Publications by authors named "Ikuko Takahashi"

72 Publications

Preoperative characteristics and intraoperative factors do not correlate with accomplishments of active straight-leg raising, standing up, and walking after primary total knee arthroplasty.

J Orthop Surg Res 2021 Aug 12;16(1):487. Epub 2021 Aug 12.

Niigata University Crisis Management Office, Niigata University Hospital, Niigata University Graduate School of Medical and Dental Sciences, 1 Asahimachi Dori Niigata, Niigata, 951-8520, Japan.

Background: The correlations between patient characteristics and early postoperative functional performances after total knee arthroplasty have not been adequately studied. The purpose of this study was to clarify the effects of preoperative characteristics (sex, age, body mass index, American Society of Anesthesiologists grade, hospital for special surgery score) and intraoperative factors (duration of surgery and tourniquet use) on the time required to accomplish active straight-leg-raising, standing up, and walking as the objective performances for the initiation of early postoperative rehabilitation.

Methods: This cross-sectional retrospective study included 307 patients (384 primary total knee arthroplasties). Postoperative times required until each activity was accomplished were measured. Various preoperative characteristics and intraoperative factors that might affect three objective performances were evaluated.

Results: The postoperative times required before each activity was accomplished were 1.5 ± 0.5 days for active straight-leg-raising, 1.2 ± 0.5 days for standing up, and 1.4 ± 0.7 days for walking. There were no significant correlations between any factor (age, body mass index, hospital for special surgery score, duration of surgery, and tourniquet use) and the three objective performances using Spearman's correlation coefficient. There were no differences in sex or American Society of Anesthesiologists grade for three objective functional assessments by Wilcoxon rank sum test.

Conclusions: Differences in patient preoperative characteristics and intraoperative factors are unlikely to affect three objective functional performances in the early postoperative period. Therefore, there is no need to consider differences between patients when initiating early postoperative rehabilitation.
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http://dx.doi.org/10.1186/s13018-021-02636-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359082PMC
August 2021

Alignment evaluation using different distal reference points after total knee arthroplasty.

J Orthop 2021 May-Jun;25:186-190. Epub 2021 May 12.

Niigata University Crisis Management Office, Niigata University Hospital, Niigata University Graduate School of Medical and Dental Sciences, 1 Asahimachi Dori Niigata, Niigata, 951-8520, Japan.

Background: To assess alignment for total knee arthroplasty, the center of the ankle has been used as the main reference point for the distal tibia; however, the true load-bearing mechanical axis should be determined as a line from the center of the femoral head to the lowest point of calcaneus. Thus, the purpose of this study was to compare the differences in alignment.

Methods: Patients with medial osteoarthritis who underwent primary total knee arthroplasty (Group A, center of ankle reference, or Group C, calcaneal contact reference) were recruited. We determined (1) the total number with calcaneal contact point lateral to the center of ankle and compared (2) percentage of displacement of the load-bearing axis at the level of the knee, (3) anatomical axis angle, (4) mechanical axis angle, and (5) tibial component angle.

Results: The study included 94 patients (128 knees), with the calcaneal contact reference point located lateral relative to the center of the ankle in 88.3% (113/128 knees). Using calcaneal contact point references, displacement of the load-bearing axis at the knee was greater (p < 0.0001, 38.7% vs 34.0%), and angles demonstrated significantly valgus alignment (p < 0.0001, 5.6° vs. 4.8° for anatomical axis angle, -3.0° vs. -4.2° for mechanical axis angle, and 89.9° vs. 88.6°for tibial component angle).

Conclusions: Varus alignment measured by the ankle reference method might correspond to the neutral alignment by the amount of valgus alignment indicated by the calcaneal reference. Surgeons should take this into account when preoperative planning, performing intraoperative procedures, and during postoperative evaluation.
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http://dx.doi.org/10.1016/j.jor.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141497PMC
May 2021

Amplification-free RNA detection with CRISPR-Cas13.

Commun Biol 2021 04 19;4(1):476. Epub 2021 Apr 19.

Molecular Physiology Laboratory, Cluster for Pioneering Research, RIKEN, Saitama, Japan.

CRISPR-based nucleic-acid detection is an emerging technology for molecular diagnostics. However, these methods generally require several hours and could cause amplification errors, due to the pre-amplification of target nucleic acids to enhance the detection sensitivity. Here, we developed a platform that allows "CRISPR-based amplification-free digital RNA detection (SATORI)", by combining CRISPR-Cas13-based RNA detection and microchamber-array technologies. SATORI detected single-stranded RNA targets with maximal sensitivity of ~10 fM in <5 min, with high specificity. Furthermore, the simultaneous use of multiple different guide RNAs enhanced the sensitivity, thereby enabling the detection of the SARS-CoV-2 N-gene RNA at ~5 fM levels. Therefore, we hope SATORI will serve as a powerful class of accurate and rapid diagnostics.
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http://dx.doi.org/10.1038/s42003-021-02001-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055673PMC
April 2021

Investigation of TSH receptor blocking antibodies in childhood-onset atrophic autoimmune thyroiditis.

Clin Pediatr Endocrinol 2021 3;30(2):79-84. Epub 2021 Apr 3.

