Publications by authors named "Takashi Sakurai"

288 Publications

The Multi-Domain Intervention Trial in Older Adults With Diabetes Mellitus for Prevention of Dementia in Japan: Study Protocol for a Multi-Center, Randomized, 18-Month Controlled Trial.

Front Aging Neurosci 2021 12;13:680341. Epub 2021 Jul 12.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan.

The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial. Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers. This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan. UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).
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http://dx.doi.org/10.3389/fnagi.2021.680341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312849PMC
July 2021

Feasibility Study of Nanoparticle Albumin-Bound-Paclitaxel and S-1 Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With Operable Breast Cancer: A Prospective Study.

Clin Breast Cancer 2021 Jun 18. Epub 2021 Jun 18.

Department of Pathology, Saitama Medical Center, Saitama, Japan.

Background: The efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel combined with S-1 in patients with operable breast cancer is uncertain. We evaluated the feasibility of this combination followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy in such patients.

Patients And Methods: This was an open-label, single-arm, phase II, single-institution prospective study of 4 cycles of nab-paclitaxel (260 mg/m) administered intravenously on day 1 in combination with S-1 (65 mg/m orally twice daily) on days 1 to 14 every 21 days followed by EC as neoadjuvant chemotherapy.

Results: Of 30 patients, 1 required a dose interruption for nab-paclitaxel combined with S-1; 4 required a dose reduction for nab-paclitaxel, 1 for S-1, and 4 for EC. Mean relative dose intensities of nab-paclitaxel, S-1, and EC were 98.0%, 99.3%, and 98.2%, respectively. Overall clinical response rate was 96.7%. In histological response, grade 3, pathological complete response (pCR; ypT0/is and ypN0) rate was 63.3% and grade 2b (near pCR) was 3.3%. pCR was observed in 57.1% of luminal B human epidermal growth factor receptor type 2 (HER2)-negative patients, 55.6% of luminal B HER2-positive patients, 100% of HER2-positive patients, and 57.1% of triple-negative breast cancer patients. Grade 3/4 neutropenia was observed in 1 patient during nab-paclitaxel combined with S-1 and in 7 during EC treatments. The most frequent nonhematological severe adverse events were grade 3 peripheral neuropathy in 2 patients and grade 3 arthralgia in 2 patients during nab-paclitaxel combined with S-1.

Conclusion: Tri-weekly nab-paclitaxel with S-1 followed by EC is effective and well tolerated as neoadjuvant chemotherapy in patients with operable breast cancer.
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http://dx.doi.org/10.1016/j.clbc.2021.06.006DOI Listing
June 2021

A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke.

Nat Commun 2021 07 13;12(1):4293. Epub 2021 Jul 13.

Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan.

Mutations in the type 1 ryanodine receptor (RyR1), a Ca release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca, inhibits halothane- and isoflurane-induced Ca release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.
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http://dx.doi.org/10.1038/s41467-021-24644-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277899PMC
July 2021

Inhibition of endothelin A receptor by a novel, selective receptor antagonist enhances morphine-induced analgesia: Possible functional interaction of dimerized endothelin A and μ-opioid receptors.

Biomed Pharmacother 2021 Jun 24;141:111800. Epub 2021 Jun 24.

Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan; Department of Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Supportive and Palliative Care Research Support Office, National Center Hospital East, Chiba, Japan; Project for Supportive Care Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan. Electronic address:

Background: The misuse of opioids has led to an epidemic in recent times. The endothelin A receptor (ETAR) has recently attracted attention as a novel therapeutic target to enhance opioid analgesia. We hypothesized that endothelin A receptors may affect pain mechanisms by heterodimerization with μ opioid receptors. We examined the mechanisms of ETAR-mediated pain and the potential therapeutic effects of an ETAR antagonist, Compound-E, as an agent for analgesia.

Methods: Real-time in vitro effect of Compound-E on morphine response was assessed in HEK293 cells expressing both endothelin A and μ opioid receptors through CellKey™ and cADDis cAMP assays. Endothelin A/μ opioid receptor dimerization was assessed by immunoprecipitation and live cell imaging. The in vivo effect of Compound-E was evaluated using a morphine analgesia mouse model that observed escape response behavior, body temperature, and locomotor activity.

Results: In CellKey™ and cAMP assays, pretreatment of cells with endothelin-1 attenuated morphine-induced responses. These responses were improved by Compound-E, but not by BQ-123 nor by bosentan, an ETAR and endothelin B receptor antagonist. Dimerization of ETARs and μ opioid receptors was confirmed by Western blot and total internal reflection fluorescence microscopy in live cells. In vivo, Compound-E potentiated and prolonged the analgesic effects of morphine, enhanced hypothermia, and increased locomotor activity compared to morphine alone.

Conclusion: The results suggest that attenuation by endothelin-1 of morphine analgesia may be caused by dimerization of Endothelin A/μ opioid receptors. The novel ETAR antagonist Compound-E could be an effective adjunct to reduce opioid use.
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http://dx.doi.org/10.1016/j.biopha.2021.111800DOI Listing
June 2021

Associations Between Polypharmacy and Gait Speed According to Cognitive Impairment Status: Cross-Sectional Study in a Japanese Memory Clinic.

J Alzheimers Dis 2021 Jun 11. Epub 2021 Jun 11.

Center for Comprehensive Care and Research on Memory Disorder, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.

Background: Polypharmacy, usually defined as the use of 5 or more drugs, is associated with reduced quality of life, adverse events, and frailty. Slow gait speed is a component of physical frailty, and some studies have suggested an association between polypharmacy and slow gait speed.

Objective: We aimed to determine the effects of polypharmacy on the gait difference according to stages of cognitive decline in a cross-sectional study of memory clinic patients.

