Publications by authors named "Yoshiaki Shimada"

78 Publications

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

J Stroke Cerebrovasc Dis 2021 Aug 6;30(8):105892. Epub 2021 Jun 6.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan. Electronic address:

Objective: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score.

Materials And Methods: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis.

Results: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores.

Conclusions: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105892DOI Listing
August 2021

Different aspects of early and late development of atrial fibrillation during hospitalization in cryptogenic stroke.

Sci Rep 2021 Mar 29;11(1):7127. Epub 2021 Mar 29.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19-15.97; p < 0.001) was associated with AF ≤ 4 days, whereas a large infarction > 3 cm in diameter (OR 3.28; 95% CI 1.35-7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.
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http://dx.doi.org/10.1038/s41598-021-86620-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007744PMC
March 2021

Transient Increase and Delay of Multifocal Electroretinograms Following Laser Photocoagulations for Diabetic Macular Edema.

J Clin Med 2021 Jan 19;10(2). Epub 2021 Jan 19.

Department of Ophthalmology, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.

Background: The acute physiological changes induced by focal retinal photocoagulation (PC) have been largely unexplored.

Methods: This was a case-series study. We recorded multifocal electroretinograms (mfERGs) just before PC, and mfERGs were also recorded 5', 15', one hour, 24 h, and one week after the PCs. Transient changes of mfERGs were analyzed in eyes which underwent PCs to treat diabetic macular edema. The mfERGs recorded from the predominantly irradiated area and that from non-irradiated areas were analyzed separately.

Results: Fifteen eyes of 15 patients were included in this study. The mfERGs elicited from non-irradiated areas did not change after PC, but the mfERGs elicited from the irradiated area changed with time; the amplitude was larger at 60' than that before ( < 0.05) and at 5' after PC ( < 0.01) and significantly smaller at 24 h and 1 week than that before and at 60' after the PC ( < 0.01). The implicit time was significantly prolonged after PC. mfERG on irradiated area with the severe diabetic change was less altered after PCs.

Conclusions: The transient increase in the amplitude at 60' likely resulted from a biological amplification of partially damaged cells adjacent to the PC spots. The mfERGs manifested the dynamic alterations of the retinal function following PCs.
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http://dx.doi.org/10.3390/jcm10020357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833362PMC
January 2021

The influence of mild cataract on ISCEV standard electroretinogram recorded from mydriatic eyes.

Doc Ophthalmol 2021 Apr 12;142(2):177-183. Epub 2020 Sep 12.

Department of Ophthalmology, Fujita Health University School of Medicine, Toyoake, Japan.

Purpose: To investigate the effect of mild cataract and its surgery on the ISCEV standard electroretinogram (ERG) by comparing pre- and postoperative ERGs elicited from fully dilated eyes.

Methods: Twenty-two patients participated. Each eye had cataract of grade 2 according to Emery-Little classification. None had complications during and after phacoemulsification and intraocular lens implantation. According to the ISCEV standard, pre- and 1-week postoperative full-field ERGs, dark adapted (DA) 0.01, DA 3, DA 3 oscillatory potentials (OPs), DA 10, and light adapted (LA) 3, and LA 3 flicker, were elicited from fully dilated eyes using skin electrodes. Photopic negative response (PhNR) 1 amplitude was measured from the baseline to the trough before the i-wave in the LA 3 ERG waveform. Statistical analysis was performed using SigmaPlot version 11.0 (Systat Software, Inc., San Jose, CA, USA). Pre- and postoperative data were compared using a paired t-test. Non-normally distributed data were evaluated using the Wilcoxon signed rank test.

Results: The pre- and 1-week postoperative amplitudes in each component were as follows: DA 0.01: 48.4 ± 19.5 μV and 57.1 ± 20.0 μV (p = 0.002), a-wave of DA3: 51.5 ± 14.8 μV and 58.3 ± 17.3 μV (p = 0.003), b-wave of DA3: 88.3 ± 27.5 μV and 101.5 ± 29.7 μV (p = 0.003), DA 3 ΣOPs (sum of DA 3 OP1, OP2, and OP3 amplitude): 30.7 ± 16.3 μV and 37.1 ± 21.9 μV (p < 0.001), a-wave of DA 10: 65.5 ± 18.8 μV and 74.2 ± 19.5 μV (p < 0.001), b-wave of DA 10: 95.5 ± 29.6 μV and 111.1 ± 29.9 μV (p < 0.001), a-wave of LA 3: 7.2 ± 2.6 μV and 8.2 ± 2.2 μV (p = 0.025), b-wave of LA 3: 30.6 ± 12.9 μV and 35.3 ± 12.7 μV (p = 0.003), PhNR1: 5.8 ± 2.5 μV and 5.5 ± 2.6 μV (p = 0.562), and LA 3 flicker: 25.4 ± 8.9 μV and 27.8 ± 8.6 μV (p = 0.039), respectively. The implicit time of all the components did not reveal significant differences before and after surgery.

Conclusions: Cataractous lens removal and intraocular lens implantation may influence ISCEV standard ERGs, even if the cataract is relatively mild.
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http://dx.doi.org/10.1007/s10633-020-09791-yDOI Listing
April 2021

Atrial Septal Aneurysm may Cause In-Hospital Recurrence of Cryptogenic Stroke.

J Atheroscler Thromb 2021 May 17;28(5):514-523. Epub 2020 Jul 17.

Department of Neurology, Juntendo University Urayasu Hospital.

Aims: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke.

Methods: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients' clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed.

