Publications by authors named "Satoshi Ueno"

221 Publications

Pregnancy prediction performance of an annotation-free embryo scoring system on the basis of deep learning after single vitrified-warmed blastocyst transfer: a single-center large cohort retrospective study.

Fertil Steril 2021 Jul 7. Epub 2021 Jul 7.

Kato Ladies Clinic, Tokyo, Japan. Electronic address:

Objective: To analyze the performance of an annotation-free embryo scoring system on the basis of deep learning for pregnancy prediction after single vitrified blastocyst transfer (SVBT) compared with the performance of other blastocyst grading systems dependent on annotation or morphology scores.

Design: A single-center large cohort retrospective study from an independent validation test.

Setting: Infertility clinic.

Patient(s): Patients who underwent SVBT cycles (3,018 cycles, mean ± SD patient age 39.3 ± 4.0 years).

Intervention(s): None.

Main Outcome Measure(s): The pregnancy prediction performances of each embryo scoring model were compared using the area under curve (AUC) for predicting the fetal heartbeat status for each maternal age group.

Result(s): The AUCs of the <35 years age group (n = 389) for pregnancy prediction were 0.72 for iDAScore, 0.66 for KIDScore, and 0.64 for the Gardner criteria. The AUC of iDAScore was significantly greater than those of the other two models. For the 35-37 years age group (n = 514), the AUCs were 0.68, 0.68, and 0.65 for iDAScore, KIDScore, and the Gardner criteria, respectively, and were not significantly different. The AUCs of the 38-40 years age group (n = 796) were 0.67 for iDAScore, 0.65 for KIDScore, and 0.64 for the Gardner criteria, and there were no significant differences. The AUCs of the 41-42 years age group (n = 636) were 0.66, 0.66, and 0.63 for iDAScore, KIDScore, and the Gardner criteria, respectively, and there were no significant differences among the pregnancy prediction models. For the >42 years age group (n = 389), the AUCs were 0.76 for iDAScore, 0.75 for KIDScore, and 0.75 for the Gardner criteria, and there were no significant differences. Thus, iDAScore AUC was either the highest or equal to the highest AUC for all age groups, although a significant difference was observed only in the youngest age group.

Conclusion(s): Our results showed that objective embryo assessment by a completely automatic and annotation-free model, iDAScore, performed as well as or even better than more traditional embryo assessment or annotation-dependent ranking tools. iDAScore could be an optimal pregnancy prediction model after SVBT, especially in young patients.
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http://dx.doi.org/10.1016/j.fertnstert.2021.06.001DOI Listing
July 2021

Comparing prediction of ongoing pregnancy and live birth outcomes in patients with advanced and younger maternal age patients using KIDScore™ day 5: a large-cohort retrospective study with single vitrified-warmed blastocyst transfer.

Reprod Biol Endocrinol 2021 Jul 2;19(1):98. Epub 2021 Jul 2.

Kato Ladies Clinic, 7-20-3, Nishi-shinjuku, Shinjuku, Tokyo, 160-0023, Japan.

Background: The KIDScore™ Day 5 (KS-D5) model, version 3, is a general morphokinetic prediction model (Vitrolife, Sweden) for fetal heartbeat prediction after embryo transfer that was developed based on a large data set that included implantation results from a range of clinics with different patient populations, culture conditions and clinical practices. However, there was no study to comparing their pregnancy and live birth prediction ability among different maternal age. The aim of this study is to analyze the performance of KS-D5 in predicting pregnancy and live birth in various maternal age groups after single vitrified-warmed blastocyst transfer (SVBT).

Methods: A total of 2486 single vitrified-warmed blastocyst transfer (SVBT) cycles were analyzed retrospectively. Confirmed fetal heartbeat positive (FHB+) and live birth (LB+) rates were stratified by Society for Assisted Reproductive Technology (SART) maternal age criteria (< 35, 35-37, 38-40, 41-42 and ≥ 43 years of age). Within each age group, the performance of the prediction model was calculated using the AUC, and the results were compared across the age groups.

Results: In all age groups, the FHB+ rates decreased as the KIDScore decreased (P <  0.05). Conversely, the AUCs increased as the maternal age increased. The AUC of the < 35 age group (0.589) was significantly lower than the AUCs of the 41-42 age group (0.673) and the ≥43 age group (0.737), respectively (P <  0.05). In all age groups, the LB+ rates decreased as the KIDScore decreased (P <  0.05). Conversely, the AUCs increased as the maternal age increased. The AUC of the ≥43 age group (0.768) was significantly higher than the AUCs of other age groups (P <  0.05; < 35 age group = 0.596, 35-37 age group = 0.640, 38-40 age group = 0.646, 41-42 age group = 0.679).

Conclusions: In the present study, we determined that the KIDScore model worked well for prediction of pregnancy and live birth outcomes in advanced age patients.
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http://dx.doi.org/10.1186/s12958-021-00767-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252298PMC
July 2021

[Long-term Quality Control Test of a Ge/Ga Generator].

Kaku Igaku 2021 ;58(1):47-58

Central Institute of Isotope Science, Hokkaido University.

Quality of the Ga solution eluted from a Ge/Ga generator (Galli Eo) was evaluated. Elution was performed 488 times from 21 to 484 days (ca. 15 months) after the calibration date. The eluted Ga activity was 329 MBq to 1,148 MBq, which decreased with the decay of Ge, but no significant change was observed in the elution yields (62.8±2.2%). The half-life of the eluted radioactivity was 67.8±0.1 min, the radionuclide purity of Ga was ≥99.9%, the Ge breakthrough was 0.000024 ±0.000004%, and the radiochemical purity of Ga was 99.7±0.2%. Fe and Zn were detected as metal impurities in the eluent, but both were ≤10 μg/GBq. The endotoxin concentration of the eluate was ≤5 EU/mL, and the eluent passed the sterility test. These results show that the generator can stably provide Ga solution over a 15-month period.
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http://dx.doi.org/10.18893/kakuigaku.tr.2102DOI Listing
January 2021

Development of delayed neurologic sequelae in acute carbon monoxide poisoning cases caused by briquette-based kotatsu: A case-control study.