Methods: Participants were 431 outpatients aged 65 year or older who were cognitively normal (CN) or had mild cognitive impairment (MCI) or Alzheimer's disease. Participants were divided into a polypharmacy group and a non-polypharmacy group in each group. Multiple regression analysis and logistic analysis were used for data analysis.

Results: There were 182 patients in the polypharmacy group and 249 patients in the non-polypharmacy group. Multiple regression analysis revealed that gait speed had significant negative associations with number of medications and polypharmacy status in the CN group (β: -0.026 [-0.041 to -0.0018] and -0.128 [-0.022 to -0.0033], respectively) and MCI group (-0.018 [-0.028 to -0.0009] and -0.100 [-0.166 to -0.0034]). Logistic regression analysis also showed that number of medications was associated with slow gait status (<  1 m/s) in the CN group (OR: 1.336 [1.115 to 1.601]) and MCI group (1.128 [1.022 to 1.244]).

Conclusion: CN and MCI patients with polypharmacy have slower gait speed. Attention should be paid to decreased gait speed in older adults with polypharmacy even when their cognitive function is relatively preserved.
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http://dx.doi.org/10.3233/JAD-201601DOI Listing
June 2021

Cross-Sectional Examination of Homocysteine Levels with Sarcopenia and Its Components in Memory Clinic Outpatients.

J Alzheimers Dis 2021 Jun 9. Epub 2021 Jun 9.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan.

Background: Homocysteine is a common risk factor for cognitive impairment and sarcopenia. However, very few studies have shown an association between sarcopenia and serum homocysteine levels after adjustment for cognitive function.

Objective: The purpose of this study was to investigate the relationship between homocysteine and sarcopenia in memory clinic patients.

Methods: This cross-sectional study investigated outpatients in a memory clinic. We enrolled 1,774 participants (≥65 years old) with measured skeletal muscle mass index (SMI), hand grip strength (HGS), and homocysteine. All participants had undergone cognitive assessments and were diagnosed with dementia, mild cognitive impairment, or normal cognition. Patient characteristics were compared according to sarcopenia presence, SMI level, or HGS. Multivariate logistic regression analysis was performed to determine the association of homocysteine with sarcopenia, low SMI, or low HGS. Next, linear regression analysis was performed using HGS as a continuous variable.

Results: Logistic regression analysis showed that low HGS was significantly associated with homocysteine levels (p = 0.002), but sarcopenia and low SMI were not. In linear regression analysis, HGS was negatively associated with homocysteine levels after adjustment for Mini-Mental State Examination score (β= -2.790, p <  0.001) or clinical diagnosis of dementia (β= -3.145, p <  0.001). These results were similar for men and women.

Conclusion: Our results showed a negative association between homocysteine and HGS after adjustment for cognitive function. Our findings strengthen the assumed association between homocysteine and HGS. Further research is needed to determine whether lower homocysteine levels lead to prevent muscle weakness.
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http://dx.doi.org/10.3233/JAD-210083DOI Listing
June 2021

Midbrain Slice Culture as an Ex Vivo Analysis Platform for Parkinson's Disease.

Methods Mol Biol 2021 ;2322:111-117

Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan.

Parkinson's disease (PD) is a neurodegenerative disorder that affects the motor system. PD is characterized by the accumulation of intracellular protein aggregates, Lewy bodies, and Lewy neurites, composed primarily of the protein α-synuclein. Thus, PD is classified as the most common synucleinopathy. The motor symptoms of the disease result from the death of cells in the region of the midbrain, leading to a dopamine deficit. While the cause of PD is unknown, it is believed to involve both inherited and environmental factors. PD has been extensively studied using in vitro and in vivo models; however, some discrepancy is observed in these results. In order to analyze progressive neurodegenerative disease, experimental platform amenable to continuous observation and experimental manipulation is required. In this chapter, we provide a practical method to slice and cultivate the midbrain tissue as an ex vivo experimental model.
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http://dx.doi.org/10.1007/978-1-0716-1495-2_11DOI Listing
January 2021

Efficacy of group-based multi-component psycho-education for caregivers of people with dementia: A randomized controlled study.

Geriatr Gerontol Int 2021 Jul 4;21(7):561-567. Epub 2021 May 4.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Aichi, Japan.

Aim: The aim of this study was to examine the ability of a group-based multi-component psycho-educational intervention (GMC-PEI) to reduce depression, and improve caregiving appraisals, coping skills of informal caregivers and the condition of people with dementia.

Methods: In this randomized controlled and blinded trial, we enrolled 54 informal caregivers of people with dementia visiting the Japan National Center of Geriatrics and Gerontology, and divided them into GMC-PEI and control groups. The intervention group received a 12-week GMC-PEI program that included six 2-h structured sessions to enhance their knowledge of dementia, caregiving skills and coping skills. The control group received leaflets containing information about dementia. We evaluated caregivers' depression, caregiving time, subjective burden, caregiving appraisal and care coping skills. We also evaluated people with dementia at baseline and 12 weeks, and reassessed 20 participants from the intervention group at 24 and 48 weeks.

Results: The GMC-PEI significantly improved depression, positive appraisals of fulfillment in caregiving, affection for care recipients, self-growth and coping skills, such as seeking formal support. Depression, fulfillment and affection for people with dementia showed a peak improvement at 24 weeks; formal support-seeking showed a linear improvement throughout the 48-week follow-up period.