Results: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p=0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p=0.030), higher frequency of right-to-left shunt (66% vs. 45%, p<0.001), and in-hospital stroke recurrence (8% vs. 3%, p=0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959-6.500, p= 0.061).

Conclusions: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA's clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.
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http://dx.doi.org/10.5551/jat.56440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193779PMC
May 2021

Unilaterally extinguished electroretinograms in an eye with normal visual acuity and visual field.

Doc Ophthalmol 2021 Feb 25;142(1):127-132. Epub 2020 Jun 25.

Department of Ophthalmology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Purpose: This study reports a case of unilateral retinopathy with extinguished full-field ERGs (ffERGs), wherein the visual acuity was 16/16 and the visual field was spared.

Methods: Observational case report.

Results: A 39-year-old female had developed nyctalopia in her left eye. Two years later, she visited an ophthalmologist who noted a bilaterally reduced pigmentation of the fundus. Her best-corrected visual acuity was 16/16 in both the eyes. Goldmann perimetry demonstrated that her visual field was bilaterally fully spared. ffERGs measurement was performed in accordance with the ISCEV standard protocol and indicated that her right eye was normal. However, all ERG responses were severely attenuated in her left eye. Multifocal ERG responses were found to be normal in the right eye and extinguished in the left eye except for residual responses that were exclusively located at the center. During the 7 years of the follow-up period, the visual field in the left eye, which was once normal, became shaded, and the development of a ring scotoma was identified. The visual field in the right eye is still full.

Conclusions: The pathogenesis of this patient's condition still remains unknown, while unilateral retinitis pigmentosa, unilateral pigmentary retinopathy, acute zonal occult outer retinopathy, and autoimmune retinopathy can all be considered as possible explanations. The uniqueness of this case study is that the extinguished ERG responses are predictive of the functional alteration in the affected eye, when the initial visual acuity and the visual field were normal.
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http://dx.doi.org/10.1007/s10633-020-09779-8DOI Listing
February 2021

Unintentional retinal artery amputation during macular peeling.

Authors:
Yoshiaki Shimada

GMS Ophthalmol Cases 2020 18;10:Doc13. Epub 2020 Mar 18.

Department of Ophthalmology, Fujita Health University Bantane Hospital, Aichi, Japan.

To report a case of unintentional retina artery amputation during macular peeling. Observational case report A 73-year-old female underwent surgery to treat epiretinal membrane (ERM) associated with severe staphyloma in her left eye. While the ERM/posterior hyaloid membrane visually enhanced with triamcinolone (TA) was peeled, a movement of the forceps unintentionally involved the inferior temporal branch artery near the inner edge of the staphyloma. The artery was avulsed and amputated. Oozing from the retinal cleft that had once enfolded the artery and microscopic bleeding from the amputation stump were observed. The vitreous hemorrhage obscured a view of the fundus more than 4 weeks after the surgery. After 8 weeks, postoperative visual acuity was improved; however, the superior nasal visual field was lost, and the patient was aware of the broken vessel as a floater in her vision. Macular peeling is technically challenging, so meticulous attention must be paid to avoid any damage on vessels. The retina tissue was stretched in a staphyloma and vessels were bulged into the vitreous space especially at the inner edge of the staphyloma. High levels of TA dye here buried the texture of the retina. Excessive TA should be removed prior to macular peeling.
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http://dx.doi.org/10.3205/oc000140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114637PMC
March 2020

Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke.

J Neurol 2020 May 3;267(5):1482-1490. Epub 2020 Feb 3.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

Background: Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebral microbleeds (CMBs) occur differently among stroke subtypes. The association of CMBs with cryptogenic stroke is essentially unknown.

Methods: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) is a multicenter registry with comprehensive data including gradient-echo T2*-weighted magnetic resonance imaging of cryptogenic stroke patients who underwent transesophageal echocardiography. Patients' clinical characteristics were compared according to the presence and location of CMBs.

Results: A total of 661 patients (68.7 ± 12.7 years; 445 males) were enrolled, and 209 (32%) had CMBs. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04, p = 0.020), male sex (OR 1.85, 95% CI 1.18-2.91, p = 0.007), hypertension (OR 1.71, 95% CI 1.03-2.86, p = 0.039), chronic kidney disease (OR 1.64, 95% CI 1.11-2.43, p = 0.013), deep and subcortical white matter hyperintensity (OR 1.82, 95% CI 1.16-2.85, p = 0.009), and periventricular hyperintensity (OR 2.18, 95% CI 1.37-3.46, p = 0.001) were independently associated with the presence of CMBs. Aortic complicated lesions (OR 1.78, 95% CI 1.12-2.84, p = 0.015) were associated with deep and diffuse CMBs, whereas prior anticoagulant therapy (OR 7.88, 95% CI, 1.83-33.9, p = 0.006) was related to lobar CMBs.

Conclusions: CMBs were common, and age, male sex, hypertension, chronic kidney disease, and cerebral white matter diseases were related to CMBs in cryptogenic stroke. Aortic complicated lesions were associated with deep and diffuse CMBs, while prior anticoagulant therapy was related to lobar CMBs.
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http://dx.doi.org/10.1007/s00415-020-09732-4DOI Listing
May 2020

Measurement of the volume of the vitrectomized space during vitrectomy in myopic patients with retinal detachment.

Jpn J Ophthalmol 2020 Mar 6;64(2):210-215. Epub 2020 Jan 6.

Department of Ophthalmology, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi, 470-1192, Japan.

