Publications by authors named "Akihiko Ueda"

61 Publications

Report from "International Workshop for Junior Fellows 2: Tocolytic treatment for prevention of preterm birth" at the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology.

J Obstet Gynaecol Res 2021 Aug 18. Epub 2021 Aug 18.

Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

At the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology, we discussed recent tocolytic treatments for the prevention of preterm birth with obstetricians from Korea and Taiwan. The rate of preterm birth in our countries has been increasing, and optimal tocolytic treatments are of great concern. Ritodrine hydrochloride was the first available drug for tocolysis in our countries and is often administered for over 48 h, although it is not recommended for maintenance therapy in Western countries. Meanwhile, there are differences in the use of other tocolytic drugs, based on approval of the drugs and the health insurance systems. Nifedipine and atosiban have not been considered first-line agents in Japan. The long-term use of unnecessary tocolysis should be avoided, and the introduction of other tocolytic drugs, including nifedipine or atosiban, should be discussed.
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http://dx.doi.org/10.1111/jog.14951DOI Listing
August 2021

Maternal near-miss attributable to haemorrhagic stroke in patients with hypertensive disorders of pregnancy in Japan: A national cohort study.

Pregnancy Hypertens 2021 Aug 23;25:240-243. Epub 2021 Jul 23.

Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan. Electronic address:

Objectives: To investigate the epidemiologic and clinical characteristics of maternal near-misses attributable to haemorrhagic stroke (HS) occurring in patients with hypertensive disorders of pregnancy (HDP), with a focus on severe neurological morbidity.

Methods: A national retrospective cohort study was conducted using the national database of health insurance claims for the period 2010 to 2017. The subjects were all insured women with a diagnosis of both HDP and HS. Severe neurological morbidity requiring rehabilitation, types of HDP, types of HS, and magnesium sulphate use were tabulated.

Results: The number of women with HDP who were diagnosed with HS was 3.4 per 100,000 deliveries between 2010 and 2017. Forty percent of HDP-related HS cases had neurological morbidities requiring rehabilitation (1.4 per 100,000 deliveries), and 4.4% were in a persistent vegetative state after HS. Of the HDP cases who developed HS, 69.2% were severe HDP, of which 55.6% were without eclampsia. The most common type of HS was intracerebral haemorrhage (2.5 per 100,000 deliveries), followed by subarachnoid haemorrhage due to cerebral aneurysm (1.2 per 100,000 deliveries). The frequency of magnesium sulphate use increased in all patients with HDP-related HS in the second half of the study period (2014-2017) compared with the first half (2010-2013) (p < 0.0001). This was more evident in cases of HDP-related HS with eclampsia (31.9% to 83.8%) compared to those without eclampsia (25.0% to 42.9%).

Conclusion: Of the maternal near-miss cases due to HDP-related HS, 40.0% were rehabilitated and 69.2% were HDP without either eclampsia or severe hypertension.
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http://dx.doi.org/10.1016/j.preghy.2021.07.244DOI Listing
August 2021

Preceding direct oral anticoagulant administration reduces the severity of stroke in patients with atrial fibrillation - K-PLUS registry.

J Clin Neurosci 2021 Jul 6;89:106-112. Epub 2021 May 6.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Amyloidosis, Nagasaki International University, Sasebo, Japan. Electronic address:

Background: Stroke severity can be mitigated by preceding anticoagulant administration in acute ischemic stroke patients with atrial fibrillation (AF). We investigated if such mitigative effects are different between warfarin and direct oral anticoagulants (DOACs).

Material And Methods: We collected data from a regional multicenter stroke registry. Ischemic stroke or transient ischemic attack patients with AF were included. Background characteristics, National Institutes of Health Stroke Scale (NIHSS) score on admission, lesion characteristics, and in-hospital death were analyzed according to preceding antithrombotic agents at onset.