Conclusions: The group-based multi-component psycho-educational intervention reduced depression, improved self-appraisal and enhanced coping skills in caregivers. However, emotional enhancements dissipated sooner than support-seeking skills, suggesting that caregivers should be reviewed every 12-24 weeks. Geriatr Gerontol Int 2021; 21: 561-567.
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http://dx.doi.org/10.1111/ggi.14175DOI Listing
July 2021

Possibility of Using Quantitative Assessment with the Cube Copying Test for Evaluation of Visuo-spatial Function in Patients with Alzheimer's Disease.

Prog Rehabil Med 2021 29;6:20210021. Epub 2021 Apr 29.

Department of Rehabilitation Medicine I, School of Medicine, Fujita Health University, Toyoake, Japan.

Objectives: The aim of this study was to investigate the clinical usefulness of the Cube Copying Test (CCT) for quantitative assessment of visuo-spatial function in patients with Alzheimer's disease (AD).

Methods: The CCT, Raven's Colored Progressive Matrices (RCPM), and other neuropsychological tests were administered to 152 AD outpatients. For the quantitative assessment of CCT, we scored the points of connection (POC) and the number of plane-drawing errors (PDE) and categorized the pattern classification (PAC). We also measured Functional Assessment Staging (FAST) to assess the severity of AD. The relationships among CCT, RCPM, and FAST were then analyzed.

Results: The mean POC and PDE scores were 2.7 and 3.6, respectively, and the median PAC score was 6.0. PDE and PAC showed a linear relationship, but POC and PDE, and POC and PAC did not. Each component of CCT showed a significant correlation with RCPM scores. PDE and PAC had closer correlations with RCPM scores than POC did. The PDE and PAC results were significantly different among most of the FAST stages.

Conclusions: Quantitative assessment using CCT may be effective for the quick determination of the visuo-spatial function in AD patients.
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http://dx.doi.org/10.2490/prm.20210021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080165PMC
April 2021

Functional categories based on cognition and activities of daily living predict all-cause mortality in older adults with diabetes mellitus: The Japanese Elderly Diabetes Intervention Trial.

Geriatr Gerontol Int 2021 Jun 22;21(6):512-518. Epub 2021 Apr 22.

Department of Diabetes, Metabolism and Endocrinology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.

Aim: Although the glycemic target in older diabetes patients is based on cognition, activities of daily living and multimorbidity in the Japanese guideline, evidence of the relationships is limited. Thus, we aimed to assess the relationship between functional category and mortality in older people with diabetes.

Methods: We evaluated the data of 843 older diabetes patients in a 6-year prospective study, and the association between functional categories and all-cause mortality. The patients were divided into three functional categories based on cognition, instrumental activities of daily living and basic activities of daily living using the Mini-Mental State Examination, Tokyo Metropolitan Institute of Gerontology Index of Competence and Barthel Index at baseline, respectively (model 1). Those with multimorbidity (≥4 of 8 morbidities) were classified into category III (model 2). The functional category assessed using eight items from the Tokyo Metropolitan Institute of Gerontology Index of Competence and Barthel Index was also constructed (model 3). Hazard ratios and 95% confidence intervals were calculated in the Cox regression analysis using age, sex, body mass index, glycated hemoglobin level, total cholesterol level, estimated glomerular filtration rate and frequency of severe hypoglycemia as covariates.

Results: During the 6-year follow up, 64 incident mortalities occurred. The hazard ratios for mortality in categories II and III (as the reference of category I) were 1.83 (95% confidence interval 1.06-3.14, P = 0.030) and 3.05 (95% confidence interval 1.12-8.26, P = 0.029) after adjustment for covariates, respectively (model 1). Models 2 and 3 showed similar associations between functional category and mortality.

Conclusions: The functional categories predicted all-cause mortality in older adults with diabetes. Geriatr Gerontol Int 2021; 21: 512-518.
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http://dx.doi.org/10.1111/ggi.14171DOI Listing
June 2021

Impact of the COVID-19 pandemic on statistical design and analysis plans for multidomain intervention clinical trials: Experience from World-Wide FINGERS.

Alzheimers Dement (N Y) 2021 11;7(1):e12143. Epub 2021 Mar 11.

Departments of Internal Medicine and Biostatistics and Data Science Wake Forest School of Medicine Winston-Salem North Carolina USA.

Introduction: The coronavirus disease-19 (COVID-19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions.

Methods: World-Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at-risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report on experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials.

Results: The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessment protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within-site stratification, interim power projections, and sensitivity analyses.

Discussion: Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The world-wide network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.
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http://dx.doi.org/10.1002/trc2.12143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948446PMC
March 2021

Sustained mood improvement by the positive photo appreciation program in older adults.

Int J Geriatr Psychiatry 2021 06 18;36(6):970-971. Epub 2021 Jan 18.

National Center for Geriatrics and Gerontology, Obu, Japan.

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http://dx.doi.org/10.1002/gps.5493DOI Listing
June 2021

The Association between Cerebral Small Vessel Disease and the Gut Microbiome: A Cross-Sectional Analysis.

J Stroke Cerebrovasc Dis 2021 Mar 7;30(3):105568. Epub 2021 Jan 7.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan; Department of Cognition and Behavioural Science, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.

Background: Recent studies have demonstrated an association between the gut microbiome and cognitive function. However, the associations between the gut microbiome and brain parenchyma damage, and their underlying mechanisms, remain unclear.

Materials And Methods: We performed a cross-sectional sub-analysis using data from our prospective cohort study to determine the association between the gut microbiome and cerebral small vessel disease (SVD). We assessed patient demographics, risk factors, cognitive function, brain imaging, voxel-based specific regional analysis system for Alzheimer's Disease (VSRAD, indicating brain atrophy), and the gut microbiome as indicated by enterotypes and faecal microbiome metabolites. We then analysed the associations between total SVD scores, cognitive function, and the gut microbiome.