Purpose: We present a novel technique for measuring volume of space replaced by air during fluid-air exchange in vitrectomy (vitrectomized space) for intravitreal gas injection. To confirm the feasibility of this technique, we assessed postoperative intraocular pressure (IOP) and the duration of injected gas. Using this technique, we found remarkable differences in volume between high myopic eyes with retinal detachment caused by peripheral break (PB-RD group) and those with macular hole retinal detachment (MH-RD group). We studied the relationships between the volume and biometric values, axial length (AL) and corneal curvature radius (CCR) in both PB-RD and MH-RD group.

Study Design: Retrospective study.

Methods: During fluid-air exchange, the aspirated fluid accumulates in the measuring cup between the infusion needle and vitrectomy instrument. Vitrectomized space volume is obtained by subtracting the volume of the tube between the infusion needle and the 3-way stopcock from the aspirated fluid volume. We performed phaco-vitrectomies by measuring the vitrectomized space volume and then injected pure SF6 at 15% of the volume into the vitreous cavity in 156 myopic eyes (AL > 26 mm) with RD consisting of 144 eyes in PB-RD group and 12 in MH-group.

Results: The IOP (mean ± SD) was 13.5 ± 3.4 mmHg preoperatively, 23.4 ± 10.4 mmHg on day 1, 18.2 ± 7.4 mmHg on day 2, and 16.1 ± 4.5 on day 7. The gas disappeared in 16.1 ± 1.9 days. Axial length was longer in the MH-RD group but the volume of vitrectomized space was larger in the PB-RD group. AL and volume were significantly correlated in both groups (P < 0.01), but the fitting lines differed. The CCR and volume significantly correlated in the PB-RD group (P < 0.01) but not in the MH-RD group.

Conclusion: Our novel technique for measuring the volume of vitrectomized space can achieve target gas concentration in the vitreous cavity. The difference in the shape of eyeballs may explain discrepancies in relationship between volume and the biometric factors.
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http://dx.doi.org/10.1007/s10384-019-00713-3DOI Listing
March 2020

Analysis of Clinical Symptoms and Brain MRI of Heat Stroke: 2 Case Reports and a Literature Review.

J Stroke Cerebrovasc Dis 2020 Feb 26;29(2):104511. Epub 2019 Nov 26.

Department of Neurology, Juntendo Urayasu Hospital, Urayasu-city, Chiba, Japan.

Introduction: Heat stroke is defined as high body temperature causing multiple organ failure, psychological change, seizure, and consciousness disturbance, which lead to its high mortality rate. However, the involvement of brain injury is rare, and heat-stroke has only been reported in a few case reports or case series. The purpose of this case study was to evaluate the clinical symptoms and radiological features of heat stroke.

Methods: We reviewed our hospital records and previously published reports to find cases of heat stroke. We excluded those with unknown clinical features or radiological findings.

Results: We retrieved 2 cases of heat stroke from our hospital, which presented as extensive lesions on brain imaging that led to disseminated intravascular coagulation and death within a few days. In 21 previously reported cases of heat stroke, similar brain lesions were noted. These were classified as infarction/posterior reversible encephalopathy syndrome (PRES)-like lesions. The patients who developed PRES-like lesions and survived often developed cerebellar sequelae.

Conclusion: The mechanism of heat stroke is presumed to be multifactorial. Ischemic-like lesions result from hypovolemia and unusual coagulation, whereas PRES-like lesions are caused by direct heat and vasogenic edema due to hypercytokinemia. We need to consider the above mentioned conditions when evaluating heat stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.104511DOI Listing
February 2020

Protective Role of Levetiracetam Against Cognitive Impairment And Brain White Matter Damage in Mouse prolonged Cerebral Hypoperfusion.

Neuroscience 2019 08 11;414:255-264. Epub 2019 Jul 11.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

White matter lesions due to cerebral hypoperfusion may be an important pathophysiology in vascular dementia and stroke, although the inherent mechanisms remain to be fully elucidated. The present study, using a mouse model of chronic cerebral hypoperfusion, examined the white matter protective effects of levetiracetam, an anticonvulsant, via the signaling cascade from the activation of cAMP-responsive element binding protein (CREB) phosphorylation. Mice underwent bilateral common carotid artery stenosis (BCAS), and were separated into the levetiracetam group (injected once only after BCAS [LEV1] or injected on three consecutive days [LEV3]), the vehicle group, or the anti-epileptic drugs with different action mechanisms phenytoin group (PHT3; injected on three consecutive days with the same condition as in LEV3). Cerebral blood flow analysis, Y-maze spontaneous alternation test, novel object recognition test, immunohistochemical and Western blot analyses, and protein kinase A assay were performed after BCAS. In the LEV3 group, SV2A expression was markedly increased, which preserved learning and memory after BCAS. Moreover, as the protein kinase A level was significantly increased, pCREB expression was also increased. The activation of microglia and astrocytes was markedly suppressed, although the number of oligodendrocyte precursor cells (OPCs) and GST-pi-positive-oligodendrocytes was markedly higher in the cerebral white matter. Moreover, oxidative stress was significantly reduced. We found that 3-day treatment with levetiracetam maintained SV2A protein expression via interaction with astrocytes, which influenced the OPC lineage through activation of CREB to protect white matter from ischemia.
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http://dx.doi.org/10.1016/j.neuroscience.2019.07.015DOI Listing
August 2019

Large aortic arch plaques correlate with CHADS and CHADS-VASc scores in cryptogenic stroke.

