Publications by authors named "Kenji Ishihara"

124 Publications

[A case suspected of Alzheimer type dementia showing multimodal (face and voice) person recognition disorder from face and voice].

Rinsho Shinkeigaku 2021 Mar 23;61(3):182-187. Epub 2021 Feb 23.

Department of Neurology, Asahi Hospital of Neurology and Rehabilitation.

A 90-year-old woman presented with a multimodal (face and voice) person recognition disorder. Although she had moderate general cognitive impairment, her visual cognitive capacity, other than face recognition, was well preserved. She could identify the faces and voices of family members but could not recall the names and voices of relatives whom she met infrequently, famous individuals, or the medical staff. She could remember the first names and some information about prominent individuals when supplied with their surnames. Therefore, we thought that her person-specific semantic memory was intact but she was unable to access it through their faces and voices. MRI revealed predominantly right-sided bilateral anterior temporal lobe and hippocampal atrophy. SPECT images showed decreased blood flow in the bilateral anterior temporal lobes and inferior parietal lobule (heavily and predominantly right-sided), right posterior cingulate gyrus, and precuneus. Progressive person recognition disorder or prosopagnosia has been considered a right temporal variant of frontotemporal lobar degeneration because abnormal behaviors and psychiatric symptoms frequently coexist. However, no such symptoms were observed in this case, therefore we suspected dementia of the Alzheimer type.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001510DOI Listing
March 2021

Pathologic basis of the preferential thinning of thecorpus callosum in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

eNeurologicalSci 2021 Mar 22;22:100310. Epub 2021 Jan 22.

Intractable Disease Care Center, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

Background: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early onset dementia characterized by axonal loss in the cerebral white matter with swollen axons (spheroids). It had been reported that the preferential thinning and "focal lesions" of the corpus callosum were observed on T2-weighted MRI in ALSP patients. The present study aimed to reveal the pathologic basis of them in relation to brain lesion staging (I ~ IV: Oyanagi et al. 2017).

Methods: Seven autopsied brains of ALSP and five controls were neuropathologically examined.

Results: Even at Stage I, corpus callosum body showed evident atrophy, and the atrophy advanced with stage progression. Spheroid size and density were maximal at Stage II in both centrum semiovale and corpus callosum body, but spheroids were larger in corpus callosum body than in centrum semiovale. Microglia in the body at Stage II had a larger cytoplasm than those in centrum semiovale. But spheroids and microglia in the "focal lesions" were identical with those of centrum semiovale.

Conclusion: Preferential thinning of corpus callosum was considered to be formed in relation to peculiar morphological alteration of microglia there in ALSP. Instead, "focal lesions" were formed in connection with the lesions in centrum semiovale.
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http://dx.doi.org/10.1016/j.ensci.2021.100310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844436PMC
March 2021

Neuroprotective effects and mechanisms of action of nicotinamide mononucleotide (NMN) in a photoreceptor degenerative model of retinal detachment.

Aging (Albany NY) 2020 12 29;12(24):24504-24521. Epub 2020 Dec 29.

Angiogenesis Laboratory, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA.

Currently, no pharmacotherapy has been proven effective in treating photoreceptor degeneration in patients. Discovering readily available and safe neuroprotectants is therefore highly sought after. Here, we investigated nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), in a retinal detachment (RD) induced photoreceptor degeneration. NMN administration after RD resulted in a significant reduction of TUNEL photoreceptors, CD11b macrophages, and GFAP labeled glial activation; a normalization of protein carbonyl content (PCC), and a preservation of the outer nuclear layer (ONL) thickness. NMN administration significantly increased NAD levels, SIRT1 protein expression, and heme oxygenase-1 (HO-1) expression. Delayed NMN administration still exerted protective effects after RD. Mechanistic studies using 661W cells revealed a SIRT1/HO-1 signaling as a downstream effector of NMN-mediated protection under oxidative stress and LPS stimulation. In conclusion, NMN administration exerts neuroprotective effects on photoreceptors after RD and oxidative injury, suggesting a therapeutic avenue to treating photoreceptor degeneration.
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http://dx.doi.org/10.18632/aging.202453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803565PMC
December 2020

Reform of the death investigation system in Japan.

Med Sci Law 2020 Jul 16;60(3):216-222. Epub 2020 Apr 16.

Department of Legal Medicine, Graduate School of Medicine, Chiba University, Japan.

The autopsy rate in Japan is lower than that in other countries, and most death investigations have historically been conducted by police officers through external inspection. Although medicolegal autopsy was not performed during the samurai administration, the European death investigation system was adopted in the second half of the 19th century and judicial autopsy began in universities' forensic medicine departments. After World War II, the medical examiner system was introduced under US influence, but it was only adopted in certain areas. Further reforms were introduced in the 21st century-in 2012, two laws relating to death investigation were enacted: , which provided foundational principles and included measures for investigating the causes of death and identification of bodies, and the , which recommended a procedure for death investigation, including a new autopsy system.The was to meant to be decided by the government in 2014. However, the relevant Act expired after it ran out of time. Later, in 2019, the , the successor to the Promotion Act, was passed. This Act is significant because it sets the basic foundational principle and imposes plans created by the government. However, it remains unclear how these measures can be implemented, so further discussion and financial investment are now required.
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http://dx.doi.org/10.1177/0025802420916590DOI Listing
July 2020

Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina.