Results: A total of 2173 patients had AF; 628 were prescribed warfarin, 272 DOACs, 429 antiplatelets alone, and 844 no antithrombotics. The NIHSS score on admission was lowest in the DOACs group compared to the other groups. In neuroimaging analysis, small ischemic lesions were observed more frequently in the DOACs group, while large ischemic lesions were less frequent in this group. When the no antithrombotics group was used as a reference, the adjusted odds ratio for moderate to severe stroke was 0.56 (95% confidence interval, 0.40-0.78) in the DOACs group, while it was 0.98 (0.77-1.24) in the warfarin group and 0.94 (0.72-1.22) in the antiplatelets group. In-hospital mortality was lowest in the DOACs group compared to the other groups.

Conclusion: Preceding DOAC administration might mitigate the severity of stroke in AF patients more strongly than other antithrombotics, possibly leading to a better outcome in patients with stroke.
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http://dx.doi.org/10.1016/j.jocn.2021.04.027DOI Listing
July 2021

Heterozygous Cysteine-sparing NOTCH3 Variant p.Val237Met in a Japanese Patient with Suspected Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Intern Med 2021 Aug 8;60(15):2479-2482. Epub 2021 Mar 8.

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.

A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. An intensive skin biopsy showed negative results (no granular osmiophilic material or positive NOTCH3 immunostaining), suggesting that the patient's definite diagnosis and pathogenicity of p.Val237Met were uncertain. We additionally reviewed previous reports of two Japanese families with p.Val237Met.
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http://dx.doi.org/10.2169/internalmedicine.6096-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381162PMC
August 2021

Plasma growth differentiation factor 15: a novel tool to detect early changes of hereditary transthyretin amyloidosis.

ESC Heart Fail 2021 04 30;8(2):1178-1185. Epub 2020 Dec 30.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan.

Aims: Hereditary transthyretin (ATTRv) amyloidosis is the most frequent and representative form of autosomal dominant hereditary systemic amyloidosis. Disease-modifying treatments of the disease are more effective during the early stages, and we require biomarkers to detect early pathological changes for prompt diagnosis. This study aimed to investigate whether plasma growth differentiation factor 15 (GDF-15) levels could aid detection of early pathological changes in ATTRv amyloidosis.

Methods And Results: We retrospectively studied 32 patients with ATTRv amyloidosis, eight asymptomatic TTR mutation carriers, and eight healthy volunteers. We evaluated plasma GDF-15 levels in these subjects as related to levels of brain natriuretic peptide and high-sensitivity troponin T, echocardiographic features, Tc-pyrophosphate (PYP) scans, and cardiac magnetic resonance imaging findings. Plasma GDF-15 levels significantly increased even in asymptomatic TTR mutation carriers compared with healthy volunteers (P < 0.01). Plasma GDF-15 levels were significantly correlated with plasma brain natriuretic peptide values (P < 0.01), serum high-sensitivity troponin T values (P < 0.05), and interventricular septal thickness at end-diastole (P < 0.01) in patients with ATTRv amyloidosis. Plasma GDF-15 levels in patients with PYP-positive ATTRv amyloidosis were significantly higher than those in patients with PYP-negative ATTRv amyloidosis (P < 0.01). Plasma GDF-15 levels in patients with late gadolinium enhancement-positive ATTRv amyloidosis were significantly higher than those in patients with late gadolinium enhancement-negative ATTRv amyloidosis (P < 0.01). Groups of patients with different TTR genotypes manifested different plasma GDF-15 levels.

Conclusions: Growth differentiation factor 15 may reflect early pathological changes of ATTRv amyloidosis.
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http://dx.doi.org/10.1002/ehf2.13176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006664PMC
April 2021

Enhanced Exciton-Exciton Collisions in an Ultraflat Monolayer MoSe Prepared through Deterministic Flattening.

ACS Nano 2021 Jan 23;15(1):1370-1377. Epub 2020 Dec 23.

Department of Chemistry, Nagoya University, Nagoya, Aichi 464-8602, Japan.