Atherosclerosis 2019 05 20;284:181-186. Epub 2019 Mar 20.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

Background And Aims: Current trends have suggested covert atrial fibrillation as a mechanism of cryptogenic stroke. However, etiological heterogeneity regarding the underlying embolic sources remains a critical issue in cryptogenic stroke.

Methods: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) is a multicenter observational registry of cryptogenic stroke patients admitted to participating hospitals, who underwent transesophageal echocardiography between April 2014 and December 2016. We obtained baseline characteristics, radiological and laboratory data, and echocardiographic findings, especially for embolic sources demonstrated on transesophageal echocardiography, and conducted comparisons according to CHADS and CHADS-VASc scores (0-1 vs. ≥2, respectively). This study was registered at http://www.umin.ac.jp/ctr/(UMIN000032957).

Results: The study comprised 677 patients (age, 68.7 ± 12.8 years; 455 males; median National Institutes of Health Stroke Scale score, 2) with cryptogenic stroke. On multiple logistic regression analysis, large aortic arch plaque ≥4 mm (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.51-3.36; p < 0.001), with ulcerative or mobile components (OR, 2.37; 95%CI, 1.38-4.06; p = 0.002), was associated with CHADS score ≥2. Large aortic arch plaque ≥4 mm (OR, 3.88; 95%CI, 2.07-7.27; p < 0.001) and ulcerative or mobile components (OR, 3.25; 95%CI, 1.44-7.34; p = 0.005) were linked to CHADS-VASc score ≥2.

Conclusions: The CHALLENGE ESUS/CS registry is a large TEE registry, and clarifies potential embolic etiologies of cryptogenic stroke using TEE. Large aortic arch plaques were associated with high CHADS and CHADS-VASc scores, and represented important embolic sources in cryptogenic stroke.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.03.009DOI Listing
May 2019

Adherence to face-down and non-supine positioning after macular hole surgery.

BMC Ophthalmol 2018 Dec 14;18(1):322. Epub 2018 Dec 14.

Department of Ophthalmology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Background: This study aimed to investigate patient adherence to face-down positioning (FDP) and non-supine positioning (NSP) following vitrectomy with gas tamponade for treating macular holes (MHs).

Methods: Nursing records of 92 patients who underwent vitrectomy with gas tamponade for small-diameter (diameter < 400 μm) MHs during April 2016-June 2017 were examined. Forty-seven and 45 patients were instructed to maintain FDP and NSP (FDP and NSP groups), respectively. Patient adherence was evaluated seven times a day for 3 days, and the adherence rate was calculated.

Results: The mean adherence rate was significantly higher in the NSP group (99.3% ± 2.7%) than in the FDP group (93.7% ± 13.3%; P < 0.001, Mann-Whitney U test). Forty-one patients (91.1%) in the NSP group had an adherence rate of 100%, which was significantly higher than that in the 24 patients in the FDP group (51.1%; P < 0.001, chi-squared test). No statistically significant difference was observed between the patients in the two groups regarding sex, age, MH diameter, and pre- and postoperative visual acuities. MH closure was achieved in all patients.

Conclusions: Almost half of the patients in the FDP group did not obtain 100% adherence rate, suggesting that patient adherence was largely compromised. Patient adherence was better in the NSP group as patient compliance to NSP was better, however, 8.9% of patients were found in face-up positioning at least once. Incompleteness of patient adherence was common, although to differing degrees.
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http://dx.doi.org/10.1186/s12886-018-0979-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295062PMC
December 2018

Phosphorylated recombinant HSP27 protects the brain and attenuates blood-brain barrier disruption following stroke in mice receiving intravenous tissue-plasminogen activator.

PLoS One 2018 24;13(5):e0198039. Epub 2018 May 24.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Loss of integrity of the blood-brain barrier (BBB) in ischemic stroke victims initiates a devastating cascade of events causing brain damage. Maintaining the BBB is important to preserve brain function in ischemic stroke. Unfortunately, recombinant tissue plasminogen activator (tPA), the only effective fibrinolytic treatment at the acute stage of ischemic stroke, also injures the BBB and increases the risk of brain edema and secondary hemorrhagic transformation. Thus, it is important to identify compounds that maintain BBB integrity in the face of ischemic injury in patients with stroke. We previously demonstrated that intravenously injected phosphorylated recombinant heat shock protein 27 (prHSP27) protects the brains of mice with transient middle cerebral artery occlusion (tMCAO), an animal stroke-model. Here, we determined whether prHSP27, in addition to attenuating brain injury, also decreases BBB damage in hyperglycemic tMCAO mice that had received tPA. After induction of hyperglycemia and tMCAO, we examined 4 treatment groups: 1) bovine serum albumin (BSA), 2) prHSP27, 3) tPA, 4) tPA plus prHSP27. We examined the effects of prHSP27 by comparing the BSA and prHSP27 groups and the tPA and tPA plus prHSP27 groups. Twenty-four hours after injection, prHSP27 reduced infarct volume, brain swelling, neurological deficits, the loss of microvessel proteins and endothelial cell walls, and mortality. It also reduced the rates of hemorrhagic transformation, extravasation of endogenous IgG, and MMP-9 activity, signs of BBB damage. Therefore, prHSP27 injection attenuated brain damage and preserved the BBB in tPA-injected, hyperglycemic tMCAO experimental stroke-model mice, in which the BBB is even more severely damaged than in simple tMCAO mice. The attenuation of brain damage and BBB disruption in the presence of tPA suggests the effectiveness of prHSP27 and tPA as a combination therapy. prHSP27 may be a novel therapeutic agent for ischemic stroke patients whose BBBs are injured following tPA injections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993064PMC
December 2018

Comparison of visual acuity, metamorphopsia, and aniseikonia in patients with an idiopathic epiretinal membrane.

