Publications by authors named "Kei Yoshida"

28 Publications

  • Page 1 of 1

Radial nerve palsy following humeral shaft fracture: a theoretical PNF rehabilitation approach for tendon and nerve transfers.

Physiother Theory Pract 2021 Jun 22:1-11. Epub 2021 Jun 22.

Athletic Training Program, Kosair Charities College of Health and Natural Sciences, Spalding University, Louisville, KY, USA.

Humerus fracture-induced radial nerve injury can create severe and permanent disabilities. Surgical management often relies on either tendon or nerve transfer. Regardless of which procedure is selected, physical therapists are challenged to restore functional outcomes without jeopardizing repair healing. Through synergistic, multi planar upper extremity movement patterns, neuromuscular irradiation, or overflow, and neuroplasticity, proprioceptive neuromuscular facilitation (PNF) may improve strength, range of motion and tone. After reviewing the literature, a five phase PNF-based treatment approach is proposed with timing differences based on the selected procedure. Phase I (2 or 4 weeks pre-surgery for tendon or nerve transfer, respectively) consists of comprehensive patient education; Phase II (4-6 or 1-2 weeks post-surgery for tendon or nerve transfer, respectively) explores variable duration peripheral and central nervous system motor learning during isometric activation to enhance central neuroplasticity; Phase III (7-12 or 3-20 weeks post-surgery for tendon or nerve transfer, respectively) incorporates low-intensity motor control including contralateral isotonic upper extremity loading to maximize overflow and neuroplastic effects; Phase IV (13-26 or 21-52 weeks post-surgery for tendon or nerve transfer, respectively) adds high-intensity strength and motor control using ipsilateral isotonic upper extremity loading to maximize overflow and neuroplastic effects. Phase V (27-52 or 53-78 weeks post-surgery for tendon or nerve transfer, respectively) progresses to more activity of daily living, vocational, or sport-specific training with higher intensity strength and motor control tasks. Through manually guided synergistic, multi planar movement, overflow, and neuroplasticity, a PNF treatment approach may optimize neuromuscular recovery. Validation strategies to confirm clinical treatment efficacy are discussed.
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http://dx.doi.org/10.1080/09593985.2021.1938310DOI Listing
June 2021

Frequent scanning using flash glucose monitoring contributes to better glycemic control in children and adolescents with type 1 diabetes.

J Diabetes Investig 2021 Jun 18. Epub 2021 Jun 18.

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

Aims/introduction: We examined the impact of scanning frequency with flash glucose monitoring on glycemic control in children and adolescents with type 1 diabetes.

Materials And Methods: The study included 85 patients, aged 14.0 ± 0.5 years, with type 1 diabetes. The median time in the target glucose range (TIR) and glycosylated hemoglobin (HbA1c) values were 50.0 ± 1.4% and 7.5 ± 0.1%, respectively.

Results: The median scanning frequency using flash glucose monitoring was 12.0 ± 0.4 times/day. Scanning frequency showed a significant positive correlation with TIR and an inverse correlation with HbA1c. Scanning frequency was identified to be the determinant of TIR and HbA1c by using multivariate analysis. The participants whose scanning frequency was <12 times/day were categorized as the low-frequency group (n = 40), and those who carried out the scanning >12 times/day were categorized as the high-frequency group (n = 45). Patients in the high-frequency group were more likely to be treated with insulin pumps compared with those in the low-frequency group; however, this difference was not significant (21.3 vs 5.3%, P = 0.073). The high-frequency group showed significantly greater TIR than the low-frequency group (57 ± 1.6 vs 42 ± 1.7%, P = 0.002). Furthermore, the high-frequency group showed significantly lower HbA1c levels than the low-frequency group (6.8 ± 0.1 vs 8.0 ± 0.1%, P < 0.001).

Conclusions: These findings showed that patients with a higher scanning frequency had better glycemic control, with greater TIRs and lower HbA1c levels, compared with those with a lower scanning frequency. Scanning frequency of >12 times/day might contribute to better glycemic outcomes in real-world practice in children with type 1 diabetes.
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http://dx.doi.org/10.1111/jdi.13618DOI Listing
June 2021

Significance of "Time below Range" as a Glycemic Marker Derived from Continuous Glucose Monitoring in Japanese Children and Adolescents with Type 1 Diabetes.

Horm Res Paediatr 2020 18;93(4):251-257. Epub 2020 Sep 18.

Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.

Introduction: We evaluated the frequencies of various glycemic markers derived from continuous glucose monitoring in Japanese children and adolescents with type 1 diabetes and assessed the significance of hypoglycemia duration.

Methods: We enrolled 85 children and adolescents (36 boys and 49 girls) with type 1 diabetes who used FreeStyle® Libre in the present study. Frequencies of blood glucose levels as time within target range (TIR; 70-180 mg/dL), time below target range (TBR; <70 mg/dL), time below extreme hypoglycemia range (TBER; <54 mg/dL), and time above range (TAR; >180 mg/dL) were assessed during a 3-month study period. Furthermore, we evaluated the intraday frequencies of TBR and TBER.

