Case Report: An Adult Case of Poretti-Boltshauser Syndrome Diagnosed by Medical Checkup.

This report describes an adult case of Poretti-Boltshauser syndrome (PTBHS) and with novel variants of LAMA1. A 65-year-old Japanese woman with cerebellar malformation identified during a medical checkup was referred to our hospital. Subsequently, neurological examination, brain imaging, and genetic investigation via whole-exome sequencing were performed. The patient presented with mild cerebellar ataxia and intellectual disability. Magnetic resonance imaging revealed cerebellar dysplasia and cysts and an absence of molar tooth sign. Genetic analysis revealed a novel homozygous variant of c.1711_1712del in LAMA1 (NM_005559.4). Most cases with PTBHS are reported in pediatric patients; however, our patient expressed a mild phenotype and was undiagnosed until her 60 s. These findings suggest that PTBHS should be considered in not only pediatric cerebellar dysplasia but also adult cerebellar ataxia with mild presentation.

Sofosbuvir Suppresses the Genome Replication of DENV1 in Human Hepatic Huh7 Cells.

Dengue virus (DENV) causes dengue fever and dengue hemorrhagic fever, and DENV infection kills 20,000 people annually worldwide. Therefore, the development of anti-DENV drugs is urgently needed. Sofosbuvir (SOF) is an effective drug for HCV-related diseases, and its triphosphorylated metabolite inhibits viral RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of HCV. (2'R)-2'-Deoxy-2'-fluoro-2'-methyluridine (FMeU) is the dephosphorylated metabolite produced from SOF. The effects of SOF and FMeU on DENV1 replication were analyzed using two DENV1 replicon-based methods that we previously established. First, a replicon-harboring cell assay showed that DENV1 replicon replication in human hepatic Huh7 cells was decreased by SOF but not by FMeU. Second, a transient replicon assay showed that DENV1 replicon replication in Huh7 cells was decreased by SOF; however, in hamster kidney BHK-21 cells, it was not suppressed by SOF. Additionally, the replicon replication in Huh7 and BHK-21 cells was not affected by FMeU. Moreover, we assessed the effects of SOF on infectious DENV1 production. SOF suppressed infectious DENV1 production in Huh7 cells but not in monkey kidney Vero cells. To examine the substrate recognition of the HCV and DENV1 RdRps, the complex conformation of SOF-containing DENV1 RdRp or HCV RdRp was predicted using AlphaFold 2. These results indicate that SOF may be used as a treatment for DENV1 infection.

Kaposi's Sarcoma-Associated Herpesvirus ORF21 Enhances the Phosphorylation of MEK and the Infectivity of Progeny Virus.

Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causative agent of Kaposi's sarcoma, Castleman's disease, and primary effusion lymphoma. Although the functions of the viral thymidine kinases (vTK) of herpes simplex virus-1/2 are well understood, that of KSHV ORF21 (an ortholog of vTK) is largely unknown. Here, we investigated the role of ORF21 in lytic replication and infection by generating two ORF21-mutated KSHV BAC clones: ORF21-kinase activity deficient KSHV (21KD) and stop codon-induced ORF21-deleted KSHV (21del). The results showed that both ORF21 mutations did not affect viral genome replication, lytic gene transcription, or the production of viral genome-encapsidated particles. The ORF21 molecule-dependent function, other than the kinase function of ORF21, was involved in the infectivity of the progeny virus. ORF21 was expressed 36 h after the induction of lytic replication, and endogenously expressed ORF21 was localized in the whole cytoplasm. Moreover, ORF21 upregulated the MEK phosphorylation and anchorage-independent cell growth. The inhibition of MEK signaling by U0126 in recipient target cells suppressed the number of progeny virus-infected cells. These suggest that ORF21 transmitted as a tegument protein in the progeny virus enhances the new infection through MEK up-regulation in the recipient cell. Our findings indicate that ORF21 plays key roles in the infection of KSHV through the manipulation of the cellular function.

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.

Adaptive optics dioptric scanning ophthalmoscope with a wider field of view similar to those of normal ophthalmoscopes.

