Publications by authors named "Yusuke Aoki"

29 Publications

  • Page 1 of 1

Cerebrovascular diseases in two patients with entire NSD1 deletion.

Hum Genome Var 2021 May 24;8(1):20. Epub 2021 May 24.

Department of human genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.

We describe two patients with NSD1 deletion, who presented with early-onset, or recurrent cerebrovascular diseases (CVDs). A 39-year-old female showed developmental delay and abnormal gait in infancy, and developed slowly-progressive intellectual disability and movement disorders. Brain imaging suggested recurrent parenchymal hemorrhages. A 6-year-old male had tremor as a neonate and brain imaging revealed subdural hematoma and brain contusion. This report suggests possible involvement of CVDs associated with NSD1 deletion.
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http://dx.doi.org/10.1038/s41439-021-00151-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144564PMC
May 2021

Reconstruction of the elbow using pedicle joint freezing after wide excision for soft tissue sarcoma: A case report.

Mol Clin Oncol 2021 Jun 8;14(6):115. Epub 2021 Apr 8.

Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0125, Japan.

A 35-year-old man presented with a four-year history of a growing mass on the anterior aspect of his left elbow. Magnetic resonance imaging revealed a soft tissue tumor in the brachialis muscle extending to the cubital fossa. Following an open biopsy, the tumor was diagnosed as a monophasic fibrous synovial sarcoma. After neoadjuvant chemotherapy, the patient underwent wide excision and reconstruction of the elbow joint with a pedicle frozen autograft. At the final follow-up four years after surgery, the elbow range of motion was 0-120˚. Although there were signs of osteoarthritis, there was no narrowing of the joint -, and the patient experienced only mild pain. To the best of our knowledge, the present case report is the first to describe wide tumor excision and reconstruction using a pedicle frozen autograft of the elbow. This method should be considered after excision of malignant bone and soft tissue tumors, especially in non-weight-bearing joints. Further cases have to be evaluated to understand the complications and long-term prognosis of this procedure.
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http://dx.doi.org/10.3892/mco.2021.2277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060848PMC
June 2021

SCN8A-related developmental and epileptic encephalopathy with ictal asystole requiring cardiac pacemaker implantation.

Brain Dev 2021 Apr 4. Epub 2021 Apr 4.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Introduction: SCN8A-related epilepsy has various phenotypes. In particular, patients with developmental and epileptic encephalopathy (DEE) are resistant to antiepileptic drugs and may present with autonomic symptoms, such as marked bradycardia and apnea during seizures, and thus have an increased risk of sudden death. Herein, we report a case of very severe SCN8A-related epilepsy necessitating cardiac pacemaker implantation because of repetitive ictal asystole.

Case Report: The patient was a 14-month-old girl. Tremor and generalized tonic seizure occurred after birth. During seizures, bradycardia and perioral cyanosis occurred, and then, after developing tachycardia and apnea, marked bradycardia and generalized cyanosis occurred, which sometimes resulted in ictal asystole requiring cardiopulmonary resuscitation. Her seizures were refractory to antiepileptic drugs. As the seizures requiring resuscitation did not decrease, cardiac pacemaker implantation was performed four months after birth. Exome sequencing revealed a heterozygous de novo variant in SCN8A (NM_014191.3:c.4934T>C,p.(Met1645Thr)). Even though phenytoin was effective, seizures with bradycardia remained approximately once a month, and pacemaker activity was observed.

Conclusions: This is, to our knowledge, the first reported case of SCN8A-related DEE in whom pacemaker implantation was performed. Pacemaker implantation should be considered as a treatment option for critical patients with SCN8A-related DEE as in the present case, because the incidence of sudden unexpected death in epilepsy is reported to be approximately 10% in patients with SCN8A-related DEE.
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http://dx.doi.org/10.1016/j.braindev.2021.03.004DOI Listing
April 2021

Eribulin Inhibits Osteosarcoma in a Clinically-accurate Bone-tumor-insertion PDOX Mouse Model.

Anticancer Res 2021 Apr;41(4):1779-1784

AntiCancer Inc, San Diego, CA, U.S.A.;

Background/aim: Osteosarcoma is a rare type of bone cancer that affects mostly children and adolescents. First-line chemotherapy for osteosarcoma has not been improved for many decades. Eribulin has been used to treat breast cancer and liposarcoma in the clinic.

Materials And Methods: A patient-derived orthotopic xenograft (PDOX) mouse model of osteosarcoma was established by tumor insertion within the tibia. This model more closely mimics osteosarcoma in clinical settings and was used to test the efficacy of eribulin. Tibia-insertion osteosarcoma PDOX mouse models were randomized into two groups: a control group (n=4) and an eribulin-treatment group (n=5). Mice were treated for fourteen days, four weeks after initial implantation. Tumor size and body weight were measured, and tumor histology was examined.