Results: The mean frequencies of TIR, TBR, and TAR were 52.7 ± 11.3%, 10.8 ± 5.4%, and 36.5 ± 10.8%, respectively, whereas the mean frequency of TBER was 1.1 ± 0.9% (0-3.0%); there was no clinical episode of severe hypoglycemia. The mean frequency of TBR was significantly greater in 0-6 h (16.9 ± 5.2%) than in 6-12 h (7.8 ± 2.9%) and 18-24 h (6.8 ± 4.8%; p < 0.01) time zones, respectively.

Discussion/conclusion: We found similar TIR and comparatively higher TBR frequencies, particularly during sleep, than those that were previously reported. Possible reasons for the higher frequency of TBR include differences in the quality of insulin treatment and diabetes care between the present study and the European studies. The utilization of advanced technologies, such as a predictive low-glucose suspend-function pump or closed-loop therapy, can reduce the frequency of TBR, with a consequent increase in TIR frequency and comprehensive improvement in glycemic control.
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http://dx.doi.org/10.1159/000510454DOI Listing
September 2020

A Concise Enantioselective Total Synthesis of (-)-Deoxoapodine.

Angew Chem Int Ed Engl 2020 12 15;59(51):23089-23093. Epub 2020 Oct 15.

Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.

We have established a highly convergent 10-step route for the total synthesis of (-)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C-H palladation/alkylation cascade at the indole 2-position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.
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http://dx.doi.org/10.1002/anie.202010759DOI Listing
December 2020

Glucagon stimulation test as a possible predictor of residual β-cell function.

Pediatr Int 2021 May 7;63(5):536-542. Epub 2021 May 7.

Department of Pediatrics and Child Health, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Japan.

Background: We aimed to investigate the significance of the C-peptide levels on a glucagon stimulation test (GST) conducted soon after diagnosis as a predictive marker for residual β-cell function over time in Japanese children with type 1 diabetes (TD1).

Methods: We retrospectively enrolled 65 Japanese children (25 male, 40 female; age <16 years) with new-onset TD1. A GST was conducted within 1 month of diagnosis, when glucose toxicity improved. One- to 2-h postprandial serum C-peptide values were measured at 0, 3, 6, 12, 24, 36, 60, and 120 months after diagnosis.

Results: Receiver operating characteristic analysis showed that the cutoff values of peak serum C-peptide levels used to predict the complete destruction of β-cells at 3, 6, and 12 months after diagnosis were all 0.20 ng/mL (area under the curve [AUC] 0.867, 95% confidence interval [CI] 0.745-0.990; AUC 0.774, 95% CI 0.634-0.914; and AUC 0.804, 95% CI 0.695-0.914, respectively); the values at 24, 36, and 60 months were 0.69 ng/mL (AUC 0.828, 95% CI 0.721-0.936), 0.60 ng/mL (AUC 0.777, 95% CI 0.636-0.918), and 0.70 ng/mL (AUC 0.848, 95% CI 0.715-0.982), respectively. On multivariate analysis, peak serum C-peptide level on a GST, diabetic ketoacidosis, age, and HbA1c level at diagnosis were associated with residual β-cell function over time.

Conclusions: Peak serum C-peptide levels on a GST conducted soon after diagnosis in Japanese children with TD1 could predict the time to decrease in postprandial serum C-peptide values to < 0.20 ng/mL.
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http://dx.doi.org/10.1111/ped.14462DOI Listing
May 2021

Association between scanning frequency of flash glucose monitoring and continuous glucose monitoring-derived glycemic makers in children and adolescents with type 1 diabetes.

Pediatr Int 2021 Feb 15;63(2):154-159. Epub 2021 Feb 15.

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

Background: We assessed the association between scanning frequency of flash glucose monitoring (FGM) and continuous glucose monitoring (CGM)-derived glycemic markers in children and adolescents with type 1 diabetes.

Methods: Subjects consisted of 85 children and adolescents with type 1 diabetes using FGM. We assessed the association between scanning frequencies of FGM- and CGM-derived metrics: Time in range (TIR) (70-180 mg/dL), time below range (TBR) (<70 mg/dL), time above range (>180 mg/dL), and other glycemic markers - laboratory-measured HbA1c and CGM-estimated glucose and HbA1c (eA1c) levels in the subjects.

Results: The mean number of scans was 11.5 ± 3.5 (5-20) times per day, and scanning was most frequently conducted during a period of 18-24 h. Scanning frequency showed significant positive correlation with TIR (r = 0.719, P < 0.0001) and inverse correlation with time above range (r = -0.743, P < 0.0001), but did not correlate with TBR. There were also significant inverse correlations between scanning frequency and glucose, HbA1c, and eA1c levels (r = -0.765, -0.815, and -0.793, respectively, P < 0.0001).

Conclusions: Frequent glucose testing with FGM decreased hyperglycemia with increased TIR, but did not reduce TBR. Coping with a rapid fall of glucose and unexpected hypoglycemia with more advanced technology might contribute to a reduction in TBR.
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http://dx.doi.org/10.1111/ped.14412DOI Listing
February 2021

Three short children born small for gestational age who developed impaired glucose tolerance during growth hormone treatment.

Pediatr Int 2020 07 6;62(7):876-877. Epub 2020 Jul 6.

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/ped.14208DOI Listing
July 2020

Individualization of recommendations from the international consensus on continuous glucose monitoring-derived metrics in Japanese children and adolescents with type 1 diabetes.