We introduce a newly developed adaptive optics dioptric scanning ophthalmoscope (AO-DSO) in which all powered optical parts were refractive lenses instead of concave or convex mirrors. By designing dioptric optics, we were able to achieve a compact instrument with a 10 deg field of view (FOV10) and 1.5 deg field of view (FOV1.5) high-resolution imaging. Although the resolution of FOV10 was sacrificed because of the variation of aberrations of the eye over the 10 deg field, our system works with AO in the case of FOV1.5 and can be used as a scanning laser ophthalmoscope with good optical slicing in the case of FOV10. To test the ability of the AO-DSO, we performed imaging on a normal subject and on a patient with occult macular dystrophy.

Evaluation of choroidal melanin-containing tissue in healthy Japanese subjects by polarization-sensitive optical coherence tomography.

In this study, the choroidal melanin content in healthy eyes was evaluated with polarization-sensitive optical coherence tomography (PS-OCT). We evaluated 105 healthy eyes of 105 Japanese subjects. The mean thickness of melanin-containing tissue in the choroid (thickness of MeCh) and the choroidal melanin occupancy rate within a 5-mm circular region from the foveal center were calculated using the degree of polarization uniformity obtained by PS-OCT and compared with the choroidal thickness, patient age, and axial length. To evaluate regional variations, the 5-mm circular region was divided into a center area and an outer ring area, and the outer ring area was further divided into four areas (nasal, temporal, superior, and inferior). The mean thickness of MeCh showed a significant positive correlation with the choroidal thickness. The mean choroidal melanin occupancy rate showed a significant positive correlation with age. The mean choroidal melanin occupancy rate of the center area was significantly larger than that of the outer ring area. The mean thickness of MeCh and choroidal melanin occupancy rate of the nasal area were significantly lower than those of other areas. The distribution of melanin-containing tissue in the choroid varies significantly with age and location.

Extending field-of-view of retinal imaging by optical coherence tomography using convolutional Lissajous and slow scan patterns.

Optical coherence tomography (OCT) is a high-speed non-invasive cross-sectional imaging technique. Although its imaging speed is high, three-dimensional high-spatial-sampling-density imaging of in vivo tissues with a wide field-of-view (FOV) is challenging. We employed convolved Lissajous and slow circular scanning patterns to extend the FOV of retinal OCT imaging with a 1-µm, 100-kHz-sweep-rate swept-source OCT prototype system. Displacements of sampling points due to eye movements are corrected by post-processing based on a Lissajous scan. Wide FOV three-dimensional retinal imaging with high sampling density and motion correction is achieved. Three-dimensional structures obtained using repeated imaging sessions of a healthy volunteer and two patients showed good agreement. The demonstrated technique will extend the FOV of simple point-scanning OCT, such as commercial ophthalmic OCT devices, without sacrificing sampling density.

Objective evaluation of choroidal melanin loss in patients with Vogt-Koyanagi-Harada disease using polarization-sensitive optical coherence tomography.

In this study, sunset glow fundus was evaluated in patients with Vogt-Koyanagi-Harada (VKH) disease using polarization-sensitive optical coherence tomography (PS-OCT). We evaluated 40 VKH eyes (20 patients) and 59 healthy eyes (59 age-matched controls). VKH eyes were divided into three groups according to color fundus images: sunset (17 eyes), potential sunset (13 eyes), and non-sunset (10 eyes). Choroidal melanin thickness (ChMeT) and the choroidal melanin thickness ratio (ChMeTratio) were calculated based on the degree of polarization uniformity from PS-OCT. ChMeT was significantly lower in sunset eyes than in non-sunset or control eyes (P = 0.003). The ChMeTratios of sunset or potential sunset eyes were significantly lower than those of non-sunset or control eyes (P = 0.04). Regional evaluation of ChMeT and the ChMeTratio showed that choroidal depigmentation predominantly occurred in the macula's outer ring area (P = 0.002). The areas under receiver operating characteristic curves discriminating combined sunset (sunset and potential sunset) from non-sunset eyes were 0.983 and 0.997 for ChMeT and the ChMeTratio, respectively. Time course evaluation of 12 eyes from disease onset showed that ChMeT and the ChMeTratio significantly decreased over time. PS-OCT may be useful for objectively evaluating choroidal depigmentation in patients with VKH disease.

Birefringence-derived scleral artifacts in optical coherence tomography images of eyes with pathologic myopia.