Medicine (Baltimore) 2021 Apr;100(16):e25009

Department of Emergency and Critical Care Medicine, Fukushima Medical University, Fukushima City, Fukushima, Japan.

Abstract: Briquette-based kotatsu, a traditional Japanese heating system, is still used in rural areas and has been linked to the development of acute carbon monoxide (CO) poisoning. This study aimed to investigate the occurrence of delayed neurologic sequelae (DNS) in patients with acute CO poisoning caused by briquette-based kotatsu.This retrospective study included 17 patients treated for acute CO poisoning due to briquette-based kotatsu, between April 2017 and March 2020. Patients were divided into either a sequelae group (3 patients) or a non-sequelae group (14 patients) based on the presence or absence, respectively, of DNS. Demographic data, kotatsu characteristics, clinical findings, and therapies were compared between the 2 groups.Significant differences were noted in patient posture during their initial discovery. Specifically, all non-sequelae patients only had their legs under the kotatsu quilt and all sequelae patients had their entire bodies under the kotatsu quilt (P = .001). There were no statistically significant differences in carbon monoxide levels in hemoglobin (CO-Hb) or the creatine-kinase myocardial band (CK-MB), between the 2 groups; however, troponin-I levels were significantly higher in the sequelae group (P = .026). Abnormal head imaging findings were noted in 2 sequelae-group patients, with a significant difference between the groups (P = .025).We speculate that acute CO poisoning, caused by briquette-based kotatsu, may lead to DNS more frequently in patients in who cover their entire body with the kotatsu quilt and are found in this position. Patients should be warned about the dangers of acute CO poisoning when using briquette-based kotatsu.
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http://dx.doi.org/10.1097/MD.0000000000025009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078257PMC
April 2021

Comparison of Embryo and Clinical Outcomes in Different Types of Incubator Between Two Different Embryo Culture Systems.

Reprod Sci 2021 08 9;28(8):2301-2309. Epub 2021 Mar 9.

Kato Ladies Clinic, 7-20-3, Nishi-shinjuku, Shinjuku, Tokyo, 160-0023, Japan.

This study aimed to compare the clinical outcomes of an oxidative stress-reducing embryo culture system (ORES) containing compounds that minimize intercellular oxidative stress, with those of a standard embryo culture system (StES). Furthermore, we investigated the efficiency of the ORES regarding the type of incubator used (time-lapse incubator [TLI] or non-time-lapse dry incubator [non-TLI]) and maternal age. In this retrospective study, we analyzed 3610 oocyte retrieval cycles (in 2537 patients) and 1726 single vitrified-warmed blastocyst transfer (SVBT) cycles (in 1726 patients) performed in a single center between April 2018 and July 2019. Transfers of single vitrified-warmed blastocysts, confirmed by fetal heartbeat, were used to assess clinical outcomes. The clinical outcomes of ORES and StES were compared in both TLI and non-TLI. Groups were stratified according to maternal age (≤39 years old, young age group; ≥40 years old, advanced age group). A significant difference in ongoing pregnancy rates was observed between the ORES and StES groups when non-TLI was used (34.9 vs. 27.0%, respectively; p < 0.05), unlike when TLI was used. Furthermore, ongoing pregnancy rates were significantly higher in the ORES group (24.8%) than in the StES group (14.9%) in the advanced age group, unlike in the young age group when non-TLI was used. In conclusion, compared to StEs, the ORES during all in vitro fertilization procedures improved ongoing pregnancy rates in the advanced age group using the non-TLI.
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http://dx.doi.org/10.1007/s43032-021-00504-7DOI Listing
August 2021

Establishment of day 7 blastocyst freezing criteria using blastocyst diameter for single vitrified-warmed blastocyst transfer from live birth outcomes: a single-center, large cohort, retrospectively matched study.

J Assist Reprod Genet 2020 Sep 21;37(9):2327-2335. Epub 2020 Jul 21.

Kato Ladies Clinic, 7-20-3, Nishi-Shinjuku, Shinjuku, Tokyo, 160-0023, Japan.

Purpose: To establish blastocyst freezing criteria for day 7 blastocyst (day 7 BL) for single vitrified-warmed blastocyst transfer (SVBT) by examining the diameter of blastocysts.

Methods: Patients who underwent day 7 BL transfer cycles (1143 cycles, mean age: 38.5 ± 3.5) and randomly selected patients after 1:1 matching who underwent day 6 BL transfer cycles and day 2-single-embryo transfer (SET) cycles were used for analysis. Comparison of the miscarriage (per clinical pregnancy) and live birth rates were made among day 2-SET, day 7 BL, and day 6 BL. These blastocyst groups were stratified into six groups based on blastocyst diameter, namely, 180 μm, 190 μm, 200 μm, 210 μm, over 220 μm, and hatched, for making the freezing criteria.

Results: For each diameter, 180 μm, 190 μm, 200 μm, 210 μm, over 220 μm, and hatched, the live birth rates of day 7 BL after SVBT were 9.0%, 11.9%, 11.5%, 15.6%, 20.0%, and 19.9%, respectively. Compared with the 14.6% live birth rate of the day 2-SET group, the live birth rate of 220 μm day 7 BL was significantly higher (P < 0.05) and was around the same in other diameter groups.