Jpn J Ophthalmol 2018 May 6;62(3):280-285. Epub 2018 Apr 6.

Department of Ophthalmology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Purpose: The clinical course of reduced visual acuity, metamorphopsia, and aniseikonia are dissimilar in patients with an epiretinal membrane (ERM). We measured and compared the best-corrected visual acuity (BCVA), metamorphopsia, and aniseikonia of patients with ERM.

Methods: We measured metamorphopsia and aniseikonia horizontally as well as vertically with the M-CHART (MH and MV) and New Aniseikonia Test (NATH and NATV) in 61 patients with unilateral idiopathic ERM. We compared the BCVA with the other values. Comparisons between the MH and the NATV and between the MV and the NATH were performed, because the MH assesses vertical metamorphopsia, and the MV, horizontal metamorphopsia.

Results: BCVA was not significantly correlated with the other values (MH vs BCVA: P = .69; MV vs BCVA: P = .114; NATH vs BCVA: P = .656; NATV vs BCVA: P = .935). The MH and NATV magnitudes were significantly correlated, but the correlation coefficient was small (P = .007, r = 0.343); no significant correlation was found between the MV and NATH magnitudes (P = .065). We found patients with aniseikonia, but no metamorphopsia (n = 6), and more patients with metamorphopsia, but no aniseikonia (n = 11). Only 23 patients had coincident directions of metamorphopsia and aniseikonia.

Conclusions: The magnitudes of metamorphopsia and aniseikonia were not closely correlated and their directions did not coincide in most patients. Neither the M-CHARTS nor the NAT measurements correlated with the BCVA. Quantitative testing of metamorphopsia and aniseikonia in addition to that for BCVA is necessary to assess visual function in patients with ERM.
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http://dx.doi.org/10.1007/s10384-018-0581-xDOI Listing
May 2018

Adherence to the face-down positioning after vitrectomy and gas tamponade: a time series analysis.

BMC Res Notes 2018 Feb 20;11(1):142. Epub 2018 Feb 20.

Department of Ophthalmology, Fujita Health University School of Medicine, Fujita Health University Hospital, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Objective: To determine the adherence to the face-down positioning (FDP) in 296 patients who had undergone vitrectomy and gas tamponade.

Results: We studied 119 female and 177 male patients who had undergone primary vitrectomy and gas tamponade for a macular hole (MH) or for rhegmatogenous retinal detachments (RRDs). Adherence was assessed and recorded four times per day for 3 days postsurgery. The mean ± standard deviation adherence rate was 88.3 ± 11.7 (range 50.0-100.0). Female patients (90.8 ± 10.0) had significantly better adherence than male patients (86.7 ± 13.3; P < 0.02, U test). The adherence was significantly better after MH surgery (90.8 ± 11.7) than after RRD surgery (87.5 ± 12.5; P < 0.02). There were diurnal variations in adherence, being highest in the evening and significantly lower at midnight, and we evidenced a decline in adherence over time, with it being significantly low on the last follow-up day. Adherence to the FDP varied considerably among patients. Adherence was higher in female than in male patients, and higher in patients with MH than in those with RRD. We found patients age had no effect on adherence. Adherence also varied with time, being worst at midnight and declining over time.
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http://dx.doi.org/10.1186/s13104-018-3257-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819221PMC
February 2018

A Conjunctival Retractor during Strabismus Surgery.

Strabismus 2018 03 20;26(1):42-44. Epub 2017 Dec 20.

a Department of Ophthalmology , Fujita Health University Hospital , Toyoake , Aichi , Japan.

The use of a conjunctival retractor that expands a small incision in the conjunctiva/Tenon's capsule facilitated the performance of strabismus surgery through a fornix incision. A wide field of exposure revealed the entire area of the muscle insertion. While there is a risk of conjunctival tearing in elderly patients, the use of the retractor is valuable.
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http://dx.doi.org/10.1080/09273972.2017.1415363DOI Listing
March 2018

Glycyl-alanyl-histidine protects PC12 cells against hydrogen peroxide toxicity.

BMC Biochem 2017 11 22;18(1):14. Epub 2017 Nov 22.

Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, Japan.

Background: Peptides with cytoprotective functions, including antioxidants and anti-infectives, could be useful therapeutics. Carnosine, β-alanine-histidine, is a dipeptide with anti-oxidant properties. Tripeptides of Ala-His-Lys, Pro-His-His, or Tyr-His-Tyr are also of interest in this respect.

Results: We synthesized several histidine-containing peptides including glycine or alanine, and tested their cytoprotective effects on hydrogen peroxide toxicity for PC12 cells. Of all these peptides (Gly-His-His, Ala-His-His, Ala-His-Ala, Ala-Ala-His, Ala-Gly-His, Gly-Ala-His (GAH), Ala-His-Gly, His-Ala-Gly, His-His-His, Gly-His-Ala, and Gly-Gly-His), GAH was found to have the strongest cytoprotective activity. GAH decreased lactate dehydrogenase (LDH) leakage, apoptosis, morphological changes, and nuclear membrane permeability changes against hydrogen peroxide toxicity in PC12 cells. The cytoprotective activity of GAH was superior to that of carnosine against hydrogen peroxide toxicity in PC12 cells. GAH also protected PC12 cells against damage caused by actinomycin D and staurosporine. Additionally, it was found that GAH also protected SH-SY5Y and Jurkat cells from damage caused by hydrogen peroxide, as assessed by LDH leakage.