We investigated birefringence-derived scleral artifacts in optical coherence tomography (OCT) images of eyes with pathologic myopia. This study included 76 eyes of 42 patients with pathologic myopia. Five sets of OCT B-scan images of the macula were obtained using commercial swept-source OCT. A dataset of prototype swept-source polarization-diversity OCT images was used to identify polarization-dependent OCT images (i.e., complex averaging of OCT signals from two polarization channels) and polarization-independent OCT images (i.e., intensity averaging of two OCT signals). Polarization-dependent OCT images and commercial OCT images were assessed for the presence of birefringence-derived artifacts by comparison with polarization-independent OCT images. Both polarization-dependent OCT images and commercial OCT images contained scleral vessel artifacts. Scleral vessel artifacts were present in 46 of 76 eyes (60.5%) imaged by polarization-dependent OCT and 17 of 76 eyes (22.4%) imaged by commercial OCT. The proportion of images that showed scleral vessel artifacts was significantly greater among polarization-dependent OCT images than among commercial OCT images (P < 0.001). Additionally, polarization-dependent OCT images showed low-intensity band artifacts. This study demonstrated the existence of birefringence-derived scleral artifacts in commercial OCT images and indicated that polarization-diversity OCT is an effective tool to evaluate the presence of these artifacts.

[Retinal sensitivity following subthreshold diode laser micropulse photocoagulation for diabetic macular edema].

PURPOSE: To report the retinal sensitivity after subthreshold diode laser micropulse photocoagulation(SDM) to evaluate its safety. METHODS: Eight eyes of 8 diabetic patients with clinically significant macular edema were treated with SDM. SDM was applied with a 15% duty cycle, 0.2 to 0.3 sec, 200 microm, at 700 to 800 mW. Postoperative retinal sensitivity (1-2 weeks) was compared to preoperative retinal sensitivity measured by microperimeter-1 (MP-1, Nidek technologies, Padova, Italy) using a 1 x 1 mm square test grid with 49 stimulus locations. RESULTS: The retinal sensitivity improved (more than 2 dB) in 3 eyes and remained stable (within 2 dB) in 5 eyes. The median retinal sensitivity increased significantly in 5 eyes and decreased significantly in 3 eyes. The average retinal sensitivity of 8 eyes was 12.04 +/- 3.69 dB before laser treatment, and 13.20 3.47 dB after laser treatment and there was no statistically significant change in retinal sensitivity at 2 weeks (p = 0.09). CONCLUSION: Short duration SDM for diabetic macular edema has no significant effect on retinal sensitivity.

Evaluation of retinal pigment epithelium changes in serous pigment epithelial detachment in age-related macular degeneration.

The purpose of this study was to quantitatively evaluate retinal pigment epithelium (RPE) changes in serous pigment epithelial detachment (PED) among patients with age-related macular degeneration by means of prototype multi-contrast optical coherence tomography (OCT), which is capable of simultaneous collection of OCT angiography, polarization-sensitive OCT, and standard OCT images. We evaluated 26 eyes of 21 patients with serous PED. RPE-melanin OCT images were calculated from the multi-contrast OCT dataset and compared with near-infrared autofluorescence images. An active RPE lesion was defined as an area of thickened RPE-melanin (≥ 70 µm; RPE70) on RPE-melanin OCT. Each PED area was divided into peak and slope regions. RPE70 area ratios were compared with the maximum PED height, PED area, PED volume, and slope area ratio (area of slope region/area of whole PED). RPE-melanin OCT images were consistent with near-infrared autofluorescence images. The RPE70 area ratio in the slope region was significantly negatively correlated with the slope area ratio. Development of active RPE lesions in the slope region was correlated with the PED configuration. Multi-contrast OCT is useful for objective evaluation of changes in the RPE in patients with age-related macular degeneration.

Accurately motion-corrected Lissajous OCT with multi-type image registration.

Passive motion correction methods for optical coherence tomography (OCT) use image registration to estimate eye movements. To improve motion correction, a multi-image cross-correlation that employs spatial features in different image types is introduced. Lateral motion correction using en face OCT and OCT-A projections on Lissajous-scanned OCT data is applied. Motion correction using OCT-A projection of whole depth and OCT amplitude, OCT logarithmic intensity, and OCT maximum intensity projections were evaluated in retinal imaging with 76 patients. The proposed method was compared with motion correction using OCT-A projection of whole depth. The comparison shows improvements in the image quality of motion-corrected superficial OCT-A images and image registration.

Comparison of methods of detecting bacterial biofilm.

Fresh bacterial biofilm produced by Staphylococcus epidermidis was sensitively detected by using a chemiluminescent probe. Its lower detection limit was around 10(-5) - 10(-4) dilution (equivalent to 10(-5) - 10(-4) cm2 biofilm) - 10(2) - 10(3) times as sensitive as ordinary colorimetric methods. The linearity and dynamic range were slightly better than those of fluorometry.