Squeezing bubbles and impurities out of interlayer spaces by applying force through a few-layer graphene capping layer leads to van der Waals heterostructures with the ultraflat structure free from random electrostatic potential arising from charged impurities. Without the graphene capping layer, a squeezing process with an AFM tip induces applied-force-dependent charges of Δ ∼ 2 × 10 cm μN, resulting in the significant intensity of trions in photoluminescence spectra of MoSe at low temperature. We found that a hBN/MoSe/hBN prepared with the "graphene-capping-assisted AFM nano-squeezing method" shows a strong excitonic emission with negligible trion peak, and the residual line width of the exciton peak is only 2.2 meV, which is comparable to the homogeneous limit. Furthermore, in this high-quality sample, we found that the formation of biexciton occurs even at extremely low excitation power (Φ ∼ 2.3 × 10 cm s) due to the enhanced collisions between excitons.
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http://dx.doi.org/10.1021/acsnano.0c08642DOI Listing
January 2021

Rethinking uterine compression suture for atonic postpartum hemorrhage.

Acta Obstet Gynecol Scand 2021 01;100(1):5-6

Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.1111/aogs.14035DOI Listing
January 2021

Apolipoprotein AI amyloid deposits in the ligamentum flavum in patients with lumbar spinal canal stenosis.

Amyloid 2021 Jun 11;28(2):107-112. Epub 2020 Dec 11.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Amyloidosis is a protein-misfolding disease characterised by insoluble amyloid deposits in the extracellular space of various organs and tissues, such as the brain, heart, kidneys, and ligaments. We previously reported the frequent occurrence of amyloid deposits in the ligament flavum in the presence of lumbar spinal canal stenosis (LSCS), which is a common spinal disorder in older individuals. Our earlier clinicopathological studies revealed that amyloid deposits derived from transthyretin (TTR) were involved in the pathogenesis of LSCS. ATTR amyloid was the most common form in the ligamentum flavum, but amyloid deposits that were not identified still existed in more than 50% of patients with LSCS. In this study, we found apolipoprotein AI (AApoAI) amyloid deposits in the ligamentum flavum of patients with LSCS. The deposits occurred in 12% of patients with LSCS. Biochemical studies revealed that the amyloid deposits consisted mainly of full-length ApoAI. As a notable finding, the lumbar ligamentum flavum of patients who had LSCS with double-positive amyloid deposits-positive for both ATTR and AApoAI-was significantly thicker than that of patients who had LSCS with single-positive-that is, positive for either ATTR or AApoAI-amyloid deposits. We thus suggest that lumbar AApoAI amyloid formation may enhance the pathological changes of lumbar ATTR amyloidosis in patients with LSCS.
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http://dx.doi.org/10.1080/13506129.2020.1858404DOI Listing
June 2021

Predictive factors for flares of established stable systemic lupus erythematosus without anti-phospholipid antibodies during pregnancy.

J Matern Fetal Neonatal Med 2020 Nov 3:1-6. Epub 2020 Nov 3.

Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

Purpose: To identify predictors of systemic lupus erythematosus (SLE) flares during pregnancy in patients previously considered to be at low risk.

Materials And Methods: The retrospective cohort study included 54 singleton pregnancies, managed between 2005 and 2019, involving maternal diagnosed SLE at a low disease activity (SLE Disease Activity Index ≤4) for ≥12 months before conception and without anti-phospholipid antibodies. Pregnancy outcomes were compared between patients who had SLE exacerbations during pregnancy (flare group,  = 21) and patients that did not have a flare (non-flare group,  = 33).

Results: The flare group had shorter gestational durations ( = .01), lower birth weights ( = .02), and a higher risk of emergent cesarean section ( = .002) compared with the non-flare group. The flare group demonstrated higher doses of prednisone ( = .04) at the time of conception as well as an increased rate of low 50% hemolytic complement (CH50) activity ( = .03) in the first trimester compared to the non-flare group. A decision tree drawn using a prednisone dose ≥10.5 mg/day and a low CH50 predicted SLE flares with a net accuracy of 78%.