Endocr J 2020 Oct 20;67(10):1055-1062. Epub 2020 Jun 20.

Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.

We assessed the significance of recommendations from the international consensus on continuous glucose monitoring (CGM)-derived metrics in Japanese children and adolescents with type 1 diabetes. Eighty-five patients (age, 13.5 ± 4.7 years) who wore the FreeStyle Libre for a 28-day period were enrolled in this study. Seventy-three patients were treated with multiple daily injections of insulin and 12 with insulin pump therapy without using a sensor-augmented pump or a predictive low-glucose suspend-function pump. We evaluated the relationship between CGM-derived metrics: time in range (TIR: 70-180 mg/dL), time below range (TBR: <70 mg/dL), and time above range (TAR: >180 mg/dL), and laboratory-measured HbA1c and estimated HbA1c (eA1c) levels calculated from the mean glucose values. The TIR was 50.7 ± 12.2% (23-75%), TBR was 11.8 ± 5.8% (2-27%), and TAR was 37.5 ± 13.5% (9-69%). The TIR was highly correlated with HbA1c level, eA1c level, and TAR, but not with TBR. An HbA1c level of 7.0% corresponded to a TIR of 55.1% (95% CI: 53.7-56.5%), whereas a TIR of 70% corresponded to an HbA1c level of 6.1% (95% CI: 5.9-6.3%). The results of eA1c levels were similar to those observed for HbA1c levels. From these findings, we conclude that low rates of a recommended TIR of 70% may be due to less use of advanced technology and insufficient comprehensive diabetes care. Ethnic characteristics including lifestyle and eating customs may have contributed to the result. CGM-derived targets must be individualized based on ethnic characteristics, insulin treatment and diabetes care, and needs of individuals with diabetes.
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http://dx.doi.org/10.1507/endocrj.EJ20-0193DOI Listing
October 2020

Aerobic Dehydrogenation of N-Heterocycles with Grubbs Catalyst: Its Application to Assisted-Tandem Catalysis to Construct N-Containing Fused Heteroarenes.

Chemistry 2020 Dec 6;26(68):15793-15798. Epub 2020 Oct 6.

Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.

An aerobic dehydrogenation of nitrogen-containing heterocycles catalyzed by Grubbs catalyst is developed. The reaction is applicable to various nitrogen-containing heterocycles. The exceptionally high functional group compatibility of this method was confirmed by the oxidation of an unprotected dihydroindolactam V to indolactam V. Furthermore, by taking advantage of the oxygen-mediated structural change of the Grubbs catalyst, we integrated ring-closing metathesis and subsequent aerobic dehydrogenation to develop the novel assisted-tandem catalysis using molecular oxygen as a chemical trigger. The utility of the assisted-tandem catalysis was demonstrated by the concise synthesis of N-containing fused heteroarenes including a natural antibiotic, pyocyanine.
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http://dx.doi.org/10.1002/chem.202001961DOI Listing
December 2020

Efficacy of zinc supplementation on growth and IGF-1 in prepubertal children with idiopathic short statures and low serum zinc levels.

Clin Pediatr Endocrinol 2020 16;29(2):63-68. Epub 2020 Apr 16.

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

We investigated the effect of zinc supplementation on growth and serum IGF-1 levels in 10 prepubertal Japanese children with idiopathic short statures, who had serum zinc levels of less than 80 µg/dL. Subjects were started on oral zinc supplementation at a dose of 25 mg once daily. In three children, the doses were increased by 50 mg once daily during the study period of 12 mo. The serum zinc levels rose in all subjects and reached a normal range (beyond 80 µg/dL). However, it was found that zinc supplementation did not promote growth. Although the mean IGF-1 standard deviations significantly increased, the majority did not reach the normal range. There were no significant adverse events other than mild gastrointestinal symptoms in 4 out of 10 subjects during the supplementation period. The most likely reason why growth was not promoted is that the zinc supplementation dosage was not enough to stimulate IGF-1 generation and subsequent growth velocity.
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http://dx.doi.org/10.1297/cpe.29.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160462PMC
April 2020

Case of type 2 diabetes possibly caused by excessive accumulation of visceral fat in a child born small-for-gestational age.

J Diabetes Investig 2020 Sep 26;11(5):1366-1369. Epub 2020 Mar 26.

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

We encountered a 12-year-old boy with type 2 diabetes who was born small-for-gestational age. We described his clinical characteristics and a possible etiological factor for development of hyperglycemia. He developed well with sufficient nutrition and progressed to being overweight at 6 years-of-age as a result of a high-calorie, high-protein intake diet. He showed a diabetic pattern with a normal insulin response on an oral glucose tolerance test carried out with the urine glucose screening program at schools. He showed a large total fat area of 239.4 cm ; in particular, his visceral fat area was 103.0 cm with a high ratio of visceral fat area to subcutaneous fat area (0.76). The present case might show that insulin resistance, possibly as a result of accumulation of a great amount of visceral fat, might be attributed to the pathogenesis of type 2 diabetes in children born small-for-gestational age.
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http://dx.doi.org/10.1111/jdi.13246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477531PMC
September 2020

Juvenile case with the coexistence of maturity-onset diabetes of the young 1 and later-onset latent autoimmune diabetes in youth.