Results: We analysed data from 87 patients without dementia or a history of stroke, 64 of whom exhibited mild cognitive impairment. Higher total SVD scores were associated with cognitive decline and behavioural and psychological symptoms. Compared with all other patients, patients with enterotype I (Bacteroides >30%) were more likely to have cognitive decline (median scores: Mini-Mental State Examination, 25 vs. 27, P = 0.047; Clinical Dementia Rating-Sum of Boxes, 1.5 vs. 0.5, P = 0.002) and present with cerebral SVD and high VSRAD scores (1.01 vs. 0.57, P = 0.012). Furthermore, faecal metabolites were significantly higher in patients with higher total SVD scores compared with those with lower scores. Multivariable logistic regression analyses indicated that certain gut microbiomes may double the risk of white matter hyperintensity.

Conclusions: The gut microbiome is associated with cerebral SVD.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105568DOI Listing
March 2021

Mild hyponatremia is associated with low skeletal muscle mass, physical function impairment, and depressive mood in the elderly.

BMC Geriatr 2021 01 6;21(1):15. Epub 2021 Jan 6.

Departments of Community Healthcare and Geriatrics, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya City, Aichi, 466-8550, Japan.

Background: Mild hyponatremia (serum sodium 130-135 mEq/L) is a common electrolyte disorder in the elderly. However, its association with both sarcopenia and cognitive function remains to be clarified. Therefore, here we investigated the association of mild hyponatremia with skeletal muscle mass, physical function, and cognitive function in the elderly.

Methods: We enrolled 75 participants with mild hyponatremia and 2907 with normonatremia (serum sodium, 136-145 mEq/L) aged ≥70 years who visited the Memory Disorder Outpatient Center of Japan's National Center for Geriatrics and Gerontology. Skeletal muscle mass index (SMI), grip strength (GS), walking speed (WS), one-leg standing (OLS) test times, and neuropsychological test scores were determined.

Results: One-way analysis of covariance showed that elderly participants with mild hyponatremia had lower SMI (7.1 ± 0.2, 7.2 ± 0.2 kg/m, p = 0.04), weaker GS (19.1 ± 1.9 vs 21.4 ± 1.8 kg, p = 0.01), slower WS (0.9 ± 0.1 vs 1.1 ± 0.1 m/s, p = 0.001), and higher GDS- 15 score (6.4 ± 0.9 vs 5.2 ± 0.9, p = 0.002) than those with normonatremia. Multiple logistic regression analysis indicated that mild hyponatremia was independently associated with sarcopenia (odds ratio [OR]: 2.2, p = 0.02), slower WS (OR: 5.3, p = 0.04) and shorter OLS time (OR: 2.5, p = 0.02) as well as with severe depressive mood (OR: 2.6 p = 0.006) but not with SMI (OR: 1.6, p = 0.2) or GS (OR: 1.9, p = 0.09).

Conclusions: Our results suggest that elderly people with even mild hyponatremia had physical function impairment and depressive mood.
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http://dx.doi.org/10.1186/s12877-020-01955-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788730PMC
January 2021

Functional Decline and Body Composition Change in Older Adults With Alzheimer Disease: A Retrospective Cohort Study at a Japanese Memory Clinic.

Alzheimer Dis Assoc Disord 2021 Jan-Mar 01;35(1):36-43

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Aichi.

Background: There is a dearth of longitudinal data on body composition, function, and physical performance in persons with Alzheimer's disease (AD).

Objectives: The aim was to describe the trajectories of function, body composition, and physical performance in older adults with AD.

Methods: In this retrospective cohort study, data were collected from older adults (n=1402) diagnosed with AD (mean age: 78.1 y old, women: 69.3%). Cognitive function was assessed using the mini-mental state examination. Proxy-reported instrumental and basic activities of daily living were assessed using the Lawton and Barthel indexes. Body composition was assessed using bioelectrical impedance analysis. Physical performance was assessed using the timed up and go test and grip strength.

Results: Median (interquartile range) of follow-up time was 2.2 (1.2 to 3.6) years. Participants' mini-mental state examination score, Barthel index, and Lawton index declined over time. Skeletal muscle mass index and physical performance (timed up and go test and grip strength) decreased, while fat mass index increased with time. No significant changes or slight decline in weight and body mass index was observed.

Conclusions: Muscle mass and physical performance are likely to decline in older adults with AD. Clinicians should assess muscle mass and physical performance trajectories regularly in these patients and intervene appropriately.
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http://dx.doi.org/10.1097/WAD.0000000000000426DOI Listing
October 2019

Prognosis prediction model for conversion from mild cognitive impairment to Alzheimer's disease created by integrative analysis of multi-omics data.

Alzheimers Res Ther 2020 11 10;12(1):145. Epub 2020 Nov 10.

Medical Genome Center, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.

Background: Mild cognitive impairment (MCI) is a precursor to Alzheimer's disease (AD), but not all MCI patients develop AD. Biomarkers for early detection of individuals at high risk for MCI-to-AD conversion are urgently required.

Methods: We used blood-based microRNA expression profiles and genomic data of 197 Japanese MCI patients to construct a prognosis prediction model based on a Cox proportional hazard model. We examined the biological significance of our findings with single nucleotide polymorphism-microRNA pairs (miR-eQTLs) by focusing on the target genes of the miRNAs. We investigated functional modules from the target genes with the occurrence of hub genes though a large-scale protein-protein interaction network analysis. We further examined the expression of the genes in 610 blood samples (271 ADs, 248 MCIs, and 91 cognitively normal elderly subjects [CNs]).