Proc Natl Acad Sci U S A 2019 11 7;116(47):23724-23734. Epub 2019 Nov 7.

Angiogenesis Laboratory, Ophthalmology Department, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;

The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
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http://dx.doi.org/10.1073/pnas.1906643116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876195PMC
November 2019

RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.

Proc Natl Acad Sci U S A 2019 11 4;116(47):23705-23713. Epub 2019 Nov 4.

Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114;

Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1 mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4-activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis.
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http://dx.doi.org/10.1073/pnas.1908355116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876205PMC
November 2019

Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells.

Biochem Biophys Res Commun 2020 01 28;521(2):414-419. Epub 2019 Oct 28.

Angiogenesis Laboratory, Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA. Electronic address:

Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells.
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http://dx.doi.org/10.1016/j.bbrc.2019.10.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935401PMC
January 2020

[A case of Hashimoto's encephalopathy showing improvement in higher brain functions after a low-dose steroid therapy].

Rinsho Shinkeigaku 2019 Sep 30;59(9):570-574. Epub 2019 Aug 30.

Department of Neurology, Asahi Hospital of Neurology and Rehabilitation.

Here, we describe a case involving an 83-year-old woman who was admitted to our hospital for rehabilitation after pseudogout treatment. She had temporal and spatial disorientation. Neuropsychological assessment revealed frontal dysfunction, memory impairment, and executive dysfunction, in addition to general cognitive impairment. Subsequent laboratory examination revealed euthyroid status and elevated titers of anti-thyroid autoantibodies. MRI of the brain revealed no abnormal finding. However, electroencephalography revealed diffuse slowness. We diagnosed Hashimoto's encephalopathy on the basis of the clinical symptoms and laboratory findings. Administration of low-dose prednisolone (5 mg/day) alleviated general cognitive impairment and the laboratory findings; however, memory impairment and construction disorder remained. Previous studies suggest that the characteristics and clinical course of higher brain-function disorder associated with Hashimoto's encephalopathy vary on an individual basis, wherein some patients may respond well to low-dose steroid therapy. Here, we also encountered such a case, that showed good response to a low-dose steroid therapy.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001301DOI Listing
September 2019

Parallel detection of Jones-matrix elements in polarization-sensitive optical coherence tomography.

Biomed Opt Express 2019 May 8;10(5):2318-2336. Epub 2019 Apr 8.

Ikuno Eye Center, 2-9-10 3F Juso-Higashi, Yodogawaku, Osaka, Osaka, 532-0023, Japan.

The polarization properties of a sample can be characterized using a Jones matrix. To measure the Jones matrix without assumptions of the sample, two different incident states of polarization are usually used. This requirement often causes certain drawbacks in polarization-sensitive optical coherence tomography (PS-OCT), e.g., a decrease in the effective A-scan rate or axial depth range, if a multiplexing scheme is used. Because both the A-scan rate and axial depth range are important for clinical applications, including the imaging of an anterior eye segment, a new PS-OCT method that does not have these drawbacks is desired. Here, we present a parallel-detection approach that maintains the same A-scan rate and axial measurement range as conventional OCT. The interferometer consists of fiber-optic components, most of which are polarization-maintaining components with fast-axis blocking free from polarization management. When a parallel detection is implemented using swept-source OCT (SS-OCT), synchronization between the A-scans and synchronization between the detection channels have critical effects on the Jones-matrix measurement. Because it is difficult to achieve perfect synchronization using only hardware, we developed a solution using a numerical correction with signals from a static mirror. Using the developed system, we demonstrate the imaging of an anterior eye segment from the cornea to the back surface of the crystalline lens.
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http://dx.doi.org/10.1364/BOE.10.002318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524579PMC
May 2019

[An Autopsy Case of Amiotrophic Lateral Sclerosis Characterized by Upper Motor Neuron Degeneration and Progressive Pseudobulbar Palsy].

Brain Nerve 2019 Jan;71(1):75-80

Department of Neurology, Ushioda General Hospital.