Ten-year follow-up of photorefractive keratectomy for myopia.

BACKGROUND: The aim of this study is to evaluate the long-term (10-year) outcome of excimer laser photorefractive keratectomy (PRK) on myopic eyes. METHODS: This retrospective study included 42 eyes of 29 patients (13 male, 16 female; mean age 33.4 years, range 21 to 60) who were treated with myopic PRK at St. Luke's International Hospital, Tokyo, Japan, from May 1 1995 to December 31 1998, and followed up for more than 10 years. The main outcome measures were efficacy, predictability, stability, safety, and complications. We also evaluated the progress of intraocular pressure, corneal thickness, and endothelial cell density after the surgery. The cases of retreatments were excluded from this study. RESULTS: Ten years after the surgery, 17 eyes (40%) had 20/20 vision or better, and 35 eyes (81%) had 20/40 or better. With regard to the refractive predictability, 55 percent of the eyes were within ± 1.0D and 76% were within ± 2.0D, 10 years after the surgery. There was myopic regression with a mean change in refraction of-0.51 ± 1.78D. Best spectacle-corrected visual acuity (BCVA) was unchanged or improved in 95%, and only two eyes lost 1 line of BCVA. The mean corneal haze score was 0.19 ± 0.40, and the decreasing rate of endothelial cell was 8.30 ± 9.94% at 10 years, which was slightly higher than the spontaneous decreasing rate with age. CONCLUSIONS: PRK is safe and effective in refraction even 10 years after surgery; however, further long-term follow-up is needed to evaluate the decreasing of endothelial cells.

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.

Evaluation of Retinal Pigment Epithelium Layer Change in Vogt-Koyanagi-Harada Disease With Multicontrast Optical Coherence Tomography.

Purpose: Clinical evaluation of retinal pigment epithelium (RPE) change is important for the therapeutic management of chronic Vogt-Koyanagi-Harada (VKH) disease. We evaluated long-term change in the RPE layer in VKH disease, using near-infrared (NIR; 817 nm) images and autofluorescence images at 488 nm (short-wavelength [SW]-AF) and 785 nm (NIR-AF), and compared those images with images from multicontrast optical coherence tomography (MC-OCT). MC-OCT is capable of simultaneous measurement of OCT angiography, polarization-sensitive OCT, and standard OCT. Methods: We evaluated 24 eyes of 12 patients with chronic VKH disease. RPE changes were assessed using NIR, NIR-AF, SW-AF, and MC-OCT imaging performed from 6 to 48 months after disease onset. RPE-melanin-specific contrast OCT images were calculated using the dataset from MC-OCT. Results: Granular hyper NIR-AF lesions were observed in 8 of 24 eyes (33%). Eyes with granular hyper NIR-AF lesions showed a sunset glow fundus appearance significantly more frequently than did eyes without such lesions (P < 0.0001). MC-OCT imaging confirmed that there was melanin accumulation at the RPE-Bruch's membrane band at the location of granular hyper NIR-AF lesions. Granular hyper NIR-AF lesions were unclear in SW-AF and color fundus images, but clearly detectable in NIR images. Areas of hyper NIR-AF lesions gradually decreased over time. Conclusions: Melanin accumulation in the RPE layer at the location of granular hyper NIR-AF lesions was confirmed with MC-OCT imaging. Long-term follow-up showed the reversible nature of this accumulation. MC-OCT is useful for the evaluation of change at the RPE layer in chronic VKH disease.

Evaluation of focal damage in the retinal pigment epithelium layer in serous retinal pigment epithelium detachment.

The purpose of this study was to evaluate focal damage in the retinal pigment epithelium (RPE) layer in serous retinal pigment epithelium detachment (PED) with multi-contrast optical coherence tomography (OCT), which is capable of simultaneous measurement of OCT angiography, polarization-sensitive OCT and standard OCT images. We evaluated 37 eyes with age-related macular degeneration that had serous PED. Focal RPE damage was indicated by hyper-transmission beneath the RPE-Bruch's membrane band in standard OCT images. Distribution of RPE melanin was calculated using the dataset from multi-contrast OCT. Twenty-four points with hyper-transmission were detected in 21 of the 37 eyes. Standard OCT images failed to show disruption of the RPE-Bruch's membrane band at 5 of the 24 hyper-transmission points. Conversely, multi-contrast OCT images clearly showed melanin defects in the RPE-Bruch's membrane band at all points. Areas of melanin defects with disruption of the RPE-Bruch's membrane band were significantly larger than those without disruption. The volume of intraretinal hyper-reflective foci was significantly larger in eyes with hyper-transmission than that in eyes without hyper-transmission. Multi-contrast OCT is more sensitive than standard OCT for displaying changes at the RPE-Bruch's membrane band when there are small areas of RPE damage.