Conclusion: Thus, a novel tripeptide, GAH, has been identified as having broad cytoprotective effects against hydrogen peroxide-induced cell damage.
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http://dx.doi.org/10.1186/s12858-017-0089-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700669PMC
November 2017

Synthesis and structure activity relationships of carbamimidoylcarbamate derivatives as novel vascular adhesion protein-1 inhibitors.

Bioorg Med Chem 2017 11 23;25(21):6024-6038. Epub 2017 Sep 23.

Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1, which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c, which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity. We also found that conversion of the pyrimidine ring in 20c into saturated rings was effective for improving aqueous solubility. This led to the identification of 28a and 35 as moderate VAP-1 inhibitors with excellent aqueous solubility. Further optimization led to the identification of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate (40b), which showed similar human VAP-1 inhibitory activity to 1 with improved aqueous solubility. 40b showed more potent ex vivo efficacy than 1, with rat plasma VAP-1 inhibitory activity of 92% at 1h after oral administration at 0.3mg/kg. In our pharmacokinetic study, 40b showed good oral bioavailability in rats, dogs, and monkeys, which may be due to its improved stability in dog and monkey plasma.
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http://dx.doi.org/10.1016/j.bmc.2017.09.036DOI Listing
November 2017

Analysis of the Usefulness of the WORSEN Score for Predicting the Deterioration of Acute Ischemic Stroke.

J Stroke Cerebrovasc Dis 2017 Dec 4;26(12):2834-2839. Epub 2017 Aug 4.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. Electronic address:

Background: Early neurological worsening is associated with increased mortality and long-term functional disability. We developed the WORSEN score for predicting whether patients with stroke will deteriorate during the week after stroke onset and investigated its usefulness.

Patients And Methods: We retrospectively investigated the cases of 478 patients who were admitted to Juntendo University Hospital between April 2007 and March 2009. Neurological deterioration was defined as a worsening of 4 points or higher on the National Institute of Health Stroke Scale score within 1 week of admission. Based on a previous study, we developed the WORSEN score, which was derived from the following factors: wrong (poor) blood sugar control (W), old myocardial infarction (O), radiological findings (R), infarct size (S), elevated low-density lipoprotein cholesterol (E), and neurological findings (N). Next, we investigated the utility of this scoring system in 456 other patients who were admitted to Juntendo University Hospital and Juntendo Urayasu Hospital between October 2013 and December 2014.

Results: First, we checked the utility of the WORSEN score for detecting worsening in cases of stroke. In the first patient group, deterioration was noted in 32.5% of the patients with scores higher than 3 points (sensitivity: .704 and specificity: .744). For checking reproductivity on using the second group, deterioration was detected in 36.1% of the patients with WORSEN scores higher than 3 points (sensitivity: .740 and specificity: .835).

Conclusions: Careful attention should be paid to patients with acute stroke with high WORSEN scores. The WORSEN score might become a valuable tool for detecting the neurological deterioration of ischemic stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.07.005DOI Listing
December 2017

Patient adherence to the face-down positioning after macular hole surgery.

Clin Ophthalmol 2017 8;11:1099-1104. Epub 2017 Jun 8.

Department of Ophthalmology, Fujita Health University Hospital, Aichi, Japan.

Purpose: To determine adherence to face-down positioning (FDP) among patients who underwent vitrectomy and gas tamponade for macular hole (MH) repair.

Method: A total of 69 patients (37 females and 32 males) who underwent primary vitrectomy for MH repair were studied. Nurses recorded whether the patient complied with FDP each time they examined the patient. FDP score was obtained from the nursing records; patients were given a score of 1 if they complied with the FDP and 0 if they did not. The score was recorded four times per day for the first 3 postoperative days. A perfect FDP score was 12.

Results: The mean ± standard deviation of the FDP scores was 10.6±1.8 (range: 4-12). Overall, 32 (46.4%) patients scored a perfect 12, and 7 (10.1%) patients scored <8. Failure of the MH closure was observed in only one patient (1.4%), who showed the poorest adherence to FDP (score =4). Consequently, the closure rate in patients with FDP score <7 (2/3, 66.7%) was significantly lower than in patients with an FDP score ≥7 (66/66, 100%) (<0.05, Fisher's exact probability test).

Conclusion: While adherence to FDP after MH surgery was better than that observed after vitrectomy for rhegmatogenous retinal detachments in our previous study, the percentage of patients with FDP scores <8 did not differ. Statistically, the poor adherence to FDP can negatively impact the effectiveness of the surgery for MH repair.
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http://dx.doi.org/10.2147/OPTH.S135144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472416PMC
June 2017

Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition.

Bioorg Med Chem 2017 08 31;25(15):4110-4122. Epub 2017 May 31.

Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.
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http://dx.doi.org/10.1016/j.bmc.2017.05.059DOI Listing
August 2017

The Effect of an Inverted Internal Limiting Membrane Flap on Retinal Function after Macular Hole Surgery.

Ophthalmol Retina 2017 Sep - Oct;1(5):421-427. Epub 2017 Mar 14.

Department of Ophthalmology, Fujita Health University School of Medicine, Toyoake, Japan; Banbuntabe Hospital, Fujita Health University School of Medicine, Toyoake, Japan.

Purpose: To study the effect of an inverted internal limiting membrane (ILM) flap on the retina.

Design: Prospective case series.

Participants: Twenty-nine patients with large (>400 μm) unilateral macular holes underwent surgery using a modified inverted ILM flap technique.