Conclusion: Our study demonstrates that sufficient live birth rates can be obtained after SVBT even from blastocysts on day 7 when blastocysts were vitrified at expanded blastocyst stage of over 180 μm of diameter or at hatched blastocyst stage and were transferred at the optimal time. This is the first study to establish a day 7 blastocyst freezing criteria using blastocyst diameter, which is an objective assessment way.
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http://dx.doi.org/10.1007/s10815-020-01882-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492317PMC
September 2020

Discovery of a Potent Anticancer Agent PVHD303 with Activity.

ACS Med Chem Lett 2020 Jun 8;11(6):1287-1291. Epub 2020 May 8.

Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.

As a part of our continuous structure-activity relationship (SAR) studies on 1-(quinazolin-4-yl)-1-(4-methoxyphenyl)ethan-1-ols, the synthesis of derivatives and their cytotoxicity against the human lung cancer cell line A549 were explored. This led to the discovery of 1-(2-(furan-3-yl)quinazolin-4-yl)-1-(4-methoxyphenyl)ethan-1-ol (PVHD303) with potent antiproliferative activity. PVHD303 disturbed microtubule formation at the centrosomes and inhibited the growth of tumors dose-dependently in the HCT116 human colon cancer xenograft model .
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http://dx.doi.org/10.1021/acsmedchemlett.0c00119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294709PMC
June 2020

Success rates in minimal stimulation cycle IVF with clomiphene citrate only.

J Assist Reprod Genet 2020 Feb 23;37(2):297-304. Epub 2019 Dec 23.

Kato Ladies Clinic, 7-20-3 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To determine age-adjusted overall success rates for patients undergoing clomiphene citrate only minimal stimulation cycle (mini) in vitro fertilization (IVF) without any gonadotropin administration.

Methods: Eight hundred thirty-nine women (mean age: 38.4 ± 0.1 years; 2488 cycles) underwent clomiphene citrate only mini-IVF. Their first oocyte retrieval was between January 2009 and December 2009, with follow-up until December 2014. The cumulative live birth rate (CLBR) per oocyte retrieval cycle started and live birth rate per oocyte was retrospectively analyzed. The basic CLBR was calculated as the number of women who achieved a live birth divided by the total number of women who started oocyte retrieval.

Results: The mean number of oocytes retrieved was 1.5. The basic CLBRs for all ages after the first and third cycles were 22.6% and 39.2%, respectively. For ≤ 34 years, 35-37 years, 38-40 years, 41-42 years, and ≥ 43 years, CLBRs after the first and third cycles were 42.5% and 70.1%, 32.9% and 49.1%, 20.0% and 38.6%, 12.6% and 25.2%, and 4.4% and 8.8%, respectively. These rates had a significant relationship with age (P < 0.01). The LBR per oocyte for all ages was 9.6%.

Conclusion: Acceptable overall IVF success rates can be achieved in clomiphene citrate only mini-IVF, as well as acceptable LBR. The CLBRs and LBRs per oocyte are evidently influenced by women's age.
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http://dx.doi.org/10.1007/s10815-019-01662-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056817PMC
February 2020

Intermittent Hypoxia Up-Regulates Gene Expressions of in Enteroendocrine Cells.

Int J Mol Sci 2019 Apr 15;20(8). Epub 2019 Apr 15.

Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.

The patients with sleep apnea syndrome are exposed to intermittent hypoxia (IH) during sleep. We previously demonstrated the IH-induced up-regulation of the mRNA levels of anorexigenic peptides proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART) in human neuronal cells. Appetite is regulated not only by the central nervous system but also by the peptides from gastrointestinal tract. Here, we investigated the effects of IH on the gene expression(s) of appetite-inhibiting gut hormones. Human enteroendocrine Caco-2 and mouse STC-1 cells were exposed to IH [64 cycles of 5 min hypoxia (1% O₂) and 10 min normoxia (21% O₂)] or normoxia for 24 h. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of (), (), and () in Caco-2 and STC-1 cells. ELISA showed that the concentrations of PYY, GLP-1, and NTS in the culture medium were significantly increased by IH. The mRNA levels of , , and were significantly up-regulated even in normoxia by Trichostatin A (TSA) and were significantly decreased even in IH by 5-azacytidine (5AZC), suggesting that IH increases , , and mRNAs via alterations in the chromatin structure in enteroendocrine cells. IH might have an anorexigenic influence on the enteric nervous system.
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http://dx.doi.org/10.3390/ijms20081849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514992PMC
April 2019

Closed embryo culture system improved embryological and clinical outcome for single vitrified-warmed blastocyst transfer: A single-center large cohort study.

Reprod Biol 2019 Jun 1;19(2):139-144. Epub 2019 Apr 1.

Kato Ladies Clinic, 7-20-3, Nishi-shinjuku, Shinjuku, Tokyo 160-0023, Japan. Electronic address:

While some studies have shown that the closed embryo culture system (CCS) is a possible improvement over standard embryo culture systems (STS) in terms of early embryonic development, information on clinical outcomes of culturing blastocysts following single vitrified-warmed blastocyst transfer (SVBT) in the CCS and STS remains limited. Therefore, the objective of this single-center, large-cohort, retrospective study was to compare embryonic development until the blastocyst stage and clinical outcomes following SVBT between CCS and STS. From May 2017 to October 2018, 2420 oocytes from 1402 patients who underwent in vitro fertilization and blastocyst culture after minimal stimulation were divided into two groups (CCS and STS). The main outcome measures in the two groups were embryological (blastocyst formation rates and utilized blastocyst rates) and clinical outcomes (ongoing pregnancy rates) after a single vitrified-warmed blastocyst transfer (SVBT). There were no significant differences in the blastocyst formation rates between the CCS and STS groups (59.6% versus 59.1%, p = 0.81). However, there were significant differences in utilized blastocyst rates (51.0% versus 46.6%, p < 0.05). Ongoing pregnancy rates per SVBT cycle were significantly higher in the CCS group than in the STS group (41.4% versus 34.4%, p < 0.05). Moreover, after applying multivariable logistic regression analysis, the type of embryo culture system (CCS to STS, adjusted odds ratios: 1.41, 95% CI: 1.04-1.91) was correlated with ongoing pregnancy. Our study suggests that compared to STS, CCS could improve utilized blastocyst rates and ongoing pregnancy rates to a greater extent, following SVBT.
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http://dx.doi.org/10.1016/j.repbio.2019.03.004DOI Listing
June 2019

Prolonged blastomere movement induced by the delay of pronuclear fading and first cell division adversely affects pregnancy outcomes after fresh embryo transfer on Day 2: a time-lapse study.