Conclusions: A prednisone dose ≥10.5 mg daily and CH50 hypocomplementemia in early pregnancy are useful in the early detection of patients at a high risk of SLE exacerbation.
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http://dx.doi.org/10.1080/14767058.2020.1843626DOI Listing
November 2020

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan.

Front Aging Neurosci 2020 14;12:216. Epub 2020 Jul 14.

Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan.

Objectives: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed.

Methods: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire.

Results: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 ( = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan.

Conclusion: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.
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http://dx.doi.org/10.3389/fnagi.2020.00216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381163PMC
July 2020

Novel dot-blot assay for detection of vascular Notch3 aggregates in patients with CADASIL.

J Neurol Sci 2020 08 21;415:116931. Epub 2020 May 21.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; Department of Amyloidosis Research, Nagasaki International University, Sasebo 859-3298, Japan.

To detect vascular Notch3 extracellular domain aggregates in CADASIL, we developed a novel dot-blot assay with both autopsy and biopsy skin samples. We obtained samples from 11 patients with CADASIL and 12 control patients, and we performed dot-blot analyses by using sequential biochemical tissue extractions with three different antibodies against specific regions of the Notch3 extracellular domain. We also analyzed clinical features and vascular accumulations of Notch3 by immunohistochemistry. Via the dot-blot assay with the antibody against the C-terminal region of the Notch3 extracellular domain, we successfully detected Notch3 extracellular domain aggregates in skin tissue homogenates obtained from patients with CADASIL. Our novel method may therefore aid the diagnosis of CADASIL.
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http://dx.doi.org/10.1016/j.jns.2020.116931DOI Listing
August 2020

De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature.

Eur J Med Genet 2020 Apr 16;63(4):103825. Epub 2019 Dec 16.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations.

Case Report: We report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge.

Results: Targeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy.

Conclusions: This case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age.
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http://dx.doi.org/10.1016/j.ejmg.2019.103825DOI Listing
April 2020

Reply: The Kyoto balloon system for postpartum hemorrhage: A hard balloon shaft offers an easier and surer way to apply direct pressure on bleeding sites.

Acta Obstet Gynecol Scand 2020 02 10;99(2):292-293. Epub 2019 Nov 10.

Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.1111/aogs.13742DOI Listing
February 2020

Transthyretin amyloid-related cerebral angiitis after liver transplantation.

Amyloid 2019;26(sup1):11-12

a Department of Neurology, Graduate School of Medical Sciences, Kumamoto University , Kumamoto , Japan.

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http://dx.doi.org/10.1080/13506129.2019.1583179DOI Listing
January 2020

Novel intrauterine balloon tamponade systems for postpartum hemorrhage.

Acta Obstet Gynecol Scand 2019 12 12;98(12):1612-1617. Epub 2019 Sep 12.

Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

Introduction: Postpartum hemorrhage is the most common cause of maternal death worldwide. Although intrauterine balloon tamponade has been widely used as an effective procedure to control atonic postpartum hemorrhage, intrauterine balloon tamponade fails to control postpartum hemorrhage in approximately one-fifth of cases. The aim of this study was to evaluate the efficacy of novel intrauterine balloon tamponade systems for postpartum hemorrhage.

Material And Methods: We have developed two novel intrauterine balloon tamponade systems to maintain proper balloon placement. One was a shaft cover with its fixture system and the other was "the Kyoto balloon system" designed to provide direct pressure onto the upper uterine cavity. The efficacy of the intrauterine balloon tamponade systems was evaluated using a silicone three-dimensionally printed postpartum uterine cavity model.

Results: Measurements of balloon displacement during inflation showed that the shaft cover significantly prevented the Bakri balloon from being displaced. The residual fluid volume in the upper uterine cavity was significantly less with the Kyoto balloon system than with the Bakri balloon system, indicating the effectiveness of the Kyoto balloon for upper uterine cavity tamponade.

Conclusions: These innovative intrauterine balloon tamponade systems were effective for prevention of balloon displacement and for balloon tamponade of the upper uterine cavity in a 3D-printed postpartum-specific uterine cavity model.
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http://dx.doi.org/10.1111/aogs.13692DOI Listing
December 2019

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.