This is a case report of autopsy findings for a male Japanese patient who presented with progressive gait disturbance and dysarthria. Neurological examination at the age of 61 years revealed pseudobulbar palsy and upper motor neuron disorder. The patient appeared unaware of his illness. Electrophysiological examination showed lower neuron damage. The patient was diagnosed with amyotrophic lateral sclerosis characterized by lower motor neuron damage. He died of pneumonia 2 years and 3 months after diagnosis. Neuropathological examination demonstrated severe degeneration of the upper neurons and mild degeneration of the lower neurons. Immunohistological examination indicated transactivation-responsive DNA-binding protein-43-positive pathology in the frontal and temporal lobes, amygdala, corpus striatum, and spinal cord. We believe the neuropathological findings correlate well with the clinical features. Furthermore, we also discuss the lesions involved in the patient's dementia. (Received March 28, 2017; Accepted September 19, 2018; Published November 1, 2018).
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http://dx.doi.org/10.11477/mf.1416201219DOI Listing
January 2019

Olfactory Dysfunction in Patients With CNGB1-Associated Retinitis Pigmentosa.

JAMA Ophthalmol 2018 07;136(7):761-769

Smell and Taste Clinic, Department of Otorhinolaryngology-Head and Neck Surgery, Technische Universität Dresden, Dresden, Germany.

Importance: Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause.

Objective: To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons.

Design, Setting, And Participants: This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP.

Main Outcomes And Measures: Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing.

Results: Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050delGGAAATC) and 5 previously reported mutations in CNGB1.

Conclusions And Relevance: Mutations in CNGB1 may cause an autosomal recessive RP-olfactory dysfunction syndrome characterized by a slow progression of retinal degeneration and variable anosmia or hyposmia.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.1621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136054PMC
July 2018

Characterization of mycosporine-like amino acids in the cyanobacterium Nostoc verrucosum.

J Gen Appl Microbiol 2018 Nov 30;64(5):203-211. Epub 2018 Apr 30.

Division of Life Science, Graduate School of Natural Science and Technology, Kanazawa University.

The aquatic cyanobacterium Nostoc verrucosum forms macroscopic colonies in streams, and its appearance is superficially similar to that of the terrestrial cyanobacterium Nostoc commune. N. verrucosum is sensitive to desiccation, unlike N. commune, although these Nostoc cyanobacterial species share physiological features, including massive extracellular polysaccharide production and trehalose accumulation capability. In this study, water-soluble sunscreen pigments of mycosporine-like amino acids (MAAs) were characterized in N. verrucosum, and the mysABCD genes responsible for MAA biosynthesis in N. verrucosum and N. commune were compared. N. verrucosum produced porphyra-334 and shinorine, with porphyra-334 accounting for >90% of the total MAAs. Interestingly, porphyra-334 is an atypical cyanobacteial MAA, whereas shinorine is known as a common and dominant MAA in cyanobacteria. Porphyra-334 from N. verrucosum showed little or no radical scavenging activity in vitro, although the glycosylated derivatives of porphyra-334 from N. commune are potent radical scavengers. The presence of the mysABCD gene cluster in N. commune strain KU002 (genotype A) supported its porphyra-334 producing capability via the Nostoc-type mechanism, although the genotype A of N. commune mainly produces the arabinose-bound porphyra-334. The mysABC gene cluster was conserved in N. verrucosum, but the mysD gene was not included in the cluster. These results suggest that the mysABCD gene products are involved in the biosynthesis of porphyra-334 commonly in these Nostoc species, and that the genotype A of N. commune additionally acquired the glycosylation of porphyra-334.
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http://dx.doi.org/10.2323/jgam.2017.12.003DOI Listing
November 2018

Choriocapillaris flow deficit in Bietti crystalline dystrophy detected using optical coherence tomography angiography.

Br J Ophthalmol 2018 09 2;102(9):1208-1212. Epub 2017 Dec 2.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto City, Japan.

Background/aims: This study aimed to evaluate blood flow in the choriocapillaris in patients with Bietti crystalline dystrophy (BCD) with mutations using optical coherence tomography angiography (OCTA), and to explore the parameters associated with visual function.

Methods: This prospective case-series study included 13 eyes of 13 consecutive patients with BCD with mutations and 20 healthy eyes. Using OCTA, we obtained en face images of blood flow in the choriocapillaris. The residual choriocapillaris area on en face images in a 10°×10° macular cube was manually measured and graded according to whether the choriocapillaris remained at the subfovea. We also investigated factors associated with visual acuity (VA) and the mean deviation (MD) value using a Humphrey field analyser with a 10-2 Swedish Interactive Threshold Algorithm standard program among OCTA-derived parameters.

Results: Choriocapillaris blood flow deficit was observed in 12 eyes (92%), whereas this was observed in none of healthy eyes. The adjusted residual choriocapillaris area was 2.47±1.79 mm. The presence of the choriocapillaris at the subfovea was significantly correlated with VA and the MD value (P=0.006, r=0.71; P=0.04, r=-0.59, respectively).