J Diabetes Investig 2020 Jul 20;11(4):1010-1013. Epub 2020 Feb 20.

Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.

We present the case of a 12-year-old Japanese girl, who was positive for markers of both maturity-onset diabetes of the young and latent autoimmune diabetes in youth. She was initially diagnosed with maturity-onset diabetes of the young 1 based on the molecular analysis, and she later developed an autoimmune response, leading to β-cell-associated antibody-positive diabetes. She was treated with incretin-associated drugs and maintained adequate glycemic control. Pathophysiologically, there was an overlap between the two different types of diabetes, because the hyperglycemia and β-cell stress seen in non-autoimmune diabetes can cause β-cell autoimmunity over time.
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http://dx.doi.org/10.1111/jdi.13215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378418PMC
July 2020

Effect of mechanical vibration stress in cell culture on human induced pluripotent stem cells.

Regen Ther 2019 Dec 6;12:27-35. Epub 2019 Jun 6.

Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya, 464-8601, Japan.

The development of induced pluripotent stem cell (iPSC) techniques has solved various limitations in cell culture including cellular proliferation and potency. Hence, the expectations on wider applications and the quality of manufactured iPSCs are rapidly increasing. To answer such growing expectations, enhancement of technologies to improve cell-manufacturing efficiency is now a challenge for the bioengineering field. Mechanization of conventional manual operations, aimed at automation of cell manufacturing, is quickly advancing. However, as more processes are being automated in cell manufacturing, it is need to be more critical about influential parameters that may not be as important in manual operations. As a model of such parameters, we focused on the effect of mechanical vibration, which transmits through the vessel to the cultured iPSCs. We designed 7 types of vertical vibration conditions in cell culture vessels using a vibration calibrator. These conditions cover a wide range of potential situations in cell culture, such as tapping or closing an incubator door, and examined their effects by continuous passaging (P3 to P5). Detailed evaluation of cells by time-course image analysis revealed that vibrations can enhance cell growth as an early effect but can negatively affect cell adhesion and growth profile after several passages as a delayed effect. Such unexpected reductions in cell quality are potentially critical issues in maintaining consistency in cell manufacturing. Therefore, this work reveals the importance of continuous examination across several passages with detailed, temporal, quantitative measurements obtained by non-invasive image analysis to examine when and how the unknown parameters will affect the cell culture processes.
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http://dx.doi.org/10.1016/j.reth.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933472PMC
December 2019

The Characteristics Of Abdominal Fat Distribution In Japanese Adolescents With Type 2 Diabetes Mellitus.

Diabetes Metab Syndr Obes 2019 1;12:2281-2288. Epub 2019 Nov 1.

Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.

Purpose: The aim was to investigate the characteristics of abdominal fat distribution in Japanese adolescents with type 2 diabetes mellitus.

Patients And Methods: Eighty-six Japanese adolescents with simple obesity or type 2 diabetes mellitus treated between 2002 and 2018 were included. The subjects were classified into the simple obesity group (SO group, n=38) and type 2 diabetes mellitus group (DM group, n=23) by matching average age and gender ratio. The metabolic parameters VFA, SFA, and V/S ratio were compared between the 2 groups. Multivariate logistic regression analysis was performed to identify clinical factors associated with type 2 diabetes mellitus. Linear regression analysis was performed between hemoglobin A1c (HbA1c) and visceral fat area (VFA), subcutaneous fat area (SFA), or VFA-to-SFA ratio (V/S ratio) among all enrolled subjects. Finally, correlation analyses were performed to determine the relationships between VFA, SFA, and V/S ratio and metabolic parameters of the DM group. For the metabolic parameters, serum lipids, alanine aminotransferase (ALT), and HbA1c were measured without fasting. The VFA and SFA at umbilical level were investigated using computed tomography.

Results: VFA and V/S ratio in DM group were higher than those in SO group (p=0.04 and p<0.01, respectively). SFA in DM group was lower than that in SO group (p<0.01). VFA and SFA, and non-high density lipoprotein (HDL) cholesterol were identified as being independently associated with type 2 diabetes mellitus (odds ratio, 1.05, 0.98, and 1.04, respectively, p<0.05). HbA1c was correlated with VFA and V/S ratio (p<0.01). In DM group, VFA and SFA were positively correlated with systolic blood pressure (p<0.01), ALT (p<0.05), total cholesterol (p<0.05), and non-HDL cholesterol (p<0.01); however, V/S ratio was not correlated.

Conclusion: Abdominal fat distribution in Japanese adolescents with type 2 diabetes mellitus was different from those with simple obesity and might associate with glucose and lipid metabolism.
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http://dx.doi.org/10.2147/DMSO.S223049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830372PMC
November 2019

Zinc deficiency in Japanese children with idiopathic short stature.

J Pediatr Endocrinol Metab 2019 Oct;32(10):1083-1087

Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.