Reprod Biomed Online 2019 May 22;38(5):659-668. Epub 2018 Dec 22.

Kato Ladies Clinic, Tokyo 160-0023, Japan. Electronic address:

Research Question: What is the incidence, origin and clinical significance of blastomere movement after the first cell division in the human embryo?

Design: A total of 1096 embryos, cultured in the EmbryoScope+ ® time-lapse system and subjected to a single fresh cleaved embryo transfer, were retrospectively analysed. Type and duration of blastomere movement (dBMov) between the first (t2) and second cell division (t3) was monitored, and the ratio of dBMov during the 2-cell stage [dBMov/(t3-t2)] was calculated. Morphological evaluation of embryos was performed by referring to the size of the blastomere and fragmentation after first division in addition to Veeck's criteria on Day 2. The correlation between dBMov and ongoing pregnancy was evaluated and the association of dBMov with patient and embryonic characteristics was determined.

Results: Both movement type and the value of dBMov/(t3-t2) were significantly associated with asymmetrical first division, fragment formation and morphological grade on Day 2. Multivariate logistic regression analysis revealed that a higher value of dBMov/(t3-t2) significantly correlated with a decreased ongoing pregnancy rate, even after adjustment for co-founders (odds ratio 0.399, P = 0.0419). The time intervals of pronuclear (PN) alignment and PN fading were significantly correlated with the dBMov/(t3-t2) value.

Conclusions: Embryos with extended blastomere movement after the first cell division, which is associated with the delay of PN fading and first cell division, have a lower competence to initiate an ongoing pregnancy after fresh embryo transfer on Day 2. Thus, blastomere movement could be a useful predictive parameter for selecting embryos at the early cleavage stage.
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http://dx.doi.org/10.1016/j.rbmo.2018.12.014DOI Listing
May 2019

New tailored approach using a revised assessment of fragmented potentials for persistent atrial fibrillation: Early area defragmentation by modified CFAE module.

J Cardiovasc Electrophysiol 2019 06 10;30(6):844-853. Epub 2019 Mar 10.

Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Introduction: Pulmonary vein isolation (PVI) is widely performed for atrial fibrillation (AFib). However, it is insufficient to maintain sinus rhythm (SR) in persistent and long persistent atrial fibrillation (Per-AFib). Ablation of complex fractionated atrial electrograms (CFAEs) is currently classified as class IIb, However, the concept of length of potential was different between the current CFAE module of CARTO system and the definition of CFAE potential. The current CFAE module was configured in the shortest complex interval (SCI) mode, in which the meaning of length of potential was the interval of each component of fragmented potentials. That was a part of the potential. On the other hand, the meaning of the definition of CFAE potential was the length of fragmented potential itself. The purpose of this study was to essentially evaluate fragmented potentials by revisiting in interval confidence level (ICL) mode and express them on the map and prospectively investigate the efficacy and prognosis of a new tailored approach for defragmentation, which is called early area defragmentation (EADF).

Methods And Results: We acquired atrial potentials by modified CFAE module in ICL mode (K-CFAE potential) and visualized the distribution of K-CFAE potential (K-CFAE map). We performed PVI, and we ablated the fragmented areas based on the K-CFAE map. We enrolled 77 patients in this study (control group: 84 patients). After 24-month follow-up, 75.3% were able to maintain SR.

Conclusions: K-CFAE mapping faithfully represented the distribution of fragmented areas. PVI, together with our new tailored approach, EADF, was successful in treating Per-AFib.
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http://dx.doi.org/10.1111/jce.13888DOI Listing
June 2019

Rivastigmine Improves Appetite by Increasing the Plasma Acyl/Des-Acyl Ghrelin Ratio and Cortisol in Alzheimer Disease.

Dement Geriatr Cogn Dis Extra 2018 Jan-Apr;8(1):77-84. Epub 2018 Mar 13.

Department of Neurology, Nara Medical University, Kashihara, Japan.

Background: Weight loss accelerates cognitive decline and increases mortality in patients with dementia. While acetylcholinesterase (AChE) inhibitors are known to cause appetite loss, we sometimes encounter patients in whom switching from donepezil (AChE inhibitor) to rivastigmine (AChE and butyrylcholinesterase [BuChE] inhibitor) improves appetite. Since BuChE inactivates ghrelin, a potent orexigenic hormone, we speculated that rivastigmine improves appetite by inhibiting BuChE-mediated ghrelin inactivation.

Methods: The subjects were patients with mild to moderate Alzheimer disease treated with either rivastigmine patch ( = 11) or donepezil ( = 11) for 6 months. Before and after treatment, we evaluated appetite (0, decreased; 1, slightly decreased; 2, normal; 3, slightly increased; 4, increased), cognitive function, and blood biochemical variables, including various hormones.