Conclusions: Using OCTA, choriocapillaris blood flow deficit could be observed in most patients with BCD with mutations. The presence of the choriocapillaris at the subfovea was significantly correlated with visual function in these patients. Analysis of choriocapillaris blood flow using OCTA allows non-invasive assessment of the patient's state.
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http://dx.doi.org/10.1136/bjophthalmol-2017-311313DOI Listing
September 2018

Diabetic Neuroglial Changes in the Superficial and Deep Nonperfused Areas on Optical Coherence Tomography Angiography.

Invest Ophthalmol Vis Sci 2017 11;58(13):5870-5879

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Purpose: To evaluate the relationship between lamellar capillary nonperfusion on optical coherence tomography angiography (OCTA) images and neuroglial changes on structural optical coherence tomography (OCT) images in diabetic retinopathy (DR).

Methods: We retrospectively reviewed 101 consecutive eyes of 69 patients with DR. OCTA and OCT images within a 3 × 3-mm square centered on the fovea were acquired simultaneously. The nonperfused areas (NPAs) in the superficial capillary layer (sNPA) (from the nerve fiber layer [NFL] to the inner plexiform layer [IPL]), the deep layer (dNPA) (corresponding mainly to the inner nuclear layer [INL]), or both layers (bNPA) were measured individually along 10 transverse lines. The corresponding lamellar neuroglial changes also were evaluated on OCT images.

Results: The transverse lengths of the sNPA, dNPA, and bNPA were 2.34% (interquartile range, 0.81-5.55), 0.61% (0-1.99), and 5.96% (4.02-10.88), respectively. The length of the sNPA was correlated significantly with the lengths of no boundary between the NFL and ganglion cell layer (GCL)/IPL and the spots with inverted OCT reflectivity in the sNPA. The transverse length of the dNPA was associated with the length of cystoid spaces in the INL or Henle's fiber layer (HFL) in the dNPA. There was a significant correlation between the transverse lengths of the bNPA and no boundary between the NFL and GCL/IPL within the bNPA.

Conclusions: Systematic evaluation of the OCTA-OCT association showed structural changes in the neuroglial tissues corresponding to the lamellar NPAs and suggested the feasibility of layer-by-layer evaluation of the capillary nonperfusion in DR.
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http://dx.doi.org/10.1167/iovs.17-22156DOI Listing
November 2017

Choroidal Vasculature in Bietti Crystalline Dystrophy With CYP4V2 Mutations and in Retinitis Pigmentosa With EYS Mutations.

Invest Ophthalmol Vis Sci 2017 08;58(10):3871-3878

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.

Purpose: We compare the choroidal vascular area between Bietti crystalline dystrophy (BCD) patients with CYP4V2 mutations, retinitis pigmentosa (RP) patients with EYS mutations, and normal controls, and investigate the correlation between choroidal vascular area and associated parameters.

Methods: This prospective case-series study included consecutive nine eyes of nine BCD patients with CYP4V2 mutations (BCD group), 16 eyes of 16 RP patients with EYS mutations (EYS-RP group), and 16 eyes of 16 normal volunteers matched for age and axial length (control group). Using swept-source optical coherence tomography, we obtained en face images of the choroidal vasculature at the midpoint of the choriocapillaris layer-Sattler's layer (inner choroid) and Haller's layer (outer choroid). After binarization, we compared the inner and outer choroidal vascular areas among the three groups and identified associated factors.

Results: The outer choroidal vascular area was 43.34 ± 5.76%, 53.73 ± 4.92%, and 52.80 ± 4.10% in the BCD, EYS-RP, and control groups, respectively. This value was significantly smaller in the BCD group than in the EYS-RP and control groups (P < 0.001 in both; no significant difference between the EYS-RP and control groups). In the BCD group, the outer choroidal vascular area was correlated strongly with the subfoveal inner choroidal thickness (P = 0.001, r = 0.91, respectively). The inner choroidal vasculature could not be identified in eight of nine eyes in the BCD group.

Conclusions: The outer choroidal vascular narrowing might progress with the inner choroidal thinning in BCD, and the inner choroidal vasculature might be extinguished in advanced-stage BCD. Our findings may help to clarify the etiology of BCD.
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http://dx.doi.org/10.1167/iovs.17-21515DOI Listing
August 2017

Clinical relevance of reduced decorrelation signals in the diabetic inner choroid on optical coherence tomography angiography.

Sci Rep 2017 07 12;7(1):5227. Epub 2017 Jul 12.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Diabetes induces lesions of the retinal and choroidal capillaries, which promote the pathogenesis of diabetic retinopathy (DR). The decorrelation signals in optical coherence tomography angiography (OCTA) represent the blood flow and vascular structure, and three-dimensional OCTA images enable individual capillary layers to be evaluated separately. The current study documented that en-face OCTA images revealed spots of flow void in the choriocapillaris layer in eyes with DR. Quantitative investigation demonstrated that non-flow areas within the central subfield (CSF) increased in eyes with more severe DR grades. The non-flow areas in the choriocapillaris layer were also associated with poorer visual acuity (VA) in all 108 eyes. A modest correlation was noted between the areas of flow void and poorer VA in 69 eyes without DME, whereas the non-flow areas were not related to VA or to CSF thickness measured by OCT in 39 eyes with DME. In 12 eyes with ischemic maculopathy, the choriocapillaris layer beneath the disrupted ellipsoid zone of the photoreceptor (EZ) had greater areas of flow void than did the area beneath an intact EZ. These data suggested that disrupted choroidal circulation has clinical relevance and contributes to the pathogenesis of DR.
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http://dx.doi.org/10.1038/s41598-017-05663-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507874PMC
July 2017

Characterization of the scrambling domain of the TMEM16 family.