Department of Pediatrics, Jichi Medical University, Tochigi, Japan.

Atrophic autoimmune thyroiditis (AAT) is a type of autoimmune hypothyroidism without goiter. TSH receptor-blocking antibodies (TSBAb) are involved in its etiology in adults. Reportedly, this disease is extremely rare in children. In this study, we aimed to investigate the prevalence of TSBAb during AAT onset in children using a commercially available cell-based bioassay TSAb kit. We conducted a multicenter retrospective observational study. We collected data of patients with AAT who were < 15 yr old, enrolled in a collaborative research group, and diagnosed since July 2003. AAT was defined as acquired autoimmune hypothyroidism without thyroid enlargement. Eighteen patients (including 15 females) whose TSH receptor antibody (TRAb) or TSBAb levels were measured within a year from the initial visit were included. The median age at diagnosis was 9.3 years, and the estimated time between onset and diagnosis was 2.6 yr. The positive rate for either TSBAb or TRAb was 38.8% (95% confidence interval: 18.3-59.5%). There were no significant differences in age, the estimated time between onset and diagnosis, and FT4 levels at diagnosis between the TSBAb-positive and -negative groups. Unlike previous reports, we showed that the prevalence of TSBAb-positivity in childhood-onset AATs is not rare, as in adults.
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http://dx.doi.org/10.1297/cpe.30.79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022035PMC
April 2021

Characteristics of hidden blood loss following hybrid total knee arthroplasty.

J Orthop Sci 2021 Nov 6;26(6):1064-1068. Epub 2020 Dec 6.

Niigata University Crisis Management Office, Niigata University Hospital, Niigata University Graduate School of Medical and Dental Sciences, 1 Asahimachi Dori Niigata, Niigata, 951-8520, Japan. Electronic address:

Background: Hidden blood loss (HBL) unrecognized by the usual practice of assessing intraoperative loss and postoperative drainage comprises a considerable proportion of total blood loss (TBL) during primary total knee arthroplasty (TKA). However, HBL has not been adequately investigated in hybrid TKA (uncemented femur, cemented tibia). The purpose of this study was to clarify the amount and influential factors of HBL in hybrid TKA.

Methods: A consecutive series of 151 knees in 137 patients with knee osteoarthritis who underwent hybrid TKA were retrospectively evaluated. We examined the correlations between HBL and various factors of concern for their effects on TBL, including age, sex, body weight (BW), body height, body mass index, operation time, tourniquet time, and visible blood loss (VBL) in three periods (intraoperative: VBL; until 3 h postoperatively: VBL; from 3 h to 1 day postoperatively: VBL).

Results: Median (interquartile range) HBL and TBL were 528 (388, 711) mL and 725 (582, 926) mL, respectively. HBL relative to TBL (H/T) was 73%. There were weak correlations between HBL and BW (r = 0.249, p = 0.002) and between HBL and VBL (r = -0.261, p = 0.001). Multivariate analyses confirmed a positive correlation between HBL and BW (β = 0.296, p < 0.001) and a negative correlation between HBL and VBL (β = -0.270, p < 0.001).

Conclusions: Hybrid TKA showed comparable values of HBL and H/T to those reported for cemented TKA. Therefore, management strategies for HBL in hybrid TKA can follow the same protocols used for cemented TKA. High BW and low VBL may be predictors of postoperative HBL in hybrid TKA.
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http://dx.doi.org/10.1016/j.jos.2020.10.011DOI Listing
November 2021

PlexinA1 deficiency in BALB/cAJ mice leads to excessive self-grooming and reduced prepulse inhibition.

IBRO Rep 2020 Dec 22;9:276-289. Epub 2020 Oct 22.

Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.

PlexinA1 (PlxnA1) is a transmembrane receptor for semaphorins, a large family of proteins that act as axonal guidance cues during nervous system development. However, there are limited studies on PlxnA1 function in neurobehavior. The present study examined if PlxnA1 deficiency leads to behavioral abnormalities in BALB/cAJ mice. PlxnA1 knockout (KO) mice were generated by homologous recombination and compared to wild type (WT) littermates on a comprehensive battery of behavioral tests, including open field assessment of spontaneous ambulation, state anxiety, and grooming, home cage grooming, the wire hang test of muscle strength, motor coordination on the rotarod task, working memory on the Y maze alternation task, cued and contextual fear conditioning, anxiety on the elevated plus maze, sociability to intruders, and sensory processing as measured by prepulse inhibition (PPI). Measures of motor performance, working memory, fear memory, and sociability did not differ significantly between genotypes, while PlxnA1 KO mice displayed excessive self-grooming, impaired PPI, and slightly lower anxiety. These results suggest a crucial role for PlxnA1 in the development and function of brain regions controlling self-grooming and sensory gating. PlxnA1 KO mice may be a valuable model to investigate the repetitive behaviors and information processing deficits characteristic of many neurodevelopmental and psychiatric disorders.
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http://dx.doi.org/10.1016/j.ibror.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607060PMC
December 2020

Retrospective study of the renal function using estimated glomerular filtration rate and congenital anomalies of the kidney-urinary tract in pediatric Turner syndrome.

