Objective In late-stage Parkinson's disease (PD), wheelchair mobility becomes essential, yet little is known about the endurance and efficiency of wheelchairs. For individuals who struggle with manual wheelchair (MW) propulsion, a cycling wheelchair (CW) may provide an alternative. In this study, endurance and efficiency were compared between MWs and CWs during continuous driving, including turning tasks, in late-stage PD. Methods Nine participants with late-stage PD performed the 6-minute push test using both MWs and CWs. Total distance, average speed, and the Physiological Cost Index (PCI) were measured. The PCI was calculated from the pre-and post-driving heart rates. Results Compared with the use of MWs, the use of CWs resulted in a significantly greater total distance and a lower PCI, and similar patterns were observed among participants at Hoehn and Yahr stage V (n=6). Conclusion Compared with MW use, CW use may enable more enduring and efficient mobility in late-stage PD. Further studies are needed to validate these preliminary findings.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. Patients with ALS often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models and induced pluripotent stem (iPS) cells derived from patients with ALS and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising non-invasive neuromodulation approach for addressing gait impairments in Parkinson's disease (PD). However, evidence regarding its effects on daily-life gait remains limited. We report a case of a 67-year-old woman with PD and freezing of gait (FOG), based on the hypothesis that taVNS may enhance gait automaticity under daily-life conditions. A single-case A-B-C design was used, consisting of baseline, sham stimulation, and taVNS phases. Gait performance was assessed using wearable accelerometry in both experimental and daily-life settings. While no significant changes were observed in gait parameters during experimental assessments, daily-life walking measures-step velocity, step length, variability, and asymmetry-showed improvements during the taVNS phase. Importantly, no falls or FOG episodes were observed during the taVNS phase. These findings support the feasibility of taVNS and provide preliminary support for its potential therapeutic role in enhancing gait automaticity in daily life. Further controlled studies are warranted.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant upregulation of glutamatergic synaptic genes through dysfunction of the master transcriptional repressor REST during early postnatal development in a mouse model of SBMA (AR-97Q mice). Reducing mutant AR or restoring REST function using antisense oligonucleotides during the neonatal period attenuated the upregulation of glutamatergic synaptic genes and ameliorated the disease phenotype and histopathology in AR-97Q mice. Furthermore, we observed increased calcium activity in induced pluripotent stem cell-derived motor neurons from SBMA patients compared to those from healthy controls, reflecting neuronal hyperexcitability. Late-onset neurodegeneration in SBMA is attributable to early synaptic defects and the resulting hyperexcitability of motor neurons, which may represent therapeutic targets.

