Publications by authors named "Yuji Takahashi"

383 Publications

The influence of edema on the bisoprolol blood concentration after bisoprolol dermal patch application: A case-control study.

Medicine (Baltimore) 2021 Sep;100(38):e27354

Department of Emergency and Critical Care Medicine, Hitachi General Hospital, 2-1-1, Jonan-cho, Hitachi, Ibaraki, Japan.

Background: Beta-blocking is important for critically ill patients. Although some patients are required to continue taking beta-blockers after they no longer need critical care, some of these patients have impaired swallowing abilities. Bisoprolol dermal patches have recently been introduced and appear to be a good alternative to oral bisoprolol tablets. However, it is still unclear whether the pharmacodynamics of such patches are affected by edema in patients who have experienced critical care. This study aimed to clarify the effects of systemic edema on beta-blocker absorption from dermal patches in critically ill patients.

Method: Patients who exhibited tachycardia and impaired swallowing function after critical care were included in this study. They were assigned to either the edema group (n = 6) or no edema group (n = 6) depending on the presence/absence of edema in the lower extremities. A bisoprolol dermal patch was pasted onto each subject, and the blood bisoprolol concentration was checked at 8 timepoints over the next 24 hours. The area under the serum concentration time curve, maximum concentration observed (Cmax), and time of maximum concentration observed were also examined.

Result: The mean blood bisoprolol concentrations of the 2 groups were not significantly different at 2, 4, 6, 8, 10, 12, 16, or 24 hours after the patch application. The area under the serum concentration time curve and maximum concentration observed were not different between the groups. The mean heart rates of the 2 groups were not significantly different at 6, 12, or 24 hours after the patch application (Student t test, P = .0588, P = .1080, and P = .2322, respectively).

Conclusion: In this study, the blood concentration of bisoprolol and its heart rate-reducing effects after bisoprolol dermal patch application might not be affected by systemic edema in the lower extremities.
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http://dx.doi.org/10.1097/MD.0000000000027354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462653PMC
September 2021

Operation of the percutaneous endoscopic gastrostomy-jejunostomy tube without endoscopy in patients with Parkinson's disease on levodopa-carbidopa intestinal gel infusion therapy.

Clin Park Relat Disord 2020 17;3:100079. Epub 2020 Nov 17.

Department of Neurology, National Center Hospital, Parkinson's Disease & Movement Disorders Center, National Center of Neurology and Psychiatry, Japan.

Introduction: Tube-related adverse events (AEs) occur frequently in patients with Parkinson's disease (PD) receiving levodopa-carbidopa intestinal gel therapy. Endoscopy has become evasive since the beginning of the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to evaluate methods that use the percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tubes without endoscopy.

Methods: We included 19 patients in this study. The contrast agent was injected into the PEG-J tube to clarify the AEs related to the use of the tube. When the kink of the PEG-J tube was found, it was pulled approximately 5-10 cm. When placing or replacing the PEG-J tube, the percutaneous endoscopic gastrostomy (PEG) tube was pushed into the gastrostomy hole to bring its tip closer to the pylorus before a new PEG-J tube was inserted into it.

Results: The mean patient age was 63.1 ± 9.9 years, while the mean duration of PD was 16.7 ± 6.3 years. Tube-related AEs included PEG-J tube kinks (32 events), connector failures (20 events), and PEG-J tube entanglements without/with bezoars (9 events/5 events). All PEG-J tube kinks were resolved by tube manipulation with a fluoroscopic guide. In 66 of 85 events (77.6%), the PEG-J tube was placed or replaced without endoscopy. We believe that the use of the antispasmodic agent just before PEG-J operation reduced this rate.

Conclusion: Our methods were able to resolve most AEs associated with PEG-J tube use without endoscopy.
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http://dx.doi.org/10.1016/j.prdoa.2020.100079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298846PMC
November 2020

Grip Strength Correlates with Mental Health and Quality of Life after Critical Care: A Retrospective Study in a Post-Intensive Care Syndrome Clinic.

J Clin Med 2021 Jul 8;10(14). Epub 2021 Jul 8.

Department of Emergency and Critical Care Medicine, Hitachi General Hospital, 2-1-1, Jonan-cho, Hitachi, Ibaraki 317-0077, Japan.

Post-intensive care syndrome (PICS) is characterized by several prolonged symptoms after critical care, including physical and cognitive dysfunctions as well as mental illness. In clinical practice, the long-term follow-up of PICS is initiated after patients have been discharged from the intensive care unit, and one of the approaches used is a PICS clinic. Although physical dysfunction and mental illness often present in combination, they have not yet been examined in detail in PICS patients. Grip strength is a useful physical examination for PICS, and is reported to be associated with mental status in the elderly. We herein investigated the relationship between grip strength and the mental status using data from our PICS clinic. We primarily aimed to analyze the correlation between grip strength and the Hospital Anxiety and Depression Scale (HADS) score. We also analyzed the association between grip strength and the EuroQol 5 Dimension (EQ5D) score as quality of life (QOL). Subjects comprised 133 patients who visited the PICS clinic at one month after hospital discharge between August 2019 and December 2020. Total HADS scores were 7 (4, 13) and 10 (6, 16) ( = 0.029) and EQ5D scores were 0.96 (0.84, 1) and 0.77 (0.62, 0.89) ( ≤ 0.0001) in the no walking disability group and walking disability group, respectively. Grip strength negatively correlated with HADS and EQ5D scores. Correlation coefficients were r = -0.25 ( = 0.011) and r = -0.47 ( < 0.0001) for HADS and EQ5D scores, respectively. Grip strength was a useful evaluation that also reflected the mental status and QOL.
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http://dx.doi.org/10.3390/jcm10143044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304889PMC
July 2021

Decreased Virus-Neutralizing Antibodies Against Equine Herpesvirus type 1 In Nasal Secretions of Horses After 12-hour Transportation.

