Simple and efficient differentiation of human iPSCs into contractible skeletal muscles for muscular disease modeling.

Pathophysiological analysis and drug discovery targeting human diseases require disease models that suitably recapitulate patient pathology. Disease-specific human induced pluripotent stem cells (hiPSCs) differentiated into affected cell types can potentially recapitulate disease pathology more accurately than existing disease models. Such successful modeling of muscular diseases requires efficient differentiation of hiPSCs into skeletal muscles.

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients.

Background: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS.

Methods: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants.

Recurring Weakness in Rhabdomyolysis Following Pfizer-BioNTech Coronavirus Disease 2019 mRNA Vaccination.

Rhabdomyolysis is a well-known clinical syndrome of muscle injury. Rhabdomyolysis following coronavirus disease 2019 (COVID-19) vaccination has recently been reported. The patients' weakness gradually subsided and did not recur.

A 47-Year-Old Japanese Woman with Symptoms of Increased Salty and Reduced Sweet Taste Perception Preceding a Diagnosis of Thymoma-Associated Myasthenia Gravis.

BACKGROUND Myasthenia gravis (MG) is an autoimmune neuromuscular disorder, which is often accompanied by various complications. Partial dysgeusia is an uncommon nonmotor symptom of MG, and dysgeusia preceding typical MG symptoms is rare. Although ageusia and hypogeusia have been reported in patients with MG, increased perception of taste has not been reported.

Antiparkinsonian drugs as potent contributors to nocturnal sleep in patients with Parkinson's disease.

Objective: To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD).

Background: Although the major antiparkinsonian drugs L-dopa and dopamine agonists (DAs) have been found to affect sleep, little is known about the effects of specific drugs on sleep in PD patients.

Methods: The study participants consisted of 112 PD patients (median age 72.

Aberrant Expression of Nodal and Paranodal Molecules in Neuropathy Associated With IgM Monoclonal Gammopathy With Anti-Myelin-Associated Glycoprotein Antibodies.

To clarify the pathogenesis of anti-myelin-associated glycoprotein (MAG) antibody neuropathy associated with IgM monoclonal gammopathy (anti-MAG neuropathy), sural nerve biopsy specimens from 15 patients were investigated. Sodium channels, potassium channels, contactin-associated protein 1 (Caspr1), contactin 1, and neurofascin were evaluated by immunofluorescence in teased-fiber preparations. Immunoreactivity to the pan-sodium channel in both anti-MAG neuropathy patients and in normal controls was concentrated at the node of Ranvier unless there was demyelination, which was defined as the widening of the node of Ranvier.

Motor Improvement-Related Regional Cerebral Blood Flow Changes in Parkinson's Disease in Response to Antiparkinsonian Drugs.

Little is known about the relationship between regional cerebral blood flow (rCBF) change and clinical improvement in patients with Parkinson's disease (PD). Single-photon emission computed tomography (SPECT) measurement of cerebral blood flow allows evaluation of temporal changes in brain function, and using SPECT, we aimed to identify motor improvement-related rCBF changes in response to the administration of antiparkinsonian drugs. Thirty PD patients (16 without dementia; 14 with dementia) were scanned with technetium-99m labeled ethyl cysteinate dimer SPECT and were rated with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III, both before and after a single administration of antiparkinsonian drugs.

Maximum Walking Speed at Discharge Could Be a Prognostic Factor for Vascular Events in Patients With Mild Stroke: A Cohort Study.

Objective: To identify the prognostic value of physical activity-related factors as well as known vascular risk factors for vascular events in mild ischemic stroke (MIS).

Design: Single-center prospective cohort study.

Setting: University hospital.

[Dyskinesia-hyperpyrexia syndrome in a patient with Parkinson's disease: a case report].

Non-physiological, excessive dopaminergic stimulation can cause dyskinesia-hyperpyrexia syndrome (DHS), which was initially reported by Gil-Navarro and Grandas in 2010. A 70-years-old woman with a 13-years history of Parkinson's disease (PD) was hospitalized due to difficulty walking, despite being treated with levodopa/carbidopa (600 mg/day), immediate-release pramipexole (3 mg/day), and selegiline (5 mg/day). Immediate-release pramipexole was changed to extended-release pramipexole without changing the dose or levodopa equivalent dose (LED).

Open-label study to evaluate the pharmacodynamics, clinical efficacy, and safety of meropenem for adult bacterial meningitis in Japan.

The aim of this study was to assess the efficacy, safety, and concentration of meropenem in cerebrospinal fluid when meropenem (2 g every 8 h) was administered to Japanese adult patients with bacterial meningitis. Five Japanese patients (mean age 60.6 years [range 35-71]) were enrolled.

RNP2 of RNA recognition motif 1 plays a central role in the aberrant modification of TDP-43.

Phosphorylated and truncated TAR DNA-binding protein-43 (TDP-43) is a major component of ubiquitinated cytoplasmic inclusions in neuronal and glial cells of two TDP-43 proteinopathies, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Modifications of TDP-43 are thus considered to play an important role in the pathogenesis of TDP-43 proteinopathies. However, both the initial cause of these abnormal modifications and the TDP-43 region responsible for its aggregation remain uncertain.