Congenit Anom (Kyoto) 2020 Nov 4;60(6):175-179. Epub 2020 Aug 4.

Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Although Turner syndrome (TS) is frequently associated with congenital anomalies of the kidney-urinary tract (CAKUT), which is a major cause of pediatric chronic kidney disease, renal function in TS is usually considered normal. The present study aimed to analyze the frequency of renal dysfunction and CAKUT in pediatric patients with TS. Our study included 122 patients with TS between the ages of 2 and 18 years from 30 hospitals across Japan. Clinical data related to renal function and CAKUT were retrospectively collected. The estimated glomerular filtration rate (eGFR) was calculated using the serum creatinine-based formula recommended by the Japanese Society for Pediatric Nephrology. An eGFR <90 mL/min/1.73 m for two consecutive years was defined as renal dysfunction. Fifteen (13.5%) of 122 patients had CAKUT, and four patients had renal dysfunction (3.2%, 95% confidence interval: 0%-6.7%). Three of the four did not have CAKUT. Of the CAKUT manifestations, horseshoe kidney, renal hypodysplasia, and multicystic dysplastic kidney were seen in nine, two, and one patient, respectively. Eight of the nine patients with horseshoe kidney had a normal renal function; however, the remaining patient with renal hypodysplasia had renal dysfunction. A small percentage of patients with pediatric TS may had an eGFR below 90 mL/min/1.73 m which was not necessarily associated with CAKUT.
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http://dx.doi.org/10.1111/cga.12384DOI Listing
November 2020

Levothyroxine Dosage as Predictor of Permanent and Transient Congenital Hypothyroidism: A Multicenter Retrospective Study in Japan.

Horm Res Paediatr 2019 25;92(1):45-51. Epub 2019 Sep 25.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Background: Congenital hypothyroidism (CH) can be divided into 2 types, transient CH (T-CH) and permanent CH (P-CH), depending on the requirement of levothyroxine (LT4) for life-long treatment. Several studies have recently reported that the LT4 dosage is useful for predicting the LT4 requirement, but none of the studies followed their patients to puberty.

Objective: To determine the cutoff value for the LT4 dosage as a predictor of the LT4 requirement after puberty in patients with CH.

Methods: The LT4 dosage and clinical data on 99 patients with CH who were followed at the participating hospitals from the neonatal period to 15 years of age or older were retrospectively analyzed. Based on their LT4 requirement at their last hospital visit, the participants were divided into the P-CH group (n = 75), who were treated with LT4, and the T-CH group (n = 24), who were not.

Results: At age 1 year, a higher LT4 dosage was required for the P-CH group (median 3.75 vs. 2.88 µg/kg/day; p < 0.001). When the LT4 dosage cutoff value at age 1 year was set at 4.79 and 1.74 µg/kg/day, the specificity of P-CH and T-CH (for denying T-CH and P-CH, respectively) was 100 and 97%, respectively.

Conclusions: An LT4 dosage above 4.7 µg/kg/day and below 1.8 µg/kg/day at age 1 year may help predict P-CH and T-CH, respectively.
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http://dx.doi.org/10.1159/000502418DOI Listing
April 2020

PlexinA1 is crucial for the midline crossing of callosal axons during corpus callosum development in BALB/cAJ mice.

PLoS One 2019 20;14(8):e0221440. Epub 2019 Aug 20.

Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.

The corpus callosum (CC) is the biggest commissure that links cerebral hemispheres. Guidepost structures develop in the cortical midline during CC development and express axon guidance molecules that instruct neurons regarding the proper direction of axonal elongation toward and across the cortical midline. Neuropilin-1 (Npn1), a high affinity receptor for class 3 semaphorins (Sema3s) localized on cingulate pioneering axons, plays a crucial role in axon guidance to the midline through interactions with Sema3s. However, it remains unclear which type of Plexin is a component of Sema3 holoreceptors with Npn1 during the guidance of cingulate pioneering axons. To address the role of PlexinA1 in CC development, we examined with immunohistochemistry the localization of PlexinA1, Npn1, and Sema3s using embryonic brains from wild-type (WT) and PlexinA1-deficient (PlexinA1 knock-out (KO)) mice with a BALB/cAJ background. The immunohistochemistry confirmed the expression of PlexinA1 in callosal axons derived from the cingulate and neocortex of the WT mice on embryonic day 17.5 (E17.5) but not in the PlexinA1 KO mice. To examine the role of PlexinA1 in the navigation of callosal axons, the extension of callosal axons toward and across the midline was traced in brains of WT and PlexinA1 KO mice at E17.5. As a result, callosal axons in the PlexinA1 KO brains had a significantly lower incidence of midline crossing at E17.5 compared with the WT brains. To further examine the role of PlexinA1 in CC development, the CC phenotype was examined in PlexinA1 KO mice at postnatal day 0.5 (P0.5). Most of the PlexinA1 KO mice at P0.5 showed agenesis of the CC. These results indicate the crucial involvement of PlexinA1 in the midline crossing of callosal axons during CC development in BALB/cAJ mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221440PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701775PMC
March 2020

Three novel MTM1 pathogenic variants identified in Japanese patients with X-linked myotubular myopathy.