J Equine Vet Sci 2021 08 24;103:103665. Epub 2021 May 24.

Department of Agriculture and Food Sciences, University of Bologna, Bologna, Italy.

This study evaluated the effects of 12-hour transportation on immune responses to equine herpesvirus type 1 (EHV-1) and type 4 (EHV-4). Possible replication of EHV-1 and EHV-4 was monitored by real-time PCR of nasal swabs and peripheral blood mononuclear cells (PBMCs), and changes in systemic and mucosal antibodies were investigated. Six healthy Thoroughbreds with transport experience were transported in commercial trucks, repeating the same three-hour route four times. Blood samples for cortisol measurement were taken before departure and every three hours. Nasal swabs, PBMCs, nasal wash and serum samples were collected before departure, at unloading, two and six days after arrival. Cortisol concentration increased significantly after three and six hours of transport (P < 0.05), confirming acute transport stress. However, no evidence of viral replication or lytic infection was observed, and serum virus neutralization (VN) titers for EHV-1 and EHV-4 were unchanged, except for one horse that showed a four-fold decrease in titer against EHV-1 after transportation. Urea and total IgA concentration in nasal washes increased significantly after transportation (P < 0.05), while total IgA/protein ratio was unchanged. A transient, ≥4-fold decrease in VN titers for EHV-1 in nasal wash concentrates was observed in four out of six horses after transportation (geometric mean titer declined from 202 to 57, P < 0.05), suggesting suppression of VN capacity in the nasal mucosa may contribute to susceptibility to EHV-1 after transportation. VN antibodies against EHV-4 in nasal secretion were not detected at any timepoint.
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http://dx.doi.org/10.1016/j.jevs.2021.103665DOI Listing
August 2021

Serological Evidence of Filovirus Infection in Nonhuman Primates in Zambia.

Viruses 2021 06 30;13(7). Epub 2021 Jun 30.

Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia.

Ebolaviruses and marburgviruses are filoviruses that are known to cause severe hemorrhagic fever in humans and nonhuman primates (NHPs). While some bat species are suspected to be natural reservoirs of these filoviruses, wild NHPs often act as intermediate hosts for viral transmission to humans. Using an enzyme-linked immunosorbent assay, we screened two NHP species, wild baboons and vervet monkeys captured in Zambia, for their serum IgG antibodies specific to the envelope glycoproteins of filoviruses. From 243 samples tested, 39 NHPs (16%) were found to be seropositive either for ebolaviruses or marburgviruses with endpoint antibody titers ranging from 100 to 25,600. Interestingly, antibodies reactive to Reston virus, which is found only in Asia, were detected in both NHP species. There was a significant difference in the seropositivity for the marburgvirus antigen between the two NHP species, with baboons having a higher positive rate. These results suggest that wild NHPs in Zambia might be nonlethally exposed to these filoviruses, and this emphasizes the need for continuous monitoring of filovirus infection in wild animals to better understand the ecology of filoviruses and to assess potential risks of outbreaks in humans in previously nonendemic countries.
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http://dx.doi.org/10.3390/v13071283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309988PMC
June 2021

A symptomatic male carrier of Duchenne muscular dystrophy with Klinefelter's syndrome mimicking Becker muscular dystrophy.

Neuromuscul Disord 2021 07 27;31(7):666-672. Epub 2021 Apr 27.

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

Duchenne and Becker muscular dystrophy (DMD/BMD) are commonly inherited muscle disorders. We report a 31-year-old male who had muscle symptoms with left-right differences and intellectual disability. He was diagnosed with BMD at age 15 primarily based on muscle biopsy findings. A few years later, DMD gene analysis revealed that he was a heterozygous carrier of a normal copy of the gene and a mutated copy with an exon 45-54 deletion, which is expected to result in an out-of-frame mutation. A karyotype analysis was compatible with XXY Klinefelter's syndrome. The analysis of X-chromosome inactivation (XCI) using his skeletal muscle sample revealed a skewed XCI pattern. This is the first reported case of a symptomatic male carrier of DMD caused by skewed XCI in Klinefelter's syndrome with a genetically proven heterozygous mutation of the DMD gene. The skewed XCI pattern could also explain the left-right differences in skeletal muscle symptoms observed in this patient.
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http://dx.doi.org/10.1016/j.nmd.2021.04.006DOI Listing
July 2021

Accuracy and Stability of a Subcutaneous Flash Glucose Monitoring System in Critically Ill Patients.

J Diabetes Sci Technol 2021 Jun 11:19322968211017203. Epub 2021 Jun 11.

Department of Emergency and Critical Care Medicine, Hitachi General Hospital, Hitachi, Ibaraki, Japan.

Background: Flash glucose monitoring (FGM) systems can reduce glycemic variability and facilitate blood glucose management within the target range. However, in critically ill patients, only small ( < 30) studies have examined the accuracy of FGM and none have assessed the stability of FGM accuracy. We evaluated the accuracy and stability of FGM in critically ill patients.

