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PbWO4 heavily doped with trivalent rare-earth ions like La3+, Gd3+, Y3+, etc. has recently been proposed as an excellent new, heavy and radiation-hard Cherenkov radiator, and the upper limit of the remaining scintillation light yield (LY) was obtained from measurement of radioisotope γ-rays. Since then, we have made a quantitative study of the remaining scintillation LY using a 0.5–1 GeV/c π+/p/d beam. Compared with a standard PbWO4 : Gd(80 at ppm) scintillator, the scintillation LY is quenched to 4.8%, 6.0%, and 11.6% for La3+ concentration of 8 at%, La3+ of 5 at% and Gd3+ of 3 at%, respectively. The scintillation LY remaining in PbWO4 : La(8 at%) was as weak as 15% of the Cherenkov LY for relativistic charged particles. [Copyright &y& Elsevier]

Background: We developed a novel method to measure the angle of subjective postural vertical (SPV) and showed that the SPV may be related to the exacerbation of the forward flexed posture., Objectives: The present study prospectively tested the effects of the subjective postural vertical on the exacerbation of the forward flexion of trunk (FFT) through long-term observation of Parkinson's disease patients., Methods: Evaluation of the posture included measuring FFT, the angle of lateral flexion of trunk, and the angle at the position that the patient subjectively perceived as the vertical position at a stationary upright position immediately after standing up at the time of initial observation, 6 months later, and 1 year later., Results: The SPV angles worsened significantly at 6 months and 1 year compared to the first measurements (9.3 ± 6.7° vs. 10.8 ± 8.2° and 10.6 ± 7.8°, P < 0.05), and the FFT angles worsened significantly at one year compared to the first measurements (11.1 ± 8.1° vs. 12.2 ± 8.8°, P = 0.004). Furthermore, using a hierarchical multiple regression model, the difference in SPV from the first visit to the first half year was considered a factor contributing to annual FFT change (P = 0.002)., Conclusions: This longitudinal study of a large number of cases suggested that changes in SPV may precede changes in FFT., Competing Interests: Declaration of Competing Interest This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (No. 21K11321, 22H00547, 24K14361). Outside this funding, none of the authors has conflicts of interest relevant to this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Scorpions, a seemingly primitive, stinging arthropod taxa, are known to exhibit marked diversity in their venom components. These venoms are known for their human pathology, but they are also important as models for therapeutic and drug development applications. In this study, we report a high-quality genome assembly and annotation of the striped bark scorpion, Centruroides vittatus, created with several shotgun libraries. The final assembly is 760 Mb in size, with a BUSCO score of 97.8%, a 30.85% GC, and an N50 of 2.35 Mb. We estimated 36,189 proteins with 37.32% assigned to Gene Ontology (GO) terms in our GO annotation analysis. We mapped venom toxin genes to 18 contigs and 2 scaffolds. We were also able to identify expression differences between venom gland (telson) and body tissue (carapace) with 19 sodium toxin and 14 potassium toxin genes to 18 contigs and 2 scaffolds. This assembly, along with our transcriptomic data, provides further data to investigate scorpion venom genomics., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Both transient epileptic amnesia (TEA) and transient global amnesia (TGA) are clinically characterized by temporary amnesic symptoms. TEA involves recurring amnesic episodes, while TGA typically manifests as a singular occurrence. TGA rarely occurs repeatedly, known as recurrent TGA (r-TGA), which complicates differentiation, and raises the possibility of overlap between two disorders. Given the effectiveness of suitable antiseizure medications (ASMs) in treating TEA, accurate diagnosis of the initial event is crucial. In this study, We retrospectively analyzed cases of sudden-onset amnesia at Juntendo University Hospital over the past 14 years. Our investigation identified a total of 17 patients with TEA who met the criteria established by Zeman, along with a total of 9 patients with r-TGA meeting Hodges' criteria. Compared to r-TGA, TEA exhibited a higher recurrent rate, shorter symptoms, more additional symptoms, and increased structural abnormalities on head magnetic resonance imaging (MRI), and more abnormalities electroencephalography (EEG). Moreover, individual amnestic episode duration varied in both TEA and r-TGA. Our study reveals that TGA retains key features in recurrent cases and demonstrates distinctions from TEA. Nevertheless, distinguishing between the two conditions based solely on initial episodes remains challenging., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Introduction: Multiple system atrophy (MSA) is clinically characterized by various neurological symptoms. According to the diagnostic criteria, MSA is classified into parkinsonian-dominant type (MSA-P) or cerebellar ataxia-dominant type (MSA-C) based on the predominant signs displayed. Recently, N-isopropyl-p-[ 123 I] iodoamphetamine ( 123 I-IMP) single-photon emission computed tomography (SPECT), a radiological examination evaluating brain perfusion, has been successful in detecting cerebellar hypoperfusion in MSA-P patients, demonstrating its utility in the early detection of cerebellar dysfunction. In this study, we further explored whether this cerebellar hypoperfusion impacts the clinical features of MSA-P, whether it is observable in patients without cerebellar symptoms, and, most importantly, whether it influences the prognosis of MSA-P., Methods: We conducted a retrospective analysis of 88 MSA patients who were admitted to our department for the last fifteen years. Clinical data were collected, and cerebellar perfusion was examined using 123 I-IMP SPECT. This analysis includes the application of the three-dimensional stereotactic surface projection (3D-SSP) technique and Z-score., Results: Cerebellar perfusion decreased in MSA-P patients without cerebellar ataxia, compared to healthy individuals (p = 0.0017). The Receiver Operating Characteristic (ROC) curve demonstrated a moderate ability to distinguish MSA-P patients without cerebellar ataxia (MSA-Pp) from healthy controls (AUC = 0.6832). Among MSA-Pp, those exhibiting cerebellar hypoperfusion showed relatively improved neurological prognosis, although the difference was not statistically significant when compared to those with normal cerebellar perfusion., Conclusion: Assessing cerebellar perfusion through IMP-SPECT proves valuable in detecting subclinical cerebellar dysfunction in MSA-Pp. Importantly, cerebellar hypoperfusion does not correlate with a poorer neurological prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Patients with bone metastases often face physical, mental, and social challenges that require multidisciplinary management. To improve treatment and practice, we conducted a questionnaire survey to assess nurses' opinions of problems related to caring for patients with bone metastases. In addition, we investigated nurses' perceptions of bone metastases after participating in a Bone Metastasis Cancer Board (BMCB)., Methods: An anonymous questionnaire survey on problems in bone metastasis treatment and the BMCB was conducted. The respondents were nurses with more than 1 year of clinical experience working in wards where patients with bone metastases were admitted., Results: The number of valid responses was 224. Almost all the nurses felt anxiety about the risk of pathological fracture and paralysis while caring for patients with bone metastases. To reduce this anxiety, about 90% of the nurses supported the suggestion that "patients should be referred to an orthopedic surgeon in advance to obtain opinions on load restrictions". Nurses who had participated in the BMCB had higher expectations regarding treatment, multidisciplinary collaboration, and sharing and accumulating knowledge and experience., Conclusion: To improve treatment and nursing care for patients with bone metastases, it is important to make regular BMCB meetings more functional and to actively consult with specialists.