Results: Rivastigmine treatment significantly improved appetite (from 1.6 ± 0.5 to 2.6 ± 0.7), whereas donepezil treatment did not (from 2.0 ± 0.0 to 1.8 ± 0.4). Simultaneously, rivastigmine, but not donepezil, significantly decreased the serum cholinesterase activity (from 304.3 ± 60.5 to 246.8 ± 78.5 IU/L) and increased the cortisol level (from 11.86 ± 3.12 to 14.61 ± 3.29 μg/dL) and the acyl/des-acyl ghrelin ratio (from 4.03 ± 2.96 to 5.28 ± 2.72). The levels of leptin, insulin, total ghrel-in, and cognitive function were not significantly affected by either treatment.

Conclusions: Our results suggest that compared with donepezil, rivastigmine has the advantage of improving appetite by increasing the acyl/des-acyl ghrelin ratio and cortisol level, thereby preventing weight loss.
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http://dx.doi.org/10.1159/000487358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921190PMC
March 2018

A Patient With Encephalomyeloradiculoneuropathy Exhibiting a Relapsing-Remitting Clinical Course: Correlation of Serum and Cerebrospinal Fluid Anti-Neutral Glycosphingolipids Antibodies With Clinical Relapse.

Front Neurol 2018 4;9:206. Epub 2018 Apr 4.

Department of Neurology, Nara Medical University, Kashihara, Japan.

Several patients who had a progressive clinical course involving both the central and peripheral nervous systems have been reported, but the diagnostic marker has been remained uncertain. More recently, such patients were reported to have namely "encephalomyeloradiculoneuropathy (EMRN)" associated with anti-neutral glycosphingolipid (GSL) antibodies. These antibodies were reported to disappear from the serum in the recovery phase, but whether this finding applies to the cerebrospinal fluid (CSF) remains uncertain. We describe a 67-year-old man with EMRN in whom we measured anti-neutral GSL antibodies in serial serum and CSF samples. During the disease course, the optical densities of the positive band against the background intensity ratio (-<0.3; ±≥0.3 to <0.6; +≥0.6 to <1.0; 2+≥1.0 to <2.0; 3 +≥2.0) for serum and CSF anti-lactosylceramide (LacCer) antibodies were found to be as follows: 2+ and 1+ at the first admission, ± and - when the consciousness level improved after immunotherapy, - and 1+ at clinical relapse, and ± and - when the consciousness level improved after immunotherapy. This is the first time to document that clinical relapse occurred in EMRN, and at this time the negative anti-LacCer antibodies in CSF after the first course of immunotherapy turned positive, but this was not seen in serum samples.
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http://dx.doi.org/10.3389/fneur.2018.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893640PMC
April 2018

Cryostorage duration does not affect pregnancy and neonatal outcomes: a retrospective single-centre cohort study of vitrified-warmed blastocysts.

Reprod Biomed Online 2018 Jun 14;36(6):614-619. Epub 2018 Mar 14.

Kato Ladies Clinic, 7-20-3 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. Electronic address:

A retrospective cohort study of 8736 autologous single vitrified-warmed blastocyst transfer cycles was conducted in a single centre to investigate the effect of cryostorage on clinical and neonatal outcomes. Cryostorage duration was classified into three groups: (A) 0-2 months (n = 4702); (B) 2-13 months (n = 2853) and (C) 13-97 months (n = 1181). Blastocysts were vitrified using the Cryotop method. No significant differences were observed in live birth rates: (A) 37.3%; (B) 34.9%; (C) (35.2%). Gestational period was significantly shorter in group C: (A) 38.7 ± 1.8; (B) 38.6 ± 1.6; (C) 38.1 ± 1.7; P < 0.05. This was clinically unimportant as the average gestational age was more than 38 weeks. No significant differences between groups were observed in birth weight: (A) 3060 ± 455 g; (B) 3052 ± 449 g; (C) 2992 ± 445 g, or congenital malformation rates: (A) 2.2%; (B) 1.9%; (C) 1.8%. The limitation of this study was that maximum storage duration was 8 years; most blastocysts were in cryostorage for much shorter periods. Long-term storage of blastocysts that are vitrified using an open device vitrification system has no negative effect on pregnancy and neonatal outcomes.
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http://dx.doi.org/10.1016/j.rbmo.2018.03.008DOI Listing
June 2018

OPTIMIZATION OF A RADIOPHOTOLUMINESCENT GLASS DOSEMETER FOR OCCUPATIONAL EYE LENS DOSIMETRY IN INTERVENTIONAL RADIOLOGY/CARDIOLOGY.

Radiat Prot Dosimetry 2018 Dec;182(2):177-183

Universitair Ziekenhuis, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, Belgium.

Hospital based workers that perform interventional radiology are at risk of reaching the eye lens dose limit of 20 mSv/y. These workers are exposed to the radiation scattered by the patient, which creates a complex field, with low radiation energy reaching the eyes of the medical staff from wide angles. Therefore, the dosemeter used in the assessment of the eye lens dose of interventional radiologists needs to respond accurately in such conditions. In this study, the angular response of a commercially available radiophotoluminescent glass dosemeter, GD-352M, was optimized via Monte Carlo simulations, aiming at its use as eye lens dosemeter in interventional radiology. The improved dosemeter was manufactured and then characterized in terms of Hp(3), the quantity recommended for eye lens dosimetry. Its response was compared to the IEC 62387:2012 requirements for Hp(3) and to requirements proposed specifically for eye lens dosemeters used in interventional radiology. The improved dosemeter meets the IEC 62387:2012 requirements for energy and angular response for Hp(3) and also shows good agreement with the more strict requisites proposed for eye lens dosemeters to be used in interventional radiology.
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http://dx.doi.org/10.1093/rpd/ncy046DOI Listing
December 2018

Step Numbers and Hoehn-Yahr Stage after Six Years.

Eur Neurol 2018 22;79(3-4):118-124. Epub 2018 Feb 22.

Department of Neurology, Nara Medical University, Kashihara, Japan.

Background: Freezing of gait (FOG) has been linked to increased numbers of steps taken while walking. We tested the hypothesis that an increased number of steps associated with FOG might predict the exacerbation of the severity of Parkinson's disease (PD).