Results: The final prediction model, composed of 24 miR-eQTLs and three clinical factors (age, sex, and APOE4 alleles), successfully classified MCI patients into low and high risk of MCI-to-AD conversion (log-rank test P = 3.44 × 10 and achieved a concordance index of 0.702 on an independent test set. Four important hub genes associated with AD pathogenesis (SHC1, FOXO1, GSK3B, and PTEN) were identified in a network-based meta-analysis of miR-eQTL target genes. RNA-seq data from 610 blood samples showed statistically significant differences in PTEN expression between MCI and AD and in SHC1 expression between CN and AD (PTEN, P = 0.023; SHC1, P = 0.049).

Conclusions: Our proposed model was demonstrated to be effective in MCI-to-AD conversion prediction. A network-based meta-analysis of miR-eQTL target genes identified important hub genes associated with AD pathogenesis. Accurate prediction of MCI-to-AD conversion would enable earlier intervention for MCI patients at high risk, potentially reducing conversion to AD.
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http://dx.doi.org/10.1186/s13195-020-00716-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656734PMC
November 2020

Determinants and impact of physical impairment in patient-reported outcomes among older patients with type 2 diabetes mellitus in Japan.

Curr Med Res Opin 2021 Mar 23;37(3):393-402. Epub 2020 Nov 23.

Kita-Harima Medical Center,Ono,Japan.

Objective: To investigate the predictive factors associated with physical impairment among older patients with type 2 diabetes mellitus (T2DM) in Japan and to examine the potential impact of physical impairment on patient-reported health outcomes in this population.

Methods: A cross-sectional analysis was conducted using patient-reported data from the 2012-2014 Japan National Health and Wellness Survey. Physical impairment was measured using the Physical Component Summary (PCS) score of the Short-Form 36-Item Health Survey (SF-36) three-component model (using Japanese norms). Older T2DM patients (≥65 years old;  = 1511) were dichotomized into physically impaired (PCS ≤ 25th percentile;  = 378) and non-physically impaired (PCS > 25th percentile;  = 1133). Work productivity (absenteeism, presenteeism and overall work impairment), activity impairment and healthcare resource utilization were compared between these groups.

Results: Age, female sex, low and high body mass index (BMI), diabetes-related complications, cardiovascular events, unawareness of having hypoglycemic events in the past 3 months, and lack of regular exercise were significant factors associated with physical impairment in multivariable analysis. The physically impaired group reported significantly more regular outpatient visits (13.48 vs. 10.16, respectively,  < .001), 1% or greater absenteeism (16.7% vs. 4.1%,  = .005), greater presenteeism (27.8% vs. 12.2%,  = .001), overall work impairment (30.0% vs. 13.0%,  = .001) and overall activity impairment (39.5% vs. 17.2%,  .001) than the non-physically-impaired group after adjusting for covariates.

Conclusions: This study identified age, BMI, diabetes-related comorbidities, history of cardiovascular events and lack of exercise as key predictors associated with physical impairment in older patients with T2DM in Japan, which predicted low work productivity as well as activity impairment. This study provides support that physical impairment in patients with T2DM may lead to low work productivity and activity impairment.

Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1846170.
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http://dx.doi.org/10.1080/03007995.2020.1846170DOI Listing
March 2021

A novel MRI-based predictive index can identify patients suitable for preservation of the nipple-areola complex in breast reconstructive surgery.

Eur J Surg Oncol 2021 02 23;47(2):225-231. Epub 2020 Aug 23.

Department of Pathology, Saitama Medical Center, Saitama, 330-0074, Japan.

Introduction: Accurately predicting nipple-areola complex (NAC) involvement in breast cancer is necessary for identifying patients who may be candidates for a nipple-sparing mastectomy. Although multiple risk factors are indicated in the guidelines, it is difficult to predict NAC involvement (NAC-i) preoperatively even if these factors are evaluated individually. This study aimed to develop a more accurate and practical preoperative NAC-i prediction model using magnetic resonance imaging (MRI).

Materials And Methods: All tumors in 252 patients were evaluated using postcontrast T1-weighted subtraction on MRI.

Results: The receiver operating characteristic curves identified cut-off values for tumor size and tumor-to-nipple distance (TND) as 4 cm and 1.2 cm, respectively. Multivariate analysis demonstrated that TND (p < 0.001), ductal enhancement extending to the nipple (DEEN) (p < 0.001), and nipple enhancement (NE) (p = 0.005) were independent clinical risk factors for pathological NAC-i. A formula was constructed using odds ratios for these three independent preoperative risk factors in multivariate analysis: the MRI-based NAC-i predictive index (mNACPI) = TND × 4 + DEEN × 3 + NE × 1. A total score of ≤4 points was defined as low risk and ≥5 points as high risk. NAC-i rates were 2.4% in the low-risk group and 89.4% in the high-risk group; a significant correlation was observed between the risk group and permanent pathological NAC-i (p < 0.001). Assuming that the NAC was preserved in low-risk patients and resected in high-risk patients, NAC-i was verified using the mNACPI.

Conclusion: mNACPI may contribute greatly to the improvement of selecting suitable patients for NAC preservation in breast reconstructive surgery while maintaining oncological safety.
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http://dx.doi.org/10.1016/j.ejso.2020.08.010DOI Listing
February 2021

[In Memoriam: Dr. Koichi Yokono, Professor Emeritus, Kobe University].

Authors:
Takashi Sakurai

Nihon Ronen Igakkai Zasshi 2020 ;57(3):Mourning3

National Center for Longevity Medicine.

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http://dx.doi.org/10.3143/geriatrics.57.Mourning3DOI Listing
April 2021

An evaluation of the amyloid cascade model using in vivo positron emission tomographic imaging.

Psychogeriatrics 2021 Jan 11;21(1):14-23. Epub 2020 Aug 11.

Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan.

Aim: The amyloid cascade hypothesis posits that the accumulation of amyloid β (Aβ) is the triggering factor for Alzheimer's disease, which consecutively induces aggregation of tau, synaptic loss, and cell death. Most experimental and clinical evidence supports this model, but the available data are largely qualitative. Here, we tested the amyloid cascade hypothesis by using in vivo evaluation of positron emission tomography and magnetic resonance imaging.

Methods: Path analysis was used to estimate the relationships among Aβ accumulation (PiB standardized uptake value ratio (SUVR)), tau aggregation and its related neuroinflammation (THK5351 SUVR), grey matter atrophy in the medial temporal region, and memory function in Aβ-positive subjects. We also performed additional regression analyses to evaluate the effect of Aβ on the toxicity of tau aggregation/neuroinflammation.

Results: Path analysis supported our hypothesized model: Aβ accumulation affected tau aggregation/neuroinflammation in the medial temporal region, and these pathological changes caused of the grey matter atrophy and memory dysfunction. In separate regression analyses, THK5351 SUVR had a significant effect on grey matter atrophy only in PiB-positive subjects. The analysis of the interaction effect showed that the effects of THK5351 SUVR on grey matter atrophy were significantly different between PiB-positive and PiB-negative groups. When we included the effect of being an apolipoprotein E ε4 carrier as a covariate, the interaction effect remained significant.

Conclusion: Our in vivo evaluation of positron emission tomographic and magnetic resonance imaging data supported the amyloid cascade hypothesis. In addition, it indicated that Aβ not only accelerates tau aggregation/neuroinflammation but promotes its toxicity. Our findings showed the importance of understanding the role and therapeutic potential of the interaction between amyloid and tau aggregation/neuroinflammation in Alzheimer's disease.
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http://dx.doi.org/10.1111/psyg.12589DOI Listing
January 2021

Identification of potential blood biomarkers for early diagnosis of Alzheimer's disease through RNA sequencing analysis.

Alzheimers Res Ther 2020 07 16;12(1):87. Epub 2020 Jul 16.

Medical Genome Center, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, 474-8511, Aichi, Japan.

Background: With demographic shifts toward older populations, the number of people with dementia is steadily increasing. Alzheimer's disease (AD) is the most common cause of dementia, and no curative treatment is available. The current best strategy is to delay disease progression and to practice early intervention to reduce the number of patients that ultimately develop AD. Therefore, promising novel biomarkers for early diagnosis are urgently required.

Methods: To identify blood-based biomarkers for early diagnosis of AD, we performed RNA sequencing (RNA-seq) analysis of 610 blood samples, representing 271 patients with AD, 91 cognitively normal (CN) adults, and 248 subjects with mild cognitive impairment (MCI). We first estimated cell-type proportions among AD, MCI, and CN samples from the bulk RNA-seq data using CIBERSORT and then examined the differentially expressed genes (DEGs) between AD and CN samples. To gain further insight into the biological functions of the DEGs, we performed gene set enrichment analysis (GSEA) and network-based meta-analysis.

Results: In the cell-type distribution analysis, we found a significant association between the proportion of neutrophils and AD prognosis at a false discovery rate (FDR) < 0.05. Furthermore, a similar trend emerged in the results of routine blood tests from a large number of samples (n = 3,099: AD, 1,605; MCI, 994; CN, 500). In addition, GSEA and network-based meta-analysis based on DEGs between AD and CN samples revealed functional modules and important hub genes associated with the pathogenesis of AD. The risk prediction model constructed by using the proportion of neutrophils and the most important hub genes (EEF2 and RPL7) achieved a high AUC of 0.878 in a validation cohort; when further applied to a prospective cohort, the model achieved a high accuracy of 0.727.

Conclusions: Our model was demonstrated to be effective in prospective AD risk prediction. These findings indicate the discovery of potential biomarkers for early diagnosis of AD, and their further improvement may lead to future practical clinical use.
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http://dx.doi.org/10.1186/s13195-020-00654-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367375PMC
July 2020

World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia.

Alzheimers Dement 2020 07 5;16(7):1078-1094. Epub 2020 Jul 5.

Unit for Early and Exploratory Clinical Development, The University of Tokyo Hospital, Tokyo, Japan.

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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http://dx.doi.org/10.1002/alz.12123DOI Listing
July 2020

Optimization of stereospecific targeting technique for selective production of monoclonal antibodies against native ephrin type-A receptor 2.

J Immunol Methods 2020 Sep - Oct;484-485:112813. Epub 2020 Jun 25.

Division of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Kurima-Machiya-cho, Tsu, Mie 514-8507, Japan. Electronic address:

High priority stereospecific targeting (SST) featuring selective production of conformation-specific monoclonal antibodies was directed against a native receptor, EphA2 (ephrin type-A receptor 2). A critical point for this technology is selection of sensitized B lymphocytes by antigen-expressing myeloma cells through their B-cell receptors (BCRs). The essential point is that antigens expressed on myeloma cells retain their original three dimensional structures and only these are recognized. Immunization with recombinant plasmid vectors as well as antigen-expressing CHO cells elicits enhanced sensitization of target B lymphocytes generating stereospecific antibodies. More than 24% of hybridoma-positive wells were identified to be cell-ELISA positive, confirming high efficiency. IgG-typed conformation-specific monoclonal antibodies could be also produced by the SST technique. Immunofluorescence analysis confirmed specific binding of sensitized B lymphocytes to antigen-expressing myeloma cells. Furthermore, stereospecific monoclonal antibodies to EphA2 specifically recognized EphA2-expressing cancer cells as demonstrated by Cell-ELISA. In the present study, we were able to develop priority technology for selective production of conformation-specific monoclonal antibodies against an intact receptor EphA2, known to be overexpressed by epithelial tumor cells of multiple cancer types.
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http://dx.doi.org/10.1016/j.jim.2020.112813DOI Listing
March 2021

Impact of Cognitive Frailty on Activities of Daily Living, Cognitive Function, and Conversion to Dementia Among Memory Clinic Patients with Mild Cognitive Impairment.