Parkinson's disease (PD) is characterized by the pathological deposition of a-synuclein (a-syn) inclusions, known as Lewy bodies/neurites. Emerging evidence suggests that extracellular vesicles (EVs) play a role in facilitating the spreading of Lewy pathology between the peripheral nervous system and the central nervous system. We analyzed serum EVs obtained from patients with PD (n = 142), multiple system atrophy (MSA) (n = 18), progressive supranuclear palsy (PSP) (n = 28), rapid eye movement sleep behavior disorder (n = 31), and controls (n = 105). While we observed a significant reduction in the number of EVs in PD compared to controls (p = 0.006), we also noted a substantial increase in filamentous α-synuclein within EVs in PD compared to controls (p < 0.0001), MSA (0.012), and PSP (p = 0.03). Further analysis unveiled the role of EVs in facilitating the transmission of filamentous α-synuclein between neurons and from peripheral blood to the CNS. These findings highlight the potential utility of serum α-synuclein filaments within EVs as diagnostic markers for synucleinopathies and underscore the significance of EVs in promoting the dissemination of filamentous α-synuclein throughout the entire body., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Mutations in the SNCA gene, which encodes α-synuclein (α-syn), play a key role in the development of genetic Parkinson's disease (PD). α-Syn is a major component of Lewy bodies in PD and glial cytoplasmic inclusions in multiple system atrophy (MSA). Rapid eye movement sleep behavior disorder patients often progress to PD, dementia with Lewy bodies, or MSA, which are collectively known as α-synucleinopathies. The loss of dopaminergic neurons with Lewy bodies precedes motor dysfunction in these diseases, but the mechanisms of neurodegeneration due to α-syn aggregation are poorly understood. Monitoring α-syn aggregation in vivo could serve as a diagnostic biomarker and help elucidate pathogenesis, necessitating a simple and accurate detection method. Seed amplification assays (SAAs), such as real-time quaking-induced conversion and protein misfolding cyclic amplification, are used to detect small amounts of abnormally structured α-syn protofibrils, which are central to aggregation. These methods are promising for the early diagnosis of α-synucleinopathy. Differences in α-syn filament structures between α-synucleinopathies, as observed through transmission electron microscopy and cryo-electron microscopy, suggest their role in the pathogenesis of neurodegeneration. SAAs may differentiate between subtypes of α-synucleinopathy and other diseases. Efforts are also being made to identify α-syn from blood using various methods. This review introduces body fluid α-syn biomarkers based on pathogenic α-syn seeds, which are expected to redefine α-synucleinopathy diagnosis and staging, improving clinical research accuracy and facilitating biomarker development.