J Biol Chem 2019 07 5;294(29):11259-11275. Epub 2019 Jun 5.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81-127, is highly amyloidogenic , even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81-127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils , and pyrvinium pamoate also stabilized the tetrameric structure of TTR in patient plasma. We conclude that our TTR81-127-based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis.
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http://dx.doi.org/10.1074/jbc.RA119.007851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643022PMC
July 2019

Intracervical elastomeric sealant in an model.

J Matern Fetal Neonatal Med 2021 Apr 19;34(7):1109-1111. Epub 2019 Jun 19.

Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

Background: Premature rupture of membranes occurring in previable midtrimester patients is associated with perinatal mortality, and optimal therapeutic methods are yet to be established.

Objective: This study's objective was to investigate whether an elastomeric sealant, which has been used as a hemostatic agent for arterial anastomosis, could plug the uterine endocervical canal to prevent leakage of intrauterine fluid in an model.

Methods: The elastomeric sealant or fibrin glue was applied to the cervix of uteri removed for benign gynecological disease ( = 4). Normal saline was administered into the uterine cavity through a catheter using a pressure infusion bag. Intrauterine pressure was measured using a digital pressure gauge, and the pressure at which normal saline started leaking out of the uterine cervix was compared between both the sealants.

Results: No fluid leakage was observed with the elastomeric sealant until the pressure exceeded 20 kPa (150 mmHg), while the leakage onset pressure with fibrin sealant was 6.6 ± 1.8 kPa (50 ± 14 mmHg). The threshold leak pressure where the onset of liquid flow was initiated was significantly different between both the sealants ( < .0001).

Conclusions: Intracervical elastomeric sealant exhibited powerful fluid leakage prevention in an model. The sealant would have potential to prevent the leakage of amniotic fluid in pregnancies with previable premature rupture of membranes.
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http://dx.doi.org/10.1080/14767058.2019.1626367DOI Listing
April 2021

Development of a glue-free bimorph mirror for use in vacuum chambers.

Rev Sci Instrum 2019 Feb;90(2):021702

Department of Precision Science and Technology, Graduate School of Engineering, Osaka University, 2-1, Yamadaoka, Suita, Osaka 565-0871, Japan.

PZT (lead zirconate titanate)-glued bimorph deformable mirrors are widely used in hard X-ray regimes; however, they have not yet been used in soft X-ray regimes because they are less compatible for usage under high vacuum. In this study, we developed a glue-free bimorph deformable mirror, in which silver nano-particles were employed to bond PZT actuators to mirror substrates. Under an appropriate bonding condition, the bonding layer was confirmed to be uniform and the mirror's bending characteristics were demonstrated to be sufficiently stable; its gas emission rate was also shown to be acceptable. Piezo responses before and after additional heating at 200 °C showed the thermal stability of its bonding and bending properties.
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http://dx.doi.org/10.1063/1.5066105DOI Listing
February 2019

A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1.

J Pathol 2019 04 21;247(4):444-455. Epub 2018 Dec 21.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5203DOI Listing
April 2019

A Japanese CADASIL patient with homozygous NOTCH3 p.Arg544Cys mutation confirmed pathologically.

J Neurol Sci 2018 11 29;394:38-40. Epub 2018 Aug 29.

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2018.08.029DOI Listing
November 2018

Serum amyloid P component: A novel potential player in vessel degeneration in CADASIL.