Background and methods We investigated the frequency of zinc deficiency in Japanese children with idiopathic short stature, and evaluated whether serum zinc levels correlated with background factors, including age and standard deviation scores (SDSs) for height and serum insulin-like growth factor (IGF)-1 levels. The study subjects consisted of 89 Japanese children. Results The mean serum zinc level was 79 ± 12 (49-108) μg/dL. Of all the children, 48.3% had a low zinc level, in the 60-80 μg/dL range, and 6.7% had zinc deficiency with a zinc level below 60 μg/dL. The majority with a low zinc level and zinc deficiency were asymptomatic other than for short stature. We found no significant correlations of serum zinc with age, or the SDSs for height and serum IGF-1 levels, in either the entire subject population or those with a zinc level below 80 μg/dL. Conclusions We found a low zinc level to be common in Japanese children with idiopathic short stature, whereas actual zinc deficiency was rare. However, other as yet unknown mechanisms not associated with the growth hormone (GH)-IGF-1 axis could be involved in growth retardation in idiopathic short stature.
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http://dx.doi.org/10.1515/jpem-2019-0129DOI Listing
October 2019

Changes in the incidence of cervical lesions owing to the development of rheumatoid arthritis treatment and the impact of cervical lesions on patients' quality of life.

Mod Rheumatol 2020 May 13;30(3):495-501. Epub 2019 Jun 13.

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

To clarify changes in the incidence of cervical lesions in rheumatoid arthritis (RA) patients with advanced treatment and the impact of cervical lesions on the patients' quality of life (QOL).: Incidence of radiographic cervical lesions in 1333 RA patients in 2015 was compared with that in our 1999 survey. The association between cervical lesions and QOL evaluated using three different patient-based questionnaires was also analyzed. The incidence of atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS) in 2015 decreased by 50%, 75%, and 5%, respectively, compared to the 1999 survey. Although QOL, evaluated using the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ; specific to myelopathy), deteriorated as the cervical lesion progressed, there was no association between cervical lesion progression and QOL evaluated using the Short Form-8™ (SF-8™; comprehensive health-related QOL). Cervical lesion progression was also associated with QOL deterioration evaluated using the Health Assessment Questionnaire Disability Index (HAQ-DI; specific to RA), but age and disease duration had stronger influences. The incidence of cervical lesions decreased in 2015 compared to 1999. Cervical lesion progression may be associated with QOL deterioration due to myelopathy. Age and disease duration have more impact on disease-specific QOL.
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http://dx.doi.org/10.1080/14397595.2019.1621428DOI Listing
May 2020

Time-course colony tracking analysis for evaluating induced pluripotent stem cell culture processes.

J Biosci Bioeng 2019 Aug 7;128(2):209-217. Epub 2019 Feb 7.

Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8602, Japan; Stem Cell Evaluation Technology Research Association (SCA), Hacho-bori, Chuou-ku, Tokyo 104-0032, Japan; Institute of Nano-Life-Systems, Institute of Innovation for Future Society, Nagoya University, Division of Micro-Nano Mechatronics, Furocho, Chikusa-ku, Nagoya 464-8602, Japan. Electronic address:

Increasing the yield and maintaining a high quality of induced pluripotent stem cells (iPSCs) is necessary for manufacturing iPSCs at the industrial scale. However, because iPSCs are delicate, it is important to evaluate their quality during processing. To examine the status of cultured iPSCs non-invasively, morphology-based iPSC colony evaluation may be an efficient technology for cellular status monitoring and analysis. In this study, we examined the effectiveness of time-course colony tracking analysis for evaluating the iPSC culture process. Particularly, we obtained detailed time-course data to evaluate the effect of the pipetting technique on cell dissociation before seeding. Although the pipetting process causes severe shear stress to cells, which affects their quality, these effects have not been quantitatively analyzed because of their complex and uncontrollable parameters. By analyzing the heterogeneity and time-course responses of individual colonies, our colony tracking analysis revealed a critically damaged population caused by pipetting stress which could not be detected in conventional bulk analysis. Moreover, by comprehensively analyzing colony tracking data, which links the time-course morphology and marker staining results with each colony, we found that colony morphology is only highly correlated with the undifferentiated marker in the final stage, with a lower correlation in the early stages. Thus, colony tracking analysis provides a way to quantify cellular morphological information when evaluating complex iPSC manufacturing processes.
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http://dx.doi.org/10.1016/j.jbiosc.2019.01.011DOI Listing
August 2019

Economic Impact of Diabetes in Japan.

Curr Diab Rep 2019 01 16;19(1). Epub 2019 Jan 16.

Department of Pediatrics, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo, Japan.

Purpose Of Review: The economic burden of diabetes in Japan is already serious and will become greater in the future. We review the economic impact of diabetes in Japan to examine viable options for mitigating its effects.

Recent Findings: Medical costs for diabetes have been increasing by US $1 million annually, reaching US $11 million in 2009, of which US $7 million was accounted for by people aged 65 years or older. The quality of treatment of diabetes in Japan is higher than in other regions in the world. This can be more effective for achieving glycemic control, but is also more expensive compared with conventional treatment. Because of the high cost of diabetes in Japan, a coordinated response is needed. Intervention trials for people with prediabetes aimed at preventing the occurrence of diabetes seem to be the most cost-effective method for lowering the medical costs of diabetes, rather than the use of new, expensive antidiabetic drugs in patients with established diabetes.
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http://dx.doi.org/10.1007/s11892-019-1122-9DOI Listing
January 2019

In-process evaluation of culture errors using morphology-based image analysis.