Background: Chronic constipation is a common digestive complication of Parkinson's disease (PD)., Objectives: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD., Methods: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed., Results: The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported., Conclusions: Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation., Trial Registration Information: Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172)., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Rehabilitation therapy for patients with severe coronavirus disease 2019 (COVID-19) is crucial; however, studies regarding rehabilitation strategies for intensive care unit (ICU) patients with COVID-19 are limited. We report a case of severe COVID-19 in an ICU patient whose physical function and basic movement ability rapidly improved after the initiation of active aerobic exercise in the supine position., Case: A 70-year-old man with hypertension and obesity was admitted to the ICU and managed with a ventilator because of severe COVID-19. Physical therapy started on postadmission day 34. Problems encountered during physical therapy included low saturation of percutaneous oxygen (SpO 2 ; <90%), dyspnea with a light exercise load, advancing muscle weakness, and endurance decline. The rehabilitation program included getting out of bed and resistance training of the upper and lower limbs twice daily while maintaining SpO 2 at ≥90%. After ventilator weaning, we initiated aerobic training using a supine ergometer with varying load volume. On discharge from the ICU on postadmission day 45, the patient's physical function (handgrip strength, Medical Research Council score, and Borg scale) and basic movement ability (Functional Status Score for ICU) rapidly improved., Conclusion: Rehabilitation therapy involving aerobic cycling training based on a quantitative load setting may be effective in treating COVID-19.

Background: Bone metastases can cause severe pain, pathological fractures, and spinal cord paralysis, which interrupt treatment for tumors and cause patients to be bedridden. In this study, we aimed to clarify therapists' problems in the rehabilitation of patients with bone metastases and their countermeasures using the results of questionnaires to therapists and recommend safer and more rational rehabilitation., Methods: Questionnaire forms were sent to 21 therapists in our department. The questionnaire was conducted anonymously about problems during the rehabilitation procedure such as the risk of pathological fractures and paralysis., Results: All of the therapists had strong anxiety (43%) or some anxiety (57%) about the risk of pathological fractures or paralysis during a procedure. However, no therapist responded that this had ever occurred. Many of the respondents had changed a procedure to a milder one (81%) or interrupted a procedure (48%) due to the patient's condition on the day. Therapists chose many options to reduce the risk of pathological fractures and paralysis during the procedure. Among them, "pre-rehabilitation referral to orthopedic surgeon" (86%), "consultation with a doctor about changes in patient's symptoms and findings" (86%), and "regular cooperation between multiple occupations" (67%) were frequently selected., Conclusions: Our questionnaire survey of therapists regarding the treatment of patients with bone metastases found that there was considerable anxiety about the risk of pathological fractures and paralysis during treatment. Our findings suggest that it is necessary to strengthen cooperation with multiple occupations, especially those in the orthopedic field.