Methods: We prospectively studied 26 patients. Clinical assessments were performed and balance was evaluated in 30 patients with Hoehn-Yahr stage III PD 6 years previously. Gait parameters were analyzed with the use of an originally designed, suddenly narrowed path. PD-related independent variables, balance investigation-related variables, and gait-independent-related variables were analyzed by multiple logistic regression analysis.

Results: The Hoehn-Yahr stage increased in 14 patients and was unchanged in 12 patients. The 36-item Short-Form Health Survey score (OR 1.079, p = 0.041, 95% CI 1.003-1.161) and the number of steps on the suddenly narrow path (OR 1.605, p = 0.047, 95% CI 1.006-2.56) were related to an increase in the Hoehn-Yahr stage. The number of steps was significantly higher on the suddenly narrowed path (11.3 ± 3.6) than on a straightly narrowed path (10.1 ± 3.2) at the time of final follow-up in the 26 patients (p < 0.001).

Conclusions: An increased number of steps associated with FOG, which was elicited by the suddenly narrowed path, might be one predictor of an upgrade of stage in patients with Hoehn-Yahr stage III PD.
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http://dx.doi.org/10.1159/000487331DOI Listing
January 2019

Up-regulation of POMC and CART mRNAs by intermittent hypoxia via GATA transcription factors in human neuronal cells.

Int J Biochem Cell Biol 2018 02 21;95:100-107. Epub 2017 Dec 21.

Department of Neurology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.

Sleep apnea syndrome (SAS) is characterized by intermittent hypoxia (IH) during sleep. SAS and obesity are strongly related to each other. Here, we investigated the effect of IH on the expression of major appetite regulatory genes in human neuronal cells. We exposed NB-1, SH-SY5Y, and SK-N-SH human neuronal cells to IH (64 cycles of 5 min hypoxia and 10 min normoxia), normoxia, or sustained hypoxia for 24 h and measured the mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), galanin, galanin-like peptide, ghrelin, pyroglutamylated RFamide peptide, agouti-related peptide, neuropeptide Y, and melanocortin 4 receptor by real-time RT-PCR. IH significantly increased the mRNA levels of POMC and CART in all the neuronal cells. Deletion analysis revealed that the -705 to -686 promoter region of POMC and the -950 to -929 region of CART were essential for the IH-induced promoter activity. As possible GATA factor binding sequences were found in the two regions, we performed real-time RT-PCR to determine which GATA family members were expressed and found that GATA2 and GATA3 mRNAs were predominantly expressed. Therefore, we introduced siRNAs against GATA2 and GATA3 into NB-1 cells and found that GATA2 and GATA3 siRNAs abolished the IH-induced up-regulation of both POMC and CART mRNAs. These results indicate that IH stress up-regulates the mRNA levels of anorexigenic peptides, POMC and CART, in human neuronal cells via GATA2 and GATA3. IH can have an anorexigenic effect on SAS patients through the transcriptional activation of POMC and CART in the central nervous system.
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http://dx.doi.org/10.1016/j.biocel.2017.12.012DOI Listing
February 2018

Intrajejunal Infusion of Levodopa-Carbidopa Gel Can Continuously Reduce the Severity of Dropped Head in Parkinson's Disease.

Front Neurol 2017 16;8:547. Epub 2017 Oct 16.

Department of Neurology, Nara Medical University, Kashihara, Japan.

Dropped head can occur in patients with Parkinson's disease and make their quality of life unpleasant because they cannot obtain a frontal view. The pathophysiologic involvement of dopamine agonist or central or peripheral mechanisms has been proposed. Levodopa therapy with the withdrawal of dopamine agonists was sometimes effective, but the effect in most patients did not persist for the entire day. We describe a patient with Parkinson's disease whose dropped head responded throughout the day to the continuous intrajejunal infusion of levodopa-carbidopa intestinal gel (LCIG). During off-periods before treatment with LCIG, severe akinesia and freezing of gait were evident, and she could not continuously obtain a frontal view because of the dropped head. About 20 min after the intrajejunal infusion of LCIG, these features remarkably improved, and she could obtain a frontal view. The angle of dropped head was improved from 39.39 to 14.04°. This case suggests that infusion of LCIG can reduce the severity of dropped head for a longer period than oral levodopa.
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http://dx.doi.org/10.3389/fneur.2017.00547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650705PMC
October 2017

Abnormalities on Brain Susceptibility-weighted Imaging in Neuro-Sweet Disease.

Intern Med 2017 11 25;56(21):2961-2962. Epub 2017 Sep 25.

Department of Neurology, Nara Medical University School of Medicine, Japan.

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http://dx.doi.org/10.2169/internalmedicine.8674-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709651PMC
November 2017

Parkin mutation may be associated with serious akinesia in a patient with Parkinson's disease.

J Neurol Sci 2017 Aug 31;379:119-121. Epub 2017 May 31.

Department of Neurology, Nara Medical University, Kashihara, Nara, Japan.

Acute akinesia (AA) is an unusual motor complication in Parkinson's disease (PD). Reported risk factors for AA include infection, trauma, surgical intervention, and the withdrawal of antiparkinsonian medication. Recently, patients with genetic PD were reported to have a three-fold risk of AA than patients with non-genetic PD. We describe a patient with PD associated with a Parkin mutation in whom serious akinesia developed. A 42-year-old man with exon 2 heterozygous deletion and exon 4 heterozygous deletion in the PARK2 gene showed five unexpected AA for several 12h. At fifth AA, he could not move any part of the body while lying in front of a stove in his house all night. He was admitted to our hospital because a third-degree burn had developed on 16% of the body surface area. Parkin mutation in addition to POLG1 or PINK1 mutation may be associated with serious AA.
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http://dx.doi.org/10.1016/j.jns.2017.05.065DOI Listing
August 2017

Can levodopa prevent cognitive decline in patients with Parkinson's disease?