Method: This was a single-center, retrospective observational study. We included a total of 116 critically ill patients who underwent FGM for glycemic control. The accuracy of FGM was assessed as follows using blood gas glucose values as a reference: (1) numerical accuracy using the mean absolute relative difference, (2) clinical accuracy using consensus error grid analysis, and (3) stability of accuracy assessing 14-day trends in consensus error grid distribution.

Results: FGM sensors remained in situ for a median of 6 [4, 11] days. We compared 2014 pairs of measurements between the sensor and blood gas analysis. Glucose values from the sensor were consistently lower, with a mean absolute relative difference of 13.8% (±16.0%), than those from blood gas analysis. Consensus error grid analysis demonstrated 99.4% of the readings to be in a clinically acceptable accuracy zone. The accuracy of FGM was stable across the 14 days after device insertion.

Conclusions: FGM had acceptable reliability and accuracy to arterial blood gas analysis in critically ill patients. In addition, the accuracy of FGM persisted for at least 14 days. Our study promotes the potential usefulness of FGM for glycemic monitoring in critically ill patients.
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http://dx.doi.org/10.1177/19322968211017203DOI Listing
June 2021

Metabolomic analysis of skeletal muscle before and after strenuous exercise to fatigue.

Sci Rep 2021 05 27;11(1):11261. Epub 2021 May 27.

Sports Science Division, Equine Research Institute, Japan Racing Association, 1400-4 Shiba, Shimotsuke-shi, Tochigi, 329-0412, Japan.

Thoroughbreds have high maximal oxygen consumption and show hypoxemia and hypercapnia during intense exercise, suggesting that the peripheral environment in skeletal muscle may be severe. Changes in metabolites following extreme alterations in the muscle environment in horses after exercise may provide useful evidence. We compared the muscle metabolites before and after supramaximal exercise to fatigue in horses. Six well-trained horses ran until exhaustion in incremental exercise tests. Biopsy samples were obtained from the gluteus medius muscle before and immediately after exercise for capillary electrophoresis-mass spectrometry analysis. In the incremental exercise test, the total running time and speed of the last step were 10.4 ± 1.3 (mean ± standard deviation) min and 12.7 ± 0.5 m/s, respectively. Of 73 metabolites, 18 and 11 were significantly increased and decreased after exercise, respectively. The heat map of the hierarchical cluster analysis of muscle metabolites showed that changes in metabolites were clearly distinguishable before and after exercise. Strenuous exercise increased many metabolites in the glycolytic pathway and the tricarboxylic acid cycle in skeletal muscle. Targeted metabolomic analysis of skeletal muscle may clarify the intramuscular environment caused by exercise and explain the response of working muscles to strenuous exercise that induces hypoxemia and hypercapnia in Thoroughbred horses.
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http://dx.doi.org/10.1038/s41598-021-90834-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160181PMC
May 2021

Time in blood glucose range 70 to 180 mg/dL and survival rate in critically ill patients: A retrospective cohort study.

PLoS One 2021 27;16(5):e0252158. Epub 2021 May 27.

Department of Emergency and Critical Care Medicine, Hitachi General Hospital, Hitachi, Ibaraki, Japan.

Background: While time in targeted blood glucose range (TIR) 70-140 mg/dL is a known factor associated with mortality in critically ill patients, it remains unclear whether TIR is associated with 28-day mortality under the glycemic control with a less tight target glucose range of 70-180 mg/dL. We aimed to examine whether TIR 70-180 mg/dL was associated with 28-day mortality.

Methods: This is a retrospective cohort study using data from a tertiary care center in Japan collected from January 2016 through October 2019. We included adult patients (aged ≥20 years) admitted to the ICU. We excluded patients 1) with diabetic ketoacidosis patients, 2) discharged within 48 hours, 3) with repeated ICU admissions. We calculated TIR 70-180 mg/dL using the measured blood glucose values (≥3 times per day). The primary outcome was 28-day mortality. We examined the association between TIR and 28-day mortality using a logistic regression and Cox proportional hazard models with a stratification by glycosylated hemoglobin (HbA1c) level of 6.5%. Additionally, we repeated the analyses using the TIR category to assess the optimal TIR. For the sensitivity analysis, we repeated the primary analysis using TIR during the first three days from ICU admission.

Results: Of 1,230 patients, the median age was 72 years, 65% were male, and 250 patients (20%) had HbA1c ≥6.5% on admission. In patients with HbA1c <6.5%, TIR <80% was associated with an increased risk of 28-day mortality, with an adjusted odds ratio (OR) of 1.88 (95%CI: 1.36-2.61). Likewise, when using 10% incremental TIR as a categorical variable, lower TIR was associated with a worse 28-day mortality compared with TIR ≥90% (e.g., adjusted OR of TIR <60%, 3.62 [95%CI 2.36-5.53]). Similar associations were found in the analyses using Cox proportional hazards model and using TIR during the first three days. By contrast, in patients with HbA1c ≥6.5%, there was no consistent association of TIR with 28-day mortality.

Conclusions: We found that lower TIR 70-180 mg/dL was associated with a higher 28-day mortality in critically ill patients with HbA1c <6.5%, whereas there was no consistent association in patients with HbA1c ≥6.5%.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252158PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158903PMC
May 2021

Vasopressin Loading for Refractory Septic Shock: A Preliminary Analysis of a Case Series.

Front Med (Lausanne) 2021 4;8:644195. Epub 2021 May 4.