Proc Natl Acad Sci U S A 2017 06 30;114(24):6274-6279. Epub 2017 May 30.

Laboratory of Biochemistry and Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan

The TMEM16 protein family has 10 members, each of which carries 10 transmembrane segments. TMEM16A and 16B are Ca-activated Cl channels. Several other members, including TMEM16F, promote phospholipid scrambling between the inner and outer leaflets of a cell membrane in response to intracellular Ca However, the mechanism by which TMEM16 proteins translocate phospholipids in plasma membranes remains elusive. Here we show that Ca-activated, TMEM16F-supported phospholipid scrambling proceeds at 4 °C. Similar to TMEM16F and 16E, seven TMEM16 family members were found to carry a domain (SCRD; scrambling domain) spanning the fourth and fifth transmembrane segments that conferred scrambling ability to TMEM16A. By introducing point mutations into TMEM16F, we found that a lysine in the fourth transmembrane segment of the SCRD as well as an arginine in the third and a glutamic acid in the sixth transmembrane segment were important for exposing phosphatidylserine from the inner to the outer leaflet. However, their role in internalizing phospholipids was limited. Our results suggest that TMEM16 provides a cleft containing hydrophilic "stepping stones" for the outward translocation of phospholipids.
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http://dx.doi.org/10.1073/pnas.1703391114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474828PMC
June 2017

Novel glycosylated mycosporine-like amino acid, 13-O-(β-galactosyl)-porphyra-334, from the edible cyanobacterium Nostoc sphaericum-protective activity on human keratinocytes from UV light.

J Photochem Photobiol B 2017 Jul 15;172:102-108. Epub 2017 May 15.

Division of Life Science, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan; School of Natural System, College of Science and Engineering, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan; Division of Biological Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.

A UV-absorbing compound was purified and identified as a novel glycosylated mycosporine-like amino acid (MAA), 13-O-β-galactosyl-porphyra-334 (β-Gal-P334) from the edible cyanobacterium Nostoc sphaericum, known as "ge xian mi" in China and "cushuro" in Peru. Occurrence of the hexosylated derivative of shinorine (hexosyl-shinorine) was also supported by LC-MS/MS analysis. β-Gal-P334 accounted for about 86.5% of total MAA in N. sphaericum, followed by hexosyl-shinorine (13.2%) and porphyra-334 (0.2%). β-Gal-P334 had an absorption maximum at 334nm and molecular absorption coefficient was 46,700 at 334nm. Protection activity of β-Gal-P334 from UVB and UVA+8-methoxypsoralen induced cell damage on human keratinocytes (HaCaT) was assayed in comparison with other MAA (porphyra-334, shinorine, palythine and mycosporine-glycine). The UVB protection activity was highest in mycosporine-glycine, followed by palythine, β-Gal-P334, porphyra-334 and shinorine in order. β-Gal-P334 had highest protection activity from UVA+8-methoxypsoralen induced cell damage followed by porphyra-334, shinorine, mycosporine-glycine and palythine. We also found an antioxidant (radical-scavenging) activity of β-Gal-P334 by colorimetric and ESR methods. From these findings, β-Gal-P334 was suggested to play important roles in stress tolerant mechanisms such as UV and oxidative stress in N. sphaericum as a major MAA. We also consider that the newly identified MAA, β-Gal-P334 has a potential for use as an ingredient of cosmetics and toiletries.
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http://dx.doi.org/10.1016/j.jphotobiol.2017.05.019DOI Listing
July 2017

Relation between macular morphology and treatment frequency during twelve months with ranibizumab for diabetic macular edema.

PLoS One 2017 13;12(4):e0175809. Epub 2017 Apr 13.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Purpose: To investigate whether baseline optical coherence tomography (OCT) parameters can predict the treatment frequency of intravitreal ranibizumab (IVR) injections during the first year in patients with diabetic macular edema (DME) treated with pro re nata (PRN) IVR injections.

Methods: We retrospectively reviewed 68 eyes of 63 patients with center-involved DME who received IVR injections for 12 months or longer according to three monthly IVR injections followed by the PRN dosing. We measured the mean retinal thicknesses in the individual subfields of the Early Treatment Diabetic Retinopathy Study grid and evaluated the qualitative and quantitative parameters on OCT sectional images. We investigated the relationship between these OCT parameters at baseline and the number of IVR injections during the 12-month follow-up.