Results: Significant tumor growth inhibition (p=0.044) was observed in mice treated with eribulin compared to the control group. Histology demonstrated necrosis in the eribulin-treated tumors. There was no body-weight loss in the treated mice.

Conclusion: Eribulin may be a clinically-effective, off-label chemotherapy for recalcitrant osteosarcoma that has failed first- and second-line therapy.
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http://dx.doi.org/10.21873/anticanres.14943DOI Listing
April 2021

Oral-recombinant Methioninase Converts an Osteosarcoma from Docetaxel-resistant to -Sensitive in a Clinically-relevant Patient-derived Orthotopic-xenograft (PDOX) Mouse Model.

Anticancer Res 2021 Apr;41(4):1745-1751

AntiCancer Inc, San Diego, CA, U.S.A.;

Background/aim: Osteosarcoma is the most frequent malignant bone tumor. Failure of first-line therapy results in poor prognosis of osteosarcoma. In the present report, we examined the efficacy of the combination of oral recombinant methioninase (o-rMETase) and docetaxel (DOC) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model.

Materials And Methods: Osteosarcoma-PDOX models were established by tumor insertion within the tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups (4-5 mice per group): control; o-rMETae alone; DOC alone; o- rMETase combined with DOC. The treatment period was 3 weeks.

Results: The combination of o-rMETase and DOC showed significant efficacy compared to the control group (p=0.03). In contrast, there was no significant efficacy of o-rMETase alone or DOC alone (p=0.65, 0.60, respectively).

Conclusion: o-rMETase converted an osteosarcoma PDOX from DOC-resistant to -sensitive. This combination therapy may be effective against recalcitrant osteosarcoma and other recalcitrant cancers.
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http://dx.doi.org/10.21873/anticanres.14939DOI Listing
April 2021

Reversion from Methionine Addiction to Methionine Independence Results in Loss of Tumorigenic Potential of Highly-malignant Lung-cancer Cells.

Anticancer Res 2021 Feb;41(2):641-643

AntiCancer Inc, San Diego, CA, U.S.A.;

Background/aim: Methionine addiction, a fundamental and general hallmark of cancer, is due to the excess use of methionine for transmethylation, and is described as the Hoffman-effect. Methionine-addicted cancer cells can revert at low frequency to methionine independence when selected under methionine-restriction. We report here that highly-malignant methionine-addicted H460 human lung-cancer cells, when selected for methionine independence, have greatly-reduced tumorigenic potential.

Materials And Methods: Methionine-addicted H460 parental cancer cells and methionine-independent revertant H460-R1 cells were injected in nude mice subcutaneously.

Results: When the parental H460 methionine-addicted cells were injected in nude mice at 2.5×10, 1×10 and 5×10, the cells could form tumors. In contrast, the H460-R1 methionine-independent revertant cells could not form tumors when the above-listed cell numbers were injected in nude mice.

Conclusion: There is a tight linkage between methionine addiction and malignancy.
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http://dx.doi.org/10.21873/anticanres.14815DOI Listing
February 2021

Haprin-deficient spermatozoa are incapable of in vitro fertilization.

Mol Reprod Dev 2020 05 20;87(5):534-541. Epub 2020 Apr 20.

Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki, Japan.

Haprin (TRIM36) is a ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. It is expressed in the testes in both mice and humans and is thought to be involved in spermiogenesis, the acrosome reaction, and fertilization. However, the functional role of Haprin is poorly understood. The aim of this study was to investigate the physiological role of Haprin in fertility. Homozygous haprin-deficient mice were generated and these mice, and their spermatozoa, were analyzed to detect morphological and fertility-related abnormalities. In these models, normal spermatogenesis was observed but sperm quality was reduced with haprin-deficient mice having poorer sperm morphology and motility than wild-type mice. Interestingly, haprin-deficient mice showed normal in vivo fertility but could not fertilize oocytes under standard in vitro fertilization conditions. In conclusion, this study demonstrated that Haprin deficiency causes morphological abnormalities in spermatozoa, indicating that Haprin is involved in spermiogenesis.
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http://dx.doi.org/10.1002/mrd.23344DOI Listing
May 2020

Malignant melanoma of the male urethra with increased 5--cysteinyldopa: A case report.

IJU Case Rep 2019 Jul 11;2(4):215-217. Epub 2019 Jun 11.

Department of Urology Saitama Cancer Center Ina-machi Saitama Japan.

Introduction: We herein present a case of malignant melanoma of the male urethra with an increased serum 5--cysteinyldopa concentration.