Mol Genet Genomic Med 2019 05 18;7(5):e621. Epub 2019 Mar 18.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background: X-linked myotubular myopathy (XLMTM) is a form of the severest congenital muscle diseases characterized by marked muscle weakness, hypotonia, and feeding and breathing difficulties in male infants. It is caused by mutations in the myotubularin gene (MTM1).

Methods: Evaluation of clinical history and examination of muscle pathology of three patients and comprehensive genome analysis on our original targeted gene panel system for muscular diseases.

Results: We report three patients, each of whom presents distinct muscle pathological features. The three patients have novel hemizygous MTM1 variants, including c.527A>G (p.Gln176Arg), c.595C>G (p.Pro199Ala), or c.688T>C (p.Trp230Arg).

Conclusions: All variants were assessed as "Class 4 (likely pathogenic)" on the basis of the guideline of American College of Medical Genetics and Genomics. These distinct pathological features among the patients with variants in the second cluster of PTP domain in MTM1 provides an insight into microheterogeneities in disease phenotypes in XLMTM.
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http://dx.doi.org/10.1002/mgg3.621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503166PMC
May 2019

En Bloc Spondylectomy for Spinal Metastases: Detailed Oncological Outcomes at a Minimum of 2 Years after Surgery.

Asian Spine J 2019 Apr 29;13(2):296-304. Epub 2018 Nov 29.

Department of Orthopedic Surgery, Niigata University Medical and Dental Hospital, Niigata, Japan.

Study Design: Retrospective case series.

Purpose: To investigate the oncological outcomes, including distant relapse, after en bloc spondylectomy (EBS) for spinal metastases in patients with a minimum of 2-year follow-up.

Overview Of Literature: Although EBS has been reported to be locally curative and extend survival in select patients with spinal metastases, detailed reports regarding the control of distant relapse after EBS are lacking.

Methods: We conducted a retrospective review of 18 consecutive patients (median age at EBS, 62 years; range, 40-77 years) who underwent EBS for spinal metastases between 1991 and 2015. The primary cancer sites included the kidney (n=7), thyroid (n=4), liver (n=3), and other locations (n=4). Survival rates were estimated using the Kaplan-Meier method, and groups were compared using the log-rank method.

Results: The median operative time and intraoperative blood loss were 767.5 minutes and 2,375 g, respectively. Twelve patients (66.7%) experienced perioperative complications. Five patients (27.8%) experienced local recurrence of the tumor at a median of 12.5 months after EBS, four of which had a positive resection margin status. Thirteen patients (72.2%) experienced distant relapse at a median of 21 months after EBS. The estimated median survival period after distant relapse was 20 months (95% confidence interval, 0.71-39.29 months). No association was found between resection margin status and distant relapse. Overall, the 2-year, 5-year, and 10-year survival rates after EBS were 72.2%, 48.8%, and 27.1%, respectively. Importantly, the era in which EBS was performed did not impact the oncological outcomes.

Conclusions: Our results suggest that EBS by itself, even if margin-free, cannot prevent further dissemination, which occurred in >70% of patients at a median of 21 months after EBS. These results should be considered and conveyed to patients for clinical decision-making.
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http://dx.doi.org/10.31616/asj.2018.0145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454284PMC
April 2019

Hashimoto's encephalopathy mimicking a brain tumor and its pathological findings: A case report.

J Neurol Sci 2018 11 8;394:141-143. Epub 2018 Sep 8.

Department of Neurology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo 060-8638, Japan.

Hashimoto's encephalopathy is characterized by the presence of anti-thyroid antibodies with no alternative cause. Patients with Hashimoto's encephalopathy present with various clinical symptoms and magnetic resonance imaging (MRI) findings. To our knowledge, this is the first documented report of Hashimoto's encephalopathy with MRI findings mimicking a brain tumor. The patient was a 41-year-old woman with a history of Hashimoto's disease. She experienced gradually worsening Parkinsonism and an MRI revealed a brain tumor-like lesion at the left caudate nucleus. She underwent a brain biopsy that revealed diffuse gliosis and perivascular lymphocyte infiltration with CD3+ T-cell predominance. No pathological signs of a brain tumor were found. Hashimoto's encephalopathy was suspected based on the patient's history and the presence of anti-thyroid antibodies. Her symptoms and the MRI findings improved with glucocorticoid treatment. Although there exist only a few studies on the pathology of Hashimoto's encephalopathy, our findings were consistent with those of previous reports. Our findings suggest cerebral vasculitis as an underlying etiology of Hashimoto's encephalopathy. We also emphasize the importance of considering Hashimoto's encephalopathy as a differential diagnosis of brain tumors.
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http://dx.doi.org/10.1016/j.jns.2018.09.008DOI Listing
November 2018

Tremor during orthostatism as the initial symptom of Machado-Joseph disease.

Clin Neurol Neurosurg 2018 10 10;173:173-175. Epub 2018 Aug 10.

Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

A 60-year-old man was admitted to our hospital. He had mild tremor in his four extremities when supine or sitting, which was markedly exacerbated when standing. We diagnosed him with Machado-Joseph disease according to the genetic test. His tremor improved with clonazepam, trihexyphenidyl, and a rotigotine patch.
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http://dx.doi.org/10.1016/j.clineuro.2018.08.009DOI Listing
October 2018

Biopsy-proven acute interstitial nephritis due to fosfomycin in a child.