Loss of TDP-43 causes age-dependent progressive motor neuron degeneration.

Amyotrophic lateral sclerosis is a devastating, progressive neurodegenerative disease that affects upper and lower motor neurons. Although several genes are identified as the cause of familial cases, the pathogeneses of sporadic forms, which account for 90% of amyotrophic lateral sclerosis, have not been elucidated. Transactive response DNA-binding protein 43 a nuclear protein regulating RNA processing, redistributes to the cytoplasm and forms aggregates, which are the histopathological hallmark of sporadic amyotrophic lateral sclerosis, in affected motor neurons, suggesting that loss-of-function of transactive response DNA-binding protein 43 is one of the causes of the neurodegeneration.

The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by the loss of motor neurons. Despite substantial research, the causes of ALS remain unclear. Glycoprotein nonmetastatic melanoma protein B (GPNMB) was identified as an ALS-related factor using DNA microarray analysis with mutant superoxide dismutase (SOD1(G93A)) mice.

[Potent primary leptomeningeal lymphoma masquerading as tuberculous meningitis - a case report].

A 45-year-old man presented with fever, progressive mutism and memory loss, was admitted to our hospital. MR imaging and angiography suggested multiple foci of infarctions and vasculitis without Gadrinium-enhancement. CSF examination revealed pleocytosis with mononuclear cell dominance and elevated protein content.

[Living situation of the in-home patients suffering from amyotrophic lateral sclerosis in Aichi prefecture, Japan].

It is essential that we know the real situation of at-home patients with amyotrophic lateral sclerosis (ALS) in order to improve their medical support system. We indirectly investigated the daily living status of ALS patients and their families at home by conducting on individual questionnaires survey for nurses working at public health centers in Aichi prefecture, Japan. Detailed information about 136 cases was obtained, and we could clarify the need for variety of communication methods, plasticity of medical interrelations and care between neurologists and home doctors, incomplete utilization of social resources including various official support, overwork among single caregivers, and underdeveloped immature individual medical care support programs for them.

Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies.

TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive inclusion of TDP-43 proteinopathies including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions, which is now referred to as FTLD-TDP. TDP-43 in the aberrant inclusion is known to be hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re-distribute from nucleus to cytoplasm or neurite. The pathogenic role of these modifications, however, has not been clarified.

Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by progressive motor neuron degeneration and leads to death within a few years of diagnosis. One of the pathogenic mechanisms of ALS is proposed to be a dysfunction in the protein quality-control machinery. Dorfin has been identified as a ubiquitin ligase (E3) that recognizes and ubiquitinates mutant SOD1 proteins, thereby accelerating their degradation and reducing their cellular toxicity.

TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases.

The 43-kDa TAR DNA-binding protein (TDP-43) is known to be a major component of the ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Although TDP-43 is a nuclear protein, it disappears from the nucleus of affected neurons and glial cells, implicating TDP-43 loss of function in the pathogenesis of neurodegeneration. Here we show that the knockdown of TDP-43 in differentiated Neuro-2a cells inhibited neurite outgrowth and induced cell death.

[Exploration of pathogenesis-associated molecules and development of disease models for sporadic ALS].

The mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS and by the development and analysis of mutant SOD1 transgenic animal models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established.

Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1.

Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS) through the gain of a toxic function; however, the nature of this toxic function remains largely unknown. Ubiquitylated aggregates of mutant SOD1 proteins in affected brain lesions are pathological hallmarks of the disease and are suggested to be involved in several proposed mechanisms of motor neuron death. Recent studies suggest that mutant SOD1 readily forms an incorrect disulfide bond upon mild oxidative stress in vitro, and the insoluble SOD1 aggregates in spinal cord of ALS model mice contain multimers cross-linked via intermolecular disulfide bonds.

Gene expressions specifically detected in motor neurons (dynactin 1, early growth response 3, acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to pathologic markers in sporadic amyotrophic lateral sclerosis.

In a differential gene expression profile, we showed previously that dynactin 1 (DCTN1), early growth response 3 (EGR3), acetyl-CoA transporter (ACATN), death receptor 5 (DR5), and cyclin C (CCNC) were prominently up- or downregulated in motor neurons of sporadic amyotrophic lateral sclerosis (ALS). In the present study, we examined the correlation between the expression levels of these genes and the levels of pathologic markers for motor neuron degeneration (i.e.

Gene expression profiling toward understanding of ALS pathogenesis.

Although more than 130 years have gone by since the first description in 1869 by Jean-Martin Charcot, the mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS (FALS) and by the development and analysis of mutant SOD1 transgenic mouse models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established.

Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity.

The ubiquitin-proteasome system (UPS) is involved in the pathogenetic mechanisms of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Dorfin is a ubiquitin ligase (E3) that degrades mutant SOD1 proteins, which are responsible for familial ALS. Although Dorfin has potential as an anti-ALS molecule, its life in cells is short.