Tissue-engineered three-dimensional (3D) skeletal muscles can be potentially used in contractile force-based phenotypic screening to elucidate the mechanisms of skeletal muscle dysfunction and develop preventive and therapeutic strategies. Human induced pluripotent stem cells (hiPSCs) expressing tetracycline-inducible myogenic differentiation 1 (MYOD1) are a promising cell source for construction of tissue-engineered skeletal muscles. Although we successfully constructed contractile tissues using these hiPSCs in a previous study, further improvements are required because of their weak contractile force and inefficient screening capabilities. In this study, we aimed to construct iPSC-derived muscle tissues with high contractile force using a 96-well scale microdevice that we had previously developed. To increase the contractile force, we optimized the time of supplementation of the transforming growth factor-β (TGF-β) inhibitor, SB431542 (SB), to identify culture conditions that enhance contractile force. The maximum contractile force with addition of SB was approximately five times greater than that without SB (58.45 ± 20.14 μN with SB compared to 11.64 ± 4.86 μN without SB). Various analyses, including immunostaining, transmission electron microscopy, gene expression analysis, and proteomics, revealed enhanced myotube differentiation and muscle tissue maturation in the presence of SB. Experiments using inhibitors indicated that TGFβ1, not myostatin, is partially involved in these effects. Furthermore, we confirmed that tissues constructed from iPSCs derived from patients with Duchenne muscular dystrophy also showed improved contractility following addition of SB. Therefore, iPSC-derived muscle tissues cultured with SB on the 96-well microdevice provide a promising platform for screening compounds that can ameliorate disease pathology.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by the expansion of the polyglutamine tract in the androgen receptor (AR). Motor neurons (MNs) derived from patient-specific induced pluripotent stem cells (iPSCs) robustly recapitulated early SBMA phenotypes driven by endogenous mutant AR in the absence of testosterone (dihydrotestosterone) and detectable mutant AR aggregation. Notably, endoplasmic reticulum stress markedly exacerbated SBMA pathology. Cross-species integrative analyses of patient-derived neurons and spinal cords of transgenic mouse models revealed high expression of multiple disease-associated neuropeptides, including urotensin II (UTS2), in patient spinal MNs that was correlated with disease onset and progression in iPSC-derived MNs. Downstream signaling analyses of these neuropeptides revealed convergent molecular pathways whose pharmacological inhibition rescued cellular phenotypes. Together, these results establish a human disease model harboring endogenous mutant AR that closely reproduces early SBMA pathology and provides molecular leads for elucidating disease mechanisms and biomarkers and developing therapeutic targets. ### Competing Interest Statement H.O. is a paid member of the Scientific Advisory Board of SanBio Co., Ltd. Y.O. is a scientific advisor at Kohjin Bio Co., Ltd. Japan Society for the Promotion of Science, https://ror.org/00hhkn466, JP19H03576, JP22K15739, JP22J40195, JP22H02988, JP23K24249, JP23K06975 Japan Society for the Promotion of Science, https://ror.org/00hhkn466, JP24K18712, JP25K02585 Japan Agency for Medical Research and Development, https://ror.org/004rtk039, JP19ek0109243, JP22bm0804020, JP25bm1423003, JP23bm1123046, JP23kk0305024 Japan SBMA Association Hori Science and Arts Foundation

BACKGROUND:Patients with Parkinson's disease (PwPDs) experience a progressive decline in their sit-to-stand (STS) ability, including a prolonged STS time, rising failure, and seat-off failure. The clinical and biomechanical factors contributing to this decline are unclear. OBJECTIVES:We investigated clinical and biomechanical factors associated with the different stages of STS decline in PwPDs. METHODS:This cross-sectional study included 23 healthy controls (HCs) plus 40 PwPDs who we categorized by STS ability: 18 successful STS (SS), 12 failure-to-rise (FR), and 10 failure-to-seat-off (FS). Clinical assessments included motor symptoms (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale), balance (Mini-Balance Evaluation Systems Test), and lower-limb strength. Biomechanical parameters measured using force plates included repetitive movements, slope of first-peak loading, and amplitude and temporal parameters. We conducted group comparisons and determined the age-adjusted area under the receiver operating characteristic curve (AAUC) and Spearman's correlations with the STS time (P < 0.05). RESULTS:In the SS group, prolonged STS time was significantly correlated with amplitude and temporal parameters (rs = -0.849 to 0.986), for example, first-peak feet loading and its slope, reflecting impaired weight shifting from the buttocks onto the soles. These parameters effectively differentiated FR from SS (AAUC = 0.778-0.884) and FS from FR (AAUC = 0.758-0.992). Lower-limb bradykinesia differentiated FR from SS (AAUC = 0.870). All balance-related measures also strongly distinguished FS from FR (AAUC = 0.817-0.925). CONCLUSIONS:These findings highlight that weight-shifting impairments, along with bradykinesia in the earlier stages and balance deficits in the later stages, play pivotal roles in the progressive STS decline in PwPDs. Interventions targeting weight shifting, as well as bradykinesia, and postural control, could potentially help mitigate this decline.