Nephrology (Carlton) 2018 09;23(9):890

Department of Pediatrics, Akita University School of Medicine, Akita City, Japan.

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http://dx.doi.org/10.1111/nep.13197DOI Listing
September 2018

The Natural Course of Compensatory Lumbar Curves in Nonoperated Patients With Thoracic Adolescent Idiopathic Scoliosis.

Spine (Phila Pa 1976) 2019 Jan;44(2):E89-E98

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Study Design: A retrospective, long-term follow-up study.

Objective: We investigated the natural course of compensatory lumbar curves in patients with primary thoracic adolescent idiopathic scoliosis (AIS).

Summary Of Background Data: The natural course of compensatory lumbar curves in primary thoracic AIS remains unknown.

Methods: Inclusion criteria were right-sided primary thoracic AIS ≥30° with a Lenke lumbar modifier of A or B at skeletal maturity and ≥30 years of age at the time of the survey. Fifty-one patients (mean age, 40.2 yr) returned for a follow-up evaluation (follow-up rate, 34.2%). Patients were classified into three groups based on the lumbar modifier (A or B) and direction of L4 tilt [right (R) or left (L)] (AR, n.11; AL, n.18; and B, n.22). At the time of the survey, 42 patients underwent radiological examinations and 37 underwent lumbar magnetic resonance imaging. Quality of life questionnaires were completed in all patients and in a 1:1 matched control group (no history of scoliosis).

Results: The thoracic curves had significantly progressed in all patient groups, while the compensatory lumbar curve progressed only in the B group. The C7 translation and L4 tilt shifted to the right in the AR and AL groups, but did not change in the B group. As a result, the L4 tilt (median, 11°) and C7 translation (18.6 mm) tended to be the greatest in the AR group. The incidences of Modic changes at L4/5 discs and ≥3 cm on the visual analogue scale for low back pain were significantly higher in the AR group (77.8% and 54.5%, respectively) compared with that in the other groups.

Conclusion: The natural course of compensatory lumbar curves is dependent on the lumbar modifier and direction of L4 tilt. Adolescent patients with right-sided primary thoracic AIS (≥30°) with L4 tilted to the right should be considered for periodic follow-ups into adulthood.

Level Of Evidence: 4.
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http://dx.doi.org/10.1097/BRS.0000000000002779DOI Listing
January 2019

A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N mutation and clinical findings.

Brain Dev 2018 Oct 24;40(9):760-767. Epub 2018 May 24.

Department of Pediatrics, Akita University Graduate School of Medicine, Akita, Akita, Japan. Electronic address:

Objective: To reveal a molecular lesion in the ZC4H2 gene in a Japanese family with arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), and to characterize clinical features of patients with ZC4H2 gene mutations through a literature review.

Patients: The probands are male siblings. The elder brother is an 11-year-old boy who showed AMC and ID and frequent postprandial hypoglycemia since 3 years of age. The younger brother also showed AMC, ID, and subclinical postprandial hypoglycemia. The boys' mother also showed a minor malformation of the left toes.

Method And Result: Using Sanger sequencing, a hemizygous one base substitution designated c.627G > C, which is predicted to substitute asparagine for lysine at amino acid residue 209 (K209N), was identified in the siblings. The mother was heterozygous for this mutation. In silico analysis predicted K209N to be a constituent of a motif required for subcellular localization of the ZC4H2 protein in the nucleus. Transient expression studies of subcellular localization in COS-7 cells showed that compared to the wild-type protein, the transport of the mutant protein into the nucleus was inhibited, thus confirming K209N as a molecular lesion in this family. The literature reviews revealed postprandial hypoglycemia as a new clinical feature that should be considered in ZC4H2 gene-mutation disorders.

Conclusion: A Japanese family with AMC and ID caused by a novel ZC4H2 gene mutation was reported. Hypoglycemia should be considered one of the features in this disorder.
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http://dx.doi.org/10.1016/j.braindev.2018.05.003DOI Listing
October 2018

A novel S269C mutation in fibroblast growth factor receptor 3 in a Japanese child with hypochondroplasia.

Hum Genome Var 2018 12;5. Epub 2018 Apr 12.

Department of Pediatrics, Akita University Graduate School of Medicine, Akita, Japan.

Functionally activating mutations in fibroblast growth factor receptor 3 (FGFR3) can cause four types of autosomal dominant skeletal dysplasia with short-limbed dwarfism that include the mildest phenotype, hypochondroplasia (HCH). A novel mutation (c.805A>T, p.S269C) was identified in a Japanese infant with HCH through direct sequencing of all exons and exon/intron boundaries. This mutation creates an additional cysteine residue in the extracellular region of FGFR3 that results in the functional activation of FGFR3.
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http://dx.doi.org/10.1038/s41439-018-0001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933720PMC
April 2018

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury.

BMJ Open 2018 05 5;8(5):e019083. Epub 2018 May 5.

G-SPIRIT Study Group, Chiba, Japan.

Introduction: Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial.

Methods And Analysis: The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients).