Objective: This study examined how clients' selection and preference for noninvasive prenatal testing (NIPT) for aneuploidy changed with genetic counseling (GC) performed by certified geneticists at a primary hospital specializing in obstetrics, where other multiple prenatal genetic tests options were available., Methods: A total of 334 couples who underwent GC between 2017 and 2019 were included in the study. The average age of the pregnant women who underwent GC was 35.1 years., Results: Among the 95 couples (28.4%) who wanted NIPT at the start of GC, 10 (10.5%) switched to other tests, and 4 (4.2%) chose not to undergo any test. Among the 106 (31.7%) couples who wanted the combination of ultrasonography and the serum marker test, 12 (11.3%) chose not to undergo the test. Among the 92 (27.5%) couples who were undecided before GC, 21 (22.8%) wanted NIPT, 31 (33.7%) selected combined tests, and 18 (19.6%) did not undergo any test., Conclusion: We have demonstrated the significance of GC before prenatal genetic testing under widespread use of NIPT. Ideally, obstetric facilities should provide GC, or at least, pre-counseling at their own facilities, and offer multiple prenatal genetic testing options or refer to other facilities for the same., (© 2023 Japan Society of Obstetrics and Gynecology.)

Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95-0.99)/AUC: 0.93 (95% CI 0.84-1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49-0.79)/AUC: 0.73 (95% CI 0.49-0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74-0.99)) and MSA (AUC: 0.80 (95% CI 0.65-0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples., (© 2023. The Author(s).)

We experienced a young patient who presented with progressive parkinsonism and cerebellar ataxia. Brain magnetic resonance imaging revealed progressive brain calcification, expanding from the bilateral basal ganglia to the central pons, caused by a delayed reaction to the radiation therapy that she had received to treat craniopharyngioma 14 years earlier. Heterogeneous clinical symptoms due to radiation-induced brain calcification have been described, but parkinsonism has never been reported. While dopamine transporter-single photon emission computed tomography revealed only slight damage to the dopaminergic striatal pathway, the extension of calcification to the periventricular white matter was likely responsible for her parkinsonism.

The prevalence of urticaria has been reported mostly in Europe and North America. However, precise information regarding its subtypes and clinical characteristics in primary care practice, especially in Asian countries, are scant. Patients with urticaria and/or angioedema who visited nine primary clinics of accredited dermatologists and allergologists in Japan were recruited from October to November 2020. The information of age, sex, disease duration, urticaria control test (UCT), and concomitant urticaria subtypes were collected. A total of 1061 patients participated. The number of patients was high in the 20 to 50 age groups with a peak in the 40s. The most frequent urticaria subtype was chronic spontaneous urticaria (CSU) followed by dermographism, acute spontaneous urticaria (ASU), angioedema, and cholinergic urticaria (CholU) (66.8%, 22.7%, 18.9%, 14.1% and 5.7% in all patients with urticaria). CSU development increased with age from the 20s to 50s, especially in females. Dermographism had a peak in the 40s. ASU had bimodal peaks in childhood and in the 30s. CholU was common in males in the 10-20s. Most angioedema patients were female with an increase in their 30s. Angioedema was solely present in 14 of 1061 participants (1.3%), while 136 (12.8%) had angioedema concomitant with urticaria. UCT showed poorly controlled urticaria with lower scores in patients with concomitant CSU and other subtypes than in those with CSU alone. Urticaria tends to develop in young to middle-aged females. The most common urticaria subtype is CSU, while the number of patients with CholU is high and that of angioedema is low in Japan., (© 2022 Japanese Dermatological Association.)

Retrograde transport of lysosomes is recognised as a critical autophagy regulator. Here, we found that acrolein, an aldehyde that is significantly elevated in Parkinson's disease patient serum, enhances autophagy by promoting lysosomal clustering around the microtubule organising centre via a newly identified JIP4-TRPML1-ALG2 pathway. Phosphorylation of JIP4 at T217 by CaMK2G in response to Ca 2+ fluxes tightly regulated this system. Increased vulnerability of JIP4 KO cells to acrolein indicated that lysosomal clustering and subsequent autophagy activation served as defence mechanisms against cytotoxicity of acrolein itself. Furthermore, the JIP4-TRPML1-ALG2 pathway was also activated by H 2 O 2 , indicating that this system acts as a broad mechanism of the oxidative stress response. Conversely, starvation-induced lysosomal retrograde transport involved both the TMEM55B-JIP4 and TRPML1-ALG2 pathways in the absence of the JIP4 phosphorylation. Therefore, the phosphorylation status of JIP4 acts as a switch that controls the signalling pathways of lysosoma l distribution depending on the type of autophagy-inducing signal., (©2022 The Authors. Published under the terms of the CC BY 4.0 license.)