Regen Ther 2018 Dec 9;9:15-23. Epub 2018 Jul 9.

Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8601, Japan.

Introduction: Advancing industrial-scale manufacture of cells as therapeutic products is an example of the wide applications of regenerative medicine. However, one bottleneck in establishing stable and efficient cell manufacture is quality control. Owing to the lack of effective in-process measurement technology, analyzing the time-consuming and complex cell culture process that essentially determines cellular quality is difficult and only performed by manual microscopic observation. Our group has been applying advanced image-processing and machine-learning modeling techniques to construct prediction models that support quality evaluations during cell culture. In this study, as a model of errors during the cell culture process, intentional errors were compared to the standard culture and analyzed based only on the time-course morphological information of the cells.

Methods: Twenty-one lots of human mesenchymal stem cells (MSCs), including both bone-marrow-derived MSCs and adipose-derived MSCs, were cultured under 5 conditions (one standard and 4 types of intentional errors, such as clear failure of handlings and machinery malfunctions). Using time-course microscopic images, cell morphological profiles were quantitatively measured and utilized for visualization and prediction modeling. For visualization, modified principal component analysis (PCA) was used. For prediction modeling, linear regression analysis and the MT method were applied.

Results: By modified PCA visualization, the differences in cellular lots and culture conditions were illustrated as traits on a morphological transition line plot and found to be effective descriptors for discriminating the deviated samples in a real-time manner. In prediction modeling, both the cell growth rate and error condition discrimination showed high accuracy (>80%), which required only 2 days of culture. Moreover, we demonstrated the applicability of different concepts of machine learning using the MT method, which is effective for manufacture processes that mostly collect standard data but not a large amount of failure data.

Conclusions: Morphological information that can be quantitatively acquired during cell culture has great potential as an in-process measurement tool for quality control in cell manufacturing processes.
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http://dx.doi.org/10.1016/j.reth.2018.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222266PMC
December 2018

Morphology-Based Analysis of Myoblasts for Prediction of Myotube Formation.

SLAS Discov 2019 01 13;24(1):47-56. Epub 2018 Aug 13.

1 Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Aichi, Japan.

The development of new drugs depends on the efficiency of drug screening. Phenotype-based screening has attracted interest due to its considerable potency for the discovery of first-in-class drugs. In general, fluorescently labeled imagery is the leading technique for phenotype-based screening; however, there are growing requirements to understand total culture profiles, which are unclear after end-point assays. In this study, we demonstrate that morphology-based cellular evaluation of unlabeled cells is an efficient approach to evaluate myotube formation assays. One of our aims was to study the myogenic differentiation process in C2C12 cells to discern the differences between cellular responses to different medium conditions (serum concentrations and insulin dosages). Our results show that predictive morphological profiles that strongly correlate with myogenic differentiation can be generated from myotube images, even in the confluent stage. The differentiation rate after 14 days can be quantitatively predicted with the highest accuracy by means of images taken on days 0-11.5. In addition, for the application of our morphology-based cellular evaluation, the effect of cyclic guanosine monophosphate (cGMP) on myogenic differentiation was analyzed. Our results show that the quantitated morphological profile from these images can be an effective descriptor for analysis of the myotube-recovering effect of cGMP.
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http://dx.doi.org/10.1177/2472555218793374DOI Listing
January 2019

Changes in annual incidence of school children with type 2 diabetes in the Tokyo Metropolitan Area during 1975-2015.

Pediatr Diabetes 2018 12 5;19(8):1385-1392. Epub 2018 Sep 5.

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

Objective: To analyze changes in the annual incidence of school students with type 2 diabetes detected by urine glucose screening at schools in the Tokyo Metropolitan Area during 1975-2015.

Methods: Trend in temporal changes in the annual incidence rate were analyzed using a joinpoint regression model and the joinpoints. Annual percent change (APC) was calculated for each segmented line regression. Average annual percent change (AAPC) was also calculated for the whole period analyzed.

Results: In total, 301 students, including 64 primary school students and 237 junior high school students, were diagnosed with type 2 diabetes. The overall incidence of type 2 diabetes (per 100 000/year) during the entire study period was 2.58 in all students, 0.80 in primary school students, and 6.41 in junior high school students. AAPC during the entire study period was estimated at -1.5 (not significant), and the incidence significantly increased during 1975-1982 (APC = 17.49, P < 0.05), but tended to decrease during 1982-2015 (APC = -1.01). In primary school students, the incidence significantly increased during1975-2010 (APC = 3.30, P < 0.05), and tended to decrease during 2010-2015 (APC = -29.61). In junior high school students, the incidence did not significantly change during the entire study period (APC = 0.06).

Conclusions: We found increasing trend in the overall incidence of school students with type 2 diabetes during 1975-1982, but a decreased tendency in recent years. This could be due to changes observed during the same time period in the primary school students. Lifestyle changes might contribute to improved incidence of childhood type 2 diabetes.
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http://dx.doi.org/10.1111/pedi.12750DOI Listing
December 2018

Renal glucosuria in schoolchildren: Clinical characteristics.

Pediatr Int 2018 Jan;60(1):35-40

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

Background: We conducted an annual urine glucose screening program at schools, and diagnosed schoolchildren with diabetes at an early stage of the disease. We also identified some cases of renal glucosuria (RG), based on positive urine glucose with normal glucose tolerance.