Ethics And Dissemination: The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper.

Trial Registration Number: UMIN000018752.
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http://dx.doi.org/10.1136/bmjopen-2017-019083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942478PMC
May 2018

Long-term Outcome of Adenosine A2A Receptor Antagonist on Lower Urinary Tract Symptoms in Male Parkinson Disease Patients.

Clin Neuropharmacol 2018 May/Jun;41(3):98-102

Departments of Renal and Genitourinary Surgery and.

Objectives: In addition to motor symptoms, bladder dysfunction is a major clinical issue in patients with Parkinson disease (PD). Istradefylline is adenosine A2A receptor antagonist approved for PD patients with wearing-off symptoms. The aim of this study was to determine the long-term effects of istradefylline on lower urinary tract symptoms (LUTSs) in PD patients.

Methods: We enrolled 14 male PD patients. The mean age of patients was 73 years (61-77 years), the Hoehn-Yahr stage was 2 (2-3), and disease duration was 9 years (3-28 years). The effects of istradefylline (20 mg/d) on LUTSs in PD patients with motor complications after 3, 6, and 12 months of therapy were evaluated based on the International Prostate Symptom Score and Overactive Bladder Symptom Score before and after its administration.

Results: Motor symptoms significantly improved at 12 months' administration (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III: 30.0 ± 12.9 vs 13.8 ± 8.1; P < 0.01). Significant improvements were also observed in the answers provided on urinary questionnaires (International Prostate Symptom Score, 14.4 ± 7.6 vs 8.5 ± 6.8; Overactive Bladder Symptom Score, 6.9 ± 2.8 vs 5.5 ± 3.7; P < 0.05). Nighttime urinary frequency and the percentage of the nocturnal urine volume also improved significantly at 3 months' administration (P < 0.01).

Conclusions: Istradefylline effectively improved not only motor symptoms, but also LUTSs in patients with PD.
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http://dx.doi.org/10.1097/WNF.0000000000000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965927PMC
September 2018

[A retrospective study of the effects of 3,4-diaminopyridine treatment in Lambert-Eaton myasthenic syndrome].

Rinsho Shinkeigaku 2018 Feb 31;58(2):83-87. Epub 2018 Jan 31.

Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University.

In this independent clinical study, we analyzed retrospectively the clinical features of 9 cases (6 male and 3 female) of Lambert-Eaton myasthenic syndrome that were administered 3,4-diaminopyridine (3,4-DAP). Four cases showed no cancer and 5 cases had small cell lung carcinoma. Seven cases were positive for anti voltage-gated calcium channel antibodies. Activities of daily living (ADL) were improved by 3,4-DAP in 8 cases that showed mainly weakness of the extremities, but did not improve ADL in 1 case with cerebellar ataxia of paraneoplastic cerebellar degeneration (PCD). Seven cases showed autonomic symptoms, and 6 cases were improved with 3,4-DAP. The maintenance dose varied widely among individuals, with a single dose ranging from 10 to 40 mg. Each patient was prescribed a maintenance dose 3 to 7 times a day. The daily dosage ranged from 36 to 100 mg. Two cases showed adverse effects to the treatment. Of those 2 cases, 1 case treated at 45 mg/day discontinued treatment, but another case treated at 100 mg/day reduced the dosage and continued treatment. The administration period was 1 to 149 months. Three cases have continued 3,4-DAP for more than 10 years. Four cases have discontinued 3,4-DAP, with 2 cases discontinuing due to death, 1 case discontinuing due to progression of cancer, and 1 case discontinuing due to an adverse reaction. Our results suggest that 3,4-DAP treatment is effective for weakness and autonomic symptoms, but may be ineffective for ataxia of PCD. Treatment with 3,4-DAP can be tolerated for a long period, but the optimal dosage varies widely among individuals.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001106DOI Listing
February 2018

Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome.

Sci Rep 2018 01 16;8(1):819. Epub 2018 Jan 16.

Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Clinical diagnosis of progressive supranuclear palsy (PSP) is sometimes difficult because various phenotypes have been identified. Here, we report a mutation in the bassoon (BSN) gene in a family with PSP-like syndrome. Their clinical features resembled not only those of PSP patients but also those of individuals with multiple system atrophy and Alzheimer's disease. The neuropathological findings showed a novel three + four repeat tauopathy with pallido-luysio-nigral degeneration and hippocampal sclerosis. Whole-exome analysis of this family identified a novel missense mutation in BSN. Within the pedigree, the detected BSN mutation was found only in affected individuals. Further genetic analyses were conducted in probands from four other pedigrees with PSP-like syndrome and in 41 sporadic cases. Three missense mutations in BSN that are very rarely listed in databases of healthy subjects were found in four sporadic cases. Western blot analysis of tau following the overexpression of wild-type or mutated BSN revealed the possibility that wild-type BSN reduced tau accumulation, while mutated BSN lost this function. An association between BSN and neurological diseases has not been previously reported. Our results revealed that the neurodegenerative disorder associated with the original proband's pedigree is a novel tauopathy, differing from known dementia and parkinsonism syndromes, including PSP.
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http://dx.doi.org/10.1038/s41598-018-19198-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770378PMC
January 2018

Genomic copy number variation analysis in multiple system atrophy.