Adaptive optics fundus camera to examine localized changes in the photoreceptor layer of the fovea.

PURPOSE: To examine highly localized photoreceptor disruptions in the fovea by a high-resolution adaptive optics (AO) fundus camera combined with Fourier-domain optical coherence tomography (FD OCT). DESIGN: Observational case series. PARTICIPANTS: Three eyes of 3 patients who showed dark foveal spots by slit-lamp biomicroscopy. METHODS: Three patients who reported metamorphopsia but showed no changes in the retina in conventional fundus photographs were examined. High-resolution retinal images were obtained with the AO fundus camera and by FD OCT. The images were compared with the findings obtained by standard clinical tests, including Amsler charts and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Quantitative measurements of the area of photoreceptor disruption. RESULTS: Slit-lamp biomicroscopy revealed an irregularly shaped dark spot in the fovea centralis but no changes in FA in the 3 cases. The photoreceptor mosaic was absent in a highly localized area of the fovea in the images obtained by the AO fundus camera, and the photoreceptor outer segment was absent or disturbed at the corresponding area by FD OCT in all 3 cases. The horizontal and vertical sizes of the area of disturbance of the photoreceptor mosaic in the AO images in the 3 eyes were 400x200 microm, 300x120 microm, and 300x200 microm. These sizes were comparable to the photoreceptor outer segment disturbances in the OCT images which were 330x150 microm, 280x100 microm, 200x150 microm, respectively. CONCLUSIONS: Localized OS disturbances were able to be detected in eyes with a dark foveal spot by AO fundus camera 2-dimensionally and by FD OCT axially. The good correspondence of the sizes of the area of photoreceptor disturbances obtained by AO images to those by FD OCT images indicate that the AO images can be used to evaluate and follow the 2-dimensional area of focal changes of the photoreceptors in the fovea quantitatively.

Binocular open-view Shack-Hartmann wavefront sensor with consecutive measurements of near triad and spherical aberration.

We have developed a binocular open-view Shack-Hartmann wavefront sensor for measuring time variation of binocular accommodation, vergence, pupil sizes (i.e., the binocular near triad), and monochromatic aberrations. The device measures these values16 times per second for up to 1 min. Our purpose is to introduce the new instrument. We have confirmed the accuracy of the device. Refractions for a 4 mm pupil were accurate across the range of measurements of model eyes and normal human eyes. We measured binocular dynamics of accommodation, vergence, and spherical aberrations.

Efficacy and retention times of intravitreal triamcinolone acetonide for macular edema.

PURPOSE: To evaluate the retention of intravitreal triamcinolone acetonide (TA) particles and the efficacy of TA therapy for patients with cystoid macular edema in branch retinal vein occlusion (BRVO) or diabetic macular edema (DME). We monitored the TA particles until absorption from the vitreous cavity was complete. The correlation between the intravitreal retention time of TA and its efficacy was evaluated based on central macular thickness (CMT). RESULTS: The intravitreal TA retention time was a mean 141.8 +/- 139.6 days in BRVO patients and 114.5 +/- 59.6 days in DME patients. Patient age and retention time were negatively correlated (r = -0.46; P = 0.013). At 6 months posttreatment the mean CMT decreased from 544.1 +/- 143.7 to 322.4 +/- 131.9 mum in BRVO patients and from 454.5 +/- 119.0 to 371.2 +/- 209.4 mum in DME patients. Retention time and CMT reduction were positively correlated in BRVO patient (r = 0.56, P = 0.02) but not in DME patients (P = 0.06). CONCLUSIONS: Intravitreal TA reduced the CMT in BRVO and DME patients over 6 months. The retention time was longer in younger individuals. The efficacy of the therapy depended on the intravitreal TA retention time observed clinically in BRVO patients. Biomicroscopic examination of intravitreal TA is useful for evaluation of its efficacy.