Am J Neurodegener Dis 2017 15;6(2):9-14. Epub 2017 Jun 15.

Department of Neurology, Nara Medical UniversityKashihara, Nara, Japan.

Cognitive impairment in Parkinson's disease (PD) will become more important since the number of elderly patients with PD is increasing. We prospectively studied non-demented patients with PD over the course of 3 years to identify factors associated with PD that contribute to a decline in cognitive function. From among 100 consecutive patients, we registered 79 patients with PD. A total of 55 patients completed the study during 3 years and were divided to two groups: patients with a decline in cognitive function and those without a decline in cognitive function after 3 years. Seventeen independent variables were evaluated with the use of logistic regression models. The increase in the daily levodopa dose was related to a decline in cognitive function on univariate logistic regression analysis (OR = 0.279, p = 0.024, 95% CI = 0.092-0.848). Other variables were not related to a decline in cognitive function. The increase in the daily dose of levodopa was greater in patients without a decline in cognitive function than those with a decline in cognitive function; on the other hand, the cognitive function unchanged. Our results suggest that the treatment with levodopa might prevent a decline in cognitive function in PD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498848PMC
June 2017

Can postural abnormality really respond to levodopa in Parkinson's disease?

J Neurol Sci 2017 Jun 17;377:179-184. Epub 2017 Apr 17.

Department of Neurology, Nara Medical University, Kashihara, Nara, Japan.

Objective: Abnormal postures affect motor function in Parkinson's disease (PD), potentially compromising the quality of life. The clinical efficacy of dopaminergic medications remains uncertain. Knowing what type of abnormal posture clearly responds to dopaminergic medication would facilitate the clinical management of PD. We investigated whether abnormal posture responded to dopamine challenge testing.

Methods: We studied 24 consecutive patients with PD who had anterior trunk flexion (ATF) (n=13), antecollis (n=4), or lateral trunk flexion (LTF) (n=7). Levodopa was infused intravenously over the course of 30min. Before and after the levodopa infusion, the angle of the posture was measured with the use of "Image J" software.

Results: After the infusion of levodopa, the angle of the overall abnormal posture significantly decreased (p<0.001). The angle of the abnormal posture significantly decreased in both natural position (p<0.001, p=0.002) and in a position with the back averted (p=0.003, p=0.029) in patients with ATF or antecollis, but did not change significantly in patients with LTF (p=0.099). The change in the angle differed significantly between patients with ATF and those with antecollis (p=0.017) and between patients with antecollis and those with LTF (p=0.008), but did not differ significantly between patients with ATF and those with LTF (p=0.052). The change in the angle in patients with abnormal posture related to the 'off' state was significantly greater than that in patients without abnormal posture related to the 'off' state (p<0.001).

Conclusion: Patients with LTF and some patients with ATF poorly respond to levodopa. Two phenotypes of levodopa-responsiveness exist in patients with abnormal posture, and this observation is associated with an 'off' state, especially in patients with ATF.
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http://dx.doi.org/10.1016/j.jns.2017.04.025DOI Listing
June 2017

Risk of Unsuccessful Noninvasive Ventilation for Acute Respiratory Failure in Heterogeneous Neuromuscular Diseases: A Retrospective Study.

Neurol Int 2017 Feb 28;9(1):6904. Epub 2017 Mar 28.

Department of Neurology, Nara Medical University, Kashihara, Japan.

If invasive ventilation can be avoided by performing noninvasive mechanical ventilation (NIV) in patients with acute respiratory failure (ARF), the disease can be effectively managed. It is important to clarify the characteristics of patients with neuromuscular diseases in whom initial NIV is likely to be unsuccessful. We studied 27 patients in stable neuromuscular condition who initially received NIV to manage fatal ARF to identify differences in factors immediately before the onset of ARF among patients who receive continuous NIV support, patients who are switched from NIV to invasive ventilation, and patients in whom NIV is discontinued. Endpoints were evaluated 24 and 72 hours after the initiation of NIV. After 24 hours, all but 1 patient with amyotrophic lateral sclerosis (ALS) received continuous NIV support. 72 hours later, 5 patients were switched from NIV to invasive ventilation, and 5 patients continued to receive NIV support. 72 hours after the initiation of NIV, the proportion of patients with a diagnosis of ALS differed significantly among the three groups (P=0.039). NIV may be attempted to manage acute fatal respiratory failure associated with neuromuscular diseases, but clinicians should carefully manage the clinical course in patients with ALS.
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http://dx.doi.org/10.4081/ni.2017.6904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391512PMC
February 2017

Early progression of brain atrophy in patients with anti-N-methyl-D-aspartate receptor encephalitis: Case reports.

Medicine (Baltimore) 2017 Apr;96(17):e6776

Department of Neurology, Nara Medical University, Kashihara, Nara, Japan.

Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis responds to immunnotherapy, and approximately 80% of patients with this disorder fully recover or have only minor sequelae. Brain magnetic resonance imaging (MRI) does not show a specific abnormality, but some patients have progressive cerebral atrophy. The cerebral atrophy can become reversible after clinical improvement.

Methods: We describe 3 patients with diffuse cerebral atrophy (DCA) on serial brain MRI.

Results: Two women had the typical spectrum of this disorder, and one man had mainly psychiatric symptoms. In a woman with an ovarian tumor, DCA was reversible and DCA developed within about a half month. In another woman without a tumor, DCA was evident within 19 days and had progressed over the course of 4 years. The titers of anti-NMDAR antibodies in serum and cerebrospinal fluid (CSF) initially decreased, and low titers of the antibodies persisted. In a man without a tumor, DCA progressed within 14 days, and during this short period, he did not receive prolonged treatment with corticosteroids, various antiepileptic agents, or propofol, and he was free of seizures and ventilatory support.