Case Presentation: A 77-year-old man visited our hospital complaining dysuria and a dark brown mass protruding from the external urethral meatus. His serum 5--cysteinyldopa concentration was elevated beyond the upper limit of the reference range. Biopsy of the tumor was performed, and the histological diagnosis was malignant melanoma. He underwent total penectomy, and the serum 5--cysteinyldopa concentration was normalized. He remained alive without evidence of locoregional recurrence or distant metastases for 6 months after surgery.

Conclusion: Malignant melanoma of the male urethra is uncommon. The prognosis is favorable if it is detected in its early stages. This case report suggests that measurement of the serum concentration of 5--cysteinyldopa, a melanin metabolite, is useful for early diagnosis of male urethral melanoma.
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http://dx.doi.org/10.1002/iju5.12086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292080PMC
July 2019

Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1.

J Hum Genet 2019 Jul 19;64(7):665-671. Epub 2019 Apr 19.

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Whole-exome sequencing of a female patient with unknown spastic paraplegia was performed to obtain a molecular diagnosis. As a result, a de novo heterozygous single-nucleotide deletion in PLP1 [NM_000533.5(PLP1_v001):c.783del; p.Thr262Leufs*20] was identified. RNA sequencing was performed in a patient-derived lymphoblastoid cell line, confirming mono-allelic expression of the mutated allele and abnormal inactivation of the wild-type allele. The patient-derived lymphoblastoid cell line was then treated with VX680 or 5azadC, which resulted in restored expression of the wild-type allele. These two agents thus have the potential to reverse inappropriately-skewed inactivation of the X-chromosome.
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http://dx.doi.org/10.1038/s10038-019-0600-xDOI Listing
July 2019

Renal medullary carcinoma in a young mixed-race man in Japan.

Pathol Int 2019 Apr 7;69(4):241-245. Epub 2019 Mar 7.

Department of Pathology and Oncology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan.

Renal medullary carcinoma (RMC) is a rare and aggressive cancer associated with the sickle cell trait. The diagnosis of RMC depends on recognition of its histologic features and immunohistochemical deficiency of INI1, but correct diagnosis is sometimes difficult, especially if a patient's information on race, past, and family medical history is unclear. At present, this is the first report on RMC in Japan.
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http://dx.doi.org/10.1111/pin.12783DOI Listing
April 2019

Effect of on in vitro fertilization via improvement in acrosome reaction and motility of mouse and human sperm.

Reprod Med Biol 2019 Jan 24;18(1):57-64. Epub 2018 Oct 24.

Department of Urology Juntendo University Graduate School of Medicine Tokyo Japan.

Purpose: The direct effects of (Maca) on sperm remain unclear. Herein, we examined the direct effect of Maca on in vitro fertilization.

Methods: We examined the fertilization rate in a mouse model and the rate of acrosome reaction in sperm from transgenic mice expressing enhanced green fluorescent protein (EGFP) in a Maca extract-containing human tubal fluid (HTF) medium. Using human sperm, we assessed acrosome status via fluorescein isothiocyanate-conjugated peanut agglutinin (FITC-PNA) staining and performed detailed analysis using a sperm motility analysis system (SMAS).

Results: In the mouse model, the fertilization rate in the Maca extract-containing HTF was significantly higher than that in the control medium. The acrosome reaction rate in sperm from transgenic mice expressing EGFP was also significantly higher in the Maca extract-containing HTF than that in the control medium. Similarly, a high acrosome reaction rate, identified via FITC-PNA staining of human sperm samples, was found in the Maca extract-containing HTF compared with that in the control medium. Human sperm motility in the Maca extract-containing HTF was also increased compared with that in the control medium as measured using an SMAS.

Conclusions: Maca improved in vitro fertilization rates by inducing an acrosome reaction and increasing sperm motility.
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http://dx.doi.org/10.1002/rmb2.12251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332831PMC
January 2019

The Gata2 repression during 3T3-L1 preadipocyte differentiation is dependent on a rapid decrease in histone acetylation in response to glucocorticoid receptor activation.

Mol Cell Endocrinol 2019 03 4;483:39-49. Epub 2019 Jan 4.

Department of Pharmacy, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan. Electronic address:

The transcription factor GATA2 is an anti-adipogenic factor whose expression is downregulated during adipocyte differentiation. The present study attempted to clarify the molecular mechanism underlying the GATA2 repression and found that the repression is dependent on the activation of the glucocorticoid receptor (GR) during 3T3-L1 preadipocyte differentiation. Although several recognition sequences for GR were found in both the proximal and distal regions of the Gata2 locus, the promoter activity was not affected by the GR activation in the reporter assays, and the CRISPR-Cas9-mediated deletion of the two distal regions of the Gata2 locus was not involved in the GR-mediated Gata2 repression. Notably, the level of histone acetylation was markedly reduced at the Gata2 locus during 3T3-L1 differentiation, and the GR-mediated Gata2 repression was significantly relieved by histone deacetylase inhibition. These results suggest that GR regulates the Gata2 gene by reducing histone acetylation in the early phase of adipogenesis.
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http://dx.doi.org/10.1016/j.mce.2019.01.002DOI Listing
March 2019

Oral L-citrulline and Transresveratrol Supplementation Improves Erectile Function in Men With Phosphodiesterase 5 Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Crossover Pilot Study.