Methods: The macular ILM was peeled, and a large (2-3 disc diameter) ILM flap was made on the superior side of the hole, and then the flap was inverted on the inferior side.

Main Outcome Measures: In all patients, multifocal electroretinograms (mfERGs) were recorded from operated eyes and normal fellow eyes. The peak time and amplitude of N1, P1, and N2 in the focal ERG from the upper retina without the ILM flap and those from the lower retina with the ILM flap were evaluated. In 14 patients, microperimetry was also performed in both eyes, and the averaged sensitivity was measured from the upper and lower areas.

Results: The peak times of P1 and N2 from the upper and lower retina were significantly longer in operated eyes than in the fellow eyes (P1 upper and lower: P < 0.04, N2 upper: P < 0.01, and N2 lower: P < 0.04), although we could not identify a significant difference in peak time and amplitude of N1, P1, and N2 between the upper retina and lower retina in both eyes (fellow eye-N1 amplitude: P > 0.2, N1 peak time: P > 0.5, P1 amplitude: P > 0.9, P1 peak time: P > 0.4, N2 amplitude: P > 0.9, N2 peak time: P > 0.9; operated eye-N1 amplitude: P > 0.8, N1 peak time: P > 0.4, P1 amplitude: P > 0.6, P1 peak time: P > 0.4, N2 amplitude: P > 0.9, N2 peak time: P > 0.9). We could not observe a significant difference in sensitivity between the upper and lower retinas in both eyes (fellow eye: P = 0.28, operated eye: P = 0.66).

Conclusions: The results of this study revealed no significant difference between the upper retina without the ILM flap and the lower retina with the ILM flap, suggesting that an inverted ILM flap has little effect on retinal function.
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http://dx.doi.org/10.1016/j.oret.2017.01.010DOI Listing
March 2017

Genotype-phenotype correlations of cysteine replacement in CADASIL.

Neurobiol Aging 2017 02 2;50:169.e7-169.e14. Epub 2016 Nov 2.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan. Electronic address:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by cerebral infarction related to mutations in the notch homolog protein 3 (NOTCH3). We enrolled 10 patients whose brain magnetic resonance imaging (MRI) fluid-attenuated inversion recovery images showed hyperintensities (HIs) in the deep white matter and the external capsule. We then investigated the mutations in NOTCH3 using direct sequencing within the region of intron-exon boundaries in exons 2-24 of NOTCH3. Eight patients harboring NOTCH3 mutations (8 of 10) were identified, including a novel mutation, p.C162Y, and 3 cases with a sporadic form. Seven patients with cysteine replacement showed HI in the anterior part of the temporal lobes (ATLs), whereas these changes were not detected in 1 patient without cysteine replacement, p.R75P. Reviewing previous reports, we conclude that the patients can clearly be divided in 2 groups: those with cysteine replacement who showed HI in the ATL and those without cysteine replacement who showed no HI in the ATL. Our findings expand the understanding of genotype-phenotype correlations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.10.026DOI Listing
February 2017

Equatorial Staphyloma Associated with Neurofibromatosis Type 1.

Case Rep Ophthalmol 2016 May-Aug;7(2):384-388. Epub 2016 Aug 10.

Department of Ophthalmology, Fujita Health University Hospital, Toyoake, Japan.

We report a case of a 38-year-old man who presented with a recently self-detected lump under his left eyebrow. Previous ophthalmological history was unremarkable except for unilateral high myopia (left eye) since childhood. The appearance of the left eye was seemingly normal; however, with the top lid pulled up on downward gaze, a dark brown bulge emerged. The bulge was 10 × 7 mm and approximately 4 mm in height, and was covered by the extended superior rectus muscle. The diagnosis of equatorial staphyloma was made after coronal T1-weighted magnetic resonance imaging of the orbit revealed the dilatation of the vitreous cavity. Ocular movements were fully maintained and visual acuity was largely spared: 20/15 in the right eye without correction and 20/25 in the left eye with -10.00 spheres and -4.00 × 80 degrees cylinders. His past and family histories were unremarkable; however, small neurofibromas and café au lait spots all over his body led to the diagnosis of neurofibromatosis type 1 (NF1). From this case, similar to previous reports, we suggest that manifestations of NF1 are extremely variable and unpredictable.
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http://dx.doi.org/10.1159/000448211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043359PMC
August 2016

A late foveal response component of multifocal electroretinograms in healthy subjects.

Doc Ophthalmol 2016 Oct 21;133(2):121-128. Epub 2016 Sep 21.

Department of Ophthalmology, Fujita Health University, Toyoake, Aichi, Japan.

Purpose: To investigate the characteristics of the late foveal response component (lfrc) that presents on the first slice of the second-order kernel (K2.1) in multifocal electroretinograms (mfERGs).

Methods: mfERGs with 37 hexagonal stimulus elements were obtained from 27 healthy subjects under a stimulus intensity of 2.67 cds/m, base rate of 75 Hz, and a net recording time of 1 min 49.2 s, using bipolar contact lens electrodes. The responses on the centermost hexagon (with a diameter of 4.5°-5.2°) were designated as foveal mfERGs.

Results: The foveal mfERG of the first-order kernel (K1) was shaped similarly to the K1 of the surrounding mfERGs. The foveal mfERG of K2.1 differed from the K2.1s of the surrounding mfERGs. This difference varied among subjects; however, the potential (0.34 ± 0.10 µV: mean ± SD) of the lfrc acutely changed at approximately 50 ms (range 48.56 ± 1.02-56.86 ± 1.99 ms). Whereas the amplitudes of the other major components of K1 and K2.1 significantly decreased with increasing refractive error, the amplitude of lfrc was not significantly correlated with refraction in this cohort.