J Alzheimers Dis 2020 ;76(3):895-903

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan.

Background: Very few studies have investigated the impact of cognitive frailty in clinical settings, especially in memory clinic populations.

Objective: To examine the impact of cognitive frailty on activities of daily living (ADL), cognitive function, and conversion to dementia among memory clinic patients with mild cognitive impairment (MCI).

Methods: The subjects of this retrospective study were 248 MCI patients (mean age, 76.3±5.4 years; females, 60.9%). All subjects completed a comprehensive geriatric assessment at baseline and at least one assessment during 3-year follow-up. Frailty was defined by generating a frailty index (FI), and MCI patients with frailty (FI≥0.25) were considered to represent cognitive frailty. As primary outcomes, the Barthel Index, Mini-Mental State Examination, and incident dementia were evaluated during follow-up. At baseline, patients were assessed for apolipoprotein E (APOE) phenotype. A linear mixed model, as well as a Cox proportional hazards regression model with adjustment for confounding variables, was performed.

Results: Of these patients, 75 (30.2%) were classified as cognitive frail. APOEɛ4 carriers accounted for 26.7% of those with cognitive frailty and 44.5% of those without (p = 0.008). Cognitive frail patients showed a faster ADL decline (estimate, -1.04; standard error, 0.38; p = 0.007) than patients without cognitive frailty. Cognitive frailty was not associated with cognitive decline and incident dementia.

Conclusion: Our findings demonstrated cognitive frailty increases the risk of dependence but not cognitive outcomes. Cognitive frailty may have heterogeneous conditions, including APOEɛ4-related pathologies, which may affect the cognitive trajectories of patients with MCI.
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http://dx.doi.org/10.3233/JAD-191135DOI Listing
June 2021

Relationship between dementia and gut microbiome-associated metabolites: a cross-sectional study in Japan.

Sci Rep 2020 05 18;10(1):8088. Epub 2020 May 18.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Aichi, Japan.

Dysregulation of the gut microbiome is associated with dementia. However, the relationship between microbiome-associated metabolites and dementia has yet to be identified. Outpatients visiting a memory clinic in Japan enrolled in this cross-sectional study; 107 subjects were eligible for the study, 25 of which had dementia. We collected demographics, activities of daily living, risk factors, cognitive function, and brain imaging data. The gut microbiome was assessed using terminal restriction fragment length polymorphism analysis. Concentrations of faecal metabolite were measured. We used multivariable logistic regression analyses to identify whether metabolites were independently related to dementia. The concentrations of metabolites were significantly different between subjects with and those without dementia. Every 1 standard deviation increment in faecal ammonia concentration was associated with around a 1.6-fold risk for the presence of dementia. A higher faecal lactic acid concentration was related to a lower risk of dementia, by around 60%. A combination of higher faecal ammonia and lactic acid concentrations was indicative of the presence of dementia, and had a similar predictive value as traditional biomarkers of dementia. Thus, faecal ammonia and lactic acid are related to dementia, independently of the other risk factors for dementia and dysregulation of the gut microbiome.
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http://dx.doi.org/10.1038/s41598-020-65196-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235213PMC
May 2020

Nicotinamide mononucleotide administration after sever hypoglycemia improves neuronal survival and cognitive function in rats.

Brain Res Bull 2020 07 5;160:98-106. Epub 2020 May 5.

National Center for Geriatrics and Gerontology, Japan.

Hypoglycemia-induced brain injury is a potential complication of insulin therapy in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may lead to neuronal death and cognitive impairment even after glucose normalization. Oxidative stress and the activation of poly (ADP-ribose) polymerase-1 (PARP-1) are key events in this cascade. The production of reactive oxygen species (ROS) induces DNA damage and the consequent PARP-1 activation, which depletes NAD and ATP, resulting in brain injury. One of the key precursors of NAD is nicotinamide mononucleotide (NMN), which is converted to NAD and reduces production of ROS. Here we investigated whether NMN could reduce brain injury after severe hypoglycemia. We used a rat model of insulin-induced severe hypoglycemia and injected NMN (500 mmg/kg, i.p., one week) following 30 min of severe hypoglycemia, at the time of glucose administration. One week after severe hypoglycemia, hippocampal long-term potentiation (LTP), an electrophysiogic assay of synaptic plasticity, was examined and neuronal damage was assessed by Hematoxylin-Eosin staining. ROS accumulation, PARP-1 activation, NAD and ATP levels in hippocampus were also measured. Cognitive function was assessed using the Morris water maze 6 weeks after severe hypoglycemia. The addition of NMN reduced neuron death by 83 ± 3% (P < 0.05) after severe hypoglycemia. The hippocampal LTP was significantly reduced by severe hypoglycemia but showed recovery in the NMN addition group. NMN treatment also attenuated the severe hypoglycemia-induced spatial learning and memory impairment. Mechanically, we showed that NMN administration decreased ROS accumulation, suppressed PARP-1 activation, and restored levels of NAD and ATP in hippocampus. All these protective effects were reversed by 3-acetylpyridine (3-AP), which generates inactive NAD. In summary, NMN administration following severe hypoglycemia could ameliorate neuronal damage and cognitive impairment caused by severe hypoglycemia. These results suggest that NMN may be a promising therapeutic drug to prevent hypoglycemia-induced brain injury.
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http://dx.doi.org/10.1016/j.brainresbull.2020.04.022DOI Listing
July 2020

Redox injectable gel protects osteoblastic function against oxidative stress and suppresses alveolar bone loss in a rat peri-implantitis model.