Results: Three loading doses were administered to 10 eyes; four to seven annualized IVR injections were administered to 34 eyes. The number of eyes that received IVR injections decreased gradually until month 6 and was almost constant from months 7 to 11. No relationships were seen between the treatment frequency and baseline systemic factors and the ophthalmic examination findings. Univariate analyses showed that the number of IVR injections during the first year was associated with the mean retinal thickness in the individual subfields and the transverse length of the disrupted external limiting membrane (ELM) and ellipsoid zone of the photoreceptors. Multivariate analysis showed a significant association with the thickness in the inferior subfield alone. The treatment frequency during the 12-month follow-up was not correlated with improved visual acuity but was associated with the decrease in the central subfield thickness and disrupted ELM.

Conclusion: The retinal thickness in the inferior subfield predicts the treatment frequency during the first year in eyes with DME treated with PRN IVR injections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391111PMC
April 2017

Optical Coherence Tomography Angiography to Estimate Retinal Blood Flow in Eyes with Retinitis Pigmentosa.

Sci Rep 2017 04 13;7:46396. Epub 2017 Apr 13.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin Kawahara-cho 54, Sakyo-ku, Kyoto, Japan.

Ophthalmologists sometimes face difficulties in identifying the origin of visual acuity (VA) loss in a retinitis pigmentosa (RP) patient, particularly before cataract surgery: cataract or the retinal disease state. Therefore, it is important to identify the significant factors correlating with VA. Nowadays, retinal blood flow in superficial and deep layers can be estimated non-invasively using optical coherence tomography angiography (OCTA). We estimated blood flow per retinal layer by using OCTA; investigated the correlation between VA and other parameters including blood flow and retinal thickness; and identified the most associated factor with VA in patients with RP. OCTA images in 68 of consecutive 110 Japanese RP patients were analysable (analysable RP group). Thirty-two age- and axial length-matched healthy eyes (control group) were studied. In the analysable RP group, the parafoveal flow density in superficial and deep layers was 47.0 ± 4.9% and 52.4 ± 5.5%, respectively, which was significantly lower than that in controls. Using multivariate analysis, we found that the parafoveal flow density in the deep layer and superficial foveal avascular area were the factors associated with VA. Non-invasive estimation of retinal blood flow per retinal layer using OCTA is useful for predicting VA in RP patients.
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http://dx.doi.org/10.1038/srep46396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390317PMC
April 2017

Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells.

Bioorg Med Chem 2017 05 14;25(9):2601-2608. Epub 2017 Mar 14.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan. Electronic address:

Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW™ and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1mM, respectively, and a sustained effect was observed 12h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10mM concentration and a sustained effect was not observed even at 6h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients.
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http://dx.doi.org/10.1016/j.bmc.2017.03.024DOI Listing
May 2017

Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.

FASEB J 2017 05 9;31(5):2195-2209. Epub 2017 Feb 9.

Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80/CD11b macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80/CD11b macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficient mice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA activity in these splenic macrophages and secretion of the resistance-inducing lipid mediator, lysophosphatidylcholine(24:1). These studies identify a novel and unexpected function for GPR120 and suggest that antagonists of this receptor might be effective agents to limit development of chemotherapy resistance.-Houthuijzen, J. M., Oosterom, I., Hudson, B. D., Hirasawa, A., Daenen, L. G. M., McLean, C. M., Hansen, S. V. F., van Jaarsveld, M. T. M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.
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http://dx.doi.org/10.1096/fj.201601248RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388545PMC
May 2017

Restoration of foveal photoreceptors after intravitreal ranibizumab injections for diabetic macular edema.

Sci Rep 2016 12 14;6:39161. Epub 2016 Dec 14.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Anti-vascular endothelial growth factor drugs are the first-line treatment for diabetic macular edema (DME), although the mechanism of the visual acuity (VA) improvement remains largely unknown. The association between photoreceptor damage and visual impairment encouraged us to retrospectively investigate the changes in the foveal photoreceptors in the external limiting membrane (ELM) and ellipsoid zone (EZ) on spectral-domain optical coherence tomography (SD-OCT) images in 62 eyes with DME treated with intravitreal ranibizumab (IVR) injections. The transverse lengths of the disrupted EZ and ELM were shortened significantly (P < 0.001 and P = 0.044, respectively) at 12 months. The qualitative investigation also showed restoration of the EZ and ELM lines on SD-OCT images. The EZ at 12 months lengthened in 34 of 38 eyes with discontinuous EZ and was preserved in 16 of 21 eyes with complete EZ at baseline. VA improvement was positively correlated with shortening of the disrupted EZ at 12 months (ρ = 0.463, P < 0.001), whereas the decrease in central subfield thickness was associated with neither VA improvement nor changes in EZ status (ρ = 0.215, P = 0.093 and (ρ = 0.209, P = 0.103, respectively). These data suggested that photoreceptor restoration contributes to VA improvement after pro re nata treatment with IVR injections for DME independent of resolved retinal thickening.
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http://dx.doi.org/10.1038/srep39161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155247PMC
December 2016

Characterization of fermented seaweed sauce prepared from nori (Pyropia yezoensis).