The use of cephalopod beaks in ecological and population dynamics studies has allowed major advances of our knowledge on the role of cephalopods in marine ecosystems in the last 60 years. Since the 1960's, with the pioneering research by Malcolm Clarke and colleagues, cephalopod beaks (also named jaws or mandibles) have been described to species level and their measurements have been shown to be related to cephalopod body size and mass, which permitted important information to be obtained on numerous biological and ecological aspects of cephalopods in marine ecosystems. In the last decade, a range of new techniques has been applied to cephalopod beaks, permitting new kinds of insight into cephalopod biology and ecology. The workshop on cephalopod beaks of the Cephalopod International Advisory Council Conference (Sesimbra, Portugal) in 2022 aimed to review the most recent scientific developments in this field and to identify future challenges, particularly in relation to taxonomy, age, growth, chemical composition (i.e., DNA, proteomics, stable isotopes, trace elements) and physical (i.e., structural) analyses. In terms of taxonomy, new techniques (e.g., 3D geometric morphometrics) for identifying cephalopods from their beaks are being developed with promising results, although the need for experts and reference collections of cephalopod beaks will continue. The use of beak microstructure for age and growth studies has been validated. Stable isotope analyses on beaks have proven to be an excellent technique to get valuable information on the ecology of cephalopods (namely habitat and trophic position). Trace element analyses is also possible using beaks, where concentrations are significantly lower than in other tissues (e.g., muscle, digestive gland, gills). Extracting DNA from beaks was only possible in one study so far. Protein analyses can also be made using cephalopod beaks. Future challenges in research using cephalopod beaks are also discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xavier, Golikov, Queirós, Perales-Raya, Rosas-Luis, Abreu, Bello, Bustamante, Capaz, Dimkovikj, González, Guímaro, Guerra-Marrero, Gomes-Pereira, Kubodera, Laptikhovsky, Lefkaditou, Lishchenko, Luna, Liu, Pierce, Pissarra, Reveillac, Romanov, Rosa, Roscian, Rose-Mann, Rouget, Sánchez, Sánchez-Márquez, Seixas, Souquet, Varela, Vidal and Cherel.)

After establishing latent infection, some viruses can be reactivated by the alteration of host immunological conditions. First, we reviewed viruses that can cause neuronal damage by reactivation. Then we focused on the herpes simplex virus (HSV). The reactivation leads to neuronal damages through two possible mechanisms; "reactivation of a latent herpes virus" by which viruses can cause direct virus neurotoxicity, and "post-infectious immune inflammatory response" by which a focal reactivation of HSV leads to an inflammatory reaction. The former is radiologically characterized by cortical lesions, the latter is characterized by subcortical white matter lesions. We experienced a female, who underwent the right posterior quadrantectomy and then developed recurrent herpes encephalitis caused by herpes simplex reactivation, which pathologically demonstrated inflammation in the white matter, suggesting a post-infectious immune inflammatory response. The patient was successfully treated with immunosuppressants. The reactivation of the HSV is extremely rare in Japan. Neurologists should recognize this condition because this disorder will increase as epilepsy surgery gains more popularity.

Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson's disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology., (© 2022. The Author(s).)