Methods: During 2000-2015, 3 309 631 schoolchildren participated in the screening program. The positive rate for glucosuria in the first test was approximately 0.1%, whereas on repeat urine test it was approximately 0.05%. In total 350 schoolchildren were positive for glucosuria on detailed examination. Oral glucose tolerance test (OGTT) was also used to evaluate glucose intolerance.

Results: One hundred and two schoolchildren (29.7%) were diagnosed with diabetes, whereas RG was identified in 246 (70.3%) with normal glucose metabolism. In regard to the characteristics of RG, the percentage of boys was 50.3%, and the mean age at diagnosis was 11.2 ± 2.4 years. Twenty-eight children (11.4%) were overweight (body mass index standard deviation score [BMI-SDS] > +2.0 SD), whereas five (2.0%) were underweight (BMI-SDS < -2.0 SD). First-degree family history was suspected in 176 cases (71.5%). All RG subjects had normal glucose tolerance in the absence of insulin resistance and decreased insulin secretion (homeostasis model assessment for β-cell function, 78.8 ± 59.5%) on OGTT.

Conclusions: RG is not rare in Japanese schoolchildren with glucosuria. This disorder seems to have a strong genetic background, and to involve less growth retardation and weight loss than expected despite continuous excretion of glucose in urine.
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http://dx.doi.org/10.1111/ped.13456DOI Listing
January 2018

Image-based cell quality evaluation to detect irregularities under same culture process of human induced pluripotent stem cells.

J Biosci Bioeng 2017 May 8;123(5):642-650. Epub 2017 Feb 8.

Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8601, Japan. Electronic address:

To meet the growing demand for human induced pluripotent stem cells (iPSCs) for various applications, technologies that enable the manufacturing of iPSCs on a large scale should be developed. There are several technological challenges in iPSC manufacturing technology. Image-based cell quality evaluation technology for monitoring iPSC quality in culture enables the manufacture of intact cells for further applications. Although several studies have reported the effectiveness of image-based evaluation of iPSCs, it remains challenging to detect irregularities that may arise using the same processing operations during quality evaluation of automated processing. In this study, we investigated the evaluation performance of image-based cell quality analysis in detecting small differences that can result from human measurement, even when the same protocol is followed. To imitate such culture conditions, by image-analysis guided colony pickup, we changed the proportions of morphologically different subpopulations: "good morphology, regular morphology correlated with undifferentiation marker expression" and "bad morphology, irregular morphology correlated with loss of undifferentiation marker expression". In addition, comprehensive gene-expression and metabolomics analyses were carried out for the same samples to investigate performance differences. Our data shows an example of investigating the usefulness and sensitivity of quality evaluation methods for iPSC quality monitoring.
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http://dx.doi.org/10.1016/j.jbiosc.2016.12.015DOI Listing
May 2017

Acetic acid promoted metal-free aerobic carbon-carbon bond forming reactions at α-position of tertiary amines.

Org Lett 2014 Aug 25;16(16):4194-7. Epub 2014 Jul 25.

Graduate School of Pharmaceutical Sciences, Tohoku University , Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.

The oxidative functionalization of the benzylic C-H bonds in tetrahydroisoquinolines and tetrahydro-β-carboline derivatives was investigated. C-C bond forming reactions proceeded with a range of nucleophiles (nitroalkane, enol silyl ether, indole, allylstannane, and tetrabutylammonium cyanide) under metal-free conditions and an oxygen atmosphere. Acetic acid caused a significant acceleration effect.
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http://dx.doi.org/10.1021/ol5018883DOI Listing
August 2014

[Evaluation of dectin-1 and BAFF expression in conjunctival epithelial cells].

Nippon Ganka Gakkai Zasshi 2014 Apr;118(4):368-77

Purpose: To investigate the expression of dectin-1 protein in conjunctival epithelial cells and the expression of dectin-1 and B-cell activating factor belonging to the tumor necrosis factor family (BAFF) mRNA in in vivo conjunctival epithelial cells (CECs) and in vitro cultured CECs, and its difference in topographical change and etiology of disorders.

Subjects And Methods: 1. Investigation of dectin-1 and BAFF expression by cytodiagnosis of CECs. The subjects were 12 eyes of 12 healthy volunteers (control group), 6 eyes of 6 patients with Sjögren syndrome (Sjögren group) and 10 eyes of 10 patients with vernal keratoconjuctivitis (VKC group). CECs were sampled by impression cytology using nitrocellulose membrane. The expression of dectin-1 in CECs was detected by immunofluorescence and the quantitative determination of dectin-1 mRNA and BAFF mRNA expression was performed by real-time polymerase chain reaction(real-time PCR). 2. Investigation of dectin-1 and BAFF expression using cultured CECs. Cultured CECs which were divided into an OK-432 addition group (addition concentrations: 0.02, 0.1, 0.5KU/mL), a lipopolysaccharide (LPS) addition group (addition concentrations : 80, 160, 320 microg/mL) and an additive-free group were cultured. Quantitative determination of dectin-1 mRNA and BAFF mRNA expression in cultured CECs was performed by real-time PCR.