J Biosci Bioeng 2017 Mar 24;123(3):327-332. Epub 2016 Oct 24.

Mie University Community-University Research Cooperation Center, 1-3-3 Yumegaoka, Iga, Mie 518-0131, Japan.

High-salt content seaweed sauces were prepared for the first time using nori (Pyropia yezoensis) by fermentation and characterized. Components and taste of the two nori sauces (NSs) prepared separately were compared with those of soy and fish sauces. The NSs were rich in total nitrogen compounds (1.5 g N/100 ml on average) and potassium (880 mg/100 g), and had a unique free amino acid composition (e.g., taurine 617 mg/100 g), explaining their unique taste as evaluated by a taste sensing system. As for their food function, inhibitory activity of angiotensin-converting enzyme was observed. As for their food safety, arsenic was detected at a 0.8 mg/100 g level in total, but inorganic arsenic was not detected (<0.05 mg/100 g) and not regarded as a problem. Allergy-causing substances contained in wheat, soy beans, and crustaceans were not detected (<0.1 mg/100 g) with NSs. These results suggest that the nori sauce has a high potential as a novel nutritional source for humans.
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http://dx.doi.org/10.1016/j.jbiosc.2016.10.003DOI Listing
March 2017

Recognition of, interest in, and understanding of induced pluripotent stem cells and regenerative medicine in Japanese students.

Regen Ther 2016 Dec 11;5:96-106. Epub 2016 Oct 11.

Course for School Nurse Teacher, Faculty of Education, Ibaraki University, Japan.

We studied the recognition of, interest in, and understanding of induced pluripotent stem (iPS) cells and regenerative medicine in a total of 2659 junior high school, senior high school, and university students. The number of valid responses received was 2396 (90.1%). We report the following seven observations [1]. More than 80% of students reported recognition of iPS cells, regenerative medicine, and Professor Shinya Yamanaka, and a similar number were interested in and supportive of regenerative medicine [2]. Regenerative medicine was viewed as a medical treatment option. However, females were more cautious regarding use of regenerative medicine as a treatment compared with males [3]. Approximately 90% of students were interested in the latest medical care. Among the new treatment methods, they more frequently selected those that they were more familiar with and perceived less invasive to be ideal [4]. Regarding organ or tissue donation in regenerative medicine, students focused more on the characteristics of the donors [5]. Approximately 90% were supportive of storing their own cells. However, approximately 50% of students supported storing iPS cells for use in regenerative medicine [6]. Most students were anxious regarding the side effects, safety, and treatment costs of regenerative medicine, but supported the need of education regarding regenerative medicine [7]. More than 70% of students thought that education of regenerative medicine was necessary for the public. These findings suggest the importance of social approach, in addition to medical approach such as research and development, to improve QOL in community by developing the public understanding of regenerative medicine through science communication and school education, for the establishment of systems to promote this field.
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http://dx.doi.org/10.1016/j.reth.2016.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581836PMC
December 2016

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu-Hakola disease: lesion staging and dynamic changes of axons and microglial subsets.

Brain Pathol 2017 11 2;27(6):748-769. Epub 2017 Mar 2.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.

The brains of 10 Japanese patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) and eight Japanese patients with Nasu-Hakola disease (N-HD) and five age-matched Japanese controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets. In both diseases, the pathognomonic neuropathological features included spherically swollen axons (spheroids and globules), axon loss and changes of microglia in the white matter. In ALSP, four lesion stages based on the degree of axon loss were discernible: Stage I, patchy axon loss in the cerebral white matter without atrophy; Stage II, large patchy areas of axon loss with slight atrophy of the cerebral white matter and slight dilatation of the lateral ventricles; Stage III, extensive axon loss in the cerebral white matter and dilatation of the lateral and third ventricles without remarkable axon loss in the brainstem and cerebellum; Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. Internal capsule and pontine base were relatively well preserved in the N-HD, even at Stage IV, and the swollen axons were larger with a higher density in the ALSP. Microglial cells immunopositive for CD68, CD163 or CD204 were far more obvious in ALSP, than in N-HD, and the shape and density of the cells changed in each stage. With progression of the stage, clinical symptoms became worse to apathetic state, and epilepsy was frequently observed in patients at Stages III and IV in both diseases. From these findings, it is concluded that (i) shape, density and subsets of microglia change dynamically along the passage of stages and (ii) increase of IBA-1-, CD68-, CD163- and CD204-immunopositive cells precedes loss of axons in ALSP.
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http://dx.doi.org/10.1111/bpa.12443DOI Listing
November 2017

Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids.