Sex Med 2018 Dec 24;6(4):291-296. Epub 2018 Aug 24.

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

Introduction: Phosphodiesterase type 5 inhibitors (PDE5i) are first-line therapy for most men with erectile dysfunction (ED). If ineffective, vacuum erection devices, intracavernous injections, and penile prosthesis implantation are suitable as second- or third-line therapies. However, very few patients select these therapies. It is critically important to improve erectile function with oral administration of effective agents. Administration of L-citrulline or transresveratrol in animal experiments has been reported to improve erectile function, but few such experiments have been performed on humans with ED.

Aim: We aimed to investigate the efficacy of combination therapy of L-citrulline and transresveratrol in patients with ED despite their use of PDE5i.

Methods: In this randomized, double-blind, placebo-controlled crossover pilot study, men with ED (Sexual Health Inventory for Men [SHIM] score below 16) despite on-demand use of PDE5i received a placebo for 1 month or the active treatment (L-citrulline 800 mg/day and transresveratrol 300 mg/day) for another month. Patients continued on-demand use of PDE5i.

Main Outcome Measure: The SHIM score, Erection Hardness Score (EHS), Aging Male Symptoms Scale-sexual domain (AMS-SD), and adverse events were examined.

Results: 20 patients ages 29-78 years were enrolled, and after 6 men withdrew, 13 concluded the study without adverse events. Mean SHIM score for the active treatment increased significantly (10.96 ± 1.21) compared with baseline (8.32 ± 1.21) and placebo (8.31 ± 1.23) (both P < .05). Mean EHS score for the active treatment (2.56 ± 0.26) also increased from baseline (2.31 ± 0.26), but not significantly (P = .79). Mean AMS-SD score was not significantly different in either group.

Conclusion: To our knowledge, this is the first study to show that combination therapy of L-citrulline and transresveratrol is effective for ED treatment in men with added on-demand use of PDE5i. This combination supplement may be added if PDE5i is insufficient. Shirai M, Hiramatsu I, Aoki Y, et al. Oral L-citrulline and Transresveratrol Supplementation Improves Erectile Function in Men With Phosphodiesterase 5 Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Crossover Pilot Study. Sex Med 2018;6:291-296.
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http://dx.doi.org/10.1016/j.esxm.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302103PMC
December 2018

Enzymatically cleavable traceless biotin tags for protein PEGylation and purification.

Chem Commun (Camb) 2018 Feb;54(15):1913-1916

School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.

Here we report an example of a protein-PEG conjugate with a biotin tag cleavable by lipase-catalyzed hydrolysis. Very mild cleavage conditions, heterogeneous, easily separable catalysts, and traceless design make this method attractive for the preparation and purification of PEGylated proteins.
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http://dx.doi.org/10.1039/c7cc05814dDOI Listing
February 2018

Relation between histological prostatitis and lower urinary tract symptoms and erectile function.

Prostate Int 2017 Sep 12;5(3):119-123. Epub 2017 Apr 12.

Department of Urology, Juntendo University Urayasu Hospital, Urayasu, Japan.

Background: Chronic prostatitis (CP) significantly worsens a patient's quality of life (QOL), but its etiology is heterogeneous. Although the inflammatory process must be associated with CP symptoms, not all patients with benign prostatic hyperplasia and histological prostatitis complain of CP symptoms. The relation between the severity of histological inflammation and lower urinary tract symptoms (LUTS) and erectile function is not fully understood.

Methods: This study comprised 26 men with suspected prostate cancer but with no malignant lesion by pathological examination of prostate biopsy specimens. LUTS were assessed by several questionnaires including the International Prostate Symptom Score (IPSS), QOL index, Overactive Bladder Symptom Score (OABSS), and the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), and erectile function was assessed by the Sexual Health Inventory for Men. Prostate volume (PV) measured by transabdominal ultrasound, maximum flow rate by uroflowmetry, and serum concentration of prostate-specific antigen were also evaluated. All data collections were performed before prostate biopsy. Histological prostatitis was assessed by immunohistochemical staining with anti-CD45 antibody as the Quick score. The relation between the Quick score and several factors was assessed by Pearson correlation coefficient and a multivariate linear regression model after adjustment for PV.

