treatment groups. CONCLUSIONS: Because the refractive indices between the anterior and the posterior surfaces differed greatly, eyes that undergo DSAEK have lower anterior corneal HOAs compared with PK or DALK eyes. However, the anterior and posterior corneal HOAs in DSAEK eyes still were greater than those in control eyes.

Higher-order aberrations due to the posterior corneal surface in patients with keratoconus.

PURPOSE: This study was designed to investigate higher-order aberrations (HOAs) due to the posterior corneal surface in keratoconic eyes compared with normal eyes. METHODS: We studied 24 normal and 28 keratoconic eyes. The anterior/posterior corneal heights and pachymetric data were obtained with a rotating Scheimpflug camera. HOAs for 6 mm pupils were calculated from the differences between the height data and the best-fit sphere, using an original program for each corneal surface. The reference axes of the measurements were aligned with the primary line of sight. The HOAs were expanded with normalized Zernike polynomials. For each pair of standard Zernike terms for trefoil, coma, tetrafoil, and secondary astigmatism, one value for the magnitude and axis was calculated by Zernike vector analysis. RESULTS: The mean total corneal HOAs (root mean square [microm]) from the anterior/posterior surfaces were significantly (P < 0.001) higher in keratoconic (4.34/1.09, respectively) than in control eyes (0.46/0.15). The mean magnitude of each Zernike vector terms for trefoil, coma, and spherical aberration from the anterior/posterior surfaces was significantly (P < 0.001) higher in keratoconic (0.77/0.19, 3.57/0.87, -0.44/0.17) than control eyes (0.09/0.04, 0.33/0.07, 0.25/-0.07), respectively. The mean axes by vector calculation for coma due to the anterior (63.6 degrees ) and posterior surfaces (241.9 degrees ) were in opposite directions. CONCLUSIONS: Corneal HOAs on both corneal surfaces in keratoconic eyes were higher than in control eyes. Coma from the posterior surface compensated partly for that from the anterior surface. Residual irregular astigmatism in patients with keratoconus wearing rigid gas permeable contact lenses can be estimated by measuring the HOA from the posterior corneal surface.