Competing Interests: None

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent., Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset., Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo., Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks., Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set., Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups., Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period., Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

Objective: This study aimed to determine the prevalence and clinical features of Parkinson's disease (PD)/PD dementia (PD/PDD) or dementia with Lewy bodies (DLB) in idiopathic normal pressure hydrocephalus (iNPH)., Methods: Patients with iNPH who were admitted to the Department of Neurology, Juntendo University School of Medicine over the past 10 years have been retrospectively analyzed. The diagnosis of iNPH and concomitant PD/PDD or DLB was established using diagnostic criteria. Motor symptoms were assessed by the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III. 123 I-ioflupane single-photon emission computed tomography (DaT-SPECT) and cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC)-based assay were performed for alpha synuclein aggregation., Results: Overall, 79 patients met the criteria for iNPH, of which 34 developed iNPH without accompanying disorders (iNPHa; 43%), 23 developed iNPH with comorbid PD/PDD (iNPHc + PD/PDD; 29.1%), and 8 developed iNPH with comorbid DLB (iNPHc + DLB; 10.1%). Significant differences in facial expansion and upper-limb parkinsonism were observed with a comorbidity of either PD/PDD or DLB. The specific binding ratio (SBR) of DaTscan was reduced in iNPHa (p = 0.02), but it reduced further with comorbid PD/PDD (p < 0.01) or DLB (p < 0.01). RT-QuIC was positive for all 13 comorbid PD/PDD and negative for all 19 iNPHa., Conclusion: These results highlight that synucleinopathies coexist with iNPH. These can be differentiated by performing DaTscan and RT-QuIC, which can affect its clinical features., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The objective of this study was to analyze the effect of concomitant Parkinson's disease (PD) and PD dementia (PD/PDD) on the course of idiopathic normal pressure hydrocephalus (iNPH), especially as related to the outcome of lumboperitoneal shunt (LPS) surgery., Methods: The authors retrospectively analyzed patients with iNPH without accompanying disorders (iNPH alone [iNPHa]) and iNPH concomitant with PD/PDD (iNPHc+PD/PDD) who had presented to their department between 2010 and 2019. The diagnosis of iNPHc+PD/PDD was established using the diagnostic criteria of the Movement Disorder Society. The effect of LPS surgery on clinical symptoms and striatum volumes was evaluated., Results: Thirty-three patients with iNPHa and 23 patients with iNPHc+PD/PDD were identified. Comorbid PD/PDD significantly worsened clinical outcome as measured by the iNPH grading scale, modified Rankin Scale (mRS), and Hoehn and Yahr (HY) scale. LPS surgery improved the iNPH score including gait disturbance (p < 0.01), cognitive impairment (p = 0.02), and urinary disturbance (p < 0.01) in iNPHa and improved gait disturbance (p = 0.01) and urinary disturbance (p = 0.03) in iNPHc+PD/PDD for 1 year. Comorbid synucleinopathies maintained worse mRS scores and HY stages for 3 years, and LPS surgery extended overall survival (p = 0.003), as well as the period of sustained mRS scores (p = 0.04) and HY stages (p = 0.004) in iNPHc+PD/PDD. Both caudate and putamen volumes were reduced in iNPHa (p < 0.01) compared to those in controls and in patients with iNPHc+PD/PDD compared to those in patients with PD/PDD (p < 0.01), and LPS surgery restored caudate volumes in both groups., Conclusions: These results revealed that comorbid PD/PDD deteriorates the clinical course of iNPH and that LPS surgery is recommended regardless of this comorbidity.