Department of Emergency Medicine, Osaka Medical College Hospital, Takatsuki, Japan.

Vasopressin is one of the strong vasopressor agents associated with ischemic events. Responses to the administration of vasopressin differ among patients with septic shock. Although the administration of a high dose of vasopressin needs to be avoided, the effects of bolus loading have not yet been examined. Since the half-life of vasopressin is longer than that of catecholamines, we hypothesized that vasopressin loading may be effective for predicting responses to its continuous administration. We retrospectively analyzed consecutive cases of septic shock for which vasopressin was introduced with loading under noradrenaline at >0.2 μg/kg/min during the study period. Vasopressin was administered in a 1 U bolus followed by its continuous administration at 1 U/h. The proportion of patients with a negative catecholamine index (CAI) change 6 h after the introduction of vasopressin was set as the primary outcome. We defined non-responders for exploration as those with a mean arterial pressure change <18 mmHg 1 min after vasopressin loading, among whom none had a change in CAI <0. Twenty-one consecutive cases were examined in the present study, and included 14 responders and 7 non-responders. The primary outcome accounted for 71.4% of responders and 0% of non-responders, with a significant difference ( = 0.0039). Median CAI changes 2, 4, and 6 h after the administration of vasopressin were 0, -5, and -10 in responders and +20, +10, and +10 in non-responders, respectively. CAI was not reduced in any non-responder. Outcomes including mortality were not significantly different between responders and non-responders. Digital ischemia (1/21) and mesenteric ischemia (1/21) were observed. Vasopressin loading may predict responses to its continuous administration in septic shock patients. Further investigations involving a safety analysis are needed.
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http://dx.doi.org/10.3389/fmed.2021.644195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129171PMC
May 2021

[Amyotrophic lateral sclerosis with muscle weakness and dropped head during the course of Parkinson's disease: an autopsy case].

Rinsho Shinkeigaku 2021 Jun 20;61(6):373-377. Epub 2021 May 20.

Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry.

A 64-year-old female developed Parkinson's disease at the age of 52 years. She experienced muscle weakness in the upper right extremities and dropped head at 62 and 63 years, respectively; both symptoms were considered to be associated with Parkinson's disease (PD). The dosage of L-DOPA was increased from 200 mg/day to 900 mg/day; however, her neurological symptoms did not improve. Eventually, she was diagnosed with amyotrophic lateral sclerosis (ALS) at 64 years. She was placed under palliative care, and died of respiratory failure and malnutrition. Neuropathologic findings were consistent with the coexistence of PD and ALS. In fact, there were α-synuclein immunoreactive Lewy bodies (Braak stage 4) as well as TDP-43 immunoreactive deposits in the motor nuclei at the level of brainstem and spinal cord. Therefore, coexisting pathologies must be taken into account in a patient showing multi-system symptoms.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001546DOI Listing
June 2021

Initiative on Rare and Undiagnosed Disease in Japan.

JMA J 2021 Apr 8;4(2):112-118. Epub 2021 Apr 8.

National Center of Neurology and Psychiatry, Tokyo, Japan.

The Initiative on Rare and Undiagnosed Diseases (IRUD) has established a unified all-Japan diagnostic and research scheme for rare and undiagnosed diseases covering the entire geographic areas and specialty/subspecialty fields. The fundamental IRUD scheme consists of six components: coordinating center (IRUD-CC), clinical center (IRUD-CL), clinical specialty subgroup (IRUD-CSS), analysis center (IRUD-AC), data center (IRUD-DC), and resource center (IRUD-RC). IRUD has registered many pedigrees with undiagnosed diseases, established their diagnoses with high diagnostic rate, identified novel causative genes and new disease entities, and promoted extensive data sharing and international collaboration. IRUD plays an important role in the national medical support network for rare and intractable diseases together with academic societies and national centers. Promotion of IRUD would be essential in elucidating causes and ultimately providing cures for rare and undiagnosed diseases.
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http://dx.doi.org/10.31662/jmaj.2021-0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119020PMC
April 2021

Effects of Fatigue on Stride Parameters in Thoroughbred Racehorses During Races.

J Equine Vet Sci 2021 06 16;101:103447. Epub 2021 Mar 16.

Sports Science Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.

Exercise intensity during races is considerably high. To understand how Thoroughbreds adapt to fatigue conditions, stride parameters for the first and second lap of the race (2400-m, turf) were compared. A high-speed video system was set in a right lateral position about 20 m before the finishing post, with a field view width of about 16 m. The stride frequency, the length between each limb (hind step, diagonal step, fore step, and airborne step), and stride length were measured and analyzed using a generalized linear mixed model. Compared with the first lap, the mean ± standard deviation values in the second lap for running speed (17.3 ± 1.3 to 16.0 ± 0.9 m/s, P < .01), stride frequency (2.34 ± 0.08 to 2.21 ± 0.09 strides/s, P < .01) and stride length (7.42 ± 0.52 to 7.25 ± 0.38 m, P = .04) significantly decreased. Furthermore, significant changes (P < .01) were observed in the diagonal step length (2.32 ± 0.34 to 1.88 ± 0.23 m), hind step (1.19 ± 0.09 to 1.26 ± 0.10 m) and airborne step length (2.43 ± 0.25 to 2.61 ± 0.18 m). When controlled for speed, stride frequency (P = .02) and diagonal step length (P < .01) decreased, while the length of the hind step (P < .01), fore step (P < .01), airborne step (P < .01), and stride (P = .02) increased with fatigue in the second lap. These results suggest that horses could not extend their body when fatigued.
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http://dx.doi.org/10.1016/j.jevs.2021.103447DOI Listing
June 2021

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for status epilepticus: study protocol for a multicenter non-inferiority designed randomized control trial.