Acta Biomater 2020 07 27;110:82-94. Epub 2020 Apr 27.

Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan; Master's School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8573, Japan; Center for Research in Isotopes and Environmental Dynamics (CRiED), University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8573, Japan. Electronic address:

Dental implant surgery is a routine treatment in clinical dentistry. However, implant surgery is associated with an increased risk of bacterially induced peri-implantitis and the production of reactive oxygen species (ROS), with no established treatment. We recently designed a new redox injectable gel (RIG) containing nitroxide radicals for the treatment of peri-implantitis. Here, we investigated the antioxidative effect of RIG as a preventive therapy for ROS-associated peri-implantitis in a rat model of alveolar bone resorption and in vitro. In each rat, the maxillary first molar tooth was replaced with a screw-type implant, and rats were assigned to one of four groups: an implant alone, an implant with infection, implant with infection and treatment with nRIG (a non-nitroxide radical-containing injectable hydrogel) or RIG. We confirmed the long-term retention of RIG in the peri-implant region and found that RIG significantly protected the alveolar bone volume and decreased lipid peroxidation. In culture, we found that RIG restored osteoblast proliferation and differentiation in the presence of hydrogen peroxide (HO)-induced oxidative stress. Moreover, using a malondialdehyde assay of lipid peroxidation, we found that RIG suppressed oxidative stress in HO-treated rat osteoblasts. Overall, RIG is anticipated as a prophylactic treatment for peri-implantitis and may help preserve oral function. Statement of Significance 1. Implant surgery is associated with an increased risk of bacterially induced peri-implantitis and the production of reactive oxygen species (ROS). We designed a novel redox injectable gel (RIG) containing nitroxide radicals for the treatment of peri-implantitis. In this study, we investigated the antioxidative effect of RIG as a preventive therapy for ROS-associated peri-implantitis in a rat model and in vitro. 2. We showed that treatment with RIG reduces oxidative damage in a rat peri-implantitis model, protecting against bone resorption and a loss of bone density. We showed that RIG inhibits HO-mediated decreases in proliferation, osteoblast differentiation, and mineralization, and also against lipid peroxidation in vitro. Our results indicate that RIG has an antioxidative effect of peri-implantitis.
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http://dx.doi.org/10.1016/j.actbio.2020.04.003DOI Listing
July 2020

Conformational diversity of dynactin sidearm and domain organization of its subunit p150.

Mol Biol Cell 2020 06 2;31(12):1218-1231. Epub 2020 Apr 2.

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan.

Dynactin is a principal regulator of the minus-end directed microtubule motor dynein. The sidearm of dynactin is essential for binding to microtubules and regulation of dynein activity. Although our understanding of the structure of the dynactin backbone (Arp1 rod) has greatly improved recently, structural details of the sidearm subcomplex remain elusive. Here, we report the flexible nature and diverse conformations of dynactin sidearm observed by electron microscopy. Using nanogold labeling and deletion mutant analysis, we determined the domain organization of the largest subunit p150 and discovered that its coiled-coil (CC1), dynein-binding domain, adopted either a folded or an extended form. Furthermore, the entire sidearm exhibited several characteristic forms, and the equilibrium among them depended on salt concentrations. These conformational diversities of the dynactin complex provide clues to understanding how it binds to microtubules and regulates dynein.
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http://dx.doi.org/10.1091/mbc.E20-01-0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353146PMC
June 2020

Delving into the caregiver burden associated basic activity of daily living disability among caregivers of patients with mild-to-moderate Alzheimer's disease.

Geriatr Gerontol Int 2020 Mar;20(3):263-265

Department of Public Health, Kobe University Graduate School of Health Sciences, Kobe, Japan.

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http://dx.doi.org/10.1111/ggi.13862DOI Listing
March 2020

Utility of the periareolar incision technique for breast reconstructive surgery in patients with breast cancer.

Surg Today 2020 Sep 12;50(9):1008-1015. Epub 2020 Feb 12.

Division of Pathology, Saitama Medical Center, Saitama, 330-0074, Japan.

Purpose: Periareolar incisions for nipple-sparing mastectomy offer the advantages of smaller inconspicuous wounds and easier resection below the nipple-areolar complex. However, they provide a narrow surgical field, which complicates the procedure and carries a risk of nipple necrosis. This study evaluated the clinical outcomes and safety of periareolar incisions for breast reconstructive surgery in patients with breast cancer.

Methods: The study included 181 patients with primary operable breast cancer who underwent nipple-sparing mastectomy for reconstructive breast procedures without intraoperative nipple-areolar complex resection. The clinical outcomes and complications were retrospectively evaluated. The recurrence-free survival was compared using Kaplan-Meier curves.

Results: Nipple-sparing mastectomy was performed via inframammary fold and periareolar incisions in 31 and 150 patients, respectively. There were no significant differences in clinical outcomes related to surgery, frequency of complications, nipple necrosis (inframammary fold incision vs. periareolar incision: 0% vs. 3.3%, P = 0.590), or the recurrence-free survival (P = 0.860) between the 2 groups.

Conclusion: Our results showed that the clinical outcomes and complication rates of periareolar incisions for breast reconstruction were equivalent to those of inframammary fold incisions, suggesting that the periareolar incision technique for breast reconstructive surgery may safely improve cosmetic outcomes if done with adequate care.
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http://dx.doi.org/10.1007/s00595-020-01975-yDOI Listing
September 2020
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