Results: 1. Investigation of dectin-1 and BAFF expression by cytodiagnosis of CECs. In the control group, there was no significant topographical difference in the expression of dectin-1 and the amount of dectin-1 mRNA among superior, inferior tarsal conjunctiva and temporal bulbar conjunctiva. The levels of dectin-1 mRNA expression were 1.5 (0.1-4.0) [median value (range)] for the control group, 2.6 (1.1-4.8) for the Sjögren group and 3.6 (1.7-16.6) for the VKC group. The VKC group showed a significantly higher level of dectin-1 mRNA than the control group (p < 0.01, Kruskal-Walles H-test). The levels of BAFF mRNA expression were 2.8 (0.2-13.8) [median value (range)] for the control group, 6.3 (2.1-15.1) for the Sjögren group and 11.2 (3.5-70.8) for the VKC group. The VKC group showed a significantly higher level of dectin-1 mRNA than the control group (p < 0.01, Kruskal-Walles H-test). Moreover, regarding the relationship between expression level of dectin-1 mRNA and that of BAFF mRNA in all the subjects, there was a significant correlation between them (r = 0.75, p < 0.001, Spearman's rank coefficient). The levels of dectin-1 mRNA expression in the moderate and severe VKC group 9.2 (2.6-16.6) [median value (range)] were significantly higher than those in mild VKC group 2.8 (1.7-3.8) (p < 0.05, Mann-Whitney U-test). The levels of BAFF mRNA expression in the severe and moderate VKC groups 17.4 (9.1-70.8) [median value (range)] were significantly higher than those in the mild VKC group 4.3 (3.5-11.2) (p < 0.05, Mann-Whitney U-test). 2. Investigation of dectin-1 and BAFF expression by cultured CECs. In the OK-432 addition group, the expression levels of dectin-1 mRNA were increased dose-dependently due to the OK-432 stimulation (p < 0.05, Kruskal-Wallis H-test). Moreover, regarding the relationship between the expression level of dectin-1 mRNA and that of BAFF mRNA in all the cultured conjunctival epithelial cells stimulated by OK-432, there was a significant correlation between them (r = 0.85, p < 0.005, Spearman's rank coefficient).

Conclusions: We concluded that dectin-1 expression in CECs was demonstrated, and expression of both dectin-1 and BAFF in CECs is thought to be involved in pathologic aggravation of allergic inflammatory in patients with VKC.
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April 2014

In-line type micropulse lidar with an annular beam: theoretical approach.

Appl Opt 2005 Dec;44(34):7467-74

Faculty of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522, Japan.

An in-line type micropulse lidar (MPL) with an annular beam was designed and the transmitting and receiving characteristics were analyzed. Because the in-line MPL utilizes a common telescope for a transmitter and a receiver and the annular beam always overlaps with the receiver's field of view (FOV), it can measure near-range lidar echoes with a narrow FOV. The transmitting annular beam changes its shape to a nearly nondiffractive beam through propagation. It improves the spatial resolution of the lidar observation. The receiving characteristics showed the ideal lidar echo variation, which was inversely proportional to the square of the distance the beam propagated, even if it was in the near range.
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http://dx.doi.org/10.1364/ao.44.007467DOI Listing
December 2005

In-line type micropulse lidar with an annular beam: experiment.

Appl Opt 2005 Dec;44(34):7407-13

Faculty of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522, Japan.

An in-line type compact micropulse lidar (MPL) with an annular beam was developed for low-altitude cloud measurement. An optical circulator and a couple of axicon prisms for an annular beam were installed on the lidar optics. The advantage of using the in-line MPL is its ability to obtain a near-range measurement with a narrow field of view of 0.1 mrad and to obtain a depolarization measurement of the orthogonally polarized echoes caused by ice crystals of a low-altitude cloud. The total insertion loss of the lidar optics was 3 dB. Detectors such as avalance photodiode detectors can be operated in an analog mode near the breakdown voltage because of the high isolation of the optical circulator. The ideal lidar echo variation from the nearest distance was verified by measuring the mountain echoes at various distances. The depolarization measurement of a low-altitude ice cloud was also demonstrated.
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http://dx.doi.org/10.1364/ao.44.007407DOI Listing
December 2005

Characterization of low molecular weight organic acids from beech wood treated in supercritical water.

Appl Biochem Biotechnol 2005 ;121-124:795-806

Graduate School of Energy Science, Kyoto University, Yoshida-honmachi, Sakyo-ku, Kyoto 422, Japan.

Japanese beech (Fagus crenata Blume), its cell wall components, and model compounds were treated by supercritical water (380 degrees C, 100 MPa) for 5 s using a batch-type reactor to investigate the production behavior of low molecular weight organic acids. It was found that cellulose and hemicellulose were decomposed to formic acid, pyruvic acid, glycolic acid, acetic acid, and lactic acid, whereas lignin was barely decomposed to such organic acids under the given conditions. However, after prolonged treatment (380 degrees C, 100 MPa, 4 min) of lignin, some organic acids were recovered owing perhaps to the decomposition of the propyl side chain of lignin. It was additionally revealed that the predominant organic acid recovered was acetic acid, which might be derived from the acetyl group of hemicellulose in Japanese beech.
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http://dx.doi.org/10.1385/abab:123:1-3:0795DOI Listing
June 2005