Trials 2021 May 2;22(1):317. Epub 2021 May 2.

Department of Emergency and Critical Care Medicine, Tsukuba University Hospital, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.

Background: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE.

Methods: This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is "continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance." In both groups, diazepam is initially administered at 1-20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000-3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes.

Discussion: The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application.

Trial Registration: Japan Registry of Clinical Trials jRCTs031190160 . Registered on December 13, 2019.
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http://dx.doi.org/10.1186/s13063-021-05269-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091776PMC
May 2021

Garcinielliptone G from Induces Apoptosis in Acute Leukemia Cells.

Molecules 2021 Apr 21;26(9). Epub 2021 Apr 21.

School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.

Cytotoxicity and apoptosis-inducing properties of compounds isolated from leaves were investigated. The hexane-soluble portion of MeOH extracts of leaves that showed cytotoxic activity was separated to yield seven compounds -. Chemical structure analysis using NMR spectroscopy and mass spectrometry confirmed that compound was canophyllol, and compounds - were garcinielliptones N, O, J, G, F, and garcinielliptin oxide, respectively. Among them, garcinielliptone G () showed growth inhibition by causing apoptosis in THP-1 and Jurkat cells derived from human acute monocytic leukemia and T lymphocyte cells, respectively. Apoptosis induced by garcinielliptone G () was demonstrated by the detection of early apoptotic cells with fluorescein-labeled Annexin V and increases in cleaved caspase-3 and cleaved PARP protein levels. However, the addition of caspase inhibitor Z-VAD-FMK did not affect growth arrest or apoptosis induction. These results suggest that garcinielliptone G () can induce both caspase-3 activation and caspase-independent apoptosis. Therefore, garcinielliptone G () may be a potential candidate for acute leukemia treatment.
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http://dx.doi.org/10.3390/molecules26092422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122622PMC
April 2021

Intravenous Immunoglobulin for Overwhelming Postsplenectomy Infection.

J Glob Infect Dis 2021 Jan-Mar;13(1):44-51. Epub 2021 Jan 29.

Department of Emergency and Critical Care Medicine, Hitachi General Hospital, Hitachi, Ibaraki, Japan.

Overwhelming postsplenectomy infection (OPSI) is a life-threatening condition causing fulminant bacteremia in asplenic patients. Intravenous immunoglobulin (IVIG) therapy is theoretically effective for OPSI. Herein, we present a case of OPSI treated successfully with IVIG, along with results of a literature review. An asplenic 70-year-old male with acute ischemic stroke presented with rapid and fulminant septic shock from pneumococcus pneumonia and bacteremia. Resuscitation and antibiotics including IVIG therapy were instituted. The patient survived with favorable outcomes. We analyzed all case reports or case series of OPSI from 1971 through 2017. Cases with IVIG treatment showed a significantly higher survival rate than those without IVIG, even with multivariable regression analysis, suggesting IVIG as an independent predictive factor for survival. It suggests that IVIG is effective for OPSI and that it can be regarded as an adjunctive treatment option for OPSI.
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http://dx.doi.org/10.4103/jgid.jgid_93_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054784PMC
January 2021

Functional validation of epitope-tagged ATF5 knock-in mice generated by improved genome editing of oviductal nucleic acid delivery (i-GONAD).

Cell Tissue Res 2021 Jul 7;385(1):239-249. Epub 2021 Apr 7.

Laboratory of Environmental Molecular Physiology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1, Horinouchi, Hachioji, Tokyo, 192-0392, Japan.

Activating transcription factor 5 (ATF5) is a stress-responsive transcription factor that belongs to the cAMP response element-binding protein (CREB)/ATF family, and is essential for the differentiation and survival of sensory neurons in murine olfactory organs. However, the study of associated proteins and target genes for ATF5 has been hampered due to the limited availability of immunoprecipitation-grade ATF5 antibodies. To overcome this issue, we generated hemagglutinin (HA)-tag knock-in mice for ATF5 using CRISPR/Cas9-mediated genome editing with one-step electroporation in oviducts (i-GONAD). ATF5-HA fusion proteins were detected in the nuclei of immature and some mature olfactory and vomeronasal sensory neurons in the main olfactory epithelium and vomeronasal organ, respectively, as endogenous ATF5 proteins were expressed, and some ATF5-HA proteins were found to be phosphorylated. Chromatin immunoprecipitation (ChIP) experiments revealed that ATF5-HA bound to the CCAAT/enhancer-binding protein (C/EBP)-ATF response element site in the promotor region of receptor transporting protein 1 (Rtp1), a chaperone gene responsible for proper olfactory receptor expression. These knock-in mice may be used to examine the expression, localization, and protein-protein/-DNA interactions of endogenous ATF5 and, ultimately, the function of ATF5 in vivo.
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http://dx.doi.org/10.1007/s00441-021-03450-7DOI Listing
July 2021

Urinary Titin N-Fragment Evaluation in a Randomized Controlled Trial of Beta-Hydroxy-Beta-Methylbutyrate for Acute Mild Trauma in Older Adults.

Nutrients 2021 Mar 10;13(3). Epub 2021 Mar 10.