Results: The Pearson correlation coefficient showed a correlation between the Quick score and several factors including PV, IPSS, QOL index, OABSS, and NIH-CPSI. A multivariate linear regression model after adjustment for PV showed only the NIH-CPSI to be associated with the Quick score. The relation between the Quick score and each domain score of the NIH-CPSI showed only the subscore of urinary symptoms to be an associated factor.

Conclusion: We found a correlation only between histological prostatitis and LUTS, but not erectile dysfunction. Especially, the subscore of urinary symptoms (residual feeling and urinary frequency) was associated with histological prostatitis.
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http://dx.doi.org/10.1016/j.prnil.2017.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551917PMC
September 2017

Atherosclerosis is associated with erectile function and lower urinary tract symptoms, especially nocturia, in middle-aged men.

Prostate Int 2017 Jun 13;5(2):65-69. Epub 2017 Feb 13.

Men's Health Clinic Tokyo, Marunouchi Chiyoda-ku, Tokyo, Japan.

Background: Atherosclerosis is a systematic disease in which plaque builds up inside the arteries that can lead to serious problems related to quality of life (QOL). Lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and late-onset hypogonadism (LOH) are highly prevalent in aging men and are significantly associated with a reduced QOL. However, few questionnaire-based studies have fully examined the relation between atherosclerosis and several urological symptoms.

Materials And Methods: The study comprised 303 outpatients who visited our clinic with symptoms of LOH. Several factors influencing atherosclerosis, including serum concentrations of triglyceride, fasting blood sugar, and total testosterone measured by radioimmunoassay, were investigated. We also measured brachial-ankle pulse wave velocity (baPWV) and assessed symptoms by specific questionnaires, including the Sexual Health Inventory for Men (SHIM), Erection Hardness Score (EHS), International Prostate Symptom Score (IPSS), QOL index, and Aging Male Symptoms rating scale (AMS). Stepwise associations between the ratio of measured/age standard baPWV and clinical factors including laboratory data and the scores of the questionnaires were compared using the Jonckheere-Terpstra test for trend. The associations between the ratio of measured/age standard baPWV and each IPSS score were assessed in a multivariate linear regression model after adjustment for serum triglyceride, fasting blood sugar, and total testosterone.

Results: Regarding ED, a higher level of the ratio of measured/age standard baPWV was associated with a lower EHS, whereas no association was found with SHIM. Regarding LUTS, a higher ratio of measured/age standard baPWV was associated with a higher IPSS and QOL index. However, there was no statistically significant difference between the ratio of measured/age standard baPWV and AMS. A multivariate linear regression model showed only nocturia to be associated with the ratio of measured/age standard baPWV for each IPSS score.

Conclusion: Atherosclerosis is associated with erectile function and LUTS, especially nocturia.
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http://dx.doi.org/10.1016/j.prnil.2017.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448724PMC
June 2017

Characteristics of epilepsy in patients with Kabuki syndrome with KMT2D mutations.

Brain Dev 2017 Sep 9;39(8):672-677. Epub 2017 Apr 9.

Department of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, Japan.

Background: The characteristics of epilepsy in patients with Kabuki syndrome with KMT2D mutations (KABUK1) have not yet been well documented. This is the first review to explore this.

Materials & Methods: We enrolled 14 patients with KABUK1, whose median age was 13.6years (range=4.1-21.3years). Their medical records from October 1981 to May 2016 were retrospectively analyzed.

Results: Epilepsy was present in 5 (36%) patients. Four of these patients presented with nonsense mutations and one with missense mutations. None presented with brain abnormalities. Four patients presented with annual or monthly focal seizures, of which three evolved to bilateral convulsive seizures. Median onset age of focal epilepsy was 11.8years (range=9.5-12.8years). One presented with monthly myoclonic seizures from age 11.2, whose mother with no other KABUK1 features, had focal epilepsy. The cumulative incidence of epilepsy related to KABUK1 up until age 13 was 45%. Interictal electroencephalogram revealed focal paroxysmal epileptiform discharges (in frontal, central, and parietal regions) in three patients, diffuse high-voltage spike-and-waves in one patient, and normal sleep record in one patient. Myoclonic seizures were rapidly controlled by levetiracetam. In contrast, focal seizures were not controlled in the early period of antiepileptic therapy.

Conclusion: This long-term follow-up of patients with KABUK1 revealed a higher prevalence of epilepsy than previously reported. The age of epilepsy onset and rate of focal seizures evolving to bilateral convulsive seizures in KABUK1 were also higher than previously reported in patients with clinically diagnosed Kabuki syndrome. Although seizure outcome is reported to be favorable in Kabuki syndrome, focal seizures in patients with KABUK1 were not immediately responsive to medication.
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http://dx.doi.org/10.1016/j.braindev.2017.03.025DOI Listing
September 2017

Hypophosphatemia is a common complication in severely disabled individuals with neurological disorders and is caused by infection, refeeding and Fanconi syndrome.