Polyglutamine (polyQ) diseases are inherited neurological disorders caused by an expansion of the cytosine-adenine-guanine (CAG) repeat in the causative genes. These include Huntington’s disease, spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). Clinical trials have been conducted using nucleic acid therapeutics to silence the causative gene for these diseases, but none have been approved for use. Furthermore, while oligonucleotides targeting the CAG repeats are an attractive therapeutic option, concomitant silencing of the wild-type allele with normal CAG repeats can result in neuronal dysfunction. In this study, we developed an acyclic serinol nucleic acid (SNA)-modified small interfering RNA (siRNA) targeting CAG repeats. We also evaluated the safety and efficacy of the siRNA in different mouse models of polyQ diseases. Intracerebroventricularly administered siRNA was widely distributed throughout the central nervous system, where it selectively silenced the alleles encoding polyQ proteins without affecting their wild-type counterparts. Consequently, the intranuclear aggregation of polyQ proteins was reduced in mouse models of SBMA and SCA type 3. The siRNA attenuated neuromuscular degeneration and improved the lifespan and motor function of the SBMA mice. These findings suggest that SNA-modified siRNAs targeting CAG repeats represent a promising approach for treating polyQ diseases.

[This corrects the article DOI: 10.1371/journal.pone.0016182.].

BACKGROUND Cutaneous ureterostomy (CU) is a commonly used urinary diversion procedure, particularly for patients with poor prognosis, such as those with advanced cancer, a single kidney, or older age. CU is technically easier and faster to perform than other procedures, such as ileal conduit and ileal neobladder, as it does not involve the intestines, thus reducing the risk of postoperative intestinal complications and metabolic abnormalities. However, CU has several drawbacks, including difficulty in achieving a catheter-free status, frequent urinary tract infections, and concerns about long-term renal function, which can negatively impact a patient's quality of life. Recent advancements in the treatment of advanced metastatic urothelial cancer, particularly with immune checkpoint inhibitors and antibody-drug conjugates, have significantly improved the prognosis of patients with urothelial carcinoma. As a result, some patients who underwent CU and were initially considered to have poor prognosis achieved long-term remission. For these patients, the next goal is to establish a stable urinary diversion method that minimizes management effort and reduces the risk of infection and renal dysfunction. CASE REPORT This report presents 2 cases of revisional urinary diversion from CU to ileal conduit in patients with locally advanced bladder cancer who initially underwent CU and achieved long-term remission with pembrolizumab. Both patients achieved catheter-free status and preserved renal function postoperatively. CONCLUSIONS These cases highlight the potential benefits of staged urinary diversion in improving the quality of life of bladder cancer survivors in an era of targeted immunotherapy.

OBJECTIVE:People with Parkinson's disease (PwPD) experience a gradual decline in bed mobility independence as the disease progresses. Identifying factors associated with nonindependence in daytime bed mobility is crucial for developing effective interventions to increase independence. We investigated factors associated with nonindependence in daytime bed mobility in PwPD. METHODS:This cross-sectional study included 109 PwPD (Hoehn and Yahr [HY] stage 2-4). Patients' bed mobility ability (turning in bed, supine-to-sitting, and sitting-to-supine) was assessed during the daytime, and they were categorized into independent and nonindependent groups. Potential factors associated with bed mobility independence, including components of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (rigidity, bradykinesia, tremor, axial symptoms), neck/trunk/hip strength, the Mini-Mental State Examination, and the Trail Making Test-A and B, were evaluated. RESULTS:The nonindependent group presented significantly increased axial symptoms, increased rigidity in the upper and lower limbs and neck, increased upper limb bradykinesia, and decreased trunk flexion/extension strength in all bed mobility tasks (p<0.05). Multivariate regression analyses revealed that axial symptoms, upper limb rigidity, and trunk extension strength were highly discriminative for nonindependence in turning in bed (the area under the curve [AUC]=0.84). Similarly, upper limb rigidity and axial symptoms were predictive of nonindependence in supine-to-sitting and sitting-to-supine movements (AUC=0.78, 0.92). A significant difference in axial symptoms between the HY stage 4 subgroups was observed only in the sitting-to-supine movement. CONCLUSION:Our findings indicate that axial symptoms and upper limb rigidity are key factors contributing to nonindependence in daytime bed mobility tasks among PwPD. Targeting these factors in rehabilitation may help mitigate the decline in bed mobility independence in PwPD.