Department of Emergency and Critical Care Medicine, Hitachi General Hospital, Hitachi, Ibaraki 317-0077, Japan.

The effects of beta-hydroxy-beta-methylbutyrate (HMB) complex administration and the significance of titin, a biomarker of muscle injury, in elderly minor trauma patients in acute phase has not been established. In this single-center, randomized controlled study, trauma patients aged ≥ 70 years with an injury severity score < 16 were included. Titin values on days 1 and 3 were measured and the intervention group received HMB complex (2.4 g of HMB + 14 g of glutamine + 14 g of arginine) and the control group received glutamine complex (7.2 g of protein including 6 g of glutamine). The cross-sectional area of the rectus femoris (RFCSA) on ultrasound, grip strength, and the Barthel Index were assessed on the first day of rehabilitation and after 2 weeks. We analyzed 24 HMB and 25 control participants. Titin values on day 3 correlated with grip strength ( = -0.34, = 0.03) and the Barthel Index ( = -0.39, = 0.01) at follow-up. HMB complex supplementation had no effect on the RFCSA (2.41 vs. 2.45 cm, = 0.887), grip strength (13.3 vs. 13.1 kg, = 0.946), or the Barthel Index (20.0 vs. 50.0, = 0.404) at follow-up. Titin values might associate with subsequent physical function. Short-term HMB complex supplementation from acute phase did not ameliorate muscle injury.
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http://dx.doi.org/10.3390/nu13030899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001392PMC
March 2021

ATF5 deficiency causes abnormal cortical development.

Sci Rep 2021 03 31;11(1):7295. Epub 2021 Mar 31.

Laboratory of Environmental Molecular Physiology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.

Activating transcription factor 5 (ATF5) is a member of the cAMP response element binding protein (CREB)/ATF family of basic leucine zipper transcription factors. We previously reported that ATF5-deficient (ATF5) mice exhibited behavioural abnormalities, including abnormal social interactions, reduced behavioural flexibility, increased anxiety-like behaviours, and hyperactivity in novel environments. ATF5 mice may therefore be a useful animal model for psychiatric disorders. ATF5 is highly expressed in the ventricular zone and subventricular zone during cortical development, but its physiological role in higher-order brain structures remains unknown. To investigate the cause of abnormal behaviours exhibited by ATF5 mice, we analysed the embryonic cerebral cortex of ATF5 mice. The ATF5 embryonic cerebral cortex was slightly thinner and had reduced numbers of radial glial cells and neural progenitor cells, compared to a wild-type cerebral cortex. ATF5 deficiency also affected the basal processes of radial glial cells, which serve as a scaffold for radial migration during cortical development. Further, the radial migration of cortical upper layer neurons was impaired in ATF5 mice. These results suggest that ATF5 deficiency affects cortical development and radial migration, which may partly contribute to the observed abnormal behaviours.
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http://dx.doi.org/10.1038/s41598-021-86442-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012588PMC
March 2021

Prefrontal network dysfunctions in rapid eye movement sleep behavior disorder.

Parkinsonism Relat Disord 2021 04 13;85:72-77. Epub 2021 Mar 13.

Integrative Brain Imaging Center, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Integrated Neuroanatomy and Neuroimaging, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address:

Introduction: Resting-state functional connectivity magnetic resonance imaging (rsfcMRI) of rapid eye movement (REM) sleep behavior disorder (RBD) may provide an early biomarker of α-synucleinopathy. However, few rsfcMRI studies have examined cognitive networks. To elucidate brain network changes in RBD, we performed rsfcMRI in patients with polysomnography-confirmed RBD and healthy controls (HCs), with a sufficiently large sample size in each group.

Methods: We analyzed rsfcMRI data from 50 RBD patients and 70 age-matched HCs. Although RBD patients showed no motor signs, some exhibited autonomic and cognitive problems. Several resting-state functional networks were extracted by group independent component analysis from HCs, including the executive-control (ECN), default-mode (DMN), basal ganglia (BGN), and sensory-motor (SMN) networks. Functional connectivity (FC) was compared between groups using dual regression analysis. In the RBD group, correlation analysis was performed between FC and clinical/cognitive scales.

Results: Patients with RBD showed reduced striatal-prefrontal FC in ECN, consistent with executive dysfunctions. No abnormalities were found in DMN. In the motor networks, we identified reduced midbrain-pallidum FC in BGN and reduced motor and somatosensory cortex FC in SMN.

Conclusion: We found abnormal ECN and normal DMN as a possible hallmark of cognitive dysfunctions in early α-synucleinopathies. We replicated abnormalities in BGN and SMN corresponding to subclinical movement disorder of RBD. RsfcMRI may provide an early biomarker of both cognitive and motor network dysfunctions of α-synucleinopathies.
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http://dx.doi.org/10.1016/j.parkreldis.2021.03.005DOI Listing
April 2021

Four weeks of high-intensity training in moderate, but not mild hypoxia improves performance and running economy more than normoxic training in horses.

Physiol Rep 2021 02;9(4):e14760

Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.