Brain Dev 2014 Nov 18;36(10):878-83. Epub 2013 Dec 18.

Department of Child Neurology, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.

Aim: To describe the characteristics of hypophosphatemia in severely disabled individuals with neurological disorders and to identify its causative factors.

Method: We retrospectively reviewed clinical data from 82 individuals with motor skills classified as sitting, rollover or bedridden. Age, gender and body mass index were compared in individuals with (n=19) and without (n=63) a history of hypophosphatemia (serum phosphate levels <2.0 mg/dl). The clinical course of each patient with hypophosphatemia was reviewed and the cause identified. Laboratory data during hypophosphatemia was compared with that after recovery.

Results: The age, gender and body mass index did not differ significantly between the individuals with and without hypophosphatemia. Nineteen patients experienced 25 episodes of hypophosphatemia. The causes included febrile illnesses (n=17), refeeding syndrome (n=4) and Fanconi syndrome (n=3), but was unidentifiable in one episode. Significant elevations in C-reactive protein levels and reductions in sodium levels were observed during hypophosphatemia episodes.

Interpretation: Hypophosphatemia is a common complication in severely disabled individuals with frequent bacterial infections, refeeding following malnutrition and valproate administration for epilepsy treatment. Because severe hypophosphatemia is life threatening, serum phosphate levels should be closely monitored in this population.
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http://dx.doi.org/10.1016/j.braindev.2013.12.001DOI Listing
November 2014

Photodegradation and inhibition of drug-resistant influenza virus neuraminidase using anthraquinone-sialic acid hybrids.

Chem Commun (Camb) 2013 Feb 3;49(12):1169-71. Epub 2013 Jan 3.

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan.

The anthraquinone-sialic acid hybrids designed effectively degraded not only non-drug-resistant neuraminidase but also drug-resistant neuraminidase, which is an important target of anti-influenza therapy. Degradation was achieved using long-wavelength UV radiation in the absence of any additives and under neutral conditions. Moreover, the hybrids efficiently inhibited neuraminidase activities upon photo-irradiation.
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http://dx.doi.org/10.1039/c2cc38742eDOI Listing
February 2013

A survey on levels and seasonal changes of assimilable organic carbon (AOC) and its precursors in drinking water.

Environ Technol 2011 Oct;32(13-14):1605-13

Graduate School of Global Environmental Studies, Kyoto University, Kyoto, Japan.

In Japan, customers' concerns about chlorinous odour in drinking water have been increasing. One promising approach for reducing chlorinous odour is the minimization of residual chlorine in water distribution, which requires stricter control of organics to maintain biological stability in water supply systems. In this investigation, the levels and seasonal changes of assimilable organic carbon (AOC) and its precursors in drinking water were surveyed to accumulate information on organics in terms of biological stability. In tap water samples purified through rapid sand filtration processes, the average AOC concentration was 174 microgC/L in winter and 60 microgC/L in summer. This difference seemed to reflect the seasonal changes of AOC in the natural aquatic environment. On the other hand, very little or no AOC could be removed after use of an ozonation-biological activated carbon (BAC) process. Especially in winter, waterworks should pay attention to BAC operating conditions to improve AOC removal. The storage of BAC effluent with residual chlorine at 0.05-0.15 mgCl2/L increased AOC drastically. This result indicated the possibility that abundant AOC precursors remaining in the finished water could contribute to newly AOC formation during water distribution with minimized residual chlorine. Combined amino acids, which remained at roughly equivalent to AOC in finished water, were identified as major AOC precursors. Prior to minimization of residual chlorine, enhancement of the removal abilities for both AOC and its precursors would be necessary.
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http://dx.doi.org/10.1080/09593330.2010.545439DOI Listing
October 2011

A microfluidic in situ analyzer for ATP quantification in ocean environments.

Lab Chip 2011 Oct 30;11(20):3508-15. Epub 2011 Aug 30.

Institute of Industrial Science, University of Tokyo, Tokyo, Japan.