J Neurol Sci 2017 Aug 26;379:69-76. Epub 2017 May 26.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan. Electronic address:

In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), granular osmiophilic material (GOM) may play some roles in inducing cerebrovascular events. To elucidate the pathogenesis of CADASIL, we used laser microdissection and liquid chromatography-tandem mass spectrometry to analyze cerebrovascular lesions of patients with CADASIL for GOM. The analyses detected serum amyloid P component (SAP), annexin A2, and periostin as the proteins with the largest increase in the samples, which also demonstrated NOTCH3. For the three proteins, anti-human SAP antibody had the strongest reaction in the lesions where the anti-human NOTCH3 antibody showed positive staining. Moreover, immunofluorescence staining with the two antibodies clearly showed co-localization of SAP and NOTCH3. mRNA analyses indicated no positive SAP expression in the brain materials, which suggested that the source of SAP found in the GOM was only the liver. A solid phase enzyme-linked immunosorbent assay confirmed the binding of SAP with NOTCH3. Serum SAP concentrations were neither up-regulated nor down-regulated in CADASIL patients, when compared with those in control subjects. SAP may play an important role in GOM formation although precise mechanisms remain to be elucidated.
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http://dx.doi.org/10.1016/j.jns.2017.05.033DOI Listing
August 2017

A case of foetal intra-abdominal umbilical vein varix with adjacent extra-abdominal vein constriction.

J Obstet Gynaecol 2017 Nov 28;37(8):1093-1095. Epub 2017 Jun 28.

a Department of Obstetrics and Gynecology , Kurashiki Central Hospital , Okayama , Japan.

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http://dx.doi.org/10.1080/01443615.2017.1318270DOI Listing
November 2017

A Case of Extra-Gastrointestinal Anisakidosis With Incidental Detection of a Live Larva During Laparoscopic Cystectomy.

J Minim Invasive Gynecol 2017 Sep - Oct;24(6):882-883. Epub 2016 Dec 9.

Department of Obstetrics and Gynecology, Saiseikai Noe Hospital, Osaka, Japan.

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http://dx.doi.org/10.1016/j.jmig.2016.12.003DOI Listing
December 2016

CADASIL Presenting as Acute Bilateral Multiple Subcortical Infarcts without a Characteristic Temporal Pole or Any External Capsule Lesions.

Intern Med 2016;55(19):2873-2876. Epub 2016 Oct 1.

Department of Neurology, Kasugai Municipal Hospital, Japan.

A 37-year-old man was hospitalized for an evaluation of acute bilateral multiple subcortical infarcts. There were no specific signal abnormalities in the temporal pole or external capsule. An abdominal skin biopsy showed granular, electron-dense, osmiophilic material (GOM) in the smooth muscle cells on electron microscopy. A direct sequencing analysis of NOTCH3 revealed a heterozygous c.986G>A substitution in exon 6, resulting in a Cys329Tyr amino acid replacement. According to these findings, the patient was diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencehalopathy (CADASIL). Thus, early phases of CADASIL can present as acute bilateral multiple subcortical infarcts without a characteristic temporal pole or any external capsule lesions.
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http://dx.doi.org/10.2169/internalmedicine.55.7123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088552PMC
February 2017

'Tandem balloon tamponade' for arterial bleeding from the uterine fundus: two case reports.

J Obstet Gynaecol 2016 Aug 22;36(6):769-771. Epub 2016 Mar 22.

a Department of Gynecology and Obstetrics , Kyoto University , Kyoto , Japan.

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http://dx.doi.org/10.3109/01443615.2016.1159669DOI Listing
August 2016

Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation.

Amyloid 2016 13;23(1):39-45. Epub 2016 Jan 13.

a Department of Neurology .

Background: Liver transplantation halts production of mutated transthyretin (TTR), and thus it is an accepted treatment, with improved survival, in patients with hereditary (familial) amyloidosis with polyneuropathy (FAP). However, the effects of transplantation on the clinical manifestations of FAP have not yet been adequately clarified. This study aimed to investigate whether liver transplantation would improve the long-term clinical manifestations in FAP patients who had undergone transplantations.

Patients And Methods: We assessed 29 non-transplant and 36 transplant FAP V30M patients using an FAP clinical scoring system.

Results: The total clinical score of the non-transplant group increased and was significantly correlated with FAP duration; that of the transplant group increased slowly after transplantation. In patients 5 years or more after FAP onset, the total clinical scores of the transplant group were significantly lower than those of the non-transplant group. In the same patients, scores for sensory, motor, autonomic and organ impairments of the transplant group were significantly lower than those of the non-transplant group.