We investigated whether horses trained in moderate and mild hypoxia demonstrate greater improvement in performance and aerobic capacity compared to horses trained in normoxia and whether the acquired training effects are maintained after 2 weeks of post-hypoxic training in normoxia. Seven untrained Thoroughbred horses completed 4 weeks (3 sessions/week) of three training protocols, consisting of 2-min cantering at 95% maximal oxygen consumption under two hypoxic conditions (H16, F O  = 16%; H18, F O  = 18%) and in normoxia (N21, F O  = 21%), followed by 2 weeks of post-hypoxic training in normoxia, using a randomized crossover study design with a 3-month washout period. Incremental treadmill tests (IET) were conducted at week 0, 4, and 6. The effects of time and groups were analyzed using mixed models. Run time at IET increased in H16 and H18 compared to N21, while speed at was increased significantly only in H16. in all groups and cardiac output at exhaustion in H16 and H18 increased after 4 weeks of training, but were not significantly different between the three groups. In all groups, run time, , , , and lactate threshold did not decrease after 2 weeks of post-hypoxic training in normoxia. These results suggest that 4 weeks of training in moderate (H16), but not mild (H18) hypoxia elicits greater improvements in performance and running economy than normoxic training and that these effects are maintained for 2 weeks of post-hypoxic training in normoxia.
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http://dx.doi.org/10.14814/phy2.14760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897453PMC
February 2021

Highly sensitive screening of antisense sequences for different types of DMD mutations in patients' urine-derived cells.

J Neurol Sci 2021 04 15;423:117337. Epub 2021 Feb 15.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. Electronic address:

Exon skipping using short antisense oligonucleotides (AONs) is a promising treatment for Duchenne muscular dystrophy (DMD). Several exon-skipping drugs, including viltolarsen (NS-065/NCNP-01), have been approved worldwide. Immortalized human skeletal muscle cell lines, such as rhabdomyosarcoma cells, are frequently used to screen efficient oligonucleotide sequences. However, rhabdomyosarcoma cells do not recapitulate DMD pathophysiology as they express endogenous dystrophin. To overcome this limitation, we recently established a direct human somatic cell reprogramming technology and successfully developed a cellular skeletal muscle DMD model by using myogenic differentiation 1 (MYOD1)-transduced urine-derived cells (MYOD1-UDCs). Here, we compared in vitro drug screening systems in MYOD1-UDCs and rhabdomyosarcoma cells. We collected UDCs from patients with DMD amenable to exon 51 skipping, and obtained MYOD1-UDCs. We then compared the efficiency of exon 51 skipping induced by various morpholino-based AONs, including eteplirsen in differentiated MYOD1-UDCs (UDC-myotubes) and rhabdomyosarcoma cells. Exon skipping was induced more efficiently in UDC-myotubes than in rhabdomyosarcoma cells even at a low AON concentration (1 μM). Furthermore, exon 51 skipping efficiency was higher in UDC-myotubes with a deletion of exons 49-50 than in those with a deletion of exons 48-50, suggesting that the skipping efficiency may vary depending on the DMD mutation pattern. An essential finding of this study is that the sequence of eteplirsen consistently leads to much lower efficiency than other sequences. These findings underscore the importance of AON sequence optimization by our cellular system, which enables highly sensitive screening of exon skipping drugs that target different types of DMD mutations.
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http://dx.doi.org/10.1016/j.jns.2021.117337DOI Listing
April 2021

Spinocerebellar ataxia type 6 presenting with hallucination.

Psychogeriatrics 2021 05 18;21(3):446. Epub 2021 Feb 18.

Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

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http://dx.doi.org/10.1111/psyg.12669DOI Listing
May 2021

Pneumomediastinum while using mechanical insufflation-exsufflation after recovery from riluzole-induced interstitial lung disease.

eNeurologicalSci 2021 Mar 2;22:100326. Epub 2021 Feb 2.

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8551, Japan.

We, herein, report a 61-year-old male patient with amyotrophic lateral sclerosis (ALS) complicated pneumomediastinum while using mechanical insufflation-exsufflation (MI-E) after recovery from riluzole (RZ)-induced interstitial lung disease (RZ-ILD). After the treatment of RZ-ILD, he required non-invasive mechanical ventilation (NIV) at minimal pressure settings and MI-E to manage ALS-related breathing and airway-clearance issues, respectively. After a while, he developed progressive worsening dyspnoea, and chest computed tomography revealed extensive pneumomediastinum that had spread to the area surrounding the oesophagus, the retrosternal space, and the pericardial space. He was treated with immediate discontinuation of MI-E; however, he had to keep using NIV to support his severe respiratory muscle involvement. Pneumomediastinum gradually reduced in size and no recurrence of pneumomediastinum occurred. The clinical course of our patient suggests that excessive coughing associated with MI-E combined with his previous RZ-ILD, which potentially renders his lungs vulnerable to airway pressure, may have been the aetiological factors for secondary pneumomediastinum, i.e. barotrauma. Clinicians should be aware of the risk of pneumomediastinum while using MI-E in patients with ALS, who have other pre-existing risk factors for pneumomediastinum, such as drug-induced ILD in our case.
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http://dx.doi.org/10.1016/j.ensci.2021.100326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868606PMC
March 2021

More prominent fibrosis of the cricopharyngeal muscle in inclusion body myositis.

J Neurol Sci 2021 Mar 23;422:117327. Epub 2021 Jan 23.

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan.

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http://dx.doi.org/10.1016/j.jns.2021.117327DOI Listing
March 2021

Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature.

J Mol Neurosci 2021 Sep 12;71(9):1796-1801. Epub 2021 Jan 12.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.