We have developed and tested a functionally integrated in situ analyzer, the IISA-ATP system, for microbial activity assays based on a quantitative determination of the total (particulate and dissolved) ATP in ocean environments. The IISA-ATP utilizes a PDMS-glass hybrid microfluidic device as its core functional element, which can perform cell lysis and total ATP quantification by a luciferin-luciferase bioluminescence assay in situ. Transparent heaters and a temperature sensor fabricated on a glass substrate provide temperature control. As a result of the evaluation using the microfluidic device with ATP standard solutions, the bioluminescence intensity was linearly correlated with 2 × 10(-12) to 2 × 10(-8) M of ATP. A detection limit of 1.1 × 10(-11) M was determined using the completed IISA-ATP system, which includes a miniature pumping module and a control module. As a result of the evaluation using the environmental seawater sample collected from Tokyo Bay, Japan, 2.7 × 10(-10) M of total ATP was successfully determined in the laboratory by the IISA-ATP. The system was operated at a shallow submarine hot spring area in Okinawa, Japan for an in situ trial. The result shows the system was successfully operated in situ and the total ATP was determined to be 3.4 × 10(-10) M.
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http://dx.doi.org/10.1039/c1lc20523dDOI Listing
October 2011

Mutation in the Q28SDD31SD site, but not in the two SQ sites of the survival of motor neuron protein, affects its foci formation.

Int J Mol Med 2010 Nov;26(5):667-71

Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.

The survival of motor neuron (SMN) protein forms a multiprotein complex (SMN complex) with Gemin proteins. The complex is known to play a crucial role in RNA metabolism. Several lines of evidence show that SMN is phosphorylated at serine and/or threonine residues. In this study, we hypothesized that SMN is phosphorylated at two kinds of serine residues, the Q28SDD31SD site and two SQ sites (80SQ and 163SQ). A FLAG-tagged wild-type construct (SMNfull) and three FLAG-tagged mutant constructs were made: an SMNAQ mutant with two AQ sites instead of two SQ sites at residues 80 and 163, an SMNQADDAD mutant with QADDAD instead of Q28SDD31SD, and an SMNAQ/QADDAD mutant with the two AQ sites and QADDAD. We expressed these mutants in HeLa cells and analyzed their phosphorylated bands by immunoblotting, the protein stability using cycloheximide, binding to Gemin 2 and foci formation. Mutations in Q28SDD31SD, but not in two SQ sites reduced the intensity of phosphorylation bands, indicating that Q28SDD31SD is the major phosphorylation site in SMN. Mutations in the two SQ sites and Q28SDD31SD did not affect protein stability and binding to Gemin 2. Whereas mutations in the two SQ sites did not cause apparent changes in foci formation, mutations in Q28SDD31SD resulted in a reduced number of large foci in the cytosol. We demonstrated that phosphorylation in Q28SDD31SD may be important in cytosolic foci formation.
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http://dx.doi.org/10.3892/ijmm_00000512DOI Listing
November 2010

Escherichia coli O-157-induced hemolytic uremic syndrome: Usefulness of SCWP score for the prediction of neurological complication.

Pediatr Int 2009 Feb;51(1):107-9

Department of Pediatrics, Graduate School of Medicine, Gifu University, Yanagido, Gifu, Japan.

Background: Hemolytic uremic syndrome (HUS) is commonly caused by hemorrhagic colitis with Shiga toxin-producing Escherichia coli O-157. Central nervous system (CNS) involvements, including seizures, encephalopathy and brain infarction, are serious complications, but there are no useful scores for the prediction of CNS complications.

Methods: Routine laboratory data at onset of HUS were re-evaluated in 14 patients to find useful parameters for the prediction of CNS complication.

Results: Serum sodium and total protein were significantly lower and C-reactive protein (CRP) and white blood cell counts were significantly higher in patients with CNS complications than in patients without. A cumulated score, SCWP score (sodium, CRP, white blood cell count, and total protein) discriminated better between patients with/without CNS complications than individual values.

Conclusions: SCWP score would be useful for prediction of CNS complications.
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http://dx.doi.org/10.1111/j.1442-200X.2008.02672.xDOI Listing
February 2009

Treatment with OK-432 for persistent congenital chylothorax in newborn infants resistant to octreotide.

J Pediatr Surg 2009 Mar;44(3):e37-9

The Department of Pediatrics, Nagara Medical Center, Gifu 502-8558, Japan.

Chylothorax is a relatively uncommon condition defined as an abnormal collection of lymphatic fluid within the pleural space. We are reporting the use of OK-432 for treatment of prolonged idiopathic congenital chylothorax in 2 newborn infants who failed to respond to conservative medical therapy, including octreotide injection.
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http://dx.doi.org/10.1016/j.jpedsurg.2008.12.008DOI Listing
March 2009

A novel single-base substitution (c.1124A>G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene.

Mol Genet Metab 2008 Aug 3;94(4):417-21. Epub 2008 Jun 3.

Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan. address:

Most mutations related to aberrant splicing occur in conserved splice acceptor and donor sites. Some exonic mutations also affect splicing. We identified and characterized a point mutation (c.1124A>G) in an Australian patient (GK43) with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. GK43 is a homozygote of c.1124A>G, which activates a cryptic splice donor site 5 bases upstream from c.1124A>G within exon 11, causing aberrant splicing in most transcripts. The aberrant splicing results in c.1120-1163 (44-base) deletion, causing a frameshift in T2 mRNA. A mini-gene splicing experiment confirmed that the c.1124A>G substitution was responsible for this aberrant splicing. This cryptic splice site has a Shapiro and Senapathy score (70.0) in a normal sequence but if mutated, the score (84.3) becomes higher than the one in the authentic splice donor site of intron 11 (81.4). This is an example in which a point mutation activates a cryptic splice donor site motif that is used preferentially over a downstream authentic splice site.
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http://dx.doi.org/10.1016/j.ymgme.2008.04.014DOI Listing
August 2008

Successful treatment of neonatal herpes simplex-type 1 infection complicated by hemophagocytic lymphohistiocytosis and acute liver failure.

Tohoku J Exp Med 2008 Jan;214(1):1-5

Department of Neonatology, Gifu Prefectural General Medical Center, Gifu, Japan.

Neonatal disseminated herpes simplex virus (HSV) infection with acute liver failure (ALF) and neonatal hemophagocytic lymphohistiocytosis (HLH) are severe diseases. We recently experienced a male infant with HLH and ALF induced by HSV type 1 (HSV-1). The infant, born at 39 weeks of gestation by normal delivery, developed a fever on day 4. On day 9, laboratory investigations showed progressive liver dysfunction and coagulopathy, and the serum ferritin was excessively elevated. Furthermore, the blood levels of interleukin (IL)-6, IL-10, and interferon-gamma were also elevated. HSV-1 DNA was detected in the serum and cerebrospinal fluid by the real-time PCR method. A diagnosis of HLH was established based upon the following criteria: fever, splenomegaly, cytopenia (two cell lines), serum ferritin (> 500 mug/l) and hypofibrinogenemia (< 150 mg/dl). High-dose acyclovir therapy, steroid pulse therapy using methylprednisolone, high-dose gamma globulin therapy and a blood transfusion were given. The patient recovered without neurological deficit. Neonatal disseminated HSV infections may be complicated by the development of HLH and hypercyokinemia. If HLH is suspected, not only high-dose acyclovir therapy but also anti-cytokine therapy should be considered.
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http://dx.doi.org/10.1620/tjem.214.1DOI Listing
January 2008

Identification of an Alu-mediated tandem duplication of exons 8 and 9 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.

Mol Genet Metab 2007 Dec 23;92(4):375-8. Epub 2007 Aug 23.

Department of Pediatrics, Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu 501-1194, Japan.

A tandem repeat of exons 8 and 9 was identified in the cDNA for mitochondrial acetoacetyl-CoA thiolase (T2) in a typical T2 deficient patient. Routine mutation analysis using PCR at the genomic level had failed to identify any mutations. Alu element-mediated unequal homologous recombination between an Alu-Jo in intron 7 and another Alu-Jo in intron 9 appears to be responsible for this duplication.
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http://dx.doi.org/10.1016/j.ymgme.2007.07.007DOI Listing
December 2007

Identification of Alu-mediated, large deletion-spanning introns 19-26 in PHKA2 in a patient with X-linked liver glycogenosis (hepatic phosphorylase kinase deficiency).

Mol Genet Metab 2007 Sep-Oct;92(1-2):179-82. Epub 2007 Jun 19.

Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.

X-linked liver glycogenosis (XLG) is one of the most common glycogen storage diseases. We present the first case of a large PHKA2 gene deletion from intron 19 to intron 26 in an XLG patient. An aberrant cDNA with skipping of exons 20-26 was detected. Alu element-mediated unequal homologous recombination between an Alu-Jo in intron 19 and another Alu-Sg in intron 26 appears to be responsible for this deletion.
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http://dx.doi.org/10.1016/j.ymgme.2007.05.007DOI Listing
November 2007

Design on semiconductor coupled SAW convolver.

IEEE Trans Ultrason Ferroelectr Freq Control 2002 Apr;49(4):466-74

Kanagawa Institute of Technology, Japan.

This paper presents results of a design study on a semiconductor coupled surface acoustic wave (SAW) convolver in which bi-directionally propagating SAWs, on a piezoelectric substrate with a high coupling coefficient, couple with bonded semiconductor diodes through multistrips. To obtain convolution signals with a high efficiency, we adopted a diode-balanced bridge structure for the non-linear operation. We also found that the tapping pitches of the multi-strip electrodes have robustness against operation frequency variation and temperature-dependent variation on the delay of the SAW. We verified the effectiveness of the device in a circuit simulation and an experiment on a test circuit, which was fabricated by using an epitaxial lift-off film-bonding process.
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http://dx.doi.org/10.1109/58.996565DOI Listing
April 2002