Introduction: Chronic constipation worsens the quality of life (QOL) of patients with Parkinson's disease (PD). Elobixibat, an ileal bile acid transporter inhibitor, is a useful laxative, but its effect on chronic constipation in patients with PD remains unclear. Therefore, we designed a placebo-controlled, randomised, double-blind study to investigate the efficacy and safety of elobixibat in patients with PD with chronic constipation., Methods and Analysis: The study will consist of 2-week observation and 4-week treatment periods. Patients with clinically established PD will record the status of spontaneous bowel movements and use of rescue medications/concomitant medications in a Bowel Movement Diary from the start of the observation period at visit 1 (week -2). At visit 2 (week 0), patients will be assessed for final registration based on the diary records and physical examinations, and allocated to either the elobixibat or placebo group. Daily intake of the investigational drug will be recorded in the diary. Patients will undergo laboratory tests and answer constipation-related, PD-related and QOL-related questionnaires at visits 2 and 4 (week 4). Subjective symptoms and objective findings will be collected at visits 2, 3 (week 2) and 4. Since patients' motor function might be improved by treatment of constipation, the use of dopamine preparations will also be monitored. Bowel movement data and other parameters will be compared between groups.Safety information will be collected as adverse events, specifically focusing on those occurring in association with study conduct., Ethics and Dissemination: This study will be conducted in accordance with the Helsinki Declaration, the Clinical Trials Act of the Japan Ministry of Health, Labour and Welfare, and related laws and regulations. The study was approved by the Juntendo University Certified Review Board. The results will be disseminated through an online study registry (Japan Registry of Clinical Trials), presented at scientific conferences, and published in medical journals., Trial Registration Number: JPRN-jRCTs031200172; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We previously introduced the Five-Parameter System (FPS), which exclusively evaluates keratinized cellular findings, for use in cytology examinations of oral well-differentiated squamous cell carcinoma (SCC) and carcinoma in situ (CIS) specimens, as they occasionally lack nuclear atypia and can be challenging for categorization by The Bethesda System (TBS). This study was conducted to determine whether FPS parameters are detectable even in oral SCC/CIS specimens with apparent nuclear atypia., Summary: Oral cytology specimens were obtained together with biopsy tissue samples. They were obtained from 59 malignant (HSIL and SCC) and 29 not-definitely malignant (NILM to ASC-H) specimens diagnosed using TBS. Following re-confirmation of the original TBS categorization, the specimens were re-evaluated using FPS. One or more of the FPS parameters were noted in 69 of 70 malignant specimens examined, of which 11 had been diagnosed by TBS as not-definitely malignant. The remaining one malignant specimen was diagnosed as SCC with only TBS. FPS parameters #1 (concentric arrangement), #2 (large cell number), #3 (bizarre-shaped cells), #4 (keratoglobules), and #5 (uneven filamentous cytoplasm) were observed only in malignant cases, while none were revealed in not-definitely malignant specimens. Finally, TBS supplemented with FPS achieved sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 100%., Key Messages: FPS parameters are included in most examinations of oral cytology specimens. Thus, FPS is highly recommended for use in cytology examinations of oral SCC regardless of differentiation degree to confirm judgment based on TBS, a mandatory standard, as well as to cover its limitation of mainly evaluating nuclear atypia. FPS is considered to be an important diagnostic tool for oral cytology, especially in triage cases, which are challenging for TBS. Cytopathology should not be limited to only nuclear findings but be based on whole-cell morphology., (© 2022 S. Karger AG, Basel.)

Body tissue and venom glands from an eastern population of the scorpion Centruroides vittatus (Say, 1821) were homogenized and molecular constituents removed to characterize putative sodium β toxin gene diversity, RT-qPCR, transcriptomic, and proteomic variation. We cloned sodium β toxins from genomic DNA, conducted RT-qPCR experiments with seven sodium β toxin variants, performed venom gland tissue RNA-seq, and isolated venom proteins for mass spectrophotometry. We identified >70 putative novel sodium β toxin genes, 111 toxin gene transcripts, 24 different toxin proteins, and quantified sodium β toxin gene expression variation among individuals and between sexes. Our analyses contribute to the growing evidence that venom toxicity among scorpion taxa and their populations may be associated with toxin gene diversity, specific toxin transcripts variation, and subsequent protein production. Here, slight transcript variation among toxin gene variants may contribute to the major toxin protein variation in individual scorpion venom composition.

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Alpha synuclein (α-Syn), a presynaptic protein with unknown function, is accumulated in Lewy bodies/neurites that are one of the hallmark pathologies of Parkinson's disease (PD). Missense or multiplication mutations in SNCA, which codes α-Syn, result in a genetic form of PD, further indicating the involvement of α-Syn in PD pathogenesis. Recent pathological and experimental studies suggest that α-Syn possesses a secretory feature, as it is detected in the culture media, in the cerebrospinal fluid, and even in the blood. Secreted α-Syn can spread throughout the body and invade the CNS, disseminating the α-Syn associated pathology. Exosomes are small extracellular vesicles that carry many proteins, lipids, or miRNA. We and others have discovered α-Syn in exosomes and revealed that exosomes may regulate intracellular α-Syn levels by transporting outside the cells. In this chapter, we describe a protocol to measure α-Syn levels in exosomes.