Conclusion: Not only a woman but also a man with anti-NMDAR encephalitis can have DCA in the early phase of this disorder. However, DCA can be reversible after clinical improvements. The early progression of DCA is not necessarily a poor prognostic factor.
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http://dx.doi.org/10.1097/MD.0000000000006776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413277PMC
April 2017

A giant uterine tumor in a woman with myotonic dystrophy.

Clin Case Rep 2017 Apr 23;5(4):539-540. Epub 2017 Feb 23.

Department of Neurology Nara Medical University Kashihara Nara Japan.

Patients with myotonic dystrophy are at particularly high risk for cancer arising in the endometrium, brain, colon, or ovary. Giant leiomyoma can occur in patients with myotonic muscular dystrophy, a disease accompanied by muscle wasting.
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http://dx.doi.org/10.1002/ccr3.864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378841PMC
April 2017

Severe Cold Lower Limbs in Patients with Parkinson's Disease During the Summer.

Neurol Int 2016 Nov 2;8(4):6676. Epub 2016 Nov 2.

Department of Neurology, Nara Medical University , Kashihara, Nara, Japan.

Parkinson's disease (PD) is frequently associated with vasomotor symptoms such as distal cold limbs or sensitivity to cold. Coldness of the lower limbs (COL) usually occurs in winter and is often accompanied by pain, potentially causing difficulty in walking or standing. A standard dopaminergic treatment for such symptoms is yet to be established. We describe two patients with PD, who had severe COL during summer. For example, the patients wore many pairs of socks or used heating appliances in the summer. Severe COL can occur in summertime and can be intolerable or unpleasant, since it can worsen disability. The treatment with a dopamine agonist did not sufficiently decrease the severity of COL.
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http://dx.doi.org/10.4081/ni.2016.6676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5136751PMC
November 2016

Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples.

PLoS One 2016 8;11(12):e0165109. Epub 2016 Dec 8.

Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Introduction And Objectives: Oncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples.

Materials And Methods: The RNA-FISH assay was developed and validated using a mouse xenograft model with human BC cell lines. Next, we assessed the consistency of the RNA-FISH assay using 104 human BC samples. In this study, primary BC tissues were stored as frozen and FFPE tissues. FGFR3-TACC3 fusions were independently detected in FFPE sections by the RNA-FISH assay and in frozen tissues by RT-PCR. We also analyzed the presence of FGFR3 mutations by targeted sequencing of genomic DNA extracted from deparaffinized FFPE sections.

Results: FGFR3-TACC3 fusion transcripts were identified by RNA-FISH and RT-PCR in mouse xenograft FFPE tissues using the human BC cell lines RT112 and RT4. These cell lines have been reported to be fusion-positive. Signals for FGFR3-TACC3 fusions by RNA-FISH were positive in 2/60 (3%) of non-muscle-invasive BC (NMIBC) and 2/44 (5%) muscle-invasive BC (MIBC) patients. The results of RT-PCR of all 104 patients were identical to those of RNA-FISH. FGFR3 mutations were detected in 27/60 (45%) NMIBC and 8/44 (18%) MIBC patients. Except for one NMIBC patient, FGFR3 mutation and FGFR3-TACC3 fusion were mutually exclusive.

Conclusions: We developed an RNA-FISH assay for detection of the FGFR3-TACC3 fusion in FFPE samples of human BC tissues. Screening for not only FGFR3 mutations, but also for FGFR3-TACC3 fusion transcripts has the potential to identify additional patients that can be treated with FGFR inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165109PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145148PMC
July 2017

Hypotrophic muscle ipsilateral to the bending side is not a therapeutic target in recurrent and alternating lateral trunk flexion in Parkinson disease: Case report.

Ann Phys Rehabil Med 2016 Dec 23;59(5-6):346-348. Epub 2016 Aug 23.

Department of Neurology, Nara Medical University, Kashihara, Nara, Japan.

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http://dx.doi.org/10.1016/j.rehab.2016.07.001DOI Listing
December 2016

Complete zona pellucida removal from vitrified-warmed human blastocysts facilitates earlier in-vitro attachment and outgrowth.

Reprod Biomed Online 2016 Aug 24;33(2):140-8. Epub 2016 May 24.

Kato Ladies Clinic, 7-20-3 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Electronic address:

Partial removal of the zona pellucida (ZP) has been performed using a laser system to promote hatching of vitrified-warmed blastocysts. However, low-viability blastocysts cannot hatch even after partial ZP removal. This study examined whether complete removal of the ZP improves embryonic adhesion and outgrowth of vitrified-warmed blastocysts compared with partial removal, using a blastocyst outgrowth model. In all, 217 vitrified human blastocysts, which were discarded and donated for research by consenting couples, were warmed and subjected to assisted hatching to remove the ZP partially or completely, or did not undergo assisted hatching (zona intact controls). Blastocysts were cultured using time-lapse microscopy to monitor hatching, adhesion and outgrowth. Despite partial ZP removal, 36% of blastocysts failed to hatch. Blastocyst outgrowth assays showed improved adhesion rate, shorter time for adhesion and larger outgrowth area in the blastocysts with completely removed ZP compared with those with partially-removed ZP. mRNA expression of integrin α5 and β1 was upregulated in blastocysts with completely removed ZP compared with those with partially-removed ZP. Study findings reveal the advantages of complete ZP removal for assisted hatching. In conclusion, complete ZP removal increases the chance of blastocyst adhesion and subsequent outgrowth in vitro after the vitrification-warming procedure.
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http://dx.doi.org/10.1016/j.rbmo.2016.05.007DOI Listing
August 2016
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