Ann Neurol 2016 10 4;80(4):554-65. Epub 2016 Sep 4.

Department of Pathology, Brain Research Institute, Niigata University, Niigata.

Objective: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R).

Methods: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed.

Results: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow.

Interpretation: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations. Ann Neurol 2016;80:554-565.
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http://dx.doi.org/10.1002/ana.24754DOI Listing
October 2016

Clustering of Combined 24-2 and 10-2 Visual Field Grids and Their Relationship With Circumpapillary Retinal Nerve Fiber Layer Thickness.

Invest Ophthalmol Vis Sci 2016 06;57(7):3203-10

Purpose: The purpose of this study was to cluster the test points of the combined 24-2 and 10-2 visual fields (VFs) and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) sectors using explanatory factor analyses (EFAs). The correlations between the VF clusters and cpRNFLT clusters were determined, and a new function-structure relationship map was determined.

Methods: Two hundred fifty-four eyes of 166 subjects (13 normal eyes and 241 eyes with glaucoma) were studied retrospectively. All eyes had an axial length <27 mm and had undergone 24-2 and 10-2 VF tests using the Swedish Interactive Threshold Algorithm (SITA-standard) and cpRNFLT examinations by spectral domain optical coherence tomography within a 3-month period. Explanatory factor analysis was performed to group the 116 test points of the combined 24-2/10-2 VF test grids into a smaller number of VF clusters. Another EFA was performed to cluster the 24 cpRNFLT sectors. The correlations between the VF clusters and the cpRNFLT clusters were evaluated by Pearson's correlation analysis.

Results: The combined 24-2/10-2 VF test grids were grouped into seven VF clusters by EFA. Another EFA grouped the cpRNFLT sectors into 11 clusters. The correlation coefficients between the corresponding VF and cpRNFLT clusters ranged from 0.304 (P < 1 × 10-6) to 0.794 (P < 2.2 × 10-16).

Conclusions: Explanatory factor analysis revealed detailed patterns of glaucomatous VF defects and glaucomatous cpRNFL thinning. Their significant correlations indicate that they have common latent factors that might be derived from a developing pattern of glaucomatous optic neuropathy. These findings support the function-structure relationship theory in glaucoma.
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http://dx.doi.org/10.1167/iovs.15-18798DOI Listing
June 2016

Role of Ca(2+) in the Stability and Function of TMEM16F and 16K.

Biochemistry 2016 06 3;55(23):3180-8. Epub 2016 Jun 3.

Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University , 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.

There are 10 transmembrane protein (TMEM) 16-family proteins in humans and mice. Among them, TMEM16F acts as a Ca(2+)-dependent phospholipid scramblase at the plasma membrane. However, how Ca(2+) activates TMEM16F's phospholipid-scramblase activity has not been elucidated. Here we found that in the presence of Ca(2+), TMEM16K (whose function is unknown) directly binds Ca(2+) to form a stable complex that can be detected by blue-native polyacrylamide gel electrophoresis. In the absence of Ca(2+), TMEM16K and TMEM16F aggregated, suggesting that their structure is stabilized by Ca(2+). Comprehensive mutagenesis of acidic residues in TMEM16K's cytoplasmic and transmembrane regions identified five residues that are critical for binding Ca(2+). These residues were well conserved between TMEM16F and 16K, and point mutations of these residues in TMEM16F reduced its ability to support Ca(2+)-dependent phospholipid scrambling. Our results suggest that Ca(2+) binds TMEM16F directly and induces conformational changes that support its stability and function.
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http://dx.doi.org/10.1021/acs.biochem.6b00176DOI Listing
June 2016

Japanese university students' views on lesbian, gay, bisexual, and transgender individuals based on previous encounters.

Int J Adolesc Med Health 2016 Apr 18;30(1). Epub 2016 Apr 18.

Department of Health and Education, Ibaraki University College of Education, Ibaraki, Japan.

Objective: To elucidate the acceptability of sexual minorities according to Japanese youth, we conducted a survey targeting university students.

Methods: Participants were second- to fourth-year students (n=945) at Ibaraki University, Japan, who were randomly chosen for the survey to measure their attitudes toward lesbian, gay, bisexual, and transgender (LGBT) individuals. We divided the respondents into two groups: one group who had encounters with LGBT people, and one group with no such experience. Chi-square tests were used to compare responses between the groups.

Results: More than 60% of the students considered LGBT people to be acceptable; the group with prior encounters had greater levels of acceptance compared to the group without such encounters.

Conclusion: This is the first study to clarify the acceptability of sexual minorities among university students in Japan. Our data suggested that having contact with LGBT people in school life may help build an inclusive educational system.
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http://dx.doi.org/10.1515/ijamh-2015-0121DOI Listing
April 2016