Introduction: Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thromboembolic events, including ischemic stroke or complications in pregnancy, and the presence of antiphospholipid antibodies. Cervical artery dissection (CAD) is not an uncommon cause of stroke in young adults. The concomitant presence of APS and CAD is extremely rare., Methods: Two cases with APS who developed acute ischemic strokes related to CAD are reported. A comprehensive systematic literature search using the PubMed database was also conducted., Results: In Case 1, a 36-year-old woman who had been diagnosed with systemic lupus erythematosus and had been repeatedly positive for lupus anticoagulant tests developed an ischemic stroke caused by a vertebral artery dissection (VAD). After admission, she had a recurrent ischemic stroke, followed by considerable changes in steno-occlusive lesions of the vertebrobasilar artery system. In Case 2, a 36-year-old man developed multiple brain infarcts due to bilateral VAD with aneurysmal formations and associated with pulmonary embolism. The anticardiolipin antibody titer was repeatedly elevated after stroke. The literature review identified 8 patients with CAD associated with APS, involving the internal carotid artery in 6 patients and the middle cerebral artery and vertebral artery in 1 patient each. The patients were predominantly young and female, infrequently had atherosclerotic vascular risk factors, and were positive for various antiphospholipid antibodies., Conclusions: The current report described two rare cases of ischemic stroke caused by CAD secondary to APS, along with a review of the literature; the patients displayed characteristic clinical manifestations, implying specific mechanisms for cerebral artery disorders secondary to APS.

Glucocerebrosidase (GCase), which is encoded by the GBA1 gene, has lysosomal glycoside hydrolase activity that hydrolyzes glucosylceramide. Defects in GCase lead to the accumulation of glucosylceramide, which causes the development of the lysosomal storage disease known as Gaucher's disease. Loss-of-function mutations in the GBA1 gene are the most important genetic risk factor for synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. Recent studies on PD genes associated with lysosomal function suggest that GCase activity is decreased in cell models of PD and in neurons derived from PD patients. In this chapter, we describe a protocol to measure GCase activity in cultured cells.

The pathologic hallmark of Parkinson's disease is the accumulation of α-synuclein-containing Lewy bodies/neurites almost exclusively in neurons, and rarely in glial cells. However, emerging evidence suggests that glia such as astrocytes play an important role in the development of α-synuclein pathology. Using induced pluripotent stem-derived dopaminergic neurons and astrocytes from healthy subjects and patients carrying mutations in lysosomal ATP13A2 , a monogenic form of synucleinopathy, we found that astrocytes rapidly internalized α-synuclein, and exhibited higher lysosomal degradation rates compared with neurons. Moreover, coculturing astrocytes and neurons led to decreased accumulation of α-synuclein in neurons and consequently diminished interneuronal transfer of α-synuclein. These protective functions of astrocytes were attenuated by ATP13A2 deficiency, suggesting that the loss of ATP13A2 function in astrocytes at least partially contributes to neuronal α-synuclein pathology. Together, our results highlight the importance of lysosomal function in astrocytes in the pathogenesis of synucleinopathies. SIGNIFICANCE STATEMENT While most neurodegenerative disorders are characterized by the accumulation of aggregated mutant proteins exclusively in neurons, the contribution of glial cells in this process remains poorly explored. Here, we demonstrate that astrocytes contribute to the removal of extracellular α-synuclein and that disruption of this pathway caused by mutations in the Parkinson's disease-linked gene ATP13A2 result in α-synuclein accumulation in human dopaminergic neurons. We found that astrocytes also protect neurons from α-synuclein propagation, whereas ATP13A2 deficiency in astrocytes compromises this protective function. These results highlight astrocyte-mediated α-synuclein clearance as a potential therapeutic target in disorders characterized by the accumulation of α-synuclein, including Parkinson's disease., (Copyright © 2020 the authors.)

Pharmacological reactivation of the γ-globin gene for the production of fetal hemoglobin (HbF) is a promising approach for the management of β-thalassemia and sickle cell disease (SCD). We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules that could induce HbF, which resulted in identification of the hit compound 1. Exploration of structure-activity relationships and optimization of ADME properties led to 2-azaspiro[3.3]heptane derivative 18, which is more rigid and has a unique structure. In vivo using cynomolgus monkeys, compound 18 induced a significant dose-dependent increase in globin switching, with developable properties. Moreover, compound 18 showed no genotoxic effects and was much safer than hydroxyurea. These findings could facilitate the development of effective new therapies for the treatment of β-hemoglobinopathies, including SCD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)