Mol Brain 2017 11 29;10(1):54. Epub 2017 Nov 29.

Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.

Genomic variation includes single-nucleotide variants, small insertions or deletions (indels), and copy number variants (CNVs). CNVs affect gene expression by altering the genome structure and transposable elements within a region. CNVs are greater than 1 kb in size; hence, CNVs can produce more variation than can individual single-nucleotide variations that are detected by next-generation sequencing. Multiple system atrophy (MSA) is an α-synucleinopathy adult-onset disorder. Pathologically, it is characterized by insoluble aggregation of filamentous α-synuclein in brain oligodendrocytes. Generally, MSA is sporadic, although there are rare cases of familial MSA. In addition, the frequencies of the clinical phenotypes differ considerably among countries. Reports indicate that genetic factors play roles in the mechanisms involved in the pathology and onset of MSA. To evaluate the genetic background of this disorder, we attempted to determine whether there are differences in CNVs between patients with MSA and normal control subjects. We found that the number of CNVs on chromosomes 5, 22, and 4 was increased in MSA; 3 CNVs in non-coding regions were considered risk factors for MSA. Our results show that CNVs in non-coding regions influence the expression of genes through transcription-related mechanisms and potentially increase subsequent structural alterations of chromosomes. Therefore, these CNVs likely play roles in the molecular mechanisms underlying MSA.
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http://dx.doi.org/10.1186/s13041-017-0335-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708077PMC
November 2017

Utilization effect of floor plan sketches in hypothetical cases assuming a community care meeting.

Nihon Koshu Eisei Zasshi 2017 ;64(9):556-566

Department of Nursing, Faculty of Health Care, Teikyo Heisei University.

Objective Floor plan sketches (FPSs) are schematic representations of floors in a home. FPSs display information gathered from observations and interviews on people's way of dwelling. To elucidate the effects of utilizing FPSs in case reviews assuming a community care meeting attended by multidisciplinary professionals, we conducted reviews of hypothetical cases created for experimental purposes.Methods Two hypothetical cases (Cases 1 and 2) were developed, and each case was reviewed with and without FPSs. Two groups (Groups A and B) were created, each consisting of five health care and welfare professionals involved in actual case reviews. Group A reviewed Case 1 without FPSs followed by Case 2 with FPSs, while Group B reviewed Case 2 without FPSs followed by Case 1 with FPSs. Case conferences and group interviews conducted after the completion of these reviews. Based on the verbatim transcripts of the reviews and interviews, we investigated differences between case reviews with and without FPSs with regard to the time required for the review and the number and contents of participants' comments.Results Review content could largely be divided into two categories: (1) the living conditions and support for the case subjects and their families, and (2) their homes and their way of dwelling at home. These categories were common to case reviews both with and without FPSs. In discussions about the homes and ways of dwelling, however, confirmation of the locations of rooms consumed a large amount of time in case reviews without FPSs. In case reviews with FPSs, discussions were more specific and included details such as room usage and paths by which residents move. The mean time required for a review was 41 minutes per case (range: 36 to 44 minutes), which did not greatly differ based on whether or not FPSs were used. Participants made more comments and seemed to interact more actively with each other when they had the FPSs than when they did not. The impressions of participants were that FPSs allowed the visualization of the case subjects and their families in their homes and fostered a greater feeling of familiarity with the case.Conclusion The use of FPSs in case reviews reduces the time spent on information sharing and allows more detailed review contents. Furthermore, FPSs enhance the ability to imagine the daily lives of case subjects and their families, thereby potentially broadening assessments in case reviews.
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http://dx.doi.org/10.11236/jph.64.9_556DOI Listing
February 2019

The Efficacy of Istradefylline for Treating Mild Wearing-Off in Parkinson Disease.

Clin Neuropharmacol 2017 Nov/Dec;40(6):261-263

*Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University; and †Department of Neurology, Sapporo Teishinkai Hospital, Sapporo, Japan.

Objectives: The adenosine A2A antagonist istradefylline has been used to treat Parkinson disease (PD) with symptoms of wearing-off since 2013 in Japan. Previous randomized controlled trials of istradefylline compared with placebo included PD patients experiencing an average daily OFF time of more than 2 hours. The purpose of this study is to assess the efficacy of 20 mg/d istradefylline in PD subjects experiencing an average daily OFF time of 3 hours or less.

Methods: Fifteen patients were enrolled into this retrospective study. They received 20 mg/d istradefylline for 12 weeks. Changes in the Unified Parkinson's Disease Rating Scale part III scores in the ON state (ON-UPDRS-III) scores and daily OFF time were assessed at baseline and after 4, 8, and 12 weeks of administration of istradefylline.

Results: At baseline, all subjects had shorter daily OFF times, lower doses of L-DOPA and higher ON-UPDRS-III scores than those in previous randomized controlled trials. Twelve weeks of istradefylline significantly reduced ON-UPDRS-III scores (P < 0.001, Wilcoxon signed rank test). Eleven patients (73%) showed more than 50% reductions in ON-UPDRS-III scores. Improvement of ON-UPDRS-III was significantly correlated with baseline ON-UPDRS-III, and the mean ON-UPDRS-III score at end point was 12.1.