Conclusions: Liver transplantation had beneficial effects on FAP clinical manifestations in patients with FAP TTR V30M. Liver transplantation should therefore be considered as an effective treatment in the clinical management of patients with FAP TTR V30M.
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http://dx.doi.org/10.3109/13506129.2015.1123149DOI Listing
December 2016

[Skin Biopsy is a Useful Tool for the Diagnosis of Atypical CADASIL: A Case Report].

Brain Nerve 2015 Dec;67(12):1533-7

Department of Neurology, Fukuoka University.

A 57-year-old man developed migraine at the age of 25 years. Thereafter, he developed depression at the age of 50 years, and was admitted to a psychiatric hospital at the age of 54 years because of deteriorating depression. He returned to his work after receiving treatment for depression; however, he made mistakes several times in his work. He was referred to our hospital for further neurological evaluation. The results of the neurological examination performed on admission were unremarkable. His Mini Mental State Examination (MMSE) score was 24/30, and neuropsycological evaluations revealed executive dysfunction. There was no family history of dementia or cerebral infarction. Magnetic resonance fluid attenuated inversion recovery (MR FLAIR) image of the brain showed hyperintense lesions around the lateral ventricle without involvement in the temporal pole and external capsule. Despite a lack of family history of dementia and cerebral infarction and non-specific brain MRI findings, his history of headache and depression were suggestive of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, skin biopsy was performed; electron microscopy of the biopsied sample revealed granular osmiophilic material deposits. Genetic analysis of the NOTCH3 gene showed a missense mutation with substitution of R427C in exon 8, i.e., out of the hot-spot, exon 3, and 4. Thus, skin biopsy is a useful tool for diagnosing atypical CADASIL.
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http://dx.doi.org/10.11477/mf.1416200333DOI Listing
December 2015

Magnesium sulphate can prolong pregnancy in patients with severe early-onset preeclampsia.

J Matern Fetal Neonatal Med 2016 Oct 14;29(19):3115-20. Epub 2016 Jan 14.

a Department of Gynecology and Obstetrics , Kyoto University , Kyoto , Japan.

Objective: To assess whether long-term use of magnesium sulphate prolongs pregnancy in patients with severe early-onset preeclampsia.

Methods: Retrospective cohort study included all singleton pregnancies with severe early-onset preeclampsia, expectantly managed in our institution between 2005 and 2013. Obstetric and perinatal outcomes were compared between patients managed using a current protocol that tolerates long-term (over 48 h) use of magnesium sulphate (long-term group, n = 26) and a historical control group (control group, n = 15) that underwent conventional treatment (up to 48 h use of magnesium sulphate).

Results: Long-term group showed significant prolongation of pregnancy compared with the control group (9.2 ± 7.9 versus 16.6 ± 9.3 d, log-rank test, p = 0.021), which was also observed in patients with severe preeclampsia occurring before 28 weeks' gestation (n = 11, 4.5 ± 5.2 versus 13.2 ± 6.8 d, log-rank test, p = 0.035). In contrast to a progressive decrease of platelet count in patients managed without magnesium sulphate, administration of magnesium sulphate for 7 d prevented the decrease of platelet count (p = 0.001). Thirty two percent of patients (13/41) experienced a major complication irrespective of duration of magnesium sulphate use.

Conclusions: Long-term use of magnesium sulphate prolonged pregnancy in patients with severe early-onset preeclampsia and can help alleviate progression of preeclampsia.
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http://dx.doi.org/10.3109/14767058.2015.1114091DOI Listing
October 2016

Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer.

J Clin Oncol 2015 Dec 8;33(34):4015-22. Epub 2015 Sep 8.

Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan.

Purpose: Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer.

Patients And Methods: Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014.

Results: Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination.

Conclusion: This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).
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http://dx.doi.org/10.1200/JCO.2015.62.3397DOI Listing
December 2015
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