The phenotypes of patients with disease-associated variants in DNMT1 have been classified into two syndromes: hereditary sensory and autonomic neuropathy type 1E (HSAN1E, MIM614116, https://www.omim.org/ ) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN, MIM604121). The amino acid codon 511 is a hotspot, and p.Y511C is the most frequently observed disease-associated variant among those in HSAN1E patients, whereas there have been only a few reports on patients with p.Y511H. In this study, we report on the cases of a kindred carrying the DNMT1 variant NM_001130823.2:c.1531 T > C (p.Y511H) presenting with the ADCA-DN phenotype. The review of the literature further revealed that later ages at onset and the presence of cerebellar ataxia are the main characteristics of patients carrying the DNMT1 p.Y511H as compared with those carrying DNMT1 p.Y511C. Although HSAN1E and ADCA-DN are proposed to be called DNMT1-complex disorders owing to their overlapping symptoms, this finding suggests a distinct genotype-phenotype correlation regarding the DNMT1 p.Y511H and p.Y511C variants.
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http://dx.doi.org/10.1007/s12031-020-01784-5DOI Listing
September 2021

Epidemiology of jockey falls and injuries in flat and jump races in Japan (2003-2017).

J Equine Sci 2020 18;31(4):101-104. Epub 2020 Dec 18.

Equine Department, Japan Racing Association, Tokyo 106-8401, Japan.

Jockey safety is of paramount importance from the standpoint of welfare and public perception. Thus, an understanding of the epidemiology and associated risk factors is necessary to implement measures to reduce the jockey falls (JFs) and jokey injuries (JIs). This descriptive epidemiological study investigated the occurrence of JFs and JIs in 715,210 and 25,183 rides in flat and jump races, respectively, from 2003 to 2017. In flat races, the incidence rates of JFs and JIs were 1.4 and 0.6 per 1,000 rides, respectively. In jump races, they were 44.4 and 18.1 per 1,000 rides, respectively. In flat races, 56.8% of JFs at corners resulted in JIs. In jump races, the major causes of JFs and JIs were lost balance and hampered by a fallen horse at an obstacle. Our findings provide a basis to design a future study analyzing risk factors for JFs.
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http://dx.doi.org/10.1294/jes.31.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750638PMC
December 2020

Hypoalbuminemia on Admission as an Independent Risk Factor for Acute Functional Decline after Infection.

Nutrients 2020 Dec 23;13(1). Epub 2020 Dec 23.

Department of Emergency and Critical Care Medicine, Hitachi General Hospital, Ibaraki 317-0077, Japan.

The risk of acute functional decline increases with age, and concepts including frailty and post-acute care syndrome have been proposed; however, the effects of the nutritional status currently remain unclear. Patients admitted to the emergency department of Hitachi General Hospital for infectious diseases between April 2018 and May 2019 were included. To identify risk factors for functional decline at discharge, defined as Barthel Index <60, we investigated basic characteristics, such as age, sex, disease severity, the pre-morbid care status, and cognitive impairment, as well as laboratory data on admission, including albumin as a nutritional assessment indicator. In total, 460 surviving patients out of 610 hospitalized for infection were analyzed. In a multivariable logistic regression analysis, factors independently associated with Barthel Index <60 at discharge were age (adjusted OR 1.03, 95%CI 1.01-1.06, = 0.022), serum albumin (adjusted OR: 0.63, 95%CI: 0.41-0.99, = 0.043), and the need for care prior to admission (adjusted OR: 5.92, 95%CI: 3.15-11.15, < 0.001). Hypoalbuminemia on admission in addition to age and the need for care prior to admission were identified as risk factors for functional decline in patients hospitalized for infection. Functional decline did not correlate with the severity of illness.
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http://dx.doi.org/10.3390/nu13010026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823478PMC
December 2020

Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy.

Neurol Genet 2020 Dec 19;6(6):e531. Epub 2020 Nov 19.

Department of Neurology (T.I., T.O., Y. Saitoh, S.O., Y.T.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Human Genetics (K.S., A.F., H.F., N. Miyake, T.M., N. Matsumoto), Yokohama City University Graduate School of Medicine, Kanagawa; Department of Pathology and Laboratory Medicine (T.S., Y. Saito), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (T.Y.), Iida Municipal Hospital, Shinshu University School of Medicine, Nagano; Department of Medicine (Neurology and Rheumatology) (Y.M., Y. Sekijima), Shinshu University School of Medicine, Nagano; and Department of Neurology and Stroke Medicine (H.F.), Yokohama City University, Japan.

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http://dx.doi.org/10.1212/NXG.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713717PMC
December 2020

Visualization of Motor Cortex Involvement by 18F-THK5351 PET Potentially Strengthens Diagnosis of Amyotrophic Lateral Sclerosis.

Clin Nucl Med 2021 Mar;46(3):243-245

From the Department of Neurology, National Center Hospital.

Abstract: Amyotrophic lateral sclerosis (ALS) involves both upper motor neurons (UMNs) and lower motor neurons. The detection of UMN involvement, a core component of ALS criteria, is primarily dependent on neurological examination because of a lack of definitive biomarkers. We present the 18F-THK5351 PET images of a 76-year-old man diagnosed with ALS comorbid with Alzheimer disease, demonstrating marked accumulation of 18F-THK5351 in the bilateral precentral gyri. Because 18F-THK5351 binds to monoamine oxidase B highly expressed in astrocytes, where the neurodegenerative process is ongoing, our case highlights that 18F-THK5351 tracer should be a useful marker for detecting UMN neurodegeneration in ALS.
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http://dx.doi.org/10.1097/RLU.0000000000003456DOI Listing
March 2021
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