Conclusions: Our result suggests that 20 mg/d istradefylline significantly improved motor functions in PD patients with mild wearing-off.
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http://dx.doi.org/10.1097/WNF.0000000000000249DOI Listing
June 2018

Validity and reliability of a pilot scale for assessment of multiple system atrophy symptoms.

Cerebellum Ataxias 2017 3;4:11. Epub 2017 Jul 3.

Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638 Japan.

Background: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder for which brief yet sensitive scale is required in order for use in clinical trials and general screening. We previously compared several scales for the assessment of MSA symptoms and devised an eight-item pilot scale with large standardized response mean [handwriting, finger taps, transfers, standing with feet together, turning trunk, turning 360°, gait, body sway]. The aim of the present study is to investigate the validity and reliability of a simple pilot scale for assessment of multiple system atrophy symptoms.

Methods: Thirty-two patients with MSA (15 male/17 female; 20 cerebellar subtype [MSA-C]/12 parkinsonian subtype [MSA-P]) were prospectively registered between January 1, 2014 and February 28, 2015. Patients were evaluated by two independent raters using the Unified MSA Rating Scale (UMSARS), Scale for Assessment and Rating of Ataxia (SARA), and the pilot scale. Correlations between UMSARS, SARA, pilot scale scores, intraclass correlation coefficients (ICCs), and Cronbach's alpha coefficients were calculated.

Results: Pilot scale scores significantly correlated with scores for UMSARS Parts I, II, and IV as well as with SARA scores. Intra-rater and inter-rater ICCs and Cronbach's alpha coefficients remained high (> 0.94) for all measures.

Conclusion: The results of the present study indicate the validity and reliability of the eight-item pilot scale, particularly for the assessment of symptoms in patients with early state multiple system atrophy.
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http://dx.doi.org/10.1186/s40673-017-0067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496135PMC
July 2017

Childbirth and fertility preservation in childhood and adolescent cancer patients: a second national survey of Japanese pediatric endocrinologists.

Clin Pediatr Endocrinol 2017 22;26(2):81-88. Epub 2017 Apr 22.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Although existing guidelines recommend long-term follow-up of childhood cancer survivors (CCSs), their fertility has not been fully investigated in Japan. To address this issue, we organized a working panel consisting of medical specialists in foundation hospitals. We conducted questionnaire surveys targeting pediatric endocrinologists regarding reproduction in pediatric and adolescent cancer patients in collaboration with the CCS committee of the Japanese Society for Pediatric Endocrinology (JSPE). The first questionnaire was sent to 178 directors or councilors of the JSPE, and the second was sent to those who had provided answers on their experience with childbirth or fertility preservation. A total of 151 responses (84.8%) were obtained in the first survey. In the second survey, the response rate was 100% (39 respondents). There were 27 answers describing experiences with childbirth (16 from partners of male CCSs, 22 from female CCSs). A few cases of premature birth and low birth weight were reported. There were 25 answers describing experiences with fertility preservation; 21 were from male and 17 from female CCSs. It was mainly physicians who recommended fertility preservation. This nationwide questionnaire survey revealed that a limited number of Japanese pediatric endocrinologists had experience with childbirth and fertility preservation in CCSs. A further long-term follow-up study of their fertility is needed.
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http://dx.doi.org/10.1297/cpe.26.81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402309PMC
April 2017

Elevated Urinary Levels of 8-Hydroxy-2'-deoxyguanosine in a Japanese Child of Xeroderma Pigmentosum/Cockayne Syndrome Complex with Infantile Onset of Nephrotic Syndrome.

Tohoku J Exp Med 2016 07;239(3):231-5

Department of Pediatrics, Akita University Graduate School of Medicine.

Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. XP/CS complex is an extremely rare type of NER disorder with a distinct phenotype that is characterized by the skin and eye pathology of XP and the somatic and neurological abnormalities of CS. Some of CS cases have been reported to be complicated with renal failure, but the genetic background or the etiology of the renal failure has not been reported. We herein report a 1-year-old Japanese boy with XP/CS complex, complicated by nephrotic syndrome. Diagnosis was confirmed by the presence of compound heterozygous mutations, G47R (c.139G>A) and R616G (c.1846C>G), in the excision repair cross-complementation group 2 (ERCC2) gene. The kidney biopsies, performed at the age of 1 year and 2 months, revealed diffuse expansion of the mesangial matrix and segmental glomerulosclerosis under light microscopy, and diffused thin capillary walls with partially lamellated regions under electron microscopy. Notably, high levels of urinary 8-hydroxy-2'-deoxyguanosin, known as an oxidative stress marker, were observed during the clinical course. The patient died at the age of 1 year and 11 months because of renal failure. We suggest the involvement of oxidative stress in the pathogenesis of nephrotic syndrome in NER disorders.
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http://dx.doi.org/10.1620/tjem.239.231DOI Listing
July 2016

Clinical efficacy of istradefylline on lower urinary tract symptoms in Parkinson's disease.

Int J Urol 2016 10 8;23(10):893-894. Epub 2016 Jul 8.

Departments of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

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http://dx.doi.org/10.1111/iju.13160DOI Listing
October 2016
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