Conclusions: The lfrc was obtained only on the centermost hexagon within an appropriate recording time (<2 min). This finding reflects the particular structure and peculiar adaptiveness of the fovea, a specialized area of the human retina, and enables the estimation of foveal function in clinical practice.
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http://dx.doi.org/10.1007/s10633-016-9562-xDOI Listing
October 2016

Leber Hereditary Optic Neuropathy Associated with Bilateral Macular Holes.

Neuroophthalmology 2016 May 9;40(3):125-129. Epub 2016 Mar 9.

Department of Ophthalmology, Fujita Health University Hospital , Aichi, Japan.

Leber hereditary optic neuropathy (LHON) causes visual loss, predominantly in healthy young men. We recently examined a patient who previously had bilateral macular holes and subsequently developed LHON at 74 years of age. Although his central scotomas were initially attributed to the macular holes, his visual acuity declined following an initial improvement after operative closure of the macular holes; thus, other diagnoses, including LHON, were considered. Furthermore, macular optical coherence tomography (OCT) images remained unchanged in this time. A mitochondrial genetic analysis identified a 11778G→A mutation. From this case, we propose that LHON remains in the differential diagnosis even in older patients, as has previously been reported.
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http://dx.doi.org/10.3109/01658107.2016.1148744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898147PMC
May 2016

Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice.

Stroke 2016 05 15;47(5):1328-35. Epub 2016 Mar 15.

From the Department of Neurology, Juntendo University, Tokyo, Japan (T.K., R.T., K.Y., Y.U., N.H.); and Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan (Y.S., H.S., T.U.).

Background And Purpose: Admission hyperglycemia is an independent risk factor for poor outcome of ischemic stroke. Amelioration of hyperglycemia by insulin has not been shown to improve the poststroke outcome. Glucagon-like peptide 1 receptor agonists, which modulate glucose levels by stimulating insulin secretion, have been shown to exert cytoprotective effects by inhibiting inflammation and oxidative stress. This study aimed to evaluate whether the glucagon-like peptide 1 receptor agonist exendin-4 could reduce glucose levels and exert protective effects after acute focal ischemia in hyperglycemic mice.

Methods: Hyperglycemia was induced by intraperitoneal injection of dextrose 15 minutes before transient middle cerebral artery occlusion was performed for 60 minutes using an intraluminal thread. We assessed 4 groups: (1) normal glucose (vehicle control), (2) induced hyperglycemia, (3) induced hyperglycemia with insulin treatment, and (4) induced hyperglycemia with exendin-4 treatment. Neurovascular injuries in brains from each group were evaluated 24 hours and 7 days post ischemia.

Results: Hyperglycemia significantly increased infarct volume (36.3±1.20 versus 26.9±1.28; P<0.001), brain edema (P<0.05), and hemorrhagic transformation compared with control (P<0.001). This increase in infarct volume was associated with increased blood-brain barrier disruption and matrix metalloproteinase-9 activation. Exendin-4, but not insulin, attenuated matrix metalloproteinase-9 activation, proinflammatory cytokine (tumor necrosis factor-α) release, and biomarkers of oxidative stress and showed significant inhibition of infarct growth at 24 hours (23.6±0.97 versus 36.3±1.20; P<0.001) and at 7 days after ischemia (21.0±0.92 versus 29.3±1.41; P<0.001).

Conclusions: Treatment with exendin-4 could be a potentially useful therapeutic option for treatment of acute ischemic stroke with transient hyperglycemia.
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http://dx.doi.org/10.1161/STROKEAHA.116.012934DOI Listing
May 2016

Impact of BNP on cryptogenic stroke without potential embolic sources on transesophageal echocardiography.

J Neurol Sci 2015 Dec 11;359(1-2):287-92. Epub 2015 Nov 11.

Department of Neurology, Juntendo University, School of Medicine, Japan.

Background: Clinical characteristics are important for determining the etiologies of embolic stroke, including patent foramen ovale and complex aortic plaques demonstrated on transesophageal echocardiography (TEE). This study sought to analyze the clinical signs of cryptogenic stroke (CS) without such embolic etiologies and to examine the association between CS and brain natriuretic peptide (BNP), which is currently unknown.

Methods: Patients with CS after routine examinations who underwent TEE were included in this single-center observational study. Patients were classified into the potential embolic sources (PES) group (patients having PES on TEE) and the no potential embolic source (NPES) group. Patients were also categorized according to the tertile of BNP.

Results: A total of 158 patients (age, 64.0 ± 13.9 years; 119 males) with CS were enrolled. The PES group had 108 (68%) patients, and the NPES group had 50 (32%). Hypertension was more common, and glucose, D-dimer, and BNP were higher in the NPES than in the PES group (p<0.05). NPES was independently associated with high-BNP tertile (OR: 5.61; 95% CI: 1.91 to 16.44; p=0.002).

Conclusions: BNP, an indicator of cardioembolism, was closely associated with NPES. Cardiogenic mechanisms may be implicated in the etiology of CS without potential embolic etiologies on TEE.
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http://dx.doi.org/10.1016/j.jns.2015.11.014DOI Listing
December 2015

Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus.

PLoS One 2015 26;10(6):e0131554. Epub 2015 Jun 26.

Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.

Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 μg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 μg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 μg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 μg/kg BW) or ghrelin (1 μg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H2 receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482737PMC
May 2016
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